ABSTRACT
Pneumoconiosis is a common occupational disease that can worsen with accompanying infection. Torque teno virus (TTV) is a prevalent human virus with multiple genotypes that can chronically and persistently infect individuals. However, the prevalence of TTV in pneumoconiosis patients is still unclear. This research aims to detect the presence and prevalence of TTV in the alveolar lavage fluid of pneumoconiosis patients in the Hunan Province of China using PCR. As a result, a 65.5% positive rate (19 out of 29) of TTV was detected. The TTV detection rate varies among different stages of silicosis and different pneumoconiosis patient ages. Nine novel TTV genomes ranging in size from 3719 to 3908 nt, named TTV HNPP1, HNPP2, HNPP3, HNPP4, HNPP5, HNPP6-1, HNPP6-2, HNPP7-1 and HNPP7-2, were identified. A genomic comparison and phylogenetic analysis indicated that these nine TTVs represent five different species with high genetic diversity which belong to the genus Alphatorquevirus. HNPP6-1 and HNPP6-2 belong to TTV3, HNPP5 belongs to TTV13, HNPP1 belongs to TTV24, HNPP4 belongs to TTV20, and the others belong to TTV19. The genomes of TTV HNPP1, HNPP6-1, and HNPP6-2 contain three putative open reading frames (ORFs) coding for proteins, ORF1, ORF2, and ORF3, while the other six TTV genomes contain two ORFs coding for proteins, ORF1 and ORF2. These results provide the first description of TTV epidemiology in pneumoconiosis patients in China. The newly identified TTV genome sequences reveal the high genetic diversity of TTV in pneumoconiosis patients and could contribute to a deeper understanding of TTV retention and infection in humans.
Subject(s)
Genome, Viral , Phylogeny , Pneumoconiosis , Torque teno virus , Humans , Torque teno virus/genetics , Torque teno virus/isolation & purification , Torque teno virus/classification , China/epidemiology , Pneumoconiosis/virology , Pneumoconiosis/epidemiology , Pneumoconiosis/genetics , Male , Middle Aged , Aged , DNA Virus Infections/virology , DNA Virus Infections/epidemiology , Genetic Variation , Genotype , Adult , Genomics/methods , Female , Bronchoalveolar Lavage Fluid/virology , DNA, Viral/geneticsABSTRACT
Enfortumab vedotin is a fully human monoclonal antibody directed to Nectin-4 and conjugated to monomethyl auristatin E (MMAE), approved for treatment of previously treated locally advanced or metastatic urothelial carcinoma (mUC). This population analysis characterized pharmacokinetics of enfortumab vedotin and free (unconjugated) MMAE, identified covariates affecting pharmacokinetics, and evaluated weight-based dosing for enfortumab vedotin. Exposure-response analyses characterized relationships between enfortumab vedotin and free MMAE exposures and efficacy/safety endpoints. Data from 748 patients with locally advanced or mUC in 5 clinical studies were analyzed using nonlinear mixed-effects modeling. Patients received enfortumab vedotin 0.50-1.25 mg/kg every 3 weeks or on days 1, 8, and 15 of a 28-day cycle. Relevant covariates retained in final models were evaluated for clinical relevance to enfortumab vedotin and free MMAE exposures. Although some covariates produced differences in exposure, the magnitude of changes was not clinically meaningful. Simulations indicated weight-based dosing yielded more consistent exposures across body weight groups vs. a hypothetical fixed-dose regimen of enfortumab vedotin 95 mg (calculated for median body weight, 75 kg). Exposure-response analysis showed average enfortumab vedotin concentrations were not a statistically significant predictor of overall survival (hazard ratio 0.91, 95% confidence interval: 0.72-1.14; P = 0.41); all exposure quartiles had a greater median overall survival than chemotherapy (11.0-12.6 vs. 9.0 months). Enfortumab vedotin and free MMAE exposures were statistically significant predictors of grade ≥ 3 treatment-related adverse events (both P < 0.0001). This analysis supports enfortumab vedotin 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle.
ABSTRACT
Cigarette smoking is the acknowledged major cause of cancers of the lung and oral cavity and is an established important risk factor for multiple other cancers. DNA addition products (DNA adducts) caused by cigarette smoking are critical factors in its mechanism of carcinogenesis. However, most DNA adducts detected to date in humans cannot be specifically ascribed to smoking but rather have multiple exogenous and endogenous sources. In the study reported here, we prepared [13C]-labeled tobacco to address this problem. We report for the first time the successful growth from seeds to flowering under hydroponic conditions of highly [13C]-labeled tobacco in a controlled 13CO2 environment. The standard growth procedure with optimized conditions is described in detail. The [13C]-enrichment rate was assessed by quantifying nicotine and sugars and their [13C]-isotopologues in this tobacco using high-resolution mass spectrometry, reaching >94% in the tobacco leaves. The [13C]-labeled leaves after curing will be used to make cigarettes, allowing investigation of the specific contributions of tobacco smoke carcinogens to identified DNA adducts in smokers.
Subject(s)
Carbon Isotopes , DNA Damage , Hydroponics , Nicotiana , Nicotiana/chemistry , Nicotiana/growth & development , Nicotiana/metabolism , Carbon Isotopes/analysis , Carbon Isotopes/metabolism , Humans , DNA Adducts/metabolism , DNA Adducts/analysis , Smokers , Plant Leaves/chemistry , Plant Leaves/growth & development , Plant Leaves/metabolism , Nicotine/metabolismABSTRACT
The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials, decreases the efficiency of programmed -1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion. Carrimycin binds directly to the coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes. Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses. Because the FSE mechanism is essential in all coronaviruses, carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA. This finding may open a new direction in antiviral drug discovery for coronavirus variants.
ABSTRACT
Paclitaxel (PTX) is one of the first-line drugs for prostate cancer (PC) treatment. However, the poor water solubility, inadequate specific targeting ability, multidrug resistance, and severe neurotoxicity are far from being fully resolved, despite diverse PTX formulations in the market, such as the gold-standard PTX albumin nanoparticle (Abraxane) and polymer micelles (Genexol-PM). Some studies attempting to solve the multiple problems of chemotherapy delivery fall into the trap of an extremely complicated formulation design and sacrifice druggability. To better address these issues, this study designed an efficient, toxicity-reduced paclitaxel-ginsenoside polymeric micelle (RPM). With the aid of the inherent amphiphilic molecular structure and pharmacological effects of ginsenoside Rg5, the prepared RPM enhances the water solubility and active targeting of PTX, inhibiting chemotherapy resistance in cancer cells. Moreover, the polymeric micelles demonstrated favorable anti-inflammatory and neuroprotective effects, providing ideas for the development of new clinical anti-PC preparations.
Subject(s)
Drug Resistance, Neoplasm , Ginsenosides , Micelles , Paclitaxel , Ginsenosides/chemistry , Ginsenosides/pharmacology , Paclitaxel/pharmacology , Paclitaxel/chemistry , Humans , Drug Resistance, Neoplasm/drug effects , Animals , Male , Mice , Cell Line, Tumor , Prostatic Neoplasms/drug therapy , Drug Carriers/chemistry , Solubility , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Drug Delivery Systems/methods , Polymers/chemistryABSTRACT
OBJECTIVE: To understand the prevalence rate of obstructive pulmonary dysfunction in workers exposed to silica dust and analyze its risk factors, so as to provide reference for the formulation of diagnostic criteria for chronic obstructive pulmonary disease caused by occupational dust. METHODS: Data collection and structured questionnaire were used to collect the data of 2064 workers exposed to silica dust who underwent health examination in Hunan Occupational Disease Prevention and Control Hospital and Yuanling Second People's Hospital from January 1, 2021 to June 30, 2022. The prevalence rate of obstructive pulmonary ventilation dysfunction was analyzed and the risk factors were analyzed. RESULTS: The prevalence rate of obstructive pulmonary ventilation dysfunction (FEV1/FVC < 70%) was 2.3% in 2064 silica dust exposed workers. The prevalence of restrictive pulmonary ventilation dysfunction (FVC/Pre < 80%) was 8.1%. The prevalence of obstructive pulmonary ventilation dysfunction in the high level exposure group was higher than that in the low level exposure group, 8.2 vs0.9% (P < 0.05). The rate of obstructive pulmonary ventilation dysfunction in female group was higher than that in male group (5.3% vs. 1.7%, p = 0.00). Workers with obstructive pulmonary dysfunction were older and worked longer than workers without obstructive pulmonary dysfunction, but there was no statistical difference. Multivariate regression analysis showed that high exposure level was a risk factor for obstructive pulmonary ventilation dysfunction in silica dust exposed workers (P < 0.05). Females were the risk factors for obstructive pulmonary ventilation dysfunction (P < 0.05). CONCLUSION: Silica dust exposure can cause obstructive pulmonary ventilation dysfunction and lead to chronic obstructive pulmonary disease. High level of exposure is a risk factor for obstructive pulmonary ventilation dysfunction. Women exposed to dust are more prone to obstructive pulmonary ventilation dysfunction than men. Early diagnosis of chronic obstructive pulmonary disease caused by silica dust and timely intervention measures are very important to delay the decline of lung function and protect the health of workers.
Subject(s)
Dust , Occupational Exposure , Silicon Dioxide , Humans , Female , Male , Silicon Dioxide/adverse effects , Risk Factors , Cross-Sectional Studies , Occupational Exposure/adverse effects , Prevalence , Middle Aged , Adult , China/epidemiology , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/physiopathology , Occupational Diseases/epidemiology , Occupational Diseases/etiology , Surveys and Questionnaires , Lung Diseases, Obstructive/epidemiology , Lung Diseases, Obstructive/physiopathology , Multivariate AnalysisABSTRACT
Vegetation degradation in arid and semi-arid regions reduces plant C inputs to the soil, which can impede soil nutrient cycling because of the limited C source for microbial metabolism. However, whether vegetation degradation aggravates microbial nutrient limitation in degraded ecosystems in arid and semi-arid regions is not fully understood. Here, we investigated changes in soil enzyme activity and microbial nutrient limitation along a well-documented gradient of degraded seabuckthorn (Hippophae rhamnoides L.) (slightly degraded, canopy dieback <25 %, moderately degraded, canopy dieback 25 %-75 %, and severely degraded, canopy dieback >75 %) in Liang (long ridge) and gully channel locations in the Pisha Sandstone region of the Loess Plateau, China. We found that as the magnitude of seabuckthorn degradation increased, activities of C-acquiring enzymes and ratios of C:N and C:P enzymes (0.54-0.80 and 0.52-0.77, respectively) increased whereas the N:P enzyme ratio (0.93-0.99) decreased. Stoichiometric modelling further indicated that microorganisms were limited by soil C and P (vector angle >45°) in the seabuckthorn plantation region, and the degradation of seabuckthorn plantation aggravated microbial C and P limitations. Partial least squares path modelling revealed that seabuckthorn degradation (canopy dieback) was the main factor explaining microbial C limitation variations, while soil physicochemical properties (pH and soil moisture content) and understory plant parameters (litter biomass) were the major factors underlying microbial P limitation of long ridge and gully channel formations, respectively. Our findings highlight synergistic changes between aboveground and belowground processes, suggesting an unexpected negative effect of vegetation degradation on soil microbial community and nutrient cycling. These insights offer a direction for the development of plantation nutrients management strategies in semi-arid and arid areas.
Subject(s)
Hippophae , Phosphorus , Soil Microbiology , Soil , China , Phosphorus/analysis , Phosphorus/metabolism , Soil/chemistry , Carbon/metabolism , Ecosystem , Nitrogen/metabolism , Nitrogen/analysisABSTRACT
Betulinic acid (BA) is a lupane-type triterpenoid with potent anticancer and anti-HIV activities. Its great potential in clinical applications necessitates the development of an efficient strategy for BA synthesis. This study attempted to achieve efficient BA biosynthesis in Saccharomyces cerevisiae using systematic metabolic engineering strategies. First, a de novo BA biosynthesis pathway in S. cerevisiae was constructed, which yielded a titer of 14.01 ± 0.21 mg/L. Then, by enhancing the BA synthesis pathway and dynamic inhibition of the competitive pathway, a greater proportion of the metabolic flow was directed toward BA synthesis, achieving a titer of 88.07 ± 5.83 mg/L. Next, acetyl-CoA and NADPH supply was enhanced, which increased the BA titer to 166.43 ± 1.83 mg/L. Finally, another BA synthesis pathway in the peroxisome was constructed. Dual regulation of the peroxisome and cytoplasmic metabolism increased the BA titer to 210.88 ± 4.76 mg/L. Following fed-batch fermentation process modification, the BA titer reached 682.29 ± 8.16 mg/L. Overall, this work offers a guide for building microbial cell factories that are capable of producing terpenoids with efficiency.
Subject(s)
Betulinic Acid , Metabolic Engineering , NADP , Pentacyclic Triterpenes , Saccharomyces cerevisiae , Triterpenes , Metabolic Engineering/methods , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae/genetics , Pentacyclic Triterpenes/metabolism , Triterpenes/metabolism , NADP/metabolism , Acetyl Coenzyme A/metabolism , Fermentation , Biosynthetic Pathways/geneticsABSTRACT
Previously, we documented the synthesis and assessed the biological effects of chalcones containing selenium against HT-29 human colorectal adenocarcinoma cells, demonstrating their significant potential. As research on selenium-containing flavonoids remains limited, this article outlines our design and synthesis of three selenium-based flavonols and three 2-styrylchromones. We conducted evaluations of these compounds to determine their impact on human lung cancer cells (A549, H1975, CL1-0, and CL1-5) and their influence on normal lung fibroblast MRC5 cells. Additionally, we included selenium-based chalcones in our testing for comparative purposes. Our findings highlight that the simplest compound, designated as compound 1, exhibited the most promising performance among the tested molecules.
ABSTRACT
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.
Subject(s)
Fatty Acid-Binding Proteins , Fatty Liver , Glutathione Transferase , Up-Regulation , Glutathione Transferase/metabolism , Glutathione Transferase/genetics , Animals , Humans , Mice , Fatty Acid-Binding Proteins/metabolism , Fatty Acid-Binding Proteins/genetics , Fatty Liver/metabolism , Fatty Liver/drug therapy , Up-Regulation/drug effects , Liver/metabolism , Liver/pathology , Liver/drug effects , Diet, High-Fat/adverse effects , Male , Mice, Inbred C57BL , Hepatocytes/metabolism , Hepatocytes/drug effects , Lipid Metabolism/drug effects , Oleic Acid/metabolism , Hep G2 Cells , Triglycerides/metabolism , IsoenzymesABSTRACT
We performed a Bayesian network meta-analysis to indirectly compare the relative efficacy and safety of the latest JAK inhibitors for moderate-to-severe alopecia areata (AA). 13 trials totaling 3,613 patients were included. Two low-dose groups of oral formulations (ritlecitinib 10mg and ivarmacitinib 2mg) and two topical formulations (delgocitinib ointment and ruxolitinib cream) appeared to be relatively ineffective against moderate-to-severe AA. Ranking analysis suggested that brepocitinib 30mg has the best relative effect in reducing the SALT score (sucra = 0.9831), and demonstrated comparable efficacy to deuruxolitinib 12mg (sucra = 0.9245), followed by deuruxolitinib 8mg (sucra = 0.7736). Regarding the SALT50 response, brepocitinib 30mg ranked highest (sucra = 0.9567), followed by ritlecitinib 50mg (sucra = 0.8689) and deuruxolitinib 12mg (sucra = 0.7690). For achieving the SALT75 response, deuruxolitinib 12mg had the highest probability (sucra = 0.9761), followed by deuruxolitinib 8mg (sucra = 0.8678) and brepocitinib 30mg (sucra = 0.8448). Deuruxolitinib 12mg might be the most effective therapy for patients with severe AA (sucra = 0.9395), followed by ritlecitinib 50mg (sucra = 0.8753) and deuruxolitinib 8mg (sucra = 0.8070). Deuruxolitinib 12mg/8mg demonstrated notable efficacy for moderate-to-severe AA, and is expected to be a new treatment option for AA. It was worth noting that deuruxolitinib exhibit a greater likelihood of causing adverse events in comparison to other JAK inhibitors. Ritlecitinib 50mg seemed to exhibit fewer adverse effects in the high-dose groups of oral JAK inhibitors and might be an optimal choice to balance safety and efficacy. The majority of JAK inhibitors exhibited acceptable short-term safety profiles. To enhance the applicability and accuracy of our research, further head-to-head trials with longer follow-up periods are needed. Systematic Review Registration: identifier [CRD42022368012].
ABSTRACT
During investigations of invertebrate-associated fungi in Yunnan Province of China, a new species, Sporodiniella sinensis sp. nov., was collected. Morphologically, S. sinensis is similar to Sporodiniella umbellata; however, it is distinguished from S. umbellata by its greater number of sporangiophore branches, longer sporangiophores, larger sporangiospores, and columellae. The novel species exhibits similarities of 91.62â% for internal transcribed spacer (ITS), 98.66-99.10â% for ribosomal small subunit (nrSSU), and 96.36-98.22â% for ribosomal large subunit (nrLSU) sequences, respectively, compared to S. umbellata. Furthermore, phylogenetic analyses based on combined sequences of ITS, nrLSU and nrSSU show that it forms a separate clade in Sporodiniella, and clusters closely with S. umbellata with high statistical support. The phylogenetic and morphological evidence support S. sinensis as a distinct species. Here, it is formally described and illustrated, and compared with other relatives.
Subject(s)
Fatty Acids , Mucorales , Animals , Phylogeny , China , Sequence Analysis, DNA , Base Composition , RNA, Ribosomal, 16S/genetics , DNA, Bacterial/genetics , Bacterial Typing Techniques , Fatty Acids/chemistry , InvertebratesABSTRACT
Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.
Subject(s)
Antibodies, Monoclonal , Immunoconjugates , Nectins , Humans , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Immunoconjugates/pharmacokinetics , Immunoconjugates/administration & dosage , Immunoconjugates/pharmacology , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , Oligopeptides/pharmacokinetics , Oligopeptides/administration & dosage , Oligopeptides/therapeutic use , Oligopeptides/pharmacology , Oligopeptides/adverse effects , Urologic Neoplasms/drug therapy , Urologic Neoplasms/pathology , Dose-Response Relationship, Drug , Carcinoma, Transitional Cell/drug therapy , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacologyABSTRACT
BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 and REST corepressor 1, components of the corepressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing histone deacetylase 1 and REST corepressor 1 interaction, thus increasing the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha ( HNF4A ), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to histone deacetylase 1 inhibitors especially in combination with lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional corepressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.
ABSTRACT
OBJECTIVES: To examine the effectiveness of shared medical appointments (SMAs) compared with one-to-one appointments in primary care for improving health outcomes and reducing demand on healthcare services by people with one or more long-term conditions (LTCs). DESIGN: A systematic review of the published literature. DATA SOURCES: Six databases, including MEDLINE and Web of Science, were searched 2013-2023. Relevant pre-2013 trials identified by forward and backward citation searches of the included trials were included. ELIGIBILITY CRITERIA: Randomised controlled trials of SMAs delivered in a primary care setting involving adults over 18 years with one or more LTCs. Studies were excluded if the SMA did not include one-to-one patient-clinician time. All countries were eligible for inclusion. DATA EXTRACTION AND SYNTHESIS: Data were extracted and outcomes narratively synthesised, meta-analysis was undertaken where possible. RESULTS: Twenty-nine unique trials were included. SMA models varied in terms of components, mode of delivery and target population. Most trials recruited patients with a single LTC, most commonly diabetes (n=16). There was substantial heterogeneity in outcome measures. Meta-analysis showed that participants in SMA groups had lower diastolic blood pressure than those in usual care (d=-0.086, 95% CI=-0.16 to -0.02, n=10) (p=0.014). No statistically significant differences were found across other outcomes. Compared with usual care, SMAs had no significant effect on healthcare service use. For example, no difference between SMAs and usual care was found for admissions to emergency departments at follow-up (d=-0.094, 95% CI=-0.27 to 0.08, n=6, p=0.289). CONCLUSIONS: There was a little difference in the effectiveness of SMAs compared with usual care in terms of health outcomes or healthcare service use in the short-term (range 12 weeks to 24 months). To strengthen the evidence base, future studies should include a wider array of LTCs, standardised outcome measures and more details on SMA components to help inform economic evaluation. PROSPERO REGISTRATION NUMBER: CRD42020173084.
Subject(s)
Shared Medical Appointments , Humans , Appointments and Schedules , Hospitalization , Outcome Assessment, Health Care , Primary Health Care , Randomized Controlled Trials as TopicABSTRACT
Sickle cell disease (SCD) is a type of hemoglobinopathy due to an autosomal recessive genetic defect, causing significant red cell sickling, multi-organ damage and long-term severe morbidities. Due to its complicated care and the impact on quality of life, a curative treatment for SCD is highly desirable. In recent years, gene therapy is emerging as a curative option for SCD, where autologous haematopoietic stem cells are collected from SCD patients and genetically modified ex vivo to reduce its sickling tendency before reinfusion. Although still largely investigational, a limited number of gene therapy options have been recently granted approval for SCD patients. Published data are still currently limited, but early studies have so far demonstrated the intended outcomes of less vaso-occlusive crisis and haemolysis. Nonetheless, despite its curative potential, larger clinical trials and longer follow-up period are still necessary to evaluate the safety of this treatment option, especially the risk of unintended genetic modifications. Furthermore, SCD patients frequently have limited access to specialty care; hence, the issues of affordability and accessibility to SCD gene therapy must also be addressed for it to benefit the appropriate patient population.
Subject(s)
Anemia, Sickle Cell , Genetic Therapy , Anemia, Sickle Cell/therapy , Anemia, Sickle Cell/genetics , Humans , Genetic Therapy/methods , Hematopoietic Stem Cell Transplantation/methodsABSTRACT
Human dissections in the current medical curriculum are conducted using a checklist approach to prioritize the exposure of anatomical structures. In this setting, anatomy educators are labored to enhance their engagement during the dissection. To address this issue, we considered the current medical education pedagogies and identified a novel approach of studio-based learning (SBL) for application in a Human Dissection Workshop. This study aimed to (1) evaluate students' perceptions of SBL, (2) appraise the impact of SBL on anatomical knowledge learning, and (3) interpret the results of a validated questionnaire. Workshop participants were recruited from Year 2 medical students at the Chinese University of Hong Kong from the 2020 and 2021 cohorts. Fifty-one students participated in the workshop (N = 24 [2020], N = 27 [2021]), and 50 of them completed the postworkshop questionnaire rated on a 5-point Likert scale. Nineteen items were validated using a factor analysis. The interpretation of the questionnaire results demonstrated the different learning outcomes of the workshop, which included (1) enhancing students' knowledge and spatial understanding of anatomical structures, (2) strengthening students' appreciation of gross pathologies and clinical relevance, and (3) promoting higher-order thinking skills. To our knowledge, this is the first study to introduce SBL in medical education. The successful implementation of the workshop reflects the promising potential of SBL for enhancing human dissection and supplementing the medical curriculum.
ABSTRACT
Objective: This study explored whether anticoagulation is safe for frail and non-frail elderly patients who have nonvalvular atrial fibrillation (NVAF). Methods: At hospital discharge, the anticoagulant regimen and frailty status were recorded for 361 elderly patients (aged ≥75 y) with NVAF. The patients were followed for 12 months. The endpoints included occurrence of thrombosis; bleeding; all-cause death; and cardiovascular events. Results: At hospital discharge, frailty affected 50.42% of the population and the anticoagulation rate was 44.04%. At discharge, age (OR 0.948, P = 0.006), paroxysmal NVAF (OR 0.384, P < 0.001), and bleeding history (OR 0.396, P = 0.001) were associated with a decrease in rate of receiving anticoagulation, while thrombotic events during hospitalization (OR 2.281, P = 0.021) were associated with an increase. Relative to non-frail patients, those with frailty showed a higher rate of ischemic stroke (5.33% cf. 3.01%), bleeding (P = 0.006) events, and all-cause mortality (P = 0.001). Relative to the group without anticoagulation, in those with anticoagulation the rate of thrombotic events was lower (6.99 cf. 10.98%) and bleeding events were higher (20.98 cf. 12.72%), but the risk of major bleeding was comparable. Conclusion: In the elderly patients with NVAF, the decision toward anticoagulation therapy at hospital discharge was influenced by age, bleeding history, paroxysmal atrial fibrillation diagnosis, and absence of thrombosis. Frail patients were at greater risk of bleeding and all-cause mortality. Anticoagulation tended to reduce the risk of thrombotic events.
Subject(s)
Atrial Fibrillation , Frailty , Stroke , Thrombosis , Aged , Humans , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Stroke/epidemiology , Stroke/etiology , Stroke/prevention & control , Frailty/complications , Anticoagulants/adverse effects , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Thrombosis/chemically induced , Risk FactorsABSTRACT
Gut microbiota plays an essential role in the progression of nonalcoholic fatty liver disease (NAFLD), making the gut-liver axis a potential therapeutic strategy. Bacteroides genus, the enriched gut symbionts, has shown promise in treating fatty liver. However, further investigation is needed to identify specific beneficial Bacteroides strains for metabolic disorders in NAFLD and elucidate their underlying mechanisms. In this study, we observed a positive correlation between the abundance of Bacteroides thetaiotaomicron (B. theta) and the alleviation of metabolic syndrome in the early and end stages of NAFLD. Administration of B. theta to HFD-fed mice for 12 weeks reduced body weight and fat accumulation, decreased hyperlipidemia and insulin resistance, and prevented hepatic steatohepatitis and liver injury. Notably, B. theta did not affect these indicators in low-fat diet (LFD)-fed mice and exhibited good safety. Mechanistically, B. theta regulated gut microbial composition, characterized by a decreased Firmicutes/Bacteroidetes ratio in HFD-Fed mice. It also increased gut-liver folate levels and hepatic metabolites, alleviating metabolic dysfunction. Additionally, treatment with B. theta increased the proportion of polyunsaturated fatty acid in the mouse liver, offering a widely reported benefit for NAFLD improvement. In conclusion, this study provides evidence that B. theta ameliorates NAFLD by regulating gut microbial composition, enhancing gut-liver folate and unsaturated fatty acid metabolism, highlighting the therapeutic role of B. theta as a potential probiotic for NAFLD.