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Chi-Ho Chan,1 Shun-Fa Yang,2,3 Han-Wei Yeh,4 Ying-Tung Yeh,5–7 Yu-Hsun Wang,2 Ying-Hock Teng,8,9 Chao-Bin Yeh8,9 1Department of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 2Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China; 3Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 4School of Medicine, Chang Gung University, Taoyuan City, Taiwan, Republic of China; 5Graduate School of Dentistry, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 6School of Dentistry, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 7Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China; 8Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 9Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China Background: Burns are the main cause of accidental injury, and pneumonia is a common respiratory disease in humans.Aim: The purpose of this study was to investigate the relationship between burn injury and pneumonia.Patients and methods: A nationwide population-based cohort study was conducted using data from the National Health Insurance Research Database in Taiwan. We identified and enrolled 2,893 subjects with burn injury, who were individually matched to 2,893 subjects in the comparison group by using the propensity score. Furthermore, we used a self-controlled case-series design to estimate the temporal association between burn injury and pneumonia.Results: Exposure to burn injury revealed a higher risk of pneumonia than that to non-burn injury within 1 year. The Cox proportional hazards model revealed that, compared with the non-burn injury, burn injury yielded a 2.39-fold (95% CI=1.44–3.96) increase in risk of pneumonia. The exposure period of burn injury within 30 days showed 2.76-fold increase in risk of pneumonia (95% CI=1.44–3.96) compared with that in the baseline period.Conclusion: Burn injury was associated with a significant increased risk of pneumonia, especially occurring within 30 days. Keywords: burn injury, pneumonia, odds ratio

Cancer cells frequently alter their lipids to grow and adapt to their environment 1-3 . Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8 + T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Test an obesity intervention for families with low incomes., Methods: A total of 208 families were included (a parent with a body mass index [BMI] ≥ 30 and a child aged 6-12 years). A 12-month randomized controlled trial combining family health coaching (motivational interviewing) and connection to community resources. Comparison group: referrals for basic needs, written educational materials. Questionnaires, accelerometry, and anthropometrics. Intention-to-treat analysis of change in outcomes. Two-sided t test with multiple imputation., Results: Parents were 95% female, 31% Black, and 27% Hispanic. Children had a mean BMI-Z score of 1.15. Primary outcomes did not differ between groups at 12 months. Both groups significantly (P < 0.05) improved on the Family Nutrition and Physical Activity Scale for behaviors related to childhood obesity (mean ± SE: comparison, 2.8 ± 1.0; intervention, 2.2 ± 0.9), increased child sedentary activity (comparison, 32.5 ± 12.1; intervention, 39.9 ± 12.4 min/d), and decreased child moderate-vigorous physical activity (comparison, -9.6 ± 3.3; intervention -7.0 ± 3.0 min/d). Parents had no change in BMI., Conclusions and Implications: We successfully embedded screening and referral to address social needs within an obesity intervention. The coaching intervention did not provide additional benefits. Future research could explore ways to make these interventions more accessible, valuable, and effective for families., (Copyright © 2024 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Background: Means restriction is an approach to suicide prevention that has been shown to be effective but is underutilized in the United States. For the current study, we sought to determine if a webinar-based education intervention could impact caregiver means restriction knowledge and behaviors., Methods: Nine webinars for caregivers were offered by a children's hospital in conjunction with community groups. Education on raising teenagers was paired with information about suicide prevention, including the importance of securing medications and firearms. Participants completed surveys prior to the presentation, immediately following and two weeks later to measure change in knowledge and storage of medications and firearms. Participants were provided a safety toolkit to secure medications and firearms., Results: Of the 327 participants who completed the baseline survey, 299 and 257 completed the second and third surveys. By the conclusion of the study, 46.6% of participants reported they had disposed of unneeded medications and 44.1% had locked up medications. Among firearm owners, use of a cable gun lock rose from 13.7% to 25.8%. In addition, 40.2% of firearm owners reported learning more about how their firearms were stored at the final survey. Most participants (88.3%) strongly agreed that the presentation provided value., Conclusion: This study shows that a webinar on safe storage appears to have some impact on behavior changes for caregivers of adolescents. A controlled study could help to clarify if the webinar format or the timing during the Covid-19 pandemic might have played a role in the degree of behavior change reported., (© 2024. The Author(s).)

Human Cep57 is a coiled-coil scaffold at the pericentriolar matrix (PCM), controlling centriole duplication and centrosome maturation for faithful cell division. Genetic truncation mutations of Cep57 are associated with the mosaic-variegated aneuploidy (MVA) syndrome. During interphase, Cep57 forms a complex with Cep63 and Cep152, serving as regulators for centrosome maturation. However, the molecular interplay of Cep57 with these essential scaffolding proteins remains unclear. Here, we demonstrate that Cep57 undergoes liquid-liquid phase separation (LLPS) driven by three critical domains (NTD, CTD, and polybasic LMN). In vitro Cep57 condensates catalyze microtubule nucleation via the LMN motif-mediated tubulin concentration. In cells, the LMN motif is required for centrosomal microtubule aster formation. Moreover, Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity. Overexpression of competitive constructs for multivalent interactions, including an MVA mutation, leads to excessive centrosome duplication. In Cep57-depleted cells, self-assembly mutants failed to rescue centriole disengagement and PCM disorganization. Thus, Cep57's multivalent interactions are pivotal for maintaining the accurate structural and functional integrity of human centrosomes., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: Youth unmet behavioral health needs are at public health crisis status and have worsened since the onset of the coronavirus disease 2019 pandemic (Covid-19). Integrating behavioral health services into pediatric primary care has shown efficacy in addressing youth behavioral health needs. However, there is limited guidance on facilitating equitable access to care in this setting, including in triaging access to co-located services (i.e., onsite outpatient behavioral health services with only the behavioral health provider) or to specialty behavioral health services in other clinics within larger health systems., Methods: A retrospective, comparative study was conducted to examine variability in access to co-located and specialty behavioral health (SBH) services for a pre-Covid-19 cohort (April 2019 to March 2020; n = 367) and a mid-Covid-19 cohort (April 2020 to March 2021; n = 328), while accounting for integrated primary care consultation services. The sample included children 1-18 years old served through a large, inner-city primary care clinic. Logistic regression models were used to examine the association between scheduled and attended co-located and SBH visits, pre- and mid-Covid-19 effects, and sociodemographic factors of race and ethnicity, language, health insurance (SES proxy), age, and sex., Results: The majority of youth were not directly scheduled for a co-located or SBH visit but the majority of those scheduled attended their visit(s). The odds of not being directly scheduled for a co-located or SBH visit were greater for the mid-Covid-19 cohort, Black youth, and older youth. Accounting for integrated primary care consultation visits addressed these disparities, with the exception of persisting significant differences in scheduled and attended co-located and SBH visits for Black youth even while accounting for IPC consultation., Implication: Findings from the current study highlight the effective role of integrated primary care consultation services as facilitating access to initial behavioral health services, especially given that referrals to integrated primary care co-located and SBH services within the larger health system often involve barriers to care such as longer wait-times and increased lack of referral follow through. Ongoing research and equitable program development are needed to further this work., 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., (Copyright © 2024 Chakawa, Crawford, Belzer and Yeh.)

Objective: The safety of early post-operative cardiac catheterisation has been described following congenital heart surgery. Optimal timing of early post-operative cardiac catheterisation remains uncertain. The aim of this study was to describe the safety of early post-operative cardiac catheterisation and its impact on cardiac ICU and hospital length of stay, duration of mechanical ventilation, and extracorporeal support., Methods: This single-centre retrospective cohort study compared clinical and outcome variables between "early" early post-operative cardiac catheterisation (less than 72 hours after surgery) and "late" early post-operative cardiac catheterisation (greater than 72 hours after surgery) groups using Chi-squared, Student's t, and log-rank test (or appropriate nonparametric test)., Results: In total, 132 patients were included, 22 (16.7%) "early" early post-operative cardiac catheterisation, and 110 (83.3%) "late" early post-operative cardiac catheterisation. Interventions were performed in 63 patients (51.5%), 7 (11.1%) early and 56 (88.9%) late. Complications of catheterisation occurred in seven (5.3%) patients, two early and five late. There were no major complications. Patients in the late group trended towards a longer stay in the cardiac ICU (19 days [7, 62] versus 11.5 days [7.2, 31.5], p = 0.6) and in the hospital (26 days [9.2, 68] versus 19 days [13.2, 41.8], p = 0.8) compared to the earlier group., Conclusion: "Early" early post-operative cardiac catheterisation was associated with an overall low rate of complications. Earlier catheterisations trended towards shorter cardiac ICU and hospital length of stays. Earlier catheterisations may lead to earlier recovery for patients not following an expected post-operative course.

Objective: To assess the association between antenatal corticosteroids exposure and postnatal growth in infants born at 23-29 weeks' gestation., Study Design: This retrospective study used data from the Pediatrix Clinical Data Warehouse. Maternal-infant dyads from 2018 to 2020 were included. Inverse propensity weighting (IPW) was applied to balance pre-treatment confounders. Primary outcomes included postnatal weight, length, and head circumference growth trajectory percentiles., Result: The unadjusted cohort consisted of 11,912 dyads. After IPW adjustment, there were 23,231 dyads. Exposed infants showed higher postnatal trajectory percentiles for weight (by 3.4%), length (by 1.8%), and head circumference (by 2.5%) when compared to non-exposed infants. The positive association between antenatal corticosteroids and postnatal growth was only observed in infants not exposed to preeclampsia/eclampsia/HELLP syndrome or without fetal growth restriction., Conclusion: Antenatal corticosteroids exposure is associated with better postnatal growth. The study is limited by its retrospective nature., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: A tension pneumothorax is a condition that results in elevated pressure within the pleural space. The effective management of tension pneumothorax relies on needle decompression, commonly performed at the second intercostal space (ICS) midclavicular line (MCL). However, some literature suggests that catheters placed in the second intercostal space midclavicular line are prone to higher failure rates compared to the fifth intercostal space midaxillary line (MAL) (42.5% versus 16.7%, respectively). In this study, we aim to identify and scrutinize the prevalence of prehospital needle decompression from one tertiary care center over eight years and examine their trends, efficacies, or pitfalls. It is hypothesized that preclinical providers are performing needle decompression prematurely and unnecessarily., Methods: A set of 90 patient records obtained using the trauma registry at Saint Francis Hospital, Tulsa, Oklahoma, were retrospectively reviewed to evaluate the management and outcomes of tension pneumothorax, as well as the indications documented for needle decompression. Patient charts were reviewed via Epic Hyperspace (Epic, Madison, WI). The Oklahoma Emergency Medical Service Information System (OKEMSIS) also provided information contributing to the sample population., Results: The most documented indications for needle decompressions included diminished or absent breath sounds (52.70%), hypoxia (15.54%), hypotension, and hemodynamic instability (6.76%). Emergency medical services (EMS) reported improvements in 51 (56.67%) patients after needle thoracostomy. Improvements in vital signs after needle decompression were sporadic. The most common complication was catheter dislodging, which occurred most in the second intercostal space midclavicular line. Only nine patients had an oxygen saturation (SpO 2 ) below 92% and a systolic blood pressure (SBP) below 100 mm Hg prior to receiving needle decompression., Conclusion: Current practices for tension pneumothorax show little improvement in vital signs before and after needle decompression. Vital signs prior to needle decompression often do not indicate tension pneumothorax physiology. Preclinical providers may be inappropriately performing needle decompressions, an invasive procedure with complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Parikh et al.)

Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are associated with inborn errors of metabolism, cancer, and neurodegenerative disorders, studying the limiting role of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus thermophilus (GshF), which possesses both glutamate-cysteine ligase and glutathione synthase activities. GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis induction, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes further revealed genes required for cell proliferation under cellular and mitochondrial GSH depletion. Among these, we identified the glutamate-cysteine ligase modifier subunit, GCLM, as a requirement for cellular sensitivity to buthionine sulfoximine, a glutathione synthesis inhibitor. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the limiting role of GSH in physiology and disease., Competing Interests: Conflict of interest K. B. is scientific advisor to Nanocare Pharmaceuticals and Atavistik Bio. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Kernicterus spectrum disorder (KSD) resulting from neonatal hyperbilirubinemia remains a common cause of cerebral palsy worldwide. This 12-month prospective cohort study followed neonates with hyperbilirubinemia to determine which clinical measures best predict KSD., Methods: The study enrolled neonates ≥35 weeks gestation with total serum bilirubin (TSB) ≥ 20 mg/dl admitted to Aminu Kano Hospital, Nigeria. Clinical measures included brain MRI, TSB, modified bilirubin-induced neurologic dysfunction (BIND-M), Barry-Albright Dystonia scale (BAD), auditory brainstem response (ABR), and the modified KSD toolkit. MRI signal alteration of the globus pallidus was scored using the Hyperbilirubinemia Imaging Rating Tool (HIRT)., Results: Of 25 neonates enrolled, 13/25 completed 12-month follow-up and six developed KSD. Neonatal BIND-M ≥ 3 was 100% sensitive and 83% specific for KSD. Neonatal ABR was 83% specific and sensitive for KSD. Neonatal HIRT score of 2 was 67% sensitive and 75% specific for KSD; this increased to 100% specificity and sensitivity at 12 months. BAD ≥ 2 was 100% specific for KSD at 3-12 months, with 50-100% sensitivity., Conclusions: Neonatal MRIs do not reliably predict KSD. BIND-M is an excellent screening tool for KSD, while the BAD or HIRT score at 3 or 12 months can confirm KSD, allowing for early diagnosis and intervention., Impact: The first prospective study of children with acute bilirubin encephalopathy evaluating brain MRI findings over the first year of life. Neonatal MRI is not a reliable predictor of kernicterus spectrum disorders (KSD). Brain MRI at 3 or 12 months can confirm KSD. The modified BIND scale obtained at admission for neonatal hyperbilirubinemia is a valuable screening tool to assess risk for developing KSD. The Barry Albright Dystonia scale and brain MRI can be used to establish a diagnosis of KSD in at-risk infants as early as 3 months., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objectives: Many patients with Fontan physiology are unable to achieve the minimum criteria for peak effort during cardiopulmonary exercise testing. The purpose of this study is to determine the influence of physical activity and other clinical predictors related to achieving peak exercise criteria, signified by respiratory exchange ratio ≥ 1.1 in youth with Fontan physiology., Methods: Secondary analysis of a cross-sectional study of 8-18-year-olds with single ventricle post-Fontan palliation who underwent cardiopulmonary exercise testing (James cycle protocol) and completed a past-year physical activity survey. Bivariate associations were assessed by Wilcoxon rank-sum test and simple regression. Conditional inference forest algorithm was used to classify participants achieving respiratory exchange ratio > 1.1 and to predict peak respiratory exchange ratio., Results: Of the n = 43 participants, 65% were male, mean age was 14.0 ± 2.4 years, and 67.4% (n = 29) achieved respiratory exchange ratio ≥ 1.1. Despite some cardiopulmonary exercise stress test variables achieving statistical significance in bivariate associations with participants achieving respiratory exchange ratio > 1.1, the classification accuracy had area under the precision recall curve of 0.55. All variables together explained 21.4% of the variance in respiratory exchange ratio, with peak oxygen pulse being the most informative., Conclusion: Demographic, physical activity, and cardiopulmonary exercise test measures could not classify meeting peak exercise criteria (respiratory exchange ratio ≥ 1.1) at a satisfactory accuracy. Correlations between respiratory exchange ratio and oxygen pulse suggest the augmentation of stroke volume with exercise may affect the Fontan patient's ability to sustain high-intensity exercise.

Neuroticism is a heritable trait and a risk factor for mental health due to its relevance to poor control of negative events. To examine the relationship between genetic propensity for neuroticism and control processing, we used the polygenic risk score (PRS) approach and a stop signal task during fMRI. We hypothesized that genetic propensity for neuroticism may moderate control processing as a function of control difficulty. PRSs for neuroticism were computed from a transdiagnostic group of individuals (n=406) who completed the stop signal task. The level of control difficulty was a function of the stop signal asynchrony: shorter asynchrony allows easier stopping whereas longer asynchrony makes stopping difficult. The relationship between PRS for neuroticism and neural activity for controlling responses was examined by the stop signal asynchrony. Although PRS for neuroticism did not relate to the overall inhibitory control, individuals with high PRS for neuroticism showed greater activity in left dorsal prefrontal cortex, middle temporal gyrus, and dorsal posterior cingulate cortex for difficult control. Thus, the genetic propensity for neuroticism affects neural processing in a difficult control context, which may help to explain why individuals with high levels of neuroticism exert poor control of negative events in difficult situations., Competing Interests: Declaration of Competing Interest MPP is an advisor to Spring Care, Inc., a behavioral health startup, and he has received royalties for an article about methamphetamine in UpToDate. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Intake-balance assessments measure energy intake (EI) by summing energy expenditure (EE) with concurrent change in energy storage (ΔES). Prior work has not examined the validity of such calculations when EE is estimated via open-source techniques for research-grade accelerometry devices. The purpose of this study was to test the criterion validity of accelerometry-based intake-balance methods for a wrist-worn ActiGraph device., Methods: Healthy adults (n = 24) completed two 14-day measurement periods while wearing an ActiGraph accelerometer on the non-dominant wrist. During each period, criterion values of EI were determined based on ΔES measured by dual X-ray absorptiometry and EE measured by doubly labeled water. A total of 11 prediction methods were tested, 8 derived from the accelerometer and 3 from non-accelerometry methods (e.g., diet recall; included for comparison). Group-level validity was assessed through mean bias, while individual-level validity was assessed through mean absolute error, mean absolute percentage error, and Bland-Altman analysis., Results: Mean bias for the three best accelerometry-based methods ranged from -167 to 124 kcal/day, versus -104 to 134 kcal/day for the non-accelerometry-based methods. The same three accelerometry-based methods had mean absolute error of 323-362 kcal/day and mean absolute percentage error of 18.1-19.3%, versus 353-464 kcal/day and 19.5-24.4% for the non-accelerometry-based methods. All 11 methods demonstrated systematic bias in the Bland-Altman analysis., Conclusions: Accelerometry-based intake-balance methods have promise for advancing EI assessment, but ongoing refinement is necessary. We provide an R package to facilitate implementation and refinement of accelerometry-based methods in future research (see paulhibbing.com/IntakeBalance)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Most growth references for very preterm infants were developed using measurements taken at birth, and were thought to represent intrauterine growth. However, it remains unclear whether the goal of approximating an intrauterine growth rate as stated by the American Academy of Pediatrics is attainable by very preterm infants. Using real-world measurement data from very preterm infants born between 2010 through 2020, we develop models to characterize the patterns of postnatal growth, and compare them to intrauterine growth. By assessing the weight growth rate, we show three phases of postnatal growth not evident in intrauterine growth. Furthermore, postnatal length and head circumference growth exhibit a slow rate after birth, followed by an acceleration. Collectively, postnatal and intrauterine growth are distinctly different. Although postnatal growth models do not represent optimal growth of very preterm infants, they can serve as a practical tool for clinical assessment of growth and for nutrition research., (© 2023. Springer Nature Limited.)

Objective: To identify robust and reproducible factors associated with suicidal thoughts and behaviors (STBs) in college students., Methods: 356 first-year university students completed a large battery of demographic and clinically-relevant self-report measures during the first semester of college and end-of-year ( n  = 228). Suicide Behaviors Questionnaire-Revised (SBQ-R) assessed STBs. A machine learning (ML) pipeline using stacking and nested cross-validation examined correlates of SBQ-R scores., Results: 9.6% of students were identified at significant STBs risk by the SBQ-R. The ML algorithm explained 28.3% of variance (95%CI: 28-28.5%) in baseline SBQ-R scores, with depression severity, social isolation, meaning and purpose in life, and positive affect among the most important factors. There was a significant reduction in STBs at end-of-year with only 1.8% of students identified at significant risk., Conclusion: Analyses replicated known factors associated with STBs during the first semester of college and identified novel, potentially modifiable factors including positive affect and social connectedness.

This study aimed to investigate the potential association between glaucoma and peripheral arterial occlusive disease. The study recruited patients, including 101,309 with glaucoma and 1,860,528 without a glaucoma diagnosis, from a population of 2 million patients in the Longitudinal Health Insurance Database. Propensity score matching was performed between the two groups, matching for age, sex, and comorbidities. In total, 95,575 patients with glaucoma and 95,575 patients without glaucoma were analyzed for their risk of developing peripheral arterial occlusive disease. The analysis of the data revealed that the glaucoma group had a higher incidence density (ID = 4.13) of peripheral arterial occlusive disease than the non-glaucoma group (ID = 3.42). The relative risk for the glaucoma group was 1.21 (95% C.I. = 1.15-1.28). Cox proportional hazard model analysis indicated that the glaucoma group had a higher risk of developing peripheral arterial occlusive disease (HR = 1.18; 95% C.I. = 1.12-1.25). The subgroup analysis of the risk of PAOD showed that the glaucoma group had a higher risk of developing peripheral arterial occlusive disease in the age group of 20 to 39 ( p for interaction = 0.002). In conclusion, patients with glaucoma were associated with a higher risk of subsequent peripheral arterial occlusive disease compared with those without a diagnosis of glaucoma.

Background: Eating Disorders (ED) affect up to 5% of youth and are associated with reward system alterations and compulsive behaviors. Naltrexone, an opioid antagonist, is used to treat ED behaviors such as binge eating and/or purging. The presumed mechanism of action is blockade of reward activation; however, not all patients respond, and the optimal dose is unknown. Developing a tool to detect objective drug response in the brain will facilitate drug development and therapeutic optimization. This pilot study evaluated neuroimaging as a pharmacodynamic biomarker of opioid antagonism in adolescents with ED., Methods: Youth aged 13-21 with binge/purge ED completed functional magnetic resonance imaging (fMRI) pre- and post-oral naltrexone. fMRI detected blood oxygenation-level dependent (BOLD) signal at rest and during two reward probes (monetary incentive delay, MID, and passive food view, PFV) in predefined regions of interest associated with reward and inhibitory control. Effect sizes for Δ%BOLD (post-naltrexone vs. baseline) were estimated using linear mixed effects modeling., Results: In 12 youth (16-21 years, 92% female), BOLD signal changes were detected following naltrexone in the nucleus accumbens during PFV (Δ%BOLD -0.08 ± 0.03; Cohen's d - 1.06, p  = 0.048) and anterior cingulate cortex during MID (Δ%BOLD 0.06 ± 0.03; Cohen's d 1.25, p  = 0.086)., Conclusion: fMRI detected acute reward pathway modulation in this small sample of adolescents with binge/purge ED. If validated in future, larger trials, task-based Δ%BOLD detected by fMRI may serve as a pharmacodynamic biomarker of opioid antagonism to facilitate the development of novel therapeutics targeting the reward pathway, enable quantitative pharmacology trials, and inform drug dosing., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04935931, NCT#04935931., 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., (Copyright © 2023 Stancil, Yeh, Brucks, Bruce, Voss, Abdel-Rahman, Brooks and Martin.)

Boronic acid-containing fluorescent molecules have been widely used to sense hydrogen peroxide and peroxynitrite, which are important reactive oxygen and nitrogen species in biological systems. However, it has been challenging to gain specificity. Our previous studies developed genetically encoded, green fluorescent peroxynitrite biosensors by genetically incorporating a boronic acid-containing noncanonical amino acid (ncAA), p -boronophenylalanine ( p BoF), into the chromophore of circularly permuted green fluorescent proteins (cpGFPs). In this work, we introduced p BoF to amino acid residues spatially close to the chromophore of an enhanced circularly permuted red fluorescent protein (ecpApple). Our effort has resulted in two responsive ecpApple mutants: one bestows reactivity toward both peroxynitrite and hydrogen peroxide, while the other, namely, pnRFP, is a selective red fluorescent peroxynitrite biosensor. We characterized pnRFP in vitro and in live mammalian cells. We further studied the structure and sensing mechanism of pnRFP using X-ray crystallography, 11 B-NMR, and computational methods. The boron atom in pnRFP adopts an sp 2 -hybridization geometry in a hydrophobic pocket, and the reaction of pnRFP with peroxynitrite generates a product with a twisted chromophore, corroborating the observed "turn-off" fluorescence response. Thus, this study extends the color palette of genetically encoded peroxynitrite biosensors, provides insight into the response mechanism of the new biosensor, and demonstrates the versatility of using protein scaffolds to modulate chemoreactivity.

Objective: Exposure-based therapy (EXP) and behavioral activation (BA) are empirically-supported behavioral intervention techniques that target avoidance and approach behavior to alleviate symptoms. Although EXP is an established treatment for generalized anxiety disorder (GAD), the effectiveness of BA for GAD has not been directly tested or compared with that of EXP. This study examined the efficacy of EXP and BA for adults with GAD., Method: In a randomized clinical trial (clinicaltrials.gov: NCT02807480) with partial blinding in Tulsa, OK, 102 adults with GAD were allocated to manualized, 10-session EXP or BA between April 2016-April 2021. Primary analyses were intention-to-treat and included the 94 (46 EXP, 48 BA) participants who started treatment. The GAD-7 self-report scale was the primary outcome measure., Results: Similar GAD-7 declines were observed at post-treatment for EXP ( d =-0.97 [95% CI -1.40 to -0.53]) and BA ( d =-1.14 [95% CI -1.57 to -0.70]), and were maintained through 6-month follow-up (EXP: d =-2.13, BA: d =-1.98). Compared to EXP, BA yielded more rapid declines in anxiety and depression scores during therapy ( d =0.75-0.77), as well as lower anxiety and depression scores ( d =0.13-0.14) and greater participant-rated improvement ( d =0.64) at post-treatment. Bayesian analyses indicated 74-99% probability of greater change in BA than EXP at post-treatment., Conclusions: BA and EXP are both effective in treating GAD, and BA may confer greater benefit during treatment. Future research is warranted to inform personalized treatment approaches., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, Robin Aupperle reports financial support was provided by National Institute of Mental Health. Christopher Martell reports receiving royalties for four books on the topic of behavioral activation. Martin Paulus has received royalties for an article about methamphetamine published in UpToDate. The other authors have no conflicts of interest to declare.

Background: Repetitive negative thinking (RNT) is a symptom that can negatively impact the treatment and course of common psychiatric disorders such as depression and anxiety. We aimed to characterize behavioral and genetic correlates of RNT to infer potential contributors to its genesis and maintenance., Methods: We applied a machine learning (ML) ensemble method to define the contribution of fear, interoceptive, reward, and cognitive variables to RNT, along with polygenic risk scores (PRS) for neuroticism, obsessive compulsive disorder (OCD), worry, insomnia, and headaches. We used the PRS and 20 principal components of the behavioral and cognitive variables to predict intensity of RNT. We employed the Tulsa-1000 study, a large database of deeply phenotyped individuals recruited between 2015 and 2018., Results: PRS for neuroticism was the main predictor of RNT intensity (R 2 =0.027,p<0.001). Behavioral variables indicative of faulty fear learning and processing, as well as aberrant interoceptive aversiveness, were significant contributors to RNT severity. Unexpectedly, we observed no contribution of reward behavior and diverse cognitive function variables., Limitations: This study is an exploratory approach that must be validated with a second, independent cohort. Furthermore, this is an association study, limiting causal inference., Conclusions: RNT is highly determined by genetic risk for neuroticism, a behavioral construct that confers risk to a variety of internalizing disorders, and by emotional processing and learning features, including interoceptive aversiveness. These results suggest that targeting emotional and interoceptive processing areas, which involve central autonomic network structures, could be useful in the modulation of RNT intensity., Competing Interests: Declaration of competing interest The authors have no competing interests to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: A variety of quality control (QC) approaches are employed in resting-state functional magnetic resonance imaging (rs-fMRI) to determine data quality and ultimately inclusion or exclusion of a fMRI data set in group analysis. Reliability of rs-fMRI data can be improved by censoring or "scrubbing" volumes affected by motion. While censoring preserves the integrity of participant-level data, including excessively censored data sets in group analyses may add noise. Quantitative motion-related metrics are frequently reported in the literature; however, qualitative visual inspection can sometimes catch errors or other issues that may be missed by quantitative metrics alone. In this paper, we describe our methods for performing QC of rs-fMRI data using software-generated quantitative and qualitative output and trained visual inspection., Results: The data provided for this QC paper had relatively low motion-censoring, thus quantitative QC resulted in no exclusions. Qualitative checks of the data resulted in limited exclusions due to potential incidental findings and failed pre-processing scripts., Conclusion: Visual inspection in addition to the review of quantitative QC metrics is an important component to ensure high quality and accuracy in rs-fMRI data analysis., 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., (Copyright © 2023 Lepping, Yeh, McPherson, Brucks, Sabati, Karcher, Brooks, Habiger, Papa and Martin.)

Purpose: To provide guidance to hospitals that are developing suicide screening programs, we identified rates of positive screens across outpatient visits within a tertiary care children's hospital., Methods: Suicide screening results from healthcare encounters occurring between February 2019 and January 2020 were estimated for ambulatory clinics (OP), urgent care (UC) clinics, and the emergency department (ED)., Results: Positive screens (95% confidence interval [CI]) occurred in 10.8% (10.6, 11.0)%) of visits overall. Rates of positive screens were 14.5 (14.1, 14.9)%, 9.9 (9.7, 10.1)%, and 9.3 (8.9, 9.7)% in the ED, OP, and UC, respectively. Rates of positive screens in outpatient clinics were highest in child abuse (33.4 (28.0, 39.2) %) and adolescent specialty (19.2 (17.3, 21.1) %)., Discussion: Some outpatient clinics had rates of positive suicide screens that surpass those seen in the ED. These findings could inform targeted suicide screening in hospital systems with limited resources to do universal screening., (Copyright © 2022 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Abstract: Hepatocellular carcinoma (HCC) is a fatal cancer worldwide, and surgical resection remains the standard treatment. Postoperative opioid prescription has been believed to affect cancer recurrence through complex biological pathways. We conducted a retrospective cohort study using the Longitudinal Health Insurance Database of Taiwan to evaluate the relationship between postoperative opioid use and long-term surgical outcomes of patients with HCC. This study had a retrospective cohort design. In total, 812 patients older than 20 years who underwent hepatectomy because of HCC were included. The exposure group comprised patients who used opioids during hospitalization postoperatively. The comparison group included those who never used opioids during hospitalization postoperatively. A Cox proportional hazards model was used to evaluate the overall survival or recurrence-free survival rate between the opioid group and the nonopioid group. A total of 530 patients received opioids postoperatively and 282 patients did not. The hazard ratios of overall survival and recurrence-free survival were 1.10 (95% confidence interval [CI], 0.85-1.41) and 1.15 (95% CI, 0.91-1.46), respectively. Total postoperative opioids were converted into oral morphine milligram equivalents and then divided into 3 equal subgroups: low dose, <40 mg; medium dose, 40 to 144 mg; and high dose, ≥145 mg. The hazard ratios of overall survival were 0.88 (95% CI, 0.63-1.24) for the low-dose group, 1.27 (95% CI, 0.92-1.74) for the medium-dose group, and 1.14 (95% CI, 0.83-1.58) for the high-dose group. Postoperative opioids do not affect overall and recurrence-free survival in patients undergoing hepatectomy or liver transplantation because of HCC. Cancer recurrence should not be a clinical concern regarding postoperative opioid prescription., (Copyright © 2022 International Association for the Study of Pain.)

Background: Sepsis related acute lung injury (ALI) is established in adults but has not been investigated in premature infants. Herein, we used pulmonary severity score (PSS) trajectories and C-reactive protein (CRP) to examine the relation between sepsis and ALI in premature infants., Methods: This retrospective study identified 211 sepsis and 123 rule out (RO) events in 443 infants born <31 weeks and <1500 grams. The PSS was calculated prior to, at the time of, and up to 1 week after each event. Initial and peak CRP values were collected for each event., Results: PSS significantly increased at 0 h from baseline (-72h) and remained increased at all subsequent time points (all p < 0.002) in sepsis events. Mean PSS in sepsis episodes were also higher compared to RO events at +24 h, +48 h, +72 h, and +168 h (all p < 0.004). A positive correlation was noted between peak CRP values in sepsis events and PSS at 0 h, +24 h, +48 h, and +72 h., Conclusions: The temporal PSS trends and correlation with CRP levels observed in sepsis but not in RO events supports the hypothesis that neonatal sepsis is associated with ALI and contributes to the accumulating evidence that neonatal ARDS occurs., Impact: To evaluate pulmonary severity scores and c-reactive protein values over time to establish an association between preterm neonatal sepsis and acute lung injury (ALI). Though sepsis is well established as the most common indirect cause of ALI leading to acute respiratory distress syndrome (ARDS) in adults and pediatrics, this phenomenon remains undefined in neonates. This study validates the proposal by the Neonatal ARDS Project that ARDS also occurs in neonates by demonstrating acute and sustained changes in markers of pulmonary injury temporally related to a diagnosis of neonatal sepsis in preterm infants., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Transosseous-equivalent suture-bridge (TOE-SB) and independent double-row (IDR) repair techniques were developed to treat rotator cuff tears. The study was designed to prove that both TOE-SB and IDR techniques provided comparable clinical results and retear rate for medium to massive posterosuperior rotator cuff tears, while the surgical time and number of suture anchor used were less in the IDR group., Study Design: Level of evidence: level III, Retrospective comparative study., Methods: Patients with medium to massive posterosuperior rotator cuff tears receiving arthroscopic TOE-SB and IDR between November 2016 to October 2019 were retrospectively enrolled. All patients were confirmed to have grade ≤ 2 fatty infiltration in the muscles of the torn tendons. Revision, concomitant subscapularis tear, acromiohumeral distance < 7 mm, glenohumeral osteoarthritis, partial repair, incomplete repair, partial thickness, or irreparable posterosuperior cuff tear were excluded. Surgical time, number of suture anchor used for the surgery, pre-operative, and post-operative clinical scores such as Constant-Murley score, subjective shoulder value (SSV), and visual analog scale (VAS) were compared. The retear rates between groups were evaluated by ultrasound., Results: Thirty-five IDR and thirty-five TOE-SB repairs were enrolled. The IDR technique required much fewer anchors than TOE-SB did to complete the cuff repair. The mean operation time in IDR and TOE-SB group were 86(18.23), and 114(18.7) (min), respectively (P <  0.01). The mean number of anchors used to complete the cuff repair was 2(0.17) in IDR and 3(0.61) in TOE-SB (P <  0.01). The Constant-Murley score improved from 34.9 ± 6.6 to 80.6 ± 9.4 in the IDR group, and 37.4 ± 6 to 81.9 ± 4.6 in the TOE-SB group (both P <  0.001). SSV improved from 24.6 ± 9.6 to 79.3 ± 10.6 in the IDR, and 27.9 ± 9 to 82.9 ± 6.9 in the TOE-SB group (both P <  0.001). VAS improved from 7.9 ± 0.6 to 1.5 ± 0.7 in the IDR, and 8 ± 0.5 to 1.3 ± 0.6 in the TOE-SB group (both P <  0.001) at final follow-up. No significant difference was found between the retear rates (14.3% in the IDR vs. 17.1% in the TOE-SB, respectively) in the 2-year follow-up., Conclusions: Both IDR and TOE-SB group provided comparable clinical results and retear rates for medium to massive posterosuperior rotator cuff tears. The surgical time and number of anchors used were less in the IDR group than in the TOE-SB group., (© 2023. The Author(s).)

Background: The new bronchopulmonary dysplasia (BPD) grading system was developed based on its correlation with long-term respiratory and neurodevelopmental outcomes and may provide better personalized prognostication. Identifying early-life predictors for accurate BPD grade prediction may allow interventions to be tailored to individual needs. This study aimed to assess whether oxygenation index (OI) dynamics in the first three weeks of life are a predictor of BPD grade., Methods: A single-center retrospective study was performed. Generalized additive mixed modeling was used to model OI trajectories for each BPD grade subgroup. A multinomial regression model was then developed to quantify the association between OI dynamics and BPD grade., Results: Two hundred fifty-four infants were identified for inclusion in the trajectory modeling. A total of 6,243 OI data points were available for modeling. OI trajectory estimates showed distinct patterns in the three groups, most prominent during the third week of life. The average daily OI change was -0.33 ± 0.52 (n = 85) in the No-BPD group, -0.04 ± 0.75 (n = 82) in the Low-Grade BPD group, and 0.22 ± 0.65 (n = 75) in the High-Grade BPD group (p < 0.001). A multinomial regression analysis showed the initial OI value and the average daily OI change both independently correlated with BPD grade outcomes after adjusting for birth gestation, birth weight z-score, sex, and the duration of invasive ventilation., Conclusion: Early-life OI dynamics may be a useful independent marker for BPD grade prediction. Prospective studies may be warranted to further validate the findings., (© 2023. The Author(s).)

The central nervous system (CNS) exerts a strong regulatory influence over the cardiovascular system in response to environmental demands. Floatation-REST (Reduced Environmental Stimulation Therapy) is an intervention that minimizes stimulation from the environment, yet little is known about the autonomic consequences of reducing external sensory input to the CNS. We recently found that Floatation-REST induces a strong anxiolytic effect in anxious patients while paradoxically enhancing their interoceptive awareness for cardiorespiratory sensations. To further investigate the physiologic nature of this anxiolytic effect, the present study measured acute cardiovascular changes during Floatation-REST using wireless and waterproof equipment that allowed for concurrent measurement of heart rate, heart rate variability (HRV), breathing rate, and blood pressure. Using a within-subjects crossover design, 37 clinically anxious participants with high levels of anxiety sensitivity and 20 non-anxious comparison participants were randomly assigned to undergo a 90-min session of either Floatation-REST or an exteroceptive comparison condition that entailed watching a relaxing nature film. Measures of state anxiety and serenity were collected before and after each session, while indices of autonomic activity were measured throughout each session. HRV was calculated using both time-series and frequency domain analyses. Linear mixed-effects modeling revealed a significant main effect of condition such that relative to the film condition, Floatation-REST elicited significant decreases ( p < 0.001) in diastolic blood pressure, systolic blood pressure, breathing rate, and certain metrics of HRV including the standard deviation of the interbeat interval (SDNN), low-frequency HRV, and very low-frequency HRV. Heart rate showed a non-significant trend ( p = 0.073) toward being lower in the float condition, especially toward the beginning of the session. The only metric that showed a significant increase during Floatation-REST was normalized high-frequency HRV ( p < 0.001). The observed physiological changes were consistent across both anxious and non-anxious participants, and there were no significant group by condition interactions. Blood pressure was the only cardiac metric significantly associated with float-related reductions in state anxiety and increases in serenity. These findings suggest that Floatation-REST lowers sympathetic arousal and alters the balance of the autonomic nervous system toward a more parasympathetic state., Clinical Trial Registration: [https://clinicaltrials.gov/show/NCT03051074], identifier [NCT03051074]., 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., (Copyright © 2022 Flux, Fine, Poplin, Al Zoubi, Schoenhals, Schettler, Refai, Naegele, Wohlrab, Yeh, Lowry, Levine, Smith, Khalsa and Feinstein.)

Objective: People with 22q11.2 deletion syndrome (22q11DS) can present with a wide variety of findings. Various airway anomalies have been described intermittently within this syndrome, but this feature has not been extensively investigated. Increased provider awareness of these findings may help guide clinical decision-making and improve overall patient outcomes. The objectives of this review are to identify the types of airway anomalies in 22q11DS and the prevalence of airway anomalies within symptomatic individuals., Methods: PubMed/MEDLINE, Cochrane Library, and EMBASE databases were searched in February 2022 for all available articles. Search terms included those that described 22q11DS or one of its synonymous conditions AND those that described airway anatomy and anomalies. The term airway anomaly was defined as any structural aberration in the conductive airway from the oral or nasal vestibule region to the mainstem bronchus. Studies were screened by two authors. A review of references was conducted. Eligible manuscripts underwent full-text review for quality appraisal and data extraction., Results: From a total of 909 unique manuscripts, 58 studies were selected, describing 328 people. The prevalence of airway anomaly diagnosis within symptomatic individuals ranged from 14% to 74%. Twenty-two unique airway anomalies were described. Laryngeal web was the most frequently described anomaly, followed by airway malacia and subglottic stenosis. Laryngeal web was 40% sensitive for suggesting a diagnosis of 22q11DS. Among affected individuals, as many as 46% had multiple concomitant airway anomalies. Aside from respiratory symptoms, other features that prompted airway evaluation included difficult intubation or failed extubation., Conclusion: The findings within this review support the notion that a wide variety of airway anomalies may be seen in people with 22q11DS and that these findings have been discovered frequently in those with airway symptoms. Providers should maintain a low threshold to perform an airway examination in those with 22q11DS, especially when airway symptoms are present., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Transcranial direct current stimulation (tDCS) has been studied as a therapeutic option to alter maladaptive brain functions associated with chronic substance use. We present a randomized, triple-blind, sham-controlled, clinical trial to determine the neural substrates of tDCS effects on drug craving. Sixty participants with methamphetamine use disorder were assigned to two groups: active tDCS (5 x 7 cm 2 , 2 mA, 20 min, anode/cathode over the F4/Fp1) and sham stimulation. Neuroimaging data of a methamphetamine cue reactivity task were collected immediately before and after stimulation. There was a significant reduction in self-reported craving after stimulation without any significant effect of time-by-group interaction. Our whole-brain analysis demonstrated that there was a global decrease in brain reactivity to cues following sham but not active tDCS. There were significant time-by-group interactions in five main clusters in middle and inferior frontal gyri, anterior insula, inferior parietal lobule, and precuneus with higher activations after active stimulation. There was a significant effect of stimulation type in the relationship between electrical current at the individual level and changes in task-modulated activation. Brain regions with the highest electric current in the prefrontal cortex showed a significant time-by-group interaction in task-modulated connectivity in the frontoparietal network. In this trial, there was no significant effect of the one session of active-F4/Fp1 tDCS on drug craving self-report compared to sham stimulation. However, activation and connectivity differences induced by active compared to sham stimulation suggested some potential mechanisms of tDCS to modulate neural response to drug cues., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background/purpose: There is controversial evidence on the best choice for root-end filling materials in follow-up periods and treatment protocols. The purpose of this study was to evaluate the effectiveness of different root-end filling materials in modern surgical endodontic treatment., Materials and Methods: A total of 16 studies with a minimum follow-up of 12-months were qualified to be reviewed, involving randomized control trials and observational studies in PubMed, Cochrane library and Scopus until September 1, 2021. The outcome of modern surgical endodontic treatment was assessed based on clinical and radiographic success. Direct comparisons were combined to estimate indirect comparisons, and the estimated effect size was analyzed using the odds ratio (OR). The comparative effectiveness of all materials for target outcomes were shown as P-score., Results: Within this network meta-analysis, mineral trioxide aggregate (MTA) had superior effects among all root-end filling materials at 12-months follow-up. (MTA: OR, 2.03; 95% CI, 0.84-4.91; P-score, 0.86; reference material, gutta-percha). In further sensitivity analyses, MTA, calcium silicate-based root repair material (RRM) and super EBA cement (Super EBA) were associated with significantly higher success rates at 12-months follow-up. (MTA: OR, 5.62; 95% CI, 1.58-19.99; P-score, 0.88; RRM: OR, 5.23; 95% CI, 1.05-25.98; P-score, 0.74; Super EBA: OR, 3.99; 95% CI, 1.06-15.04; P-score, 0.54; reference material, gutta-percha)., Conclusion: MTA remains the best choice for root-end filling materials of modern surgical endodontic treatment at the 12-month follow-up. Comparative randomized clinical trials in the long-term follow-up are warranted in future investigations., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background: An inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown., Methods: Serum samples were provided by 56 depressed individuals before BA therapy and 29 of these individuals also provided samples after 10 weeks of therapy to measure cytokines and KP metabolites. The PROMIS Depression Scale (PROMIS-D) and the Sheehan Disability Scale were administered weekly and the Beck depression inventory was administered pre- and post-therapy. Data were analyzed with linear mixed-effect, general linear, and logistic regression models. The primary outcome for the biomarker analyses was the ratio of kynurenic acid to quinolinic acid (KynA/QA)., Results: BA decreased depression and disability scores ( p 's < 0.001, Cohen's d 's > 0.5). KynA/QA significantly increased at post-therapy relative to baseline ( p < 0.001, d = 2.2), an effect driven by a decrease in QA post-therapy ( p < 0.001, uncorrected, d = 3.39). A trend towards a decrease in the ratio of kynurenine to tryptophan (KYN/TRP) was also observed ( p = 0.054, uncorrected, d = 0.78). Neither the change in KynA/QA, nor baseline KynA/QA were associated with response to BA therapy., Conclusion: The current findings together with previous research show that electronconvulsive therapy, escitalopram, and ketamine decrease concentrations of the neurotoxin, QA, raise the possibility that a common therapeutic mechanism underlies diverse forms of anti-depressant treatment but future controlled studies are needed to test this hypothesis.

We designed a protein biosensor that uses thermodynamic coupling for sensitive and rapid detection of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in serum. The biosensor is a switchable, caged luciferase-receptor-binding domain (RBD) construct that detects serum-antibody interference with the binding of virus RBD to angiotensin-converting enzyme 2 (ACE-2) as a proxy for neutralization. Our coupling approach does not require target modification and can better distinguish sample-to-sample differences in analyte binding affinity and abundance than traditional competition-based assays., (© 2022. The Author(s).)

Lenrispodun is a potent and highly selective inhibitor of phosphodiesterase (PDE) type 1, which is thought to prolong intracellular second messenger signaling within cortical and subcortical dopaminergic brain regions. This is the first study of a PDE1 inhibitor in healthy volunteers using behavioral and neuroimaging approaches to examine its effects on neural targets and to provide a safety and tolerability assessment. The primary objectives were to determine whether lenrispodun induces changes in BOLD fMRI signals in the inferior frontal gyrus (IFG) during the stop signal task, and the dorsal anterior insula (dAI) during the extinction phase of a fear conditioning/extinction task. Using a double-blind, placebo-controlled, within-subjects design, 26 healthy individuals (22 completed all fMRI sessions) received in random order a single oral dose of placebo, lenrispodun 1.0 milligram (mg) or lenrispodun 10.0 mg and completed several tasks in the scanner including the stop signal (n = 24) and fear conditioning/extinction tasks (n = 22). Prespecified region-of-interest analyses for the IFG and dAI were computed using linear mixed models. Lenrispodun induced increases in IFG activity during the stop signal task at 1.0 mg (Cohen's d = 0.63) but not 10.0 mg (Cohen's d = 0.07) vs. placebo. Lenrispodun did not induce changes in dAI activity during fear extinction at either dose. Exploratory outcomes revealed changes in cardiac interoception. Lenrispodun administration was well-tolerated. These results provide evidence that 1.0 mg lenrispodun selectively improved neural inhibitory control without altering fear extinction processing. Future investigations should determine whether lenrispodun improves inhibitory control in target populations such as individuals with attention deficit hyperactivity disorder. Trial registration: ClinicalTrials.gov identifier: NCT03489772., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Elevated serum concentrations (>3 mg/L) of the acute-phase protein, C-reactive protein (CRP), is used as a clinical marker of inflammation and is reported to be a strong risk factor for cardiovascular disease. In psychiatric populations, CRP concentration is reported to be higher in depressed versus healthy individuals. Positive associations between CRP and depression have been established in both clinical and community samples, but effect sizes are attenuated after controlling for confounding variables. Similarly, emerging research has begun to draw a link between inflammation, symptoms of anxiety, and substance abuse. Given the high level of comorbid anxiety and substance use disorders in many depressed populations, this study examined whether depression (Patient Health Questionnaire 9 [PHQ-9]) and substance use-related (Drug Abuse Screening Test [DAST]) symptoms were associated with CRP concentrations in the blood after adjusting for relevant medical, social, and demographic covariates in a large sample undergoing screening for several transdiagnostic psychiatric research studies. A total of 1,724 participants were analyzed for association of CRP with variables using multivariate linear regression. An unadjusted model with no covariates showed that PHQ-9 was significantly associated with CRP in All (β = 0.125), Female (β = 0.091), and Male (β = 0.154) participants, but DAST was significantly associated with CRP in males only (β = 0.120). For the adjusted model, in both males and females, mood-stabilizer treatment (β = 0.630), opioid medication (β = 0.360), body mass index (β = 0.244), percent body fat (β = 0.289), nicotine use (β = 0.063), and self-reported sleep disturbance (β = 0.061) were significantly associated with increased CRP concentrations. In females, oral contraceptive use (β = 0.576), and waist-to-hip ratio (β = 0.086), and in males, non-steroidal anti-inflammatory drug use (β = 0.367) were also associated with increased CRP concentrations. There was no significant association between CRP and individual depressive, anxiety, or substance use-related symptoms when covariates were included in the regression models. These results suggest that associations between circulating CRP and the severity of psychiatric symptoms are dependent on the type of covariates controlled for in statistical analyses., (© 2022. The Author(s).)

Generally, those patients with dysarthria utter a distorted sound and the restrained intelligibility of a speech for both human and machine. To enhance the intelligibility of dysarthric speech, we applied a deep learning-based speech enhancement (SE) system in this task. Conventional SE approaches are used for shrinking noise components from the noise-corrupted input, and thus improve the sound quality and intelligibility simultaneously. In this study, we are focusing on reconstructing the severely distorted signal from the dysarthric speech for improving intelligibility. The proposed SE system prepares a convolutional neural network (CNN) model in the training phase, which is then used to process the dysarthric speech in the testing phase. During training, paired dysarthric-normal speech utterances are required. We adopt a dynamic time warping technique to align the dysarthric-normal utter-ances. The gained training data are used to train a CNN - based SE model. The proposed SE system is evaluated on the Google automatic speech recognition (ASR) system and a subjective listening test. The results showed that the proposed method could notably enhance the recognition performance for more than 10% in each of ASR and human recognitions from the unprocessed dysarthric speech. Clinical Relevance- This study enhances the intelligibility and ASR accuracy from a dysarthria speech to more than 10.

Safe storage of lethal means is an evidence-based approach to suicide prevention that is underutilized. This naturalistic study investigated whether a presentation on parenting teenagers that includes education about safe storage of firearms and medications, paired with tools to enact change, can impact storage practices. Ten community presentations for parents were given between November 2018 and September 2019 in the Midwest region of the United States. Multiple topics pertinent to parenting adolescents were included with an emphasis on safe storage of firearms and medications to reduce suicide risk. Toolkits including medication storage boxes and cable gun locks were offered to help parents enact recommended changes. Surveys were completed prior to the presentation (T1), immediately following the presentation (T2), and 2 weeks after the presentation (T3). Five-hundred eighty-one parents comprised the initial study sample, of whom 410 (70.6%) completed the primary study endpoint. Generalized linear mixed models with and without worst-case imputation were used to evaluate changes in safe storage practices. Results suggested the odds of storing firearms in the safest manner possible increased 5.9 times (95% CI 2.6-13.5, p < 0.001) without imputation and increased 2.0 times (95% CI 1.1-3.4, p = 0.02) with the worst-case imputation. Among participants with unlocked medications at baseline, 56.5% reported they had disposed of old medications and 53.0% reported locking up bottles of medication by the primary study endpoint. This study provides preliminary evidence that safe storage education paired with tools for behavior change motivates parents to enact safe storage measures., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.

OLA1 is a P-loop ATPase, implicated in centrosome duplication through the interactions with tumor suppressors BRCA1 and BARD1. Disruption of the interaction of OLA1 with BARD1 results in centrosome amplification. However, the molecular interplay and mechanism of the OLA1-BARD1 complex remain elusive. Here, we use a battery of biophysical, biochemical, and structural analyses to elucidate the molecular basis of the OLA1-BARD1 interaction. Our structural and enzyme kinetics analyses show this nucleotide-dependent interaction enhances the ATPase activity of OLA1 by increasing the turnover number (k cat ). Unlike canonical GTPase activating proteins that act directly on the catalytic G domain, the BARD1 BRCT domain binds to the OLA1 TGS domain via a highly conserved BUDR motif. A cancer related mutation V695L on BARD1 is known to associate with centrosome abnormality. The V695L mutation reduces the BARD1 BRCT-mediated activation of OLA1. Crystallographic snapshot of the BRCT V695L mutant at 1.88 Å reveals this mutation perturbs the OLA1 binding site, resulting in reduced interaction. Altogether, our findings suggest the BARD1 BRCT domain serves as an ATPase activating protein to control OLA1 allosterically., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Rapid development and deployment of vaccines is crucial to control the continuously evolving COVID-19 pandemic. The placebo-controlled phase 3 efficacy trial is still the standard for authorizing vaccines in the majority of the world. However, due to a lack of eligible participants in parts of the world, this has not always been feasible. Recently, the Taiwan Food and Drug Administration, following the consensus of the International Coalition of Medicines Regulatory Authorities (ICMRA), adopted the use of immunobridging studies as acceptable for authorizing COVID-19 vaccines in lieu of efficacy data. Here, we describe a study in which our candidate vaccine, MVC-COV1901, an adjuvanted protein subunit vaccine, has been granted emergency use authorization (EUA) in Taiwan based on a noninferiority immunobridging study. Immunogenicity results from the per protocol immunogenicity (PPI) subset ( n = 903) from the MVC-COV1901 phase 2 trial were compared with results from 200 subjects who had received an adenovirus vector vaccine, AstraZeneca ChAdOx nCOV-19 (AZD1222), in a separate study. The lower bound of the 95% confidence interval (CI) of the geometric mean titer (GMT) ratio comparing MVC-COV1901 to AZD1222 was 3.4. The lower bound of the 95% CI of the sero-response rate was 95.5%. Both the GMT ratio and sero-response rate exceeded the criteria established by the Taiwan regulatory authority, leading to EUA approval of MVC-COV1901 in Taiwan.

Attenuated heart rate recovery (HRR) following peak exercise has been shown to be a predictor of mortality in populations of adults with Fontan palliation, coronary artery disease, heart failure, and heart transplantation. However, few have studied HRR in children and adolescents with congenital heart disease (CHD). This case-control study compared HRR patterns from exercise stress testing in children and adolescents with and without repaired acyanotic CHD (raCHD). Retrospective analysis included patients aged 10-18 years who had exercise testing between 2007 and 2017. The raCHD cohort included patients with Tetralogy of Fallot, transposition of the great arteries, coarctation, truncus arteriosus, atrioventricular septal defect, pulmonary outflow obstruction, aortic stenosis and/or insufficiency, or septal defects. Those in the control cohort were matched for age, sex, BMI, peak METs achieved, and peak heart rate (HR). HR at 1-min intervals throughout the 10-min recovery period and HRR patterns were analyzed. The study included n = 584 individuals (raCHD: n = 146), median age 14 years old, 67.1% male. The cohorts had similar resting and peak HRs. Linear mixed-effects models (LMM) suggested statistically significant cohort-by-time interaction for HR in exercise recovery, with the largest mean difference at minute-6 (2.9 bpm, p = 0.008). When comparing lesion types, LMM found no cohort or cohort-by-time interaction. While minute-6 of exercise recovery was statistically significant, the difference was 2.9 bpm and may not have clinical significance. These results suggest that HRR in pediatric raCHD patients should not vary from their healthy peers, and an attenuated HRR may not be directly attributed to underlying raCHD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Fluoroquinolones are first-line antibiotics recommended for the treatment of complicated urinary tract infections (UTIs), with frequent reports of adverse effects of aortic aneurysm (AA) and aortic dissection (AD). We examined whether fluoroquinolones can increase the risk of AA and AD in patients with UTIs in the Taiwanese population. Methods and Results We used the National Health Insurance Research Database to identify patients diagnosed with UTIs under single antibiotic treatment of fluoroquinolones and first-, second-, or third-generation cephalosporins. An AA and AD diagnosis within a year constituted the study event. Multivariable analysis with a multiple Cox regression model was applied for comparing the hazard risk of AA and AD between fluoroquinolones and first- or second-generation cephalosporins. Propensity score matching was performed to reduce the potential for bias caused by measured confounding variables. Among 1 249 944 selected patients with UTIs, 28 568 patients were assigned to each antibiotic group after propensity score matching. The incidence of AA and AD was not significantly different between the fluoroquinolones and first- or second-generation cephalosporins (adjusted HR [aHR], 0.86 [95% CI, 0.59-1.27]). However, the mortality increased in the fluoroquinolones group (aHR, 1.10 [95% CI, 1.04-1.16]). Conclusions Compared with first- or second-generation cephalosporins, fluoroquinolones were not associated with increased risk of AA and AD in patients with UTI. However, a significant risk of mortality was still found in patients treated with fluoroquinolones. The priority is to control infections with adequate antibiotics rather than exclude fluoroquinolones considering the risk of AA and AD for patients with UTI.