A potent dual inhibitor targeting COX-2 and HDAC of acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is an aggressive cancer with complex issues of drug resistance and a poor prognosis; thus, effective therapeutics is urgently needed for AML. In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

Differentiation of pathological subtypes and Ki-67 and TTF-1 expression by dual-energy CT (DECT) volumetric quantitative analysis in non-small cell lung cancer.

BACKGROUND: To explore the value of dual-energy computed tomography (DECT) in differentiating pathological subtypes and the expression of immunohistochemical markers Ki-67 and thyroid transcription factor 1 (TTF-1) in patients with non-small cell lung cancer (NSCLC). METHODS: Between July 2022 and May 2024, patients suspected of lung cancer who underwent two-phase contrast-enhanced DECT were prospectively recruited. Whole-tumor volumetric and conventional spectral analysis were utilized to measure DECT parameters in the arterial and venous phase. The DECT parameters model, clinical-CT radiological features model, and combined prediction model were developed to discriminate pathological subtypes and predict Ki-67 or TTF-1 expression. Multivariate logistic regression analysis was used to identify independent predictors. The diagnostic efficacy was assessed by the area under the receiver operating characteristic curve (AUC) and compared using DeLong's test. RESULTS: This study included 119 patients (92 males and 27 females; mean age, 63.0 ± 9.4 years) who was diagnosed with NSCLC. When applying the DECT parameters model to differentiate between adenocarcinoma and squamous cell carcinoma, ROC curve analysis indicated superior diagnostic performance for conventional spectral analysis over volumetric spectral analysis (AUC, 0.801 vs. 0.709). Volumetric spectral analysis exhibited higher diagnostic efficacy in predicting immunohistochemical markers compared to conventional spectral analysis (both P < 0.05). For Ki-67 and TTF-1 expression, the combined prediction model demonstrated optimal diagnostic performance with AUC of 0.943 and 0.967, respectively. CONCLUSIONS: The combined predictive model based on volumetric quantitative analysis in DECT offers valuable information to discriminate immunohistochemical expression status, facilitating clinical decision-making for patients with NSCLC.

Association between serum vitamin D, uric acid, C-reactive protein, and disease severity in ulcerative colitis: A retrospective study.

Ulcerative colitis (UC) is an inflammatory disease of the intestinal mucosa, and immunodeficiency is the main cause. Vitamin D (VD) has been shown to regulate many immune diseases, and studies have found that the level of uric acid (UA) and C-reactive protein (CRP) may also affect the severity of UC. This study aimed to investigate the correlation between VD levels and disease severity in UC patients. To determine serum VD levels in patients with UC of different ages and genders in China, and to study its correlation with UC, and to analyze its correlation with serum UA levels and CRP, so as to provide guidance for the prevention, diagnosis, and treatment of UC. One hundred three UC patients (64 males and 39 females, aged 16-75 years) were diagnosed with varying severity (mild, moderate, and severe). Serum VD levels, UA levels, and CRP levels were measured by electrochemiluminescence. The serum VD level of patients with severe UC was significantly lower than that of patients with mild UC. Gender was significantly correlated with serum UA, CRP, and disease severity in UC patients. Serum VD levels may affect the disease severity of UC patients, and patients with low serum VD content may have more severe disease. Gender affects serum UA, CRP, and disease severity. Males have significantly higher serum UA and CRP levels than females, while disease severity is generally lower than that of females. However, the mechanism of abnormal serum vitamin and trace element levels in UC patients remains to be further studied.

The Analgesic Mechanism and Recent Clinical Application of Erector Spinae Plane Block: A Narrative Review.

Now, the erector spinae plane block (ESPB) is widely used in various thoracolumbar surgeries. It has unique advantages: simple and convenient operation, low safety risks, and reduced opioid use. The ESPB is used in thoracic surgery, abdominal surgery, and spinal surgery. There are also relevant research reports on postoperative analgesia during general anesthesia surgery. This article searches the PubMed and Web of Science databases to find and screen relevant studies on ESPB since 2019 and retrospectively summarizes the current indications of ESPB. The methodological quality of the included studies was assessed using the Cochrane bias risk tool. The results showed that the current research on ESPB generally provides low-level clinical evidence. The complex anatomy of the erector spinae muscles is both responsible for its unique advantages and restricts its development. Few anatomical studies have clearly and completely demonstrated the diffusion relationship of local anesthetics among the anatomical structures of the erector spinal muscles. The uncontrollability of the diffusion plane prevents ESPB from being applied on a wider scale with a high level of evidence. To further clarify the scope of application of ESPB and achieve the best analgesic effect, in the future, we should focus on the unique anatomical course and distribution of the erector spinal muscles and their fascia and nerves. It is necessary to combine anatomical, imaging, and histological methods to obtain high-quality evidence to guide clinical application.

Huaier inhibits autophagy and promotes apoptosis in T-cell acute lymphoblastic leukemia by down-regulating SIRT1.

Objective: Due to the high drug resistance and relapse rate of T-cell acute lymphoblastic leukemia (T-ALL), the prognosis is usually poor. Therefore, there is an urgent need to find safer and more effective therapeutic drugs. Huaier and its preparations, as adjuvant drugs, have been widely used in the treatment of solid tumors and other diseases. However, the application of Huaier in leukemia is rarely reported. In this study, we investigated the anti-tumor effect of Huaier on T- ALL and its underlying mechanism. Methods: Jurkat and MOLT-4 cells were treated with Huaier. Cell viability was evaluated by CCK-8 assay. The morphological changes of apoptotic cells were observed by Hoechst 33258 staining. Cell apoptosis was analyzed by flow cytometry. The expression levels of related proteins were assessed by Western blot. Results: The results showed that Huaier significantly inhibited the proliferation of Jurkat and MOLT-4 cells in a dose- and time-dependent manner, with IC50 of 2.37 ± 0.10 and 1.93 ± 0.07 mg/mL at 48 h, respectively. Morphological changes and increased number of apoptotic cells were observed by Hoechst 33258 staining and flow cytometry. The apoptosis rates of Jurkat and MOLT-4 cells in 4 mg/mL group were 50.67 ± 1.36 % and 49.97 ± 5.43 %, respectively. Huaier promoted the expression of Cytochrome c, Cleaved Caspase-3, Cleaved PARP, p53, LC3-Ⅱ and p62 proteins, while inhibited the expression of SIRT1, ATG7 and Beclin 1 proteins. Treatment with SRT1720 (SIRT1 agonist) combined with Huaier rescued Huaier-induced apoptosis and increased the expression of autophagy-related proteins. Conclusion: Huaier inhibits autophagy and promotes apoptosis of T-ALL cells by down-regulating SIRT1, which may be a potential drug for the treatment of T-ALL.

Aligned fibrous scaffolds promote directional migration of breast cancer cells via caveolin-1/YAP-mediated mechanosensing.

Tumorigenesis and metastasis are highly dependent on the interactions between the tumor and the surrounding microenvironment. In 3D matrix, the fibrous structure of the extracellular matrix (ECM) undergoes dynamic remodeling during tumor progression. In particular, during the late stage of tumor development, the fibers become more aggregated and oriented. However, it remains unclear how cancer cells respond to the organizational change of ECM fibers and exhibit distinct morphology and behavior. Here, we used electrospinning technology to fabricate biomimetic ECM with distinct fiber arrangements, which mimic the structural characteristics of normal or tumor tissues and found that aligned and oriented nanofibers induce cytoskeletal rearrangement to promote directed migration of cancer cells. Mechanistically, caveolin-1(Cav-1)-expressing cancer cells grown on aligned fibers exhibit increased integrin ß1 internalization and actin polymerization, which promoted stress fiber formation, focal adhesion dynamics and YAP activity, thereby accelerating the directional cell migration. In general, the linear fibrous structure of the ECM provides convenient tracks on which tumor cells can invade and migrate. Moreover, histological data from both mice and patients with tumors indicates that tumor tissue exhibits a greater abundance of isotropic ECM fibers compared to normal tissue. And Cav-1 downregulation can suppress cancer cells muscle invasion through the inhibition of YAP-dependent mechanotransduction. Taken together, our findings revealed the Cav-1 is indispensable for the cellular response to topological change of ECM, and that the Cav-1/YAP axis is an attractive target for inhibiting cancer cell directional migration which induced by linearization of ECM fibers.

Notch-1 regulates collective breast cancer cell migration by controlling intercellular junction and cytoskeletal organization.

Pathological observations show that cancer cells frequently invade the surrounding normal tissue in collective rather than individual cell migration. However, general principles governing collective cell migration remain to be discovered. Different from individual cell migration, we demonstrated that the Notch-1-activation reduced collective cells speed and distances. In particular, Notch-1-activation induced cellular cytoskeletal remodelling, strengthened the intercellular junctions and cell-matrix adhesions. Mechanistically, Notch-1 activation prevented the phosphorylation of GSK-3ß and the translocation of cytoplasmic free ß-catenin to the nucleus, which increased E-cadherin expression and tight intercellular junctions. Moreover, Notch-1 signalling also activated the RhoA/ROCK pathway, promoting reorganization of F-actin and contractile forces produced by myosin. Further, Notch-1 activation increased cell adhesion to the extracellular substrate, which inhibited collective cell migration. These findings highlight that cell adhesions and cell-cell junctions contribute to collective cell migration and provide new insights into mechanisms of the modulation of Notch-1 signalling pathway on cancer cell malignancy.

Discovery of clinical isolation of drug-resistant Klebsiella pneumoniae with overexpression of OqxB efflux pump as the decisive drug resistance factor.

Background emergence of multidrug-resistant (MDR) bacterial strains is a public health concern that threatens global and regional security. Efflux pump-overexpressing MDR strains from clinical isolates are the best subjects for studying the mechanisms of MDR caused by bacterial efflux pumps. A Klebsiella pneumoniae strain overexpressing the OqxB-only efflux pump was screened from a clinical strain library to explore reverse OqxB-mediated bacterial resistance strategies. We identified non-repetitive clinical isolated K. pneumoniae strains using a matrix-assisted laser desorption/ionization time-of-flight (TOF) mass spectrometry clinical TOF-II (Clin-TOF-II) and susceptibility test screening against levofloxacin and ciprofloxacin. And the polymorphism analysis was conducted using pulsed-field gel electrophoresis. Efflux pump function of resistant strains is obtained by combined drug sensitivity test of phenylalanine-arginine beta-naphthylamide (PaßN, an efflux pump inhibitor) and detection with ethidium bromide as an indicator. The quantitative reverse transcription PCR was performed to assess whether the oqxB gene was overexpressed in K. pneumoniae isolates. Additional analyses assessed whether the oqxB gene was overexpressed in K. pneumoniae isolates and gene knockout and complementation strains were constructed. The binding mode of PaßN with OqxB was determined using molecular docking modeling. Among the clinical quinolone-resistant K. pneumoniae strains, one mediates resistance almost exclusively through the overexpression of the resistance-nodulation-division efflux pump, OqxB. Crystal structure of OqxB has been reported recently by N. Bharatham, P. Bhowmik, M. Aoki, U. Okada et al. (Nat Commun 12:5400, 2021, https://doi.org/10.1038/s41467-021-25679-0). The discovery of this strain will contribute to a better understanding of the role of the OqxB transporter in K. pneumoniae and builds on the foundation for addressing the threat posed by quinolone resistance.IMPORTANCEThe emergence of antimicrobial resistance is a growing and significant health concern, particularly in the context of K. pneumoniae infections. The upregulation of efflux pump systems is a key factor that contributes to this resistance. Our results indicated that the K. pneumoniae strain GN 172867 exhibited a higher oqxB gene expression compared to the reference strain ATCC 43816. Deletion of oqxB led a decrease in the minimum inhibitory concentration of levofloxacin. Complementation with oqxB rescued antibiotic resistance in the oqxB mutant strain. We demonstrated that the overexpression of the OqxB efflux pump plays an important role in quinolone resistance. The discovery of strain GN 172867 will contribute to a better understanding of the role of the OqxB transporter in K. pneumoniae and promotes further study of antimicrobial resistance.

Research progress on the correlation between cataract occurrence and nutrition.

Cataract is a common eye disease characterized by lens opacity, leading to blurred vision and progressive blindness of the eye. Factors affecting the development of cataracts include nutrition, oxidative stress, micronutrients and inflammatory factors, and also include genetics, toxicity, infrared exposure, hyperuricemia, and mechanical injuries. Among the nutritional factors, a balanced diet, vegetarian diet, dairy products and vegetables are protective against cataracts; high-sodium diet, high intake of carbohydrates and polyunsaturated fatty acids may increase the risk of cataracts; and increased intake of proteins, especially animal proteins, may prevent nuclear cataracts. Intake of antioxidants such as ß-carotene, lutein, or zeaxanthin is associated with a reduced risk of cataracts. Minerals such as zinc, selenium, calcium and sodium have also been associated with cataract development. Oxidative stress plays an important role in the development of cataracts and is associated with several antioxidative enzymes and biomarkers such as glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Insulin resistance is also an essential risk factor for cataracts, especially in diabetic patients. In conclusion, understanding these influencing factors helps us to better prevent cataracts. And in this article, we will focus on the important factor of diet and nutrition for a detailed discussion.

What is said about #donateliver or #liverdonor? Reflexive thematic analysis of Twitter (X) posts from 2012 to 2022.

BACKGROUND: There is sustained interest in understanding the perspectives of liver transplant recipients and living donors, with several qualitative studies shedding light on this emotionally charged subject. However, these studies have relied primarily on traditional semi-structured interviews, which, while valuable, come with inherent limitations. Consequently, there remains a gap in our comprehension of the broader public discourse surrounding living liver donation. This study aims to bridge this gap by delving into public conversations related to living liver donation through a qualitative analysis of Twitter (now X) posts, offering a fresh perspective on this critical issue. METHODS: To compile a comprehensive dataset, we extracted original tweets containing the hashtags "#donateliver" OR "#liverdonor", all posted in English from January 1, 2012, to December 31, 2022. We then selected tweets from individual users whose Twitter (X) accounts featured authentic human names, ensuring the credibility of our data. Employing Braun and Clarke's reflexive thematic analysis approach, the study investigators read and analysed the included tweets, identifying two main themes and six subthemes. The Health Policy Triangle framework was applied to understand the roles of different stakeholders involved in the discourse and suggest areas for policy improvement. RESULTS: A total of 361 unique tweets from individual users were analysed. The major theme that emerged was the persistent shortage of liver donors, underscoring the desperation faced by individuals in need of life-saving liver transplants and the urgency of addressing the organ shortage problem. The second theme delved into the experiences of liver donors post-surgery, shedding light on a variety of aspects related to the transplantation process, including the visibility of surgical scars, and the significance of returning to physical activity and exercise post-surgery. CONCLUSION: The multifaceted experiences of individuals involved in the transplantation process, both recipients and donors, should be further studied in our efforts to improve the critical shortage of liver donors.

Viral shedding pattern of severe fever with thrombocytopenia syndrome virus in severely ill patients: A prospective, Multicenter cohort study.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is spreading rapidly in Asia. The pathway of SFTS virus shedding from patient and specific use of personal protective equipments (PPEs) against viral transmission have rarely been reported. The study was to determine SFTS virus (SFTSV) shedding pattern from the respiratory, digestive and urinary tract to outside in patients. Methods: Patients were divided into mild and severe groups in three sentinel hospitals for SFTS in Anhui province from April 2020 to October 2022. SFTSV level from blood, throat swabs, fecal/anal swabs, urine and bedside environment swabs of SFTS patients were detected by qRT-PCR. Specific PPEs were applied in healthcare workers contacting with the patients who had oropharyngeal virus shedding and hemorrhagic signs. Results: A total of 189 SFTSV-confirmed patients were included in the study, 54 patients died (case fatality rate, 28.57 %). Positive SFTSV in throat swabs (T-SFTSV), fecal/anal swabs (F-SFTSV) and urine (U-SFTSV) were detected in 121 (64.02 %), 91 (48.15 %) and 65 (34.4 %) severely ill patients, respectively. The levels of T-SFTSV, F-SFTSV and U-SFTSV were positively correlated with the load of SFTSV in blood. We firstly revealed that SFTSV positive rate of throat swabs were correlated with occurrence of pneumonia and case fatality rate of patients (P < 0.0001). Specific precaution measures were applied by healthcare workers in participating cardiopulmonary resuscitation and orotracheal intubation for severely ill patients with positive T-SFTSV, no event of SFTSV human-to-human transmission occurred after application of effective PPEs. Conclusions: Our research demonstrated SFTSV could shed out from blood, oropharynx, feces and urine in severely ill patients. The excretion of SFTSV from these parts was positively correlated with viral load in the blood. Effective prevention measures against SFTSV human-to-human transmission are needed.

A robust ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous determination of 10 components in glutathione cycle.

Glutathione (GSH) is an important antioxidant that is generated and degraded via the GSH cycle. Quantification of the main components in the GSH cycle is necessary to evaluate the process of GSH. In this study, a robust ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of 10 components (GSH; γ-glutamylcysteine; cysteinyl-glycine; n-acetylcysteine; homocysteine; cysteine; cystine; methionine; glutamate; pyroglutamic acid) in GSH cycle was developed. The approach was optimized in terms of derivative, chromatographic, and spectrometric conditions as well as sample preparation. The unstable thiol groups of GSH, γ-glutamylcysteine, cysteinyl-glycine, n-acetylcysteine, cysteine, and homocysteine were derivatized by n-ethylmaleimide. The derivatized and underivatized analytes were separated on an amino column with gradient elution. The method was further validated in terms of selectivity (no interference), linearity (R2 > 0.99), precision (% relative standard deviation [RSD%] range from 0.57 to 10.33), accuracy (% relative error [RE%] range from -3.42 to 10.92), stability (RSD% < 5.68, RE% range from -2.54 to 4.40), recovery (RSD% range from 1.87 to 7.87) and matrix effect (RSD% < 5.42). The validated method was applied to compare the components in the GSH cycle between normal and oxidative stress cells, which would be helpful in clarifying the effect of oxidative stress on the GSH cycle.

Diagnostic indicators and lifestyle interventions of metabolic-associated fatty liver disease.

MAFLD has become a major global health problem and is the leading cause of liver disease worldwide. The disease progresses from a simple fatty liver to gradual fibrosis, which progresses to cirrhosis and even hepatocellular liver cancer. However, the methods currently used for diagnosis are invasive and do not facilitate clinical assessment of the condition. As a result, research on markers for the diagnosis of MAFLD is increasing. In addition, there are no clinical medications for the treatment of MAFLD, and lifestyle interventions remain effective in the prevention and treatment of MAFLD. In this review, we attempt to make a summary of the emerging diagnostic indicators and effective lifestyle interventions for MAFLD and to provide new insights into the diagnosis and treatment of MAFLD.

Clinical Management of Patients With Relapsed/Refractory Multiple Myeloma Treated With Talquetamab.

BACKGROUND: Talquetamab is a bispecific antibody targeting the multiple myeloma-associated antigen G protein-coupled receptor family C group 5 member D (GPRC5D). In the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552), overall responses rates were > 71% in patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Due to the distribution of the target antigen, a unique pattern of GPRC5D-associated adverse events (AEs) was observed, together with T-cell redirection-associated AEs. Management strategies for talquetamab-associated AEs are described. DISCUSSION: GPRC5D-associated AEs included dermatologic (rash, nonrash, and nail toxicities) and oral AEs (dysgeusia, dysphagia, and dry mouth). The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were consistent with other T-cell redirection therapies. The incidence of high-grade infections was lower than observed with B-cell maturation antigen-targeting bispecific antibodies, with less frequent use of intravenous immunoglobulin required. GPRC5D-associated AEs were mostly low grade and led to few discontinuations. Skin toxicities were managed with emollients, topical corticosteroids, and oral corticosteroids (for high-grade, persistent, or AEs that progress). Nail toxicities were commonly managed with emollients. Based on investigator experience, dose modification may be effective for controlling oral events. Observation for potential weight changes is required. Infections were managed per standard of care. CRS and ICANS were effectively managed, consistent with other trials of T-cell redirection therapies. CONCLUSION: Although talquetamab had a distinct safety profile, AEs were considered clinically manageable and mostly low grade. With appropriate education and support, health care practitioners can ensure patients with RRMM maintain quality of life and treatment adherence. VIDEO ABSTRACT.

Characteristics of methane and carbon dioxide in ice caves at a high-mountain glacier of China.

The exploration of the spatiotemporal distribution of greenhouse gas (GHG) exchange in the cryosphere (including ice sheet, glaciers, and permafrost) is important for understanding its future feedback to the atmosphere. Mountain glaciers and ice sheets may be potential sources of GHG emissions, but the magnitude and distribution of GHG emissions from glaciers and ice sheets remain unclear because observation data are lacking. In this study, in situ CH4 and CO2 and the mixing ratios of their carbon isotope signatures in the air inside an ice cave were measured, and CH4 and CO2 exchange in the meltwater of Laohugou glacier No. 12, a high-mountain glacier in an arid region of western China, was also analyzed and compared with the exchange in downstream rivers and a reservoir. The results indicated elevated CH4 mixing ratios (up to 5.7 ppm) and depleted CO2 (down to 168 ppm) in the ice cave, compared to ambient levels during field observations. The CH4 and CO2 fluxes in surface meltwater of the glacier were extremely low compared with their fluxes in rivers from the Tibetan Plateau (TP). CH4 and CO2 mixing ratios in the air inside the ice cave were mainly controlled by local meteorological conditions (air temperature, wind speed and direction) and meltwater runoff. The carbon isotopic compositions of CH4 and CO2 in the ice cave and terminus meltwater indicated δ13C-CH4 depletion compared to ambient air, suggesting an acetate fermentation pathway. The abundances of key genes for methanogenic archaea/genes encoding methyl coenzyme M reductase further indicated the production of CH4 by methanogenic archaea from the subglacial meltwater of high-mountain glaciers. The discovery of CH4 emissions from even small high-mountain glaciers indicates a more prevalent characteristic of glaciers to produce and release CH4 from the subglacial environment than previously believed. Nevertheless, further research is required to understand the relationship between this phenomenon and glacial dynamics in the third pole.

Comparative policy analysis of national rare disease funding policies in Australia, Singapore, South Korea, the United Kingdom and the United States: a scoping review.

BACKGROUND: Rare diseases pose immense challenges for healthcare systems due to their low prevalence, associated disabilities, and attendant treatment costs. Advancements in gene therapy, such as treatments for Spinal Muscular Atrophy (SMA), have introduced novel therapeutic options, but the high costs, exemplified by Zolgensma® at US$2.1 million, present significant financial barriers. This scoping review aimed to compare the funding approaches for rare disease treatments across high-performing health systems in Australia, Singapore, South Korea, the United Kingdom (UK), and the United States (US), aiming to identify best practices and areas for future research. METHODS: In accordance with the PRISMA-ScR guidelines and the methodological framework by Arksey and O'Malley and ensuing recommendations, a comprehensive search of electronic databases (Medline, EMBASE, and Cochrane) and grey literature from health department websites and leading national organizations dedicated to rare diseases in these countries was conducted. Countries selected for comparison were high-income countries with advanced economies and high-performing health systems: Australia, Singapore, South Korea, the UK, and the US. The inclusion criteria focused on studies detailing drug approval processes, reimbursement decisions and funding mechanisms, and published from 2010 to 2024. RESULTS: Based on a thorough review of 18 published papers and grey literature, various strategies are employed by countries to balance budgetary constraints and access to rare disease treatments. Australia utilizes the Life Saving Drugs Program and risk-sharing agreements. Singapore depends on the Rare Disease Fund, which matches public donations. South Korea's National Health Insurance Service covers specific orphan drugs through risk-sharing agreements. The UK relies on the National Institute for Health and Care Excellence (NICE) to evaluate treatments for cost-effectiveness, supported by the Innovative Medicines Fund. In the US, a combination of federal and state programs, private insurance and non-profit support is used. CONCLUSION: Outcome-based risk-sharing agreements present a practical solution for managing the financial strain of costly treatments. These agreements tie payment to actual treatment efficacy, thereby distributing financial risk and promoting ongoing data collection. Countries should consider adopting and expanding these agreements to balance immediate expenses with long-term benefits, ultimately ensuring equitable access to crucial treatments for patients afflicted by rare diseases.

A Systematic Review of the Reliability and Validity of the Patient Activation Measure Tool.

Patient activation, broadly defined as the ability of individuals to manage their health and navigate the healthcare system effectively, is crucial for achieving positive health outcomes. The Patient Activation Measure (PAM), a popularly used tool, was developed to assess this vital component of health care. This review is the first to systematically examine the validity of the PAM, as well as study its reliability, factor structure, and validity across various populations. Following the PRISMA and COSMIN guidelines, a search was conducted in MEDLINE, EMBASE, and Cochrane Library, from inception to 1 October 2023, using combinations of keywords related to patient activation and the PAM. The inclusion criteria were original quantitative or mixed methods studies focusing on PAM-13 or its translated versions and containing data on psychometric properties. Out of 3007 abstracts retrieved, 39 studies were included in the final review. The PAM has been extensively studied across diverse populations and geographical regions, including the United States, Europe, Asia, and Australia. Most studies looked at populations with chronic conditions. Only two studies applied the PAM to community-dwelling individuals and found support for its use. Studies predominantly showed a high internal consistency (Cronbach's alpha > 0.80) for the PAM. Most studies supported a unidimensional construct of patient activation, although cultural differences influenced the factor structure in some cases. Construct validity was established through correlations with health behaviors and outcomes. Despite its strengths, there is a need for further research, particularly in exploring content validity and differential item functioning. Expanding the PAM's application to more diverse demographic groups and community-dwelling individuals could enhance our understanding of patient activation and its impact on health outcomes.

Semisynthesis and antitumor activity of endertiin B and related triterpenoids from Ganoderma lucidum.

Ganoderma lucidum, a fungus used in traditional Chinese medicine, is known for its medicinal value attributed to its active components called Ganoderma triterpenoids (GTs). However, the limited isolation rate of these GTs has hindered their potential as promising drug candidates. Therefore, it is imperative to achieve large-scale preparation of GTs. In this study, four GTs were effectively synthesised from lanosterol. The antitumor activity of these GTs was evaluated in vivo. Endertiin B exhibited potent inhibitory activity against breast cancer cells (9.85 ± 0.91 µM and 12.12 ± 0.95 µM). Further investigations demonstrated that endertiin B significantly upregulated p21 and p27 and downregulated cyclinD1 expression, arresting the cell cycle at the G0/G1 phase and inducing apoptosis by decreasing BCL-2 and increasing BAX and BAK levels. Additionally, endertiin B was found to reduce the expression of proteins associated with the PI3K-AKT signaling pathway. To summarize, endertiin B effectively inhibited cell proliferation by blocking the cell cycle and inducing apoptosis through the PI3K-AKT pathway.

A systematic review of the association between environmental risk factors and the development of irritable bowel syndrome.

BACKGROUND AND AIM: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with roots in genetic, immune, psychological, and dietary factors. Recently, the potential correlation between environmental exposures, such as air pollution, and IBS has gained attention. This review aimed to systematically examine existing studies on environmental factors associated with IBS, elucidating this interplay and guiding future research. METHODS: A literature search was conducted in Medline, EMBASE, Scopus, and Cochrane databases from database inception to October 10, 2023, using the keywords "Irritable Bowel" or IBS or "Irritable Colon" or "Mucous Colitis" or "Spastic Colitis" or "Spastic Colon" AND "environment* exposure*". Studies were included if they were original, published in English, described defined environmental exposure(s), and had documented diagnosis of IBS. For the purposes of this review, articles reporting physical (e.g. radiation and climate change), biological (e.g. bacteria and viruses), and chemical (e.g. harmful gases) exposures were included while psychological and dietary factors, which have been reviewed in detail elsewhere, are outside of the scope. RESULTS: A total of seven studies focusing on air quality, microbial exposure, and other environmental factors were reviewed. Studies highlighted a potential association between air pollutants and increased IBS incidence. Microbial exposure, post-natural disaster or due to poor sanitation, was linked to IBS development and gut dysbiosis. Other exposures, such as early pet ownership, were also associated with IBS risk. CONCLUSION: Existing research demonstrates an epidemiologic relationship between environmental exposures and the development of IBS. Further research is needed to understand these associations.

Psychological Resilience in Post-acute Care: A Cross-Sectional Study of Health Care Workers in Singapore Community Hospitals.

OBJECTIVES: Psychological resilience is a crucial component of mental health and well-being for health care workers. It is positively linked to compassion satisfaction and inversely associated with burnout. The current literature on health care worker resilience has mainly focused on primary care and tertiary hospitals, but there is a lack of studies in post-acute and transitional care settings. Our study aims to address this knowledge gap and evaluate the factors associated with psychological resilience among health care professionals working in community hospitals. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Physicians, nurses, rehabilitation therapists (consisting of physiotherapists, occupational therapists, and speech therapists), pharmacists, dietitians, and social workers in 2 community hospitals in Singapore. METHODS: Eligible health care workers were invited to fill in anonymous, self-reported questionnaires consisting of sociodemographic, lifestyle, and work-related factors together with the Connor-Davidson Resilience Scale (CD-RISC-10). Univariate analysis and multiple linear regression were conducted to study the relationship between each factor and resilience scores. RESULTS: A total of 574 responses were received, giving a response rate of 81.1%. The mean CD-RISC-10 score reported was 28.4. Multiple linear regression revealed that male gender (B = 1.49, P = .003), Chinese (B = -3.18, P < .001), active smokers (B = -3.82, P = .01), having perceived work crisis support (B = 2.95, P < .001), work purpose (B = 1.84, P = .002), job satisfaction (B = 1.01, P = .04), and work control (B = 2.53, P < .001) were significantly associated with psychological resilience scores among these health care workers. CONCLUSION AND IMPLICATIONS: Our study highlights the importance of certain individual and organizational factors that are associated with psychological resilience. These findings provide valuable insight into developing tailored interventions to foster resilience, such as strengthening work purpose and providing effective work crisis support, thus reducing burnout among health care workers in the post-acute care setting.