ABSTRACT
BACKGROUND: This meta-analysis seeks to assess the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. METHODS: Databases from PubMed, Embase, and the Cochrane Library were all thoroughly searched for pertinent research. Outcomes include complete response (CR), partial response (PR), stable disease (SD), disease progression (PD), overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and adverse events (AEs) were retrieved for further analysis. RESULTS: Ten trials with 721 patients were included in this meta-analysis. The pooled results for patients with cervical cancer receiving pembrolizumab were as follows: CR (0.06, 95%CI: 0.02-0.10), PR (0.15, 95%CI: 0.08-0.22), SD (0.16, 95%CI: 0.13-0.20), PD (0.50, 95%CI: 0.25-0.75), ORR (0.26, 95%CI: 0.11-0.41) and DCR (0.42, 95%CI: 0.13-0.71), respectively. Regarding survival analysis, the pooled mPFS and mOS were 3.81 and 10.15 months. Subgroup analysis showed that pembrolizumab in combination was more beneficial in CR (0.16 vs. 0.03, p = 0.012), PR (0.24 vs. 0.08, p = 0.032), SD (0.11 vs. 0.19, p = 0.043), ORR (0.42 vs. 0.11, p = 0.014), and mPFS (5.54 months vs. 2.27 months, p < 0.001) than as single agent. The three most common AEs were diarrhoea (0.25), anaemia (0.25), and nausea (0.21), and the incidence of grade 3-5 AEs was significantly lower, rarely surpassing 0.10. CONCLUSIONS: For patients with advanced or recurrent cervical cancer, this systematic review and meta-analysis demonstrated that pembrolizumab had a favourable efficacy and tolerability. Future research will primarily focus on optimising customised regiments that optimally integrate pembrolizumab into new therapies and combination strategies. Designed to maximise patient benefit and efficiently control adverse effects while maintaining a high standard of living.
This study demonstrated the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. The study found that an upfront combination of chemotherapy and pembrolizumab immunotherapy appears to be a compelling strategy for these patients. More large-scale and multicentre randomised controlled trials will be required in the future to validate the precise benefits of pembrolizumab in new therapies and combination strategies for the treatment of cervical cancer.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Immunological , Neoplasm Recurrence, Local , Uterine Cervical Neoplasms , Humans , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/mortality , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Female , Neoplasm Recurrence, Local/drug therapy , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Treatment Outcome , Progression-Free Survival , Middle AgedABSTRACT
In addition to the Warburg effect, which increases the availability of energy and biosynthetic building blocks in WSSV-infected shrimp, WSSV also induces both lipolysis at the viral genome replication stage (12 hpi) to provide material and energy for the virus replication, and lipogenesis at the viral late stage (24 hpi) to complete virus morphogenesis by supplying particular species of long-chain fatty acids (LCFAs). Here, we further show that WSSV causes a reduction in lipid droplets (LDs) in hemocytes at the viral genome replication stage, and an increase in LDs in the nuclei of WSSV-infected hemocytes at the viral late stage. In the hepatopancreas, lipolysis is triggered by WSSV infection, and this leads to fatty acids being released into the hemolymph. ß-oxidation inhibition experiment reveals that the fatty acids generated by WSSV-induced lipolysis can be diverted into ß-oxidation for energy production. At the viral late stage, WSSV infection leads to lipogenesis in both the stomach and hepatopancreas, suggesting that fatty acids are in high demand at this stage for virion morphogenesis. Our results demonstrate that WSSV modulates lipid metabolism specifically at different stages to facilitate its replication.
Subject(s)
Penaeidae , White spot syndrome virus 1 , Animals , Lipid Metabolism , White spot syndrome virus 1/physiology , Oxidation-Reduction , Fatty Acids/metabolismABSTRACT
Introduction: Dexmedetomidine is a potent, highly selective α-2 adrenoceptor agonist with sedative, analgesic, anxiolytic, and opioid-sparing properties. A large number of dexmedetomidine-related publications have sprung out in the last 2 decades. However, no bibliometric analysis for clinical research on dexmedetomidine has been published to analyze hot spots, trends, and frontiers in this field. Methods: The clinical articles and reviews related to dexmedetomidine, published from 2002 to 2021 in the Web of Science Core Collection, were retrieved on 19 May 2022, using relevant search terms. VOSviewer and CiteSpace were used to conduct this bibliometric study. Results: The results showed that a total of 2,299 publications were retrieved from 656 academic journals with 48,549 co-cited references by 2,335 institutions from 65 countries/regions. The United States had the most publications among all the countries (n = 870, 37.8%) and the Harvard University contributed the most among all institutions (n = 57, 2.48%). The most productive academic journal on dexmedetomidine was Pediatric Anesthesia and the first co-cited journal was Anesthesiology. Mika Scheinin is the most productive author and Pratik P Pandharipande is the most co-cited author. Co-cited reference analysis and keyword analysis illustrated hot spots in the dexmedetomidine field including pharmacokinetics and pharmacodynamics, intensive care unit sedation and outcome, pain management and nerve block, and premedication and use in children. The effect of dexmedetomidine sedation on the outcomes of critically ill patients, the analgesic effect of dexmedetomidine, and its organ protective property are the frontiers in future research. Conclusion: This bibliometric analysis provided us with concise information about the development trend and provided an important reference for researchers to guide future research.
ABSTRACT
Background: Neuraxial analgesia is widely used to relieve labor pain; its effects on long-term neurodevelopment of offspring remain unclear. This study was designed to investigate the influence of maternal neuraxial labor analgesia on offspring mental development. Methods: This was a predefined secondary analysis of a 2-year prospective longitudinal study. Nulliparous women with single-term cephalic pregnancy preparing for vaginal delivery self-selected neuraxial analgesia or not during labor. Mothers and their offspring were followed up 2 years later. children's mental development was assessed with the bayley scales of infant development. A multivariable logistic model was used to identify factors associated with below-average mental development (Mental Development Index <90). Results: A Total of 508 pairs of mothers and children completed a 2-year follow-up. after propensity score matching, 387 pairs were included in the analysis. In both cohorts, the proportions with below-average mental development were slightly lower in children whose mothers received neuraxial labor analgesia, although not statistically significant [in the full cohort: 9.8 % (36/368) vs. 15.7% (22/140), P = 0.060; In the matched cohort: 8.3% (21/254) vs. 14.3% (19/133), P = 0.065]. A higher 2-year depression score (in the full cohort: Odds Ratio 1.15, 95% CI 1.08-1.22, P < 0.001; In the matched cohort: Odds Ratio 1.09, 95% CI 1.01-1.18, P = 0.037), but not neuraxial analgesia exposure, was associated with an increased risk of below-average mental development. Conclusions: Maternal depression at 2 years was associated with the risk of below-average mental development, whereas maternal exposure to neuraxial labor analgesia was not. Clinical Trial Registration: The study was registered with www.chictr.org.cn (ChiCTR-OCH-14004888) and ClinicalTrials.gov (NCT02823418).
Subject(s)
Analgesia, Obstetrical , Prenatal Exposure Delayed Effects , Analgesia, Obstetrical/adverse effects , Child, Preschool , Female , Humans , Longitudinal Studies , Pregnancy , Propensity Score , Prospective StudiesABSTRACT
White spot syndrome virus (WSSV) is the causative agent of a shrimp disease that inflicts in huge economic losses in shrimp-farming industry. WSSV triggers aerobic glycolysis in shrimp immune cells (hemocytes), but how this virus regulates glycolytic enzymes or pathway is yet to be characterized. Therefore, mRNA levels and activity of four important glycolytic enzymes, Hexokinase (HK), Phosphofructokinase (PFK), Pyruvate kinase (PK), and Lactate dehydrogenase (LDH), were measured in WSSV-infected shrimp hemocytes. Gene expression of HK and PFK, but not LDH or PK, was increased at the viral genome replication stage (12 hpi); furthermore, activity of these enzymes, except HK, was concurrently increased. However, there was no increased enzyme activity at the viral late stage (24 hpi). In vivo dsRNA silencing and glycolysis disruption by 2-DG further confirmed the role of glycolysis in virus replication. Based on tracing studies using stable isotope labeled glucose, glycolysis was activated at the viral genome replication stage, but not at the viral late stage. This study demonstrated that WSSV enhanced glycolysis by activating glycolytic enzyme at the viral genome replication stage, providing energy and biomolecules for virus replication.
Subject(s)
Penaeidae , White spot syndrome virus 1 , Animals , Citric Acid Cycle , Glycolysis/genetics , Hemocytes , L-Lactate Dehydrogenase/metabolism , White spot syndrome virus 1/physiologyABSTRACT
Background: The present study was designed to investigate the relationship between two malnutrition assessment scales, perioperative nutrition screen (PONS) and Nutritional Risk Screening 2002 (NRS2002), with postoperative complications in elderly patients after noncardiac surgery. Methods: This was a secondary analysis of a prospective cohort study. Elderly patients (65-90 years) undergoing noncardiac surgery were enrolled in Peking University First Hospital. Malnutrition was screened by PONS and NRS2002 at the day before surgery. Multivariable analysis was employed to analyze the relationship between PONS and NRS2002 and postoperative 30-day complications. Receiver operating characteristic (ROC) curve was generated to evaluate the predictive value of PONS and NRS2002 in predicting postoperative complications. Results: A total of 915 patients with mean age of 71.6 ± 5.2 years were consecutively enrolled from September 21, 2017, to April 10, 2019. The incidence of malnutrition was 27.3% (250/915) by PONS ≥ 1 and 53.6% (490/915) by NRS2002 ≥ 3. The overall incidence of complications within postoperative 30 days was 45.8% (419/915). After confounders were adjusted, malnutrition by PONS ≥ 1 (OR 2.308, 95% CI 1.676-3.178, P < 0.001), but not NRS2002 ≥ 3 (OR 1.313, 95% CI 0.973-1.771, P = 0.075), was related with an increased risk of postoperative complications. ROC curve analysis showed that the performances of PONS [area under the ROC curve (AUC) 0.595, 95% CI 0.558-0.633] showed very weak improvement in predicting postoperative complications than NRS2002 score (AUC 0.577, 95% CI 0.540-0.614). Conclusion: The present study found that malnutrition diagnosed by PONS was related with an increased risk of postoperative complications. The performances of PONS and NRS2002 were poor in predicting overall postoperative complications. Clinical Trial Registration: www.chictr.org.cn, identifier: ChiCTR-OOC-17012734.
Subject(s)
Malnutrition , Nutrition Assessment , Aged , Humans , Malnutrition/diagnosis , Nutritional Status , Postoperative Complications/diagnosis , Prospective StudiesABSTRACT
BACKGROUND: Delirium is one of the most common complications in older surgical patients. Although previous studies reported that preoperative malnutrition was related with postoperative delirium (POD), there was lack of evidence to illustrate the relationship between malnutrition and emergency delirium (ED). The objective of this study was to investigate the relationship between preoperative malnutrition and ED in older patients undergoing noncardiac surgery. METHODS: The study was carried out in accordance with STROBE guidelines. This was a secondary analysis of a prospective cohort study. Older patients (65-90 years) who underwent noncardiac surgery under general anesthesia were enrolled in Peking University First Hospital. RESULTS: 915 patients were enrolled. The incidence of malnutrition was 53.6 % (490/915). The incidence of emergency delirium was 41.8 % (205/490) in malnutrition group and 31.5 % (134/425) in control group, P < 0.001. After adjusting confounding factors (i.e., age, cognitive impairment, American Society of Anesthesiologists classification (ASA), duration of surgery, pain score, low body temperature and allogeneic blood transfusion), malnutrition was not associated with increased risk of emergency delirium (OR = 1.055, 95 % CI 0.767-1.452, P = 0.742). CONCLUSIONS: Malnutrition was common in older patients undergoing non-cardiac surgery, but it's not related with emergence delirium after adjusted for confounders. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) ( ChiCTR-OOC-17,012,734 ).
Subject(s)
Emergence Delirium , Malnutrition , Aged , Aged, 80 and over , Emergence Delirium/diagnosis , Emergence Delirium/epidemiology , Humans , Malnutrition/diagnosis , Malnutrition/epidemiology , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Prospective Studies , Risk FactorsABSTRACT
BACKGROUND: The clinical significance of emergence delirium remains unclear. The purpose of this study was to investigate the association between emergence delirium and postoperative delirium in elderly after general anesthesia and surgery. METHODS: This prospective observational study was done in a tertiary hospital in Beijing, China. Elderly patients (65-90 years) who underwent major noncardiac surgery under general anesthesia and admitted to the postanesthesia care unit (PACU) after surgery were enrolled. Emergence delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit during PACU stay. Postoperative delirium was assessed with the Confusion Assessment Method during the first 5 postoperative days. The association between emergence delirium and postoperative delirium was analyzed with a multivariable logistic regression model. RESULTS: A total of 942 patients were enrolled and 915 completed the study. Emergence delirium developed in 37.0% (339/915) of patients during PACU stay; and postoperative delirium developed in 11.4% (104/915) of patients within the first 5 postoperative days. After adjusted confounding factors, the occurrence of emergence delirium is independently associated with an increased risk of postoperative delirium (OR 1.717, 95% CI 1.078-2.735, P = 0.023). Patients with emergence delirium stayed longer in PACU and hospital after surgery, and developed more non-delirium complications within 30 days. CONCLUSIONS: Emergence delirium in elderly admitted to the PACU after general anesthesia and major surgery is independently associated with an increased risk of postoperative delirium. Patients with emergence delirium had worse perioperative outcomes. Chinese Clinical Trial Registry (chictr.org.cn) ChiCTR-OOC-17012734.
Subject(s)
Delirium , Emergence Delirium , Aged , Anesthesia, General/adverse effects , Delirium/epidemiology , Delirium/etiology , Emergence Delirium/epidemiology , Emergence Delirium/etiology , Humans , Male , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Prospective Studies , Risk FactorsABSTRACT
Using two advanced sequencing approaches, Illumina and PacBio, we derive the entire Dscam gene from an M2 assembly of the complete Penaeus monodon genome. The P. monodon Dscam (PmDscam) gene is ~266 kbp, with a total of 44 exons, 5 of which are subject to alternative splicing. PmDscam has a conserved architectural structure consisting of an extracellular region with hypervariable Ig domains, a transmembrane domain, and a cytoplasmic tail. We show that, contrary to a previous report, there are in fact 26, 81 and 26 alternative exons in N-terminal Ig2, N-terminal Ig3 and the entirety of Ig7, respectively. We also identified two alternatively spliced exons in the cytoplasmic tail, with transmembrane domains in exon variants 32.1 and 32.2, and stop codons in exon variants 44.1 and 44.2. This means that alternative splicing is involved in the selection of the stop codon. There are also 7 non-constitutive cytoplasmic tail exons that can either be included or skipped. Alternative splicing and the non-constitutive exons together produce more than 21 million isoform combinations from one PmDscam locus in the P. monodon gene. A public-facing database that allows BLAST searches of all 175 exons in the PmDscam gene has been established at http://pmdscam.dbbs.ncku.edu.tw/ .
Subject(s)
Alternative Splicing , Arthropod Proteins/genetics , Exons , Penaeidae/genetics , Amino Acid Sequence , Animals , Hemocytes/metabolism , Nerve Tissue/metabolism , Phylogeny , Sequence Homology , Whole Genome SequencingABSTRACT
White spot syndrome virus (WSSV) is the causative agent of a shrimp disease that has caused huge global economic losses. Although its pathogenesis remains poorly understood, it has been reported that in the shrimp immune cells (hemocytes) targeted by WSSV, the virus triggers both the Warburg effect and glutamine metabolism at the WSSV genome replication stage (12 h post infection). Glutamine metabolism follows two pathways: an oxidative pathway mediated by α-KGDH (α-ketoglutarate dehydrogenase) and an alternative reductive pathway mediated by IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2). Here we used isotopically labeled glutamine ([U-13C]glutamine and [1-13C]glutamine) as metabolic tracers to show that, at the replication stage, both the oxidative and reductive glutamine metabolic pathways were activated. We further show that the mRNA expression levels of α-KGDH and IDH1 were increased in WSSV-infected shrimps and that silencing of α-KGDH, IDH1, and IDH2 with their respective dsRNAs led to a decrease in WSSV gene expression and WSSV replication. Taken together, our findings provide new evidence for WSSV-induced metabolic reprogramming in hemocytes and demonstrate its importance in virus replication.
Subject(s)
DNA Virus Infections/metabolism , Glutamine/metabolism , Hemocytes/metabolism , Virus Replication , White spot syndrome virus 1/physiology , Animals , DNA Virus Infections/genetics , DNA Virus Infections/veterinary , DNA Virus Infections/virology , Genome, Viral , Glutaminase/genetics , Hemocytes/virology , Isocitrate Dehydrogenase/genetics , Ketoglutarate Dehydrogenase Complex/genetics , Oxidation-Reduction , Penaeidae/metabolism , Penaeidae/virology , Virus Replication/genetics , White spot syndrome virus 1/geneticsABSTRACT
BACKGROUND: Severe labour pain is an important risk factor of postpartum depression, and early depression is associated with an increased risk of long-term depression; whereas the use of epidural analgesia during labour decreases the risk of postpartum depression. OBJECTIVE: To investigate whether neuraxial labour analgesia was associated with a decreased risk of 2-year depression. DESIGN: This was a multicentre, prospective, longitudinal study. SETTING: The study was performed in Peking University First Hospital, Beijing Obstetrics and Gynecology Hospital and Haidian Maternal and Child Health Hospital in Beijing, China, between 1 August 2014 and 25 April 2017. PATIENTS: Five hundred ninety-nine nulliparous women with single-term cephalic pregnancy preparing for vaginal delivery were enrolled. MAIN OUTCOME MEASURE: Depressive symptoms were screened with the Edinburgh Postnatal Depression Scale at delivery-room admission, 6-week postpartum and 2 years after childbirth. A score of 10 or higher was used as the threshold of depression. The primary endpoint was the presence of depression at 2 years after childbirth. The association between the use of neuraxial labour analgesia and the development of 2-year depression was analysed with a multivariable logistic regression model. RESULTS: Five hundred and eight parturients completed 2-year follow-up. Of these, 368 (72.4%) received neuraxial analgesia during labour and 140 (27.6%) did not. The percentage with 2-year depression was lower in those with neuraxial labour analgesia than in those without (7.3 [27/368] vs. 13.6% [19/140]; Pâ=â0.029). After correction for confounding factors, the use of neuraxial analgesia during labour was associated with a significantly decreased risk of 2-year depression (odds ratio 0.455, 95% confidence interval 0.230 to 0.898; Pâ=â0.023). CONCLUSION: For nulliparous women with single-term cephalic pregnancy planning for vaginal delivery, the use of neuraxial analgesia during labour was associated with a reduced risk of maternal depression at 2 years after childbirth. TRIAL REGISTRATION: www.chictr.org.cn: ChiCTR-OCH-14004888 and ClinicalTrials.gov: NCT02823418.
Subject(s)
Analgesia, Epidural/methods , Analgesia, Obstetrical/methods , Depression, Postpartum/prevention & control , Adult , Delivery, Obstetric , Female , Follow-Up Studies , Humans , Labor, Obstetric , Longitudinal Studies , Multivariate Analysis , Odds Ratio , Pain Management , Parturition , Postpartum Period , Pregnancy , Prospective Studies , Severity of Illness Index , Surveys and Questionnaires , Young AdultABSTRACT
Arthropod hypervariable Dscam (Down syndrome cell adhesion molecule) may be involved in adaptive-like immune characteristics, namely immune priming, enabling the host to "learn" and "remember" pathogens previously encountered in arthropods. However, expression of Dscam in immune-primed arthropods after a second challenge has apparently not been confirmed. Herein, working with Dscam of Australian freshwater crayfish (Cherax quadricarinatus, i.e. CqDscam), we further investigated whether immune priming is mediated by "clouds" of appropriate (or "correct") CqDscam isoforms. In crayfish that survived a first WSSV challenge (immune priming), long-lasting CqDscam expression remained higher after a second WSSV challenge. Selective CqDscam isoforms were also induced after both challenges. Based on pathogen binding assays, these WSSV-induced CqDscam isoforms had a higher WSSV binding ability, perhaps mainly mediated by Ig3-spliced variants. We therefore hypothesized that in these crayfish survivors, an unknown selection process was generating a "correct cloud" of CqDscam against a previously encountered pathogen.
Subject(s)
Arthropod Proteins/immunology , Astacoidea/physiology , Cell Adhesion Molecules/immunology , White spot syndrome virus 1/physiology , Animals , Arthropod Proteins/genetics , Astacoidea/virology , Cell Adhesion Molecules/genetics , Protein Isoforms/genetics , Protein Isoforms/immunology , Random AllocationSubject(s)
Hantavirus Infections/veterinary , Orthohantavirus/genetics , Rodent Diseases/epidemiology , Animals , China/epidemiology , Disease Reservoirs/virology , Genes, Viral , Hantavirus Infections/diagnosis , Hantavirus Infections/epidemiology , Molecular Diagnostic Techniques , Rodent Diseases/virology , Rodentia/virologyABSTRACT
To evaluate the role of small mammals as hosts of severe fever with thrombocytopenia syndrome virus (SFTSV), we tested serum samples from rodents and shrews in China, collected in 2013. SFTSV antibodies and RNA were detected, suggesting that rodents and shrews might be hosts for SFTSV.
Subject(s)
Animal Diseases/epidemiology , Animal Diseases/virology , Bunyaviridae Infections/veterinary , Rodentia , Shrews , Animal Diseases/history , Animals , China/epidemiology , History, 21st Century , Molecular Sequence Data , Phlebovirus , Phylogeny , Prevalence , RNA, ViralABSTRACT
OBJECTIVE: To study the genetic diversity of HIV-1 nef genes from a patient with AIDS dementia complex(ADC) , so as to research the amino acid variability and the pathogenesis of ADC. METHODS: The nef gene was amplified with PCR from genomic DNA which was extracted from spleen and different brain tissues(basal ganglia, frontal gray matter, meninges, temporal lobe)of a patient who died of ADC. PCR products were cloned into the pMD19-T vector, after transformation and selection by ampicillin and blue/white spotting. Five of positive clones were sequenced and confirmed with BLAST. HIV-1 nef sequences were processed with BioEdit and MEGA4 to do Neighbor-Joining tree, p-Distances, and values of ds/dn. RESULTS: The samples were all identified as HIV-1 B and genetic variation exists in HIV-1 nef gene isolated from different tissues compared with HXB2. In addition,part of the changes were different between periphery and brain. CONCLUSION: Variations exist in the HIV-1 nef gene extracted from the ADC patient and the variations from peripheral and central nerve tissues were different,these variations may change the function of Nef,and it needs more research.