ABSTRACT
Bacterial conjugation is the fundamental process of unidirectional transfer of DNAs, often plasmid DNAs, from a donor cell to a recipient cell1. It is the primary means by which antibiotic resistance genes spread among bacterial populations2,3. In Gram-negative bacteria, conjugation is mediated by a large transport apparatus-the conjugative type IV secretion system (T4SS)-produced by the donor cell and embedded in both its outer and inner membranes. The T4SS also elaborates a long extracellular filament-the conjugative pilus-that is essential for DNA transfer4,5. Here we present a high-resolution cryo-electron microscopy (cryo-EM) structure of a 2.8 megadalton T4SS complex composed of 92 polypeptides representing 8 of the 10 essential T4SS components involved in pilus biogenesis. We added the two remaining components to the structural model using co-evolution analysis of protein interfaces, to enable the reconstitution of the entire system including the pilus. This structure describes the exceptionally large protein-protein interaction network required to assemble the many components that constitute a T4SS and provides insights on the unique mechanism by which they elaborate pili.
Subject(s)
Bacterial Proteins , Cryoelectron Microscopy , Type IV Secretion Systems , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Bacterial Proteins/ultrastructure , Conjugation, Genetic , DNA/genetics , Evolution, Molecular , Fimbriae, Bacterial/metabolism , Plasmids/genetics , Type IV Secretion Systems/chemistry , Type IV Secretion Systems/metabolism , Type IV Secretion Systems/ultrastructureABSTRACT
Thousands of long noncoding RNAs (lncRNAs) have been annotated via high-throughput RNA sequencing, yet only a small fraction have been functionally investigated. Genomic knockout is the mainstream strategy for studying the biological function of protein-coding genes and lncRNAs, whereas the complexity of the lncRNA locus, especially the natural antisense lncRNAs (NAT-lncRNAs), presents great challenges. Knocking out lncRNAs often results in unintended disruptions of neighboring protein-coding genes and small RNAs, leading to ambiguity in observing phenotypes and interpreting biological function. To address this issue, we launched LncRNAway, a user-friendly web tool based on the BESST (branchpoint to 3' splicing site targeting) method, to design sgRNAs for lncRNA knockout. LncRNAway not only provides specific and effective lncRNA knockout guidelines but also integrates genotyping primers and quantitative PCR primers designing, thereby streamlining experimental procedures of lncRNA function study. LncRNAway is freely available at https://www.lncrnaway.com.
Subject(s)
Internet , RNA, Guide, CRISPR-Cas Systems , RNA, Long Noncoding , Software , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Guide, CRISPR-Cas Systems/genetics , Humans , Gene Knockout Techniques , CRISPR-Cas SystemsABSTRACT
Self-assembly of isotropically interacting particles into desired crystal structures could allow for creating designed functional materials via simple synthetic means. However, the ability to use isotropic particles to assemble different crystal types remains challenging, especially for generating low-coordinated crystal structures. Here, we demonstrate that isotropic pairwise interparticle interactions can be rationally tuned through the design of DNA shells in a range that allows transition from common, high-coordinated FCC-CuAu and BCC-CsCl lattices, to more exotic symmetries for spherical particles such as the SC-NaCl lattice and to low-coordinated crystal structures (i.e., cubic diamond, open honeycomb). The combination of computational and experimental approaches reveals such a design strategy using DNA-functionalized nanoparticles and successfully demonstrates the realization of BCC-CsCl, SC-NaCl, and a weakly ordered cubic diamond phase. The study reveals the phase behavior of isotropic nanoparticles for DNA-shell tunable interaction, which, due to the ease of synthesis is promising for the practical realization of non-close-packed lattices.
Subject(s)
Nanoparticles , Sodium Chloride , Nanoparticles/chemistry , DNA/chemistry , DiamondABSTRACT
A two-year professional MHSc program at the University of Toronto provides a unique integrated educational program to train allied health science personnel to practice as physician extenders and health care professionals in two high-demand clinical laboratory disciplines, Pathologists' Assistant {PA) and Clinical Embryologist (CE). This report describes an integrated graduate program developed and delivered in a research-intensive laboratory medicine department. The core courses in fundamental biomedical science and in general medical laboratory function and operations formed the foundation upon which the requisite clinical skills required to practice as a PA or CE were subsequently delivered as comprehensive CE and PA specialty courses and practicums. Students acquired research skills through courses that teach research methods, critical analysis of research articles and biostatistics for clinical research scientists. A capstone research project provided students the opportunity to design a research project relevant to the CE or PA fields, carryout and analyze the findings and present the project as an oral abstract and a written scientific paper. Students learn to face the clinical challenges by focusing on critical analysis of evidence-based professional practice. The PA field received a 5-year accreditation. CE and PA students presented their clinical research at national and international meetings, some receiving awards, and published scientific manuscripts. All graduates found meaningful employment in their respective fields and initial employer response has been favorable.
ABSTRACT
Advancements in comparative genomics research have led to a growing interest in studying species evolution and genetic diversity. To facilitate this research, OrthoVenn3 has been developed as a powerful, web-based tool that enables users to efficiently identify and annotate orthologous clusters and infer phylogenetic relationships across a range of species. The latest upgrade of OrthoVenn includes several important new features, including enhanced orthologous cluster identification accuracy, improved visualization capabilities for numerous sets of data, and wrapped phylogenetic analysis. Furthermore, OrthoVenn3 now provides gene family contraction and expansion analysis to support researchers better understanding the evolutionary history of gene families, as well as collinearity analysis to detect conserved and variable genomic structures. With its intuitive user interface and robust functionality, OrthoVenn3 is a valuable resource for comparative genomics research. The tool is freely accessible at https://orthovenn3.bioinfotoolkits.net.
Subject(s)
Databases, Genetic , Genomics , Phylogeny , Genome/geneticsABSTRACT
Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.
Subject(s)
Glaucoma , Retinal Ganglion Cells , Humans , Mice , Animals , Retinal Ganglion Cells/pathology , Vascular Cell Adhesion Molecule-1/metabolism , Th1 Cells/pathology , Glaucoma/metabolism , Retina/pathology , Vision Disorders/pathology , Disease Models, AnimalABSTRACT
Constructing composite catalysts with refined geometric control and optimal electronic structure provides a promising route to enhance electrocatalytic performance toward the oxygen evolution reaction (OER). Herein, a composite catalyst is prepared with multiple components using chemical vapour deposition method to transform crystalline NiFe2O4 into crystalline NiFe2O4@amorphous S-NiFe2O4 with core-shell structure (C-NiFe2O4@A-S-NiFe2O4), and Fe-NiOOH nanoparticles are subsequently in situ generated on its surface during the process of electrocatalytic OER. The C-NiFe2O4@A-S-NiFe2O4 catalyst exhibits a low overpotential of 275 mV while possessing an excellent stability for 500 h at 10 mA cm-2. The anion exchange membrane water electrolyzer with C-NiFe2O4@A-S-NiFe2O4 anode catalyst obtains a current density of 4270 mA cm- 2 at 2.0 V. Further, in situ Raman spectroscopy result demonstrates that in situ generated Fe-NiOOH nanoparticles are revealed to act as the catalytic active phase for catalyzing the OER. Besides, introducing A-S-NiFe2O4 in C-NiFe2O4@A-S-NiFe2O4 facilitates the formation of Fe-NiOOH nanoparticles with high-valency Ni, thus increasing the proportion of lattice oxygen-participated OER. This work not only provides an alternative strategy for the design of high-performance catalysts, but also lays a foundation for the exploration of catalytic mechanisms.
ABSTRACT
The ability of Epstein-Barr virus (EBV) to switch between latent and lytic infection is key to its long-term persistence, yet the molecular mechanisms behind this switch remain unclear. To investigate transcriptional events during the latent-to-lytic switch, we utilized Precision nuclear Run On followed by deep Sequencing (PRO-Seq) to map cellular RNA polymerase (Pol) activity to single-nucleotide resolution on the host and EBV genome in three different models of EBV latency and reactivation. In latently infected Mutu-I Burkitt lymphoma (BL) cells, Pol activity was enriched at the Qp promoter, the EBER region, and the BHLF1/LF3 transcripts. Upon reactivation with phorbol ester and sodium butyrate, early-phase Pol activity occurred bidirectionally at CTCF sites within the LMP-2A, EBER-1, and RPMS1 loci. PRO-Seq analysis of Akata cells reactivated from latency with anti-IgG and a lymphoblastoid cell line (LCL) reactivated with small molecule C60 showed a similar pattern of early bidirectional transcription initiating around CTCF binding sites, although the specific CTCF sites and viral genes were different for each latency model. The functional importance of CTCF binding, transcription, and reactivation was confirmed using an EBV mutant lacking the LMP-2A CTCF binding site. This virus was unable to reactivate and had disrupted Pol activity at multiple CTCF binding sites relative to the wild-type (WT) virus. Overall, these data suggest that CTCF regulates the viral early transcripts during reactivation from latency. These activities likely help maintain the accessibility of the viral genome to initiate productive replication. IMPORTANCE The ability of EBV to switch between latent and lytic infection is key to its long-term persistence in memory B cells, and its ability to persist in proliferating cells is strongly linked to oncogenesis. During latency, most viral genes are epigenetically silenced, and the virus must overcome this repression to reactivate lytic replication. Reactivation occurs once the immediate early (IE) EBV lytic genes are expressed. However, the molecular mechanisms behind the switch from the latent transcriptional program to begin transcription of the IE genes remain unknown. In this study, we mapped RNA Pol positioning and activity during latency and reactivation. Unexpectedly, Pol activity accumulated at distinct regions characteristic of transcription initiation on the EBV genome previously shown to be associated with CTCF. We propose that CTCF binding at these regions retains Pol to maintain a stable latent chromosome conformation and a rapid response to various reactivation signals.
Subject(s)
CCCTC-Binding Factor , Epstein-Barr Virus Infections , Herpesvirus 4, Human , RNA-Dependent RNA Polymerase , Virus Activation , Humans , Binding Sites , Gene Expression Regulation, Viral , Genome, Viral , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/physiology , Virus Latency , RNA-Dependent RNA Polymerase/metabolism , Cell Line, Tumor , CCCTC-Binding Factor/metabolismABSTRACT
HIV-infected macrophages are long-lived cells that represent a barrier to functional cure. Additionally, low-level viral expression by central nervous system (CNS) macrophages contributes to neurocognitive deficits that develop despite antiretroviral therapy (ART). We recently identified H3K9me3 as an atypical epigenetic mark associated with chronic HIV infection in macrophages. Thus, strategies are needed to suppress HIV-1 expression in macrophages, but the unique myeloid environment and the responsible macrophage/CNS-tropic strains require cell/strain-specific approaches. Here, we generated an HIV-1 reporter virus from a CNS-derived strain with intact auxiliary genes expressing destabilized luciferase. We employed this reporter virus in polyclonal infection of primary human monocyte-derived macrophages (MDM) for a high-throughput screen (HTS) to identify compounds that suppress virus expression from established macrophage infection. Screening ~6,000 known drugs and compounds yielded 214 hits. A secondary screen with 10-dose titration identified 24 meeting criteria for HIV-selective activity. Using three replication-competent CNS-derived macrophage-tropic HIV-1 isolates and viral gene expression readout in MDM, we confirmed the effect of three purine analogs, nelarabine, fludarabine, and entecavir, showing the suppression of HIV-1 expression from established macrophage infection. Nelarabine inhibited the formation of H3K9me3 on HIV genomes in macrophages. Thus, this novel HTS assay can identify suppressors of HIV-1 transcription in established macrophage infection, such as nucleoside analogs and HDAC inhibitors, which may be linked to H3K9me3 modification. This screen may be useful to identify new metabolic and epigenetic agents that ameliorate HIV-driven neuroinflammation in people on ART or prevent viral recrudescence from macrophage reservoirs in strategies to achieve ART-free remission. IMPORTANCE Macrophages infected by HIV-1 are a long-lived reservoir and a barrier in current efforts to achieve HIV cure and also contribute to neurocognitive complications in people despite antiretroviral therapy (ART). Silencing HIV expression in these cells would be of great value, but the regulation of HIV-1 in macrophages differs from T cells. We developed a novel high-throughput screen for compounds that can silence established infection of primary macrophages, and identified agents that downregulate virus expression and alter provirus epigenetic profiles. The significance of this assay is the potential to identify new drugs that act in the unique macrophage environment on relevant viral strains, which may contribute to adjunctive treatment for HIV-associated neurocognitive disorders and/or prevent viral rebound in efforts to achieve ART-free remission or cure.
Subject(s)
HIV Infections , HIV-1 , Histones , Macrophages , Humans , High-Throughput Screening Assays , HIV Infections/drug therapy , HIV-1/drug effects , Macrophages/virology , Nucleosides/pharmacology , Proviruses/genetics , Virus Replication , Epigenesis, Genetic , Histones/genetics , Genome, ViralABSTRACT
Chronic obstructive pulmonary disease (COPD) is a leading aging related cause of global mortality. Small airway narrowing is recognized as an early and significant factor for COPD development. Senescent fibroblasts were observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition and senescence-associated secretory phenotype (SASP). On the basis of our previous study, we further investigated the the causes for the increased levels of miR-377-3p in the blood of COPD patients, as well as its regulatory function in the pathological progression of COPD. We found that the majority of up-regulated miR-377-3p was localized in lung fibroblasts. Inhibition of miR-377-3p improved chronic smoking-induced COPD in mice. Mechanistically, miR-377-3p promoted senescence of lung fibroblasts, while knockdown of miR-377-3p attenuated bleomycin-induced senescence in lung fibroblasts. We also identified ZFP36L1 as a direct target for miR-377-3p that likely mediated its pro senescence activity in lung fibroblasts. Our data reveal that miR-377-3p is crucial for COPD pathogenesis, and may serve as a potential target for COPD therapy.
Subject(s)
Butyrate Response Factor 1 , MicroRNAs , Pulmonary Disease, Chronic Obstructive , Animals , Humans , Mice , Aging , Butyrate Response Factor 1/metabolism , Cellular Senescence/genetics , Fibroblasts/metabolism , Lung/metabolism , MicroRNAs/metabolism , Pulmonary Disease, Chronic Obstructive/metabolismABSTRACT
OBJECTIVE: PD-L1 was an important biomarker in lung adenocarcinoma. The study was to confirm the most important factor affecting the expression of PD-L1 remains undetermined. METHODS: The clinical records of 1045 lung adenocarcinoma patients were retrospectively reviewed. The High-Resolution Computed Tomography (HRCT) scanning images of all the participants were analyzed, and based on the CT characteristics, the adenocarcinomas were categorized according to CT textures. Furthermore, PD-L1 expression and Ki67 index were detected by immunohistochemistry. All patients underwent EGFR mutation detection. RESULTS: Multivariate logistic regression analysis revealed that smoking (OR: 1.73, 95% CI: 1.04-2.89, p = 0.004), EGFR wild (OR: 1.52, 95% CI: 1.11-2.07, p = 0.009), micropapillary subtypes (OR: 2.05, 95% CI: 1.46-2.89, p < 0.0001), and high expression of Ki67 (OR: 2.02, 95% CI: 1.44-2.82, p < 0.0001) were independent factors which influence PD-L1 expression. In univariate analysis, tumor size > 3 cm and CT textures of pSD showed a correlation with high expression of PD-L1. Further analysis revealed that smoking, micropapillary subtype, and EGFR wild type were also associated with high Ki67 expression. Moreover, high Ki67 expression was observed more frequently in tumors of size > 3 cm than in tumors with ≤ 3 cm size as well as in CT texture of pSD than lesions with GGO components. In addition, multivariate logistic regression analysis revealed that only lesions with micropapillary components correlated with pSD (OR: 3.96, 95% CI: 2.52-5.37, p < 0.0001). CONCLUSION: This study revealed that in lung adenocarcinoma high Ki67 expression significantly influenced PD-L1 expression, an important biomarker for immune checkpoint treatment.
Subject(s)
Adenocarcinoma of Lung , B7-H1 Antigen , Biomarkers, Tumor , ErbB Receptors , Ki-67 Antigen , Lung Neoplasms , Tomography, X-Ray Computed , Humans , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , Female , Male , Middle Aged , Aged , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/genetics , Retrospective Studies , ErbB Receptors/metabolism , Adenocarcinoma of Lung/metabolism , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/diagnostic imaging , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Ki-67 Antigen/metabolism , Adult , Mutation , Aged, 80 and over , Immunohistochemistry , Smoking/adverse effectsABSTRACT
This study was designed to evaluate the safety and feasibility of laparoscopic radical cystectomy (LRC) for male octogenarian patients with muscle-invasive bladder cancer (MIBC). Briefly, a total of 57 male octogenarian patients (A group) with bladder carcinoma were enrolled and underwent LRC and intracorporeal pelvic lymph node dissection with bilateral cutaneous ureterostomy from May 2016 to December 2022. Besides, 63 male patients (age < 80 years old) with bladder carcinoma undergoing LRC and 17 octogenarian male patients with bladder carcinoma undergoing open radical cystectomy (ORC) were enrolled in B and C groups as control. All perioperative clinical materials and outcomes of long-term follow-up, and complication were collected. The specific results were shown as follows. Compared with C group, the operation time and resected lymph node in A group was increased, and the estimated blood loss, the number of transfusion needed, duration of pelvic drainage and hospital stay after surgery was decreased. The death rate and ileus complication rate were higher in A group (12 cases) than in C group (15 cases). The cases of ureteral stricture in A group (13 cases) was decreased compared with that in C group. Overall, LRC and bilateral cutaneous ureterostomy are safe, feasible and better choices for the treatment of male octogenarian patients with MIBC. The octogenarian receiving cutaneous ureterostomy heals slowly and exists certain incomplete intestinal obstruction after surgery.
Subject(s)
Carcinoma , Laparoscopy , Urinary Bladder Neoplasms , Aged, 80 and over , Humans , Male , Cystectomy/adverse effects , Cystectomy/methods , Urinary Bladder/pathology , Octogenarians , Laparoscopy/adverse effects , Laparoscopy/methods , Feasibility Studies , Treatment Outcome , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/pathology , Carcinoma/surgery , Muscles/pathologyABSTRACT
The retinopathy of prematurity (ROP) can cause serious clinical consequences and, fortunately, it is remediable while the time window for treatment is relatively narrow. Therefore, it is urgent to screen all premature infants and diagnose ROP degree timely, which has become a large workload for pediatric ophthalmologists. We developed a retinal image-free procedure using small amount of blood samples based on the plasma Raman spectrum with the machine learning model to automatically classify ROP cases before medical intervention was performed. Statistical differences in infrared Raman spectra of plasma samples were found among the control, mild (ZIIIS1), moderate (ZIIIS2 & ZIIS1), and advanced (ZIIS2) ROP groups. With the different wave points of Raman spectra as the inputs, the outputs of our support vector machine showed that the area under the curves in the receiver operating characteristic (AUC) were 0.763 for the pair comparisons of the control with the mild groups, 0.821 between moderate and advanced groups (ZIIS2), while more than 90% in comparisons of the other four pairs: control vs. moderate (0.981), control vs. advanced (0.963), mild vs. moderate (0.936), and mild vs. advanced (0.953), respectively. Our study could advance principally the ROP diagnosis in two dimensions: the moderate ROPs have been classified remarkably from the mild ones, which leaves more time for the medical treatments, and the procedure of Raman spectrum with a machine learning model based on blood samples can be conveniently promoted to those hospitals lacking of the pediatric ophthalmologists with experience in reading retinal images.
Subject(s)
Retinopathy of Prematurity , Telemedicine , Infant, Newborn , Infant , Humans , Child , Retinopathy of Prematurity/diagnosis , Retinopathy of Prematurity/therapy , Sensitivity and Specificity , Telemedicine/methods , Algorithms , Machine Learning , Gestational AgeABSTRACT
HMOs (Human milk oligosaccharide) has an impact on maternal and infant health. Colostrum samples of 70 breastfeeding women in China were collected and recorded clinical characteristics. The major oligosaccharides and microbiota were quantitated in colostrum. The concentration of fucosylated HMOs in primipara was higher than that of multipara (p = 0.030). The concentration of N-acetylated HMOs in vaginal delivery milk was less than that of cesarean (p = 0.038). Non-fucosylated HMOs of breastfeeding women were less than that of breast pump (p = 0.038). Meanwhile, the concentration of LNT was positively correlated with Lactobacillus (r = 0.250, p = 0.037). DS-LNT was negatively correlated with Staphylococcus (r = - 0.240, p = 0.045). There was a positive correlation of Streptococcus with LNFP II (r = 0.314, p = 0.011) and 3-SL (r = 0.322, p = 0.009). In addition, there was a negative correlation between 2'-FL and 3-FL (r = - 0.465, p = 0.001). There was a positive correlation between LNT and LNnT (r = 0.778, p = 0.001). Therefore, the concentration of HMOs is related to number of deliveries, delivery mode, lactation mode and perinatal antibiotic. The concentration of HMOs is related to Lactobacillus, Streptococcus and Streptococcus in colostrum. In addition, there are connections between different oligosaccharides in content. The study protocol was also registered in the ClinicalTrails.gov (ChiCTR2200064454) (Oct. 2022).
Subject(s)
Microbiota , Milk, Human , Pregnancy , Infant , Female , Humans , Colostrum , Pilot Projects , Lactobacillus , OligosaccharidesABSTRACT
Men who have sex with men (MSM) is a high-risk population for HIV and sexually transmitted infections (STIs). Pre-exposure prophylaxis (PrEP) is effective in HIV prevention. This study aims to examine the differences in sexual behaviors, STI prevalence and HIV/STI testing across subgroups of MSM with various PrEP use. Data were collected via a cross-sectional survey in an MSM community in Xi'an, Shaanxi, from 2022.01 to 2022.09. Participants were categorized as 'PrEP-naïve and unwilling to use', 'PrEP-naïve but willing to use', and 'current or former PrEP users'. Shannon index was used to assess sexual act diversity and multivariate logistic regression analyzed factors associated with PrEP use. Of the 1,131 MSM participants, 23.52% were PrEP-naïve and unwilling, 64.98% were PrEP-naïve but willing, and 11.49% were current or former PrEP users. The PrEP-naïve but willing group had the highest recent STI testing rates at 73.06% and showed greater sexual act diversity (Shannon index 1.61). This group also had the highest syphilis rates (7.49% vs. 6.47% and2.54%, p < 0.01). Younger age (18-30: OR = 0.39 (0.18-0.85); 31-40: OR = 0.43 (0.20-0.96)) and lower education (high school/vocational: OR = 0.15 (0.04-0.58); associate degree: OR = 0.21 (0.06-0.71)) were factors that negatively influenced PrEP use. Current or former PrEP users had the highest oropharyngeal gonorrhea (14.39% vs. 9.68% and 5.80%, p < 0.01) and overall gonorrhea rates (20.86% vs. 17.17% and 8.37%, p < 0.001). 'PrEP-naïve but willing' participants consistently demonstrated high-risk sexual behavior, increased STI testing, and more diverse sexual acts, whereas PrEP users had the highest STI prevalence.
ABSTRACT
PURPOSE: Physicians may administer Nirmatrelvir-ritonavir to patients who have been symptomatic for more than 5 days. There is currently no clear evidence to support this approach. METHODS: A real-world study was conducted to investigate the potential relationship between the administration of Nirmatrelvir-ritonavir and the rates of intubation or in-hospital mortality among COVID-19 patients who experienced symptoms for more than 5 days. The end point was a composite event of intubation or in-hospital mortality. The outcomes between those patients who received Nirmatrelvir-ritonavir and those who did not were compared. RESULTS: A total of 847 patients were included in the analysis. Among them, 312 patients (36.84%) received Nirmatrelvir-ritonavir. Within the entire population, 86 patients (10.15%) experienced intubation or in-hospital mortality. The main analysis indicated that there was a significant association between the application of Nirmatrelvir-ritonavir and intubation or in-hospital mortality, with an odds ratio of 0.50 (95% confidence interval, 0.28 to 0.87; P = 0.0153) using inverse probability of treatment weighting. The finding was consistent with multiple sensitivity analyses. CONCLUSIONS: The application of Nirmatrelvir-ritonavir was associated with a significantly reduced risk of intubation or death in hospitalized COVID-19 patients who experienced symptoms for more than 5 days as compared to those who did not receive the treatment.
Subject(s)
COVID-19 Drug Treatment , Hospital Mortality , Ritonavir , Humans , Ritonavir/therapeutic use , Female , Male , Middle Aged , Aged , SARS-CoV-2 , Antiviral Agents/therapeutic use , COVID-19/mortality , Hospitalization/statistics & numerical data , Treatment Outcome , Drug Therapy, Combination , Retrospective StudiesABSTRACT
Multicolor-tunable room-temperature phosphorescence (RTP) is attracting wide attention in optoelectronic applications. Here, we propose a coordination-oriented assembly approach to achieve wide-range RTP with a benzimidazole derivative (2,7-diazabenzimidazole, DZBIM) as a luminogen. These two compounds exhibit unexpected excitation-responsive RTP emission, and the phosphorescence emission nearly covers the entire visible region with the change of the excitation wavelength from 360 to 620 nm. To the best of our knowledge, this is the first report of coordination polymers with such a full-color-tunable RTP. Compound 1 also shows white-light emission upon excitation at 280 nm. Experimental and theoretical results demonstrate that multiple intermolecular interactions and emission centers from different aggregates are responsible for the generation of multicolor emission. The white-light emission and multiple anticounterfeiting are explored. Besides, compound 1 exhibits high antibacterial activity benefiting from efficient 1O2 generation. This work provides an efficient way to prepare a color-tunable RTP.
ABSTRACT
BACKGROUND: Tricuspid regurgitation (TR) is a prevalent disease that triggers systemic pathological changes including cardiac, respiratory, hepatic and digestive, hematopoietic, renal and skin issues. The burden of extra-cardiac manifestations has not been well described in TR patients and the clinical impact is unknown. METHODS: Patients with severe or more-than-severe TR during hospitalization, who did not have any previous cardiac procedures, hemodynamically significant congenital heart disease or concomitant severe aortic or mitral valve disease, were retrospectively analyzed. Pre-specified criteria and diagnosis of baseline characteristics were used to evaluate the presence of extra-cardiac manifestations secondary to TR after excluding comorbidities that may also lead to corresponding abnormalities. Extra-cardiac involvements encompass respiratory, hepatic and, digestive, renal, hematopoietic and dermatic system. Staging criteria are defined as no extra-cardiac system involvement in Stage 1, one in Stage 2, at least two extra-cardiac involvements in Stage 3 and any end-stage organ failure in Stage 4. A telephone follow-up was conducted to record the composite endpoint namely all-cause death or cardiac rehospitalization after the index hospitalization. RESULTS: A total of 258 patients were identified with a median age of 73 (interquartile range [IQR]: 62-83) years and 52.3% were female. Severe TR and more-than-severe TR patients accounted for 92.6% and 7.4% of the cohort. There were 20.5%, 27.5%, 37.6% and 14.3% of patients from Stage 1 to 4 respectively. The follow-up time was at a median of 251 (IQR: 183-324) days. TR Patients in Stage 3&4 were at an increased risk with borderline statistical significance to experience the composite endpoint compared to patients in Stage 1&2 (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.0 to 3.7, P = 0.049). CONCLUSIONS: Approximately half of patients with at least severe TR presented with two or more extra-cardiac systemic manifestations, which may incur a 1.9-fold higher risk of all-cause death or cardiac rehospitalization than TR patients with one or less extra-cardiac involvement.
Subject(s)
Heart Valve Prosthesis Implantation , Tricuspid Valve Insufficiency , Humans , Female , Middle Aged , Aged , Aged, 80 and over , Male , Tricuspid Valve Insufficiency/etiology , Retrospective Studies , Heart Valve Prosthesis Implantation/adverse effects , Treatment Outcome , Risk Assessment , HemodynamicsABSTRACT
BACKGROUND: Numerous studies have affirmed a robust correlation between residual cholesterol (RC) and the occurrence of cardiovascular disease (CVD). However, the current body of literature fails to adequately address the link between alterations in RC and the occurrence of CVD. Existing studies have focused mainly on individual RC values. Hence, the primary objective of this study is to elucidate the association between the cumulative RC (Cum-RC) and the morbidity of CVD. METHODS: The changes in RC were categorized into a high-level fast-growth group (Class 1) and a low-level slow-growth group (Class 2) by K-means cluster analysis. To investigate the relationship between combined exposure to multiple lipids and CVD risk, a weighted quantile sum (WQS) regression analysis was employed. This analysis involved the calculation of weights for total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), which were used to effectively elucidate the RC. RESULTS: Among the cohort of 5,372 research participants, a considerable proportion of 45.94% consisted of males, with a median age of 58. In the three years of follow-up, 669 participants (12.45%) had CVD. Logistic regression analysis revealed that Class 2 individuals had a significantly reduced risk of developing CVD compared to Class 1. The probability of having CVD increased by 13% for every 1-unit increase in the Cum-RC according to the analysis of continuous variables. The restricted cubic spline (RCS) analysis showed that Cum-RC and CVD risk were linearly related (P for nonlinearity = 0.679). The WQS regression results showed a nonsignificant trend toward an association between the WQS index and CVD incidence but an overall positive trend, with the greatest contribution from TC (weight = 0.652), followed by LDL (weight = 0.348). CONCLUSION: Cum-RC was positively and strongly related to CVD risk, suggesting that in addition to focusing on traditional lipid markers, early intervention in patients with increased RC may further reduce the incidence of CVD.
Subject(s)
Cardiovascular Diseases , Male , Humans , Cardiovascular Diseases/epidemiology , Cholesterol, HDL , Cholesterol, LDL , Cholesterol , Incidence , Risk FactorsABSTRACT
BACKGROUND: The association between sarcopenia and cardiovascular disease (CVD) is well known. However, the clinical diagnosis of sarcopenia is complex and not suitable for early clinical identification and prevention of CVD. Relative muscle strength (RMS) is a relatively quantitative and straightforward indicator, but its association with CVD remains unclear. Hence, the objective of this research was to investigate the correlation between RMS and CVD incidence. METHODS: This was a cross-sectional study, using data from the China Health and Retirement Longitudinal Study (CHARLS) in 2011. CVD events were assessed through self-reported physician diagnoses. The RMS was determined by dividing the maximum grip strength by the appendicular skeletal muscle mass (ASM). This study used multivariate logistic regression and restricted cubic spline (RCS) curves to explore the correlation between RMS and CVD incidence. Additionally, we conducted subgroup analyses to provide additional evidence supporting the association between the two variables. RESULTS: A total of 8,733 people were included in our study, with 1,152 (13.19%) CVD patients and 7,581 (86.81%) non-CVD patients. When the data were grouped according to quartiles (Q) of RMS, the inverse association between CVD and RMS remained statistically significant even after controlling for all potential confounding factors. Compared with participants in Q1 of RMS, the ORs (95% CIs) of CVD among those in Q2-Q4 were 0.99 (0.83, 1.17), 0.81 (0.67, 0.98), and 0.70 (0.57, 0.85), respectively. Moreover, the RCS results showed a negative linear correlation between the RMS and CVD incidence (P for nonlinearity = 0.555). Subgroup analysis revealed no significant interaction in any of the groups except for the sex group (P for interaction = 0.046). CONCLUSION: Our study indicated a stable negative correlation between RMS and CVD incidence. RMS is helpful for the early identification and prevention of CVD.