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Bang-Bin Chen,1,2 Po-Chin Liang,1– 3 Tiffany Ting-Fang Shih,1,2 Tsung-Hao Liu,4– 6 Ying-Chun Shen,4– 6 Li-Chun Lu,4– 6 Zhong-Zhe Lin,4,6 Chiun Hsu,4– 6 Chih-Hung Hsu,4– 6 Ann-Lii Cheng,4– 7 Yu-Yun Shao4– 6 1Department of Medical Imaging, National Taiwan University Hospital, Taipei City, Taiwan; 2Department of Radiology, College of Medicine, National Taiwan University, Taipei City, Taiwan; 3Department of Medical Imaging, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu City, 300, Taiwan; 4Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan; 5Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan; 6Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; 7Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanCorrespondence: Yu-Yun Shao, Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei City, 100, Taiwan, Tel +886-2 23123456 ext. 66008, Fax +886-2 23711174, Email yuyunshao@gmail.comPurpose: We investigated whether spleen volume (SV) changes were associated with treatment outcomes in advanced hepatocellular carcinoma (HCC) patients who received immunotherapy or first-line sorafenib.Patients and Methods: Patients with advanced HCC who underwent immunotherapy or first-line sorafenib at our institute were retrospectively analyzed. CT was used to measure SV before and within 3 months of treatment initiation. Tumor assessment followed Response Evaluation Criteria in Solid Tumors version 1.1. The association between SV change and tumor response or progression-free survival (PFS) was analyzed. The inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics.Results: The immunotherapy group comprised 143 patients (124 men, mean age, 59.8 years ± 11.2 [standard deviation]), while the sorafenib group had 57 (47 men, mean age, 59.6 years ± 9.9). SV increased in 108 (75.5%) immunotherapy and 21 (36.8%) sorafenib patients. In the immunotherapy group, patients with increased SV were more likely than those with decreased SV to have a higher disease control rate (76.9% vs 57.1%, p = 0.024) and durable clinical benefit (52.8% vs 25.7%, p = 0.005). It was also associated with extended PFS in the immunotherapy group in both the univariate (p = 0.028) and multivariate (p = 0.014) analysis. By contrast, in the sorafenib group, an increased in SV was not associated with treatment response but was presumably associated with reduced PFS (p = 0.072) in the multivariate analysis. After IPTW adjustment, the increase in SV remained a significant predictor for DCB and PFS in the immunotherapy group.Conclusion: Most patients exhibited an increase in SV after the initiation of immunotherapy, which may be used to predict response and prognosis. However, this association was not observed in patients who received sorafenib.Plain Language Summary: The study provides significant evidence that an increase in spleen volume is associated with better treatment outcomes in advanced hepatocellular carcinoma patients undergoing immunotherapy. These findings offer oncologists a new potential biomarker for optimizing treatment strategies. Specifically, increased spleen volume could be used to predict higher rates of disease control and durable clinical benefits, allowing for more personalized care. Keywords: hepatocellular carcinoma, immunotherapy, sorafenib, response, survival

Po-Ming Chow,1 Yao-Chi Chuang,2 Karina Chin Po Hsu,3 Yuan-Chi Shen,2 Shih-Ping Liu1 1Department of Urology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; 2Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Medical Affairs Department, Former Employee of Astellas Pharma Taiwan, Inc., Taipei, TaiwanCorrespondence: Shih-Ping Liu, Department of Urology, National Taiwan University Hospital and College of Medicine, No. 7, Chung Shan South Road, Taipei, 10002, Taiwan, Tel +886 2 2312-3456 ext. 62135, Fax +886 2 2321-9145, Email spliu@ntuh.gov.twBackground: Stress urinary incontinence (SUI) is common among adult women with negative effects on psychosocial well-being, mental health, and health-related quality of life. The purpose of the research is to determine if SUI in women is a factor implicated in changes in health-related quality of life (HRQoL) in both physical and mental health domains and in work difficulties.Methods: Data of women 40 years or older from a cross-sectional, population-based, internet survey were examined post-hoc. The effect of SUI frequency on HRQoL (SF12 score), in physical and mental health domains, was assessed. In addition, multivariate and univariate analyses were used to show the influence of SUI on HADS (Hospital Anxiety and Depression Scale) depression score and HADS anxiety score. The effects of demographic factors and physical ailments and SUI on work difficulties were similarly analyzed using multivariate logistic regression.Results: A total of 4208 women with mean age of 60 were included in the analysis. The more frequent SUI episodes were associated with a greater reduction of HRQoL in both physical and mental health domains. In addition, both multivariate and univariate analyses showed that SUI could be correlated with a negative effect on HADS anxiety score (OR 1.617, CI 1.335– 1.958, p=0.000) and HADS depression score (OR 1.263, CI 1.044– 1.527, p=0.016). Univariate analyses suggested that work difficulties were correlated with SUI. Available data revealed that many sufferers, including up to 40% of individuals with SUI frequency rating 1 (less than once a month) to 3 (a few times a week), failed to seek treatment.Conclusion: SUI, common in women ≥ 40 years of age, impairs quality of life in both physical and mental health domains. SUI is an independent risk factor for anxiety and depression and has been linked to significant work dysfunctions.Trial Registration: This study is registered at ClinicalTrials.gov: NCT02618421 (Date of registration: December 1, 2015).Keywords: stress urinary incontinence, quality of life, China, South Korea, Taiwan

Ying-Chun Shen,1,2,* Pei-Chang Lee,3,4,* Yu-Lun Kuo,5 Wei-Kai Wu,6 Chieh-Chang Chen,7 Chengh-Hau Lei,7 Ching-Ping Yeh,8 Chiun Hsu,1,2 Chih-Hung Hsu,2,8 Zhong-Zhe Lin,1,8 Yu-Yun Shao,2,8 Li-Chun Lu,2,8 Tsung-Hao Liu,2,8 Chien-Hung Chen,7,9 Ming-Shiang Wu,7,10 Yi-Hsiang Huang,4,11,* Ann-Lii Cheng1,10,* 1Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; 2Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; 4Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 5Biotools Co., Ltd, New Taipei City, Taiwan; 6Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; 7Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 8Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 9Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Taipei, Taiwan; 10Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 11Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Ann-Lii ChengNational Taiwan University Cancer Center, No. 57, Ln. 155, Sec. 3, Keelung Road, Da-an Dist., Taipei City, 106, TaiwanEmail alcheng@ntu.edu.twYi-Hsiang HuangDepartment of Internal Medicine, Taipei Veterans General Hospital, Taipei, TaiwanEmail yhhuang@vghtpe.gov.twBackground: Gut microbiome has been associated with the efficacy of immune checkpoint inhibitors (ICI) in patients with various types of cancers but not yet in hepatocellular carcinoma (HCC).Aims: To investigate the association between gut microbiome and efficacy of ICI in patients with HCC.Methods: Patients with HCC who were scheduled to receive ICI were prospectively enrolled. Fecal samples were collected within 7 days before initiation of ICI (baseline) and 8 weeks later. Gut microbiome was assessed using 16S rRNA sequencing and shotgun whole-genome sequencing and correlated with objective response (complete or partial response), disease control (objective response or stable disease for ≥ 16 weeks), and overall survival.Results: Thirty-six patients with HCC were enrolled, and 20 of them provided both baseline and 8-week feces. Alpha diversity, richness, and compositions of baseline gut microbiome indicated no difference between responders and nonresponders or between disease control and nondisease control groups. For the 20 paired feces, immunotherapy did not change any of the major microbiome features. No specific taxa were enriched in patients with objective response. Three taxa—Bifidobacterium, Coprococcus, and Acidaminococcus—were enriched in patients with disease control. However, the baseline abundance of these three taxa did not predict overall survival benefit.Conclusions: In this exploratory study, we failed to disclose any overt association of gut microbiome with the efficacy of ICI in patients with HCC. A larger prospective study is warranted for definite conclusion.Keywords: gut microbiome, biomarkers, immune checkpoint inhibitor, hepatocellular carcinoma

Yanqiu Wu,1,2,* Yongchun Shen,1,2,* Junlong Zhang,3 Chun Wan,1,2 Tao Wang,1,2 Dan Xu,1,2 Ting Yang,1,2 Fuqiang Wen1,21Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, 2Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, 3Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workBackground: Chronic obstructive pulmonary disease (COPD) is associated with abnormal systemic inflammation, and apoptosis is one of the pathogenic mechanisms of COPD. Several studies have suggested that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors were not only involved in diseases associated with apoptosis but also in inflammatory diseases. However, limited data about the possible relationship between COPD and TRAIL/TRAIL-receptors are available.Objective: To evaluate the potential relationship between TRAIL/TRAIL-receptors and COPD.Methods: Serum levels of TRAIL, decoy receptor 5 (DR5), C-reactive protein, and tumor necrosis factor-α were analyzed using multiplex enzyme-linked immunosorbent assay kits. Then, serum levels of TRAIL and DR5 in 57 COPD patients with 35 healthy controls were compared and correlated with lung function and systemic inflammation.Results: Mean levels of serum TRAIL and DR5 were significantly higher in COPD patients than those in controls (50.17±17.70 versus 42.09±15.49 pg/mL, P=0.029; 48.15±22.88 versus 38.94±10.95 pg/mL, P=0.032, respectively). Serum levels of TRAIL and DR5 correlated inversely with forced expiratory volume in 1 second % predicted, an index of lung function in COPD (r=-0.354, P=0.007 for TRAIL; r=-0.394, P=0.002 for DR5) in all participants (r=-0.291, P=0.005 for TRAIL; r=-0.315, P=0.002 for DR5), while DR5 correlated positively with C-reactive protein (r=0.240, P=0.021 for total subjects) and TRAIL correlated positively with tumor necrosis factor-α (r=0.371, P=0.005 for COPD; r=0.349, P=0.001 for total subjects).Conclusion: Our results suggested that circulating TRAIL and DR5 increased in COPD patients and were associated with lung function and systemic inflammation in COPD. Future studies are needed to verify whether and how TRAIL and its receptors play roles in COPD.Keywords: chronic obstructive pulmonary disease, tumor necrosis factor-related apoptosis-inducing ligand, decoy receptor 5, apoptosis, inflammation

Chih-Hung Hsu,1,4 Ying-Chun Shen,1,2 Yu-Yun Shao,1,4 Chiun Hsu,1,4 Ann-Lii Cheng,1,3,41Department of Oncology, 2Department of Medical Research, 3Department of Internal Medicine, National Taiwan University Hospital, 4Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, TaiwanAbstract: The approval of sorafenib, a multikinase inhibitor targeting primarily Raf kinase and the vascular endothelial growth factor receptor, in 2007 for treating advanced hepatocellular carcinoma (HCC) has generated considerable enthusiasm in drug development for this difficult-to-treat disease. However, because several randomized Phase III studies testing new multikinase inhibitors failed, sorafenib remains the standard of first-line systemic therapy for patients with advanced HCC. Field practice studies worldwide have suggested that in daily practice, physicians are adopting either a preemptive dose modification or a ramp-up strategy to improve the compliance of their patients. In addition, accumulating data have suggested that patients with Child–Pugh class B liver function can tolerate sorafenib as well as patients with Child–Pugh class A liver function, although the actual benefit of sorafenib in patients with Child–Pugh class B liver function has yet to be confirmed. Whether sorafenib can be used as an adjunctive therapy to improve the outcomes of intermediate-stage HCC patients treated with transcatheter arterial chemoembolization or early-stage HCC patients after curative therapies is being investigated in several ongoing randomized Phase III studies. An increasing number of studies have reported that sorafenib exerts "off-target" effects, including the modulation of signaling pathways other than Raf/MEK/ERK pathway, nonapoptotic cell death mechanisms, and even immune modulation. Finally, although sorafenib in combination with chemotherapy or other targeted therapies has the potential to improve therapeutic efficacy in treating HCC, it also increases toxicity. Additional clinical studies are warranted to determine useful sorafenib-based combinations for the treatment of advanced HCC.Keywords: HCC, multikinase inhibitor, advanced stage, sorafenib

We estimate the effect of deployment location and length on risk of developing post-traumatic stress disorder (PTSD). We draw a random sample of active duty enlisted personnel serving between 2001 and 2006 from a TRICARE beneficiary database and link deployment characteristics from the contingency tracking system. Using logistic regressions, we found that deployment to Iraq/Afghanistan increases the odds of developing PTSD substantially, relative to those in other duties, with the largest effect observed for the Navy (OR = 9.06, p < 0.01) and the smallest effect for the Air Force (OR = 1.25, p < 0.01). A deployment longer than 180 days increases the odds of PTSD by 1.11 to 2.84 times compared to a short tour. For Army and Navy, a deployment to Iraq/Afghanistan further exacerbates the adverse effect of tour length. [ABSTRACT FROM AUTHOR]

Silymarin and silibinin are bioactive components isolated from Silybum marianum. They have been reported to exhibit anti-oxidative and anti-inflammatory effects. Many studies revealed that drugs with potent anti-inflammatory potential can protect animals against inflammation-associated neurodegenerative disease, e.g., stroke. In this current work we established an animal model of acute ischemic stroke injury by inducing cerebral ischemic/reperfusion (CI/R) in rats to elucidate whether silymarin or silibinin can protect animals from CI/R injury. Pretreatment with silymarin, but not silibinin, dose-dependently (1-10[mu]g/kg, i.v.) reduced CI/R-induced brain infarction by 16-40% and improved neurological deficits in rats with a stroke. Elevated pathophysiological biomarkers for CI/R-induced brain injury, including lipid peroxidation, protein nitrosylation, and oxidative stress, were all reduced by silymarin. In addition, expression of inflammation-associated proteins (e.g., inducible nitric oxide synthase, cyclooxygenase-2 and myeloperoxidase), and transcriptional factors (e.g., nuclear factor (NF)-kappa B and signal transducer and activator of transcription (STAT)-1), as well as production of proinflammatory cytokine (e.g., interleukin-1[beta] and tumor necrosis factor-[alpha]) was all significantly prevented by silymarin. Furthermore, an in vitro study on microglial BV2 cells showed that silymarin could inhibit nitric oxide and superoxide anion production, possibly by interfering with NF-[kappa]B nuclear translocation/activation. Likewise, silymarin pretreatment also inhibited I[kappa]B-[alpha] degradation and NF-[kappa]B nuclear translocation in brain tissues of ischemic rats. Our results reveal that silymarin, but not its active component silibinin, protected rats against CI/R-induced stroke injury by amelioration of the oxidative and nitrosative stresses and inflammation-mediated tissue injury through impeding the activation of proinflammatory transcription factors (e.g., NF-[kappa]B and STAT-1) in the upregulation of proinflammatory proteins and cytokines in stroke-damaged sites. In conclusion, silymarin displays beneficial effects of preventing inflammation-related neurodegenerative disease, e.g., stroke, which needs further investigation and clinical evidences. [ABSTRACT FROM AUTHOR]

Objective: Analyze trends in hospital cost and revenue, as well as price and quantity (1994-2005) as a function of health maintenance organization (HMO) penetration, HMO concentration, and for-profit (FP) HMO market share.Data: Medicare hospital cost reports, AHA Annual Surveys, HMO data from Interstudy, and other supplemental data.Study Design: A retrospective study of all short-term, general, nonfederal hospitals in metropolitan statistical areas (MSAs) in the United States from 1994 to 2005, using hospital/MSA fixed-effects translog regression models.Principal Findings: A 10 percentage point increase in HMO enrollment is associated with 4.1-4.2 percent reduction in costs and revenues in the pre-2000 period but only a 2.1-2.5 percent reduction in the post-2000 period. Hospital revenue in HMO-dominant markets (highly concentrated HMO market and competitive hospital market) is 19-27 percent lower than other types of markets, and the difference is most likely due mainly to lower prices and to a lesser extent lower utilization.Conclusions: The historical difference of lower spending in high HMO penetration markets compared with low HMO markets narrowed after 2000 and the relative concentration between HMO and hospital markets can substantially influence hospital spending. Additional research is needed to understand how different aspects of these two markets have changed and interacted and how they are causally linked to spending trends. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests that dysregulation of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate neurotransmission may be involved in the pathophysiology of schizophrenia. The NMDAR is a heteromeric protein complex consisting of subunits from three subfamilies (NR1, NR2A, 2B, 2C, 2D and NR3A, 3B). The unique ability of NR3A to modulate the NMDAR function makes it an attractive candidate gene of schizophrenia. The purpose of this study was to investigate the involvement of the gene encoding the human NR3A subunit (GRIN3A) in the liability to schizophrenia.Methods: We searched for genetic variants in the putative core promoter region and all the exons (including UTR ends) of the GRIN3A gene in 333 Han Chinese patients with schizophrenia and 369 control subjects from Taiwan using direct polymerase chain reaction (PCR) autosequencing, and assessed their association with schizophrenia.Results: We identified 22 single nucleotide polymorphisms (SNPs) in the GRIN3A gene in this sample. SNP- and haplotype-based analyses showed no association of these 22 SNPs with schizophrenia. Nevertheless, we identified two missense mutations (D133N and Q1091H), one nonsense mutation (R1024X), and two synonymous mutations (Y873Y and E889E) of the GRIN3A gene in 6 out of 333 (1.8%) patients, while no rare mutations were found in 369 control subjects (p=0.011, Fisher's exact test, one-tailed). In silico analysis showed that the R1024X and Q1091H mutations are possibly damaging.Conclusions: Although the functional significance of these mutations remains to be characterized, our study indicates that rare mutations in the GRIN3A gene may contribute to the pathogenesis of schizophrenia in certain patients. [ABSTRACT FROM AUTHOR]

Objectives: This study examines whether deployment location and the duration of deployment affects the likelihood of being screened positive for PTSD.Methods: Retrospective study of all sailors returning from an overseas deployment between 2002 and 2006 who have completed the Post-Deployment Health Assessment survey. The primary outcome is whether the sailor is screened positive for PTSD. Multivariate analysis is conducted using probit models.Results: Deployment to Iraq and Afghanistan increases the probability of screening positive for PTSD by 6.3 and 1.6 percentage points compared to those who were deployed on ships. This probability is increased by 2.2 percentage points for those deployed longer than 180 days. The negative effect of longer deployments is exacerbated if the deployment is to Iraq or Afghanistan.Conclusions: Our results highlight the importance of providing adequate mental health care resources for those returning from hostile deployments and raise concerns about combat effectiveness of long deployments. [ABSTRACT FROM AUTHOR]

BACKGROUND: This is the first study to examine variation across cohorts in lifetime risk of DSM-IV mental disorders in metropolitan China. METHOD: Face-to-face household interviews of 2633 adults in Beijing and 2568 adults in Shanghai were conducted from November 2001 to February 2002 using a multi-stage household probability sampling method. The Chinese World Mental Health (WMH) Survey Initiative version of the WHO Composite International Diagnostic Interview (WMH-CIDI) was used for assessment. RESULTS: Lifetime prevalence of any disorder was 13.2%. Alcohol abuse (4.7%), major depressive disorder (3.5%), and specific phobia (2.6%) were the most common disorders. The median age of onset was later for mood (43 years) than anxiety (17 years) and substance use (25 years) disorders. Compared to observed lifetime prevalence, the projected lifetime risk as of age 75 years increased by 106% for major depressive disorder (7.2%), and was uniformly higher for all disorders. Relative odds of any lifetime disorder were 4.7 in the most recent cohorts (ages 18-34) compared to the eldest cohorts (ages > or =65). CONCLUSIONS: The findings of this cross-sectional study tally with the view that rapid socioeconomic changes may bring about increasing incidence of mental disorders in China. However, prospective longitudinal studies are needed to confirm if the increase is real. Because of the huge size of the Chinese population, any increase in projected lifetime risk of mental disorders represents an enormous increase in the number of affected individuals. [ABSTRACT FROM AUTHOR]

Incretin-based therapies are widely used to improve glycemic control and β cell dysfunction in the treatment of type 2 diabetes. Momordica cochinchinensis (Gac fruit), a nutritious melon cultivated in many regions, has underexplored health benefits, particular its edible aril. This study comprehensively investigates the stimulatory effect of Gac aril on glucagon-like peptide 1 (GLP-1) secretion, identifies the responsible active constituents, and explores the underlying mechanisms related to its anti-diabetic effects. GLP-1-secreting STC-1 intestinal L cells were used to assess bioactivity and molecular mechanisms. Additionally, the in vivo anti-diabetic effects of Gac aril consumption were evaluated using type 2 diabetic mice induced by a high fat diet and streptozotocin injection, with or without GLP-1 receptor expression. The results demonstrated that Gac pulp and aril stimulated GLP-1 secretion, while Gac seeds did not. β-Carotene, a major constituent of Gac aril, was identified as the key mediator of GLP-1 secretion via sweet taste receptor-mediated signaling in STC-1 cells. Dietary intake of Gac aril significantly improved fasting blood glucose, glucose tolerance, insulin sensitivity, β-cell function, and hemoglobin A1c in type 2 diabetic mice. GLP-1 levels increased 2-fold, and decreased levels of ghrelin and adiponectin were restored. The anti-diabetic effects were partially diminished in GLP-1 receptor knockout mice, suggesting Gac aril's effects are mediated, in part, through GLP-1. In conclusion, Gac aril consumption may provide health benefits for managing type 2 diabetes, partially by enhancing endogenous GLP-1 levels.

There are major clinical challenges in the management of chronic obstructive pulmonary disease (COPD). Recent studies suggest that thermal vapor lung volume reduction may be an important interventional method in the treatment of emphysema phenotype of COPD. In this article, we reviewed and summarized the research and development, the current situation of clinical application, and the clinical challenges of thermal vapor lung volume reduction, to provide further clinical evidence for the standardized application of thermal vapor lung volume reduction.

The human uterus is a complex and dynamic organ whose lining grows, remodels, and regenerates every menstrual cycle or upon tissue damage. Here, we applied single-cell RNA sequencing to profile more the 50,000 uterine cells from both the endometrium and myometrium of five healthy premenopausal individuals, and jointly analyzed the data with a previously published dataset from 15 subjects. The resulting normal uterus cell atlas contains more than 167K cells, representing the lymphatic endothelium, blood endothelium, stromal, ciliated epithelium, unciliated epithelium, and immune cell populations. Focused analyses within each major cell type and comparisons with subtype labels from prior studies allowed us to document supporting evidence, resolve naming conflicts, and propose a consensus annotation system of 39 subtypes. We release their gene expression centroids, differentially expressed genes, and messenger Ribonucleic Acid (mRNA) patterns of literature-based markers as a shared community resource. We identify multiple potential progenitor cells: compartment-wide progenitors for each major cell type and potential cross-lineage multipotent stromal progenitors that may replenish the epithelial, stromal, and endothelial compartments. Furthermore, many cell types and subtypes exhibit shifts in cell number and transcriptomes across different phases of the menstrual cycle. Finally, comparisons between premenopausal, postpartum, and postmenopausal samples revealed substantial alterations in tissue composition, particularly in the proportions of stromal, endothelial, and immune cells. The cell taxonomy and molecular markers we report here are expected to inform studies of both basic biology of uterine function and its disorders., Competing Interests: Competing interests statement:The authors declare no competing interest.

Importance: It is unclear how certified stroke center expansion contributes to improved access to stroke treatment and patient outcomes, and whether these outcomes differ by baseline stroke center access., Objective: To examine changes in rates of admission to stroke centers, receipt of thrombolysis and mechanical thrombectomy, and mortality when a community gains a newly certified stroke center within a 30-minute drive., Design, Setting, and Participants: This cohort study compared changes in patient outcomes when a community (defined by area zip code) experienced a stroke center expansion relative to the same community type that did not experience a change in access. Medicare fee-for-service beneficiaries with a primary diagnosis of acute ischemic stroke who were admitted to hospitals between January 1, 2009, and December 31, 2019, were included. The data analysis was performed between October 1, 2023, and September 9, 2024., Exposure: New certification of a stroke center within a 30-minute driving time of a community., Main Outcomes and Measures: The main outcomes were rates of admission to a certified stroke center, receipt of thrombolytics (delivered using drip-and-ship and drip-and-stay methods), mechanical thrombectomy, and 30-day and 1-year mortality estimated using a linear probability model with community fixed effects., Results: Among the 2 853 508 patients studied (mean [SD] age, 79.5 [8.5] years; 56% female), 66% lived in communities that had a stroke center nearby at baseline in 2009, and 34% lived in communities with no baseline access. For patients without baseline access, after stroke center expansion, the likelihood of admission to a stroke center increased by 38.98 percentage points (95% CI, 37.74-40.21 percentage points), and receipt of thrombolytics increased by 0.48 percentage points (95% CI, 0.24-0.73 percentage points). Thirty-day and 1-year mortality decreased by 0.28 percentage points (95% CI, -0.56 to -0.01) and 0.50 percentage points (95% CI, -0.84 to -0.15 percentage points), respectively, after expansion. For patients in communities with baseline stroke center access, expansion was associated with an increase of 9.37 percentage points (95% CI, 8.63-10.10 percentage points) in admission to a stroke center but no significant changes in other outcomes., Conclusions and Relevance: In this cohort study, patients living in communities without baseline stroke center access experienced significant increases in stroke center admission and thrombolysis and a significant decrease in mortality after a stroke center expansion. Improvements were smaller in communities with preexisting stroke center access. These findings suggest that newly certified stroke centers may provide greater benefits to underserved areas and are an important consideration when deciding when and where to expand health care services.

Chiral phenylalanine derivatives are important raw materials and building blocks for the synthesis of peptides and drug molecules. Enantiomerically pure D/L-3-pyridyl- and phenylalanine has shown wide application potential in the synthesis of various drug intermediates. This article focuses on two synthetic routes from different feedstocks. The first approach is an Erlenmeyer-Plöchl route study using N-acetylglycine as starting material, whereas the second is an alkylation route study using diethyl acetamidomalonate as starting material. The key step is the resolution of N-acetamido-alanine esters using different quantities of fairly inexpensive Protamex proteinase to obtain pure enantiomeric D/L-3-pyridyl- and substituted phenylalanine or its derivative, with the ee value and purity of all products exceeding 99%. The different chiral arylalanine derivatives that can be prepared using the above two methods have good versatility., (© 2024 Wiley Periodicals LLC.)

As a double-stranded RNA-editing enzyme and an interferon-stimulated gene, double-stranded RNA-specific adenosine deaminase (ADAR1) suppresses interferon signaling and contributes to immunotherapy resistance. Suppression of ADAR1 overcomes immunotherapy resistance in preclinical models, but has not yet been translated to clinical settings. By conducting a screening of a subset of the FDA-approved drugs, we found that all-trans retinoic acid (ATRA, also known as tretinoin) caused ADAR1 protein degradation through ubiquitin-proteasome pathways and concomitantly increased PD-L1 expression in pancreatic and breast cancers. In addition, the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment and unleashed antitumor immunity and thereby impeded tumor growth in pancreatic cancer mouse models. In a pilot clinical trial, a higher dose of ATRA plus the anti-PD-1 antibody nivolumab prolonged median overall survival in patients with chemotherapy-resistant pancreatic cancer compared to a lower dose of the same regimen. In this study, ATRA was the first drug to be found to cause ADAR1 degradation. We propose translation of a promising 2-pronged antitumor strategy using ATRA and nivolumab to convert immunologically "cold" into "hot" tumors susceptible to immune checkpoint blockade.

Background: It is unknown how changes in the percutaneous coronary intervention (PCI) "built environment" have impacted PCI volumes at the community, hospital, and patient levels. This study sought to determine how PCI hospital openings and closures effect community- and hospital-level PCI volumes as well as the likelihood of receiving PCI at a low-volume hospital., Methods: We conducted a retrospective cohort study of 3,966,025 Medicare Fee-For-Service patients in 37,451 zip codes and 2564 U.S. hospitals who underwent PCI from 2006 to 2017. We conducted community-, hospital-, and patient-level analyses using ordinary least squares regressions with fixed effects to determine changes in PCI volumes after PCI hospital openings or closures., Results: Between 2006 and 2017, a total of 17% and 7% of patients lived in communities that experienced PCI hospital openings and closures, respectively. Openings were associated with a 10% increase in community PCI volume, a 2% increase in the share of elective PCI, and a doubling in the likelihood of receiving PCI at a low-volume hospital. In communities with low baseline PCI capacity, openings were associated with a 12% increase in community PCI volume, and in high-capacity communities, an 8% increase. PCI closures were associated with a 9% decrease in community PCI volume in high-capacity communities but no measurable change in low-capacity communities., Conclusions: PCI service expansion is associated with increased PCI at low-volume hospitals and a greater number of elective procedures. Increased governmental oversight may be necessary to ensure that openings and closures of these specialized services yield the desired benefits., (© 2024 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Background: There is an urgent need for new treatments to solve hair loss problem. As mesenchymal stem cells were proved to have effects on promoting tissue repair and regeneration, in which the exosome plays a vital role, we aim to investigate the influence of umbilical cord mesenchymal stem cells exosome (UCMSC-Exos) on hair growth and its mechanism., Methods: The hUCMSC-Exos were extracted by ultracentrifugation. Primary fibroblasts were cultured with or without hUCMSC-Exos and cell proliferation was evaluated by CCK-8 assay. C57BL/6 mice model of depilation-induced hair regrowth was treated with either hUCMSC-Exos (200 μg/mL) or PBS on one side of the dorsal back. Real time quantitative PCR, flow cytometry analysis, immunohistochemistry and Immunofluorescent staining were used to analyze the regulative effect of hUCMSC-Exos on hair follicle stem/progenitor cells and Wnt/β-catenin pathway., Results: The proliferation of fibroblasts incubated with hUCMSC-Exos at the concentration of 200 μg/mL was greater than other groups. Treatment with hUCMSC-Exos resulted in rapid reentry into anagen. Hair follicle stem/progenitor cell markers (K15, Lgr5, Lgr6, CD34 and Lrig1) and Wnt/β-catenin pathway related factors (Wnt5, Lef1, Lrp5 and β-catenin) were increased in hUCMSC-Exos-injected region., Conclusion: hUCMSC-Exos promote fibroblasts proliferation and accelerate mouse hair regrowth by upregulating hair follicle stem/progenitor cell and Wnt/β-catenin pathway, which suggests potential therapeutic approaches for hair loss disorders., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Objectives: To summarize the clinical characteristics and investigate the efficacy of ethanol embolotherapy in the treatment of chest well arteriovenous malformation (AVM). Treatment-associated complications were also explored., Materials and Methods: Between March 2017 and August 2021, 32 consecutive patients (mean age, 23.7 years; age range, 5-54 years) who underwent ethanol embolotherapy for chest well AVMs under general anesthesia were included in this study. Embolization was performed through a direct puncture, transarterial catheterization, or a combination of the 2 procedures. The mean follow-up duration after the last treatment was 18.0 months (range, 3-42 months). The degree of devascularization on follow-up (assessed using angiography or computed tomography), and the clinical signs and symptoms of AVMs were evaluated as the therapeutic outcomes. The major and minor complications associated with the procedures were recorded., Results: A total of 103 embolization procedures (mean, 3.2; range, 2-7) comprising 101 ethanol embolization and 2 coil embolizations were performed on 32 patients with chest wall AVMs. The AVM nidus was accessed through the transarterial approach alone in 4 patients, by direct puncture in 11, and a combined procedure in 17 patients. Overall, more than 80% of the procedures were performed using the combined approach. Complete AVM devascularization was achieved in 12 (37.5%) patients. Moreover, 76% to 99% AVM was achieved in 18 patients (56.3%), and 50% to 75% in 2 patients (6.3%). Bleeding, pain, heart failure, and cosmetic deformities were the indications for treatment. For 3 patients (3/32, 9.4%) who had bleeding, the treatment stopped the hemorrhage. Complete pain relief was reported in 8 patients (8/32, 25.0%), whereas complete relief from congestive heart failure post-embolization was observed in 5 of the 6 patients with congestive heart failure (5/6, 83.3%). Complete correction of cosmesis deformities after embolization was achieved in 10 patients (10/32, 31.3%). Two patients who underwent surgery to correct persistent deformity after embolization only showed insignificant improvement. In addition, 6 (18.8%) patients developed 13 complications including blister, necrosis, hemothorax, transient hemoglobinuria, and transient pulmonary artery hypertension., Conclusions: Ethanol embolotherapy is a safe and effective procedure for chest well AVMs. Surgery is required for some patients with residual cosmesis deformity., Clinical Impact: Currently, there is no standard treatment for chest well AVMs due to their rarity and high heterogeneity. The present study shows that thanol embolotherapy is a safe and clinically effective treatment procedure for the chest well AVMs. Transarterial embolization in combination with direct puncture embolization can reach the AVM nidus. Ethanol embolotherapy can achieve complete obliteration of the AVM nidus in the majority of patients. Surgery may still be needed to correct cosmetic deformity after embolization. The present study provides valuable evidence to inform clinical decision-making., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To describe the practice patterns of intravitreal injections (IVIs) among ophthalmologists in China., Methods: This was a cross-sectional online survey. Ophthalmologists who had performed accumulated more than 100 injections were contacted by the Brightness Center, a hospital-based national network, to complete an anonymous, 24-question, internet-based survey. They were surveyed on practices in injection techniques, pre-, and post-injections procedures., Results: A total of 333 ophthalmologists from 28 provinces/municipalities/autonomous regions responded to the survey (50.68% response rate). The 91.29% of the respondents evaluated systemic risk factors by medical history, electrocardiogram (ECG) and blood test. All the respondents used pre-injection prophylactic antibiotics. Most checked intraocular pressure (IOP, 99.1%) and blood pressure (96.1%) before injections. A majority of the respondents performed injections in the operating room (98.8%), wore masks (99.7%), gloves (99.4%) and sterile surgical clothing (96.1%), performed topical anesthetics (97.9%), and applied povidone-iodine (95.8%) pre-injection. The 61.26% of the respondents dilated pupil. About half of the respondents (51.05%) performed bilateral injections in the same setting. Superior temporal quadrant (40.54%) was the most frequent site of injection. Around three quarters used 30-gauge needles. Most respondents (97.9%) measured the site of injection from limbus. More than half (53.45%) performed conjunctiva displacement prior to injection. The 32.43% of the respondents checked IOP post-injection and 87.99% physicians checked hand motion (HM) or counting fingers (CF) after injection, while 36.94% observed optic nerve perfusion. All participants used topical antibiotics post-injections. Most physicians (91.89%) reviewed patients on the following day., Conclusion: This study provides a description of the real-world practice patterns in IVIs in China and offers critical information regarding education and training of ophthalmologists and amendment of local society guidelines., Competing Interests: Conflicts of Interest: Su L, None; Shen YC, None; Li H, None; Mou B, None; Liu K, None; Xu X, None., (International Journal of Ophthalmology Press.)

High dietary sugar (HDS), a contemporary dietary concern due to excessive intake of added sugars and carbohydrates, escalates the risk of metabolic disorders and concomitant cancers. However, the molecular mechanisms underlying HDS-induced cancer progression are not completely understood. We found that phosphoenolpyruvate carboxykinase 1 (PEPCK1), a pivotal enzyme in gluconeogenesis, is paradoxically upregulated in tumors by HDS, but not by normal dietary sugar (NDS), during tumor progression. Targeted knockdown of pepck1, but not pepck2, specifically in tumor tissue in Drosophila in vivo, not only attenuates HDS-induced tumor growth but also significantly improves the survival of Ras/Src tumor-bearing animals fed HDS. Interestingly, HP1a-mediated heterochromatin interacts directly with the pepck1 gene and downregulates pepck1 gene expression in wild-type Drosophila. Mechanistically, we demonstrated that, under HDS conditions, pepck1 knockdown reduces both wingless and TOR signaling, decreases evasion of apoptosis, reduces genome instability, and suppresses glucose uptake and trehalose levels in tumor cells in vivo. Moreover, rational pharmacological inhibition of PEPCK1, using hydrazinium sulfate, greatly improves the survival of tumor-bearing animals with pepck1 knockdown under HDS. This study is the first to show that elevated levels of dietary sugar induce aberrant upregulation of PEPCK1, which promotes tumor progression through altered cell signaling, evasion of apoptosis, genome instability, and reprogramming of carbohydrate metabolism. These findings contribute to our understanding of the complex relationship between diet and cancer at the molecular, cellular, and organismal levels and reveal PEPCK1 as a potential target for the prevention and treatment of cancers associated with metabolic disorders., (© 2024. The Author(s).)

Rationale: Approximately one-fifth ischemic stroke are attributed to cardioembolism. Patients with cardioembolic stroke often develop a more severe disability and a higher risk of stroke recurrence. Cardiac myxoma, although uncommon, can serve as a potentially curable cause of acute embolic strokes., Patient Concerns: A 55-year-old male patient presented to the emergency department with acute vertigo and unsteady gait, accompanied by left upper limb numbness. Concurrently, purple-like lesions on the left hand were noticed., Diagnoses: Brain magnetic resonance imaging showed multiple infarctions in the posterior circulation. Additionally, skin examination showed Janeway lesions, Osler nodes and splinter hemorrhages. There was no evidence of systemic infection. Subsequently, transthoracic echocardiogram revealed a left atrial myxoma., Intervention: Early surgical resection of cardiac myxoma was performed., Outcomes: The patient recovered well from the surgery. No recurrent embolic event was reported at 3-month postoperatively., Lessons: Clinicians should be vigilant for skin manifestations of cardiac embolism. In patients with acute ischemic strokes, the presence of cutaneous embolic phenomena could serve as a warning sign of cardioembolism., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: Active duty service members have higher mental health stress and cannot choose where to live. It is imperative to understand how geographic access may be associated with their ability to obtain mental health treatment and how the COVID-19 pandemic was associated with these patterns., Objective: To identify changes in the prevalence and intensity of mental health care use when service members experienced changes in core mental health clinician (defined to include psychiatrists, psychiatric nurse practitioners, clinical psychologists and social workers, and marriage and family therapists) capacity in their communities and whether patterns changed from before to after the onset of the COVID-19 pandemic., Design, Setting, and Participants: This retrospective cohort study of the active duty population between January 1, 2016, and December 31, 2022, was conducted using individual fixed-effects models to estimate changes in the probability of mental health care visits and visit volume when a person moved across communities with adequate core mental health clinician capacity (≥1 clinician/6000 beneficiaries), shortage areas (<1 clinician/6000 beneficiaries), and areas with 0 clinicians within a 30-minute drive time. All US active duty service members stationed in the continental US, Hawaii, and Alaska were included. Data were analyzed from January through July 2024., Main Outcomes and Measures: The first set of outcomes captured the probability of making at least 1 mental health care visit in a given quarter; the second set of outcomes captured the intensity of visits (ie, the number of visits log transformed)., Results: This study included 33 039 840 quarterly observations representing 2 461 911 unique active duty service members from the Army, Navy, Marines, and Air Force (1 959 110 observations among Asian or Pacific Islander [5.9%], 5 309 276 observations among Black [16.1%], 5 287 168 observations among Hispanic [16.0%], and 18 739 827 observations among White [56.7%] individuals; 27 473 563 observations among males [83.2%]; mean [SD] age, 28.20 [7.78] years). When an active duty service member moved from a community with adequate capacity at military treatment facilities to one with 0 clinicians within a 30-minute drive, the probability of a mental health visit to any clinician decreased by 1.13 percentage points (95% CI, -1.21 to -1.05 percentage points; equivalent to a 11.6% relative decrease) and the intensity of total visits was reduced by 7.7% (95% CI, -9.0% to -6.5%). The gap increased from before to after the onset of the COVID-19 pandemic, from 8.5% (equivalent to -0.82 percentage points [95% CI, -0.92 to -0.73 percentage points]) to 16.2% (equivalent to -1.58 percentage points [95% CI, -1.70 to -1.46 percentage points]) in the probability of visiting any clinician type for mental health., Conclusions and Relevance: In this study, active duty personnel assigned to locations without core military mental health clinicians within a 30-minute drive time were less likely to obtain mental health care and had fewer mental health care visits than those in communities with adequate military mental health capacity even if there was adequate coverage from the civilian sector. The care disparity increased after the onset of the COVID-19 pandemic.

Ekbom's syndrome (ES), also referred to as delusional parasitosis, is a psychiatric disorder that is relatively uncommon. It is characterized by a robust and unwavering belief in infestation despite the absence of predominant hallucinations or formal thought disorders. Ekbom syndrome presents in 2 main forms: primary, marked by delusions and abnormal tactile sensations; and secondary, where symptoms arise due to another underlying organic condition. In primary ES, the therapeutic approach primarily relies on antipsychotic (AP) medications. This article presents a case with primary ES showing that atypical APs with aripiprazole and brexpiprazole effectively treat this disease. Brexpiprazole, compared to aripiprazole, induced less tremor and akathisia in the case report, suggesting it might be more suitable for treating this condition., Competing Interests: Declaration of Interests: The authors have no conflicts of interest to declare., (2024 authors.)

The intricately orchestrated progression of mammary tissue development involves the precise coordination of gland differentiation and cellular proliferation. Nevertheless, the understanding of the role and regulatory mechanisms governing the DNA replication machinery in mammary gland development remains limited. Given the essential role of DNA replication in the viability of living cells, any genetic disturbance to its replicative function, in any form, will impede organ development. This circumstance poses a technical challenge in elucidating the potential function of cell proliferation in mammary morphogenesis. PCNA is crucial in DNA replication, playing a pivotal role in the development of complete eukaryotic organisms. The phosphorylation of PCNA at tyrosine 211 (Y211) has been demonstrated to play a significant role in supporting replication forks and, consequently, cell proliferation. Therefore, the utilization of a knock-in mouse model, wherein the Y211 residue of PCNA is replaced with phenylalanine (211F), presents an opportunity to evaluate the impact of reduced cell proliferation potential on mammary gland development. Interestingly, the lack of Y211 phosphorylation did not significantly impact the rates of proliferation or cell death in the mammary gland. In contrast, the absence of Y211PCNA led to an increased, rather than reduced, growth of the mammary gland. This was evident in assessments of gland length and the number of terminal end buds (TEBs) in both postnatal and virgin mammary glands. Notably, this observation correlated with an elevation in tissue stemness within the 211F glands compared to the WT glands. Additionally, it was consistent with the greater body weight gains observed in 211F pups compared to WT pups during the weaning period. Our findings unveil an unexpected aspect that may carry significance for mammary development. This newfound is associated with the regulation of a central component within the DNA replication machinery, providing insights into the intricate interplay governing mammary tissue expansion., Competing Interests: Conflicts of interest: The authors declare no conflict of interest., (© the Author(s).)

Background and Purpose: The role of asymptomatic diffusion-weighted imaging-positive (aDWI+) lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients remains unclear, and their radiographic features may differ from those of symptomatic diffusion-weighted imaging-positive (sDWI+) lesions. We aimed to investigate the clinicoradiographic characteristics of aDWI+ lesions in CADASIL patients., Methods: We conducted a retrospective analysis using data from the Taiwan CADASIL Registry. aDWI+ lesions were defined as incidentally detected DWI+ lesions without corresponding acute neurological deficits. We compared the baseline clinical characteristics of patients with and without aDWI+ lesions and analyzed their radiological features and evolution in relation to sDWI+ lesions., Results: Among 154 enrolled patients (mean age 62 ± 10 years), 17 (11%) had aDWI+ lesions. Baseline clinical characteristics were similar in the two groups, but those with aDWI+ lesions had more lacunes (median 8 vs. 2), multiple cerebral microbleeds (CMBs; 85% vs. 40%), and anterior temporal white matter hyperintensity (WMH; 47% vs. 14%). Multivariable analysis showed that aDWI+ lesions were associated with anterior temporal WMH (odds ratio 5.7, 95% confidence interval 1.5-21.0) after adjusting for multiple lacunes, multiple CMBs, and total WMH score. Compared to sDWI+ lesions, aDWI+ lesions were more often small infarcts (<1 cm; 89% vs. 23%) and less likely to involve the corticospinal tract (11% vs. 96%). Among the 11 aDWI+ lesions with follow-up magnetic resonance imaging, seven became microinfarcts, three became lacunes, and one disappeared., Conclusions: aDWI+ lesions in CADASIL are not uncommon and are associated with higher burdens of small vessel disease and anterior temporal WMH. Further research is needed to assess their long-term impact on CADASIL., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: Mechanical thrombectomy (MT) improves outcomes for acute ischemic stroke (AIS) due to large vessel occlusion, but is time sensitive and requires specialized infrastructure. Professional organizations and certification bodies have promulgated minimum procedural volume standards for centers and for individual proceduralists but it is unclear whether enforcing these requirements would decrease geographic access to MT. Therefore, we sought to evaluate the potential impact of applying a minimum procedural volume threshold on geographic access to MT., Methods: We identified all hospital discharges for stroke where an MT procedure was performed at any nonfederal hospital in Florida in 2019 using statewide hospital discharge data. We then generated geographic service area maps based on prespecified ground transport distances for the subset of hospitals that performed at least 1 MT and for those that performed at least 15 MTs that year, the minimum volume threshold required for thrombectomy capable and comprehensive stroke centers by the Joint Commission. Then, using zip code centroids and patient-level discharge hospital data, we computed the proportion of patients with AIS who lived within each of the generated service areas., Results: A total of 105 of 297 hospitals performed MT; of those, 51 (17%) were low-volume centers (1-14 MTs/year) and 54 (18%) were high-volume centers (≥15 MTs/year). High-volume centers accounted for nearly 95% of all MTs performed in the state. Most patients hospitalized with AIS (87%) lived within 20 miles (or an estimated as a 1-hour driving time) of a hospital that performed at least 1 MT, and all (100%) lived within 115 miles (or estimated as 3-hour driving time). Setting a minimum MT volume threshold of 15 would decrease the proportion of stroke patients living within 1-hour driving time of an MT center from 87% to 77%., Discussion: In 2019, most Florida stroke patients lived within a 1-hour ground transport time to a center that performed at least 1 MT and all lived within 3-hour driving time of an MT center, irrespective of whether a minimum procedural volume threshold of 15 cases per year was applied or not., Competing Interests: A.S. Kim reports grant funding from NIH/NINDS, NIH/NCATS, NIH/NIMHD, AHA/ASA, and PCORI. R.Y. Hsia reports grant funding from NIH/NHLBI and NIH/NIMHD. E.L. Guterman reports grant funding from NIH/NINDS, NIH/NIA, American Academy of Neurology, and personal fees from JAMA Neurology, REMO Health, Inc, and Marinus Pharmaceuticals which are unrelated to the submitted work. L. Solovey, Y. Shen, and J.C. Choi report no disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Neurological deterioration within 24 h after intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with poor outcomes in patients with acute ischemic stroke (AIS). This study aimed to elucidate the features of neurological deterioration specifically during tPA infusion in these patients., Methods: We analyzed patients with AIS receiving thrombolysis between January 2018 and December 2021. Very early neurological deterioration (VEND) was defined as an increase of 4 or more points in the National Institutes of Health Stroke Scale (NIHSS) score during tPA infusion. Poor functional outcome was defined as a modified Rankin Scale score of 3-6 at three months., Results: Among the 345 patients with AIS who received tPA, 8.4% had VEND; all of which were caused by ischemic progression. Patients with VEND had a higher prevalence of intracranial atherosclerotic disease (41% vs. 17%, P = 0.005). VEND independently predicted poor functional outcome in both groups with minor (NIHSS score <6) and non-minor (NIHSS score >6) stroke. Among patients with minor stroke, those with VEND were more likely to undergo endovascular thrombectomy (EVT) than those without (38% vs. 5%, P = 0.019). In patients receiving EVT after VEND, the NIHSS scores at 24 h, which were correlated with 3-month functional outcome, were lower in those with successful recanalization than in those without (12 ± 9 vs. 26 ± 7, P = 0.047)., Conclusion: VEND predicted poor functional outcomes in patients with AIS. Timely and successful recanalization using EVT potentially alleviates the negative impact of VEND on long-term outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Purpose: Durable partial response (PR) and durable stable disease (SD) are often seen in patients with hepatocellular carcinoma (HCC) receiving atezolizumab plus bevacizumab (atezo-bev). This study investigates the outcome of these patients and the histopathology of the residual tumors., Patients and Methods: The IMbrave150 study's atezo-bev group was analyzed. PR or SD per RECIST v1.1 lasting more than 6 months was defined as durable. For histologic analysis, a comparable real-world group of patients from Japan and Taiwan who had undergone resection of residual tumors after atezo-bev was investigated., Results: In the IMbrave150 study, 56 (77.8%) of the 72 PRs and 41 (28.5%) of the 144 SDs were considered durable. The median overall survival was not estimable for patients with durable PR and 23.7 months for those with durable SD. The median progression-free survival was 23.2 months for patients with durable PR and 13.2 months for those with durable SD. In the real-world setting, a total of 38 tumors were resected from 32 patients (23 PRs and nine SDs) receiving atezo-bev. Pathologic complete responses (PCRs) were more frequent in PR tumors than SD tumors (57.7% v 16.7%, P = .034). PCR rate correlated with time from atezo-bev initiation to resection and was 55.6% (5 of 9) for PR tumors resected beyond 8 months after starting atezo-bev, a time practically corresponding to the durable PR definition used for IMbrave150. We found no reliable radiologic features to predict PCR of the residual tumors., Conclusion: Durable PR patients from the atezo-bev group showed a favorable outcome, which may be partly explained by the high rate of PCR lesions. Early recognition of PCR lesions may help subsequent treatment decision.

Flight safety in helicopters is a critical aspect of overall aircraft operational safety management, particularly during engine failures requiring autorotative glide, which makes it extremely challenging for the pilot to land the helicopter successfully. In this study, we evaluated the workload and attention allocation of helicopter pilots under such circumstances. In the experiment, a helicopter flight simulator was used to simulate level flight followed by autorotative glide, with the two phases divided into time segments for data collection. First, the data were visualized using heat maps and saccade sequence diagrams, while changes in eye movement metrics (such as peak value and standard deviation) were statistically analyzed. Finally, the criteria through the inter-criteria correlation (CRITIC) method was used to calculate the weight coefficient for each area of interest. This evaluation system was further applied to analyze and compare the changes in eye-movement data and attention to areas of interest during the two phases. The results revealed a shorter fixation duration, but a greater fixation number during the autorotative glide phase. Further, the mean pupil diameter changed over a larger range than during level flight (in level flight, the mean was 5.229 mm, while the standard deviation was 0.059 mm; in autorotative glide the corresponding values were 5.326 mm and 0.126 mm, respectively). For the tachometer, the weight coefficient matched the color of the heat map (2.7 % and colorless during level flight, but 23.8 % and red during autorotative glide), while those for the airspeed indicator and forward view differed significantly between the two phases. This discrepancy stemmed from the fact that during autorotative glide, the pilots prioritized monitoring aircraft rotation speed and attitude, with a particular focus on the forward view, rotor speed, and airspeed, resulting in a more concentrated attention distribution compared to that achieved during level flight. These results confirmed a significant increase in pilot workload during autorotative glide landing, while a shift was observed from low-frequency long gaze time during level flight to high-frequency short gaze time during autorotative glide. Furthermore, the pilots allocated 81 % of their attention to the tachometer, airspeed indicator, and forward views. Adopting this strategy can improve pilots' landing success and provide flight students with valuable training advice to prevent landing failures when helicopters lose power., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Electron Beam Ion Traps (EBITs) serve as efficient tools for producing and studying highly charged ions. In response to the diagnostic requirements of upcoming magnetic confinement fusion devices, a medium-energy atomic spectra research platform based on a compact EBIT is developed. This platform achieves a central magnetic field of up to 1.0 T, with electron beam currents reaching 20 mA and electron energies up to 30 keV, similar to the electron temperature on fusion reactors. The developed atomic spectra platform successfully provided spectral data for elements such as argon, xenon, iron, and tungsten. This platform stands as a valuable asset for advancing research in nuclear fusion, particularly concerning impurity spectroscopic diagnostics., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The Laser Blow-Off (LBO) impurity injection system is a crucial tool for studying impurity transport and plasma behavior. Conducting proactive impurity transport research is challenging on experimental advanced superconducting tokamak (EAST) due to the uncontrollable generation of impurity sources; therefore, it is necessary to develop a laser blow-off impurity injection system for injecting controlled trace impurity particles. This study presents the design and test results of an LBO system for the EAST. The system aims to provide precise and repeatable control over the timing and quantity of impurity injection. The system primarily consists of a laser source, two mirrors, a moveable focusing lens, a target material, and a vacuum system. The movement of the focusing lens is achieved by a three-dimensional displacement system. The operation of the system is completed by a remote control system. With the accurate control system, the laser spot diameter is adjustable, allowing for modification of impurity injection quantity. The test results demonstrate that the system can rapidly detect external trigger signals and ensure precise timing for the impurity injection. Furthermore, this system can also quickly change the focal point of the laser spot, addressing the requirements for impurity injections during the experiments with less than 0.4 mm position error for laser spot focusing. Test results have shown that the aluminum film material can be peeled off by the LBO system when the laser energy exceeds 650 mJ and the smallest ablation spot is about 1 mm. This study is of significant importance for conducting plasma impurity transport research on the EAST., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

We report on an experimental simulation of the spin-1 Heisenberg model with composite bosons in a one-dimensional chain based on the two-component Bose-Hubbard model. Exploiting our site- and spin-resolved quantum gas microscope, we observed faster superexchange dynamics of the spin-1 system compared to its spin-1/2 counterpart, which is attributed to the enhancement effect of multi-bosons. We further probed the nonequilibrium spin dynamics driven by the superexchange and single-ion anisotropy terms, unveiling the linear expansion of the spin-spin correlations, which is limited by the Lieb-Robinson bound. Based on the superexchange process, we prepared and verified the entangled qutrits pairs with these composite spin-1 bosons, potentially being applied in qutrit-based quantum information processing.

This study aims to explore the efficacy of group music and game therapy in enhancing the well-being of the institutionalised elderly. The implementation of group music and game therapy have significantly improved the well-being of the participating elderly residents in Long-Term Care Facilities. These participants demonstrated increased engagement and achieved interpersonal interaction objectives during the sessions.