Developing a Screening Strategy to Identify Hepatotoxicity and Drug Interaction Potential of Botanicals.

Botanical supplements, herbal remedies, and plant-derived products are used globally. However, botanical dietary supplements are rarely subjected to robust safety testing unless there are adverse reports in post-market surveillance. Botanicals are complex and difficult to assess using current frameworks designed for single constituent substances (e.g. small molecules or discrete chemicals), making safety assessments costly and time-consuming. The liver is a primary organ of concern for potential botanical-induced hepatotoxicity and botanical-drug interactions as it plays a crucial role in xenobiotic metabolism. The NIH-funded Drug Induced Liver Injury Network noted that the number of botanical-induced liver injuries in 2017 nearly tripled from those observed in 2004-2005. New approach methodologies (NAMs) can aid in the rapid and cost-effective assessment of botanical supplements for potential hepatotoxicity. The Hepatotoxicity Working Group within the Botanical Safety Consortium is working to develop a screening strategy that can help reliably identify potential hepatotoxic botanicals and inform mechanisms of toxicity. This manuscript outlines the Hepatotoxicity Working Group's strategy and describes the assays selected and the rationale for the selection of botanicals used in case studies. The selected NAMs evaluated as a part of this effort are intended to be incorporated into a larger battery of assays to evaluate multiple endpoints related to botanical safety. This work will contribute to a botanical safety toolkit, providing researchers with tools to better understand hepatotoxicity associated with botanicals, prioritize and plan future testing as needed, and gain a deeper insight into the botanicals being tested.

Sleep apnea-specific hypoxic burden and pulse rate response in children using high flow nasal cannula therapy compared with continuous positive airway pressure.

BACKGROUND: Elevated sleep apnea-specific hypoxic burden (HB) and pulse rate response (ΔHR) are associated with a higher cardiovascular risk in adults. The clinical significance of HB and ΔHR in children with obstructive sleep apnea (OSA) and their responses to therapy have not yet been investigated. This study aimed to compare the efficacy of high flow nasal cannula (HFNC) and continuous positive airway pressure (CPAP) in reducing HB and ΔHR in children. METHODS: This analysis included 17 children (11 males, mean age: 12.6 ± 3.9 years) with obesity and/or medical complexity and moderate-to-severe OSA. Each participant underwent two additional sleep studies: one for HFNC titration and another for CPAP titration. HB and ΔHR were derived from the oximetry and pulse rate signals from overnight sleep studies, respectively. RESULTS: Both HFNC and CPAP demonstrated significant reductions in HB from baseline, with similar magnitudes [HFNC: -129 (standard error, SE 55) %min/h, p = 0.003; CPAP: -138 (SE 53) %min/h, p = 0.005]. However, for ΔHR, a significant reduction from baseline was observed only in the CPAP group [-2.7 (SE 1.1) beats/min, p = 0.049], not the HFNC group [-1.0 (SE 1.4) beats/min, p = 0.67]. CONCLUSIONS: HFNC is as effective as CPAP in treating hypoxia in children with OSA, but HFNC might be less effective than CPAP in mitigating cardiovascular stress from autonomic disturbances during obstructive events.

Identification and Potential Clinical Utility of Common Genetic Variants in Gestational Diabetes among Chinese Pregnant Women.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion: Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

SARS-CoV-2 variants divergently infect and damage cardiomyocytes in vitro and in vivo.

BACKGROUND: COVID-19 can cause cardiac complications and the latter are associated with poor prognosis and increased mortality. SARS-CoV-2 variants differ in their infectivity and pathogenicity, but how they affect cardiomyocytes (CMs) is unclear. METHODS: The effects of SARS-CoV-2 variants were investigated using human induced pluripotent stem cell-derived (hiPSC-) CMs in vitro and Golden Syrian hamsters in vivo. RESULTS: Different variants exhibited distinct tropism, mechanism of viral entry and pathology in the heart. Omicron BA.2 most efficiently infected and injured CMs in vitro and in vivo, and induced expression changes consistent with increased cardiac dysfunction, compared to other variants tested. Bioinformatics and upstream regulator analyses identified transcription factors and network predicted to control the unique transcriptome of Omicron BA.2 infected CMs. Increased infectivity of Omicron BA.2 is attributed to its ability to infect via endocytosis, independently of TMPRSS2, which is absent in CMs. CONCLUSIONS: In this study, we reveal previously unknown differences in how different SARS-CoV-2 variants affect CMs. Omicron BA.2, which is generally thought to cause mild disease, can damage CMs in vitro and in vivo. Our study highlights the need for further investigations to define the pathogenesis of cardiac complications arising from different SARS-CoV-2 variants.

A multi-center evaluation of a novel IVF cryostorage device in an active clinical setting.

The objective of this study was to evaluate the function, and usability of a novel automated software-guided cryostorage system in an active IVF laboratory setting. The investigational device (ID) was installed at 3 IVF laboratories (sites: α, ß, and γ). A total of 15 embryologists were trained to use the ID. Mock patient specimens containing mirrored live patient data were handled using the ID. Temperature readings were recorded every minute. Successful identification, storage, and retrieval of mock patient specimens by the ID were evaluated. To assess an LN2 pressure builder, the frequency of use and events of workflow interruption were logged. Student's t-test was used to determine statistical significance. The ID was in active use for 164 days total. During this time, 329 mock patient egg and embryo cohorts were handled by the ID. The mean ± SD temperatures during active use were: α, - 176.57 ± 1.83 °C; ß, - 178.21 ± 2.75 °C; γ, - 178.98 ± 1.74 and did not differ significantly. The highest recorded temperatures were: α, - 165.14 °C; ß, - 157.41 °C; γ, - 164.45 °C. A total of 1064 automation transactions on 409 specimen vessels were performed. Data was managed on 1501 eggs and embryos. The ID did not lose or misplace any specimen data or vessels, and no mock specimen was exposed to a detrimental (> - 150 °C) temperature excursion. Over the 25 LN2 pressure builder usages during 99 total days, there was 1 occurrence where usage interrupted workflow due to a lack of LN2 pressure. The ID has advantages over the current manual-based cryostorage systems, including radio frequency identification (RFID) tracking, automation of manual tasks, and software guidance to ensure accurate specimen storage and retrieval. The results of this study indicate that the ID can be integrated into active IVF laboratories.

Ferritin is a potential marker of cardiometabolic risk in adolescents and young adults with sleep-disordered breathing.

Objective: To explore markers that reflect sleep-disordered breathing (SDB) severity and investigate their associations with cardiometabolic risk factors in adolescents and young adults. Methods: Participants were recruited from our SDB epidemiological cohort. They underwent overnight polysomnography and ambulatory blood pressure (BP) monitoring. Complete blood count, ferritin, high-sensitivity C-reactive protein (hs-CRP), fasting blood glucose, and lipid profile were measured. Multiple linear regression was used to examine the association between red cell indices (RCIs), ferritin, and obstructive apnea-hypopnea index (OAHI). Subgroup analyses on participants with SDB were performed for the association of RCIs and ferritin with lipid profile, hs-CRP, and BP. Results: There were 88 participants with SDB and 155 healthy controls aged 16-25 years. Hemoglobin (Hb; p < .001), hematocrit (HCT; p < .001), and ferritin (p < .001) were elevated with increasing SDB severity and were independently associated with OAHI (ß=1.06, p < .001; ß=40.2, p < .001; ß=4.89 × 10-3, p = .024, respectively). In participants with SDB, after adjusting for age, sex, and BMI, significant associations were found between ferritin with low-density lipoprotein (LDL; ß=0.936 × 10-3, p = .008) and triglyceride (TG; ß =1.08 × 10-3, p < .001), as well as between Hb (ß=1.40, p = .007), HCT (ß=51.5, p = .010) and mean arterial pressure (MAP). Ferritin (ß=0.091, p = .002), Hb (ß=0.975, p = .005), and HCT (ß=38.8, p = .004) were associated with hs-CRP independent of age, sex, BMI, plasma LDL, and MAP. OAHI was not associated with LDL and TG in the multivariable models. Conclusions: Serum ferritin, but not OAHI, was associated with LDL and TG in participants with SDB, suggesting it is a potential marker of cardiometabolic risk in patients with SDB.

Objective monitoring tools for improved management of childhood asthma.

Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.

Efficacy and safety of transcranial pulse stimulation in young adolescents with attention-deficit/hyperactivity disorder: a pilot, randomized, double-blind, sham-controlled trial.

Background: This is the first study to evaluate the efficacy and safety of transcranial pulse stimulation (TPS) for the treatment of attention-deficit/hyperactivity disorder (ADHD) among young adolescents in Hong Kong. Methods: This double-blind, randomized, sham-controlled trial included a TPS group and a sham TPS group, encompassing a total of 30 subjects aged 12-17 years who were diagnosed with ADHD. Baseline measurements SNAP-IV, ADHD RS-IV, CGI and executive functions (Stroop tests, Digit Span) and post-TPS evaluation were collected. Both groups were assessed at baseline, immediately after intervention, and at 1-month and 3-month follow-ups. Repeated-measures ANOVAs were used to analyze data. Results: The TPS group exhibited a 30% reduction in the mean SNAP-IV score at postintervention that was maintained at 1- and 3-month follow-ups. Conclusion: TPS is an effective and safe adjunct treatment for the clinical management of ADHD. Clinical trial registration: ClinicalTrials.Gov, identifier NCT05422274.

Effects of cognitive behavioural therapy and bright light therapy for insomnia in youths with eveningness: study protocol for a randomised controlled trial.

BACKGROUND: Insomnia and eveningness are common and often comorbid conditions in youths. While cognitive behavioural therapy for insomnia (CBT-I) has been suggested as a promising intervention, it remains unclear whether it is sufficient to also address circadian issues in youths. In addition, despite that light has been shown to be effective in phase-shifting one's circadian rhythm, there has been limited data on the effects of bright light therapy and its combination with CBT-I on sleep and circadian outcomes in youths. The current protocol outlines a randomised controlled trial that examines the efficacy of CBT-I and CBT-I plus bright light therapy (BLT) in reducing insomnia severity, improving mood symptoms and daytime functioning (e.g. sleepiness, fatigue, cognitive function), and improving subjective and objective sleep and circadian measures compared to a waitlist control group. METHODS: We will carry out a randomised controlled trial (RCT) with 150 youths aged 12-24 who meet the criteria of insomnia and eveningness. Participants will be randomised into one of three groups: CBT-I with bright light therapy, CBT-I with placebo light, and waitlist control. Six sessions of CBT-I will be delivered in a group format, while participants will be currently asked to use a portable light device for 30 min daily immediately after awakening throughout the intervention period for bright light therapy. The CBT-I with light therapy group will receive bright constant green light (506 lx) while the CBT-I with placebo light group will receive the modified light device with the LEDs emitting less than 10 lx. All participants will be assessed at baseline and post-treatment, while the two active treatment groups will be additionally followed up at 1 month and 6 months post-intervention. The primary outcome will be insomnia severity, as measured by the Insomnia Severity Index. Secondary outcomes include self-reported mood, circadian, daytime functioning, and quality of life measures, as well as sleep parameters derived from actigraphy and sleep diary and neurocognitive assessments. Objective measures of the circadian phase using dim-light melatonin onset assessment and sleep parameters using polysomnography will also be included as the secondary outcomes. DISCUSSION: This study will be the first RCT to directly compare the effects of CBT-I and BLT in youths with insomnia and eveningness. Findings from the study will provide evidence to inform the clinical management of insomnia problems and eveningness in youths. TRIAL REGISTRATION: ClinicalTrials.gov NCT04256915. Registered on 5 February 2020.

Mitochondrial Raf1 Regulates Glutamine Catabolism.

Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.

Secular trends in sleep and circadian problems among adolescents in Hong Kong: From 2011-2012 to 2017-2019.

OBJECTIVE: The study aimed to investigate secular trends in sleep and circadian problems in Hong Kong Chinese adolescents. METHODS: This study analyzed cross-sectional data from two large-scale school-based sleep surveys conducted in 2011-2012 and 2017-2019. Sleep and circadian problems, including sleep-wake pattern, insomnia, chronotype, social jetlag, daytime sleepiness, and other sleep-related factors, were compared between two survey years. RESULTS: A total of 8082 adolescents (5639 students in 2011-2012 [Mean age: 14.4 years, 50.9% boys] and 2443 students in 2017-2019 [Mean age: 14.7 years, 54.0% boys]) were included in this 7-year study. The average time in bed of Hong Kong adolescents decreased from 8.38 hours to 8.08 hours from 2011-2012 to 2017-2019. There was a 0.28-hour delay in weekday bedtime, 0.54-hour advance in weekend wake-up time, and a 0.36-hour decline in average time in bed, resulting in increased trends of sleep loss (Time in bed <8h: OR = 2.06, 95%CI: 1.44-2.93, p < 0.01; Time in bed <7h: OR = 2.73, 95%CI: 1.92-3.89, p < 0.01), daytime sleepiness (OR = 1.70, 95%CI: 1.34-2.16, p < 0.01), and evening chronotype (OR = 1.26, 95%CI: 1.08-1.48, p < 0.01). The increased trend in insomnia disorder, however, was insignificant when covariates were adjusted. CONCLUSION: A secular trend of reduced time in bed, delay in weekday bedtime, advance in weekend wake-up time, increase in evening chronotype and daytime sleepiness from 2011-2012 to 2017-2019 were observed. There is a timely need for systematic intervention to promote sleep health in adolescents.

Ophthalmologic Presentations of Incontinentia Pigmenti.

Purpose: To characterize treatments and outcomes in incontinentia pigmenti. Methods: Cases of incontinentia pigmenti were consecutively identified from a retina practice. Inclusion criteria were patients with incontinentia pigmenti with at least 6 months of follow-up. All patients had a full ophthalmic examination, including imaging with widefield fundus photography and widefield fluorescein angiography. Eyes with areas of avascular retina were treated with laser photocoagulation (except for 1 eye with mild changes). Results: Thirty-six eyes of 18 patients with incontinentia pigmenti were included. The median age at presentation was 11 months. On presentation, 7 eyes had a visual acuity (VA) of 20/40 or better and 3 eyes had VA of 20/50 to 20/100. The remaining 26 eyes could fix and follow or had at least light perception (LP) VA given the patients' young age. Of the 36 eyes, 20 (56%) had retinal involvement. The mean follow-up for treated patients was 6.9 years. Seventy-four percent of treated eyes required 1 laser session only. No eye that received laser treatment subsequently developed a retinal detachment. Of the 26 eyes with initial fix-and-follow or LP VA, 12 had Snellen or Allen VA testing at follow-up. Nine of these eyes had a follow-up VA of 20/40 or better. Of 10 eyes with a Snellen or Allen VA recorded at the initial visit, 9 had a final VA that was the same or improved. Conclusions: Laser photocoagulation was effective in treating patients with retinal manifestations of incontinentia pigmenti. Except for 1 eye, VA remained stable at the final follow-up.

Cancer immunity by tissue-resident type 1 innate lymphoid cells and killer innate-like T cells.

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.

An Open-Label Pilot Trial of a Brief, Parent-Based Sleep Intervention in Children With ADHD.

OBJECTIVE: To assess the effects of a brief parent-based behavioral sleep intervention in children with ADHD. METHODS: Families with a child with ADHD and parent-reported sleep problems received a brief parent-based sleep intervention, which involved two one-to-one consultation sessions and one telephone follow-up with the parent/caregiver. Child's sleep and clinical symptoms, and parental sleep and daytime functioning were assessed at baseline, 2-week post-intervention, and 3-month follow-up. RESULTS: Sixty eligible families (mean age of the child: 9.4 ± 1.5 years; boys: 75%) were recruited, and 43 (72%) completed the whole intervention. The intervention resulted in significant improvements in the child's sleep, clinical symptoms, and parental sleep and parenting stress, and these improvements were generally maintained at 3-month follow-up. CONCLUSION: The findings supported the promising effects of a brief parent-based sleep intervention on improving sleep and clinical symptoms in children with ADHD and parental sleep and parenting stress. Further randomized clinical trials with long-term follow-up are needed to test the robustness of the effectiveness of the intervention.

Quantitative and qualitative subgenomic RNA profiles of SARS-CoV-2 in respiratory samples: A comparison between Omicron BA.2 and non-VOC-D614G.

The SARS-CoV-2 Omicron variants are notorious for their transmissibility, but little is known about their subgenomic RNA (sgRNA) expression. This study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern (non-VOC)-D614G. A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOC-D614G regardless of host gender, age and presence of pneumonia. Remarkably, such profile was lost in samples with low viral load, suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point. A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and non-VOC-D614G. The presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load (AUC â€‹= â€‹0.91, 95% CI 0.88-0.94), and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual patient. Further potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.

Which Localizing Strategy is the Most Cost-Effective in Reoperative Primary Hyperparathyroidism?

INTRODUCTION: 2%-10% of patients with primary hyperparathyroidism (PHPT) who undergo parathyroidectomy develop persistent/recurrent disease. The aim of this study was to determine which preoperative localization method is most cost-effective in reoperative PHPT. METHODS: Clinical decision analytic models comparing cost-effectiveness of localizing studies in reoperative PHPT were constructed using TreeAge Pro. Cost and probability assumptions were varied via Probabilistic Sensitivity Analysis (PSA) to test the robustness of the base case models. RESULTS: Base case analysis of model 1 revealed ultrasound (US)-guided fine-needle aspiration with PTH assay as most cost-effective after localizing US. This was confirmed on PSA of model 1. Model 2 showed four-dimensional computed tomography (4D-CT) as most cost-effective after negative US. If not localized by US, on PSA, 4D-CT was the next most cost-effective test. CONCLUSIONS: US-guided FNA with PTH is the most cost-effective confirmatory test after US localization. 4D-CT should be considered as the next best test after negative US.

Mitochondrial uncoupler and retinoic acid synergistically induce differentiation and inhibit proliferation in neuroblastoma.

Neuroblastoma is a leading cause of death in childhood cancer cases. Unlike adult malignancies, which typically develop from aged cells through accumulated damage and mutagenesis, neuroblastoma originates from neural crest cells with disrupted differentiation. This distinct feature provides novel therapeutic opportunities beyond conventional cytotoxic methods. Previously, we reported that the mitochondrial uncoupler NEN (niclosamide ethanolamine) activated mitochondria respiration to reprogram the epigenome, promoting neuronal differentiation. In the current study, we further combine NEN with retinoic acid (RA) to promote neural differentiation both in vitro and in vivo. The treatment increased the expression of RA signaling and neuron differentiation-related genes, resulting in a global shift in the transcriptome towards a more favorable prognosis. Overall, these results suggest that the combination of a mitochondrial uncoupler and the differentiation agent RA is a promising therapeutic strategy for neuroblastoma.

Effects of childhood obstructive sleep apnea with and without daytime sleepiness on behaviors and emotions.

OBJECTIVE: To investigate the relationship between obstructive sleep apnea (OSA) with and without excessive daytime sleepiness (EDS) and behavioral and emotional outcomes in non-obese prepubertal children. METHODS: This was a retrospective analysis of children aged 5-11 years who presented to our unit for assessment of their sleep-related complaints. All children underwent polysomnography (PSG). They also completed the Pediatric Daytime Sleepiness Scale (PDSS) and a sleep diary. OSA was diagnosed if the obstructive apnea-hypopnea index (OAHI) was ≥1 event/hour. EDS was defined as PDSS >15. Behavioral and emotional outcomes were assessed using the Child Behavioral Checklist (CBCL). RESULTS: Data from 391 children (mean age of 8.6 ± 1.7 years; 67 % male) were analyzed. Seventy children did not have OSA or EDS, 137 had OSA, 50 had reported having EDS but without OSA, and 134 children had both OSA and EDS. There were significantly higher CBCL total problems score in the combined group (61 ± 9) compared to the non-OSA/EDS group (54 ± 10), and the OSA-only group (54 ± 10) (p < 0.001). The presence of EDS was significantly associated with higher CBCL T score and higher odds for clinically significant behavioral problems (T score ≥65) after adjusting for age, sex, BMI z-score and average sleep duration (p < 0.001). CONCLUSION: Excessive daytime sleepiness is an important contributory factor associated with suboptimal behavioral and emotional outcomes in children with OSA.

Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.

The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.