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Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
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Imunoterapia , Lipídeos , RNA , Microambiente Tumoral , Animais , Cães , Feminino , Humanos , Camundongos , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/imunologia , Glioma/terapia , Glioma/imunologia , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Neoplasias/imunologia , RNA/química , RNA/uso terapêutico , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Lipídeos/químicaRESUMO
Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.
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Transtornos Globais do Desenvolvimento Infantil/genética , Aberrações Cromossômicas , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Quebra Cromossômica , Deleção Cromossômica , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Sistema Nervoso/crescimento & desenvolvimento , Esquizofrenia/genética , Análise de Sequência de DNA , Transdução de SinaisRESUMO
Ebola virus (EBOV) disease is characterized by lymphopenia, breach in vascular integrity, cytokine storm, and multiorgan failure. The pathophysiology of organ involvement, however, is incompletely understood. Using [18F]-DPA-714 positron emission tomography (PET) imaging targeting the translocator protein (TSPO), an immune cell marker, we sought to characterize the progression of EBOV-associated organ-level pathophysiology in the EBOV Rhesus macaque model. Dynamic [18F]-DPA-714 PET/computed tomography imaging was performed longitudinally at baseline and at multiple time points after EBOV inoculation, and distribution volumes (Vt) were calculated as a measure of peripheral TSPO binding. Using a mixed-effect linear regression model, spleen and lung Vt decreased, while the bone marrow Vt increased over time after infection. No clear trend was found for liver Vt. Multiple plasma cytokines correlated negatively with lung/spleen Vt and positively with bone marrow Vt. Multiplex immunofluorescence staining in spleen and lung sections confirmed organ-level lymphoid and monocytic loss/apoptosis, thus validating the imaging results. Our findings are consistent with EBOV-induced progressive monocytic and lymphocytic depletion in the spleen, rather than immune activation, as well as depletion of alveolar macrophages in the lungs, with inefficient reactive neutrophilic activation. Increased bone marrow Vt, on the other hand, suggests hematopoietic activation in response to systemic immune cell depletion and leukocytosis and could have prognostic relevance. In vivo PET imaging provided better understanding of organ-level pathophysiology during EBOV infection. A similar approach can be used to delineate the pathophysiology of other systemic infections and to evaluate the effectiveness of newly developed treatment and vaccine strategies.
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Doença pelo Vírus Ebola , Tomografia por Emissão de Pósitrons , Receptores de GABA , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Doença pelo Vírus Ebola/diagnóstico por imagem , Doença pelo Vírus Ebola/patologia , Pulmão/patologia , Macaca mulatta , Tomografia por Emissão de Pósitrons/métodos , Pirazóis/metabolismo , Pirimidinas/metabolismo , Receptores de GABA/metabolismo , Baço/patologiaRESUMO
PURPOSE: Elevated costs of cancer treatment can result in economic and psychological "financial toxicity" distress. This pilot study assessed the feasibility of a point-of-care intervention to connect adult patients with cancer-induced financial toxicity to telehealth-delivered financial counseling. METHODS: We conducted a three-armed parallel randomized pilot study, allocating newly referred patients with cancer and financial toxicity to individual, group accredited telehealth financial counseling, or usual care with educational material (1:1:1). We assessed the feasibility of recruitment, randomization, retention, baseline and post-intervention COmprehensive Score for Financial Toxicity (COST), and Telehealth Usability Questionnaire (TUQ) scores. RESULTS: Of 382 patients screened, 121 were eligible and enrolled. 58 (48%) completed the intervention (9 individual, 9 group counseling, 40 educational booklet). 29 completed follow-up surveys: 45% female, 17% African American, 79% white, 7% Hispanic, 55% 45-64 years old, 31% over 64, 34% lived in rural areas, 24% had cancer stage I, 21% II, 7% III, 31% IV. Baseline characteristics were balanced across arms, retention status, surveys completion. Mean (SD) COST was 12.4 (6.1) at baseline and 16.0 (8.4) post-intervention. Mean (SD) COST score differences were 6.3 (11.6) after individual counseling, 5.8 (8.5) after group counseling, and 2.5 (6.4) after usual care. Mean TUQ score among nine counseling participants was 5.5 (0.9) over 7.0. Non-parametric comparisons were not statistically meaningful. CONCLUSION: Recruitment and randomization were feasible, while study retention presented challenges. Nine participants reported good usability and satisfaction with telehealth counseling. Larger-scale trials focused on improving participation, retention, and impact of financial counseling among patients with cancer are justified.
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Neoplasias , Telemedicina , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Projetos Piloto , Sistemas Automatizados de Assistência Junto ao Leito , Estresse Financeiro , Aconselhamento , Neoplasias/terapiaRESUMO
With the global pandemic and the continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the need for effective and broadly neutralizing treatments has become increasingly urgent. This study introduces a novel strategy that targets two aspects simultaneously, using bifunctional antibodies to inhibit both the attachment of SARS-CoV-2 to host cell membranes and viral fusion. We developed pioneering IgG4-(HR2)4 bifunctional antibodies by creating immunoglobulin G4-based and phage display-derived human monoclonal antibodies (mAbs) that specifically bind to the SARS-CoV-2 receptor-binding domain, engineered with four heptad repeat 2 (HR2) peptides. Our in vitro experiments demonstrate the superior neutralization efficacy of these engineered antibodies against various SARS-CoV-2 variants, ranging from original SARS-CoV-2 strain to the recently emerged Omicron variants, as well as SARS-CoV, outperforming the parental mAb. Notably, intravenous monotherapy with the bifunctional antibody neutralizes a SARS-CoV-2 variant in a murine model without causing significant toxicity. In summary, this study unveils the significant potential of HR2 peptide-driven bifunctional antibodies as a potent and versatile strategy for mitigating SARS-CoV-2 infections. This approach offers a promising avenue for rapid development and management in the face of the continuously evolving SARS-CoV-2 variants, holding substantial promise for pandemic control.
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Anticorpos Biespecíficos , COVID-19 , Humanos , Animais , Camundongos , SARS-CoV-2/genética , Anticorpos Monoclonais/uso terapêutico , Imunoglobulina G , Peptídeos/genética , Poder PsicológicoRESUMO
PURPOSE: Defining how the in vivo immune status of peripheral tissues is shaped by the external environment has remained a technical challenge. We recently developed Functional in vivo confocal microscopy (Fun-IVCM) for dynamic, longitudinal imaging of corneal immune cells in living humans. This study investigated the effect of seasonal-driven environmental factors on the morphodynamic features of human corneal immune cell subsets. DESIGN: Longitudinal, observational clinical study. PARTICIPANTS: Sixteen healthy participants (aged 18-40 years) attended 2 visits in distinct seasons in Melbourne, Australia (Visit 1, November-December 2021 [spring-summer]; Visit 2, April-June 2022 [autumn-winter]). METHODS: Environmental data were collected over each period. Participants underwent ocular surface examinations and corneal Fun-IVCM (Heidelberg Engineering). Corneal scans were acquired at 5.5 ± 1.5-minute intervals for up to 5 time points. Time-lapse Fun-IVCM videos were created to analyze corneal immune cells, comprising epithelial T cells and dendritic cells (DCs), and stromal macrophages. Tear cytokines were analyzed using a multiplex bead-based immunoassay. MAIN OUTCOME MEASURES: Difference in the density, morphology, and dynamic parameters of corneal immune cell subsets over the study periods. RESULTS: Visit 1 was characterized by higher temperature, lower humidity, and higher air particulate and pollen levels compared with Visit 2. Clinical ocular surface parameters and the density of immune cell subsets were similar across visits. At Visit 1 , corneal epithelial DCs were larger, with a lower dendrite probing speed (0.38 ± 0.21 vs. 0.68 ± 0.33 µm/min; P < 0.001) relative to Visit 2; stromal macrophages were more circular and had less dynamic activity (Visit 1, 7.2 ± 1.9 vs. Visit 2, 10.3 ± 3.7 dancing index; P < 0.001). Corneal T cell morphodynamics were unchanged across periods. Basal tear levels of interleukin 2 and CXCL10 were relatively lower during spring-summer. CONCLUSIONS: This study identifies that the in vivo morphodynamics of innate corneal immune cells (DCs, macrophages) are modified by environmental factors, but such effects are not evident for adaptive immune cells (T cells). The cornea is a potential in vivo window to investigate season-dependent environmental influences on the human immune system. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.
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Given the significant impact of sleep on overall health, radar technology offers a promising, non-invasive, and cost-effective avenue for the early detection of sleep disorders, even prior to relying on polysomnography (PSG)-based classification. In this study, we employed an attention-based bidirectional long short-term memory (Attention Bi-LSTM) model to accurately predict sleep stages using 60 GHz frequency-modulated continuous-wave (FMCW) radar. Our dataset comprised 78 participants from an ongoing obstructive sleep apnea (OSA) cohort, recruited between July 2021 and November 2022, who underwent overnight polysomnography alongside radar sensor monitoring. The dataset encompasses comprehensive polysomnography recordings, spanning both sleep and wakefulness states. The predictions achieved a Cohen's kappa coefficient of 0.746 and an overall accuracy of 85.2% in classifying wakefulness, rapid-eye-movement (REM) sleep, and non-REM (NREM) sleep (N1 + N2 + N3). The results demonstrated that the models incorporating both Radar 1 and Radar 2 data consistently outperformed those using only Radar 1 data, indicating the potential benefits of utilising multiple radars for sleep stage classification. Although the performance of the models tended to decline with increasing OSA severity, the addition of Radar 2 data notably improved the classification accuracy. These findings demonstrate the potential of radar technology as a valuable screening tool for sleep stage classification.
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Aprendizado Profundo , Apneia Obstrutiva do Sono , Humanos , Radar , Fases do Sono , Apneia Obstrutiva do Sono/diagnóstico , SonoRESUMO
Permutation tests are widely used for statistical hypothesis testing when the sampling distribution of the test statistic under the null hypothesis is analytically intractable or unreliable due to finite sample sizes. One critical challenge in the application of permutation tests in genomic studies is that an enormous number of permutations are often needed to obtain reliable estimates of very small p-values, leading to intensive computational effort. To address this issue, we develop algorithms for the accurate and efficient estimation of small p-values in permutation tests for paired and independent two-group genomic data, and our approaches leverage a novel framework for parameterizing the permutation sample spaces of those two types of data respectively using the Bernoulli and conditional Bernoulli distributions, combined with the cross-entropy method. The performance of our proposed algorithms is demonstrated through the application to two simulated datasets and two real-world gene expression datasets generated by microarray and RNA-Seq technologies and comparisons to existing methods such as crude permutations and SAMC, and the results show that our approaches can achieve orders of magnitude of computational efficiency gains in estimating small p-values. Our approaches offer promising solutions for the improvement of computational efficiencies of existing permutation test procedures and the development of new testing methods using permutations in genomic data analysis.
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Genômica , Projetos de Pesquisa , Entropia , Algoritmos , Análise de DadosRESUMO
RATIONALE: The demand for weight loss products is increasing as slimness emerges as the new aesthetic standard and people's desire to achieve it increases. In addition, the distribution and sale of products containing illegal ingredients, pharmaceuticals, and chemicals for which safety is not guaranteed and that cannot be used as foods or dietary supplements are increasing. Thus, the development of an analytical method that could monitor these illegal products is required. METHODS: A high-performance liquid chromatography-photodiode array method capable of rapid and reliable qualitative and quantitative analyses of 43 weight loss agents was established and validated. RESULTS: The process involved dividing analytes into three groups for rapid analysis; when bisacodyl was mixed with chlorocyclopentylsibutramine, it decomposed into its metabolites: monoacetyl bisacodyl and bis-(p-hydroxypheny)-pyridyl-2-methane. This decomposition was due to NaOH that was used to prepare the chlorocyclopentylsibutramine standard solution. Bisacodyl did not degrade when mixed with neutralized chlorocyclopentylsibutramine, whereas when NaOH was added, it rapidly degraded. We identified the bisacodyl degradation products using liquid chromatography-quadrupole-Orbitrap/mass spectrometry. MS2 spectra with proposed structures of fragment peaks were also obtained. CONCLUSIONS: The developed method could be used to regulate slimming products that threaten public health, and knowledge of bisacodyl degradation will be used as the basis for developing an analytic method.
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Fármacos Antiobesidade , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Fármacos Antiobesidade/análise , Bisacodil/análise , Hidróxido de Sódio , Suplementos Nutricionais/análiseRESUMO
BACKGROUND: Clinical outcomes after catheter ablation (CA) or pacemaker (PM) implantation for the tachycardia-bradycardia syndrome (TBS) has not been evaluated adequately. We tried to compare the efficacy and safety outcomes of CA and PM implantation as an initial treatment option for TBS in paroxysmal atrial fibrillation (AF) patients. METHODS: Sixty-eight patients with paroxysmal AF and TBS (mean 63.7 years, 63.2% male) were randomized, and received CA (n = 35) or PM (n = 33) as initial treatments. The primary outcomes were unexpected emergency room visits or hospitalizations attributed to cardiovascular causes. RESULTS: In the intention-to-treatment analysis, the rates of primary outcomes were not significantly different between the two groups at the 2-year follow-up (19.8% vs. 25.9%; hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.25-2.20, P = 0.584), irrespective of whether the results were adjusted for age (HR 1.12, 95% CI 0.34-3.64, P = 0.852). The 2-year rate of recurrent AF was significantly lower in the CA group compared to the PM group (33.9% vs. 56.8%, P = 0.038). Four patients (11.4%) in the CA group finally received PMs after CA owing to recurrent syncope episodes. The rate of major or minor procedure related complications was not significantly different between the two groups. CONCLUSION: CA had a similar efficacy and safety profile with that of PM and a higher sinus rhythm maintenance rate. CA could be considered as a preferable initial treatment option over PM implantation in patients with paroxysmal AF and TBS. TRIAL REGISTRATION: KCT0000155.
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Fibrilação Atrial , Bradicardia , Estimulação Cardíaca Artificial , Ablação por Cateter , Frequência Cardíaca , Marca-Passo Artificial , Recidiva , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Ablação por Cateter/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Fibrilação Atrial/cirurgia , Bradicardia/diagnóstico , Bradicardia/terapia , Bradicardia/fisiopatologia , Estimulação Cardíaca Artificial/efeitos adversos , Fatores de Tempo , Fatores de Risco , Síndrome , Taquicardia/fisiopatologia , Taquicardia/diagnóstico , Taquicardia/terapia , Taquicardia/cirurgiaRESUMO
Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen months1,2. Identifying the cell of origin that harbours mutations that drive GBM could provide a fundamental basis for understanding disease progression and developing new treatments. Given that the accumulation of somatic mutations has been implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates3-5. However, there is a lack of direct genetic evidence from human patients with GBM4,6-10. Here we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that contains the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of (i) normal SVZ tissue away from the tumour mass, (ii) tumour tissue, and (iii) normal cortical tissue (or blood), from 28 patients with isocitrate dehydrogenase (IDH) wild-type GBM or other types of brain tumour. We found that normal SVZ tissue away from the tumour in 56.3% of patients with wild-type IDH GBM contained low-level GBM driver mutations (down to approximately 1% of the mutational burden) that were observed at high levels in their matching tumours. Moreover, by single-cell sequencing and laser microdissection analysis of patient brain tissue and genome editing of a mouse model, we found that astrocyte-like NSCs that carry driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Together, our results show that NSCs in human SVZ tissue are the cells of origin that contain the driver mutations of GBM.
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Glioblastoma/genética , Glioblastoma/patologia , Ventrículos Laterais/patologia , Mutação , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Progressão da Doença , Edição de Genes , Genoma/genética , Glioblastoma/enzimologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isocitrato Desidrogenase/genética , Ventrículos Laterais/metabolismo , Camundongos , Reprodutibilidade dos Testes , Análise de Célula ÚnicaRESUMO
INTRODUCTION: As research on the role of the Th17/IL-23 pathway gains importance, the relationship between atopic dermatitis (AD) and psoriasis is becoming elucidated. OBJECTIVE: The objective of this study wasto evaluate whether AD and its severity affect the risk for psoriasis. METHODS: This retrospective population-based study used the database from the 2009 National Health Insurance Services-Health Screening Cohort in Korea. A total of 3,957,922 adult subjects were included and observed until 2018. The primary outcome was newly diagnosed psoriasis. RESULTS: After adjusting for possible confounding factors, the moderate-to-severe AD group had the highest hazard ratio (HR) for psoriasis (HR = 2.50; 95% confidence interval (CI), 2.40-2.61), followed by the mild AD group (HR = 2.31; 95% CI: 2.19-2.44) compared with the non-AD group during a median 8.11 ± 1.19 years of follow-up. LIMITATIONS: It is difficult to define AD, which is not standardized, using a claims database and exclude patients who were misdiagnosed with AD. CONCLUSION: Patients with severe AD showed an increased risk for psoriasis compared to controls, and the risk for psoriasis was increased according to AD severity. This suggests that psoriasis and AD could share inflammatory, immune, and genetic features.
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Dermatite Atópica , Psoríase , Adulto , Humanos , Dermatite Atópica/diagnóstico , Estudos Retrospectivos , Psoríase/diagnóstico , Células Th17 , Fatores de RiscoRESUMO
The development of single-cell RNA-seq has broadened the spectrum for biological research by providing a high-resolution analysis of cellular heterogeneity. However, the requirement for sophisticated devices for the compartmentalization of cells has limited its widespread applicability. Here, we develop Onepot-Seq, a device-free method, that harnesses the transient localization of mRNA after lysis to capture single-cell transcriptomes simultaneously in a continuous fluid medium. In mixed-species experiments, we obtained high-quality single-cell profiles. Further, cell type-specific poly(A)-conjugated antibodies allow Onepot-Seq to effectively capture target cells in complex populations. Chemical perturbations to cells can be profiled by Onepot-Seq at single-cell resolution. Onepot-Seq should allow routine transcriptional profiling at single-cell resolution, accelerating clinical and scientific discoveries in many fields of science.
This article describes a strategy for single-cell RNA sequencing that avoids the usual imitation required by first physically compartmentalizing single cells. Based on the slow rate of mRNA diffusion relative to mRNA capture on beads, the authors devised a method that profiles single-cell mRNA among a multiple cell population, within one reaction mixture, termed 'Onepot-Seq'. This approach uses a time-constrained, transient reaction chamber that forms around each cell, with only slow diffusion of the cell contents after gentle lysis. The sparse distribution of cells and beads allows the beads to capture the profile of a single cell with minimal intercellular mRNA contamination.
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Análise de Célula Única , Transcriptoma , Transcriptoma/genética , RNA Mensageiro/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Perfilação da Expressão Gênica/métodosRESUMO
INTRODUCTION: This study aimed to assess the impact of positive-end-expiratory pressure (PEEP) on the non-hypoxic apnea time in infants during anesthesia induction with an inspired oxygen fraction of 0.8. METHODS: This age stratified randomized controlled trial included patients under 1 year of age. Preoxygenation was performed using an inspired oxygen fraction of 0.8 for 2 min. Inspired oxygen fraction of 0.8 was administered via a face mask with volume-controlled ventilation at a tidal volume of 6 mL.kg-1, with or without 7 cmH2O of PEEP. Tracheal intubation was performed after 3 min of ventilation; however, it was disconnected from the breathing circuit. Ventilation was resumed once the pulse oximetry readings reached 95%. The primary outcome was the non-hypoxic apnea time, defined as the time from the cessation of ventilation to achieving a pulse oximeter reading of 95%. The secondary outcome measures included the degree of atelectasis assessed by ultrasonography and the presence of gastric air insufflation. RESULTS: Eighty-four patients were included in the final analysis. In the positive end-expiratory pressure group, the atelectasis score decreased (17.0 vs. 31.5, p < .001; mean difference and 95% CI of 11.6, 7.5-15.6), while the non-hypoxic apnea time increased (80.1 s vs. 70.6 s, p = .005; mean difference and 95% CI of -9.4, -16.0 to -2.9), compared to the zero end-expiratory pressure group, among infants who are 6 months old or younger, not in those aged older than 6 months. DISCUSSION: The application of positive end-expiratory pressure reduced the incidence of atelectasis and extended the non-hypoxic apnea time in infants who are 6 months old or younger. However, it did not affect the incidence of atelectasis nor the non-hypoxic apnea time in patients aged older than 6 months.
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AIMS: This study determined the optimal positive end-expiratory pressure levels in infants in supine and prone positions under general anesthesia using electrical impedance tomography (EIT). METHODS: This prospective observational single-centre study included infants scheduled for surgery in the prone position. An electrical impedance tomography sensor was applied after inducing general anesthesia. The optimal positive end-expiratory pressure in the supine position was determined in a decremental trial based on EIT and compliance. Subsequently, the patient's position was changed to prone. Electrical impedance tomography parameters, including global inhomogeneity index, regional ventilation delay, opening pressure, the centre of ventilation, and pendelluft volume, were continuously obtained up to 1 h after prone positioning. The optimal positive end-expiratory pressure in the prone position was similarly determined. RESULTS: Data from 30 infants were analyzed. The mean value of electrical impedance tomography-based optimal positive end-expiratory pressure in the prone position was significantly higher than that in the supine position [10.9 (1.6) cmH2O and 6.1 (0.9) cmH2O, respectively (p < .001)]. Significant differences were observed between electrical impedance tomography- and compliance-based optimal positive end-expiratory pressure. Peak and mean airway, plateau, and driving pressures increased 1 h after prone positioning compared with those in the supine position. In addition, the centre of ventilation for balance in ventilation between the ventral and dorsal regions improved. CONCLUSION: The prone position required higher positive end-expiratory pressure than the supine position in mechanically ventilated infants under general anesthesia. EIT is a promising tool to find the optimal positive end-expiratory pressure, which needs to be individualized.
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Anestesia Geral , Impedância Elétrica , Respiração com Pressão Positiva , Tomografia , Humanos , Respiração com Pressão Positiva/métodos , Anestesia Geral/métodos , Decúbito Ventral/fisiologia , Decúbito Dorsal , Lactente , Estudos Prospectivos , Masculino , Feminino , Tomografia/métodos , Recém-NascidoRESUMO
BACKGROUND: Optimal pain management after insertion of a central venous catheter in children remains unclear. AIM: This study aimed to evaluate the effects of a selective supraclavicular nerve block on postoperative analgesia in pediatric patients undergoing hickman catheter or chemoport insertion. METHODS: Fifty patients aged 3-18 years scheduled for elective Hickman or chemoport insertion were randomized into two groups of 25 each: one group received an ultrasound-guided selective supraclavicular nerve block with 0.1 mL/kg of 0.5% ropivacaine (SSCNB group), and the other group did not receive a nerve block (control group). The primary outcome was the postoperative Wong-Baker Faces Pain Rating Scale score measured between 10 and 30 min after surgery. Secondary outcomes included pain scores at 1, 3, and 24 h after the surgery, block-related complications, length of stay in the postanesthesia care unit, postoperative analgesic consumption, and time to first analgesic use 24 h after surgery. RESULTS: The worst pain score within 30 min in the recovery room was significantly lower in the SSCNB group compared to the control group (6 [5-7] vs. 3 [2-4]; median difference, -3; 95% CI, -4 to -1; p < .001). Pain scores at 1, 3, and 24 h after surgery were also significantly lower in the SSCNB group. The need for both opioid and non-opioid analgesics in the postoperative period was significantly lower in the SSCNB group (36.0% vs. 0%; p = .002 and 44.0% vs. 16.0%; mean difference, -28%; 95% CI, -56 to 0.19; p = .033, respectively), while other secondary outcomes were not significantly different between the two groups. CONCLUSIONS: Ultrasound-guided SSCNB is an effective method for managing postoperative pain in children undergoing Hickman catheter or chemoport insertion, reducing the need for analgesics within 24 h after surgery.
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Bloqueio do Plexo Braquial , Cateteres Venosos Centrais , Humanos , Criança , Anestésicos Locais/uso terapêutico , Cateteres Venosos Centrais/efeitos adversos , Ultrassonografia de Intervenção/métodos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Bloqueio do Plexo Braquial/efeitos adversos , Analgésicos , Analgésicos OpioidesRESUMO
OBJECTIVE: This study aimed to describe the ultrasound, CT findings, and clinical manifestations of pathologically confirmed metastases involving the subcutaneous fat layer of the trunk and pelvis. MATERIALS AND METHODS: We included 30 patients with subcutaneous metastases in the trunk and pelvis, verified by ultrasound-guided biopsy. We comprehensively reviewed ultrasound findings of all 30 patients and contrast-enhanced CT findings of 25 patients obtained before biopsy. Medical records were reviewed, including primary malignancy type, presence of coexisting distant metastasis, and detection method leading to biopsy referral. RESULTS: Most subcutaneous metastases were heterogeneously hypoechoic (86.7%) with well-defined margins (80.0%), lobulated (46.7%) or round-to-oval (40.0%) shape, and vascularity (96.7%). Metastases frequently exhibited no contact (53.3%) or focal contact with deep peripheral fascia, resulting in acute contact angle formation (30.0%). Common CT manifestations included central low attenuation with peripheral rim-like enhancement (60.0%) or well-circumscribed lesion with heterogeneous enhancement (32.0%). Lung cancer (46.7%) was the prevalent primary malignancy. CT was the predominant detection method (56.7%). Coexisting subcutaneous metastases were present in 50.0% of cases, and distant metastases (less subcutaneous metastases) were observed in 90.0% of patients. CONCLUSION: This study describes typical imaging findings of subcutaneous metastases involving the trunk and pelvis. CT may play a crucial role in their early detection, and our results may assist radiologists in their diagnosis.
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OBJECTIVES: To analyze the characteristics of spinal metastasis in CT scans across diverse cancers for effective diagnosis and treatment, using MRI as the gold standard. METHODS: A retrospective study of 309 patients from four centers, who underwent concurrent CT and spinal MRI, revealing spinal metastasis, was conducted. Data on metastasis including total number, volume, visibility on CT (visible, indeterminate, or invisible), and type of bone change were collected. Through chi-square and Mann-Whitney U tests, we characterized the metastasis across diverse cancers and investigated the variation in the intra-individual ratio representing the percentage of lesions within each category for each patient. RESULTS: Out of 3333 spinal metastases from 309 patients, 55% were visible, 21% indeterminate, and 24% invisible. Sclerotic and lytic lesions made up 47% and 43% of the visible and indeterminate categories, respectively. Renal cell carcinoma (RCC), prostate cancer, and hepatocellular carcinoma (HCC) had the highest visibility at 86%, 73%, and 67% (p < 0.0001, p < 0.0001, and p = 0.003), while pancreatic cancer was lowest at 29% (p < 0.0001). RCC and HCC had significantly high lytic metastasis ratios (interquartile range (IQR) 0.96-1.0 and 0.31-1.0, p < 0.001 and p = 0.005). Prostate cancer exhibited a high sclerotic lesion ratio (IQR 0.52-0.97, p < 0.001). About 39% of individuals had invisible or indeterminate lesions, even with a single visible lesion on CT. The intra-individual ratio for indeterminate and invisible metastases surpassed 18%, regardless of the maximal size of the visible metastasis. CONCLUSIONS: This study highlights the variability in characteristics of spinal metastasis based on the primary cancer type through unique lesion-centric analysis.
Assuntos
Imageamento por Ressonância Magnética , Neoplasias da Coluna Vertebral , Tomografia Computadorizada por Raios X , Humanos , Masculino , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/secundário , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Idoso , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Although several biomarkers exist for patients with heart failure (HF), their use in routine clinical practice is often constrained by high costs and limited availability. OBJECTIVE: We examined the utility of an artificial intelligence (AI) algorithm that analyzes printed electrocardiograms (ECGs) for outcome prediction in patients with acute HF. METHODS: We retrospectively analyzed prospectively collected data of patients with acute HF at two tertiary centers in Korea. Baseline ECGs were analyzed using a deep-learning system called Quantitative ECG (QCG), which was trained to detect several urgent clinical conditions, including shock, cardiac arrest, and reduced left ventricular ejection fraction (LVEF). RESULTS: Among the 1254 patients enrolled, in-hospital cardiac death occurred in 53 (4.2%) patients, and the QCG score for critical events (QCG-Critical) was significantly higher in these patients than in survivors (mean 0.57, SD 0.23 vs mean 0.29, SD 0.20; P<.001). The QCG-Critical score was an independent predictor of in-hospital cardiac death after adjustment for age, sex, comorbidities, HF etiology/type, atrial fibrillation, and QRS widening (adjusted odds ratio [OR] 1.68, 95% CI 1.47-1.92 per 0.1 increase; P<.001), and remained a significant predictor after additional adjustments for echocardiographic LVEF and N-terminal prohormone of brain natriuretic peptide level (adjusted OR 1.59, 95% CI 1.36-1.87 per 0.1 increase; P<.001). During long-term follow-up, patients with higher QCG-Critical scores (>0.5) had higher mortality rates than those with low QCG-Critical scores (<0.25) (adjusted hazard ratio 2.69, 95% CI 2.14-3.38; P<.001). CONCLUSIONS: Predicting outcomes in patients with acute HF using the QCG-Critical score is feasible, indicating that this AI-based ECG score may be a novel biomarker for these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01389843; https://clinicaltrials.gov/study/NCT01389843.