The whole-blood Epstein-Barr virus DNA can serve as a valuable molecular marker for diagnosis and prognosis prediction of nasopharyngeal carcinoma.

The clinical significance and prognostic role of whole-blood EBV-DNA in EBV-associated nasopharyngeal carcinoma (NPC) have not been thoroughly investigated. This study aims to explore the diagnostic and prognostic value of EBV-DNA for NPC in a non-endemic region of China. We enrolled patients with chronic active EBV infection (CAEBV), nasopharyngitis (NA), extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), and NPC. Demographic and clinical data were collected and the diagnostic and prognostic values of EBV-DNA were analyzed. Immunohistochemistry was performed to detect EBV-encoded small ribonucleic acids (EBER), as well as the expression of p53, Ki-67, and epidermal growth factor receptor (EGFR). The levels of pretreatment Epstein-Barr virus DNA (preEBV-DNA) in new NPC cases were found to differ from those in other diseases and exhibited varying age distributions. The threshold value of preEBV-DNA for distinguishing NPC from CAEBV and NA was determined. We confirmed that epistaxis, diabetes mellitus, T3N2 or T4N0-2 stage, and IgM positivity were associated with higher levels of preEBV-DNA, and identified risk factors associated with the prognosis of locoregionally advanced NPC (La-NPC). Patients with intermittently or persistently positive EBV-DNA (IPCP), higher preEBV-DNA levels, and positive Epstein-Barr virus-encoded small RNA (EBER) status (EBERpos) had worse survival. New cases of NPC with elevated levels of EBV in the whole-blood and positive EBER status were shown to have a poor prognosis upon progression to La-NPC. EBV-DNA was found to be an indicator for predicting prognosis in La-NPC and could also be used to distinguish new NPC cases.

High plasma EBV-DNA load and positive EBER status associated with viral recurrence and persistent infection in early treatment of lymphoma.

The relationship between plasma EBV-DNA load (PEDL) and Epstein-Barr virus (EBV)-encoded small RNA (EBER) during the early treatment of lymphoma remains unclear. We explored discrepancies in PEDL and variables associated with EBER and evaluated the consistency between EBER and qualitative analysis of PEDL (qPEDL). Serial measurements of PEDL were performed to determine the dynamic changes of PEDL in early treatment of lymphoma. As a result, the median PEDL of non-Hodgkin's lymphoma NKT cell subtype (NHL-NKT) was higher than that of non-Hodgkin's lymphoma B cell subtype (NHL-B), the median PEDL of extranodal NK/T cell lymphoma (ENKTCL) was higher than that of diffuse large B cell lymphoma (DLBCL), and the median PEDL of EBER positive was higher than that of EBER negative. Age, Ki-67 ≧ 80%, Bcl-2 ≧ 80%, p53, and qPEDL were related to EBER. The PEDL could distinguish NHL-B, DLBCL, NHL-NKT, and ENKTCL from other lymphoma subtypes. EBER-positive patients spent more time with viral "turn negative (TN)" and "continuous positive (CP)" and less time with viral "continuous negative (CN)." The median PEDL of CP was higher than that of TN. In conclusion, although EBER affects the levels of PEDL in general, it has poor concordance with qPEDL. Our results show, for the first time, that high PEDL and positive EBER present a strong association with viral recurrence and persistent infection in the early treatment of lymphoma.

Comparative efficacy and safety of pharmacological interventions for severe COVID-19 patients: An updated network meta-analysis of 48 randomized controlled trials.

BACKGROUND: To date, there has been little agreement on what drug is the "best" drug for treating severe COVID-19 patients. This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19. METHODS: We searched databases for randomized controlled trials (RCTs) published up to February 28, 2022, with no language restrictions, of medications recommended for patients (aged 16 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). RESULTS: We identified 4021 abstracts and of these included 48 RCTs comprising 9147 participants through database searches and other sources. For decrease in ACM, we found that ivermectin/doxycycline, C-IVIG (i.e., a hyperimmune anti-COVID-19 intravenous immunoglobulin), methylprednisolone, interferon-beta/standard-of-care (SOC), interferon-beta-1b, convalescent plasma, remdesivir, lopinavir/ritonavir, immunoglobulin gamma, high dosage sarilumab (HS), auxora, and imatinib were effective when compared with placebo or SOC group. We found that colchicine and interferon-beta/SOC were only associated with the TEAEs of severe COVID-19 patients. CONCLUSION: This study suggested that ivermectin/doxycycline, C-IVIG, methylprednisolone, interferon-beta/SOC, interferon-beta-1b, convalescent plasma (CP), remdesivir, lopinavir/ritonavir, immunoglobulin gamma, HS, auxora, and imatinib were efficacious for treating severe COVID-19 patients. We found that most medications were safe in treating severe COVID-19. More large-scale RCTs are still needed to confirm the results of this study.

Efficacy and safety of current treatment interventions for patients with severe COVID-19 infection: A network meta-analysis of randomized controlled trials.

This study aimed to assess the efficacy and safety of different medications available at present for severe coronavirus disease 2019 (COVID-19) infection. We searched databases for randomized controlled trials (RCTs) published up to April 30, 2021, with Chinese or English language restriction, of medications recommended for patients (aged 18 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). We identified 1855 abstracts and of these included 15 RCTs comprising 3073 participants through database searches and other sources. In terms of efficacy, compared with the standard of care (SOC) group, no significant decrease in ACM was found in α-lipoic acid, convalescent plasma (CP), azithromycin, tocilizumab, methylprednisolone, interferon beta, CP/SOC, high dosage sarilumab, low dosage sarilumab, remdesivir, lopinavir-ritonavir, auxora, and placebo group. Compared with placebo, we found that a significant decrease in ACM was only found in methylprednisolone (odds ratio [OR]: 0.16, 95% confidence interval [CI]: 0.03-0.75]. With respect to TEAEs, the CP group showed lower TEAEs than placebo (OR: 0.07, 95% CI: 0.01-0.58) or SOC (OR: 0.05, 95% CI: 0.01-0.42) group for the therapy of severe COVID-19 patients. This study only demonstrated that methylprednisolone was superior to placebo in treating patients with severe COVID-19 infection. Meanwhile, this further confirmed that the safety of other treatment interventions might be inferior to CP for the therapy of severe COVID-19 patients.

Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: an updated network meta-analysis of randomized placebo-controlled trials.

BACKGROUND: Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs). METHODS: We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates. RESULTS: From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96-393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21-30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients. CONCLUSION: We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.

Incidence Density and Predictors of Multidrug-Resistant Tuberculosis Among Individuals With Previous Tuberculosis History: A 15-Year Retrospective Cohort Study.

Background: To date, too little attention has been paid to monitoring and estimating the risk of incident multidrug-resistant tuberculosis (MDR-TB) among individuals with a previous tuberculosis history (PTBH). The purpose of this study was to assess the incidence of and risk factors for MDR-TB in those individuals. Methods: Between 2005 and 2020, a large, retrospective, population-based cohort study was performed in Hangzhou, China. A multivariable Cox regression model was used to evaluate independent predictors of incident MDR-TB among individuals with PTBH. Results: The incidence density of MDR-TB was 22.6 per 1,000 person-years (95% confidence level and an interval of 20.9-24.3) for individuals with PTBH. The incidence of MDR-TB increased significantly in individuals who • were under 60 years old. • were male. • had a history of direct contact. • came from low-income families. • worked in high-risk occupations. • lived in rural areas. • had a retreatment TB history. • had an unfavorable outcome in their previous treatment (P < 0.05). In addition, we found that the following factors were significantly linked to the MDR-TB risk among individuals with PTBH (P < 0.05): • sociodemographic factors such as the 21-30 and 31-40 year age groups, or a history of direct contact. • clinical factors like passive modes of TB case finding (PMTCF), human immunodeficiency virus infection, unfavorable treatment outcomes, retreated TB history, non-standardized treatment regimens of retreatment TB patients, and duration of pulmonary cavities (DPC). • microbiological factors, such as duration of positive sputum culture. We also found that the 21-30 year age group, low family income, and PMTCF were significantly linked to incident MDR-TB only in males with PTBH, whilst the 41-50 year age group, extended treatment course, and DPC were significantly associated with female MDR-TB only. Conclusion: The incidence of MDR-TB was high, with a higher rate among subjects with a history of direct contact and unfavorable treatment outcomes. There was a gender difference in the incidence density and risk factors of MDR-TB among individuals with PTBH. Long-term monitoring and gender-specific risk-factor modifications should be given to individuals with PTBH.

rpoB gene mutations in rifampin-resistant Mycobacterium tuberculosis isolates from rural areas of Zhejiang, China.

OBJECTIVE: The aim was to analyze genetic mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis isolates (RIFR-MTB) from Zhejiang, China. METHODS: We prospectively analyzed RIFR-associated mutations in 13 rural areas of Zhejiang. Isolates were subjected to species identification, phenotype drug susceptibility testing (DST), DNA extraction, and rpoB gene sequencing. RESULTS: A total of 103 RIFR isolates were identified by DST (22 RIFR only, 14 poly-drug resistant, 49 multidrug resistant, 13 pre-extensively drug resistant [pre-XDR], and 5 extensively drug resistant [XDR]) from 2152 culture-positive sputum specimens. Gene sequencing of rpoB showed that the most frequent mutation was S450L (37.86%, 39/103); mutations P280L, E521K, and D595Y were outside the rifampicin resistance-determining region (RRDR) but may be associated with RIFR. Mutations associated with poly-drug resistant, pre-XDR, and XDR TB were mainly located at codon 445 or 450 in the RRDR. CONCLUSIONS: The frequency of rpoB RRDR mutation in Zhejiang is high. Further studies are needed to clarify the relationships between RIFR and the TTC insertion at codon 433 in the RRDR and the P280L and D595Y mutations outside the RRDR.

Impact of different tuberculosis history at the onset of future multidrug-resistant tuberculosis: A large, retrospective, population-based cohort study.

OBJECTIVES: The impact of tuberculosis (TB) history on the risk of multidrug-resistant tuberculosis (MDR-TB) is not yet fully understood. We aimed to identify the impact of different TB history at the onset of future MDR-TB. METHODS: A large, retrospective, population-based cohort study was performed between 2005 and 2019. A multivariable Cox model was used to evaluate independent risk factors for MDR-TB for individuals with different previous TB history (PTBH), such as newly diagnosed TB history (NDTH) and re-treated TB history (RTH). RESULTS: Overall, 12 172 individuals with PTBH were included in this study. The main impacts of different PTBH at the onset of future MDR-TB were as follows: (a) low family income, high-risk occupation, TB patients with severe infection, extended or shortened treatment course, 2H3R3Z3E3/4H3R3 and frequency of sputum culture were significantly linked to incident MDR-TB only in individuals with NDTH (P < 0.05); (b) passive mode of TB case finding, individualised treatment regimens, 3HRZES/6HRE, duration of pulmonary cavities, excellent frequency of chest X-ray examination and duration of negative sputum smear were significantly associated with incident MDR-TB only in individuals with RTH (P < 0.05); (c) age <60 years, history of direct contact, human immunodeficiency virus (HIV) infection, unsuccessful treatment and duration of positive sputum culture were related to incident MDR-TB in both categories of PTBH individuals (P < 0.05). CONCLUSION: Early and differential surveillances, assessments and interventions for reducing the risk of MDR-TB among individuals with different PTBH play a key role.

Nomogram for individualized prediction of incident multidrug-resistant tuberculosis after completing pulmonary tuberculosis treatment.

The purposes of this study were to construct a comprehensive nomogram for providing a simple, precise and personalized prediction of incident multidrug-resistant tuberculosis (MDR-TB) after completing pulmonary tuberculosis treatment (CPTBT). A matched case-control study (1:2 ratios) was performed between 2005 and 2018. A multivariable Cox regression analysis was used to evaluate independent predictors of incident MDR-TB after the CPTBT. A comprehensive nomogram was developed based on the multivariable Cox model. Overall, 1, 836 participants were included in this study. We developed and validated a simple-to-use nomogram that predicted the individualized risk of incident MDR-TB by using 10 parameters after the CPTBT. The concordance index of this nomogram was 0.833 [95% confidence interval (CI) 0.807-0.859] and 0.871 (95% CI 0.773-0.969) for the training and validation sets, respectively, which indicated adequate discriminatory power. The calibration curves for the risk of incident MDR-TB showed an optimal agreement between nomogram prediction and actual observation in the training and validation sets, respectively. The high sensitivity and specificity of nomogram was indicated by using a receiver operating characteristic curve analysis. Through this clinic tool, TB control executives could more precisely monitor, estimate and intervene the risk of incident MDR-TB among individuals with CPTBT.

Genome analysis of a multidrug-resistant Streptococcus sanguis isolated from a throat swab of a child with scarlet fever.

OBJECTIVES: A multidrug-resistant strain of the opportunistic pathogen Streptococcus sanguis (S28) was isolated from a throat swab of a child with scarlet fever as a rare case. Genome sequencing and analysis of strain S28 were performed to gain a better understanding of the multidrug resistance mechanisms of S. sanguis and its relationship with scarlet fever. METHODS: The genome of S. sanguis S28 was sequenced on a Illumina HiSeq platform. Genome assembly was conducted using SOAPdenovo v.2.04 and the assembled genome sequence was submitted to NCBI for annotation. RESULTS: The 1 268 358 696bp genome of S. sanguis S28 contains 2287 coding sequences (CDS) with a GC content of 43.2%. Strain S28 possesses four antimicrobial resistance genes (ARGs), which is consistent with phenotypic analysis. A novel transposon with three genes conferring resistance to macrolide-lincosamide-streptogramin B (MLSB) antibiotics, tetracyclines and aminoglycosides was discovered. CONCLUSION: To our knowledge, this is the first report of a S. sanguis genome isolated from a throat swab of a child with scarlet fever and the first report of a transposon with three activated ARGs conferring resistance to MLSB, tetracyclines and aminoglycosides together.

The diagnostic potential of MPT63-derived HLA-A*0201-restricted CD8+ T-cell epitopes for active pulmonary tuberculosis.

MPT63 protein is found only in Mycobacterium tuberculosis complex, including M. tuberculosis and M. bovis. Detection of MPT63-specific IFN-γ-secreting T cells could be useful for the diagnosis of tuberculosis (TB) diseases. In the present study, the HLA-A*0201 restriction of ten predicted MPT63-derived CD8(+) T-cell epitopes was assessed on the basis of T2 cell line and HLA-A*0201 transgenic mice. The diagnostic potential of immunogenic peptides in active pulmonary TB patients was evaluated using an IFN-γ enzyme-linked immunospot assay. It was found that five peptides bound to HLA-A*0201 with high affinity, whereas the remaining peptides exhibited low affinity for HLA-A*0201. Five immunogenic peptides (MPT6318-26 , MPT6329-37 , MPT6320-28 , MPT635-14 and MPT6310-19 ) elicited large numbers of cytotoxic IFN-γ-secreting T cells in HLA-A*0201 transgenic mice. Each of the five immunogenic peptides was recognized by peripheral blood mononuclear cells from 45% to 73% of 40 HLA-A*0201 positive TB patients. The total diagnostic sensitivity of the five immunogenic peptides was higher than that of a T-SPOT.TB assay (based on ESAT-6 and CFP-10) (93% versus 90%). It is noticeable that the diagnostic sensitivity of the combination of five immunogenic peptides and T-SPOT.TB assay reached 100%. These MPT63-derived HLA-A*0201-restricted CD8(+) T-cell epitopes would likely contribute to the immunological diagnosis of M. tuberculosis infection and may provide the components for designing an effective TB vaccine.