ABSTRACT
Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.
Subject(s)
Bacteria , Cardiovascular Diseases , Cholesterol , Gastrointestinal Microbiome , Humans , Bacteria/metabolism , Cardiovascular Diseases/metabolism , Cholesterol/analysis , Cholesterol/blood , Cholesterol/metabolism , Feces/chemistry , Longitudinal Studies , Metabolome , Metabolomics , RNA, Ribosomal, 16S/metabolismABSTRACT
To gain a better understanding of the complexity of gene expression in normal and diseased tissues it is important to account for the spatial context and identity of cells in situ. State-of-the-art spatial profiling technologies, such as the Nanostring GeoMx Digital Spatial Profiler (DSP), now allow quantitative spatially resolved measurement of the transcriptome in tissues. However, the bioinformatics pipelines currently used to analyse GeoMx data often fail to successfully account for the technical variability within the data and the complexity of experimental designs, thus limiting the accuracy and reliability of the subsequent analysis. Carefully designed quality control workflows, that include in-depth experiment-specific investigations into technical variation and appropriate adjustment for such variation can address this issue. Here, we present standR, an R/Bioconductor package that enables an end-to-end analysis of GeoMx DSP data. With four case studies from previously published experiments, we demonstrate how the standR workflow can enhance the statistical power of GeoMx DSP data analysis and how the application of standR enables scientists to develop in-depth insights into the biology of interest.
Subject(s)
Gene Expression Profiling , Software , Transcriptome , Computational Biology , Reproducibility of Results , Workflow , Intracellular Space/geneticsABSTRACT
The Patient Similarity Network paradigm implies modeling the similarity between patients based on specific data. The similarity can summarize patients' relationships from high-dimensional data, such as biological omics. The end PSN can undergo un/supervised learning tasks while being strongly interpretable, tailored for precision medicine, and ready to be analyzed with graph-theory methods. However, these benefits are not guaranteed and depend on the granularity of the summarized data, the clarity of the similarity measure, the complexity of the network's topology, and the implemented methods for analysis. To date, no patient classifier fully leverages the paradigm's inherent benefits. PSNs remain complex, unexploited, and meaningless. We present StellarPath, a hierarchical-vertical patient classifier that leverages pathway analysis and patient similarity concepts to find meaningful features for both classes and individuals. StellarPath processes omics data, hierarchically integrates them into pathways, and uses a novel similarity to measure how patients' pathway activity is alike. It selects biologically relevant molecules, pathways, and networks, considering molecule stability and topology. A graph convolutional neural network then predicts unknown patients based on known cases. StellarPath excels in classification performances and computational resources across sixteen datasets. It demonstrates proficiency in inferring the class of new patients described in external independent studies, following its initial training and testing phases on a local dataset. It advances the PSN paradigm and provides new markers, insights, and tools for in-depth patient profiling.
Subject(s)
Computational Biology , Precision Medicine , Humans , Computational Biology/methods , Precision Medicine/methods , Neural Networks, Computer , Algorithms , Genomics/methods , Biomarkers/metabolism , Gene Expression Profiling/methods , Proteomics/methods , MultiomicsABSTRACT
Gene-set analysis (GSA) dominates the functional interpretation of omics data and downstream hypothesis generation. Despite its ability to summarise thousands of measurements into semantically interpretable components, GSA often results in hundreds of significantly enriched gene-sets. However, summarisation and effective visualisation of GSA results to facilitate hypothesis generation is still lacking. While some webservers provide gene-set visualization tools, there is still a need for tools that can effectively summarize and guide exploration of GSA results. To enable versatility, webservers accept gene lists as input, however, none provide end-to-end solutions for emerging data types such as single-cell and spatial omics. Here, we present vissE.Cloud, a webserver for end-to-end gene-set analysis, offering gene-set summarisation and highly interactive visualisation. vissE.Cloud uses algorithms from our earlier R package vissE to summarise GSA results by identifying biological themes. We maintain versatility by allowing analysis of gene lists, as well as, analysis of raw single-cell and spatial omics data, including CosMx and Xenium data, making vissE.Cloud the first webserver to provide end-to-end gene-set analysis of sub-cellular localised spatial data. Structuring the results hierarchically allows swift interactive investigations of results at the gene, gene-set, and clusters level. vissE.Cloud is freely available at https://www.vissE.Cloud.
Subject(s)
Computational Biology , Data Visualization , Software , Algorithms , Phenotype , Internet , Computational Biology/instrumentation , Computational Biology/methodsABSTRACT
Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.
Subject(s)
Angiotensin II Type 2 Receptor Blockers , Benzhydryl Compounds , Brain Neoplasms , Drug Repositioning , Glioblastoma , Isoquinolines , Receptor, Angiotensin, Type 2 , Analgesics/pharmacology , Angiotensin II/chemistry , Angiotensin II/pharmacology , Angiotensin II Type 2 Receptor Blockers/therapeutic use , Apoptosis , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Isoquinolines/therapeutic use , Protein Conformation, alpha-Helical , Receptor, Angiotensin, Type 2/chemistry , Receptor, Angiotensin, Type 2/metabolism , Tumor Burden/drug effectsABSTRACT
Magnetic anisotropy in atomically thin correlated heterostructures is essential for exploring quantum magnetic phases for next-generation spintronics. Whereas previous studies have mostly focused on van der Waals systems, here we investigate the impact of dimensionality of epitaxially grown correlated oxides down to the monolayer limit on structural, magnetic, and orbital anisotropies. By designing oxide superlattices with a correlated ferromagnetic SrRuO3 and nonmagnetic SrTiO3 layers, we observed modulated ferromagnetic behavior with the change of the SrRuO3 thickness. Especially, for three-unit-cell-thick layers, we observe a significant 1500% improvement of the coercive field in the anomalous Hall effect, which cannot be solely attributed to the dimensional crossover in ferromagnetism. The atomic-scale heterostructures further reveal the systematic modulation of anisotropy for the lattice structure and orbital hybridization, explaining the enhanced magnetic anisotropy. Our findings provide valuable insights into engineering the anisotropic hybridization of synthetic magnetic crystals, offering a tunable spin order for various applications.
ABSTRACT
Much recent research has been dedicated to exploring the utility of extracellular vesicles (EVs) as circulating disease biomarkers. Underpinning this work is the assumption that the molecular cargo of EVs directly reflects the originating cell. Few attempts have been made, however, to empirically validate this on the -omic level. To this end, we have performed an integrative multi-omic analysis of a panel of breast cancer cell lines and corresponding EVs. Whole transcriptome analysis validated that the cellular transcriptome remained stable when cultured cells are transitioned to low serum or serum-free medium for EV collection. Transcriptomic profiling of the isolated EVs indicated a positive correlation between transcript levels in cells and EVs, including disease-associated transcripts. Analysis of the EV proteome verified that HER2 protein is present in EVs, however neither the estrogen (ER) nor progesterone (PR) receptor proteins are detected regardless of cellular expression. Using multivariate analysis, we derived an EV protein signature to infer cellular patterns of ER and HER2 expression, though the ER protein could not be directly detected. Integrative analyses affirmed that the EV proteome and transcriptome captured key phenotypic hallmarks of the originating cells, supporting the potential of EVs for non-invasive monitoring of breast cancers.
Subject(s)
Breast Neoplasms , Extracellular Vesicles , Humans , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , Female , Proteomics/methods , Cell Line, Tumor , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Proteome/analysis , Proteome/metabolism , Gene Expression Profiling/methods , Transcriptome , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Receptors, Estrogen/metabolism , MultiomicsABSTRACT
Functional analysis of high throughput experiments using pathway analysis is now ubiquitous. Though powerful, these methods often produce thousands of redundant results owing to knowledgebase redundancies upstream. This scale of results hinders extensive exploration by biologists and can lead to investigator biases due to previous knowledge and expectations. To address this issue, we present vissE, a flexible network-based analysis and visualisation tool that organises information into semantic categories and provides various visualisation modules to characterise them with respect to the underlying data, thus providing a comprehensive view of the biological system. We demonstrate vissE's versatility by applying it to three different technologies: bulk, single-cell and spatial transcriptomics. Applying vissE to a factor analysis of a breast cancer spatial transcriptomic data, we identified stromal phenotypes that support tumour dissemination. Its adaptability allows vissE to enhance all existing gene-set enrichment and pathway analysis workflows, empowering biologists during molecular discovery.
Subject(s)
Breast Neoplasms , Gene Expression Profiling , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Transcriptome , PhenotypeABSTRACT
The apparent failure of global health security to prevent or prepare for the COVID-19 pandemic has highlighted the need for closer cooperation between human, animal (domestic and wildlife), and environmental health sectors. However, the many institutions, processes, regulatory frameworks, and legal instruments with direct and indirect roles in the global governance of One Health have led to a fragmented, global, multilateral health security architecture. We explore four challenges: first, the sectoral, professional, and institutional silos and tensions existing between human, animal, and environmental health; second, the challenge that the international legal system, state sovereignty, and existing legal instruments pose for the governance of One Health; third, the power dynamics and asymmetry in power between countries represented in multilateral institutions and their impact on priority setting; and finally, the current financing mechanisms that predominantly focus on response to crises, and the chronic underinvestment for epidemic and emergency prevention, mitigation, and preparedness activities. We illustrate the global and regional dimensions to these four challenges and how they relate to national needs and priorities through three case studies on compulsory licensing, the governance of water resources in the Lake Chad Basin, and the desert locust infestation in east Africa. Finally, we propose 12 recommendations for the global community to address these challenges. Despite its broad and holistic agenda, One Health continues to be dominated by human and domestic animal health experts. Substantial efforts should be made to address the social-ecological drivers of health emergencies including outbreaks of emerging, re-emerging, and endemic infectious diseases. These drivers include climate change, biodiversity loss, and land-use change, and therefore require effective and enforceable legislation, investment, capacity building, and integration of other sectors and professionals beyond health.
Subject(s)
COVID-19 , One Health , Animals , Humans , Global Health , Pandemics , Disease Outbreaks/prevention & controlABSTRACT
BACKGROUND: Radiotherapy is one of the main treatment options for patients with esophageal cancer; however, it has been linked with an increased risk of cardiac toxicities. In the current study, we evaluated the effect of planning the radiation in deep-inspiration breath hold (DIBH) on the dose sparing of cardiac substructures and lung. MATERIALS AND METHODS: In this study, we analyzed 30 radiation therapy plans from 15 patients diagnosed with esophageal cancer planned for neoadjuvant radiotherapy. Radiation plans were generated for 41.4â¯Gy and delivered in 1.8â¯Gy per fraction for free-breathing (FB) and DIBH techniques. We then conducted a comparative dosimetric analysis, evaluating target volume coverage, the impact on cardiac substructures, and lung doses across the two planning techniques for each patient. RESULTS: There was no significant disparity in target volume dose coverage between DIBH and FB plans. However, the Dmean, D2%, and V30% of the heart experienced substantial reductions in DIBH relative to FB, with values of 6.21 versus 7.02â¯Gy (pâ¯= 0.011), 35.28 versus 35.84â¯Gy (pâ¯= 0.047), and 5% versus 5.8% (pâ¯= 0.048), respectively. The Dmean of the left ventricle was notably lower in DIBH compared to FB (4.27 vs. 5.12â¯Gy, pâ¯= 0.0018), accompanied by significant improvements in V10. Additionally, the Dmean and D2% of the left coronary artery, as well as the D2% of the right coronary artery, were significantly lower in DIBH. The dosimetric impact of DIBH on cardiac substructures proved more advantageous for middle esophageal (ME) than distal esophageal (DE) tumors. CONCLUSION: Radiotherapy in DIBH could provide a method to reduce the radiation dose to the left ventricle and coronaries, which could reduce the cardiac toxicity of the modality.
Subject(s)
Breath Holding , Esophageal Neoplasms , Heart , Radiotherapy Dosage , Radiotherapy Planning, Computer-Assisted , Humans , Esophageal Neoplasms/radiotherapy , Male , Female , Heart/radiation effects , Radiotherapy Planning, Computer-Assisted/methods , Middle Aged , Organs at Risk/radiation effects , Aged , Radiation Injuries/prevention & control , Radiation Injuries/etiology , Neoadjuvant Therapy , RadiometryABSTRACT
PURPOSE: Hepatocellular carcinoma (HCC) poses a unique challenge due to its predilection for developing on compromised livers, often limiting surgical options. Stereotactic body radiotherapy (SBRT) has emerged as a promising local treatment modality for HCC. This study aims to assess the effectiveness of SBRT in HCC patients not suitable for surgery, focusing on local control, optimal radiation dosing, and prognostic factors. METHODS: In this retrospective analysis, 52 HCC patients treated with SBRT were examined. The study assessed local control, progression-free survival (PFS), and overall survival (OS) while conducting dosimetric analyses. The relationship between mean liver dose and Child-Pugh score (CPS) progression was also explored. RESULTS: SBRT demonstrated 93.4% freedom from local progression (FFLP) at 12 months. Notably, a near minimum dose (D98%) below 61â¯Gy as an equivalent dose in 2Gy fractions with α/ß 10â¯Gy (EQD2α/ß10) was associated with reduced FFLP (p-value 0.034). Logistic regression analysis revealed a dose-response relationship for FFLP and D98% with 95% and 98% probability of FFLP at a dose of 56.9 and 73.1â¯Gy, respectively. The study observed OS rates of 63.7% at 1 year and 34.3% at 3 years. Patients with portal vein tumor thrombus (PVTT) and larger tumors (≥â¯37â¯cm3) experienced decreased PFS and OS. Multivariate analysis identified PVTT, larger tumor volume, and performance status as independent predictors of reduced OS. Notably, classical radiation-induced disease (cRILD) was absent, but nonclassical (nc) RILD occurred in 7.7% of patients. Regression analysis linked a mean EQD2α/ß3-8 dose to the liver (12.8-12.6) with a 10% likelihood of ncRILD. CONCLUSION: SBRT offers a compelling option for achieving high local control and promising survival outcomes in HCC. The study supports a radiation dose range of 61-73.1â¯Gy, coupled with a mean liver dose under 12.6-12.8â¯Gy as EQD2, to achieve favorable FFLP rates, with acceptable toxicity rates.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Radiosurgery , Humans , Carcinoma, Hepatocellular/radiotherapy , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/radiotherapy , Liver Neoplasms/surgery , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Radiosurgery/methods , Retrospective Studies , Male , Female , Middle Aged , Aged , Treatment Outcome , Aged, 80 and over , Neoplasm Staging , Radiotherapy Dosage , Adult , Progression-Free Survival , PrognosisABSTRACT
The performance of gold nanospheres as substrates for surface-enhanced Raman spectroscopy (SERS) investigation has been compromised by their low adsorption efficiency, high colloidal dispersibility, and diminishing hot spots. However, gold nanosphere substrates modified using aryldiazonium gold(III) chemistry via durable gold-carbon bonds are promising for SERS enhancement due to their controlled organic layer density. In this study, arylated gold nanospheres AuNSs-COOH have shown SERS enhancement when incorporated into graphene oxide (GO) to form nanocomposites (NCs) labeled AuNSs-COOH/GO (AuNCs). Our investigation using X-ray photoelectron spectroscopy (XPS) surface analysis showed that the gold-aryl nanospheres reached their maximum SERS enhancement with an optimal coating. The evaluation included the Au 4f chemical environment and compact graphitic layers for the SERS substrate optimization. The fabricated AuNC substrates demonstrated superior efficiency and reproducibility. A broad linear range of 10-3-10-7 M 4-nitrophenol detection was obtained with exceptional repeatability, as evidenced by the relative standard deviation (RSD) of 9.32%. A detailed investigation of the energy profiles, particularly the valence band maximum (VBM) and band gap values of the substrate and analyte, depicted the electromagnetic (EM) and charge-transfer-induced enhancement and the role of GO inclusion in substrate efficiency in SERS enhancement mechanisms. The finite-difference time domain (FDTD) simulation results revealed that AuNCs incorporated with graphitic nanostructures exhibited the most substantial SERS effect through an EM field enhancement mechanism. This study demonstrated significant SERS enhancement using gold-aryl nanospheres when modified with GO, in contrast to the typical reliance on anisotropic nanostructures.
ABSTRACT
In this study, we report the modification of flexible copper films via the spontaneous reduction of aryldiazonium gold salts [X-4-C6H4N≡N]AuCl4 (XâCOOH, NO2). The electroless modification involves dipping of flexible copper films in the aryldiazonium gold solutions for a few seconds, under ambient conditions, followed by a washing step with deionized water to obtain a mechanically robust gold-aryl coating. The chemical composition, morphology, electronic structure, and optical properties of the gold-aryl layer and the flexibility of the modified copper films are supported by the results from X-ray photoelectron spectroscopy (XPS), electrochemistry, contact angle, scanning electron microscopy (SEM), and ultraviolet photoelectron spectroscopy (UPS). XPS surface analysis showed metallic gold in addition to C-C, C-O/C-N, and CâO functional groups from the grafted aryls. Cu 2p showed metallic copper as a major component and a small amount of Cu(II) ions. Wettability studies showed that Au-COOH@Cu increased the contact angle of the bare copper films from 68.0 ± 0.7° to 82.0° ± 0.7°, while Au-NO2@Cu increased the contact angle to 134.0° ± 0.3°. UPS energy profile analysis of [HOOC-4-C6H4N≡N]AuCl4 (valence band maximum = 1.91 eV) exhibited greater reducibility than [O2N-4-C6H4N≡N]AuCl4 (valence band maximum = 2.91 eV). The lower ionization potential of [HOOC-4-C6H4N≡N]AuCl4 (IP = 4.33 eV) enhanced the reactivity upon copper film contact, potentially inducing efficient energy level alignment, compared with [O2N-4-C6H4N≡N]AuCl4 (IP = 5.62 eV). UPS results were further supported by electrochemistry investigation which revealed that [HOOC-4-C6H4N≡N]AuCl4 is easily reducible compared with [O2N-4-C6H4N≡N]AuCl4. The findings presented here hold significant implications for developing flexible copper films and pave the way for future advancements in electronic material modification for industrial applications.
ABSTRACT
OBJECTIVE: We sought to prospectively evaluate the impact of previously failed SWL on subsequent URS outcomes in the treatment of upper urinary tract stones. MATERIALS AND METHODS: Between May 2021 and May 2023, one hundred thirty-six patients with proximal ureteral stones < 1.5 cm and renal stones < 2.5 cm who were candidates for URS were prospectively assigned to a non-SWL group, which included patients without a history of failed SWL before URS, and a post-SWL group, which included patients with a history of failed SWL before URS. The success rate was the primary outcome. The perioperative data of the two groups were compared. RESULTS: The stone-free rate was 83.3% in the post-SWL group versus 81.3% in the non-SWL group, and 8.3% in the post-SWL group versus 9.4% in the non-SWL group had clinically insignificant residual fragments. There was no significant difference in the stone-free rate or success rate between the groups. No significant differences in intraoperative fluoroscopy time, operative time, intraoperative stone appearance, perioperative complications, or the presence of embedded fragments in the ureteral mucosa were detected between the two groups. CONCLUSION: Compared with patients who underwent primary URS, patients who underwent salvage URS for upper urinary tract stones had similar stone-free rates, success rates, operative times, fluoroscopy times, and complication rates without any significant differences.
Subject(s)
Kidney Calculi , Lithotripsy , Treatment Failure , Ureteral Calculi , Ureteroscopy , Humans , Prospective Studies , Female , Lithotripsy/methods , Ureteroscopy/methods , Male , Middle Aged , Ureteral Calculi/therapy , Ureteral Calculi/surgery , Kidney Calculi/surgery , Kidney Calculi/therapy , Adult , Treatment Outcome , AgedABSTRACT
The first detection of a human infection with avian influenza A/H6N1 virus in Taiwan in 2013 has raised concerns about this virus. During our routine surveillance of avian influenza viruses (AIVs) in live-bird markets in Egypt, an H6N1 virus was isolated from a garganey duck and was characterized. Phylogenetic analysis indicated that the Egyptian H6N1 strain A/Garganey/Egypt/20869C/2022(H6N1) has a unique genomic constellation, with gene segments inherited from different subtypes (H5N1, H3N8, H7N3, H6N1, and H10N1) that have been detected previously in AIVs from Egypt and some Eurasian countries. We examined the replication of kinetics of this virus in different mammalian cell lines (A549, MDCK, and Vero cells) and compared its pathogenicity to that of the ancestral H6N1 virus A/Quail/HK/421/2002(H6N1). The Egyptian H6N1 virus replicated efficiently in C57BL/6 mice without prior adaptation and grew faster and reached higher titers than in A549 cells than the ancestral strain. These results show that reassortant H6 AIVs might pose a potential threat to human health and highlight the need to continue surveillance of H6 AIVs circulating in nature.
Subject(s)
Influenza A Virus, H3N8 Subtype , Influenza A Virus, H5N1 Subtype , Influenza A virus , Influenza in Birds , Animals , Mice , Chlorocebus aethiops , Humans , Influenza in Birds/epidemiology , Egypt/epidemiology , Phylogeny , Vero Cells , Influenza A Virus, H7N3 Subtype , Mice, Inbred C57BL , Animals, Wild , Ducks , MammalsABSTRACT
BACKGROUND: Bladder diaries represent a fundamental component in the assessment of patients presenting with lower urinary tract symptoms. Nevertheless, their importance often remains underappreciated and undervalued within clinical practice. This paper aims to conduct a comprehensive review of the existing literature concerning the utility of bladder diaries, underscore the criticality of their precision, elucidate the factors contributing to noncompliance with bladder diary completion, and investigate potential strategies for enhancing patient compliance. MATERIALS AND METHODS: A review of the English-language scientific literature available in the domains of Medline, Embase, Emcare, Midirs, and Cinahl was conducted. This was supplemented by discussion at the International Consultation on Incontinence Research Society Proposal session to define knowledge and identify gaps in knowledge surrounding the utility of bladder diaries. The existing evidence and outcome of the relevant discussion held in the meeting are presented. RESULTS: Bladder diaries (BD) serve to characterize the nature and severity of storage lower urinary tract symptoms (LUTS) and provide an objective record of an individual's urination patterns. They aid in the refinement and customization of treatment strategies based on the clinical responses documented in the diary, optimizing treatment outcomes. Notably, both BD and urodynamic studies (UDS) play complementary yet distinct roles in LUTS evaluation. BD offers a more comprehensive and accessible approach to assessing specific storage LUTS, particularly due to their affordability and widespread availability, especially in resource-limited settings. Nevertheless, the absence of a standardized BD format across global healthcare systems presents a significant challenge. Despite being recognized as reliable, noninvasive, validated, and cost-effective tools for evaluating patients with LUTS, the implementation and completion of BD have proven to be complex. The introduction of automated bladder diaries heralds an era of precise, real-time data collection, potentially enhancing the patient-clinician relationship. Completion of bladder diaries depends on an array of individual, social, and healthcare-specific factors. Compliance with bladder diary completion could be enhanced with clear instructions, patient education, regular follow-ups and positive re-enforcement. This study has identified four critical areas for future research: Addressing healthcare disparities between affluent and developing nations, enhancing the current functionality and effectiveness of bladder diaries, exploring the feasibility of incorporating bladder diaries into the treatment and education process and improving the quality and functionality of existing bladder diaries. CONCLUSION: Bladder diaries play a pivotal role in the evaluation and management of patients with LUTS, providing a holistic perspective. When their complete potential is harnessed, they have the capacity to revolutionize the paradigm of LUTS management, ushering in a patient-centered era of care.
Subject(s)
Lower Urinary Tract Symptoms , Urinary Bladder , Humans , Lower Urinary Tract Symptoms/physiopathology , Lower Urinary Tract Symptoms/diagnosis , Lower Urinary Tract Symptoms/therapy , Urinary Bladder/physiopathology , Patient Compliance , Urinary Incontinence/therapy , Urinary Incontinence/diagnosis , Urinary Incontinence/physiopathology , Diaries as Topic , Medical Records , Urodynamics , Urination/physiologyABSTRACT
AIMS: This International Consultation on Incontinence-Research Society report aims to summarize the evidence and uncertainties regarding the use of hormone replacement therapy by any route in the management of lower urinary tract symptoms (LUTS) including recurrent urinary tract infections (rUTI), with a review of special considerations for the elderly. Research question proposals to further this field have been highlighted. METHODS: An overview of the existing evidence, guidelines, and consensus regarding the use of topical or systemic estrogens in the management of LUTS. RESULTS: There are currently evidence and recommendations to offer topical estrogens to postmenopausal women with overactive bladder symptoms as well as postmenopausal women with rUTIs. Systemic estrogens however have been shown in a meta-analysis to have a negative effect on LUTS and, therefore are not currently recommended. CONCLUSIONS: Although available evidence and recommendations exist for the use of topical estrogens, few women are commenced on these in primary care. There remain large gaps still within our knowledge of the use of estrogens within the management of LUTS, particularly on when it should be commenced, the length of time treatment should be continued for, and barriers to prescribing.
Subject(s)
Estrogen Replacement Therapy , Lower Urinary Tract Symptoms , Postmenopause , Humans , Lower Urinary Tract Symptoms/drug therapy , Lower Urinary Tract Symptoms/physiopathology , Female , Estrogens/administration & dosage , Urinary Tract Infections/drug therapy , Urinary Tract Infections/diagnosisABSTRACT
It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17ß-estradiol (E2) signaling is also known to modulate glycolysis markers in cancer cells. However, whether the inhibition of PKM2 combined with E2 treatment could adversely affect glucose metabolism in CRC cells remains to be investigated. First, we confirmed the metabolic plasticity of CRC cells under varying environmental conditions. Next, we identified glycolysis markers that were upregulated in CRC patients and assessed in vitro mRNA levels following E2 treatment. We found that PKM2 expression, which is highly upregulated in CRC clinical samples, is not altered by E2 treatment in CRC cells. In this study, glucose uptake, generation of reactive oxygen species (ROS), lactate production, cell viability, and apoptosis were evaluated in CRC cells following E2 treatment, PKM2 silencing, or a combination of both. Compared to individual treatments, combination therapy resulted in a significant reduction in cell viability and enhanced apoptosis. Glucose uptake and ROS production were markedly reduced in PKM2-silenced E2-treated cells. The data presented here suggest that E2 signaling combined with PKM2 inhibition cumulatively targets glucose metabolism in a manner that negatively impacts CRC cell growth. These findings hold promise for novel therapeutic strategies targeting altered metabolic pathways in CRC.
Subject(s)
Colorectal Neoplasms , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Thyroid Hormones/metabolism , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Estrogens/pharmacology , Thyroid Hormone-Binding Proteins , Estradiol/pharmacology , Apoptosis/drug effects , Glucose/metabolism , Carrier Proteins/metabolism , Pyruvate Kinase/metabolism , Pyruvate Kinase/antagonists & inhibitors , Pyruvate Kinase/genetics , Glycolysis/drug effects , Membrane Proteins/metabolism , Membrane Proteins/genetics , FemaleABSTRACT
BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been presented as a potential therapeutic option for patients with cardiogenic shock complicating myocardial infarction (CS-MI). We aimed to investigate the efficacy and safety of ECMO in CS-MI. METHODS: A systematic review and meta-analysis synthesizing evidence from randomized controlled trials obtained from PubMed, Embase, Cochrane, Scopus, and Web of Science until September 2023. We used the random-effects model to report dichotomous outcomes using risk ratio and continuous outcomes using mean difference with a 95% confidence interval. Finally, we implemented a trial sequential analysis to evaluate the reliability of our results. RESULTS: We included four trials with 611 patients. No significant difference was observed between ECMO and standard care groups in 30-day mortality with pooled RR of 0.96 (95% CI: 0.81-1.13, p = 0.60), acute kidney injury (RR: 0.65, 95% CI: 0.41-1.03, p = 0.07), stroke (RR: 1.16, 95% CI: 0.38-3.57, p = 0.80), sepsis (RR: 1.06, 95% CI: 0.77-1.47, p = 0.71), pneumonia (RR: 0.99, 95% CI: 0.58-1.68, p = 0.96), and 30-day reinfarction (RR: 0.95, 95% CI: 0.25-3.60, p = 0.94). However, the ECMO group had higher bleeding events (RR: 2.07, 95% CI: 1.44-2.97, p < 0.0001). CONCLUSION: ECMO did not improve clinical outcomes compared to the standard of care in patients with CS-MI but increased the bleeding risk.
Subject(s)
Extracorporeal Membrane Oxygenation , Myocardial Infarction , Randomized Controlled Trials as Topic , Shock, Cardiogenic , Humans , Extracorporeal Membrane Oxygenation/adverse effects , Extracorporeal Membrane Oxygenation/mortality , Shock, Cardiogenic/therapy , Shock, Cardiogenic/mortality , Shock, Cardiogenic/diagnosis , Shock, Cardiogenic/etiology , Shock, Cardiogenic/physiopathology , Myocardial Infarction/mortality , Myocardial Infarction/complications , Myocardial Infarction/therapy , Myocardial Infarction/diagnosis , Treatment Outcome , Risk Factors , Male , Female , Middle Aged , Risk Assessment , Aged , Time FactorsABSTRACT
BACKGROUND: Regional anesthesia is the favored choice in ruminant animals compared to general anesthesia, primarily due to its high safety margin and reduced demand for cost-intensive equipment in addition to its field applicability. Ultrasound-guided nerve block has gained significant attention in the field of veterinary medicine. This study utilized twenty-seven sheep of the native Rahmani breed to both demonstrate and evaluate the effectiveness of the ultrasound guided inferior alveolar nerve block technique. METHODS: The research comprised three phases: Phase 1 involved an anatomical examination of mandibles and sheep heads to locate the mandibular foramen and delineate the mandibular nerve course. Phase 2 included ultrasound-guided injection of methylene blue dye at specific sites along the mandibular nerve in cadaveric sheep heads. In Phase 3, clinical implementation of ultrasound-guided inferior alveolar nerve blocks was conducted in 27 live sheep, assessing efficacy, onset, and duration. RESULTS: Vertical extraoral ultrasound-guided nerve block was achieved successfully in 25 sheep (98%). A preliminary cadaveric study showed good distribution of the injectate at the mandibular nerve site. The mean onset time was 138 ± 18 s, and the mean duration time was 54 ± 4.1 min. Prominent analgesia of the ipsilateral mandible, medial surface of the cheek, and lateral border of the tongue was observed. CONCLUSIONS: Ultrasound-guided mandibular nerve block holds promise as a technique for providing effective and safe anesthesia in sheep undergoing mandibular procedures.