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Rapid and accurate diagnostic methods are crucial for managing viral gastroenteritis in children, a leading cause of global childhood morbidity and mortality. This study introduces a novel microfluidic-Flap endonuclease 1 (FEN1)-assisted isothermal amplification (MFIA) method for simultaneously detecting major viral pathogens associated with childhood diarrhea-rotavirus, norovirus, and adenovirus. Leveraging the specificity-enhancing properties of FEN1 with a universal dspacer-modified flap probe and the adaptability of microfluidic technology, MFIA demonstrated an exceptional detection limit (5 copies/µL) and specificity in the simultaneous detection of common diarrhea pathogens in clinical samples. Our approach addresses the limitations of current diagnostic techniques by offering a rapid (turn around time <1 h), cost-effective, easy design steps (universal flap design), and excellent detection performance method suitable for multiple applications. The validation of MFIA against the gold-standard PCR method using 150 actual clinical samples showed no statistical difference in the detection performance of the two methods, positioning it as a potential detection tool in pediatric diagnostic virology and public health surveillance. In conclusion, the MFIA method promises to transform pediatric infectious disease diagnostics and contribute significantly to global health efforts combating viral gastroenteritis.
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Background: The efficacy of bright light therapy (BLT) in ameliorating depression has been validated. The present study is to investigate the changes of depressive symptoms, cognitive function and cerebellar functional connectivity (FC) following BLT in individuals with subthreshold depression (StD). Method: Participants were randomly assigned to BLT group (N = 47) or placebo (N = 41) in this randomized controlled trial between March 2020 and June 2022. Depression severity and cognitive function were assessed, as well as resting-state functional MRI scan was conducted before and after 8-weeks treatment. Seed-based whole-brain static FC (sFC) and dynamic FC (dFC) analyses of the bilateral cerebellar subfields were conducted. Besides, a multivariate regression model examined whether baseline brain FC was associated with changes of depression severity and cognitive function during BLT treatment. Results: After 8-week BLT treatment, individuals with StD showed improved depressive symptoms and attention/vigilance cognitive function. BLT also increased sFC between the right cerebellar lobule IX and left temporal pole, and decreased sFC within the cerebellum, and dFC between the right cerebellar lobule IX and left medial prefrontal cortex. Moreover, the fusion of sFC and dFC at baseline could predict the improvement of attention/vigilance in response to BLT. Conclusions: The current study identified that BLT improved depressive symptoms and attention/vigilance, as well as changed cerebellum-DMN connectivity, especially in the cerebellar-frontotemporal and cerebellar internal FC. In addition, the fusion features of sFC and dFC at pre-treatment could serve as an imaging biomarker for the improvement of attention/vigilance cognitive function after BLT in StD.
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AIMS: Inadequate preparedness of family caregivers contributes to adverse outcomes of patients with heart failure (HF). However, evidence on caregiver preparedness is limited. This study aims to examine the determinants and potential mechanisms of preparedness in family caregivers of patients with HF. METHODS AND RESULTS: In the cross-sectional study, 298 HF patient-caregiver dyads were recruited from 4 tertiary hospitals in China. Preparedness, uncertainty in illness, family relational quality, social support, and positive aspects of caregiving (PAC) were assessed in family caregivers using self-reported questionnaires. In the path analysis model, uncertainty in illness had an indirect negative effect on preparedness via reduced PAC [indirect effect = -0.020; 95% confidence interval (CI) -0.050 to -0.002]. Whereas, family relational quality had direct (ß = 0.266; P < 0.001) and indirect positive effects on preparedness through increased PAC (indirect effect = 0.027; 95% CI, 0.003-0.067). Similarly, social support also had direct (ß = 0.184; P = 0.004) and indirect positive effects on preparedness through increased PAC (indirect effect = 0.027; 95% CI, 0.004-0.065). CONCLUSION: This study highlights that diminishing uncertainty in illness may indirectly improve caregiver preparedness through the enhancement of PAC, while raising family relational quality and social support may improve caregiver preparedness both directly and indirectly by augmenting PAC. These findings provide insightful implications for healthcare professionals in developing tailored interventions to ameliorate preparedness in family caregivers of patients with HF.
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This study was aimed to examine the moderated mediating effects of exercise self-efficacy and fear of movement on the relationship between fatigue and quality of life in patients with heart failure. A total of 305 patients with heart failure were enrolled in this cross-sectional study. The results showed that fear of movement significantly mediated the relationship between fatigue and quality of life, indicating that relieving fear of movement may be beneficial to improve quality of life. Furthermore, exercise self-efficacy negatively moderated the mediating effect of fear of movement on the relationship between fatigue and physical health-related quality of life. It is suggesting that improving exercise self-efficacy may provide opportunities to buffer the negative effect of fear of movement on physical health-related quality of life in patients with heart failure, especially for those with fatigue. The findings provide additional strategies to optimize quality of life management in patients with heart failure.
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BACKGROUND: Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality. AIM: To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice. METHODS: Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP's main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP's treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2) knockdown elucidated Andro's molecular mechanisms. RESULTS: XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation, with Nrf2 knockdown reducing Andro's proliferative and endothelial protective effects. CONCLUSION: XP significantly promotes wound healing in STZ-induced diabetic models. As XP's key component, Andro activates the Nrf2/HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.
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The burden of fungal infections on human health is increasing worldwide. Aspergillus, Candida, and Cryptococcus are the top three human pathogenic fungi that are responsible for over 90% of infection-related deaths. Moreover, effective antifungal therapeutics are lacking, primarily due to host toxicity, pathogen resistance, and immunodeficiency. In recent years, nanomaterials have proved not only to be more efficient antifungal therapeutic agents but also to overcome resistance against fungal medication. This review will examine the limitations of standard antifungal therapy as well as focus on the development of nanomaterials.
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Although rare, trans-kingdom infection features an interesting infection biology concept, in which highly versatile pathogenic attributes allow successful infections in evolutionarily highly divergent species. Corynespora cassiicola is a phytopathogenic fungus and occasionally causes human infections. Herein, we report a phaeohyphomycosis case caused by C. cassiicola. Given that sporadic reports may contribute to a lack of awareness of the transmission route, clinical manifestations, and diagnostic and clinical management, we systematically reviewed the cases reported thus far. Nine patients were identified and included in the pooled analysis, 88.9% (8/9) of whom were reported after 2010. All patients were from Asian, African, and Latin American countries, among whom 77.8% (7/9) were farmers or lived in areas with active agriculture. Exposed body parts were the major affected infection area, and clinical manifestations were mainly non-specific inflammatory reactions. Although biochemical and morphological examinations confirmed the presence of fungal infection, molecular analysis was used for the final diagnosis, with 77.8% (7/9) being identified by internal transcribed spacer sequencing. Whereas voriconazole, terbinafine, and AmB, either alone or in combination, resulted in successful infection resolution in most cases (5/9; 55.5%), those suffering from invasive facial infections and CARD9 deficiency showed poor outcomes. Our patient is the third case of invasive facial infection caused by C. cassiicola and was successfully treated with intravenous LAmB followed by oral voriconazole combined with topical antifungal irrigation. Molecular identification of fungus and prompt antifungal treatment is pivotal in the clinical success of patients suspected to have phaeohyphomycosis. Moreover, as evidenced by our data, itraconazole treatment is not recommended.
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The application of interleukin-17 (IL-17) inhibitors, including secukinumab, ixekizumab, brodalumab, and bimekizumab, are associated with elevated risk of candidiasis. These medications interfere with the IL-17 pathway, which is essential for maintaining mucosal barriers and coordinating the immune response against Candida species. The observational data and clinical trials demonstrate the increased incidence of candidiasis in individuals treated with IL-17 inhibitors. Brodalumab and bimekizumab pose a greater risk than secukinumab in eliciting candidiasis, whereas the data regarding ixekizumab are equivocal. Higher doses and prolonged treatment duration of IL-17 inhibitors increase the risk of candidiasis by compromising the immune response against Candida species. Prior to prescribing IL-17 inhibitors, healthcare professionals should comprehensively evaluate patients' medical histories and assess their risk factors. Patients should be educated on the signs and symptoms of candidiasis to facilitate early detection and intervention. Future research should focus on identifying the risk factors associated with candidiasis in patients receiving IL-17 inhibitors. Prospective studies and long-term surveillance are required to explore the impact of specific inhibitors on the incidence and severity of candidiasis and to evaluate the effectiveness of combination therapies, such as concurrent use of IL-17 inhibitors and prophylactic antifungal agents.
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Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual's susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.
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Candidíase , Interleucina-17 , Humanos , Inibidores de Interleucina , Estudos Prospectivos , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Interleucina-23RESUMO
The underlying mechanisms of bright light therapy (BLT) in the prevention of individuals with subthreshold depression symptoms are yet to be elucidated. The goal of the study was to assess the correlation between midbrain monoamine-producing nuclei treatment-related functional connectivity (FC) changes and depressive symptom improvements in subthreshold depression. This double-blind, randomized, placebo-controlled clinical trial was conducted between March 2020 and June 2022. A total of 74 young adults with subthreshold depression were randomly assigned to receive 8-week BLT (N = 38) or placebo (N = 36). Depression severity was measured using the Hamilton Depression Rating Scale (HDRS). The participants underwent resting-state functional magnetic resonance imaging at baseline and after treatment. The dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and habenula seed-based whole-brain FC were analyzed. A multivariate regression model examined whether baseline brain FC was associated with changes in scores on HDRS during BLT treatment. BLT group displayed significantly decreased HDRS scores from pre- to posttreatment compared to the placebo group. BLT increased the FC between the DRN and medial prefrontal cortex (mPFC) and between the left VTA and right superior frontal gyrus (SFG). Altered VTA-SFG connectivity was associated with HDRS changes in the BLT group. Moreover, the baseline FC between DRN and mPFC could predict HDRS changes in BLT. These results suggested that BLT improves depressive symptoms and increases midbrain monoamine-producing nuclei and frontal cortex connectivity in subthreshold depression, which raises the possibility that pretreatment FC of DRN-mPFC could be used as a biomarker for improved BLT treatment in depression. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Transtorno Depressivo Maior , Adulto Jovem , Humanos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/terapia , Depressão , Fototerapia/métodos , Córtex Pré-Frontal , Mesencéfalo , Imageamento por Ressonância Magnética/métodosRESUMO
Fungal infections present a growing global public health concern, necessitating the development of novel antifungal drugs. However, many potential antifungals, particularly the expelled potential active agents (EPAAs), are often underestimated owing to their limitations in cellular entry or expulsion by efflux pumps. Herein, we identified 68 EPAAs out of 2322 candidates with activity against a Candida albicans efflux pump-deficient strain and no inhibitory activity against the wild-type strain. Using a novel conjugation strategy involving benzamidine (BM) as a mitochondrion-targeting warhead, we successfully converted EPAAs into potent antifungals against various urgent-threat azole-resistantCandida strains. Among the obtained EPAA-BM conjugates, IS-2-BM (11) exhibited excellent antifungal activities and induced negligible drug resistance. Furthermore, IS-2-BM prevented biofilm formation, eradicated mature biofilms, and exhibited excellent therapeutic effects in a murine model of systemic candidiasis. These findings provide a promising strategy for increasing the possibilities of discovering more antifungals.
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Candidíase , Micoses , Animais , Camundongos , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Candida albicans , Micoses/tratamento farmacológico , Biofilmes , Testes de Sensibilidade Microbiana , Farmacorresistência FúngicaRESUMO
BACKGROUND: Diabetic skin ulcers, a significant global healthcare burden, are mainly caused by the inhibition of cell proliferation and impaired angiogenesis. XB130 is an adaptor protein that regulates cell proliferation and migration. However, the role of XB130 in the development of diabetic skin ulcers remains unclear. AIM: To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose. Additionally, we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers, along with its molecular mechanisms. METHODS: We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers. We investigated the effects of XB130 on wound healing using histological analyses. In addition, we used reverse transcription-quantitative polymerase chain reaction, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, immunofluorescence, wound healing, and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells (HUVECs) stimulated with high glucose. Finally, we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers. RESULTS: RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers. Knockdown of XB130 promoted the healing of skin wounds in mice, leading to an accelerated wound healing process and shortened wound healing time. At the cellular level, knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs. Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130. CONCLUSION: The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs. Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway, which accelerates the healing of diabetic skin ulcers.
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BACKGROUND: Inadequate self-care management has been reported in patients with heart failure (HF) and their family caregivers. However, evidence on the influencing factors and corresponding action paths for self-care management within a dyadic context is limited. OBJECTIVE: The aim of this study was to examine dyadic associations between benefit finding and self-care management in HF patient-caregiver dyads and the mediating role of mutuality in these associations. METHODS: This cross-sectional study was conducted in China, and a convenience sample of 253 HF patient-caregiver dyads was included in the analysis. Dyadic benefit finding and mutuality, patients' self-care management, and caregivers' contributions to self-care management were measured using self-reported questionnaires. The actor-partner interdependence model and actor-partner interdependence mediation model were adopted to analyze the data. RESULTS: Patients' benefit finding had an actor effect on their own self-care management (ß = 0.134, P < .05) and a partner effect on caregivers' contributions to self-care management (ß = 0.130, P < .05). Similarly, caregivers' benefit finding had an actor effect on their contributions to self-care management (ß = 0.316, P < .01) and a partner effect on patients' self-care management (ß = 0.187, P < .01). Moreover, patients' mutuality completely mediated the actor effect of their benefit finding on self-care management (ß = 0.127; 95% confidence interval, 0.032-0.233), and caregivers' mutuality partially mediated the actor effect of their benefit finding on contributions to self-care management (ß = 0.060; 95% confidence interval, 0.012-0.124). In addition, caregivers' mutuality completely mediated the partner effect of patients' benefit finding on caregivers' contributions to self-care management (ß = 0.036; 95% confidence interval, 0.009-0.081). CONCLUSIONS: The findings revealed the importance of benefit finding and mutuality, 2 modifiable factors positively associated with dyadic HF self-care management. Dyadic interventions targeting on enhancing benefit finding and mutuality should be designed and implemented to improve HF self-care management.
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Whether the alternated microbiota in the gut contribute to the risk of allograft rejection (AR) and pulmonary infection (PI) in the setting of lung transplant recipients (LTRs) remains unexplored. A prospective multicenter cohort of LTRs was identified in the four lung transplant centers. Paired fecal and serum specimens were collected and divided into AR, PI, and event-free (EF) groups according to the diagnosis at sampling. Fecal samples were determined by metagenomic sequencing. And metabolites and cytokines were detected in the paired serum to analyze the potential effect of the altered microbiota community. In total, we analyzed 146 paired samples (AR = 25, PI = 43, and EF = 78). Notably, we found that the gut microbiome of AR followed a major depletion pattern with decreased 487 species and compositional diversity. Further multi-omics analysis showed depleted serum metabolites and increased inflammatory cytokines in AR and PI. Bacteroides uniformis, which declined in AR (2.4% vs 0.6%) and was negatively associated with serum IL-1ß and IL-12, was identified as a driven specie in the network of gut microbiome of EF. Functionally, the EF specimens were abundant in probiotics related to mannose and cationic antimicrobial peptide metabolism. Furthermore, a support-vector machine classifier based on microbiome, metabolome, and clinical parameters highly predicted AR (AUPRC = 0.801) and PI (AUPRC = 0.855), whereby the microbiome dataset showed a particularly high diagnostic power. In conclusion, a disruptive gut microbiota showed a significant association with allograft rejection and infection and with systemic cytokines and metabolites in LTRs.
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Microbioma Gastrointestinal , Transplante de Pulmão , Humanos , Microbioma Gastrointestinal/genética , Estudos Prospectivos , Citocinas , AloenxertosRESUMO
BACKGROUND: The global burden of invasive fungal infections (IFIs) has shown an upsurge in recent years due to the higher load of immunocompromised patients suffering from various diseases. The role of early and accurate diagnosis in the aggressive containment of the fungal infection at the initial stages becomes crucial thus, preventing the development of a life-threatening situation. With the changing demands of clinical mycology, the field of fungal diagnostics has evolved and come a long way from traditional methods of microscopy and culturing to more advanced non-culture-based tools. With the advent of more powerful approaches such as novel PCR assays, T2 Candida, microfluidic chip technology, next generation sequencing, new generation biosensors, nanotechnology-based tools, artificial intelligence-based models, the face of fungal diagnostics is constantly changing for the better. All these advances have been reviewed here giving the latest update to our readers in the most orderly flow. MAIN TEXT: A detailed literature survey was conducted by the team followed by data collection, pertinent data extraction, in-depth analysis, and composing the various sub-sections and the final review. The review is unique in its kind as it discusses the advances in molecular methods; advances in serology-based methods; advances in biosensor technology; and advances in machine learning-based models, all under one roof. To the best of our knowledge, there has been no review covering all of these fields (especially biosensor technology and machine learning using artificial intelligence) with relevance to invasive fungal infections. CONCLUSION: The review will undoubtedly assist in updating the scientific community's understanding of the most recent advancements that are on the horizon and that may be implemented as adjuncts to the traditional diagnostic algorithms.
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Inteligência Artificial , Infecções Fúngicas Invasivas , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Reação em Cadeia da Polimerase/métodosRESUMO
Previous studies regarding the gastrointestinal biogeography of microbiomes generally focused on longitudinal comparisons, whereas few studies have compared luminal and mucosal microbiomes. Investigations of the snake gut microbiome have attracted interest because of the unique digestive physiology and hibernation behavior, but adequate sampling methods must be developed. Here, we used an omics approach combining 16S rRNA gene sequencing with untargeted metabolomics to profile the luminal and mucosal gut microbiomes and metabolomes in oriental rat snakes, with the goal of revealing the heterogeneity and co-occurrence at these sites. The α-diversity of the gut microbiome was significantly higher at mucosal sites than at luminal sites. Microbial composition also differed according to sampling site, with significant differences in the abundances of dominant phyla and genera, as well as ß-diversity clustering and distribution. Metabolome profiling revealed differences that were mainly related to cholinergic substances and nucleic acids. Analysis of variations in Kyoto Encyclopedia of Genes and Genomes functions of microbes and metabolites showed that the mucosal microbiome was more frequently involved in genetic information processing and cellular processes, whereas the luminal microbiome generally participated in metabolic regulation. Notably, we found a greater abundance of the opportunistic pathogen genus Escherichia-Shigella at luminal sites and higher levels of the lipid-regulator metabolite fenfluramine at mucosal sites. Despite the extensive differences between the two sampling sites, the results revealed similarities in terms of amplicon sequence variant composition and dominant core microbes. This pilot exploration of luminal and mucosal microbiomes and metabolites provides key insights to guide future research. KEY POINTS: ⢠Snake luminal and mucosal microbiota was distinct in composition and function. ⢠Metabolome profiling revealed differences related to different metabolites. ⢠The pathogenic microbes are more likely to colonize the gut lumina.
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Microbioma Gastrointestinal , Microbiota , Animais , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , Metaboloma , Serpentes/genéticaRESUMO
Chemodynamic therapy (CDT) has advantages in site-specific killing tumor and avoiding systemically side effect. Although numerous nano-systems have been developed to enhance the intracellular hydrogen peroxide (H2O2) for improving CDT effect, the biocompatibility of the materials limits their further biomedical applications. Herein glycogen, as a natural biological macromolecule, was used to construct a new targeted separable GOx@GF/HC nanoparticle system to deliver glucose oxidase (GOx) for CDT/starvation tumor therapy. Amination glycogen-ferrocene (GF) as a guest core and hyaluronic acid-ß-cyclodextrin (HC) as a host shell were synthesized and self-assembled through host-guest interactions to deliver GOx. After being entered into tumor cells, GOx were released to catalyze glucose to produce gluconic acid and H2O2, which in turn cut off the nutrition of tumor cells for starvation therapy and enhanced the generation of OH with ferrous ion through Fenton reaction. Furthermore, GOx@GF/HC also exhibited remarkable tumor-targeting and tumor-suppression in vivo. Therefore, the GOx@GF/HC system can exert excellent synergistic effect of CDT and starvation therapy on cancer treatment through a cascade reaction, which have some potential application for the development of CDT tumor-treatment.
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Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Glucose Oxidase , Glicogênio , Humanos , Ácido Hialurônico/uso terapêutico , Peróxido de Hidrogênio , Neoplasias/patologiaRESUMO
The combination of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) has been commonly used for inflammation and chronic articular pain in the clinic. Nonetheless, the long-term administration of both medications might result in osteonecrosis of the knee due to repeated injections of steroids and side effects in the gastrointestinal and cardiovascular systems. To overcome these unmet medical needs, we designed a microsphere-microcrystal-gel delivery system for intra-articular injection. Dexamethasone (DEX)-loaded microspheres (DMs) were optimized by Plackett-Burman and Taguchi orthogonal designs to extend their retention time in the knee joint. Celecoxib (CLX) microcrystals (CMs) were manufactured using an ultrasonic method to improve solubility and bioavailability. Moreover, a green solvent-free method was employed to crosslink and synthesize a novel poloxamer 407/Gantrez® S97-based gel system (GZF), which can undergo the sol-gel transition at lower concentrations. Then, DM and CM were loaded by GZF to form intra-articular injectable gels (DM/CM/Gel). The in vitro release of DEX and CLX showed a fast phase in 24 h followed by a controlled release of â¼8 d. Both blank microspheres and GZF gels displayed great biocompatibility against RAW264.7 macrophages. The most suitable dosages of 5 nM DEX and 125 nM CLX in the formulation were chosen because of their significant effects against macrophage inflammation with a lower administrative amount. An In vivo animal evaluation showed that DM/CM/Gel suppressed the release of inflammatory cytokines (TNF-α and IL-6) after 21 d of treatment. In addition, a histological evaluation revealed that DM/CM/Gel interrupted the progression of cartilage surface denudation and matrix loss. Therefore, DM/CM/Gel provides a prospective strategy for reforming traditional therapy for chronic articular disease.
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Osteoartrite do Joelho , Animais , Celecoxib , Dexametasona , Géis/uso terapêutico , Inflamação/tratamento farmacológico , Injeções Intra-Articulares , Microesferas , Osteoartrite do Joelho/tratamento farmacológico , Estudos ProspectivosRESUMO
Knowledge about the clinical characteristics and prognostic factors of Talaromyces marneffei infection in children is limited, especially in HIV-positive children. We performed a retrospective study of all HIV-positive pediatric inpatients with T. marneffei infection in a tertiary hospital in Southern China between 2014 and 2019 and analyzed the related risk factors of poor prognosis using logistic regression. Overall, 28 cases were enrolled and the prevalence of talaromycosis in AIDS children was 15.3% (28/183). The median age of the onset was 8 years (range: 1-14 years). The typical manifestation of skin lesion with central umbilication was not common (21.4%). All the children had very low CD4+ cell counts (median 13.5 cells/µL, range: 3-137 cells/µL) on admission. 92.9% children were misdiagnosed and talaromycosis was only noted after positivity for HIV infection. 89.3% diagnoses of T. marneffei infections were based on positive blood cultures, with a long culture time (median 7 days, range from 3-14 days). The sensitivity of fungus 1,3-ß-D-glucan assay was 63.2%. Amphotericin B was superior to itraconazole in the induction antifungal therapy of talaromycosis in HIV-positive children. A six-month follow-up revealed a 28.6% mortality. Lower ratio of CD4+/CD8+ and amphotericin B treatment not over 7 days predicted poor prognosis. Our retrospective study provided an overview and update on the current knowledge of talaromycosis in HIV-positive children. Pediatricians in endemic areas should be aware of mycoses to prevent misdiagnosis. 1,3-ß-D-glucan assay did not show optimal sensitivity. Amphotericin B treatment over 7 days can improve poor prognosis.
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Infecções por HIV , Micoses , Talaromyces , Adolescente , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Glucanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Micoses/diagnóstico , Micoses/tratamento farmacológico , Micoses/epidemiologia , Prognóstico , Estudos RetrospectivosRESUMO
Despite recent progress in our understanding of the association between the gut microbiome and colorectal cancer (CRC), multi-kingdom gut microbiome dysbiosis in CRC across cohorts is unexplored. We investigated four-kingdom microbiota alterations using CRC metagenomic datasets of 1,368 samples from 8 distinct geographical cohorts. Integrated analysis identified 20 archaeal, 27 bacterial, 20 fungal and 21 viral species for each single-kingdom diagnostic model. However, our data revealed superior diagnostic accuracy for models constructed with multi-kingdom markers, in particular the addition of fungal species. Specifically, 16 multi-kingdom markers including 11 bacterial, 4 fungal and 1 archaeal feature, achieved good performance in diagnosing patients with CRC (area under the receiver operating characteristic curve (AUROC) = 0.83) and maintained accuracy across 3 independent cohorts. Coabundance analysis of the ecological network revealed associations between bacterial and fungal species, such as Talaromyces islandicus and Clostridium saccharobutylicum. Using metagenome shotgun sequencing data, the predictive power of the microbial functional potential was explored and elevated D-amino acid metabolism and butanoate metabolism were observed in CRC. Interestingly, the diagnostic model based on functional EggNOG genes achieved high accuracy (AUROC = 0.86). Collectively, our findings uncovered CRC-associated microbiota common across cohorts and demonstrate the applicability of multi-kingdom and functional markers as CRC diagnostic tools and, potentially, as therapeutic targets for the treatment of CRC.