Search

Obstructive sleep apnea, characterized by airway exposure to intermittent hypoxia (IH), is associated with laryngeal airway hyperreactivity (LAH) and laryngeal inflammation. The sensitization of capsaicin-sensitive superior laryngeal afferents (CSSLAs) by inflammatory mediators has been implicated in the pathogenesis of LAH. Nerve growth factor (NGF) is an inflammatory mediator that acts on tropomyosin receptor kinase A (TrkA) and the p75 neurotrophin receptor (p75 NTR ) to induce lower airway hyperresponsiveness. In this study, we investigated the role of NGF in the development of LAH and laryngeal inflammation induced by IH in anesthetized rats. Compared with rats subjected to room air exposure for 14 days, rats with 14-day IH exposure exhibited augmented reflex apneic responses to the laryngeal provocation of three different chemical stimulants of CSSLAs, resulting in LAH. The apneic responses to laryngeal stimulants were abolished by either perineural capsaicin treatment (a procedure that selectively blocks the conduction of CSSLAs) or denervation of the superior laryngeal nerves, suggesting that the reflex was mediated through CSSLAs. The IH-induced LAH was significantly attenuated by daily treatment with anti-NGF antibody, but was unaffected by daily treatment with immunoglobulin G. IH exposure also induced laryngeal inflammation as evidenced by increases in laryngeal levels of NGF, lipid peroxidation, tumor necrosis factor-α, interleukin-1β, TrkA, and p75 NTR . Similarly, IH-induced laryngeal inflammation was significantly reduced by daily treatment with anti-NGF antibody. We concluded that NGF contributes to the development of LAH and laryngeal inflammation induced by IH in rats. The LAH may result from the sensitizing effect of NGF on CSSLAs., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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: There is currently no well-accepted consensus on the association between gut microbiota and the response to treatment of immune checkpoint inhibitors (ICIs) in patients with advanced cancer., Methods: Fecal samples were collected before ICI treatment. Gut microbiota was analyzed using 16 S ribosomal RNA sequencing. We investigated the relationship between the α-diversity of fecal microbiota and patients' clinical outcomes. Microbiota profiles from patients and healthy controls were determined. Pre-treatment serum was examined by cytokine array., Results: We analyzed 74 patients, including 42 with melanoma, 8 with kidney cancer, 13 with lung cancer, and 11 with other cancers. Combination therapy of anti-PD1 and anti-CTLA-4 was used in 14 patients, and monotherapy in the rest. Clinical benefit was observed in 35 (47.3 %) cases, including 2 complete responses, 16 partial responses, and 17 stable diseases according to RECIST criteria. No significant difference in α-diversity was found between the benefiter and non-benefiter groups. However, patients with α-diversity within the range of our healthy control had a significantly longer median overall survival (18.9 months), compared to the abnormal group (8.2 months) (p = 0.041, hazard ratio = 0.546) for all patients. The microbiota composition of the benefiters was similar to that of healthy individuals. Furthermore, specific bacteria, such as Prevotella copri and Faecalibacterium prausnitzii, were associated with a favorable outcome. We also observed that serum IL-18 before treatment was significantly lower in the benefiters, compared to non-benefiters., Conclusions: The α-diversity of gut microbiota is positively correlated with more prolonged overall survival in cancer patients following ICI therapy., Competing Interests: Declaration of competing interest The authors have no financial or ethical conflicts of interest to report., (© 2024 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

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.

A space-resolved vacuum ultraviolet spectroscopy is employed to measure impurity emission profiles (500-3200 Å) on EAST. This study successfully captures C IV (1548.20 and 1550.77 Å) lines emitted from carbon ions and derives ion temperatures using Doppler broadening and a collision model based on their intensity ratios. Both the emission intensity and ion temperature profiles are determined. However, the calculated results reveal a lower temperature of around 10-20 eV with the collision model, suggesting a potential need for further correction in subsequent calculations. Furthermore, this study explores relative rotation velocities from the Doppler shift, indicating an increase in toroidal rotation velocity with applied neutral beam injection. The measured results exhibit concordance with the charge exchange recombination spectrometer data. Furthermore, during boron powder dropping discharges on EAST, B II (1623.60, 1623.79, 1623.95, 1624.02, 1624.17, and 1624.38 Å) emission lines exhibiting a similar time behavior trend with boron powder injection are identified. Ion temperatures are measured using B II (1362.46 Å) through the Doppler broadening method. These techniques hold significant promise for future impurity analysis at the edge of EAST, providing valuable insights into the behavior of carbon and boron ions., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Percutaneous coronary intervention (PCI) is a procedure that opens blocked arteries and restores blood flow to the heart. Timely access to hospitals offering PCI services can be a matter of life or death for patients experiencing a heart attack; however, hospitals' adoption of PCI services may vary between communities, posing potential barriers to critical care. Our cohort study of US general acute hospitals during the period 2000-20 examined PCI service adoption across communities stratified by race, ethnicity, income, and rurality and further classified as segregated or integrated. Of 5,260 hospitals, 1,621 offered PCI services in 2020 or before, 630 added PCI services between 2001 and 2010, and 225 added PCI services between 2011 and 2020. Hospitals serving Black, racially segregated communities were 48 percent less likely to adopt PCI services compared with hospitals serving non-Black, racially segregated communities, and hospitals serving Hispanic, ethnically segregated communities were 41 percent less likely to do so than those serving non-Hispanic, ethnically segregated communities. Hospitals in high-income, economically integrated communities were 1.8 times more likely to adopt PCI services than those in high-income, economically segregated communities, and rural hospitals were less likely to do so than urban hospitals. Understanding where services are expanding in relation to community need may aid in successful policy interventions.

Importance: Stroke center certification is granted to facilities that demonstrate distinct capabilities for treating patients with stroke. A thorough understanding of structural discrimination in the provision of stroke centers is critical for identifying and implementing effective interventions to improve health inequities for socioeconomically disadvantaged populations., Objective: To determine whether (1) hospitals in socioeconomically disadvantaged communities (defined using the Area Deprivation Index) are less likely to adopt any stroke certification and (2) adoption rates differ between entry-level (acute stroke-ready hospitals) and higher-level certifications (primary, thrombectomy capable, and comprehensive) by community disadvantage status., Design, Setting, and Participants: This cohort study used newly collected stroke center data merged with data from the American Hospital Association, Healthcare Cost Report Information datasets, and the US Census. All general acute hospitals in the continental US between January 1, 2009, and December 31, 2022, were included. Data analysis was conducted from July 2023 to May 2024., Main Outcomes and Measures: The primary outcome was the likelihood of hospitals adopting stroke care certification. Cox proportional hazard and competing risk models were used to estimate the likelihood of a hospital becoming stroke certified based on the socioeconomic disadvantage status of the community., Results: Among the 5055 hospitals studied from 2009 to 2022, 2415 (47.8%) never achieved stroke certification, 602 (11.9%) were certified as acute stroke-ready hospitals, and 2038 (40.3%) were certified as primary stroke centers or higher. When compared with mixed-advantage communities, adoption of any stroke certification was most likely to occur near the most advantaged communities (hazard ratio [HR], 1.24; 95% CI, 1.07-1.44) and least likely near the most disadvantaged communities (HR, 0.43; 95% CI, 0.34-0.55). Adoption of acute stroke-ready certification was most likely in mixed-advantage communities, while adoption of higher-level certification was more likely in the most advantaged communities (HR,1.41; 95% CI, 1.22-1.62) and less likely for the most disadvantaged communities (HR, 0.31; 95% CI, 0.21-0.45). After adjusting for population size and hospital capacity, compared with mixed-advantage communities, stroke certification adoption hazard was still 20% lower for relatively disadvantaged communities (adjusted HR, 0.80; 95% CI, 0.73-0.87) and 42% lower for the most disadvantaged communities (adjusted HR, 0.58; 95% CI, 0.45-0.74)., Conclusions and Relevance: In this cohort study examining hospital adoption of stroke services, when compared with mixed-advantage communities, hospitals located in the most disadvantaged communities had a 42% lower hazard of adopting any stroke certification and relatively disadvantaged communities had a 20% lower hazard of adopting any stroke certification. These findings suggest that there is a need to support hospitals in disadvantaged communities to obtain stroke certification as a way to reduce stroke disparities.

Background: Despite the efficacy of absolute ethanol (EtOH), its radiolucency introduces several risks in interventional therapy for treating vascular malformations. This study aims to develop a novel radiopaque ethanol injection (REI) to address this issue., Methods: Iopromide is mixed with ethanol to achieve radiopacity and improve the physicochemical properties of the solution. Overall, 82 male New Zealand white rabbits are selected for in vivo radiopacity testing, peripheral vein sclerosis [animals were divided into the following 5 groups (n = 6): negative control (NC, saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), low-dose REI (L-D REI, 0.125 ml/kg), moderate-dose REI (M-D REI, 0.250 ml/kg), and high-dose REI (H-D REI 0.375 ml/kg)], pharmacokinetic analyses (the blood sample was harvested before injection, 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, and 8 h after injection in peripheral vein sclerosis experiment), peripheral artery embolization [animals were divided into the following 5 groups (n = 3): NC (saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)], kidney transcatheter arterial embolization [animals were divided into the following 4 groups (n = 3): positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg); each healthy kidney was injected with saline as negative control], and biosafety evaluations [animals were divided into the following 5 groups (n = 3): NC (0.250 ml/kg), high-dose EtOH (0.375 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)]. Then, a prospective cohort study involving 6 patients with peripheral venous malformations (VMs) is performed to explore the clinical safety and effectiveness of REI. From Jun 1, 2023 to August 31, 2023, 6 patients [age: (33.3 ± 17.2) years] with lingual VMs received sclerotherapy of REI and 2-month follow-up. Adverse events and serious adverse events were evaluated, whereas the efficacy of REI was determined by both the traceability of the REI under DSA throughout the entire injection and the therapeutic effect 2 months after a single injection., Results: The REI contains 81.4% ethanol (v/v) and 111.3 mg/ml iodine, which can be traced throughout the injection in the animals and patients. The REI also exerts a similar effect as EtOH on peripheral venous sclerosis, peripheral arterial embolization, and renal embolization. Furthermore, the REI can be metabolized at a similar rate compared to EtOH and Ultravist® and did not cause injury to the animals' heart, liver, spleen, lungs, kidneys and brain. No REI-related adverse effects have occurred during sclerotherapy of VMs, and 4/6 patients (66.7%) have achieved complete response at follow-up., Conclusion: In conclusion, REI is safe, exerts therapeutic effects, and compensates for the radiolucency of EtOH in treating VMs., Trial Registration: The clinical trial was registered as No. ChiCTR2300071751 on May 24 2023., (© 2024. The Author(s).)

Purpose: 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., Competing Interests: Dr Chih-Hung Hsu reports grants from Roche, grants from AstraZeneca, grants from Eli Lilly, grants from Surface Oncology, personal fees from MSD, personal fees from Eisai, outside the submitted work. The authors report no other competing interests in this work., (© 2024 Chen et al.)

In patients with interstitial lung disease (ILD), accurate pattern assessment from their computed tomography (CT) images could help track lung abnormalities and evaluate treatment efficacy. Based on excellent image classification performance, convolutional neural networks (CNNs) have been massively investigated for classifying and labeling pathological patterns in the CT images of ILD patients. However, previous studies rarely considered the three-dimensional (3D) structure of the pathological patterns of ILD and used two-dimensional network input. In addition, ResNet-based networks such as SE-ResNet and ResNeXt with high classification performance have not been used for pattern classification of ILD. This study proposed a SE-ResNeXt-SA-18 for classifying pathological patterns of ILD. The SE-ResNeXt-SA-18 integrated the multipath design of the ResNeXt and the feature weighting of the squeeze-and-excitation network with split attention. The classification performance of the SE-ResNeXt-SA-18 was compared with the ResNet-18 and SE-ResNeXt-18. The influence of the input patch size on classification performance was also evaluated. Results show that the classification accuracy was increased with the increase of the patch size. With a 32 × 32 × 16 input, the SE-ResNeXt-SA-18 presented the highest performance with average accuracy, sensitivity, and specificity of 0.991, 0.979, and 0.994. High-weight regions in the class activation maps of the SE-ResNeXt-SA-18 also matched the specific pattern features. In comparison, the performance of the SE-ResNeXt-SA-18 is superior to the previously reported CNNs in classifying the ILD patterns. We concluded that the SE-ResNeXt-SA-18 could help track or monitor the progress of ILD through accuracy pattern classification., (© 2024. Australasian College of Physical Scientists and Engineers in Medicine.)

Background: Lacosamide is frequently used as a mono- or adjunctive therapy for the treatment of adults with epilepsy. Although lacosamide is known to act on both neuronal and cardiac sodium channels, potentially leading to cardiac arrhythmias, including Brugada syndrome (BrS), its adverse effects in individuals with genetic susceptibility are less understood., Case: We report a 33-year-old female with underlying epilepsy who presented to the emergency department with a four-day history of seizure clusters, and was initially treated with lacosamide therapy. During the intravenous lacosamide infusion, the patient developed sudden cardiac arrest caused by ventricular arrhythmias necessitating resuscitation. Of note, the patient had a family history of sudden cardiac death. Workup including routine laboratory results, 12-lead electrocardiogram (ECG), echocardiogram, and coronary angiogram was non-specific. However, a characteristic type 1 Brugada ECG pattern was identified by ajmaline provocation testing; thus, confirming the diagnosis of BrS. Subsequently, the genotypic diagnosis was confirmed by Sanger sequencing, which revealed a heterozygous mutation (c.2893C>T, p.Arg965Cys) in the SCN5A gene. Eventually, the patient underwent implantable cardioverter-defibrillator implantation and was discharged with full neurological recovery., Conclusion: This case highlights a rare but lethal adverse event associated with lacosamide treatment in patients with genetic susceptibility. Further research is warranted to investigate the interactions between lacosamide and SCN5A variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Shen, Wu, Lin, Chang, Su and Juang.)

Aim: To investigate the continuing education requirements and factors influencing school nurses' needs in relation to medication administration on school campuses., Design: A total of 391 school nurses working in K-12 schools in Taiwan were invited to participate in an online questionnaire survey., Methods: This cross-sectional study employed a probability proportionate to size technique along with a random sampling method. Data were collected from February to April 2023., Results: School nurses reported a significant demand for continuing education and perceived moderate levels of stress and government support related to medication administration. Among the various dimensions, the highest demand was observed for 'definition of campus medication errors' and 'regulations for campus medical orders.' Moreover, the 'identifying drug interactions' and 'adverse drug effects and referrals' dimensions were identified as the most stressful aspects. Notably, perceived stress emerged as the sole predictive factor for continuing education demand, accounting for 16.1% of the variance., Conclusions: The study found that there was a significant demand for and moderate stress related to continuing education among school nurses. Therefore, it is crucial for the government and school nursing organizations to develop targeted programs focusing on medication administration. These initiatives should be designed to enhance nurses' capabilities and reduce their stress, thereby ensuring safe medication administration on campuses., Impact: Continuing education enables school nurses to acquire up-to-date knowledge and improve the workflow in their practice. This study highlights a strong need for education in medication administration with a focus on 'campus medication error definitions' and 'campus medical order regulations.' The government and relevant school nursing organizations should prioritize the development and implementation of continuing education programs to decrease the school nurses' stress related to medication administration., Patient or Public Contribution: No patient or public contribution., Reporting Method: This study adhered to the relevant cross-sectional EQUATOR STROBE guidelines., (© 2023 John Wiley & Sons Ltd.)

The reproductive and endocrine functions of the ovary involve spatially defined interactions among specialized cell populations. Despite the ovary's importance in fertility and endocrine health, functional attributes of ovarian cells are largely uncharacterized. Here, we profiled >18,000 genes in 257 regions from the ovaries of two premenopausal donors to examine the functional units in the ovary. We also generated single-cell RNA sequencing data for 21,198 cells from three additional donors and identified four major cell types and four immune cell subtypes. Custom selection of sampling areas revealed distinct gene activities for oocytes, theca, and granulosa cells. These data contributed panels of oocyte-, theca-, and granulosa-specific genes, thus expanding the knowledge of molecular programs driving follicle development. Serial samples around oocytes and across the cortex and medulla uncovered previously unappreciated variation of hormone and extracellular matrix remodeling activities. This combined spatial and single-cell atlas serves as a resource for future studies of rare cells and pathological states in the ovary.

Background: Stroke centers are critical for the timely diagnosis and treatment of acute stroke and have been associated with improved treatment and outcomes; however, variability exists in the definitions and processes used to certify and designate these centers. Our study categorizes state stroke center certification and designation processes and provides examples of state processes across the United States, specifically in states with independent designation processes that do not rely on national certification., Methods: In this cross-sectional study from September 2022 to April 2023, we used peer-reviewed literature, primary source documents from states, and communication with state officials in all 50 states to capture each state's process for stroke center certification and designation. We categorized this information and outlined examples of processes in each category., Results: Our cross-sectional study of state-level stroke center certification and designation processes across states reveals significant heterogeneity in the terminology used to describe state processes and the processes themselves. We identify 3 main categories of state processes: No State Certification or Designation Process (category A; n=12), State Designation Reliant on National Certification Only (category B; n=24), and State Has Option for Self-Certification or Independent Designation (category C; n=14). Furthermore, we describe 3 subcategories of self-certification or independent state designation processes: State Relies on Self-Certification or Independent Designation for Acute Stroke Ready Hospital or Equivalent (category C1; n=3), State Has Hybrid Model for Acute Stroke Ready Hospital or Equivalent (category C2; n=5), and State Has Hybrid Model for Primary Stroke Center and Above (category C3; n=6)., Conclusions: Our study found significant heterogeneity in state-level processes. A better understanding of how these differences may impact the rigor of each process and clinical performance of stroke centers is worthy of further investigation., Competing Interests: Disclosures Drs Shen and Hsia and M. Feldmeier report grants from the National Institute on Aging, National Institute on Minority Health and Health Disparities, and National Heart, Lung, and Blood Institute. Dr Zachrison reports grants from the National Institute on Aging, Agency for Healthcare Research and Quality, National Institute of Neurological Disorders and Stroke, CRICO, American College of Emergency Physicians, and MGH Executive Committee on Research, employment by Partners Healthcare and Boston Bruins, and compensation from Wolters Kluwer Health, Inc, for other services. Dr Kim reports grant funding from the National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities, the American Heart Association, and Patient-Centered Outcomes Research Institute. Dr Alberts reports grant funding from the National Institute of Neurological Disorders and Stroke, Patient-Centered Outcomes Research Institute, and AstraZeneca.

Background/aim: Numerous studies have reported the over-expression of the radiation-sensitive protein 51 (RAD51) in various types of cancer. However, the role of RAD51 genotypes in lung cancer remains largely unknown. This study aimed to assess the impact of the common variant RAD51 rs1801320 (G-135C) genotypes on the risk of lung cancer in Taiwan., Materials and Methods: The contribution of RAD51 rs1801320 genotypes to lung cancer risk was investigated in a cohort comprising 358 lung cancer patients and 716 age- and sex-matched healthy controls, utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology., Results: The analysis revealed that among the control subjects, the percentages of GG, CG, and CC genotypes of RAD51 rs1801320 were 73.2%, 24.3%, and 2.5%, respectively. Among the lung cancer patients, these percentages were 71.0%, 25.1%, and 3.9%, respectively (p for trend=0.4075). Allelic frequency distributions showed no significant association between the C allele of RAD51 rs1801320 and lung cancer risk determination (p=0.2987). Specifically, the RAD51 rs1801320 CC genotypes were associated with an elevated risk of lung cancer among males [adjusted odds ratio (aOR)=2.28, 95% confidence interval (95%CI)=1.03-4.87] and smokers (aOR=2.93, 95%CI=1.23-5.87), but not among females and non-smokers., Conclusion: The RAD51 rs1801320 CC genotype was identified as a risk factor for elevated lung cancer risk in males and smokers. This genotype may serve as a molecular biomarker at the DNA level for early detection and prediction of lung cancer in Taiwan., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Low doses of brexpiprazole (0.5-2 mg per day) have been tried to treat dementia-related psychosis/agitation and Parkinson's disease psychosis. We report a 71-year-old patient with a diagnosis of probable dementia with Lewy body (DLB) whose psychotic symptoms benefit from a higher dose of brexpiprazole (4 mg per day) without adverse effects. Though more studies were needed to confirm the safety and efficacy of brexpiprazole in the treatment of DLB, this case suggests that brexpiprazole is a potential treatment choice and it is safe even at the maximum daily dose (i.e., 4 mg per day)., Competing Interests: Declaration of Interests: The authors have no conflict of interest to declare., (2024 authors.)

Introduction: The progression patterns, dispositions, and outcomes of patients with advanced hepatocellular carcinoma (HCC) who achieved durable responses with immunotherapy remain poorly characterized., Methods: Patients with advanced HCC who received immune checkpoint inhibitor (ICI)-based immunotherapy and achieved durable responses were retrospectively included. A durable response was defined as partial response (PR) or stable disease (SD) per RECIST 1.1 for more than 8 months after initiation of immunotherapy. Oligoprogression and polyprogression were defined as progression at ≤3 and >3 lesions, respectively., Results: A total of 91 durable responders (63 PR and 28 SD) were identified. The majority had chronic viral hepatitis ( n = 69, 75.8%). Forty-seven (51.6%) and 44 (48.4%) patients received the index immunotherapy as first-line and second- or beyond-line therapy, respectively. Fifty-four (59.3%) patients subsequently developed progression, with a predominant pattern of oligoprogression (66.7%). The median overall survival (OS) was 46.2 months (95% CI: 34.1-58.3). For patients with subsequent progression, employment of locoregional therapy (LRT) for progression was associated with prolonged OS (univariate analysis: hazard ratio [HR] 0.397, p = 0.009; multivariate analysis: HR 0.363, p = 0.050). Patients with oligoprogression who received LRT showed longer median OS than those who did not (48.4 vs. 20.5 months, p < 0.001). In contrast, the median OS of patients with polyprogression who received LRT was not different from those without LRT (27.7 vs. 25.5 months, p = 0.794)., Conclusion: Approximately 60% of the post-immunotherapy durable responders of HCC subsequently develop progression. Proactive LRT may further rescue patients who develop subsequent oligoprogression. Prospective studies are mandatory to clarify the proper management of durable responders with subsequent progression., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Ethnopharmacological Relevance: Achyranthes aspera, a widely recognized medicinal plant, is used in various cultures for treating different ailments, including renal dysfunction; however, there is a lack of comprehensive understanding of its protective effects and the underlying signaling networks involved., Aim of the Study: This study aimed to investigate the molecular mechanisms of the action of A. aspera by employing an integrative approach including functional and tissue imaging as well as comprehensive genomics analysis., Materials and Methods: Cisplatin-induced nephrotoxicity is a well-established animal model for acute kidney injury (AKI). In this study, we investigated the protective effects and underlying mechanisms of the action of A. aspera water-soluble extract (AAW) on a murine model of cisplatin-induced AKI. The evaluation includes measurements of blood urea nitrogen (BUN) and serum creatinine (SCr) levels, histology examination, and transcriptome analysis using RNA sequencing., Results: In male ICR mice, oral administration of AAW at doses of 0.5-1.0 g/kg significantly reduced cisplatin-induced nephrotoxicity. This effect included the amelioration of tubular injury, renal fibrosis, and the lowering of BUN and SCr levels. AAW also effectively decreased oxidative markers, such as malondialdehyde (MDA) and nitrotyrosine (NT), along with inflammation markers, including COX-2, iNOS, NLRP3, and pP65NFκB. Moreover, AAW administration induced a dose-dependent increase in the expression of two protective factors, Nrf2 and BcL2, and suppressed apoptosis, as evidenced by reduced levels of truncated caspase 3 (t-Casp3). To explore the underlying molecular mechanisms and signaling networks, next-generation sequencing (NGS) analysis was employed. The results revealed that AAW mitigated apoptosis, necroptosis, and PANoptosis pathways by inhibiting inflammation signaling pathways, such as the TNFα-, NFκB-, NETs-, and leukocyte transendothelial migration pathways. Additionally, AAW was found to enhance protective signaling pathways, including the cGMP/PKG-, cAMP-, AMPK-, and mTOR-dependent activation of autophagy and mitophagy pathways. The primary bioactive compound found in AAW was identified as 20-hydroxyecdysone (0.36%)., Conclusion: Our study demonstrates that AAW reduces cisplatin-induced nephrotoxicity. The protective effects of AAW are attributed to its modulation of multiple molecular signaling networks. Specifically, AAW downregulates genes and signaling pathways associated with oxidative stress and endoplasmic reticulum (ER) stress, inflammation, and PANoptosis. Simultaneously, it upregulates genes and signaling pathways associated with cell survival, including autophagy and mitophagy pathways., Competing Interests: Declaration of competing interest All authors of this manuscript have made significant contributions to this study, including active participation in the writing process and approval of this submitted version. This research constitutes original work and has not been previously considered for publication in any other journal. We assure you that it will not be submitted elsewhere as long as the Journal of Ethnopharmacology accepts it. Upon acceptance for publication in the Journal of Ethnopharmacology, the worldwide copyright will be transferred to the publisher on behalf of the journal., (Copyright © 2023. Published by Elsevier B.V.)

Aims: This study aims to analyse the worldwide trends in hypertensive heart disease (HHD) mortality and associations with age, period, and birth cohort and predict the future burden of HHD deaths., Methods and Results: Mortality estimates were obtained from Global Burden of Disease 2019 study. We used age-period-cohort (APC) model to examine the age, period, and cohort effects on HHD mortality between 1990 and 2019. Bayesian APC model was utilized to predict HHD deaths to 2034. The global HHD deaths were 1.16 million in 2019 and were projected to increase to 1.57 million in 2034, with the largest increment in low- and middle-income countries (LMICs). Between 1990 and 2019, middle/high-middle socio-demographic index (SDI) countries had the largest mortality reductions (annual percentage change = -2.06%), whereas low SDI countries saw a lagging performance (annual percentage change = -1.09%). There was a prominent transition in the age distribution of deaths towards old-age population in middle/high-middle SDI countries, while the proportion of premature deaths (aged under 60 years) remained at 24% in low SDI countries in 2019. Amongst LMICs, Brazil, China, and Ethiopia showed typically improving trends both over time and in recent birth cohorts, whereas 63 countries including Indonesia, the Philippines, and Pakistan had unfavourable or worsening risks for recent periods and birth cohorts., Conclusion: The HHD death burden in 2019 is vast and is expected to increase rapidly in the next decade, particularly for LMICs. Limited progress in HHD management together with high premature mortality would exact huge human and medical costs in low SDI countries. The examples from Brazil, China, and Ethiopia suggest that efficient health systems with action on improving hypertension care can reduce HHD mortality effectively in LMICs., Competing Interests: Conflict of interest: The authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Lung ultrasound (LUS) and diaphragm ultrasound (DUS) are the appropriate modalities for conservative observation to those patients who are with stable pneumothorax, as well as for the timely detection of life-threatening pneumothorax at any location, due to they are portable, real-time, relatively cost effective, and most important, without radiation exposure. The absence of lung sliding on LUS M-mode images and the abnormality of diaphragmatic excursion (DE) on DUS M-mode images are the most common and novel diagnostic criteria for pneumothorax, respectively. However, visual inspection of M-mode images remains subjective and quantitative analysis of LUS and DUS M-mode images are required., Methods: Shannon entropy of LUS M-mode image (ShanEn LM ) and DE based on the automated measurement (DE AM ) are adapted to the objective pneumothorax diagnoses and the severity quantifications in this study. Mild, moderate, and severe pneumothoraces were induced in 24 male New Zealand rabbits through insufflation of room air (5, 10 and 15, and 25 and 40 mL/kg, respectively) into their pleural cavities. In vivo intercostal LUS and subcostal DUS M-mode images were acquired using a point-of-care system for estimating ShanEn LM and DE AM ., Results: ShanEn LM and DE AM as functions of air insufflation volumes exhibited U-shaped curves and were exponentially decreasing, respectively. Either ShanEn LM or DE AM had areas under the receiver operating characteristic curves [95% confidence interval (CI)] of 1.0000 (95% CI: 1.0000-1.0000), 0.9833 (95% CI: 0.9214-1.0000), and 0.9407 (95% CI: 0.8511-1.0000) for differentiating between normal and mild pneumothorax, mild and moderate pneumothoraces, and moderate and severe pneumothoraces, respectively., Conclusions: Our findings imply that the combination of ShanEn LM and DE AM give the promising potential for pneumothorax quantitative diagnosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-636/coif). All authors report that they received research funding from China Medical University Hospital (grant No. DMR-104-024) and Ministry of Science and Technology of Taiwan (grant No. MOST 109-2221-E-039-001-MY3). The authors have no other conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Suboptimal health status (SHS) is a dynamic state in which people have not been diagnosed with a disease but tend to develop diseases. People with SHS are more prone to conditions such as cardiovascular disease and metabolic syndrome. Suitable interventions in people with SHS can prevent disease development. SHS is correlated with traditional Chinese medicine (TCM)-based constitutions, including Yang-Xu (yang deficiency), Yin-Xu (yin deficiency), and stasis types. The circadian rhythm is a potential biomarker of health and metabolism. Baduanjin exercise, a kind of mind-body exercise, has been regarded to adjust body constitution and metabolism, but few studies have evaluated the effects of Baduanjin exercise on body constitution and circadian rhythms. Therefore, this randomized controlled trial investigated the effects of Baduanjin exercise on body constitution and circadian rhythms in people with SHS., Methods: Seventy-six participants with SHS were divided into the Baduanjin exercise and control groups (watching a Baduanjin video), with the interventions lasting 12 weeks. The Body Constitution Questionnaire (BCQ), SHS Questionnaire-25 (SHSQ-25), and actigraphy for circadian rhythm measurement were conducted., Results: The scores of SHSQ-25, Yang-Xu, Yin-Xu, and BCQ stasis decreased significantly after 12 weeks in the Baduanjin exercise group, but not in the control group. Interdaily stability of the circadian rhythm increased significantly in the Baduanjin exercise group but not in the control group., Conclusion: This is the first report of improved health status, modulated body constitution, and increased interdaily stability of the circadian rhythm in participants with SHS who practiced Baduanjin exercise., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Introduction: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown., Methods: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed., Results: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35-1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12-0.85; p = 0.013)., Conclusion: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objective: Although pulmonary rehabilitation and regular exercise have improved negative emotions and cognitive capacity within cases of chronic obstructive pulmonary disease (COPD), influence by exercise training upon different cognitive and memory functions in COPD is still controversial. This investigation aimed to assess whether cognitive performance and mental health are affected by the benefits of exercise training within cases of COPD., Materials and Methods: This pilot investigation included thirty-three patients with Global Initiative for Chronic Obstructive Lung Disease stage ≥B. Based on the subjects' rights, all included patients could choose to join either the exercise group or the control group, according to their free will. Twelve patients were assigned to receive exercise treatment over a 2-month period, while the remaining 16 patients were assigned to the control group. Cognitive capacity outcomes were measured using the Wechsler Memory Scale-III Word List Test, Stroop task, and psychomotor vigilance task (PVT). Mood states were assessed through the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI)., Results: Most cases demonstrated major improvement for BDI and BAI scorings post-60-day therapy. During PVT, the omission rate decreased, while the hit rate increased, indicating an improvement in attention performance. Furthermore, this investigation found a significant increase in immediate verbal and recognition memory for word-list test. However, no major performance shifts were found on Stroop analysis., Conclusion: This investigation demonstrated that a 2-month exercise training program resulted in significant improvement in negative emotions, immediate memory, recognition memory, and attention., Competing Interests: Dr. En-Ting Chang, an editorial board member at Tzu Chi Medical Journal, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper., (Copyright: © 2023 Tzu Chi Medical Journal.)

In the present study, the undescribed schitriterpenoids, kadsujanonols A-I (1-9), and eleven reported compounds (10-20) were isolated from K. japonica L. vines. Their structures of 3,4-seco-schitriterpenoids were elucidated mainly by spectroscopic analyses including 1 H-, 13 C-, and 2D-NMR, IR, HRESIMS spectra. The spatial configurations were determined by the single-crystal X-ray diffraction analysis of kadsujapnonol A (1), 15, 17, and 18, CD data and computational analysis. Furthermore, all isolates were evaluated for the anti-neuroinflammatory activity on LPS-stimulated NO production in BV2 microglial cells and compounds 2, 4, 5, 7, 9, 11, 13-16, and 18 exposed better or comparable suppression abilities than PDTC. Among them, kadlongilactone B (14) showed the best significant inhibiting ability (IC 50  = 0.87 μg/mL) and the effect is through the attenuation of the inflammatory transcription factor p65NF-κB. Preliminary structure-activity relationship revealed that δ-lactone at the side chain and 7-member lactone at C-3/C-4, and 3,4:9,10 ring opening are important., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: We have read and understood the BMJ policy on declaration of interests and declare no competing financial interests.