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Single-gene missense mutations remain challenging to interpret. Here, we deploy scalable functional screening by sequencing (SEUSS), a Perturb-seq method, to generate mutations at protein interfaces of RUNX1 and quantify their effect on activities of downstream cellular programs. We evaluate single-cell RNA profiles of 115 mutations in myelogenous leukemia cells and categorize them into three functionally distinct groups, wild-type (WT)-like, loss-of-function (LoF)-like, and hypomorphic, that we validate in orthogonal assays. LoF-like variants dominate the DNA-binding site and are recurrent in cancer; however, recurrence alone does not predict functional impact. Hypomorphic variants share characteristics with LoF-like but favor protein interactions, promoting gene expression indicative of nerve growth factor (NGF) response and cytokine recruitment of neutrophils. Accessible DNA near differentially expressed genes frequently contains RUNX1-binding motifs. Finally, we reclassify 16 variants of uncertain significance and train a classifier to predict 103 more. Our work demonstrates the potential of targeting protein interactions to better define the landscape of phenotypes reachable by missense mutations.

Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.

Abstract Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

Abstract Background Diet and gut microbiota contribute to non-alcoholic steatohepatitis (NASH) progression. High-fat diets (HFDs) change gut microbiota compositions, induce gut dysbiosis, and intestinal barrier leakage, which facilitates portal influx of pathogen-associated molecular patterns including lipopolysaccharides (LPS) to the liver and triggers inflammation in NASH. Current therapeutic drugs for NASH have adverse side effects; however, several foods and herbs that exhibit hepatoprotection could be an alternative method to prevent NASH. Methods We investigated ginger essential oil (GEO) against palm oil-containing HFDs in LPS-injected murine NASH model. Results GEO reduced plasma alanine aminotransferase levels and hepatic pro-inflammatory cytokine levels; and increased antioxidant catalase, glutathione reductase, and glutathione levels to prevent NASH. GEO alleviated hepatic inflammation through mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome and LPS/Toll-like receptor four (TLR4) signaling pathways. GEO further increased beneficial bacterial abundance and reduced NASH-associated bacterial abundance. Conclusion This study demonstrated that GEO prevents NASH progression which is probably associated with the alterations of gut microbiota and inhibition of the LPS/TLR4/NF-κB pathway. Hence, GEO may offer a promising application as a dietary supplement for the prevention of NASH.

Abstract Background Women who suffer an early pregnancy loss require specific clinical care, aftercare, and ongoing support. In the UK, the clinical management of early pregnancy complications, including loss is provided mainly through specialist Early Pregnancy Assessment Units. The COVID-19 pandemic fundamentally changed the way in which maternity and gynaecological care was delivered, as health systems moved to rapidly reconfigure and re-organise services, aiming to reduce the risk and spread of SARS-CoV-2 infection. PUDDLES is an international collaboration investigating the pandemic’s impact on care for people who suffered a perinatal bereavement. Presented here are initial qualitative findings undertaken with UK-based women who suffered early pregnancy losses during the pandemic, about how they navigated the healthcare system and its restrictions, and how they were supported. Methods In-keeping with a qualitative research design, in-depth semi-structured interviews were undertaken with an opportunity sample of women (N = 32) who suffered any early pregnancy loss during the COVID-19 pandemic. Data were analysed using a template analysis to understand women’s access to services, care, and networks of support, during the pandemic following their pregnancy loss. The thematic template was based on findings from parents who had suffered a late-miscarriage, stillbirth, or neonatal death in the UK, during the pandemic. Results All women had experienced reconfigured maternity and early pregnancy services. Data supported themes of: 1) COVID-19 Restrictions as Impractical & Impersonal; 2) Alone, with Only Staff to Support Them; 3) Reduction in Service Provision Leading to Perceived Devaluation in Care; and 4) Seeking Their Own Support. Results suggest access to early pregnancy loss services was reduced and pandemic-related restrictions were often impractical (i.e., restrictions added to burden of accessing or receiving care). Women often reported being isolated and, concerningly, aspects of early pregnancy loss services were reported as sub-optimal. Conclusions These findings provide important insight for the recovery and rebuilding of health services in the post-pandemic period and help us prepare for providing a higher standard of care in the future and through any other health system shocks. Conclusions made can inform future policy and planning to ensure best possible support for women who experience early pregnancy loss.

Abstract We present an in‐depth analysis of dyslipidemia management strategies for patients with diabetes mellitus in Taiwan. It critically examines the disparity between established guideline recommendations and actual clinical practices, particularly in the context of evolving policies affecting statin prescriptions. The focus is on synthesizing the most recent findings concerning lipid management in patients with diabetes mellitus, with a special emphasis on establishing consensus regarding low‐density lipoprotein cholesterol treatment targets. The article culminates in providing comprehensive, evidence‐based recommendations tailored to the unique needs of those living with diabetes mellitus in Taiwan. It underscores the criticality of personalized care approaches, which incorporate multifaceted factors, and the integration of novel therapeutic options to enhance cardiovascular health outcomes.

Abstract Hip replacement is a common orthopedic surgery in the aging population. With the rising incidence of prostate cancer, metallic hip prosthetics can cause considerable beam hardening and streak artifacts, leading to difficulty in identifying the target volumes and planning process for radiation treatment. The growing use of Stereotactic Body Radiation Therapy (SBRT) to treat prostate cancer is now well established. However, the use of this treatment modality in the presence of a hip prosthesis is poorly understood. There is enough literature on planning for external beam radiation treatment without any difficulties in the presence of hip prosthesis with conventional or Hypofractionated treatment. However, there is a shortage of literature on the impact of the prosthesis in SBRT planning, and there is a need for further understanding and measures to mitigate the obstacles in planning for SBRT in the presence of hip prosthesis. We present our review of the intricacies that need to be understood while considering SBRT in the presence of hip prostheses in prostate cancer treatment.

Abstract Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.

Chin-Yi Yang,1,2,&ast; Ya-Ching Chang,2,&ast; Hao-Chih Tai,3 Yi-Hua Liao,4 Yu-Huei Huang,2 Rosaline Chung-Yee Hui,2 Yuan-Sung Kuo,3 Shyue-Yih Horng,3 Yi-Shuan Sheen,4 Tim-Mo Chen,5 Yuan-Sheng Tzeng,5 Chih-Hsin Wang,5 Shou-Cheng Teng,5 Chun-Kai Oscar Chang,5 Chang-Yi Chou5 1Department of Dermatology, New Taipei Municipal TuCheng Hospital, New Taipei City, 236, Taiwan; 2Department of Dermatology, Linkou Chang-Gung Memorial Hospital, Taoyuan, 333, Taiwan; 3Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan; 4Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan; 5Division of Plastic Surgery, Tri-Service General Hospital, Taipei, 100, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hao-Chih Tai, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Zhongshan S. Road, Zhongzheng Dist, Taipei, 100225, Taiwan, Tel +886 2 2312-3456&num;65062 65520, Email taihc1@gmail.com; taihc@ntu.edu.tw Yi-Hua Liao, Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Zhongshan S. Road, Zhongzheng Dist, Taipei, 100225, Taiwan, Tel +886 2 2312-3456&num; 265317, Email yihualiao@ntu.edu.twPurpose: Porcine-based dermal injectable collagen is effective for nasolabial fold correction. In the present study, a new dermal injectable collagen, incorporating a novel cross-linking technology and premixed with lidocaine, was introduced. The study aimed to determine the efficacy of the new dermal injectable collagen in improving bilateral nasolabial fold wrinkles, and reducing pain during injection.Patients and Methods: This prospective, double-blind, multicenter, parallel-group, randomized trial enrolled participants with moderate-to-severe bilateral nasolabial fold wrinkles from February 2019 to March 2021. Participants were randomly assigned to the test group (new dermal injectable collagen with lidocaine featuring a novel cross-linking technology) or control group (traditionally cross-linked dermal injectable collagen with lidocaine). Participants were monitored for adverse events (AEs), and for pain using the Thermometer Pain Scale (TPS) and a visual analog scale (VAS). Efficacy was measured using the Wrinkle Severity Rating Scale (WSRS) and the Global Aesthetic Improvement Scale (GAIS).Results: On the poor or better sides, the 2 groups exhibited a significant decrease in WSRS scores at 4, 12, 24, and 36 weeks after treatment, compared to baseline WSRS scores (all, p < 0.05). Compared to the control group, the test group had a greater decrease in WSRS score (poor or better sides) at 12, 24, 36, and 52 weeks after treatment (all, p < 0.05). A similar observation was also found in the WSRS response rate and GAIS score of the 2 groups. VAS and TPS scores were not significantly different between the 2 groups (p > 0.05), indicating that pain reduction was similar in the 2 groups. All AEs were anticipated AEs associated with facial aesthetic injections, and most recovered within 0 to 30 days without sequelae. There were no differences in AEs between the 2 groups (all, p > 0.05).Conclusion: The new dermal injectable collagen with lidocaine exhibited better efficacy for correcting nasolabial fold wrinkles compared to the control group. Both relieved pain and produced only transient and tolerable AEs.Keywords: adverse event, bilateral nasolabial folds, dermal filler, pain, porcine collagen, wrinkles

Delayed ischemic stroke associated with intractable vasospasm after clipping of unruptured intracranial aneurysms (UIAs) has been rarely reported. We report a patient with delayed ischemic stroke associated with intractable vasospasm following UIA clipping. A middle-aged female underwent surgery for unruptured middle cerebral artery bifurcation aneurysms. The patient tolerated the neurosurgical procedure well. Seven days postoperatively, the headache was unbearable; a postcraniotomy headache persisted and abruptly presented with global aphasia and right-sided hemiplegia after a nap. Emergency digital subtraction angiography showed severe luminal narrowing with segmental vasoconstriction, consistent with severe vasospasm. The patient’s neurological deficit improved after chemical angioplasty. Neurosurgeons should pay close attention to this treatable/preventive entity after neurological deterioration following UIA clipping, even in patients without subarachnoid hemorrhage.

Background: We evaluated the outcomes of pregnancy in women with congenital heart disease (CHD) and their offspring in Taiwan. We also investigated how different severity levels may influence the outcomes. Methods: We used data (2009–2017) from the Birth Certificate Application database in Taiwan, which is linked to the National Health Insurance Research Database and Taiwan Maternal and Child Health Database. We identified 2990 women with CHD who had 4227 births. Based on the CHD subtypes, patients were further divided into “severe CHD” and “simple CHD” groups. Results: Women with CHD have a significant risk of stillbirth. In maternal cardiac events, they had the highest risk of heart failure, followed by arrhythmia. The severity of CHD had a significant effect on the outcomes as well. The neonatal birth event that mothers with CHD have the highest risk of is preterm birth at < 32 weeks of gestation. The prominent difference in neonatal morbidities between mothers with severe and simple CHD is recurrent CHD in the offspring. The offspring of the severe CHD group had a higher risk of severe CHD, whereas those of the simple CHD group had a higher risk of simple CHD. Conclusion: During pregnancy, the monitoring of heart function and cardiac rhythm could be more intensive in mothers with CHD. In addition to accurately assessing fetal growth and development during antenatal care, mothers with severe CHD should be provided with careful fetal heart structure assessment and genetic testing along with counseling.

Background: Locoregional therapy and multi-kinase inhibitor agent have been the backbone of treatment for hepatocellular carcinoma (HCC) patients. However, the effect of combination or sequential use of locoregional therapy on HCC patients receiving multi-kinase inhibitor remain uncertain. Therefore, we aim to explore whether the subsequent locoregional therapy provides better survival in HCC patients under lenvatinib treatment. Methods: From March 2018 to April 2020, a total of 78 unresectable HCC patients receiving lenvatinib were recruited. Image response was evaluated by dynamic image using the modified RECIST criteria. Among patients with tumor progression under lenvatinib treatment, whether receiving subsequent locoregional therapy or not were documented. Overall survival between two groups and the predictors for tumor progression were also analyzed. Results: Among the 78 patients receiving lenvatinib, the median age was 67.8 years old, and 69.2 % were male. Forty-four patients (56.4 %) experienced tumor progression with time to progression 5.1 months (95 % confidence interval (CI): 4.7–6.8) months. In multivariable Cox regression analysis, albumin-bilirubin (ALBI) grade II (adjusted HR: 2.883, P = 0.0104), and treatment duration less than three months (adjusted HR: 3.801, P = 0.0014) were the independent predictive factors for tumor progression, while patients achieving objective response under lenvatinib treatment within 12 weeks was the independent protective factor for tumor progression (adjusted HR: 0.144, P = 0.0020). Among the 44 patients with tumor progression, twenty-six (59.1 %) patients received subsequent locoregional therapy after tumor progression. Comparing to those with tumor progression without locoregional treatment, patients who received subsequent locoregional therapy had significantly better survival (1st year cumulative survival rate 70 % vs 27 %, log-rank P = 0.003). Conclusion: ALBI grade, treatment duration of lenvatinib, and achieving objective image response within twelve weeks were the independent predictive factors for tumor progression. Furthermore, longer overall survival was observed in tumor progression patients with subsequent locoregional therapy and with better liver preserved function.

Abstract Background Difficulties with inhibitory control have been identified in eating disorders (EDs) and neurodevelopmental disorders (NDs; including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder), and there appear to be parallels between the expression of these impairments. It is theorised that impairments in inhibitory control within NDs may represent a unique vulnerability for eating disorders (EDs), and this same mechanism may contribute to poorer treatment outcomes. This review seeks to determine the state of the literature concerning the role of inhibitory control in the overlap of EDs and neurodivergence. Method A scoping review was conducted to summarise extant research, and to identify gaps in the existing knowledge base. Scopus, Medline, PsycInfo, Embase, and ProQuest were systematically searched. Studies were included if the study measured traits of ADHD or autism, and symptoms of ED, and required participants to complete a performance task measure of inhibitory control. Where studies included a cohort with both an ND and ED, these results had to be reported separately from cohorts with a singular diagnosis. Studies were required to be published in English, within the last 10 years. Results No studies explored the relationship between autism and EDs using behavioural measures of inhibitory control. Four studies exploring the relationship between ADHD and EDs using behavioural measures of inhibitory control met selection criteria. These studies showed a multifaceted relationship between these conditions, with differences emerging between domains of inhibitory control. ADHD symptoms predicted poorer performance on measures of response inhibition in a non-clinical sample; this was not replicated in clinical samples, nor was there a significant association with EDs. Both ADHD and ED symptoms are associated with poor performance on attentional control measures; where these diagnoses were combined, performance was worse than for those with a singular diagnosis of ADHD. This was not replicated when compared to those with only ED diagnoses. Conclusion Impairments in attentional control may represent a unique vulnerability for the development of an ED and contribute to poor treatment outcomes. Further research is needed to explore the role of inhibitory control in EDs, ADHD and autism, including the use of both self-report and behavioural measures to capture the domains of inhibitory control.

Abstract Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota–host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus–bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.

Growth mindset (belief in the malleability of intelligence) is a unique predictor of young learners' increased motivation and learning, and may have broader implications for cognitive functioning. Its role in learning in older adulthood is unclear. As part of a larger longitudinal study, we examined growth mindset and cognitive functioning in older adults engaged in a 3-month multi-skill learning intervention that included growth mindset discussions. Before, during, and after the intervention, participants reported on their growth mindset beliefs and completed a cognitive battery. Study 1 indicated that intervention participants, but not control participants, increased their growth mindset during the intervention. Study 2 replicated these results and found that older adults with higher preexisting growth mindsets showed larger cognitive gains at posttest compared to those with lower preexisting growth mindsets. Our findings highlight the potential role of growth mindset in supporting positive learning cycles for cognitive gains in older adulthood.

The study of word recognition has been influenced greatly by findings obtained when visual stimuli are presented very briefly. Under these conditions, a great deal of evidence suggests that words are perceived better than nonwords, and even single letters, and it is generally accepted that these “word superiority effects” reflect the relative efficiency with which words are perceived. For more than 50 years, a key procedure for establishing these effects has been the Reicher-Wheeler Paradigm in which potentially confounding effects of non-perceptual guesswork are cleverly suppressed. More recently, however, the actual nature of the Reicher-Wheeler paradigm and its contribution to research have become misrepresented in a range of publications, and its use in experiments has been confused and conflated with other, less sophisticated procedures. In this article we describe the actual contributions made by the Reicher-Wheeler Paradigm to word recognition research and show examples of how these important contributions have been misunderstood and misconceived in experiments reported in the recent literature.

IntroductionThere are ongoing concerns about opioid prescribing for surgical and non-surgical dental needs among adolescent/young adult and adult patients. Although there are known differences in the overall opioid prescription rates in rural areas compared to urban areas, the contribution of dental opioid prescriptions is still unclear. This study aims to examine the factors associated with receiving an opioid prescription following a dental visit.Materials and methodsThis cross-sectional study utilized the 2021 Centers for Medicare & Medicaid Services unredacted Transformed Medicaid Statistical Information System Analytic Files to examine Medicaid and CHIP adolescent/young adult beneficiaries aged 12–20 and adults aged 21–64 who are non-dually eligible for Medicare and had a dental visit in 2021. Multilevel logistic regression models were used to predict the odds of receiving a dental opioid prescription.ResultsThe results of the adolescent/young adult models show that for every percentage point increase in the percentage of non-Hispanic Black residents in a county, the odds of receiving a dental opioid prescription increase by 0.8% in rural areas. However, with every percentage point increase in the Hispanic population, the odds of receiving a dental opioid prescription decrease by 0.3% in rural areas and 0.7% in urban areas. The adult models show that compared to non-Hispanic white beneficiaries, non-Hispanic Black beneficiaries are 8% more likely to receive a dental opioid prescription if they live in rural areas and 18% more likely if they live in urban areas, while all other racial and ethnic groups are significantly less likely to receive a dental opioid prescription. With every unit increase in the concentrated disadvantage index, the odds of receiving a dental opioid prescription increase by 17% among rural adults and 24% among urban adults.DiscussionOur findings on rural–urban disparities in opioid prescriptions suggest that prescription patterns in dental settings are significant and inequitable across various beneficiary- and county-level factors and areas of residence. These variations in prescription patterns highlight the known disparities in access to preventive dental care and the need for targeted interventions to address the healthcare needs of rural residents.