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Sponges are the most basal metazoan phylum1 and may have played important roles in modulating the redox architecture of Neoproterozoic oceans2. Although molecular clocks predict that sponges diverged in the Neoproterozoic era3,4, their fossils have not been unequivocally demonstrated before the Cambrian period5-8, possibly because Precambrian sponges were aspiculate and non-biomineralized9. Here we describe a late-Ediacaran fossil, Helicolocellus cantori gen. et sp. nov., from the Dengying Formation (around 551-539 million years ago) of South China. This fossil is reconstructed as a large, stemmed benthic organism with a goblet-shaped body more than 0.4 m in height, with a body wall consisting of at least three orders of nested grids defined by quadrate fields, resembling a Cantor dust fractal pattern. The resulting lattice is interpreted as an organic skeleton comprising orthogonally arranged cruciform elements, architecturally similar to some hexactinellid sponges, although the latter are built with biomineralized spicules. A Bayesian phylogenetic analysis resolves H. cantori as a crown-group sponge related to the Hexactinellida. H. cantori confirms that sponges diverged and existed in the Precambrian as non-biomineralizing animals with an organic skeleton. Considering that siliceous biomineralization may have evolved independently among sponge classes10-13, we question the validity of biomineralized spicules as a necessary criterion for the identification of Precambrian sponge fossils.
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Fósseis , Poríferos , Animais , Teorema de Bayes , China , Filogenia , Poríferos/anatomia & histologia , Poríferos/classificaçãoRESUMO
OBJECTIVES: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk. METHODS: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses. RESULTS: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy. DISCUSSION: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required.Abbreviations: ALS: amyotrophic lateral sclerosis; CI: confidence interval; GWAS: genome-wide association study; IV: instrumental variable; IVW: iverse variance weighted; MR: Mendelian randomization; MVMR: multivariable Mendelian randomization; OR: odds ratio; RCT: randomized controlled trial; SNPs: single-nucleotide polymorphisms; UVMR: univariable Mendelian randomization.
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A new coumarin (1) and a new flavonoid (2) were isolated from the air-dried flower buds of Ochrocarpus longifolius, together with ten known compounds (3-12). The structures of two new compounds were established by 1D and 2D NMR and MS data. In addition, the new compound 2 showed significant proliferation inhibitory activity on Eca-109 and MGC-803 cells. The results of this study may enrich the diversity of compounds from O. longifolius and provide a basis for further research on its natural products and pharmacological activities.
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Bile acid diarrhea (BAD) is a multifaceted intestinal disorder involving intricate molecular mechanisms, including farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and Takeda G protein-coupled receptor 5 (TGR5). Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and 75Selenium HomotauroCholic acid test (75SeHCAT). Treatment primarily involves BAS and FXR agonists. However, due to the limited sensitivity and specificity of current diagnostic methods, as well as suboptimal treatment efficacy and the presence of side effects, there is an urgent need to establish new diagnostic and treatment methods. While prior literature has summarized various diagnostic and treatment methods and the pathogenesis of BAD, no previous work has linked the two. This review offers a molecular perspective on the clinical diagnosis and treatment of BAD, with a focus on FXR, FGFR4, and TGR5, emphasizing the potential for identifying additional molecular mechanisms as treatment targets and bridging the gap between diagnostic and treatment methods and molecular mechanisms for a novel approach to the clinical management of BAD.
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Ácidos e Sais Biliares , Medicina de Precisão , Humanos , Medicina de Precisão/efeitos adversos , Diarreia/diagnóstico , Diarreia/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , Hipolipemiantes/uso terapêuticoRESUMO
Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota-bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.
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Ácidos e Sais Biliares , Microbioma Gastrointestinal , Cirrose Hepática Biliar , Humanos , Ácidos e Sais Biliares/metabolismo , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/terapia , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/microbiologia , Animais , Disbiose/imunologiaRESUMO
The chemical constituents of ethyl acetate from Hypericum himalaicum were isolated by silica gel column chromatography, gel column chromatography, and high-performance liquid chromatography. The structure of the isolated compounds was identified by modern spectral techniques(NMR, MS, IR, and UV), and the potential anti-inflammatory targets and action pathways were analyzed and predicted by network pharmacology and molecular docking methods.Ten compounds were isolated from H. himalaicum and identified as 5,9,11-trihydroxy-3,3-dimethyl-3H,8H-benzo[6,7][1,4]dioxepino[2,3-f]chromen-8-one(1), betulinic acid(2), demethyltorosaflavone C(3), kaempferol(4), quercetin(5), hyperwightin B(6), toxyloxanthone B(7), 1,7-dihydroxy-xanthone(8), emodin(9), and 1,7-dihydroxy-4-methoxy-xanthone(10). Among them, compound 1 was a new compound, and compounds 2-10 were isolated from H. himalaicum for the first time. Network pharmacology screened 60 key anti-inflammatory targets. By acting on TNF, AKT1, CASP3, and other key targets, involving PI3K-AKT signaling pathway, IL-17 signaling pathway, VEGF signaling pathway, MAPK signaling pathway, and other signaling pathways, and phosphorylation, cell migration and movement, protein tyrosine kinase, and other biological processes were regulated to achieve anti-inflammatory effects. The results of molecular docking show that the above components have good binding properties with the core targets.
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Medicamentos de Ervas Chinesas , Hypericum , Xantonas , Farmacologia em Rede , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases , Anti-Inflamatórios/farmacologia , Proteínas Proto-Oncogênicas c-aktRESUMO
AIMS: The aim of this study was to develop a population pharmacokinetic (PK) model to simultaneously describe both total and unbound concentrations of ciprofol and its major glucuronide metabolite, M4, and to link it to the population pharmacodynamics (PD) model in subjects with various renal functions. METHODS: A total of 401 and 459 pairs of total and unbound plasma concentrations of ciprofol and M4, respectively, as well as 2190 bispectral index (BIS) data from 24 Chinese subjects with various renal functions were available. Covariates that may potentially contribute to the PK and PD variability of ciprofol were screened using a stepwise procedure. The optimal ciprofol induction dosing regimen was determined by model-based simulations. RESULTS: The PK of unbound ciprofol could best be described by a three-compartment model, while a two-compartment model could adequately describe unbound M4 PK. The concentrations of total and unbound ciprofol and M4 were linked using a linear protein binding model. The relationship between plasma concentrations of ciprofol and BIS data was best described by an inhibitory sigmoidal Emax model with a two-compartment biophase distribution compartment. Hemoglobin was the identified covariate determining the central compartment clearance of ciprofol; uric acid was a covariate affecting the central compartment clearance of M4 and protein binding rate, kB . The included covariates had no effect on the PD of ciprofol. Simulation results indicated that the label-recommended dose regimen was adequate for anaesthesia induction. CONCLUSIONS: The developed model fully characterized the population PK and PD profiles of ciprofol. No dose adjustment is required in patients with mild and moderate renal impairment.
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Rim , Modelos Biológicos , Humanos , Relação Dose-Resposta a Droga , Rim/fisiologiaRESUMO
While emerging evidence highlights the significance of gut microbiome in gastrointestinal infectious diseases, treatments like Fecal Microbiota Transplantation (FMT) and probiotics are gaining popularity, especially for diarrhea patients. However, the specific role of the gut microbiome in different gastrointestinal infectious diseases remains uncertain. There is no consensus on whether gut modulation therapy is universally effective for all such infections. In this comprehensive review, we examine recent developments of the gut microbiome's involvement in several gastrointestinal infectious diseases, including infection of Helicobacter pylori, Clostridium difficile, Vibrio cholerae, enteric viruses, Salmonella enterica serovar Typhimurium, Pseudomonas aeruginosa Staphylococcus aureus, Candida albicans, and Giardia duodenalis. We have also incorporated information about fungi and engineered bacteria in gastrointestinal infectious diseases, aiming for a more comprehensive overview of the role of the gut microbiome. This review will provide insights into the pathogenic mechanisms of the gut microbiome while exploring the microbiome's potential in the prevention, diagnosis, prediction, and treatment of gastrointestinal infections.
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Gastroenteropatias , Microbioma Gastrointestinal , Probióticos , Humanos , Transplante de Microbiota Fecal , Probióticos/uso terapêutico , Gastroenteropatias/terapia , Diarreia , Salmonella typhimuriumRESUMO
BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide. However, the effect of NSAIDS on postoperative renal function is still unclear. Few studies have assessed the effects of parecoxib on renal function. Our aim is to investigate a correlation between parecoxib and the presence or absence of AKI postoperatively after a breast cancer surgery operation. METHODS: This was a retrospective cohort study that we performed on our hospitalized database. From January 2012 to August 2021, 3542 female patients undergoing radical mastectomy were enrolled, all data including the patients' information and laboratory results were obtained from electronic medical system. The main outcome was the incidence of AKI postoperatively. AKI was defined in accordance with the KDIGO criteria. Study groups were treated with or without parecoxib. Univariable and multivariable logistic regression analyses were performed. RESULTS: In our study, about 5.76% experienced AKI. The incidence rate of postoperative AKI (3.49%) within 7 days in the parecoxib group was lower than that in the control group (6.00%, P = 0.05). Compared to the control group, the AKI's incidence was reduced by 49% (OR = 0.46; 95%CI 0.27-0.97) in parecoxib group in multivariable logistic regression analysis. There was a reduction in the incidence of postoperative AKI in other three subgroups: preoperative eGFR < 90 mL/min·1.73/m2 (OR = 0.52; 95%CI 0.27-0.97), blood loss < 1000 ml (OR = 0.48; 95%CI 0.24-0.96) and non-diabetes (OR = 0.51; 95%CI 0.26-0.98). CONCLUSIONS: Parecoxib was associated with incidence of postoperative acute kidney injury.
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Injúria Renal Aguda , Neoplasias da Mama , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Anti-Inflamatórios não Esteroides , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Humanos , Incidência , Isoxazóis , Mastectomia , Mastectomia Radical/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
This paper presents a novel two-dimensional (2-D) partial Maxwell fish-eye (PMFE) lens with the capability of wide-angle beam scanning inspired by the Gutman lens and Eaton lens, which is obtained by cutting a part from the 2-D Maxwell fish-eye (MFE) lens along a straight line. In terms of the refractive index profile, the MFE lens is similar to the Gutman lens near the center and the Eaton lens near the edge, respectively. We demonstrate the potential of the PMFE lens in wide-angle beam scanning based on its Gutman-like focusing and Eaton-like rotating characteristics corresponding to different feed points. As an example, a fully metallic PMFE lens antenna in the Ka-band composed of a bed of nails and a series of linearly arranged waveguide feeders is designed and experimentally verified. The measured results reveal wide-angle scanning ranges, especially about ±90° at 36 GHz, low reflections and low mutual couplings. The frequency scanning due to the dispersion of the lens is also discussed.
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The rhesus macaque (Macaca mulatta) is the most widely distributed nonhuman primate species, and captive populations play an important role in biomedical research due to close phylogenetic and physiological similarity to human beings. However, to our best knowledge, the spondyloarthritis (SpA) in rhesus macaques has been exclusively reported in captive or semicaptive populations rather than wild counterparts. In the present study, we report 2 cases of SpA observed in Taihangshan macaques (Macaca mulatta tcheliensis) inhabiting the Taihangshan Macaque National Nature Reserve, Henan Province, China. Among these 2 cases, one can be diagnosed as ankylosing spondylitis (AS) following accepted medical criteria, and another case showed evident fusion at the pubic symphysis which could be specific to rhesus macaque AS. We discuss the potential causes leading directly or indirectly to the development of SpA.
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Espondilartrite , Animais , China , Macaca mulatta , FilogeniaRESUMO
Phosphorites of the Ediacaran Doushantuo Formation (â¼600 million years old) yield spheroidal microfossils with a palintomic cell cleavage pattern. These fossils have been variously interpreted as sulphur-oxidizing bacteria, unicellular protists, mesomycetozoean-like holozoans, green algae akin to Volvox, and blastula embryos of early metazoans or bilaterian animals. However, their complete life cycle is unknown and it is uncertain whether they had a cellularly differentiated ontogenetic stage, making it difficult to test their various phylogenetic interpretations. Here we describe new spheroidal fossils from black phosphorites of the Doushantuo Formation that have been overlooked in previous studies. These fossils represent later developmental stages of previously published blastula-like fossils, and they show evidence for cell differentiation, germ-soma separation, and programmed cell death. Their complex multicellularity is inconsistent with a phylogenetic affinity with bacteria, unicellular protists, or mesomycetozoean-like holozoans. Available evidence also indicates that the Doushantuo fossils are unlikely crown-group animals or volvocine green algae. We conclude that an affinity with cellularly differentiated multicellular eukaryotes, including stem-group animals or algae, is likely but more data are needed to constrain further the exact phylogenetic affinity of the Doushantuo fossils.
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Diferenciação Celular , Embrião não Mamífero/citologia , Fósseis , Filogenia , Animais , Apoptose , Blástula/citologia , China , Clorófitas/citologia , Células Eucarióticas/classificação , Células Eucarióticas/citologiaRESUMO
BACKGROUND: The technical feasibility and oncological safety of laparoscopic surgery for gastric gastrointestinal stromal tumors (GISTs) larger than 5 cm has not been adequately studied. Therefore, we performed this retrospective study to investigate the clinical outcomes of gastric GIST patients treated with laparoscopic surgery compared with those who underwent open surgery. METHODS: We retrospectively evaluated the outcomes of 48 consecutive patients who underwent gastric resection for gastric GISTs larger than 5 cm. The patients were divided into 2 groups based on the surgery performed: the laparoscopic resection group (LAPG) and the open resection group (OG). We assessed all available patient data, including baseline information, tumor characteristics, surgical outcomes, pathological results, postoperative complications, and long-term patient survival. RESULTS: The 2 groups had similar baseline data. No differences were found in tumor size, location, mitotic count, and risk grade according to Fletcher's risk classification. The LAPG was superior to the OG in blood loss, time to first flatus, time to oral intake, and length of postoperative hospital stay. Perioperative complications, recurrence rate, and long-term survival, however, did not differ significantly between the groups. The mean operation time in the LAPG was 28 minutes longer than that in the OG. CONCLUSIONS: In patients with primary gastric GISTs larger than 5 cm, laparoscopic resection is a technically feasible and oncologically safe surgery when performed by experienced surgeons.
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Gastrectomia , Tumores do Estroma Gastrointestinal/cirurgia , Laparoscopia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
AIM: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic ß-cell function were also investigated. METHODS: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control. RESULTS: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg·kg(-1)·d(-1)) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice. CONCLUSION: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.
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Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Células HEK293 , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Insulina/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Transportador 1 de Glucose-Sódio/metabolismoRESUMO
Volatile organic compounds have drawn significant attention in recent years as a novel tool for non-invasive detection of a wide range of diseases, including gastrointestinal cancers, for which the need for effective, affordable, and non-invasive screening methods is substantial. Sample preparation is a fundamental step that greatly influences the quality of results and the feasibility of wide-range applications. This review summarizes sampling methods used in studies aiming at testing the diagnostic value of volatile organic compounds in gastrointestinal cancers, discussing in detail some of the recent advancements in automated sampling techniques. Finally, we propose some directions in which sample collection and processing can improve for VOC analysis to be popularized in clinical settings.
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CONTEXT: The mechanisms for the formation of the first C - C bond and lower olefins on methanol to olefins (MTO) conversion on H-ZSM-5 had been focused in dispute. In this paper, density functional theory has been used to study the reaction mechanisms of methanol to olefins on ZSM-5. The configurations of reactants, intermediates, products and transition state of the numerous reactions involved in such a process have been optimized, as well as the elementary reactions related to these configurations were determined by the calculation of corresponding activation energy barriers and reaction heats. Here, two different kinds of the mechanisms were proposed for the formation of dimethyl ether (DME), one involving an associative interaction of two methanol molecules with the zeolite Brønsted acid sites and the other occurring via a surface methoxy species and a methanol molecule. A critical intermediate of the methoxy methyl cation was theoretically verified by the reaction of the methoxy species and dimethyl ether. Besides, it was found that the first intermediates containing a C - C bond were 1,2-dimethoxyethane and 2-methoxy-ethanolare, in which the former was formed from methoxy species with dimethyl ether and the latter was formed from methanol by onium ions((CH3)2O+CH2CH2OCH3), respectively. For the whole reaction mechanism, the results in this paper indicated that the ethene formation is more favorable than propylene formation due to the low activation energy barrier for ethene formation (123.49 vs. 162.09 kJ.mol-1). From these calculations, it would be concluded that ethene is the first alkene product that induces the occurrence of the hydrocarbon pool mechanism. METHODS: All the periodic density function theory (DFT) calculations were performed by the Vienna Ab Initio Simulation package (VASP). The interaction between nucleus and valence electron was described using the pseudopotentials found in the projector augmented wave (PAW) method. PBE-D3 was used in the whole DFT calculations and CI-NEB was used to locate transition state.
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Background: Previous observational studies suggested a correlation between particulate matter 2.5 (PM2.5) and infectious diseases, but causality remained uncertain. This study utilized Mendelian randomization (MR) analysis to investigate causal relationships between PM2.5 concentrations and various infectious diseases (COVID-19 infection, hospitalized COVID-19, very severe COVID-19, urinary tract infection, bacterial pneumonia, and intestinal infection). Methods: Inverse variance weighted (IVW) was the primary method for evaluating causal associations. For significant causal estimates, multiple sensitivity tests were further performed: (i) three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) for supplementing IVW; (ii) Cochrane's Q test for assessing heterogeneity; (iii) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; (iv) leave-one-out sensitivity test for determining the stability. Results: PM2.5 concentration significantly increased the risk of hospitalized COVID-19 (OR = 1.91, 95 % CI: 1.06-3.45, P = 0.032) and very severe COVID-19 (OR = 3.29, 95 % CI: 1.48-7.35, P = 3.62E-03). However, no causal effect was identified for PM2.5 concentration on other infectious diseases (P > 0.05). Furthermore, various sensitivity tests demonstrated the reliability of significant causal relationships. Conclusions: Overall, lifetime elevated PM2.5 concentration increases the risk of hospitalized COVID-19 and very severe COVID-19. Therefore, controlling air pollution may help mitigate COVID-19 progression.
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BACKGROUND: Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear. OBJECTIVE: Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: 1) Cochrane's Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability. RESULTS: The results of IVW indicated that sepsis significantly increased the risk of Alzheimer's disease (ORâ=â1.11, 95% CI: 1.01-1.21, pâ=â0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy. CONCLUSIONS: The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis.
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Doença de Alzheimer , Doenças Neurodegenerativas , Sepse , Humanos , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/genética , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Reprodutibilidade dos Testes , Sepse/complicações , Sepse/genéticaRESUMO
Background: Gastrointestinal (GI) angiodysplasias is a potential cause of life-threatening bleeding. Thalidomide may have a certain effect on the treatment. Objectives: We aim to evaluate the efficacy and safety of thalidomide and used trial sequential analysis (TSA) to assess the need for further randomized controlled trials (RCTs). Design: Meta-analysis of RCTs. Data sources and methods: We systematically searched Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, WanFang, and China National Knowledge Infrastructure databases for RCTs evaluating thalidomide in GI angiodysplasias without language restrictions. We used a random-effects model to obtain pool data and followed Grading of Recommendations Assessment, Development and Evaluation framework. TSA was employed to control the risk of random errors and to evaluate the validity of our conclusions. Results: Three RCTs were included involving 279 patients with the proportion of small intestinal angiodysplasias of 87.1%. Thalidomide led to improved mean change of hemoglobin level [mean difference (MD): 3.06, 95% confidence interval: 2.66-3.46] without severe adverse effects occurring. Other secondary endpoints, including effective response rate, cessation of bleeding after treatment, hospitalization rate because of bleeding, change in duration of hospital stays for bleeding, transfused red cell requirements, and overall adverse effects, also showed significantly better outcomes in the thalidomide group compared to the control group. TSA for all outcomes exceeded required information sizes, and cumulative Z curve all traverse trial sequential monitoring boundary. Conclusion: Almost all of the evidence was of moderate quality, suggesting that thalidomide holds promise for treating GI angiodysplasias, with favorable safety profiles. TSA suggests that conducting large-scale real-world research is recommended over relying solely on RCTs conducted within the same population and trial design. Trial registration: This meta-analysis protocol was registered on PROSPERO (CRD42023480621).
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BACKGROUND: Acute non-variceal upper gastrointestinal bleeding (UGIB) is challenging in patients at high risk of re-bleeding in whom standard endoscopic treatment (ST) has limited effectiveness. Over-the-scope clips (OTSC) have shown promise in these patients although their precise role remains uncertain. AIMS: To confirm the role of OTSC in patients with UGIB at high risk of re-bleeding. METHODS: We systematically searched CENTRAL, MEDLINE and Embase from January 1st, 1970 to April 24, 2024 for randomised controlled trials (RCTs) comparing OTSC and ST in acute non-variceal UGIB with high re-bleeding risk. The GRADE framework assessed evidence certainty, while trial sequential analysis (TSA) controlled random errors and evaluated conclusion validity. RESULTS: We analysed four RCTs (319 patients); pooled risk ratio (RR) for clinical success at initial endoscopy favoured OTSC (RR = 1.30, 95% CI = 1.08-1.56, p = 0.006, I2 = 58%, moderate certainty of evidence). TSA showed the desired sample size was 410 and the cumulative Z curve crossing the trial sequential monitoring boundary. The pooled RR for re-bleeding within 30 days favoured OTSC (RR = 0.53, 95% CI = 0.30-0.94, p = 0.03, I2 = 0%, moderate certainty of evidence). There was no significant difference in 30-day mortality, or length of hospital or ICU stay. CONCLUSIONS: Moderate certainty evidence supports OTSC as a superior initial treatment for acute non-variceal UGIB with high re-bleeding risk. Further large-scale studies are needed to confirm OTSCs' role by exploring other prognostic outcomes and assessing cost-effectiveness and potential complications.