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The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has elicited an equally rapid response aiming to develop a COVID-19 vaccine. These efforts are encouraging; however, comprehensive efficacy and safety evaluations are essential in the development of a vaccine, and we can learn from previous vaccine development campaigns. In this Perspective, we summarize examples of vaccine-associated disease enhancement in the history of developing vaccines against respiratory syncytial virus, dengue virus, SARS-CoV and Middle East respiratory syndrome coronavirus, which highlight the importance of a robust safety and efficacy profile, and present recommendations for preclinical and clinical evaluation of COVID-19 vaccine candidates as well as for vaccine design and optimization.In this Perspective, Su, Du and Jiang discuss lessons from previous vaccine development efforts for other viruses and how the mechanisms of vaccine-associated disease enhancement seen in some viral infections can inform the development of a safe and efficacious COVID-19 vaccine.

Background Early and appropriate antibiotic treatment improves the clinical outcome of patients with sepsis. There is an urgent need for rapid identification (ID) and antimicrobial susceptibility testing (AST) of bacteria that cause bloodstream infection (BSI). Rapid ID and AST can be achieved by short-term incubation on solid medium of positive blood cultures using MALDI-TOF mass spectrometry (MS) and the BD M50 system. The purpose of this study is to evaluate the performance of rapid method compared to traditional method. Methods A total of 124 mono-microbial samples were collected. Positive blood culture samples were short-term incubated on blood agar plates and chocolate agar plates for 5 ∼ 7 h, and the rapid ID and AST were achieved through Zybio EXS2000 MS and BD M50 System, respectively. Results Compared with the traditional 24 h culture for ID, this rapid method can shorten the cultivation time to 5 ∼ 7 h. Accurate organism ID was achieved in 90.6% of Gram-positive bacteria (GP), 98.5% of Gram-negative bacteria (GN), and 100% of fungi. The AST resulted in the 98.5% essential agreement (EA) and 97.1% category agreements (CA) in NMIC-413, 99.4% EA and 98.9% CA in PMIC-92, 100% both EA and CA in SMIC-2. Besides, this method can be used for 67.2% (264/393) of culture bottles during routine work. The mean turn-around time (TAT) for obtaining final results by conventional method is approximately 72.6 ± 10.5 h, which is nearly 24 h longer than the rapid method. Conclusions The newly described method is expected to provide faster and reliable ID and AST results, making it an important tool for rapid management of blood cultures (BCs). In addition, this rapid method can be used to process most positive blood cultures, enabling patients to receive rapid and effective treatment.

For our interest in the potential biologically active and structurally unique steroidal glycosides, continued phytochemical investigation of Cynanchum taihangense was carried out; twelve new seco-pregnane glycosides, cynataihosides I–L (1–4), M-T (7–14), and two known glycosides, glaucoside A (5) and atratcynoside F (6), were isolated from the 95% ethanol extract of Cynanchum taihangense. Two new aglycones were found among compounds 10, 11, 13, and 14. The structures of the glycosides were elucidated based on 1D and 2D NMR spectroscopic data, HR-ESI-MS analysis, and chemical evidence. The cytotoxicity of compounds against three human tumor cell lines (HL-60, THP-1, and PC-3) were evaluated by MTT assay. Compound 11 displayed significant cytotoxicity against THP-1 and PC-3 cell line with IC50 values of 5.08 and 22.75 μm, respectively. Compounds 3 and 14 exhibited moderate and selective cytotoxicity on HL-60 and THP-1 with IC50 values of 17.78 and 16.02 μm, respectively.

Epigenetics regulates gene expression and has been confirmed to play a critical role in a variety of metabolic diseases, such as diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), osteoporosis, gout, hyperthyroidism, hypothyroidism and others. The term ‘epigenetics’ was firstly proposed in 1942 and with the development of technologies, the exploration of epigenetics has made great progresses. There are four main epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodelling, and noncoding RNA (ncRNA), which exert different effects on metabolic diseases. Genetic and non-genetic factors, including ageing, diet, and exercise, interact with epigenetics and jointly affect the formation of a phenotype. Understanding epigenetics could be applied to diagnosing and treating metabolic diseases in the clinic, including epigenetic biomarkers, epigenetic drugs, and epigenetic editing. In this review, we introduce the brief history of epigenetics as well as the milestone events since the proposal of the term ‘epigenetics’. Moreover, we summarise the research methods of epigenetics and introduce four main general mechanisms of epigenetic modulation. Furthermore, we summarise epigenetic mechanisms in metabolic diseases and introduce the interaction between epigenetics and genetic or non-genetic factors. Finally, we introduce the clinical trials and applications of epigenetics in metabolic diseases.

The goal of this study was to investigate the relationship between resting-state functional connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in 15 people who developed PTSD following recent trauma. Fifteen participants who experienced acute traumatic events underwent a 7.3-min resting functional magnetic resonance imaging scan within 2 days post-event. All the patients were diagnosed with PTSD within 1 to 6 months after trauma. Brain areas in which activity was correlated with that of the posterior cingulate cortex (PCC) were assessed. To assess the relationship between the severity of PTSD symptoms and PCC connectivity, contrast images representing areas positively correlated with the PCC were correlated with the subject's Clinician-Administered PTSD Scale scores (CAPS) when they were diagnosed. Furthermore, the PCC, medial prefrontal cortex and bilateral amygdala were selected to assess the correlation of the strength of functional connectivity with the CAPS. Resting state connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampus/amygdala. Furthermore, the strength of connectivity between the PCC and bilateral amygdala, and even between the bilateral amygdala could predict the severity of PTSD symptoms later. These results suggest that early altered resting-state functional connectivity of the PCC with the left superior temporal gyrus, right hippocampus and amygdala could predict the severity of the disease and may be a major risk factor that predisposes patients to develop PTSD.

Callicarpa kwangtungensis Chun (CK) is a common remedy exhibits anti-inflammatory properties and has been used in Chinese herbal formulations, such as KangGongYan tablets. It is the main component of KangGongYan tablets, which has been used to treat chronic cervicitis caused by damp heat, red and white bands, cervical erosion, and bleeding. However, the anti-inflammatory effects of CK water extract remains unknown. This study assessed the anti-inflammatory effects of CK in vivo and in vitro, characterized its main components in the serum of rats and verified the anti-inflammatory effects of serum containing CK. Nitric oxide (NO), tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) release by RAW264.7 cells was examined by ELISA and Griess reagents. Inflammation-related protein expression in LPS-stimulated RAW264.7 cells was measured by western blotting. Furthermore, rat model of foot swelling induced by λ-carrageenan and a collagen-induced arthritis (CIA) rat model were used to explore the anti-inflammatory effects of CK. The components of CK were characterized by LC–MS, and the effects of CK-containing serum on proinflammatory factors levels and the expression of inflammation-related proteins were examined by ELISA, Griess reagents and Western blotting. CK suppressed IL-6, TNF-α, and NO production, and iNOS protein expression in LPS-stimulated RAW264.7 cells. Mechanistic studies showed that CK inhibited the phosphorylation of ERK, P38 and JNK in the MAPK signaling pathway, promoted the expression of IκBα in the NF-κB signaling pathway, and subsequently inhibited the expression of iNOS, thereby exerting anti-inflammatory effects. Moreover, CK reduced the swelling rates with λ-carrageenan induced foot swelling, and reduced the arthritis score and incidence in the collagen-induced arthritis (CIA) rat model. A total of 68 compounds in CK water extract and 31 components in rat serum after intragastric administration of CK were characterized. Serum pharmacological analysis showed that CK-containing serum suppressed iNOS protein expression and NO, TNF-α, and IL-6 release. CK may be an anti-inflammatory agent with therapeutic potential for acute and chronic inflammatory diseases, especially inflammatory diseases associated with MAPK activation.

Background The reported incidence of aspergillosis among COVID-19 patients has varied significantly, which can be partly attributed to differences in diagnostic approaches and levels of physicians’ proficiency in diagnosing COVID-19-associated pulmonary aspergillosis (CAPA). Consequently, we conducted a retrospective study to investigate the potential reasons for these discrepancies and analyzed the risk factors for pulmonary aspergillosis in patients with COVID-19. Method Data were retrospectively collected from December 1, 2022, to September 30, 2023, from patients who were admitted to the First Affiliated Hospital of Wenzhou Medical University. The research platform was used to screen patients with discharge diagnoses of COVID-19 pneumonia. CAPA was defined according to the 2020 ECMM/ISHAM criteria and the Chinese expert consensus. Clinical data that were collected included data about underlying diseases, laboratory examinations and microbiological detection. Analyses were conducted with R software, with continuous variables analyzed with t-tests, categorical variables analyzed with chi-square tests, and logistic regression and ROC curves used to assess risk factors for CAPA. Results The incidence of CAPA was 13.4% in the general ward, 30.8% in the RICU, and 6.8% in other ICUs. The average time to CAPA diagnosis was 5.6 days in general wards, 3.7 days in the RICU, and 7.4 days in other ICUs. Diagnostic testing revealed the following sensitivities: 78% for BALF galactomannan (GM), 48% for serum GM, 52% for culture tests, and 71% for BALF mNGS. Risk factors for CAPA included chronic respiratory disease, chronic renal insufficiency, and diabetes. The primary Aspergillus species identified was A. fumigatus , followed by A. flavus . Conclusion Differences in incidence may arise from varying levels of physician awareness, which can influence the rate at which BALF and serum GM samples are submitted for testing. The sensitivity of BALF GM is higher than that of serum GM. Furthermore, BALF mNGS has the potential to enhance the clinical detection sensitivity of CAPA. Risk factors for CAPA include chronic respiratory disease, chronic renal insufficiency, and diabetes, which may aid in identifying at-risk patients. The primary Aspergillus species identified was A. fumigatus , followed by A. flavus , providing a reference for clinical empirical treatment. Clinical trial number Not applicable.

Background Currently, there remains insufficient focus on non-severe community-acquired pneumonia (CAP) patients who are at risk of clinical deterioration, and there is also a dearth of research on the related risk factors. Early recognition of hospitalized patients at risk of clinical deterioration will be beneficial for their clinical management. Method A retrospective study was conducted in The First Affiliated Hospital of Wenzhou Medical University, China, spanning from January 1, 2018 to April 30, 2022, and involving a total of 1,632 non-severe CAP patients. Based on whether their condition worsened within 72 h of admission, patients were divided into a clinical deterioration group and a non-clinical deterioration group. Additionally, all patients were randomly assigned to a training set containing 75% of patients and a validation set containing 25% of patients. In the training set, risk factors for clinical deterioration in patients with non-severe CAP were identified by using LASSO regression analysis and multivariate logistic regression analysis. A nomogram was developed based on identified risk factors. The effectiveness of the nomogram in both the training and validation sets was assessed using Receiver Operating Characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results Age, body mass index (BMI), body temperature, cardiovascular comorbidity, respiratory rate, LDH level, lymphocyte count and D-dimer level were identified as risk factors associated with the clinical deterioration of non-severe CAP within 72 h of admission. The area under curve (AUC) value of the nomogram was 0.78 (95% CI: 0.74–0.82) in the training set and 0.75 (95% CI: 0.67–0.83) in the validation set. Furthermore, the calibration curves for both the training and validation sets indicated that the predicted probability of clinical deterioration aligned with the actual probability. Additionally, DCA revealed clinical utility for the nomogram at a specific threshold probability. Conclusion The study successfully identified the risk factors linked to the clinical deterioration of non-severe CAP and constructed a nomogram for predicting the probability of deterioration. The nomogram demonstrated favorable predictive performance and has the potential to aid in the early identification and management of non-severe CAP patients at elevated risk of deterioration.

Purpose This study aims to evaluate the diagnostic application and performance of the metagenomic next-generation sequencing (mNGS) in patients suspected of local pulmonary infection by comparing it to the traditional pathogen detection methods in lung tissue specimens obtained by a computerized tomography-guided biopsy (CT-guided biopsy). Methods We retrospectively reviewed patients, admitted to the First Affiliated Hospital of Wenzhou Medical University, China from May 2018 to December 2020, who were suspected of local pulmonary infection. All cases received a CT-guided lung biopsy, tissue samples were sent both for conventional examinations (CE) and mNGS tests. The sensitivity and specificity of the two diagnostic approaches were compared. Results 106 patients enrolled, 76 patients were diagnosed with a pulmonary infection. Among 49 patients with identified pathogens, CE confirmed pathogenic infections in 32 cases. Mycobacterium spp. and fungi accounted for 37.5% (12/32) and 28.1% (9/32), respectively, with bacteria 34.4% (11/32). The mNGS examination detected extra pathogenic microorganisms in 22 patients that were consistent with the patients' clinical and radiographic pictures. The sensitivity of mNGS was 53.9% vs. 42.1% for the CE, while the specificity was 56.7% versus 96.7%. For detection rate, mNGS was significantly superior to CE in bacterial (96.3% vs. 40.7%, p  < 0.05), and mixed infections (100% vs. 50%, p  < 0.05), but inferior to CE in fungal (60% vs. 90%, p  > 0.05) and Mycobacterium spp. infections (66.7% vs. 100%, p  > 0.05) with no significant difference. Among 31 cases diagnosed with lung abscess, the diagnostic performance of the detection rate was 67.7% (21/31) in favour of mNGS compared to 29.0% (9/31) for CE ( p  < 0.05). Most polymicrobial infections were induced by anaerobic species that coexisted with Streptococcus constellatus . And Klebsiella pneumoniae was the most common isolated monomicrobial infection. Conclusions The most commonly detected causative pathogens for local pulmonary infections were bacteria, Mycobacterium spp. and fungi. Compared with the CE, the advantages of mNGS in the pathogens detection lie in the discovery of bacterial and mixed infections, as well as in the detection of lung abscess. Conversely, mNGS is not good enough to be recommendable for the detection of Mycobacterium spp. and fungi.

A precise transit ephemeris serves as the premise for follow-up exoplanet observations. We compare TESS Object of Interest (TOI) transit timings of 262 hot Jupiters with the archival ephemeris and find 31 of them having TOI timing offsets, among which WASP-161b shows the most significant offset of −203.7 ± 4.1 minutes. The median value of these offsets is 17.8 minutes, equivalent to 3.6σ. We generate TESS timings in each sector for these 31 hot Jupiters, using a self-generated pipeline. The pipeline performs photometric measurements to TESS images and produces transit timings by fitting the light curves. We refine and update the previous ephemeris, based on these TESS timings (uncertainty ∼1 minute) and a long timing baseline (∼10 yr). Our refined ephemeris gives the transit timing at a median precision of 0.82 minutes until 2025 and 1.21 minutes until 2030. We regard the timing offsets to mainly originate from the underestimated ephemeris uncertainty. All the targets with timing offset larger than 10σ present earlier timings than the prediction, which cannot be due to underestimated ephemeris uncertainty, apsidal precision, or Rømer effect as those effects should be unsigned. For some particular targets, timing offsets are likely due to tidal dissipation. Our sample leads to the detection of period-decaying candidates of WASP-161b and XO-3b reported previously.