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Background: Regional analgesia has been recommended to alleviate pain caused by hip fractures. Both the supra-inguinal fascia iliaca block (S-FIB) and the peri‑capsular nerve group (PENG) block provide better analgesia than conventional fascia iliaca block for patients with hip fractures, but which one is superior remains equivocal. This study aimed to determine the superiority of S-FIB or PENG block for patients awaiting hip surgery., Methods: In this prospective, double-blind, randomised comparative trial, patients with hip fractures awaiting operation were randomly allocated to receive either S-FIB with 30 ml 0.35 % ropivacaine or PENG block with 20 ml 0.35 % ropivacaine. Primary outcomes were pain scores (numeric rating scale, NRS, 0-10) at rest and during passive movement 30 min after nerve block. Secondary outcomes included pain scores at rest and during movement 10 and 20 min after nerve block and during positioning for spinal anaesthesia, time spent for performing nerve block and spinal anaesthesia, and the quality of positioning for spinal anaesthesia., Results: One-hundred patients were enrolled and 91 patients completed the trial (S-FIB group n = 46, PENG group n = 45). No significant difference was noted between these two groups in the pain scores (median [interquartile range]) either at rest (0 [0-0] vs 0 [0-0], P = 0.151) or during passive movement (3 [1-6] vs 3 [2-5], P = 0.99) at 30 min after nerve block. However, within-group analysis revealed that a significant reduction in pain score at rest was noted as early as 20 min after PENG block while that was noted only at 30 min after S-FIB. In addition, less time was required to perform PENG than S-FIB the block (3.1 [2.3-3.9] vs. 4.6 [3.1-5.6] minutes, P < 0.001)., Conclusions: Our result suggests that with a lower dose of local anaesthetic, a shorter procedure time and earlier analgesic effect, PENG block may be preferred to S-FIB for patients with hip fracture awaiting surgery., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Carbapenem-resistant Enterobacter cloacae complex is a significant global healthcare threat, particularly carbapenemase-producing Enterobacter hormaechei (CPEH). From January 2017 to January 2021, twenty-two CPEH isolates from a regional teaching hospital in central Taiwan were identified with the carriage of carbapenemase genes bla KPC-2 , bla IMP-8 , and predominantly bla OXA-48 . Over 80% of these CPEH strains clustered into the high-risk ST78 lineage, carrying a bla OXA-48 IncL plasmid (pOXA48-CREH), nearly identical to the endemic plasmid pOXA48-KP in ST11 Klebsiella pneumoniae . This OXA-48-producing ST78 lineage disseminated clonally from 2018 to 2021 and transferred pOXA48-CREH to ST66 and ST90 E. hormaechei . An IMP-8-producing ST78 strain harbouring a bla IMP-8 -carrying pIncHI2 plasmid appeared in 2018, and by late 2020, a KPC-2-producing ST78 strain was identified after acquiring a novel bla KPC-2 -carrying IncFII plasmid. These findings suggest that the high-risk ST78 lineage of E . hormaechei has emerged as the primary driver behind the transmission of CPEH . ST78 has not only acquired various carbapenemase-gene-carrying plasmids but has also facilitated the transfer of pOXA48-CREH to other lineages. Continuous genomic surveillance and targeted interventions are urgently needed to control the spread of emerging CPEH clones in hospital settings.

Duchenne muscular dystrophy (DMD), a rare pediatric disease, presents numerous challenges when designing clinical trials, mainly due to the scarcity of available trial participants and the heterogeneity of disease progression. A quantitative clinical trial simulator (CTS) has been developed based on previously published five disease progression models describing each of the longitudinal changes in the velocity at which individuals can complete specified timed functional tests, frequently used as clinical trial efficacy endpoints (supine-stand, 4-stair climb, and 10 m walk/run test or 30-foot walk/run test), as well as each of the longitudinal changes in forced vital capacity and North Star Ambulatory Assessment total score. The model-based CTS allows researchers to optimize the selection of numerous trial parameters for designing trials for the five functional measures commonly used as endpoints in DMD clinical trials. This case report serves as a demonstration of the tool's functionality while providing an easy-to-follow guide for users to reference when preparing simulations of their own design. Two case studies, using input selection based on previous DMD clinical trials, provide realistic examples of how the tool can help optimize clinical trial design without the risk of decreasing statistical significance. This optimization allows researchers to mitigate the risk of designing trials that may be longer, larger, or more inclusive/exclusive than necessary., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The traditional sulfur selenization process in Cu 2 ZnSn(S,Se) 4 (CZTSSe) solar cell fabrication often results in the creation of localized anion vacancies ( V S and V Se ). These vacancies are considered harmful defects as they can trap carriers generated by light, leading to reduced solar cell efficiency. Moreover, concrete evidence has been lacking on the extent of the impact caused by these anion vacancies. Our research introduces a novel approach: the hydrogen-assisted selenization (HAS) process, specifically designed to minimize localized anion vacancies in Cu 2 ZnSnSe 4 (CZTSe) solar cells. Our investigation, utilizing current-voltage ( I - V ) and admittance spectroscopy measurements, provides clear insights. We observed notable improvements in carrier collection efficiency and a discernible reduction in defect states. Furthermore, there was a significant decrease in the activation energy required within the solar cell device, dropping from 184 to 145 meV. To delve deeper into the structural and compositional aspects, we employed synchrotron-based X-ray nanoprobes. Through nanoscale X-ray fluorescence and hard X-ray beam-induced current measurements, we can directly observe and document the relationship between the local compositional distribution and photocurrent activity in operando. These comprehensive results furnish strong evidence that mitigating anion vacancies in the CZTSe layer can substantially improve the power conversion efficiency of the CZTSe solar cells. This advancement not only sheds light on the critical role of anion vacancies in solar cell performance but also underscores the effectiveness of the HAS process in enhancing overall device efficiency.

This study employed atomic layer deposition (ALD) to fabricate an Al 2 O 3 passivation layer to optimize the performance of ultraviolet (UV) photodetectors with a TiO 2 -nanorod-(NR)-containing active layer and a solid-liquid heterojunction (SLHJ). To reduce the processing time and enhance light absorption, a hydrothermal method was used to grow a relatively thick TiO 2 -NR-containng working electrode. Subsequently, a 5-nm-thick Al 2 O 3 passivation layer was deposited on the TiO 2 NRs through ALD, which has excellent step coverage, to reduce the surface defects in the TiO 2 NRs and improve the carrier transport efficiency. X-ray photoelectron spectroscopy revealed that the aforementioned layer reduced the defects in the TiO 2 NRs. Moreover, high-resolution transmission electron microscopy indicated that following the annealing treatment, Al, Ti, and O atoms diffused across the interface between the Al 2 O 3 passivation layer and TiO 2 NRs, resulting in the binding of these atoms to form Al-Ti-O bonds. This process effectively filled the oxygen vacancies in TiO 2 . Examination of the photodetector device revealed that the photocurrent-to-dark current ratio exhibited a difference of four orders of magnitude (10 -4 to 10 -8 A), with the switch-on and switch-off times being 0.46 and 3.84 s, respectively. These results indicate that the Al 2 O 3 passivation layer deposited through ALD can enhance the photodetection performance of SLHJ UV photodetectors with a TiO 2 active layer.

Background: Neutrophils are vital constituents of the immune response in the vaginal environment, playing a pivotal role in the defense against trichomoniasis. Earlier studies have shown that Trichomonas vaginalis (T. vaginalis) can release leukotriene B4 (LTB4), a molecule that attracts and activates neutrophils. Additionally, secretory products from this parasite can induce the production of interleukin-8 (IL-8) in mast cells and neutrophils, which further recruits neutrophils to the infection site. The precise reasons behind T. vaginalis actively promoting interaction between parasites and neutrophils rather than inhibiting the inflammatory response remain unclear., Results: In this study, we collected conditioned medium to elucidate the intricate dynamics between T. vaginalis and human neutrophils. We conducted a comprehensive profiling of soluble excretory/secretory proteins (ESPs), identifying 192 protein spots, of which 94 were successfully characterized through mass spectrometry analysis. Notably, the majority of induced ESPs from co-cultivation exhibited consistency with the trichomonad and neutrophil standalone groups, except for lactoferrin, which was observed exclusively following the interaction between neutrophils and T. vaginalis. The secretion of lactoferrin was determined to be a contact-dependent process. It was interesting to identify the ability of the iron-loaded lactoferrin to extend the survival time of T. vaginalis under iron-deficient conditions., Conclusions: This study represents the first to identify the origin of lactoferrin during T. vaginalis infection, shedding light on the potential reason for T. vaginalis's ability to attract neutrophils to the infection site: the acquisition of the iron source, lactoferrin., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To assess the public perception of the role of hospital pharmacists, their satisfaction with the pharmacy service provided, and the factors associated with their perception and satisfaction., Methods: A cross-sectional, questionnaire survey was conducted on adults older than 18 years who utilized public pharmacy services. A self-developed, validated questionnaire consisting of three parts was used, i.e., demographic data, perception, and satisfaction. The questionnaire was tested in a pilot study of 50 study participants and demonstrated good reliability results of 0.900 for the perception section and 0.836 for the satisfaction section. Therefore, all items were used in the final questionnaire., Key Findings: Four hundred and seventy-nine completed questionnaires were collected with a response rate of 91.6%. The Cronbach's α for perception and satisfaction scores were 0.938 and 0.841, respectively. The median total score for public perception was 83 (interquartile range [IQR]: 15), whereas the median total score for public satisfaction was 38 (IQR: 33). The level of public perception was significantly associated with the age groups (P = .009), ethnic groups (P < .001), respondents' locality groups (P < .001), the level of education achieved group (P = .017), and the income groups (P = .006). Satisfaction was not significantly associated with any sociodemographic factors., Conclusions: This study has found that the general public had a favorable perception of the role of hospital pharmacists, and they were generally satisfied with the pharmacy service provided., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This meta-analysis aimed at investigating the therapeutic effects of probiotics against the symptoms of depression in children and adolescents as well as to identify the potential confounders. Following PRISMA guidelines, major databases were searched for randomized controlled trials focusing on effects of probiotics against the symptoms of depression in children and adolescents to analyze the effect size (ES) for primary outcomes (i.e., improvement in depressive symptoms) expressed as standardized mean difference (SMD) and odds ratios (ORs) for continuous and categorical variables, respectively, with 95% confidence interval (CI). Meta-analysis of five studies (692 participants, mean age = 7.33 years, treatment duration 8-104 weeks) demonstrated no significant improvement in depressive symptoms in subjects receiving probiotics (SMD = 0.04, 95% CI: -0.33 to 0.41, p = 0.84, five studies, 692 participants). Subgroup analysis also showed no significant improvement associated with probiotic use relative to controls in the subgroup of studies focusing on individuals diagnosed with neurodevelopmental disorders (SMD = -0.11, 95% CI: -0.73 to 0.51, p = 0.72, three studies, 452 participants) and that recruiting the general population (SMD = 0.24, 95% CI: -0.43 to 0.91, p = 0.48, two studies, 240 participants). However, high levels of heterogeneity were found in both our primary results (I2 = 77%, p = 0.001) and subgroup analyses for those with neurodevelopmental disorders (I2 = 84%, p = 0.002) and the general population (I2 = 79%, p = 0.03). The results did not support the use of probiotics for relieving depressive symptoms compared with controls in children and adolescents diagnosed with neurodevelopmental disorders or in the general population. Nevertheless, given the high level of heterogeneity across the included trials and a lack of studies focusing on those with diagnoses of anxiety or depression in the current meta-analysis, further large-scale clinical investigations are required to elucidate the therapeutic potential of probiotics against depressive symptoms in these populations, especially in those diagnosed with neurodevelopmental disorders or depression., (© 2024. The Author(s).)

Background: Anxiety and depressive disorders, characterized by high incidence and functional impairments, are emotional disorders with shared etiological and maintenance mechanisms. Dialectical behavior therapy (DBT) is a promising approach for the transdiagnostic treatment of emotional disorders. Developing a brief DBT intervention can facilitate the adoption of evidence-based therapy., Methods: This protocol is for a 3-year single-blinded, two-arm randomized controlled trial. Individuals with depressive or anxiety disorder will be randomly allocated to a modified DBT-informed transdiagnostic psychotherapy group or a treatment-as-usual group. The intervention group will receive DBT individual therapy for 15 weeks. Power analyses revealed that the cohort should include a minimum of 250 participants. Preintervention, postintervention, and follow-up (after 3 months) assessments will be conducted. Primary outcomes will be severities of depression and anxiety rated by blind assessors. Intent-to-treat and per-protocol analyses will be conducted using the hierarchical linear model. Effect sizes will be estimated using Cohen's d., Result: To the best of our knowledge, the proposed study will be the first randomized controlled trial to evaluate the efficacy of a modified DBT intervention in managing transdiagnostic emotional disorders in Chinese individuals., Conclusion: This intervention is expected to improve clinical outcomes, daily functioning, and quality of life. The trial will enrich the empirical evidence for transdiagnostic interventions, facilitating the implementation of evidence-based therapy and reducing the high prevalence and challenges (e.g., disability) of emotional disorders in the Chinese population., Trial Registration Number: NCT05989451., (© 2024. The Author(s).)

Extracellular vesicles (EVs) are released by all cells and hold great promise as a class of biomarkers. This promise has led to increased interest in measuring EV proteins from both total EVs as well as brain-derived EVs in plasma. However, measuring cargo proteins in EVs has been challenging because EVs are present at low levels, and EV isolation methods are imperfect at separating EVs from free proteins. Thus, knowing whether a protein measured after EV isolation is truly inside EVs is difficult. In this study, we developed methods to measure whether a protein is inside EVs and quantify the ratio of a protein in EVs relative to total plasma. To achieve this, we combined a high-yield size-exclusion chromatography protocol with an optimized protease protection assay and Single Molecule Array (Simoa) digital enzyme-linked immunoassays (ELISAs) for ultrasensitive measurement of proteins inside EVs. We applied these methods to analyze α-synuclein and confirmed that a small fraction of the total plasma α-synuclein is inside EVs. Additionally, we developed a highly sensitive Simoa assay for phosphorylated α-synuclein (phosphorylated at the Ser129 residue). We found enrichment in the phosphorylated α-synuclein to total α-synuclein ratio inside EVs relative to outside EVs. Finally, we applied the methods we developed to measure total and phosphorylated α-synuclein inside EVs from Parkinson's disease and Lewy body dementia patient samples. This work provides a framework for determining the levels of proteins in EVs and represents an important step in the development of EV diagnostics for diseases of the brain, as well as other organs., Competing Interests: Competing interests statement:D.R.W. is a founder, member of the Board of Directors, and equity holder in Quanterix. His interests were reviewed and are managed by BWH and Partners HealthCare in accordance with their conflict of interest policies. G.M.C. Disclosures: https://arep.med.harvard.edu/gmc/tech.html. The authors have filed IP on methods for EV isolation and analysis.

Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy., Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 min prior to and continuing up to 90 min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy., Results: Eighty-three patients were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation., Conclusion: SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This is a budget impact analysis that compared the scenario of treating heart failure with reduced ejection fraction (HFrEF) using dapagliflozin plus standard of care (SoC) versus a scenario without dapagliflozin, from the perspective of Ministry of Health (MOH) Malaysia over a 5-year time horizon., Methods: A Microsoft Excel-based cost calculator was developed for such comparison. The estimated size of eligible population, uptake rates for dapagliflozin, as well as costs related to drugs, clinical events, and adverse events were based on published data, official tariffs, and databases, and expert opinion. Clinical data from the DAPA-HF trial were used to inform efficacy and safety inputs (i.e., hospitalization for heart failure (hHF), cardiovascular death, and adverse events). Results were reported as total annual and cumulative costs (in 2023 Malaysian Ringgits [RM], United States Dollars [USD], and European Union Euros, [EUR]; with exchange rates of 1 USD = RM 4.40 and 1 EUR = RM 4.90]), as well as the number of clinical events. Sensitivity and scenario analyses were also conducted., Findings: The base-case analysis estimated that over a five-year period, the adoption of dapagliflozin for HFrEF treatment would result in a cumulative cost-saving of RM 2.6 million (USD 0.6 million/EUR 0.5 million), representing a 0.3% reduction in costs, driven primarily by reduced expenditure on hHF. Moreover, dapagliflozin treatment would lead to 731 fewer hHF and 366 fewer cardiovascular deaths. Sensitivity and scenario analyses revealed that the results were most sensitive to assumptions regarding loop diuretic requirements and the cost of dapagliflozin. Although cost savings or a net-zero balance were projected for the first four years, an anticipated 2.5% annual increase in dapagliflozin uptake in the longer term would lead to additional costs for the MOH, starting from the fifth year., Implications: Incorporating dapagliflozin into the SoC can improve health outcomes for HFrEF patients and may generate cost savings, potentially easing the economic strain of HFrEF management on Malaysia's public healthcare system in the short term. Nonetheless, a modest increase in budget should be anticipated as more patients gain access to the treatment over time., 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 Inc. All rights reserved.)

Obesity and overweight are major health concerns, with a 19.7% prevalence among Malaysian adults, as reported in the 2019 National Health and Morbidity Survey. This study assessed the effectiveness of an educational intervention on weight control intention using the Health Belief Model (HBM). A quasi-experimental design was employed, involving 140 participants equally divided into an intervention group (IG) and a control group (CG). Post-intervention, the IG showed significant improvement in perceived self-efficacy in dieting (mean score 3.96 ± 0.85) compared to the CG (3.76 ± 0.86, p = 0.003). Perceived self-efficacy in exercise also increased in the IG (4.12 ± 0.52) compared to the CG (3.51 ± 0.94, p < 0.001). While behavioral intention scores improved in the IG (4.00 ± 0.59), the difference was not significant (p = 0.300). This study highlights that educational interventions using HBM can effectively improve self-efficacy and influence weight control behaviors., (© 2024. The Author(s).)

Background: Metastatic melanoma of the ampulla of Vater is rare. The purpose of this study was to summarize the characteristics and outcomes of metastatic melanoma in the ampulla of Vater and highlight the impact of surgery on the prognosis of patients with metastatic melanoma., Methods: Pooled data from a case encountered at our institution and from all sporadic cases published on PubMed and MEDLINE between 1996 and 2023 were analyzed., Results: Fourteen patients with metastatic melanoma in the ampulla of Vater were enrolled. Seventy-three percent of primary melanomas were cutaneous and 27% were mucosal. Jaundice was the most common symptom (86%). The size of metastatic melanoma to the ampulla ranged from 1.5 cm to 8 cm, with a median of 2.75 cm. Concomitant metastasis to other organs occurred in 82% of the patients at the time of diagnosis, most commonly in the brain, lungs, and liver (36% each). Among the reported cases, pancreaticoduodenectomy was performed in five patients. The overall 1-year survival rate was 27.3%, with a median survival of four months. Wide excision of the primary lesion and chemotherapy significantly improved survival rates (p= 0.048). There is a trend toward improved survival in patients undergoing pancreaticoduodenectomy followed by chemotherapy., Conclusion: Given the availability of effective systemic therapies, metastatic melanoma of the ampulla of Vater does not necessarily preclude major surgeries., 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 © 2024, the Chinese Medical Association.)

Malaria remains a global health challenge, affecting millions annually. Hemozoin (Hz) deposition in the bone marrow disrupts hematopoiesis and modulates immune responses, but the mechanisms are not fully understood. Here, we show that persistent hemozoin deposition induces a sustained bias toward myelopoiesis, increasing peripheral myeloid cell numbers. Hz drives this process through a cell-intrinsic, MyD88-dependent pathway, enhancing chromatin accessibility of transcription factors such as Runx1 and Etv6 in granulocyte-macrophage progenitors. These findings are confirmed by intraosseous Hz injections and bone marrow chimeras. Single-cell RNA sequencing reveals increased reactive oxygen species production in monocytes from malaria-recovered mice, correlating with enhanced bactericidal capacity. This highlights an alternative aspect of post-malarial immunity and extends our understanding of trained immunity, suggesting that pathogen by-products like Hz can induce innate immune memory. These results offer insights into therapeutic strategies that harness trained immunity to combat infectious diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cancer cells have a high demand for sugars and express diverse carbohydrate receptors, offering opportunities to improve delivery with multivalent glycopolymer materials. However, effectively delivering glycopolymers to tumors while inhibiting cancer cell activity, altering cellular metabolism, and reversing tumor-associated macrophage (TAM) polarization to overcome immunosuppression remains a challenging area of research due to the lack of reagents capable of simultaneously achieving these objectives. Here, the glycopolymer-like condensed nanoparticle (∼60 nm) was developed by a one-pot carbonization reaction with a single precursor, promoting multivalent interactions for the galactose-related receptors of the M2 macrophage (TAM) and thereby regulating the STAT3/NF-κB pathways. The subsequently induced M2-to-M1 transition was increased with the condensed level of glycopolymer-like nanoparticles. We found that the activation of the glycopolymer-like condensed galactose (CG) nanoparticles influenced monocarboxylate transporter 4 (MCT-4) function, which caused inhibited lactate efflux (similar to inhibitor effects) from cancer cells. Upon internalization via galactose-related endocytosis, CG NPs induced cellular reactive oxygen species (ROS), leading to dual functionalities of cancer cell death and M2-to-M1 macrophage polarization, thereby reducing the tumor's acidic microenvironment and immunosuppression. Blocking the nanoparticle-MCT-4 interaction with antibodies reduced their toxicity in glioblastoma (GBM) and affected macrophage polarization. In orthotopic GBM and pancreatic cancer models, the nanoparticles remodeled the tumor microenvironment from "cold" to "hot", enhancing the efficacy of anti-PD-L1/anti-PD-1 therapy by promoting macrophage polarization and activating cytotoxic T lymphocytes (CTLs) and dendritic cells (DCs). These findings suggest that glycopolymer-like nanoparticles hold promise as a galactose-elicited adjuvant for precise immunotherapy, particularly in targeting hard-to-treat cancers.

Background and Aims: Bowel smooth muscle experiences mechanical stress constantly during normal function, and pathologic mechanical stressors in disease states. We tested the hypothesis that pathologic mechanical stress could alter transcription to induce smooth muscle phenotypic class switching., Methods: Primary human intestinal smooth muscle cells (HISMCs), seeded on electrospun aligned poly-ε-caprolactone nano-fibrous scaffolds, were subjected to pathologic, high frequency (1 Hz) uniaxial 3% cyclic stretch (loaded) or kept unloaded in culture for 6 hours. Total RNA sequencing, qRT-PCR, and quantitative immunohistochemistry defined loading-induced changes in gene expression. NicheNet predicted how differentially expressed genes might impact HISMCs and other bowel cells., Results: Loading induced differential expression of 4537 genes in HISMCs. Loaded HISMCs had a less contractile phenotype, with increased expression of synthetic SMC genes, proinflammatory cytokines, and altered expression of axon guidance molecules, growth factors and morphogens. Many differentially expressed genes encode secreted ligands that could act cell-autonomously on smooth muscle and on other cells in the bowel wall., Discussion: HISMCs demonstrate remarkably rapid phenotypic plasticity in response to mechanical stress that may convert contractile HISMCs into proliferative, fibroblast-like cells or proinflammatory cells. These mechanical stress-induced changes in HISMC gene expression may be relevant for human bowel disease.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 led to the coronavirus infection diseases 2019 (COVID-19) pandemic, significantly impacting global public health and the economy. Numerous COVID-19 vaccines based on the receptor binding domain (RBD) of SARS-CoV-2 spike protein have been developed, utilizing various protein expression platforms and adjuvant systems. In a previous study, we reported using the direct fusion of the A subunit of type IIb E. coli heat-labile enterotoxin with the SARS-CoV-2 RBD protein (RBD-LTA) as an intranasal vaccine candidate (Hsieh et al., 2023). In this study, we investigated the effects of an intranasal booster of RBD-LTA/RBD mixture proteins after one or two doses of intramuscular bivalent BA.4/5 mRNA vaccination over 17 and 35 weeks. Our results indicate that the intranasal RBD-LTA/RBD mixture proteins booster maintains high levels of anti-RBD IgG and neutralizing antibodies, comparable to those elicited by a two-dose mRNA vaccination regimen. An additional RBD-LTA/RBD mixture proteins booster significantly increased antibody titers, demonstrating the potential of this approach for long-term immunity against SARS-CoV-2. Our findings suggest that combining primary mRNA vaccination with an intranasal RBD-LTA/RBD mixture proteins booster can effectively sustain antibody levels over extended periods, providing a promising strategy for long-term protection against SARS-CoV-2 and its variants., Competing Interests: Declaration of competing interest The National Tsing Hua University has filed a patent application on the RBD-based COVID-19 mucosal vaccine candidates., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the de novo design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation in cancers associated with dysregulated cyclin K activity., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. M. D. D. and W. R. have a patent issued to The Scripps Research Institute and University of Florida (US11666578B2). The authors declare no other financial interests or personal relationships that could be considered potential competing interests., (This journal is © The Royal Society of Chemistry.)

Background & Aims: Data are limited on the risk of de novo hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) after achieving sustained virologic response at off-treatment week 12 (SVR12) using direct-acting antivirals (DAAs) for HCV., Methods: A total of 1,598 eligible patients received biannual alpha-fetoprotein (AFP) and liver imaging surveillance to detect de novo HCC after achieving SVR12. MASLD was defined as presence of controlled attenuation parameter (CAP) ≥248 dB/m and ≥1 cardiometabolic risk factor (CMRF). Cumulative HCC incidence was compared between patients with/without MASLD. We built univariable and multivariable Cox proportional hazards models to evaluate factors associated with HCC. Sensitivity analysis was performed using the Fine-Gray subdistribution hazards model. Additionally, we evaluated the mediation effect of MASLD on CMRFs and of CMRFs on MASLD for HCC using mediation analysis with bootstrapping., Results: The incidence rate of HCC was 1.44 per 100 person-years of follow-up (95% CI 1.19-1.74). Patients with MASLD had a higher cumulative HCC incidence than those without MASLD (log-rank test, p <0.001). Multivariable Cox regression analysis revealed that in addition to age, sex, liver stiffness measurement, platelet count, and AFP, MASLD (adjusted hazard ratio 2.07; 95% CI 1.36-3.16; p <0.001) was independently associated with HCC. This finding was confirmed by the Fine-Gray model, which showed a subdistribution hazard ratio of 2.07 (95% CI 1.34-3.19, p <0.001) for MASLD. MASLD significantly mediated CMRFs for HCC development., Conclusion: After achieving SVR12, patients with MASLD exhibited an increased HCC risk compared to those without MASLD. Vigilant HCC surveillance and control of CMRFs to mitigate the effect of MASLD on HCC remain crucial for this population., Impact and Implications: The risk of de novo hepatocellular carcinoma (HCC) among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) after attaining a sustained virologic response to direct-acting antivirals remains to be confirmed. In this study, recruiting 1,598 patients in Taiwan, individuals with MASLD had an approximately two-fold increased risk of de novo HCC compared to those without MASLD after achieving a sustained virologic response. MASLD significantly mediated cardiometabolic risk factors for HCC development. Our findings underscore the critical importance of pharmacological interventions and proactive lifestyle modifications to control cardiometabolic risk factors in patients with MASLD, as well as the need for vigilant HCC surveillance to ensure favorable outcomes following HCV eradication., Competing Interests: Conflicts of interest All authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Modern plant physiological theory stipulates that the resistance to water movement from plants to the atmosphere is overwhelmingly dominated by stomata. This conception necessitates a corollary assumption-that the air spaces in leaves must be nearly saturated with water vapour; that is, with a relative humidity that does not decline materially below unity. As this idea became progressively engrained in scientific discourse and textbooks over the last century, observations inconsistent with this corollary assumption were occasionally reported. Yet, evidence of unsaturation gained little traction, with acceptance of the prevailing framework motivated by three considerations: (1) leaf water potentials measured by either thermocouple psychrometry or the Scholander pressure chamber are largely consistent with the framework; (2) being able to assume near saturation of intercellular air spaces was transformational to leaf gas exchange analysis; and (3) there has been no obvious mechanism to explain a variable, liquid-phase resistance in the leaf mesophyll. Here, we review the evidence that refutes the assumption of universal, near saturation of air spaces in leaves. Refining the prevailing paradigm with respect to this assumption provides opportunities for identifying and developing mechanisms for increased plant productivity in the face of increasing evaporative demand imposed by global climate change., (© 2024 The Author(s). Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Objective: To develop and validate the Mobile Adherence Satisfaction Scale (MASS) for assessing user satisfaction with mobile health applications aimed to improve medication adherence., Methods: The study involved patients over 18 with asthma, hypertension, heart failure, or diabetes, who used the CareAide® app for six months. Scale development included a literature review, expert consultations, and patient interviews, initially identifying 129 items. These were refined to 27 using a two-round Delphi technique and grouped into six dimensions: user interface, perceived usability, system quality, service quality, feature satisfaction, and general satisfaction. A pilot study with 30 participants further refined the model, which was then validated with 135 participants using exploratory and confirmatory factor analyses in SPSS 29 and SmartPLS 4. Data were collected via self-administered questionnaires., Results: A total of 135 complete questionnaires were analysed. Respondents had an average age of 66.7 years (SD = 11.6) with 42.2 % male (n = 57) and 57.8 % female (n = 78). After removal of an item due to cross loading, exploratory factor analysis resulted six dimensions and 26 items with Kaiser-Meyer-Olkin measure of 0.837 and Bartlett's Test of Sphericity (χ 2 (n = 325) = 2085.673, P < 0.001). The confirmatory factor analysis confirmed high reliability and validity: Cronbach's alpha values > 0.70 for each dimension and an overall alpha of 0.89, with Composite Reliability and Average Variance Extracted both >0.70 and >0.50, respectively, for each dimension. Structural model indicated a significant positive impact of user interface (β = 0.226, P = 0.006) and feature satisfaction (β = 0.230, P = 0.002) on general satisfaction, explaining 23.1 % of the variance (R 2  = 0.231)., Conclusion: The study developed and validated the MASS, a reliable tool for assessing user satisfaction with mHealth apps. User interface design and feature satisfaction are key for long-term engagement and consistent medication adherence., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study conducted adsorption experiments using Europium (Eu(III)) on geological materials collected from Taiwan. Batch tests on argillite, basalt, granite, and biotite showed that argillite and basalt exhibited strong adsorption reactions with Eu. X-ray diffraction (XRD) analysis also clearly indicated differences before and after adsorption. By combining X-ray absorption near-edge structure (XANES), extended X-ray absorption fine structure (EXAFS), and wavelet transform (WT) analyses, we observed that the Fe 2 O 3 content significantly affects the Eu-Fe distance in the inner-sphere layer during the Eu adsorption process. The wavelet transform analysis for two-dimensional information helps differentiate two distances of Eu-O, which are difficult to analyze, with hydrated outer-sphere Eu-O distances ranging from 2.42 to 2.52 Å and inner-sphere Eu-O distances from 2.27 to 2.32 Å. The EXAFS results for Fe 2 O 3 and SiO 2 in argillite and basalt reveal different adsorption mechanisms. Fe 2 O 3 exhibits inner-sphere surface complexation in the order of basalt, argillite, and granite, while SiO 2 forms outer-sphere ion exchange with basalt and argillite. Wavelet transform analysis also highlights the differences among these materials.

A fundamental assumption in plant science posits that leaf air spaces remain vapor saturated, leading to the predominant view that stomata alone control leaf water loss. This concept has been pivotal in photosynthesis and water-use efficiency research. However, recent evidence has refuted this longstanding assumption by providing evidence of unsaturation in the leaf air space of C 3 plants under relatively mild vapor pressure deficit (VPD) stress. This phenomenon represents a nonstomatal mechanism restricting water loss from the mesophyll. The potential ubiquity and physiological implications of this phenomenon, its driving mechanisms in different plant species and habitats, and its interaction with other ecological adaptations have. In this context, C 4 plants spark particular interest for their importance as crops, bundle sheath cells' unique anatomical characteristics and specialized functions, and notably higher water-use efficiency relative to C 3 plants. Here, we confirm reduced relative humidities in the substomatal cavity of the C 4 plants maize, sorghum, and proso millet down to 80% under mild VPD stress. We demonstrate the critical role of nonstomatal control in these plants, indicating that the role of the CO 2 concentration mechanism in CO 2 management at a high VPD may have been overestimated. Our findings offer a mechanistic reconciliation between discrepancies in CO 2 and VPD responses reported in C 4 species. They also reveal that nonstomatal control is integral to maintaining an advantageous microclimate of relatively higher CO 2 concentrations in the mesophyll air space of C 4 plants for carbon fixation, proving vital when these plants face VPD stress., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Prescribing errors (PEs) cause significant avoidable harm globally. In Malaysia, despite the prevalence of PEs in government healthcare facilities, there is limited research on how pharmacist staffing levels influence intervention frequency and effectiveness. This study aims to address this gap by analysing intervention trends and assessing their association with staffing levels, highlighting the correlation between increased pharmacist presence and the frequency of interventions., Methods: This retrospective cross-sectional study analysed data from the Ministry of Health's Pharmacy Management Form and the Pharmacy Board Registry from 2017 to 2019. Multivariate regression and two-way ANOVA assessed the association between the number of pharmacists, total prescriptions, and interventions on PEs in Health Clinic Outpatient Pharmacy, Hospital Outpatient Pharmacy, and Hospital Inpatient Pharmacy settings., Results: Annually, pharmacists intervened in approximately 1.8% of total prescriptions, with the most common errors being wrong dose, wrong medication, and wrong dosing frequency. These interventions were consistent across all settings, highlighting the uniformity in pharmacists' approach to managing PEs. The regression analysis revealed a significant positive correlation between the number of pharmacists, total prescriptions, and interventions on PEs, with an adjusted R-squared value of 0.899. Both the number of pharmacists and total prescriptions received were positively significant ( p  < 0.05), indicating that increased pharmacist presence strongly correlates with intervention frequency. No statistically significant differences were observed in intervention rates across different settings and severity levels, suggesting that pharmacists consistently provide effective interventions irrespective of the clinical context., Conclusion: In conclusion, this study confirms that increasing the number of pharmacists and total prescriptions received are critical predictors of interventions on PEs in Malaysia. It underscores the vital role of pharmacists in enhancing patient safety and healthcare quality, demonstrating their effectiveness in diverse settings and their adaptability to various patient needs and challenges., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Coxsackievirus A16 (CVA16) is one of the primary pathogens that causes hand, foot, and mouth disease (HFMD) in young children. In previous studies, CVA16 vaccine development has encountered several challenges, such as inefficient replication of the CVA16 virus in present culture systems, the induction of only mild neutralizing antibody titers, and neutralizing antibodies induced by certain vaccine candidates that are unable to protect against CVA16 viral challenge. In this study, we constructed a DNA-launched CVA16 infectious clone (CVA16ic) based on the genomic sequence of the CVA16 N5079 strain to minimize interference from viral quasispecies. The biochemical properties of this CVA16ic strain were similar to those of its parental strain. Serum-free HEK293A suspension cells, which produced higher virus titers than Vero cells, were demonstrated to improve CVA16 production yields. In addition, our study showed that inactivated EV-A71 antigens could enhance the immunogenicity of inactivated CVA16 mature/full particles (F-particles), suggesting that a bivalent CVA16 and EV-A71 vaccine may be an effective strategy for CVA16 vaccine development. These findings are expected to provide novel strategies and accelerate the development of bivalent HFMD vaccines., 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 Author(s).)

Autotaxin (ATX) is a lysophospholipase D that generates lysophosphatidic acid (LPA) and regulates cancer metastasis, therapeutic resistance, and tumor immunity. We found that myeloid cells in human melanoma biopsies abundantly express ATX and investigated its role in modulating innate tumor immunity using two models of melanoma metastasis-spontaneous and experimental. Targeted knockout of ATX in LysM+ myeloid cells in mice (LysM-KO) reduced both spontaneous and experimental B16-F10 melanoma metastases by ≥ 50%. Immunoprofiling revealed differences in M2-like alveolar macrophages, neutrophils and regulatory T cells in the metastatic lungs of LysM-WT versus LysM-KO that are model-dependent. These differences extend systemically, with LysM-KO mice bearing experimental metastasis having fewer neutrophils in the spleen than LysM-WT mice. Our results show that (1) LysM+ myeloid cells are an important source of ATX/LPA that promote melanoma metastasis by altering innate tumor immunity, and (2) intratumor and systemic immune profiles vary dynamically during disease progression and are model-dependent., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s).)

Meniscus injuries present significant therapeutic challenges due to their limited self-healing capacity and diverse biological and mechanical properties across meniscal tissue. Conventional repair strategies neglect to replicate the complex zonal characteristics within the meniscus, resulting in suboptimal outcomes. In this study, we introduce an innovative, age- and stiffness-tunable meniscus decellularized extracellular matrix (DEM)-based hydrogel system designed for precision repair of heterogeneous, zonal-dependent meniscus injuries. By synthesizing age-dependent DEM hydrogels, we identified distinct cellular responses: fetal bovine meniscus-derived DEM promoted chondrogenic differentiation, while adult meniscus-derived DEM supported fibrochondrogenic phenotypes. The incorporation of methacrylate hyaluronic acid (MeHA) further refined the mechanical properties and injectability of the DEM-based hydrogels. The combination of age-dependent DEM with MeHA allowed for precise stiffness tuning, influencing cell differentiation and closely mimicking native tissue environments. In vivo tests confirmed the biocompatibility of hydrogels and their integration with native meniscus tissues. Furthermore, advanced 3D bioprinting techniques enabled the fabrication of hybrid hydrogels with biomaterial and mechanical gradients, effectively emulating the zonal properties of meniscus tissue and enhancing cell integration. This study represents a significant advancement in meniscus tissue engineering, providing a promising platform for customized regenerative therapies across a range of heterogeneous fibrous connective tissues., Competing Interests: Competing interests The authors declare no competing interests.

Background: Deep neck infection (DNI) involves the deep neck spaces and may lead to airway compromise. An intensive care unit (ICU) is a specialized unit of the hospital that provides intensive care. ICU care is required for patients with severe DNI, although the risk factors for need of ICU care in patients with DNI have not been investigated. Methods: The clinical and laboratory parameters of 350 patients aged >18 years who were diagnosed with DNI between October 2018 and October 2023 were evaluated. Of these patients, 62 were transferred to the ICU. Univariate and multivariate analyses were applied to assess the risk factors for need of ICU care. Results: Univariate analysis revealed that older age [odds ratio (OR) = 1.0324, 95% confidence interval (CI): 1.0155-1.0496, P = .0001], a higher C-reactive protein (CRP) level (OR = 1.0076, 95% CI: 1.0049-1.0103, P < .0001), and blood glucose level (OR = 1.0057, 95% CI: 1.0023-1.0091, P = .0011), involvement ≥3 spaces (OR = 2.2366, 95% CI: 1.2827-3.8998, P = .0046), and mediastinitis (OR = 4.7134, 95% CI: 2.3537-9.4391, P < .0001) were significant risk factors for ICU transfer in patients with DNI. In multivariate analysis, older age (OR = 1.0216, 95% CI: 1.0032-1.0403, P = .0210), higher CRP level (OR = 1.0063, 95% CI: 1.0033-1.0092, P < .0001), and mediastinitis (OR = 2.6103, 95% CI: 1.1974-5.6905, P = .0158) were independent risk factors of ICU transfer in patients with DNI. The ICU group had a longer hospital stay (23.98 ± 8.53 vs 7.44 ± 4.24, P < .0001) and higher rate of tracheostomy ( P < .0001) than the non-ICU group. However, there were no significant differences in the rate of incision and drainage open surgery or pathogens between the groups (all P > .05). Conclusions: Elder patients and those with advanced CRP levels and mediastinitis are more likely to be transferred to the ICU, leading to prolonged hospital stays and a higher risk of tracheostomy. Clinicians should assess the patient's need for ICU transfer and timely manage the airway according to the aforementioned laboratory parameters and complications carefully., 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.

Background: Steatotic liver disease (SLD) is an emerging liver disease that has been associated with an increased risk for hepatocellular carcinoma (HCC). The impact of concurrent SLD on the prognosis of HCC remains unknown. This study investigates how concurrent SLD affects the outcomes of patients with HCC undergoing curative radiofrequency ablation (RFA) therapy., Methods: A retrospective analysis of patients with early-stage HCC receiving curative RFA at a tertiary medical center was conducted. Laboratory data and HCC characteristics were recorded and analyzed by a Cox proportional hazards regression model to predict recurrence and all-cause mortality after RFA., Results: A total of 598 patients with HCC were included between 2005 and 2015, with 139 and 459 classified in SLD and non-SLD groups, respectively. The SLD group exhibited a significantly better liver reserve and a lower cumulative incidence of HCC recurrence and liver-related and all-cause mortality after a median follow-up of 51 months. After adjusting for metabolic dysfunction, liver reserve, and HCC characteristics, the presence of SLD reduced all-cause mortality (adjusted hazard ratio [aHR], 0.67; 95% confidence interval [CI], 0.45-0.996; p = .048), which was supported by inverse probability weighting analysis (aHR, 0.65; 95% CI, 0.42-1.00; p = .049). Poor liver functional reserve (high albumin-bilirubin grades) increased all-cause mortality dose dependently. Barcelona Clinic Liver Cancer staging and a higher Fibrosis-4 index were predictors for HCC recurrence, whereas SLD was not., Conclusions: Among patients with HCC undergoing curative RFA, those with concurrent SLD had a lower risk of all-cause mortality compared to those with poor liver functional reserve., Plain Language Summary: The present research demonstrated that patients with both liver cancer and steatotic liver disease who received curative radiofrequency ablation for liver cancer survived longer compared to those without steatotic liver disease. Maintaining good liver function is an important prognostic factor for survival., (© 2024 American Cancer Society.)

Objectives: Descending necrotizing mediastinitis (DNM) developing after deep neck infection (DNI) is a potentially lethal disease of the mediastinum with a mortality rate as high as 40% prior to the 1990s. No standard treatment protocol is available. Here, we present the outcomes of our multidisciplinary approaches for treating DNM originating from a DNI., Methods: Between June 2016 and July 2021, there were 390 patients with DNIs admitting to our tertiary hospital. A total 21 patients with DNIs complicated with DNM were enrolled. The multidisciplinary approaches included establishment of airway security, appropriate surgery and antibiotics, extracorporeal membrane oxygenation, and intensive care unit management. The clinical variables were analyzed., Results: Two patients died and 19 survived (mortality 9.5%). The patients who died had a higher mean C-reactive protein (CRP) level than did those who survived (420.0 ± 110.3 vs 221.8 ± 100.6 mg/L) (P = .038). The most common pathogens were Streptococcus constellatus and Streptococcus anginosus. From 2001 to 2021, the average mortality rate of studies enrolling more than 10 patients was 16.1%., Conclusion: Multidisciplinary approaches, early comprehensive medical treatment, and co-ordination among departments significantly reduce mortality. Patients with severe inflammation and high CRP levels require intensive and aggressive interventions., 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.

The N-terminal domain (NTD) of the SARS-CoV-2 S protein comprises five exposed protruding loops. Deletions, insertions, and substitutions within these NTD loops play a significant role in viral evolution and contribute to immune evasion. We reported previously that introducing the glycan masking mutation R158N/Y160T in the NTD loop led to increased titers of neutralizing antibodies against the SARS-CoV-2 Wuhan-Hu-01 strain, as well as the Alpha, Beta, and Delta variants. In this study, we conducted further investigations on 10 additional glycan-masking sites in the NTD loops. Our findings indicate that the introduction of glycan masking mutations, specifically N87/G89T, H146N/N148T, N185/K187T, and V213N/D215T significantly enhanced neutralizing antibody titers against the Delta variant. The combination of dual glycan-masking mutations R158N/Y160T+V213N/D215T and R158N/Y160T+G219N results in a shift toward the Omicron BA.1. Furthermore, the introduction of the Omicron receptor binding domain (RBD) alongside these two dual glycan masking mutations of Wuhan-Hu-1 and XBB.1 NTD sequences resulted in a noticeable shift in antigenic distances, aligning with the Omicron BA.4/5, BA.2.75.2, BQ.1.1, and XBB.1 subvariants on the antigenic map. This strategic combination, which involves the dual glycan masking mutations R158N/Y160T+V213N/D215T and R158N/Y160T+G219N in the NTD loops, along with the domain swap incorporating the Omicron RBD, emerges as a promising vaccine design strategy for the continuous development of next-generation SARS-CoV-2 vaccines., (© 2024 Wiley Periodicals LLC.)

Objectves: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents., Methods: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed., Results: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate., Conclusions: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping. SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and linkage disequilibrium patterns, accounts for multiple causal variants in a genomic region and can be applied to GWAS summary statistics. We comprehensively assessed the performance of SuSiEx using simulations. We further showed that SuSiEx improves the fine-mapping of a range of quantitative traits available in both the UK Biobank and Taiwan Biobank, and improves the fine-mapping of schizophrenia-associated loci by integrating GWAS across East Asian and European ancestries., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type that urgently requires effective therapeutic strategies. Andrographolide, a labdane diterpenoid compound abundant in Andrographis paniculata, has anticancer effects against various cancer types, but its anticancer activity and mechanism against PDAC remain largely uncharacterized., Purpose: This study explores novel drug target(s) and underlying molecular mechanism of andrographolide against PDAC., Study Design and Methods: The malignant phenotypes of PDAC cells, PANC-1 and MIA PaCa-2 cells, were measured using MTT, clonogenic assays, and Transwell migration assays. A PDAC xenograft animal model was used to evaluate tumor growth in vivo. Western blot, immunofluorescence and immunohistochemistry were used for measuring protein expression. The TCGA database was analyzed to evaluate promoter methylation status, gene expression, and their relationship with patient survival rates. RT-qPCR was used for detecting mRNA expression. Reporter assays were used for detecting signal transduction pathways. Promoter DNA methylation was determined by sodium bisulfite treatment and methylation-specific PCR (MSP). The biological function and role of specific genes involved in drug effects were measured through gene overexpression., Results: Andrographolide treatment suppressed the proliferation and migration of PDAC cells and impaired tumor growth in vivo. Furthermore, andrographolide induced the mRNA and protein expression of zinc finger protein 382 (ZNF382) in PDAC cells. Overexpression of ZNF382 inhibited malignant phenotypes and cancer-associated signaling pathways (AP-1, NF-κB and β-catenin) and oncogenes (ZEB-1, STAT-3, STAT-5, and HIF-1α). Overexpression of ZNF382 delayed growth of PANC-1 cells in vivo. ZNF382 mRNA and protein expression was lower in tumor tissues than in adjacent normal tissues of pancreatic cancer patients. Analysis of the TCGA database found the ZNF382 promoter is hypermethylated in primary pancreatic tumors which correlates with its low expression. Furthermore, andrographolide inhibited the expression of DNA methyltransferase 3 beta (DNMT3B) and increased the demethylation of the ZNF382 promoter in PDAC cells. Overexpression of DNMT3B attenuated the andrographolide-suppressed proliferation and migration of PDAC cells., Conclusion: Our finding revealed that ZNF382 acts as a tumor suppressor gene in pancreatic cancer and andrographolide restores ZNF382 expression to suppress pancreatic cancer, providing a novel molecular target and a promising therapeutic approach for treating pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shu-ling Fu reports financial support was provided by the National Science and Technology Council in Taiwan. If there are other authors, they 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 GmbH. All rights reserved.)

While immune checkpoint inhibitors (ICIs) are promising in the treatment of metastatic melanoma, about half of patients do not respond well to them. Low levels of human leukocyte antigen-DR (HLA-DR) in tumors have been shown to negatively influence prognosis and response to ICIs. Lysophosphatidic acid (LPA) is produced in large amounts by melanoma and is abundantly present in the tumor microenvironment. LPA induces the release of various cytokines and chemokines from tumor cells, which affect cancer development, metastasis, and tumor immunity. In the present study, we investigated the role of LPA-induced IL-10 release in regulating HLA-DR expression and the underlying mechanisms in human melanoma cells. We showed that LPA (0.001-10 μM) dose-dependently increased DR6 transcript levels through activating LPAR1 in HEK293T cells. Knockdown of NF-κB1 abrogated the LPA-increased DR6 expression without affecting basal DR6 expression in both A2058 and A375 melanoma cell lines. LPA (10 µM) significantly increased IL-10 transcripts in A2058 and A375 melanoma cells, the effect was abolished by pharmacological inhibition of LPAR1 or knockdown of DR6. We found a statistically significant correlation between the expression of LPAR1, DR6 and IL-10 in human melanoma tissue and an association between increased expression of LPAR1 and reduced effectiveness of ICI therapy. We demonstrated that LPA (10 µM) markedly suppressed HLA-DR expression in both A375 and A2058 melanoma cells via activating the LPAR1-DR6-IL-10 pathway. These data suggest that the LPAR1-DR6-IL-10 autocrine loop could constitute a novel mechanism used by tumor cells to evade immunosurveillance by decreasing HLA-DR expression., (© 2024. The Author(s).)

Introduction: Empagliflozin demonstrates promising clinical benefits in patients with heart failure (HF). While an early study demonstrates that empagliflozin is cost-effective for treating HF patients with reduced ejection fraction (HFrEF) in Malaysia, its cost-effectiveness for HF with ejection fraction (EF)>40% remains unclear. Therefore, the current study aimed to assess the cost-effectiveness of adding empagliflozin to the standard of care (SoC) for HF patients with EF>40% from the perspective of Malaysian healthcare system. Subsequently, the results were consolidated with the findings for HFrEF to evaluate the cost-effectiveness of empagliflozin when used for all HF patients in Malaysia, irrespective of EF., Methods: A cost-utility analysis was performed using a validated Markov model, which modelled a cohort of adult patients through health states related to symptom severity and functional impairment, to estimate costs and quality-adjusted life-years (QALYs). The influence of model inputs and assumptions, sensitivity, scenario, and subgroup analyses were explored. All costs were expressed in 2022 Malaysian ringgits (RM). Costs and QALYs were discounted at an annual rate of 3.0% as per local pharmacoeconomic guideline., Results: The base-case incremental cost-effectiveness ratio (ICER) for HF patients with EF>40% was RM 40,454 per QALY gained. At a cost-effectiveness threshold of RM 47,439/QALY gained, empagliflozin was cost-effective in 57% of replications. The model outcomes were sensitive to inputs related to the treatment effect of empagliflozin in reducing HF-related hospitalisation and cardiovascular mortality, and empagliflozin cost. For the overall HF population, the ICER was RM 29,463/QALY gained., Conclusion: The findings suggest that empagliflozin is a cost-effective treatment option for the Malaysian HF population, including those with EF>40%. As such, the intervention warrants consideration by the Malaysian healthcare provider to mitigate the burden of HF and address the unmet needs of the EF>40% population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tan 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.)

Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib-tamoxifen in patients with HR+/HER2- advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib-tamoxifen or placebo-tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1-32.4) with palbociclib-tamoxifen and 11.1 months (95% CI, 7.4-14.6) with placebo-tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43-0.85; P = 0.002). Palbociclib-tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44-1.21) with palbociclib-tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib-tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo-tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2- advanced breast cancer, palbociclib-tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib-tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018., (© 2024. The Author(s).)

Pre-treatment host and viral factors may affect serum ferritin levels in patients with hepatitis C virus (HCV) infection. We delineated pre-treatment factors associated with hyperferritinemia in these patients. 1682 eligible patients underwent pre-treatment assessment for serum ferritin and various host/viral factors. Univariate and multivariate logistic regression analyses were conducted to evaluate factors associated with hyperferritinemia. Multivariate logistic regression analyses revealed that age > 50 years (adjusted odds ratio [OR]: 1.38 (95% confidence interval [CI] 1.09-1.74), p = 0.008), fibrosis stage ≥ F3 (adjusted OR: 1.36 (95% CI 1.04-1.77), p = 0.02), fibrosis index based on four parameters (FIB-4) > 3.25 (adjusted OR: 1.46 (95% CI 1.11-1.92), p = 0.01), presence of metabolic dysfunction-associated steatotic liver disease (MASLD) (adjusted OR: 1.43 (95% CI 1.21-1.76), p = 0.001), and alanine transaminase (ALT) > 2 folds upper limit of normal (ULN) (adjusted OR: 2.87 (95% CI 2.20-3.75), p < 0.001) were associated hyperferritinemia. The log 10 value of HBV or HCV viral load was not associated with the log 10 value of ferritin level (Spearman's rank correlation coefficient: - 0.025, p = 0.81 and 0.002, p = 0.92). In conclusion, host factors, rather than viral factors, are associated with hyperferritinemia in patients with HCV., (© 2024. The Author(s).)

Alzheimer's disease (AD) is an important geriatric disease that creates challenges in health policy planning. There is no previous attempt to quantify the actual direct healthcare cost of AD among older adults in Malaysia. This retrospective observational study with bottom-up micro-costing approach aimed to evaluate the direct healthcare expenditure on AD along with its potential predictors from healthcare providers' perspective, conducted across six tertiary hospitals in Malaysia. AD patients aged 65 and above who received AD treatment between 1 January 2016 and 31 December 2021 were included. Direct healthcare cost (DHC) of AD was estimated by extracting one-year follow-up information from patient medical records. As a result, 333 AD patients were included in the study. The mean DHC of AD was estimated RM2641.30 (USD 572.45) per patient per year (PPPY) from the healthcare payer's perspective. Laboratory investigations accounted for 37.2% of total DHC, followed by clinic care (31.5%) and prescription medicine (24.9%). As disease severity increases, annual DHC increases from RM2459.04 (mild), RM 2642.27 (moderate), to RM3087.61 (severe) PPPY. Patients aged 81 and above recorded significantly higher annual DHC (p = 0.003). Such real-world estimates are important in assisting the process of formulating healthcare policies in geriatric care., (© 2024. The Author(s).)

The tumor microenvironment (TME) has a significant impact on tumor growth and immunotherapy efficacies. However, the precise cellular interactions and spatial organizations within the TME that drive these effects remain elusive. Using advanced multiplex imaging techniques, we have discovered that regulatory T cells (Tregs) accumulate around lymphatic vessels in the peripheral tumor stroma. This localized accumulation is facilitated by mature dendritic cells enriched in immunoregulatory molecules (mregDCs), which promote chemotaxis of Tregs, establishing a peri-lymphatic Treg-mregDC niche. Within this niche, mregDCs facilitate Treg activation, which in turn restrains the trafficking of tumor antigens to the draining mesenteric lymph nodes, thereby impeding the initiation of anti-tumor adaptive immune responses. Disrupting Treg recruitment to mregDCs inhibits tumor progression. Our study provides valuable insights into the organization of TME and how local crosstalk between lymphoid and myeloid cells suppresses anti-tumor immune responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The Assessment of Quality of Life - 6 Dimensions (AQoL-6D), a generic preference-based measure, is an appealing alternative to EQ-5D-5L for assessing health status in patients with chronic heart failure (HF), given its expanded scope. However, without a Malaysian value set, the AQoL-6D cannot generate health state utility values (HSUVs) to support local economic evaluations. This study intended to develop algorithms for predicting EQ-5D-5L HSUVs from AQoL-6D in an HF population., Methods: Cross-sectional data from a multicenter cohort of 419 HF outpatients were used. Both direct and indirect mapping approaches were attempted using 5 sets of explanatory variables and 8 models (ordinary least squares, Tobit, censored least absolute deviations, generalized linear model, 2-part model [TPM], beta regression-based model, adjusted limited dependent variable mixture model, and multinomial ordinal regression [MLOGIT]). The models' predictive performance was assessed through 10-fold cross-validated mean absolute error [MAE] and root mean squared error [RMSE]). Potential prediction bias was also examined graphically. The best-performing models, with the lowest RMSE and no bias, were then identified., Results: Among the models evaluated, TPM, which included age, sex, and 5 AQoL-6D dimension scores as predictors, appears to be the best-performing model for directly predicting EQ-5D-5L HSUVs from AQoL-6D. TPM yielded the lowest MAE (0.0802) and RMSE (0.1116), and demonstrated predictive accuracy for HSUVs >0.2 without significant bias. A MLOGIT model developed for response mapping had suboptimal predictive accuracy., Conclusions: This study developed potentially useful mapping algorithms for generating Malaysian EQ-5D-5L HSUVs from AQoL-6D responses among patients with HF when direct EQ-5D-5L data are unavailable., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Materials section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) reduce the risk of hepatocellular carcinoma (HCC) in patients of hepatitis B. This study compared the difference between ETV and TDF on risk of HCC recurrence and mortality in patients with HBV-related HCC after curative intent treatment., Methods: Patients with HBV-related HCC who received HCC treatment (surgery or radiofrequency ablation [RFA]) and underwent long-term ETV or TDF therapy were retrospectively included. Baseline characteristics including age, sex, antiviral therapy, liver reserve, HCC stages, pathology reports and treatment modality were obtained. The risk of tumor recurrence, all-cause mortality, HCC-related mortality, and liver function were compared., Results: We identified 390 HBV-related HCC patients with curative intent treatment for HCC and treated with ETV (n = 328) or TDF (n = 62) between January 2011 and December 2020. The median age was 60 years, and 90.7% patients were males. After a median follow-up of 29 months, 186 patients developed recurrent HCC and 111 died. The baseline characteristics were comparable except more ALBI grade 3 patients in TDF group (76% vs. 48%, P < 0.001). Compared to ETV group, TDF users had lower all-cause mortality (adjusted hazard ratio [aHR]: 0.38, P = 0.003), and HCC-related mortality (aHR: 0.23, P = 0.005). Lower recurrence rate was noticed in TDF users after inverse probability of treatment weighting (IPTW). TDF users had improved ALBI grade and FIB-4 index compared with ETV groups., Conclusion: TDF therapy is associated with a reduced risk of HCC-related outcomes among patients with HBV-related HCC after curative intent treatment compared with ETV usage., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Skin cancer is the predominant form of cancer worldwide, including 75% of all cancer cases. This study aims to evaluate the effectiveness of the spectrum-aided visual enhancer (SAVE) in detecting skin cancer. This paper presents the development of a novel algorithm for snapshot hyperspectral conversion, capable of converting RGB images into hyperspectral images (HSI). The integration of band selection with HSI has facilitated the identification of a set of narrow band images (NBI) from the RGB images. This study utilizes various iterations of the You Only Look Once (YOLO) machine learning (ML) framework to assess the precision, recall, and mean average precision in the detection of skin cancer. YOLO is commonly preferred in medical diagnostics due to its real-time processing speed and accuracy, which are essential for delivering effective and efficient patient care. The precision, recall, and mean average precision (mAP) of the SAVE images show a notable enhancement in comparison to the RGB images. This work has the potential to greatly enhance the efficiency of skin cancer detection, as well as improve early detection rates and diagnostic accuracy. Consequently, it may lead to a reduction in both morbidity and mortality rates.

Purpose: Health-related quality-of-life (HRQoL) data for the chronic heart failure (HF) population in Malaysia are lacking. Using EQ-5D-5L, this study intended to describe their HRQoL, identify predictors of worse HRQoL, and derive EQ-5D-5L index scores for use in economic evaluations., Methods: A cross-sectional survey was conducted between April and September 2023 to collect EQ-5D-5L, sociodemographic, and clinical data from outpatients with HF across seven public specialist hospitals in Malaysia. Multivariable logistic and linear regression models were used to identify independent predictors of reported problems in the EQ-5D-5L dimensions, and predictors of index scores and EQ-VAS, respectively., Results: EQ-5D-5L data from 424 outpatients of multi-ethnic background (mean age: 57.1 years, 23.8% female, mean left ventricular ejection fraction: 35.7%, 89.7% NYHA class I-II) were collected using either Malay, English, or Chinese, achieving a 99.8% completion rate. Nearly half of the respondents reported issues in the Mobility, Usual Activities, and Pain/Discomfort dimensions. Mean EQ-5D-5L index was 0.820, lower than the general population, and significantly lower with NYHA class III-IV (0.747) versus NYHA class I (0.846) and NYHA class II (0.805). Besides NYHA class, independent predictors of worse HRQoL included Indian ethnicity, living alone, lower education, unemployment due to ill-health, and proxy-reported HRQoL, largely aligning with existing literature., Conclusion: Community-dwelling Malaysians with HF reported poorer HRQoL compared to the general population. The observed disparities in HRQoL among HF patients may be linked to specific patient characteristics, suggesting potential areas for targeted interventions. HRQoL assessment using EQ-5D-5L proves feasible and should be considered for routine implementation in local clinics., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: This study aimed to translate and culturally adapt the Assessment of Quality of Life (AQoL)-6D into Malay (Malay-AQoL-6D), and assesses the instrument's acceptability, reliability, and validity among Malaysians living with chronic heart failure (HF)., Methods: The translation and cross-cultural adaptation process adhered to international guidelines. The Malay-AQoL-6D underwent content and face validity assessments via expert review, and pretesting among healthy individuals and patients with chronic conditions. Subsequent psychometric validation utilised clinico-sociodemographic data and paired AQoL-6D and EQ-5D-5L data from a health-related quality-of-life (HRQoL) survey involving Malay-speaking patients with HF, which encompassed assessments of Malay-AQoL-6D acceptability, internal consistency and test-retest reliability, as well as its construct, concurrent, convergent and divergent, and known-group validity., Results: The Malay-AQoL-6D was deemed acceptable among clinicians and local patients, achieving a 90.8% completion rate among 314 patients surveyed. The instrument demonstrated strong content validity (item-level content validity index [CVI]: 0.83-1.00, average CVI: 0.98), internal consistency (Cronbach's alpha: 0.72-0.89; MacDonald's omega: 0.82-0.90, excluding the Senses dimension), and test-retest reliability (average intraclass correlation coefficients: 0.79-0.95). Confirmatory factor analysis confirmed the instrument's two-level, six-factor structure (Satorra-Bentler [SB]-scaled χ2(df: 164): 283.67, p-value < 0.001; root mean square error of approximation [RMSEA]: 0.051; comparative fix index [CFI]: 0.945, Tucker-Lewis index [TLI]: 0.937; standardised root mean-squared error [SRMR]: 0.058). The Malay-AQoL-6D's concurrent validity was evident through its good agreement with EQ-5D-5L. Multiple hypothesis tests further affirmed its construct and known-group validity. The Malay-AQoL-6D's psychometric properties remained consistent across different missing data techniques., Conclusion: The findings suggest that Malay-AQoL-6D could be a culturally acceptable, reliable, and valid HRQoL measure for quantifying HRQoL among the local HF population. Future studies are necessary to further validate the instrument against other measures and confirm the instrument's test-retest reliability and responsiveness, which are possible with the availability of the Malay-AQoL-6D., (© 2024. The Author(s).)