Utility of clinical metagenomics in diagnosing malignancies in a cohort of patients with Epstein-Barr virus positivity

BackgroundsDifferentiation between benign and malignant diseases in EBV-positive patients poses a significant challenge due to the lack of efficient diagnostic tools. Metagenomic Next-Generation Sequencing (mNGS) is commonly used to identify pathogens of patients with fevers of unknown-origin (FUO). Recent studies have extended the application of Next-Generation Sequencing (NGS) in identifying tumors in body fluids and cerebrospinal fluids. In light of these, we conducted this study to develop and apply metagenomic methods to validate their role in identifying EBV-associated malignant disease.MethodsWe enrolled 29 patients with positive EBV results in the cohort of FUO in the Department of Infectious Diseases of Huashan Hospital affiliated with Fudan University from 2018 to 2019. Upon enrollment, these patients were grouped for benign diseases, CAEBV, and malignant diseases according to their final diagnosis, and CNV analysis was retrospectively performed in 2022 using samples from 2018 to 2019.ResultsAmong the 29 patients. 16 of them were diagnosed with benign diseases, 3 patients were diagnosed with CAEBV and 10 patients were with malignant diseases. 29 blood samples from 29 patients were tested for mNGS. Among all 10 patients with malignant diagnosis, CNV analysis suggested neoplasms in 9 patients. Of all 19 patients with benign or CAEBV diagnosis, 2 patients showed abnormal CNV results. The sensitivity and specificity of CNV analysis for the identification for tumors were 90% and 89.5%, separately.ConclusionsThe application of mNGS could assist in the identification of microbial infection and malignancies in EBV-related diseases. Our results demonstrate that CNV detection through mNGS is faster compared to conventional oncology tests. Moreover, the convenient collection of peripheral blood samples adds to the advantages of this approach

Refined imaging features of culprit plaques improve the prediction of recurrence in intracranial atherosclerotic stroke within the middle cerebral artery territory

Recurrence is a significant adverse outcome of ischemic stroke (IS), particularly in cases of intracranial arteriosclerosis (ICAS). In this study, we investigated the impact of imaging features of culprit plaque using high-resolution magnetic resonance vessel wall imaging (HR-MR-VWI) on the prediction of IS recurrence. A total of 86 patients diagnosed with ICAS-related IS within the middle cerebral artery (MCA) territory were included, of which 23.25% experienced recurrent IS within one year. Our findings revealed significant differences between the recurrence and non-recurrence groups in terms of age (p = 0.007), diabetes mellitus (p = 0.031), hyperhomocysteinemia (p = 0.021), artery-artery embolism (AAE) infarction (p = 0.019), prominent enhancement (p = 0.013), and surface irregularity of the culprit plaque (p = 0.009). Age (HR = 1.063, p = 0.005), AAE infarction (HR = 5.708, p = 0.008), and prominent enhancement of the culprit plaque (HR = 4.105, p = 0.025) were identified as independent risk factors for stroke recurrence. The areas under the receiver operating characteristic curve (AUCs) for predicting IS recurrence using clinical factors, conventional imaging findings, HR-MR-VWI plaque features, and a combination of clinical and conventional imaging models were 0.728, 0.645, 0.705, and 0.814, respectively. Notably, the combination model demonstrated superior predictive performance with an AUC of 0.870. Similarly, AUC of combination model for predicting IS recurrence in validation cohort which enrolled another 37 patients was 0.865. In conclusion, the presence of obvious enhancement in culprit plaque on HR-MR-VWI is a valuable factor in predicting IS recurrence in ICAS-related strokes within the MCA territory. Furthermore, our combination model, incorporating plaque features, exhibited improved prediction accuracy

Role of Dynamic Susceptibility Contrast Perfusion MRI in Glioma Progression Evaluation

Accurately and quickly differentiating true progression from pseudoprogression in glioma patients is still a challenge. This study aims to explore if dynamic susceptibility contrast- (DSC-) MRI can improve the evaluation of glioma progression. We enrolled 65 glioma patients with suspected gadolinium-enhancing lesion. Longitudinal MRI follow-up (mean 590 days, range: 210–2670 days) or re-operation (n = 3) was used to confirm true progression (n = 51) and pseudoprogression (n = 14). We assessed the diagnostic performance of each MRI variable and the different combinations. Our results showed that the relative cerebral blood volume (rCBV) in the true progression group (1.094, 95%CI: 1.135–1.636) was significantly higher than that of the pseudoprogression group (0.541 ± 0.154) p<0.001. Among the 18 patients who had serial DSC-MRI, the rCBV of the progression group (0.480, 95%CI: 0.173–0.810) differed significantly from pseudoprogression (-0.083, 95%CI: −1.138–0.620) group p=0.015. With an rCBV threshold of 0.743, the sensitivity and specificity for discriminating true progression from pseudoprogression were 76.5% and 92.9%, respectively. The Cho/Cr and Cho/NAA ratios of the true progression group (2.520, 95%CI: 2.331–2.773; 2.414 ± 0.665, respectively) were higher than those of the pseudoprogression group (1.719 ± 0.664; 1.499 ± 0.500, respectively) (p=0.001, p<0.001, respectively). The areas under ROC curve (AUCs) of enhancement pattern, MRS, and DSC-MRI for the differentiation were 0.782, 0.881, and 0.912, respectively. Interestingly, when combined enhancement pattern, MRS, and DSC-MRI variables, the AUC was 0.965 and achieved sensitivity 90.2% and specificity 100.0%. Our results suggest that DSC-MRI can significantly improve the diagnostic performance for identifying glioma progression. DSC-MRI combined with conventional MRI may promptly distinguish true gliomas progression from pseudoprogression when the suspected gadolinium-enhancing lesion was found, without the need for a long-term follow-up

New Enhancement beyond Radiation Field Improves Survival Prediction in Patients with Post-Treatment High-Grade Glioma

The imaging signs which can accurately predict survival prognosis after standard treatment of high-grade glioma (HGG) are highly desirable. This study aims to explore the role of new enhancement beyond radiation field (NERF) in the survival prediction in patients with post-treatment HGG. The present study included 142 pathologically confirmed HGG patients who had received standard treatment. NERF, as well as other conventional MR findings and clinical variables, were included in univariate and multivariate analyses for evaluating their impactions on progression-free survival (PFS) and overall survival (OS). Univariate analysis showed that histological grade (p=0.008) and NERF (p=0.001) were the prognostic variables for poor PFS, whereas histological grade (p=0.017), NERF (p=0.001), and new subventricular zone enhancement (nSVZE) (p=0.001) were prognostic variables for poor OS. The multivariate analysis showed that NERF (HR 3.93; 95% CI 1.93–8.01; p=0.001) and nSVZE (HR 3.92; 95% CI 1.95–7.89; p=0.001) were the prognostic variables for poor OS. However, only nSVZE was (HR 3.29; 95% CI 2.04–5.28; p=0.001) the prognostic variable for poor PFS. When combining the NERF with the clinical and other MR variables, the highest AUC (0.924) and specificity (0.899) for predicting poor OS were achieved. The location of new developed enhancements relevant to high dose radiation field appears to be the main determinant of their prognostic value. Our results suggest that the new enhancement beyond radiation field can improve the survival prediction in patients with HGG after standard treatment

A one-year follow-up study of systematic impact of long COVID symptoms among patients post SARS-CoV-2 omicron variants infection in Shanghai, China

AbstractLong COVID hinders people from normal life and work, posing significant medical and economic challenges. Nevertheless, comprehensive studies assessing its impact on large populations in Asia are still lacking. We tracked over 20,000 patients infected with COVID-19 for the first time during the Omicron BA.2 outbreak in Shanghai from March-June 2022 for one year. Of the 21,799 COVID-19 patients who participated in the 6-month telephone follow-up, 1,939 (8.89%) had self-reported long COVID symptoms. 450 long COVID patients participated in the 6-month outpatient follow-up. Participants underwent healthy physical examinations and questionnaires focused on long-COVID-related symptoms and mental health. Mobility problem (P<0.001), personal care problem (P=0.003), usual activity problem (P<0.001), pain/discomfort (P<0.001), anxiety/depression (P=0.001) and PTSD (P=0.001) were more prevalent in long COVID patients than in healthy individuals, but no significant differences were found between the two groups on chest CT and laboratory examinations. Of the 856 long COVID patients who participated in the 12-month follow-up, 587 (68.5%) had their symptoms resolved. In the multivariable logistic analysis, females (P<0.001), youth (age <40 years) (P<0.001), ≥2 comorbidities (P=0.009), and severe infection in the acute phase (P=0.006) were risk factors for developing long COVID. Middle age (40-60 years) was a risk factor for persistent long COVID one year after hospital discharge (P=0.013). The study found that long COVID mainly manifested as subjective symptoms and impacts partial patients' quality of life and mental status. After one year, most (68.5%) of the patients recovered from long COVID with no impairment of organ function observed

Neural Activity Associated with Symptoms Change in Depressed Adolescents following Self-Processing Neurofeedback

Adolescent depression is prevalent, debilitating, and associated with chronic lifetime mental health disorders. Understanding the neurobiology of depression is critical to developing novel treatments. We tested a neurofeedback protocol targeting emotional regulation and self-processing circuitry and examined brain activity associated with reduced symptom severity, as measured through self-report questionnaires, four hours after neurofeedback. Depressed (n = 34) and healthy (n = 19) adolescents participated in (i) a brief neurofeedback task that involves simultaneously viewing their own happy face, recalling a positive autobiographical memory, and increasing amygdala-hippocampal activity; (ii) a self- vs. other- face recognition task with happy, neutral, and sad facial expressions before and after the neurofeedback. In depressed youth, reduced depression after neurofeedback was associated with increased self-referential and visual areas’ activity during neurofeedback, specifically, increased activity in the cuneus, precuneus and parietal lobe. Reduced depression was also associated with increased activation of emotional regulation and cross-modal areas during a self-recognition task. These areas included the cerebellum, middle temporal gyrus, superior temporal gyrus, and supramarginal gyrus. However, decreased rumination was linked to decreased precuneus, angular and temporal gyri activity during neurofeedback. These results tentatively suggest that neurofeedback may induce short-term neurobiological changes in the self-referential and emotional regulation networks associated with reduced symptom severity among depressed adolescents

Drug repurposing screens identify Tubercidin as a potent antiviral agent against porcine nidovirus infections

The emergence of new coronaviruses poses a significant threat to animal husbandry and human health. Porcine epidemic diarrhea virus (PEDV) is considered a re-emerging porcine enteric coronavirus, which causes fatal watery diarrhea in piglets. Currently, there are no effective drugs to combat PEDV. Drug repurposing screens have emerged as an attractive strategy to accelerate antiviral drug discovery and development. Here, we screened 206 natural products for antiviral activity using live PEDV infection in Vero cells and identified ten candidate antiviral agents. Among them, Tubercidin, a nucleoside analog derived from Streptomyces tubercidicus, showed promising antiviral activity against PEDV infection. Furthermore, we demonstrated that Tubercidin exhibited significant antiviral activity against both classical and variant PEDV. Time of addition assay showed that Tubercidin displayed a significant inhibitory effect on viral post-entry events but not during other periods. Molecular docking analysis indicated that Tubercidin had better docking efficiency and formed hydrophobic interactions with the active pocket of RNA-dependent RNA polymerase (RdRp) of PEDV and other nidoviruses. Additionally, Tubercidin can effectively suppress other porcine nidoviruses, such as SADS-CoV and PRRSV, demonstrating its broad-spectrum antiviral properties. In summary, our findings provide valuable evidence for the antiviral activity of Tubercidin and offer insights into the development of new strategies for the prevention and treatment of coronavirus infections

Early identification and severity prediction of acute respiratory infection (ESAR): a study protocol for a randomized controlled trial

Abstract Background The outbreak of SARS-CoV-2 at the end of 2019 sounded the alarm for early inspection on acute respiratory infection (ARI). However, diagnosis pathway of ARI has still not reached a consensus and its impact on prognosis needs to be further explored. Methods ESAR is a multicenter, open-label, randomized controlled, non-inferiority clinical trial on evaluating the diagnosis performance and its impact on prognosis of ARI between mNGS and multiplex PCR. Enrolled patients will be divided into two groups with a ratio of 1:1. Group I will be directly tested by mNGS. Group II will firstly receive multiplex PCR, then mNGS in patients with severe infection if multiplex PCR is negative or inconsistent with clinical manifestations. All patients will be followed up every 7 days for 28 days. The primary endpoint is time to initiate targeted treatment. Secondary endpoints include incidence of significant events (oxygen inhalation, mechanical ventilation, etc.), clinical remission rate, and hospitalization length. A total of 440 participants will be enrolled in both groups. Discussion ESAR compares the efficacy of different diagnostic strategies and their impact on treatment outcomes in ARI, which is of great significance to make precise diagnosis, balance clinical resources and demands, and ultimately optimize clinical diagnosis pathways and treatment strategies. Trial registration Clinicaltrial.gov, NCT04955756, Registered on July 9th 2021

Neutralization against Omicron subvariants after BA.5/BF.7 breakthrough infection weakened as virus evolution and aging despite repeated prototype-based vaccination

Background: Omicron had swept the mainland China between December 2022 and January 2023, while SARS-CoV-2 still continued to evolve. To fully prepare for the next wave, it’s urgent to evaluate the humoral immune response post BA.5/BF.7 breakthrough infection against predominant sublineages among existing vaccination strategies and the elders.Method: This study enrolled a longitudinal young-adult cohort from 2/3-dose vaccination to 1 month after breakthrough infection, and an elder cohort at 1 month after breakthrough infection. Seral samples were collected and tested for humoral immune response to SARS-CoV-2 subvariants including WT, BA.2, BA.5, BF.7, BQ.1.1, CH.1.1, XBB.1.5.Results: BA.5/BF.7 breakthrough infection induced higher neutralization activity than solely vaccination in all SARS-CoV-2 strains, while the latest Omicron subvariants, BQ.1.1, CH.1.1, XBB.1.5, exhibited the strongest neutralization evasion ability. There was a negative correlation between age and humoral immune response in WT, BA.5, BQ.1.1, and XBB.1.5. Compared to non-vaccination groups, breakthrough infection in two-dose vaccination groups had significantly higher neutralizing antibody against WT, BA.2, BA.5, BF.7 but not to BQ.1.1, CH.1.1, XBB.1.5., while booster dose against the prototype prior-breakthrough would not further significantly enhance individual’s humoral responses against the latest Omicron subvariants.Conclusions: Newer variants manifest increasing immune evasion from neutralization and repeated prototype-based booster vaccines may not further enhance neutralizing antibody against emerging new variants. Older adults have lower levels of neutralizing antibody. Future vaccination strategies should aim to enhance effective neutralization to contemporary variants