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Jinhun Park,1 Yu-Cheol Lim,2 Deok-Sang Hwang,3 In-Hyuk Ha,2 Ye-Seul Lee2 1Department of Internal Medicine, Jaseng Hospital of Korean Medicine, Seoul, Republic of Korea; 2Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea; 3Department of OB & GY in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of KoreaCorrespondence: In-Hyuk Ha; Ye-Seul Lee, Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, 2F, 540 Gangnam-daero, Gangnam-gu, Seoul, 06110, Republic of Korea, Tel +82-2-2222-2740, Fax +82-2-2222-2737, Email hanihata@gmail.com; yeseul.j.lee@gmail.comPurpose: This study is a retrospective, cross-sectional study aiming to present basic data on the treatment modalities and cost of care for primary dysmenorrhea (PD) by analyzing healthcare utilization and patient distributions using the 2010 to 2018 Health Insurance Review and Assessment Service (HIRA) data.Patients and Methods: We used the HIRA-National Patient Sample (NPS) data to analyze medical service utilization for PD (ICD-10 code: N94.4, N94.6) in Western medicine (WM) or Korean medicine (KM) care between January 2010 and December 2018.Results: There were 41,139 patients diagnosed with PD who utilized Western medicine (WM) or Korean medicine (KM) care at least once during the study period. The number of claims and patients steadily rose over the years from 7430 claims for 3989 patients in 2010 to 11,523 claims for 6226 patients in 2018. The predominant age group was 15 to 24 years. Regarding the frequency of service categories for PD in the claims, consultation was the most common and costly service category in WM (72,120 cases, 47.89%; 631,912 USD, 69.74%), while injection and analogous treatments was the most common and costly service category in KM (97,157 cases, 72.41%; 314,696 USD, 55.86%). Regarding the drug prescriptions, nonsteroidal anti-inflammatory drugs (NSAIDs) (26,617 cases, 40.47%) were the most frequently prescribed drug for PD in pharmacies and hospitals.Conclusion: The result shows an annual increase in healthcare utilization for PD with the fastest rate in individuals aged 15 to 24 years. This study provides data on the current utilization of WM and KM care for PD for policymakers. Furthermore, we analyzed the frequency and cost of common treatment modalities in WM and KM, which would be useful data for clinicians and researchers.Keywords: primary dysmenorrhea, healthcare administrative claims, health care costs, medical use

Pre-procedural ultrasound scanning has been used to facilitate spinal anaesthesia in patients with difficult anatomical landmarks and shown to improve first-attempt success rates in some studies. We studied whether pre-procedural ultrasound scanning improved first-attempt success rate and decreased time taken for the procedure in the general adult population. In this prospective, randomised controlled trial, 170 American Society of Anesthesiologists 1 to 3 patients aged between 21 and 80 years were recruited. Informed consent was obtained. Patients were randomised into two groups, ultrasound-guided identification of landmarks (Ultrasound Group) and manual palpation of landmarks (Manual Palpation Group). The primary outcome was first-attempt success rate and secondary outcomes were time taken to perform procedure, number of needle redirections, patient satisfaction and complications. The first-attempt success rate was 64% in the Ultrasound Group and 52% in the Manual Palpation Group (P=0.16). Time taken for procedure was shorter in the Ultrasound Group compared to the Manual Palpation Group (2.9±3.6 minutes versus 3.9±3.7 min, P= 0.007). Patient satisfaction was higher in the Ultrasound Group. There were no differences in complications. As there was no statistically significant difference in first-attempt success rates between the two groups, existing evidence for routine pre-procedural scanning for all patients is inadequate. The current use of pre-procedural ultrasound scanning will probably be limited to selected patients where spinal anaesthesia may be technically challenging with conventional methods. [ABSTRACT FROM AUTHOR]

C-peptide is a bioactive peptide with a potentially protective role in diabetes complications; however, its molecular mechanism of protection against cardiovascular damage caused by hyperglycemia-induced apoptosis remains unclear. We investigated the protective mechanism of C-peptide against hyperglycemia-induced apoptosis using human umbilical vein endothelial cells and streptozotocin diabetic mice. High glucose (33 mmol/L) induced apoptotic cell death in endothelial cells via sequential elevation of intracellular Ca(2+) and reactive oxygen species (ROS) as well as subsequent activation of transglutaminase 2 (TG2). C-peptide (1 nmol/L) prevented endothelial cell death by inhibiting protein kinase C- and NADPH oxidase-dependent intracellular ROS generation and by abolishing high glucose-induced TG2 activation, without affecting intracellular Ca(2+) levels. Consistently, in the aorta of streptozotocin diabetic mice, hyperglycemia stimulated transamidating activity and endothelial cell apoptosis that was inhibited by C-peptide replacement therapy (35 pmol/min/kg) using osmotic pumps (control and diabetes, n = 8; diabetes + C-peptide, n = 7). In addition, C-peptide prevented hyperglycemia-induced activation of transamidation activity and apoptosis in the heart and renal cortex of streptozotocin diabetic mice. Thus, C-peptide protects endothelial cells from hyperglycemia-induced apoptotic cell death by inhibiting intracellular ROS-mediated activation of TG2. Furthermore, TG2 may be a promising avenue of therapeutic investigation to treat diabetic vasculopathies. [ABSTRACT FROM AUTHOR]

Skip metastasis, referred to as leaping metastasis to the lateral neck without associated lymphadenopathy in the central compartment (level VI), can occur in patients with papillary thyroid carcinoma (PTC). However, there have been few studies on its predictive value in PTC patients. We reviewed the medical records of 90 patients who underwent simultaneous central and lateral neck lymph node dissection for the primary treatment of lymph node metastasis in the lateral neck of PTC patients. No patient was suspected of having metastasis in the central compartment by preoperative imaging study. The frequency of skip metastasis to the lateral neck compartment without central neck metastasis was 19% (17/90). The number of metastatic lymph nodes dissected in the lateral neck of patients with and without skip metastasis was 5.1±2.7 and 9.5±2.6, respectively (P<0.001). Skip metastasis was closely associated with significantly fewer lymphovascular invasion (P=0.009) and extracapsular spread (P=0.035). Skip metastasis can occur significantly frequently in PTC patients. The presence of lymphovascular invasion, extracapsular spread, and number of positive lymph nodes dissected were inversely correlated with skip metastasis. [ABSTRACT FROM AUTHOR]

To evaluate treatment outcomes and the role of primary definitive surgery for T(1-2), clinically N(0) oropharyngeal squamous cell carcinoma (OPSCC) patients, we performed a retrospective analysis of 46 consecutive cases treated primarily by surgery and/or postoperative radiotherapy at Yonsei University between May 1992 and December 2006. Twelve patients were T(1) and 34 were T(2). The most common location was the tonsil (54%), followed by the soft palate (19%), the base of the tongue (BOT) (15%) and the posterior wall (12%). Occult lymph node metastasis was noted in 12 cases (26%). Seventeen patients (37%) received adjuvant radiotherapy. The 5-year disease-specific survival rate (DSSR) was 83%: 100% for clinical stage I (T(1)N(0)) and 74% for clinical stage II (T(2)N(0)). The 5-year DSSR of patients with surgery alone was 86%. Thirteen of 14 patients (93%) treated with conservative surgery alone without mandible-splitting or adjuvant radiotherapy attained disease-free status. In addition, 25 of 40 patients (63%) with disease-free status were treated with surgery alone. Almost 30% of all patients may be candidates for adjuvant chemotherapy through histopathologic analysis according to the National Comprehensive Cancer Network (2007) guidelines. The results of the present study demonstrate excellent oncologic outcomes with primary surgery for the treatment of early-stage OPSCC and suggest that surgery offers the best opportunity to identify patients in whom adjuvant radio- or chemotherapy may be most appropriately applied. [ABSTRACT FROM AUTHOR]

In recent studies, green tea components have been shown to induce cell growth arrest and apoptosis in head and neck squamous cell carcinoma (HNSCC) cells. In this report, we have investigated the effects of epicatechin gallate (ECG), one of the catechins in green tea, on anti-cancer activity in vitro. We found that cyclin D1 was highly expressed in HNSCC cells, and ECG suppressed 90% of cyclin D1 expression in SCC7 cells. We have also evaluated the effect of ECG on cell growth and apoptosis, showing that ECG (50 microM) exhibited a significant inhibition (50%) on the growth of SCC7 cells via G1 cell cycle arrest. ECG suppressed cyclin D1 in SCC7 cells in a dose- and time-dependent manner, and the suppression of the beta-catenin pathway by ECG is one of the mechanism to facilitate ECG-induced cell growth arrest. These results suggest that ECG has a potential usage as a chemopreventive agent in HNSCC. [ABSTRACT FROM AUTHOR]

Microplastics (MPs) pose risks to both aquatic ecosystems and human health. This study investigated MPs in the shells and soft tissues of hard clams (Meretrix taiwanica) cultured in the inland waters of Taiwan. This study further developed two novel risk indices for assessing the potential ecological and health consequences of MPs. Moreover, the metal concentrations in the clam's soft tissues and the associated consumption health risks were investigated. Clamshells contained significant amounts of MPs with an average abundance of 16.6 ± 6.9 MPs/ind., which was higher than in the soft tissues (2.7 ± 1.7 MPs/ind.). The distribution and sizes of MPs in shells and soft tissues were similar, primarily small-sized (<2 mm, >99 %), blue (>65 %), and fibrous (>99 %). Dominant MP polymer types included rayon (83.5 %), polyethylene terephthalate (11.8 %), and polyacrylonitrile (3.6 %). The proposed MP potential ecological risk index indicates a higher potential ecological MP risk in soft tissues (302-423) than in shells (270-278) of the clams. The MP potential hazard risk index showed that the risk of exposure to MP through shellfish consumption decreased with age. The total hazard index (THI) value suggested negligible health hazards from metal exposure through shellfish consumption. Moreover, there was no significant correlation between MPs and metal concentrations in soft tissues, suggesting that metals bound to MPs contribute minimally to the total accumulated metals in clam's soft tissues. This study confirms the presence of MPs in clam shells and provides a novel tool to assess the potential ecological and health risks associated with MPs in shellfish., 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 © 2024 Elsevier B.V. All rights reserved.)

The impact of polycyclic aromatic hydrocarbons (PAHs) on the marine food web is crucially understudied in the primary trophic system. We evaluated the seasonal dynamics of PAHs in microplankton in a polluted environment (Taiwan), northeastern South China Sea. Replicate size-fractionated microplankton (55-1000 μm) were freeze-dried, and PAHs were extracted with a 1:1 v/v ratio of acetone: n-hexane, then analyzed using GC-MS. Total PAHs ranged between 68 and 2548 ng/g dw in microplankton, greatest during spring (130-2548 ng/g), followed by autumn (135-772 ng/g) and summer (44-423 ng/g). Spatial distribution varied through seasons but was higher in the southern part (S6 > S4 > S5 > S2 > S3 > S1 > S7), dominated by higher-ring PAHs from mixed pyrogenic and petrogenic sources. PAHs are significantly correlated with environmental factors, especially in colder seasons and lower salinity areas. Suspended matter and plankton influenced PAH transport and partitioning seasonally. Plankton's PAHs seasonal changes and environmental influences are revealed in an anthropic environment., 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 © 2024 Elsevier Ltd. All rights reserved.)

Marine organisms, especially top predators such as sharks, are susceptible to environmental pollutants like microplastics (MPs) and phthalate esters (PAEs), leading to ecosystem risks. Research on contamination in these apex species is, however, still limited. This study investigated MPs and PAEs in multiple shark species (Isurus oxyrinchus, Alopias superciliosus, Alopias pelagicus, Carcharhinus brevipinna, and Sphyrna zygaena) off Taiwan's eastern coast. Gastric tissue analyses revealed ubiquitous microplastics (2-31 particles), which positively correlated with body lengths and weights for Isurus oxyrinchus. Blue, fiber-shaped (1-2 mm), and rayon-based MPs are likely associated with textile fiber pollution. The PAEs concentration mean was 7035 ± 6829 ng/g, ww, having DEHP and DiNP as primary compounds. This study highlights pervasive contamination in Pacific Ocean sharks, emphasizing anthropogenic impact on top oceanic predators and providing essential insights for food safety and MP accumulation., 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 © 2024 Elsevier Ltd. All rights reserved.)

Cardiovascular disease (CVD) caused substantial morbidity among occupationally active populations. However, data regarding the longitudinal burden of CVD were limited, particularly among school teachers. The objectives of our study were to estimate the incidence rate of CVD and determine its predictors among school teachers in Peninsular Malaysia through a prospective cohort study. We followed 14,046 eligible school teachers recruited between 2013 and 2014 until 31st December 2021. We accessed three computerised, country-level registries to determine incident CVD cases during the study period from 2013 to 2021. Baseline sociodemographic, lifestyle, work-related and clinical characteristics were recorded. Cox proportional hazard regression models with adjusted hazard ratio and 95% confidence interval were reported. With a median follow-up of 7.71 yr, we observed 209 incident CVD cases (or 195.7 CVD cases per 100,000 person-years). Male gender, age ≥40 yr old, Indian or others ethnicity (as compared to Chinese), family history of CVD, laboratory-confirmed diabetes mellitus, self-reported hypertension, high low-density lipoprotein cholesterol and high triglyceride were predictors for incident CVD among school teachers. Neither work-related nor lifestyle factors were significantly associated with incident CVD. Screening at-risk teachers for diabetes mellitus, hypertension or dyslipidemia is recommended to delay the onset or progression of CVD.

Background: Xerostomia is a pathological condition characterized by decreased salivation due to salivary gland dysfunction and is frequently attributed to irreversible damage as a side effect of radiation therapy. Stem cell-derived organoid therapy has garnered attention as a promising avenue for resolving this issue. However, Matrigel, a hydrogel commonly used in organoid culture, is considered inappropriate for clinical use due to its undefined composition and immunogenicity. In this study, we aimed to develop a method for culturing collagen-based human salivary gland organoids (hSGOs) suitable for clinical applications and evaluated their therapeutic effectiveness., Methods: Human salivary gland stem cells were isolated from the salivary gland tissues and cultured in both Matrigel and collagen. We compared the gene and protein expression patterns of salivary gland-specific markers and measured amylase activity in the two types of hSGOs. To evaluate the therapeutic effects, we performed xenogeneic and allogeneic transplantation using human and mouse salivary gland organoids (hSGOs and mSGOs), respectively, in a mouse model of radiation-induced xerostomia., Results: hSGOs cultured in Matrigel exhibited self-renewal capacity and differentiated into acinar and ductal cell lineages. In collagen, they maintained a comparable self-renewal ability and more closely replicated the characteristics of salivary gland tissue following differentiation. Upon xenotransplantation of collagen-based hSGOs, we observed engraftment, which was verified by detecting human-specific nucleoli and E-cadherin expression. The expression of mucins, especially MUC5B, within the transplanted hSGOs suggested a potential improvement in the salivary composition. Moreover, the allograft procedure using mSGOs led to increased salivation, validating the efficacy of our approach., Conclusions: This study showed that collagen-based hSGOs can be used appropriately in clinical settings and demonstrated the effectiveness of an allograft procedure. Our research has laid the groundwork for the future application of collagen-based hSGOs in allogeneic clinical trials., (© 2024. The Author(s).)

This study examined the sediment metal fractions and availability to infer bioaccumulation in marine harbor benthic organisms. Total metals were analyzed using atomic absorption spectrometry and inductively coupled plasma-optical emission spectrometry for chemical fractions and organisms. The results showed similar metal concentrations and distribution driven by rivers and harbor pollution. We found significant differences in metal accumulation in marine benthic groups, highest in scavenger species. Their metal concentrations in decreasing order were 1.97-4568, 0.10-1260, 1.64-159, and 0.105-112 μg g -1 dw for hermit crabs, forams, bivalves, and polychaetes. Moreover, certain organisms, such as tusk shells, sea pens, bivalves, forams, and isopods, may exhibit selective metal accumulation. Biota-sediment accumulation factors (>1) were highest for essential metals like Cu, Zn, and Mn, while toxic metals like As, Cr, Co, and Ni increased. This concurrent assessment provides more comprehensive data for metal bioaccumulation in marine benthic ecosystems., 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 © 2024 Elsevier Ltd. All rights reserved.)

Objective: The use of reconstructive treatment with a double-overlapping stents has proven to be effective and safe in the current treatment of intracranial vertebral artery dissecting aneurysms (VADAs). We employed a combination of overlapping stents, using low-profile visualized intraluminal support (LVIS) within the Enterprise stent. This combination was chosen to minimize the outward bulging of the inner LVIS by overlapping it with the Enterprise stent while maintaining flow diversion and stability. This study aimed to evaluate the clinical and angiographic outcomes following the use of double-overlapping stents with LVIS within the Enterprise stent for the treatment of VADAs., Methods: From March 2016 to January 2022, total 28 patients with unruptured VADAs were treated with the double-overlapping stent technique using LVIS within an Enterprise stent in our institute. The Enterprise stent was deployed first, followed by the LVIS stent. Patient clinical and angiographic characteristics, procedural complications, and follow-up outcomes were retrospectively reviewed., Results: All 28 patients (18 males and 10 females) were successfully treated with double-overlapping stent deployment. There were no procedural complications or new neurological deficits in any patient. Of the 28 patients, four VADAs had posterior inferior cerebellar artery involvement. Procedure-related parent artery occlusion did not occur during the angiographic follow-up conducted 6 to 12 months after the procedure. Out of 28 patients, 24 showed complete healing, three had focal residual stenosis or dilatation with residual sac and only one had a residual dissecting flap with aneurysm. All patients, including the four patients, did not require any additional procedures. The postoperative modified Rankin scale scores were 0-1 for all patients., Conclusion: A double-overlapping stent, with a flow-diversion effect, is a safe and effective treatment for patients with VADAs. In particular, when using the LVIS stent within an Enterprise stent, it minimizes the bulging of the inner LVIS stent while maintaining flow diversion and stability. Therefore, both can be effectively utilized as overlapping stents.

Background Malaysia has been one of the most prominent destination countries for medical tourism. The industry received significant government support to create a conducive environment for its growth, such as the provision of an investment tax allowance for the facilities participating in medical tourism and the establishment of the Malaysia Healthcare Travel Council (MHTC) to coordinate collaboration between various industry stakeholders to promote medical tourism activities at the international level and facilitate inbound medical tourists. The establishment of the MHTC facilitates collaboration between various industry stakeholders. In addition to facilitating medical tourism activities, MHTC is also involved in analysing relevant data, including but not limited to the socio-demography of medical tourists, the trend of their healthcare service utilisation, revenue generated, and market intelligence to promote the industry's growth. The council serves as a medium to facilitate the collaboration of stakeholders such as the hospitals participating in medical tourism, the Association of Private Hospitals Malaysia, the Malaysian Society for Quality in Health, and various government agencies, including the Ministry of Health and the Department of Immigration, Malaysia. We explore the policy-related implications of medical tourism and its relationship with the Malaysian national healthcare system. Methodology We revisited Pocock and Phua's conceptual framework of policy implications for medical tourism to explore its relevance after more than a decade of intensive government support and the aftermath of the COVID-19 pandemic. We employed a qualitative case study design using semi-structured, in-depth interviews with stakeholders from the Ministry of Health Malaysia, the private health sector, professional bodies, academics, and health-related civil society organisations. Results Our study found that many issues identified in the original framework remain relevant after over a decade. However, we also identified additional implications, such as the role of insurance portability in encouraging the growth of international hospital accreditation and the issue of equitable access to healthcare within the context of the current Malaysian healthcare system in the aftermath of COVID-19. Conclusion Due to its vulnerability, there is a need to develop a strategic collaboration that includes incorporating medical tourism activities into a broader framework, such as promoting aged care within the retirement destinations package for expatriates, which could ensure its sustainability instead of relying solely on medical tourism activities. In the meantime, policy implications arising from the industry remain relevant and should be addressed through a comprehensive structural reform of the national healthcare system involving stakeholders from the public and private health sectors., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Medical Research and Ethics Committee of the Ministry of Health Malaysia issued approval NMRR-19-2888-45815. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Samsudin et al.)

This study investigates CD151, a protein linked to cancer progression, in non-small cell lung cancer (NSCLC) patients without epidermal growth factor receptor (EGFR) mutations. These patients often have limited treatment options. The study used retrospective analysis to examine 157 adenocarcinoma biopsy specimens and 199 patient cases from The Cancer Genome Atlas, correlating CD151 expression with patient survival. Cellular studies revealed that CD151 interacts with EGFR, influencing epidermal growth factor (EGF)-induced cell proliferation and the effectiveness of the EGFR inhibitor, erlotinib. A strong association was found between CD151 expression and EGFR mutation status. High CD151 expression in the absence of EGFR mutations is correlated with poorer survival outcomes. Biological assays showed that CD151 colocalizes and associates with EGFR, playing a crucial role in regulating EGF-induced cell proliferation via the AKT and ERK1/2 pathways. Importantly, CD151 expression was found to influence the anti-proliferative effects of the EGFR tyrosine kinase inhibitor, erlotinib. High CD151 expression, in the absence of EGFR mutations, was associated with poorer survival outcomes. It could serve as a potential prognostic marker and influence cellular responses to EGFR-targeted treatments. This study highlights CD151 as a potential novel target for therapeutic intervention in NSCLC, especially in populations lacking EGFR mutations., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Objective: Gamma Knife radiosurgery (GKRS) is an effective and noninvasive treatment for high-risk arteriovenous malformations (AVMs). Since differences in GKRS outcomes by nidus type are unknown, this study evaluated GKRS feasibility and safety in patients with brain AVMs., Methods: This single-center retrospective study included patients with AVM who underwent GKRS between 2008 and 2021. Patients were divided into compact- and diffuse-type groups according to nidus characteristics. We excluded patients who performed GKRS and did not follow-up evaluation with magnetic resonance imaging or digital subtraction angiography within 36 months from the study. We used univariate and multivariate analyses to characterize associations of nidus type with obliteration rate and GKRS-related complications., Results: We enrolled 154 patients (mean age, 32.14±17.17 years; mean post-GKRS follow-up, 52.10±33.67 months) of whom 131 (85.1%) had compact- and 23 (14.9%) diffuse-type nidus AVMs. Of all AVMs, 89 (57.8%) were unruptured, and 65 (42.2%) had ruptured. The mean Spetzler-Martin AVM grades were 2.03±0.95 and 3.39±1.23 for the compact- and diffuse-type groups, respectively (p<0.001). During the follow-up period, AVM-related hemorrhages occurred in four individuals (2.6%), three of whom had compact nidi. Substantial radiation-induced changes and cyst formation were observed in 21 (13.6%) and one patient (0.6%), respectively. The AVM complete obliteration rate was 46.1% across both groups. Post-GKRS complication and complete obliteration rates were not significantly different between nidus types. For diffuse-type nidus AVMs, larger AVM size and volume (p<0.001), lower radiation dose (p<0.001), eloquent area location (p=0.015), and higher Spetzler-Martin grade (p<0.001) were observed., Conclusion: GKRS is a safe and feasible treatment for brain AVMs characterized by both diffuse- and compact-type nidi.

Study Objective: We previously designed and validated a virtual reality-based simulator to help train novices in ultrasound-guided needling skills necessary for safe and competent ultrasound-guided regional anaesthesia. This study was designed to compare the performance and error rates of novices trained by a human faculty aided with the assistance of this virtual reality simulator (virtual reality-assisted training), versus novices trained wholly by humans (conventional training)., Design, Setting, and Participants: In this single centre, randomised controlled study, we used a standardised teaching protocol, rigorous blinding, iterative training of assessors, and validated global rating scale and composite error score checklists to assess skills learning of novice participants., Main Results: We recruited 45 novices and scored 270 assessments of performance and error rates. Inter-rater correlation coefficient of reliability of scoring between assessors for the global rating scale was 0.84 (95%CI 0.68-0.92) and for the composite error score checklist was 0.87 (95%CI 0.73-0.93). After adjustment for age, sex, Depression, Anxiety and Stress-21, and baseline score, there was no statistical difference for virtual reality-assisted training compared to conventional training in final global rating score (average treatment effect -3.30 (95%CI-13.07-6.48), p = 0.51) or in the final composite error score (average treatment effect 1.14 (95%CI -0.60-2.88), p = 0.20). Realism in the virtual reality simulator was similar to real-life when measured by the Presence Questionnaire, all components p > 0.79; and task workload assessed by the NASA-Task Load Index was not statistically different between groups, average treatment effect 5.02 (95%CI -3.51-13.54), p = 0.25. Results were achieved in the virtual reality-assisted group with half the human faculty involvement., Conclusion: Novices trained using a hybrid, virtual reality-assisted teaching program showed no superiority to novices trained using a conventional teaching program, but with less burden on teaching resources., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Adult humans cannot regenerate the enamel-forming cell type, ameloblasts. Hence, human induced pluripotent stem cell (hiPSC)-derived ameloblasts are valuable for investigating tooth development and regeneration. Here, we present a protocol for generating three-dimensional induced early ameloblasts (ieAMs) utilizing serum-free media and growth factors. We describe steps for directing hiPSCs toward oral epithelium and then toward ameloblast fate. These cells can form suspended early ameloblast organoids. This approach is critical for understanding, treating, and promoting regeneration in diseases like amelogenesis imperfecta. For complete details on the use and execution of this protocol, please refer to Alghadeer et al. 1 ., Competing Interests: Declaration of interests A.A., A.P.P., J.M., and H.R.-B. are co-inventors on a patent application entitled “A Method to Direct the Differentiation of Human Induced Pluripotent Stem Cells into Early Ameloblasts” (PCT/US2022/053517 filed 12/20/2022)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Moyamoya disease (MMD) is a rare chronic cerebrovascular disease, and the outcomes of bypass management in adult patients remain controversial., Objective: To categorize adult MMD based on asymptomatic, ischemic, and hemorrhagic onset and compare the outcomes (death, hemorrhagic stroke [HS], and ischemic stroke [IS]) of bypass surgery (direct or indirect) with those of conservative management., Design, Setting, and Participants: This retrospective, nationwide, population-based longitudinal cohort study used Korean National Health Insurance Research data to identify adults (aged ≥15 years) with MMD who were diagnosed between January 1, 2008, and December 31, 2020, and followed up until December 31, 2021 (median follow-up, 5.74 [IQR, 2.95-9.42] years). A total of 19 700 participants (3194 with hemorrhagic, 517 with ischemic, and 15 989 with asymptomatic MMD) were included. Data were analyzed from January 2 to April 1, 2023., Exposures: Bypass surgery and conservative management., Main Outcomes and Measures: Death constituted the primary outcome; secondary outcomes consisted of HS or IS. Kaplan-Meier survival curve and Cox proportional hazards regression analysis were applied. The propensity score-matching and stratified analyses were performed to control covariate effects., Results: A total of 19 700 patients (mean [SD] age, 45.43 [14.98] years; 12 766 [64.8%] female) were included. Compared with conservative management, bypass was associated with a reduced risk of death (adjusted hazard ratio [AHR], 0.50 [95% CI, 0.41-0.61]; P < .001) and HS (AHR, 0.36 [0.30-0.40]; P < .001) in hemorrhagic MMD; reduced risk of IS (AHR, 0.55 [95% CI, 0.37-0.81]; P = .002) in ischemic MMD; and reduced risk of death (AHR, 0.74 [95% CI, 0.66-0.84]; P < .001) in asymptomatic MMD. However, bypass was associated with an increased risk of HS (AHR, 1.76 [95% CI, 1.56-2.00]; P < .001) in asymptomatic MMD. Both direct and indirect bypass demonstrated similar effects in hemorrhagic and asymptomatic MMD, except only direct bypass was associated with a reduced risk of IS (AHR, 0.52 [95% CI, 0.33- 0.83]; P = .01) in ischemic MMD. After stratification, bypass was associated with a reduced risk of death in patients younger than 55 years with ischemic (AHR, 0.34 [95% CI, 0.13- 0.88]; P = .03) and asymptomatic (AHR, 0.69 [95% CI, 0.60-0.79]; P < .001) MMD, but an increased risk of HS in patients 55 years or older with ischemic MMD (AHR, 2.13 [95% CI, 1.1-4.16]; P = .03)., Conclusions and Relevance: The findings of this cohort study of bypass outcomes for patients with MMD emphasize the importance of tailoring management strategies in adult patients based on onset types.

Background: Transdural collaterals, originating mainly from the extracalvarial superficial temporal artery and intracalvarial middle meningeal artery via the external carotid artery (ECA), have been observed after revascularisation surgery. However, the origin of these collaterals in patients with stroke with perfusion insufficiency is not yet known. Therefore, we studied the revascularisation patterns and characteristics based on the origin of these collaterals., Methods: We employed erythropoietin pretreatment and performed multiple burr holes under local anaesthesia to achieve transdural revascularisation in patients with acute stroke with perfusion insufficiency. After 6 months, we reassessed the transfemoral cerebral angiography to evaluate the revascularisation patterns. The collaterals were categorised into intracalvarial ECA-dominant (originating from the middle meningeal artery), extracalvarial ECA-dominant (originating from the superficial temporal or occipital artery) and balanced groups. We compared various imaging parameters among these groups., Results: Overall, 87 patients with 103 treated hemispheres were involved. Among them, 57.3% were classified as intracalvarial ECA-dominant, 20.4% as extracalvarial ECA-dominant and 22.3% as balanced. Most of the hemispheres with intracalvarial or extracalvarial collaterals (vs balanced collaterals) showed successful revascularisation (78/80 (97.5%) vs 12/23 (52.1%)), p<0.001). In ultrasonographic haemodynamic changes according to revascularisation pattern, only the intracalvarial ECA-dominant revascularisation was significantly associated with specific changes in ECA blood flow, leading to the conversion to a low-resistance ECA Doppler sonography waveform., Conclusions: Our findings suggest that intracalvarial ECA-dominant revascularisation plays a crucial role in the formation of transdural collaterals following combined therapy. These distinct changes in ECA haemodynamics can be non-invasively identified through bedside ultrasound studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 µM against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg/kg/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.

Introduction: Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) mortality remains high despite revascularization and the use of the intra-aortic balloon pump (IABP). Advanced mechanical circulatory support (MCS) devices, such as catheter-based ventricular assist devices (cVAD), may impact mortality. We aim to identify predictors of mortality in AMI-CS implanted with IABP and the proportion eligible for advanced MCS in an Asian population. Methods: We retrospectively analyzed a cohort of Society for Cardiovascular Angiography and Intervention (SCAI) stage C and above AMI-CS patients with IABP implanted from 2017-2019. We excluded patients who had IABP implanted for indications other than AMI-CS. Primary outcome was 30-day mortality. Binary logistic regression was used to calculate adjusted odds ratios (aOR) for patient characteristics. Results: Over the 3-year period, 242 patients (mean age 64.1 ± 12.4 years, 88% males) with AMI-CS had IABP implanted. 30-day mortality was 55%. On univariate analysis, cardiac arrest ( p < 0.001), inotrope/vasopressor use prior to IABP ( p = 0.004) was more common in non-survivors. Non-survivors were less likely to be smokers ( p = 0.001), had lower ejection fraction, higher creatinine/ lactate and lower pH (all p < 0.001). On multi-variate analysis, predictors of mortality were cardiac arrest prior to IABP (aOR 4.00, CI 2.28-7.03), inotrope/vasopressor prior to IABP (aOR 2.41, CI 1.18-4.96), lower arterial pH (aOR 0.02, CI 0.00-0.31), higher lactate (aOR 2.42, CI 1.00-1.19), and lower hemoglobin (aOR 0.83, CI 0.71-0.98). Using institutional MCS criteria, 106 patients (44%) would have qualified for advanced MCS. Conclusions: Early mortality in AMI-CS remains high despite IABP. Many patients would have qualified for higher degrees of MCS.

Background: Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.) injection of TT causes vascular disruption with concomitant tumor ablation in several preclinical models of cancer, in addition to various (sub)cutaneous tumors presenting in the veterinary clinic. TT has completed Phase I dose escalation trials, with some patients showing signs of abscopal effects. However, the exact molecular details underpinning its mechanism of action (MoA), together with its immunotherapeutic potential in oncology remain unclear., Methods: A combination of microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP assays, phagocytosis assays and mixed lymphocyte reactions were used to probe the MoA of TT in vitro. In vivo studies with TT used MM649 xenograft, CT-26 and immune checkpoint inhibitor refractory B16-F10-OVA tumor bearing mice, the latter with or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb treatment. The effect of TT at injected and non-injected tumors was also assessed., Results: Here, we show that TT induces the death of endothelial and cancer cells at therapeutically relevant concentrations via a caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate that TT acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading to unfolded protein response mt/ER upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis. Consistent with binding to ER membranes, we found that TT treatment promoted activation of the integrated stress response together with the release/externalization of damage-associated molecular patterns (HMGB1, ATP, calreticulin) from cancer cells in vitro and in vivo, characteristics indicative of immunogenic cell death (ICD). Confirmation of ICD in vivo was obtained through vaccination and rechallenge experiments using CT-26 colon carcinoma tumor bearing mice. Furthermore, TT also reduced tumor volume, induced immune cell infiltration, as well as improved survival in B16-F10-OVA tumor bearing mice when combined with immune checkpoint blockade., Conclusions: These data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy., Competing Interests: Competing interests: JKC and GMB were previous recipients of research fellowships co-sponsored by QBiotics Group Ltd. GMB, GA and PGP are recipients of current contract research funding from QBiotics Group Ltd. PWR, SMO, VAG and PGP are employees of QBiotics Group Ltd. JKC became a QBiotics employee during the review process. JKC, P-YY, JJ, GMB, SMO, PWR, VAG and PGP are shareholders in QBiotics Group Ltd. The other authors declare no competing interests. The work described in this study forms the basis of two international patents: PCT/AU2020/050360, PCT/AU2018/050277., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Post Acute COVID Syndrome (PACS), a complex and poorly understood condition characterised by persistent symptoms following the acute phase of COVID-19 infection, has emerged as a significant global health concern. Healthcare workers who had been at the forefront of the pandemic response are at heightened risk of contracting the virus and subsequently developing PACS. Therefore, we aim to determine the prevalence and risk factors for PACS among healthcare workers infected with COVID-19., Methods: A cross-sectional study was conducted between October 2022 and August 2023 using an online REDCap electronic data capture tool questionnaire. PACS was defined as new or persistent symptoms lasting more than 28 days after a positive SARS-CoV-2 polymerase chain reaction or rapid test kit antigen test. Multivariable logistic regression was performed to determine predictors associated with PACS., Results: Among 609 infected healthcare workers, they were predominantly female (71.8%), Malays (84.6%), and aged 18-39 years (70.1%). 50.7% of infected healthcare workers experienced PACS. The most common PACS symptoms experienced were fatigue (27.9%), cough (25.1%), decreased physical strength (20.5%), and musculoskeletal pain (19.2%). Those who are more likely to develop PACS were females, underlying asthma, and COVID-19 severity category 3. On the other hand, those who received booster vaccinations were less likely to develop PACS., Conclusion: PACS is prevalent among healthcare workers with COVID-19 at the University Malaya Medical Centre. These findings emphasise the critical need for those with higher risk to receive regular health monitoring and checkups to detect any early signs of PACS. It underscores the need for continuous support and healthcare interventions to mitigate the impacts of PACS and ensure the physical and mental well-being of healthcare workers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to investigate the changes in lymph node surgery types and prescription patterns of postoperative medications for pain management in patients with breast cancer using national health insurance claim data from South Korea. The study population comprised patients with at least one record of a principal diagnosis of breast cancer (ICD-10 code: C50) from the national health insurance claim database between 2010 and 2019. Patients who underwent mastectomy or lumpectomy only once were selected for the analysis. Patients who underwent axillary lymph node dissection (ALND) with mastectomy or lumpectomy on the day of surgery were included in the ALND group, whereas those who underwent sentinel lymph node biopsy (SLNB) were included in the SLNB group. Prescription records of opioids before, after and on the date of breast cancer surgery were collected and categorized according to the opioid type. Multivariate logistic regression modeling was used to compare postoperative opioid prescriptions. The proportion of those undergoing ALND among 3,080 patients decreased consistently after 2014, while the proportion undergoing SLNB increased. Although the rate of pain medication prescription on the day of surgery was similar between the two groups, the rate of prescription of postoperative pain medication and anticancer agents was lower in the SLNB group than in the ALND group. Logistic regression modeling showed that the SLNB group had lower odds of receiving opioids than did the ALND group (Odds ratio (OR) = 0.727, Confidence Interval (CI) = 0.546-0.970). A consistent trend was observed when the model was adjusted for neoadjuvant chemotherapy and the use of preoperative pain medications (OR = 0.718, CI = 0.538-0.959). To manage postoperative pain and prevent chronic pain with minimal side effects, sufficient discussion among clinicians, patients, and other healthcare professionals is imperative, along with adequate treatment planning., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The contents of metals, total carbon, total nitrogen (TN), total organic carbon (TOC), and stable isotope composition (δ 13 C org and δ 15 N) of sediment organic matter (SOM) were investigated to explore the sources and spatial distribution of metals and SOM in the surface sediments (Kaohsiung Port, Taiwan). Results showed that TOC and metals in estuarine sediments are high, gradually decreasing toward the port entrances. The δ 13 C org , δ 15 N, and TOC/TN ratios indicate that SOM comes mainly from terrestrial sources. This study proposes a befitting model between metal pollution and toxicity risk index and SOM sources in port sediments by combining stable isotope composition, correlation matrix, and multiple linear regression analysis. The model indicates that the degree of metal pollution and toxicity risk in sediments are mainly affected by TOC terr content and SOM source. The results help to understand the influence of organic matter sources in port sediments on metal concentration distribution., 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 © 2024 Elsevier Ltd. All rights reserved.)