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1.
Front Microbiol ; 12: 710067, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603235

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is the most common cause of Kaposi's sarcoma (KS) and other malignant growths in humans. However, the lack of a KSHV-infected small animal model has hampered understanding of the mechanisms of KSHV infection, virus replication, pathogenesis, and persistence. This study was designed to explore the susceptibility of tree shrews as a possible KSHV-infected small animal model. A recombinant GFP (latent)/RFP (lytic)-positive rKSHV.219 strain was used to infect primary cells cultured from different tissues of tree shrews as an in vitro model and adult tree shrews as an in vivo model. KSHV latent nuclear antigen (LANA) and DNA were successfully detected in primary cells of tree shrews. Among them, tree shrew kidney epithelial cells (TSKEC) were the most susceptible cells to KSHV infection compared to other cells. KSHV genomic DNA, mRNA, and KSHV-specific proteins were readily detected in the TSKEC cultured up to 32 dpi. Moreover, KSHV DNA and mRNA transcription were also readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of tree shrews infected with KSHV. Haematoxylin and eosin (HE) staining showed lymphocyte infiltration, lymphoid tissue focal aggregation, alveolar wall thickening, hepatocyte edema, hepatic necrosis in the spleen, lung, and liver of KSHV-infected animals. Additionally, immune-histochemical (IHC) staining showed that LANA or ORF62-positive cells were present in the spleen, lung, liver, and kidney of KSHV-infected tree shrews. Here, we have successfully established in vitro and in vivo KSHV latent infection in tree shrews. This small animal model is not only useful for studying the pathogenesis of KSHV in vivo but can also be a useful model to study transmission routes of viral infection and a useful platform to characterize the novel therapeutics against KSHV.

2.
Thorac Cancer ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581484

RESUMO

OBJECTIVE: Few studies have focused on factors associated with the incremental cost of video-assisted thoracoscopic surgery (VATS) in China. We aim to systematically classify the complications after VATS major lung resection and explore their correlation with hospital costs. METHODS: Patients with pathologically stage I-III lung cancer who underwent VATS major lung resections from January 2007 to December 2018 were included. The Thoracic Mortality and Morbidity (TM&M) Classification system was used to evaluate postoperative complications. Grade I and II complications, defined as minor complications, require no therapy or pharmacologic intervention only. Grade III and IV complications, defined as major complications, require surgical intervention or life support. Grade V results in death. A generalized linear model was used to explore the correlation of incremental hospital costs and complications, as well as other clinicopathologic parameters between 2013 and 2016. RESULTS: A total of 2881 patients were enrolled in the first part, and the minor and major complications rates were 24.3% (703 patients) and 8.3% (228 patients), respectively. Six hundred and eighty-two patients were enrolled in the second part. The complications grade II (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.05-1.2, p = 0.0005), grade III (OR 1.55, 95% CI 1.26-1.9, p < 0.0001), grades IV and V (OR 1.09, 95% CI 1.04-1.13, p = 0.0002), diffusion capacity of carbon dioxide (OR 0.998, 95% CI 0.997-1.000, p = 0.004), and duration of chest drainage (OR 1.03, 95% CI 1.02-1.04, p < 0.001) and were independent risk factors for the increase in in-hospital costs of VATS major lung resections. CONCLUSIONS: The severity of complications graded by the TM&M system was an independent risk factor for increased in-hospital costs.

3.
PLoS Pathog ; 17(9): e1009947, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34543357

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) preferentially infects and causes Kaposi's sarcoma (KS) in male patients. However, the biological mechanisms are largely unknown. This study was novel in confirming the extensive nuclear distribution of the androgen receptor (AR) and its co-localization with viral oncoprotein of latency-associated nuclear antigen in KS lesions, indicating a transcription way of AR in KS pathogenesis. The endogenous AR was also remarkably higher in KSHV-positive B cells than in KSHV-negative cells and responded to the ligand treatment of 5α-dihydrotestosterone (DHT), the agonist of AR. Then, the anti-AR antibody-based chromatin immunoprecipitation (ChIP)-associated sequencing was used to identify the target viral genes of AR, revealing that the AR bound to multiple regions of lytic genes in the KSHV genome. The highest peak was enriched in the core promoter sequence of polyadenylated nuclear RNA (PAN), and the physical interaction was verified by ChIP-polymerase chain reaction (PCR) and the electrophoretic mobility shift assay (EMSA). Consistently, male steroid treatment significantly transactivated the promoter activity of PAN in luciferase reporter assay, consequently leading to extensive lytic gene expression and KSHV production as determined by real-time quantitative PCR, and the deletion of nuclear localization signals of AR resulted in the loss of nuclear transport and transcriptional activity in the presence of androgen and thus impaired the expression of PAN RNA. Oncogenically, this study identified that the AR was a functional prerequisite for cell invasion, especially under the context of KSHV reactivation, through hijacking the PAN as a critical effector. Taken together, a novel mechanism from male sex steroids to viral noncoding RNA was identified, which might provide a clue to understanding the male propensity in KS.

5.
Emerg Microbes Infect ; 10(1): 1626-1637, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34365904

RESUMO

Coronaviruses (CoVs) can infect a variety of hosts, including humans, livestock and companion animals, and pose a serious threat to human health and the economy. The current COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed millions of people. Unfortunately, effective treatments for CoVs infection are still lacking, suggesting the importance of coronavirus vaccines. Our previous work showed that CoV nonstuctural protein 14 (nsp14) functions as (guanine-N7)-methyltransferase (N7-MTase), which is involved in RNA cap formation. Moreover, we found that N7-MTase is well conserved among different CoVs and is a universal target for developing antivirals against CoVs. Here, we show that N7-MTase of CoVs can be an ideal target for designing live attenuated vaccines. Using murine hepatitis virus strain A59 (MHV-A59), a representative and well-studied model of coronaviruses, we constructed N7-MTase-deficient recombinant MHV D330A and Y414A. These two mutants are highly attenuated in mice and exhibit similar replication efficiency to the wild-type (WT) virus in the cell culture. Furthermore, a single dose immunization of D330A or Y414A can induce long-term humoral immune responses and robust CD4+ and CD8+ T cell responses, which can provide full protection against the challenge of a lethal-dose of MHV-A59. Collectively, this study provides an ideal strategy to design live attenuated vaccines for coronavirus by abolishing viral RNA N7-MTase activity. This approach may apply to other RNA viruses that encode their own conservative viral N7-methyltransferase.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Atenuadas/imunologia , Animais , Vacinas contra COVID-19/administração & dosagem , Citocinas/biossíntese , Humanos , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , Interferon Tipo I/biossíntese , Masculino , Camundongos , Mutação , Vacinas Atenuadas/administração & dosagem , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
6.
JMIR Mhealth Uhealth ; 9(8): e25415, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34387554

RESUMO

BACKGROUND: With the development and promotion of wearable devices and their mobile health (mHealth) apps, physiological signals have become a research hotspot. However, noise is complex in signals obtained from daily lives, making it difficult to analyze the signals automatically and resulting in a high false alarm rate. At present, screening out the high-quality segments of the signals from huge-volume data with few labels remains a problem. Signal quality assessment (SQA) is essential and is able to advance the valuable information mining of signals. OBJECTIVE: The aims of this study were to design an SQA algorithm based on the unsupervised isolation forest model to classify the signal quality into 3 grades: good, acceptable, and unacceptable; validate the algorithm on labeled data sets; and apply the algorithm on real-world data to evaluate its efficacy. METHODS: Data used in this study were collected by a wearable device (SensEcho) from healthy individuals and patients. The observation windows for electrocardiogram (ECG) and respiratory signals were 10 and 30 seconds, respectively. In the experimental procedure, the unlabeled training set was used to train the models. The validation and test sets were labeled according to preset criteria and used to evaluate the classification performance quantitatively. The validation set consisted of 3460 and 2086 windows of ECG and respiratory signals, respectively, whereas the test set was made up of 4686 and 3341 windows of signals, respectively. The algorithm was also compared with self-organizing maps (SOMs) and 4 classic supervised models (logistic regression, random forest, support vector machine, and extreme gradient boosting). One case validation was illustrated to show the application effect. The algorithm was then applied to 1144 cases of ECG signals collected from patients and the detected arrhythmia false alarms were calculated. RESULTS: The quantitative results showed that the ECG SQA model achieved 94.97% and 95.58% accuracy on the validation and test sets, respectively, whereas the respiratory SQA model achieved 81.06% and 86.20% accuracy on the validation and test sets, respectively. The algorithm was superior to SOM and achieved moderate performance when compared with the supervised models. The example case showed that the algorithm was able to correctly classify the signal quality even when there were complex pathological changes in the signals. The algorithm application results indicated that some specific types of arrhythmia false alarms such as tachycardia, atrial premature beat, and ventricular premature beat could be significantly reduced with the help of the algorithm. CONCLUSIONS: This study verified the feasibility of applying the anomaly detection unsupervised model to SQA. The application scenarios include reducing the false alarm rate of the device and selecting signal segments that can be used for further research.

7.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 38(4): 753-763, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34459176

RESUMO

As a low-load physiological monitoring technology, wearable devices can provide new methods for monitoring, evaluating and managing chronic diseases, which is a direction for the future development of monitoring technology. However, as a new type of monitoring technology, its clinical application mode and value are still unclear and need to be further explored. In this study, a central monitoring system based on wearable devices was built in the general ward (non-ICU ward) of PLA General Hospital, the value points of clinical application of wearable physiological monitoring technology were analyzed, and the system was combined with the treatment process and applied to clinical monitoring. The system is able to effectively collect data such as electrocardiogram, respiration, blood oxygen, pulse rate, and body position/movement to achieve real-time monitoring, prediction and early warning, and condition assessment. And since its operation from March 2018, 1 268 people (657 patients) have undergone wearable continuous physiological monitoring until January 2020, with data from a total of 1 198 people (632 cases) screened for signals through signal quality algorithms and manual interpretation were available for analysis, accounting for 94.48 % (96.19%) of the total. Through continuous physiological data analysis and manual correction, sleep apnea event, nocturnal hypoxemia, tachycardia, and ventricular premature beats were detected in 232 (36.65%), 58 (9.16%), 30 (4.74%), and 42 (6.64%) of the total patients, while the number of these abnormal events recorded in the archives was 4 (0.63%), 0 (0.00%), 24 (3.80%), and 15 (2.37%) cases. The statistical analysis of sleep apnea event outcomes revealed that patients with chronic diseases were more likely to have sleep apnea events than healthy individuals, and the incidence was higher in men (62.93%) than in women (37.07%). The results indicate that wearable physiological monitoring technology can provide a new monitoring mode for inpatients, capturing more abnormal events and provide richer information for clinical diagnosis and treatment through continuous physiological parameter analysis, and can be effectively integrated into existing medical processes. We will continue to explore the applicability of this new monitoring mode in different clinical scenarios to further enrich the clinical application of wearable technology and provide richer tools and methods for the monitoring, evaluation and management of chronic diseases.


Assuntos
Síndromes da Apneia do Sono , Dispositivos Eletrônicos Vestíveis , Frequência Cardíaca , Humanos , Monitorização Fisiológica , Movimento
9.
Cell Prolif ; 54(9): e13091, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34291856

RESUMO

OBJECTIVES: Recent studies have shown the presence of SARS-CoV-2 in the tissues of clinically recovered patients and persistent immune symptoms in discharged patients for up to several months. Pregnant patients were shown to be a high-risk group for COVID-19. Based on these findings, we assessed SARS-CoV-2 nucleic acid and protein retention in the placentas of pregnant women who had fully recovered from COVID-19 and cytokine fluctuations in maternal and foetal tissues. MATERIALS AND METHODS: Remnant SARS-CoV-2 in the term placenta was detected using nucleic acid amplification and immunohistochemical staining of the SARS-CoV-2 protein. The infiltration of CD14+ macrophages into the placental villi was detected by immunostaining. The cytokines in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens at delivery were profiled using the Luminex assay. RESULTS: Residual SARS-CoV-2 nucleic acid and protein were detected in the term placentas of recovered pregnant women. The infiltration of CD14+ macrophages into the placental villi of the recovered pregnant women was higher than that in the controls. Furthermore, the cytokine levels in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens fluctuated significantly. CONCLUSIONS: Our study showed that SARS-CoV-2 nucleic acid (in one patient) and protein (in five patients) were present in the placentas of clinically recovered pregnant patients for more than 3 months after diagnosis. The immune responses induced by the virus may lead to prolonged and persistent symptoms in the maternal plasma, placenta, umbilical cord, cord blood and amniotic fluid.


Assuntos
Citocinas/análise , Placenta/virologia , RNA Viral/isolamento & purificação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Proteínas Virais/isolamento & purificação , Adulto , Líquido Amniótico/química , COVID-19/patologia , Feminino , Sangue Fetal/química , Humanos , Recém-Nascido , Macrófagos/imunologia , Técnicas de Amplificação de Ácido Nucleico , Placenta/imunologia , Gravidez , RNA Viral/sangue , RNA Viral/genética , SARS-CoV-2/isolamento & purificação , Proteínas Virais/sangue
11.
Sci Rep ; 11(1): 14492, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262058

RESUMO

In inertial confinement fusion, quantitative and high-spatial resolution ([Formula: see text]m) measurements of the X-rays self-emitted by the hotspot are critical for studying the physical processes of the implosion stagnation stage. Herein, the 8 ± 0.39-keV monochromatic X-ray distribution from the entire hotspot is quantitatively observed in 5-[Formula: see text]m spatial resolution using a Kirkpatrick-Baez microscope, with impacts from the responses of the diagnosis system removed, for the first time, in implosion experiments at the 100 kJ laser facility in China. Two-dimensional calculations along with 2.5% P2 drive asymmetry and 0.3 ablator self-emission are congruent with the experimental results, especially for the photon number distribution, hotspot profile, and neutron yield. Theoretical calculations enabled a better understanding of the experimental results. Furthermore, the origins of the 17.81% contour profile of the deuterium-deuterium hotspot and the accurate Gaussian source approximation of the core emission area in the implosion capsule are clarified in detail. This work is significant for quantitatively exploring the physical conditions of the hotspot and updating the theoretical model of capsule implosion.

12.
Virol Sin ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196914

RESUMO

Similar to that of other enteroviruses, the replication of enterovirus 71 (EV71) occurs on rearranged membranous structures called replication organelles (ROs). Phosphatidylinositol 4-kinase III (PI4KB), which is required by enteroviruses for RO formation, yields phosphatidylinositol-4-phosphate (PI4P) on ROs. PI4P then binds and induces conformational changes in the RNA-dependent RNA polymerase (RdRp) to modulate RdRp activity. Here, we targeted 3D polymerase, the core enzyme of EV71 ROs, and found that the host factor Annexin A2 (ANXA2) can interact with 3D polymerase and promote the replication of EV71. Then, an experiment showed that the annexin domain of ANXA2, which possesses membrane-binding capacity, mediates the interaction of ANXA2 with EV71 3D polymerase. Further research showed that ANXA2 is localized on ROs and interacts with PI4KB. Overexpression of ANXA2 stimulated the formation of PI4P, and the level of PI4P was decreased in ANXA2-knockout cells. Furthermore, ANXA2, PI4KB, and 3D were shown to be localized to the viral RNA replication site, where they form a higher-order protein complex, and the presence of ANXA2 promoted the PI4KB-3D interaction. Altogether, our data provide new insight into the role of ANXA2 in facilitating formation of the EV71 RNA replication complex.

13.
PLoS Pathog ; 17(6): e1009645, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34077484

RESUMO

The presumed DNA helicase encoded by ORF44 of Kaposi's sarcoma-associated herpesvirus (KSHV) plays a crucial role in unwinding viral double-stranded DNA and initiating DNA replication during lytic reactivation. However, the regulatory mechanism of KSHV ORF44 has not been fully elucidated. In a previous study, we identified that N-Myc downstream regulated gene 1 (NDRG1), a host scaffold protein, facilitates viral genome replication by interacting with proliferating cell nuclear antigen (PCNA) and the latent viral protein latency-associated nuclear antigen (LANA) during viral latency. In the present study, we further demonstrated that NDRG1 can interact with KSHV ORF44 during viral lytic replication. We also found that the mRNA and protein levels of NDRG1 were significantly increased by KSHV ORF50-encoded replication and transcription activator (RTA). Remarkably, knockdown of NDRG1 greatly decreased the protein level of ORF44 and impaired viral lytic replication. Interestingly, NDRG1 enhanced the stability of ORF44 and inhibited its ubiquitin-proteasome-mediated degradation by reducing the polyubiquitination of the lysine residues at positions 79 and 368 in ORF44. In summary, NDRG1 is a novel binding partner of ORF44 and facilitates viral lytic replication by maintaining the stability of ORF44. This study provides new insight into the mechanisms underlying KSHV lytic replication.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Herpesvirus Humano 8/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Proteínas Imediatamente Precoces/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Replicação Viral/fisiologia , Linhagem Celular , Humanos
14.
Phys Rev Lett ; 126(18): 185001, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34018773

RESUMO

High density carbon (HDC) ablator is one of the promising candidates toward thermonuclear ignition in inertial confinement fusion (ICF), but it shows the largest ablation front instability growth as compared to other traditional ablator materials. In this Letter, we propose a novel HDC-CH capsule design, opening the way to mitigate the hydrodynamic instabilities by using CH as the outermost ablator layer, while keeping HDC as the main ablator for maintaining the advantage of short laser pulses. The CH layer is completely ablated during the shock transit phase. In the HDC-CH design, it is the first shock reflected from the HDC/CH interface that meets the ablation front first, which reduces the ablation front growth factor by about one order of magnitude at peak implosion velocity due to the Richtmyer-Meshkov and the Rayleigh-Taylor instabilities. Our 2D simulation studies demonstrate convincingly that the ablation front growth factor of the HDC-CH capsule can be significantly reduced at both the end of shock transit phase and the time at peak implosion velocity, as compared to a HDC capsule. This novel HDC-CH capsule not only keeps the main advantage of the HDC ablator, but also has the advantage of low hydrodynamic instabilities, which can provide a larger margin toward ICF ignition. It can be applicable to both indirect-drive and direct-drive targets.

15.
BMC Infect Dis ; 21(1): 448, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006230

RESUMO

BACKGROUND: In the era of anti-retroviral therapy (ART), the plasma HIV viral load (VL) is an important primary indicator for monitoring the HIV treatment response. To optimize the clinical management of HIV/AIDS patients, we investigated VL high-risk events related to virological failure (VF) and further explored the preventive factors of VL high-risk events. METHODS: The data were derived from China's HIV/AIDS Comprehensive Response Information Management System. HIV infected patients who initiated or received ART in Guangxi between 2003 and 2019 were included. The contributions of VL after 6 months of ART to VF and AIDS-related death were analysed by Kaplan-Meier curves, log-rank tests and Cox regression analyses. Both descriptive analyses and bivariate logistic regression were employed to further explore the preventive factors related to VL high-risk events of VF. RESULTS: The cumulative rates of VF in the high low-level viremia group (high LLV) (χ2 = 18.45; P <  0.001) and non-suppressed group (χ2 = 82.99; P <  0.001) were significantly higher than those in the viral suppression (VS) group. Therefore, the VL high-risk events of VF was defined as highest VL > 200 copies/ml after 6 months of ART. Compared with the VS group, the adjusted hazard risk was 7.221 (95% CI: 2.668; 19.547) in the high LLV group and 8.351 (95% CI: 4.253; 16.398) in the non-suppressed group. Compared with single patients, married or cohabiting (AOR = 0.591; 95% CI: 0.408, 0.856) and divorced or separated (AOR = 0.425, 95% CI: 0.207, 0.873) patients were negatively associated with VL high-risk events. So were patients acquired HIV homosexually (AOR = 0.572; 95% CI: 0.335, 0.978). However, patients who had ART modification were 1.728 times (95% CI: 1.093, 2.732) more likely to have VL high-risk events, and patients who used cotrimoxazole during ART were 1.843 times (95% CI: 1.271, 2.672) more likely to have VL high-risk events. CONCLUSIONS: A VL greater than 200 copies/ml is a VL high-risk event for VF. Intervention measurements should be adopted to optimize the surveillance of ART in patients who are single or widowed, who have ART modification, and who use cotrimoxazole during ART.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Antirretrovirais/uso terapêutico , HIV-1/fisiologia , Síndrome de Imunodeficiência Adquirida/epidemiologia , Síndrome de Imunodeficiência Adquirida/mortalidade , Síndrome de Imunodeficiência Adquirida/virologia , Adulto , China/epidemiologia , Feminino , HIV-1/isolamento & purificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Falha de Tratamento , Carga Viral
16.
JMIR Med Inform ; 9(4): e18803, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33856350

RESUMO

BACKGROUND: Without timely diagnosis and treatment, tachycardia, also called tachyarrhythmia, can cause serious complications such as heart failure, cardiac arrest, and even death. The predictive performance of conventional clinical diagnostic procedures needs improvement in order to assist physicians in detecting risk early on. OBJECTIVE: We aimed to develop a deep tachycardia onset prediction (TOP-Net) model based on deep learning (ie, bidirectional long short-term memory) for early tachycardia diagnosis with easily accessible data. METHODS: TOP-Net leverages 2 easily accessible data sources: vital signs, including heart rate, respiratory rate, and blood oxygen saturation (SpO2) acquired continuously by wearable embedded systems, and electronic health records, containing age, gender, admission type, first care unit, and cardiovascular disease history. The model was trained with a large data set from an intensive care unit and then transferred to a real-world scenario in the general ward. In this study, 3 experiments incorporated merging patients' personal information, temporal memory, and different feature combinations. Six metrics (area under the receiver operating characteristic curve [AUROC], sensitivity, specificity, accuracy, F1 score, and precision) were used to evaluate predictive performance. RESULTS: TOP-Net outperformed the baseline models on the large critical care data set (AUROC 0.796, 95% CI 0.768-0.824; sensitivity 0.753, 95% CI 0.663-0.793; specificity 0.720, 95% CI 0.645-0.758; accuracy 0.721; F1 score 0.718; precision 0.686) when predicting tachycardia onset 6 hours in advance. When predicting tachycardia onset 2 hours in advance with data acquired from our hospital using the transferred TOP-Net, the 6 metrics were 0.965, 0.955, 0.881, 0.937, 0.793, and 0.680, respectively. The best performance was achieved using comprehensive vital signs (heart rate, respiratory rate, and SpO2) statistical information. CONCLUSIONS: TOP-Net is an early tachycardia prediction model that uses 8 types of data from wearable sensors and electronic health records. When validated in clinical scenarios, the model achieved a prediction performance that outperformed baseline models 0 to 6 hours before tachycardia onset in the intensive care unit and 2 hours before tachycardia onset in the general ward. Because of the model's implementation and use of easily accessible data from wearable sensors, the model can assist physicians with early discovery of patients at risk in general wards and houses.

17.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 38(1): 131-137, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33899437

RESUMO

As a novel technology, wearable physiological parameter monitoring technology represents the future of monitoring technology. However, there are still many problems in the application of this kind of technology. In this paper, a pilot study was conducted to evaluate the quality of electrocardiogram (ECG) signals of the wearable physiological monitoring system (SensEcho-5B). Firstly, an evaluation algorithm of ECG signal quality was developed based on template matching method, which was used for automatic and quantitative evaluation of ECG signals. The algorithm performance was tested on a randomly selected 100 h dataset of ECG signals from 100 subjects (15 healthy subjects and 85 patients with cardiovascular diseases). On this basis, 24-hour ECG data of 30 subjects (7 healthy subjects and 23 patients with cardiovascular diseases) were collected synchronously by SensEcho-5B and ECG Holter. The evaluation algorithm was used to evaluate the quality of ECG signals recorded synchronously by the two systems. Algorithm validation results: sensitivity was 100%, specificity was 99.51%, and accuracy was 99.99%. Results of controlled test of 30 subjects: the median (Q1, Q3) of ECG signal detected by SensEcho-5B with poor signal quality time was 8.93 (0.84, 32.53) minutes, and the median (Q1, Q3) of ECG signal detected by Holter with poor signal quality time was 14.75 (4.39, 35.98) minutes (Rank sum test, P=0.133). The results show that the ECG signal quality algorithm proposed in this paper can effectively evaluate the ECG signal quality of the wearable physiological monitoring system. Compared with signal measured by Holter, the ECG signal measured by SensEcho-5B has the same ECG signal quality. Follow-up studies will further collect physiological data of large samples in real clinical environment, analyze and evaluate the quality of ECG signals, so as to continuously optimize the performance of the monitoring system.


Assuntos
Processamento de Sinais Assistido por Computador , Dispositivos Eletrônicos Vestíveis , Algoritmos , Eletrocardiografia , Eletrocardiografia Ambulatorial , Humanos , Projetos Piloto
18.
ACS Pharmacol Transl Sci ; 4(2): 1001-1013, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33860216

RESUMO

Drug induced cholestasis (DIC) is complexly associated with dysbiosis of the host-gut microbial cometabolism of bile acids (BAs). Murine animals are not suitable for transitional studies because the murine BA metabolism is quite different from human metabolism. In this work, the rifampicin (RFP) induced cholestasis was established in beagle dogs that have a humanlike BA profile to disclose how RFP affects the host-gut microbial cometabolism of BAs. The daily excretion of BA metabolites in urine and feces was extensively analyzed during cholestasis by quantitative BA profiling along the primary-secondary-tertiary axis. Oral midazolam clearance was also acquired to monitor the RFP-induced enterohepatic CYP3A activities because CYP3A is exclusively responsible for the tertiary oxidation of hydrophobic secondary BAs. RFP treatments caused a compensatory transition of the BA metabolism from the fecal disposition of secondary BAs to the urinary excretion of primary BAs in dogs, resulting in an infantile BA metabolism pattern recently disclosed in newborns. However, the tertiary BAs consistently constituted limitedly in the daily BA excretion, indicating that the detoxification role of the CYP3A catalyzed tertiary BA metabolism was not as strong as expected in this model. Multiple host-gut microbial factors might have contributed to the transition of the BA metabolism, such as inhibition of BA transporters, induction of liver-kidney interplaying detoxification mechanisms, and elimination of gut bacteria responsible for secondary BA production. Transitional studies involving more cholestatic drugs in preclinical animals with a humanlike BA profile and DIC patients may pave the way for understanding the complex mechanism of DIC in the era of metagenomics.

19.
Mol Cell ; 81(10): 2135-2147.e5, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33713597

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global pandemic. CoVs are known to generate negative subgenomes (subgenomic RNAs [sgRNAs]) through transcription-regulating sequence (TRS)-dependent template switching, but the global dynamic landscapes of coronaviral subgenomes and regulatory rules remain unclear. Here, using next-generation sequencing (NGS) short-read and Nanopore long-read poly(A) RNA sequencing in two cell types at multiple time points after infection with SARS-CoV-2, we identified hundreds of template switches and constructed the dynamic landscapes of SARS-CoV-2 subgenomes. Interestingly, template switching could occur in a bidirectional manner, with diverse SARS-CoV-2 subgenomes generated from successive template-switching events. The majority of template switches result from RNA-RNA interactions, including seed and compensatory modes, with terminal pairing status as a key determinant. Two TRS-independent template switch modes are also responsible for subgenome biogenesis. Our findings reveal the subgenome landscape of SARS-CoV-2 and its regulatory features, providing a molecular basis for understanding subgenome biogenesis and developing novel anti-viral strategies.


Assuntos
COVID-19 , Genoma Viral , Sequenciamento de Nucleotídeos em Larga Escala , RNA Viral , SARS-CoV-2 , Animais , COVID-19/genética , COVID-19/metabolismo , Células CACO-2 , Chlorocebus aethiops , Humanos , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Células Vero
20.
Drug Metab Dispos ; 49(5): 369-378, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33674269

RESUMO

Deoxycholic acid (DCA, 3α, 12α-dihydroxy-5ß-cholan-24-oic acid) is the major circulating secondary bile acid, which is synthesized by gut flora in the lower gut and selectively oxidized by CYP3A into tertiary metabolites, including 1ß,3α,12α-trihydroxy-5ß-cholan-24-oic acid (DCA-1ß-ol) and 3α,5ß,12α-trihydroxy-5ß-cholan-24-oic acid (DCA-5ß-ol) in humans. Since DCA has the similar exogenous nature and disposition mechanisms as xenobiotics, this work aimed to investigate whether the tertiary oxidations of DCA are predictive of in vivo CYP3A activities in beagle dogs. In vitro metabolism of midazolam (MDZ) and DCA in recombinant canine CYP1A1, 1A2, 2B11, 2C21, 2C41, 2D15, 3A12, and 3A26 enzymes clarified that CYP3A12 was primarily responsible for either the oxidation elimination of MDZ or the regioselective oxidation metabolism of DCA into DCA-1ß-ol and DCA-5ß-ol in dog liver microsomes. Six male dogs completed the CYP3A intervention studies including phases of baseline, inhibition (ketoconazole treatments), recovery, and induction (rifampicin treatments). The oral MDZ clearance after a single dose was determined on the last day of the baseline, inhibition, and induction phases, and subjected to correlation analysis with the tertiary oxidation ratios of DCA detected in serum and urine samples. The results confirmed that the predosing serum ratios of DCA oxidation, DCA-5ß-ol/DCA, and DCA-1ß-ol/DCA were significantly and positively correlated both intraindividually and interindividually with oral MDZ clearance. It was therefore concluded that the tertiary oxidation of DCA is predictive of CYP3A activity in beagle dogs. Clinical transitional studies following the preclinical evidence are promising to provide novel biomarkers of the enterohepatic CYP3A activities. SIGNIFICANCE STATEMENT: Drug development, clinical pharmacology, and therapeutics are under insistent demands of endogenous CYP3A biomarkers that avoid unnecessary drug exposure and invasive sampling. This work has provided the first proof-of-concept preclinical evidence that the CYP3A catalyzed tertiary oxidation of deoxycholate, the major circulating secondary bile acid synthesized in the lower gut by bacteria, may be developed as novel in vivo biomarkers of the enterohepatic CYP3A activities.

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