Clinical risk factors and outcomes of carbapenem-resistant Escherichia coli nosocomial infections in a Chinese teaching hospital: a retrospective study from 2013 to 2020.

The emergence of carbapenem-resistant Escherichia coli strains poses a considerable challenge to global public health, and little is known about carbapenemase-producing E. coli strains in Tianjin, China. This study aimed to investigate the risk factors for infections with carbapenem-resistant E. coli (CREC) strains. This retrospective case-control study was conducted at a tertiary teaching hospital. A total of 134 CREC clinical isolates were collected from the General Hospital of Tianjin Medical University between 2013 and 2020. The control group was selected at a ratio of 1:1 from patients with nosocomial carbapenem-susceptible E. coli infection. Risk factors for nosocomial CREC infection and clinical outcomes were analyzed using univariate and multivariate analyses. Multivariate analysis revealed that cephalosporin exposure (odd ratio OR = 2.01), carbapenem exposure (OR = 1.96), glucocorticoid exposure (OR = 32.45), and surgical history (OR = 3.26) were independent risk factors for CREC infection. The in-hospital mortality rate in the CREC group was 29.1%, and age >65 years (OR = 3.19), carbapenem exposure (OR = 3.54), and central venous catheter insertion (OR = 4.19) were independent risk factors for in-hospital mortality in patients with CREC infections. Several factors were identified in the development of nosocomial CREC infections. The CREC isolates were resistant to most antibiotics. Reducing CREC mortality requires a comprehensive consideration of appropriate antibiotic use, underlying diseases, and invasive procedures.IMPORTANCEEscherichia coli is an opportunistic pathogen that causes severe hospital-acquired infections. The spread of carbapenem-resistant E. coli is a global threat to public health, and only a few antibiotics are effective against these infections. Consequently, these infections are usually associated with poor prognosis and high mortality. Therefore, understanding the risk factors associated with the causes and outcomes of these infections is crucial to reduce their incidence and initiate appropriate therapies. In our study, several factors were found to be involved in nosocomial carbapenem-resistant E. coli (CREC) infections, and CREC isolates were resistant to most antibiotics. Reducing CREC mortality needs a comprehensive consideration of whether antibiotics are used appropriately, underlying diseases, and invasive interventions. These findings provide valuable evidence for the development of anti-infective therapy, infection prevention, and control of CREC-positive infections.

Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.

BACKGROUND: Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated. RESULTS: In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1ß) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed. CONCLUSIONS: We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

Multi-omics analysis reveals that linoleic acid metabolism is associated with variations of trained immunity induced by distinct BCG strains.

Trained immunity is one of the mechanisms by which BCG vaccination confers persistent nonspecific protection against diverse diseases. Genomic differences between the different BCG vaccine strains that are in global use could result in variable protection against tuberculosis and therapeutic effects on bladder cancer. In this study, we found that four representative BCG strains (BCG-Russia, BCG-Sweden, BCG-China, and BCG-Pasteur) covering all four genetic clusters differed in their ability to induce trained immunity and nonspecific protection. The trained immunity induced by BCG was associated with the Akt-mTOR-HIF1α axis, glycolysis, and NOD-like receptor signaling pathway. Multi-omics analysis (epigenomics, transcriptomics, and metabolomics) showed that linoleic acid metabolism was correlated with the trained immunity-inducing capacity of different BCG strains. Linoleic acid participated in the induction of trained immunity and could act as adjuvants to enhance BCG-induced trained immunity, revealing a trained immunity-inducing signaling pathway that could be used in the adjuvant development.

Advances in understanding immune homeostasis in latent tuberculosis infection.

Nearly one-fourth of the global population is infected by Mycobacterium tuberculosis (Mtb), and approximately 90%-95% remain asymptomatic as latent tuberculosis infection (LTBI), an estimated 5%-10% of those with latent infections will eventually progress to active tuberculosis (ATB). Although it is widely accepted that LTBI transitioning to ATB results from a disruption of host immune balance and a weakening of protective immune responses, the exact underlying immunological mechanisms that promote this conversion are not well characterized. Thus, it is difficult to accurately predict tuberculosis (TB) progression in advance, leaving the LTBI population as a significant threat to TB prevention and control. This article systematically explores three aspects related to the immunoregulatory mechanisms and translational research about LTBI: (1) the distinct immunocytological characteristics of LTBI and ATB, (2) LTBI diagnostic markers discovery related to host anti-TB immunity and metabolic pathways, and (3) vaccine development focus on LTBI. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology Infectious Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Genetics/Genomics/Epigenetics.

Natural products in anti-tuberculosis host-directed therapy.

Given that the disease progression of tuberculosis (TB) is primarily related to the host's immune status, it has been gradually realized that chemotherapy that targets the bacteria may never, on its own, wholly eradicate Mycobacterium tuberculosis, the causative agent of TB. The concept of host-directed therapy (HDT) with immune adjuvants has emerged. HDT could potentially interfere with infection and colonization by the pathogens, enhance the protective immune responses of hosts, suppress the overwhelming inflammatory responses, and help to attain a state of homeostasis that favors treatment efficacy. However, the HDT drugs currently being assessed in combination with anti-TB chemotherapy still face the dilemmas arising from side effects and high costs. Natural products are well suited to compensate for these shortcomings by having gentle modulatory effects on the host immune responses with less immunopathological damage at a lower cost. In this review, we first summarize the profiles of anti-TB immunology and the characteristics of HDT. Then, we focus on the rationale and challenges of developing and implementing natural products-based HDT. A succinct report of the medications currently being evaluated in clinical trials and preclinical studies is provided. This review aims to promote target-based screening and accelerate novel TB drug discovery.

A multistage Sendai virus vaccine incorporating latency-associated antigens induces protection against acute and latent tuberculosis.

One-quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb). After initial exposure, more immune-competent persons develop asymptomatic latent tuberculosis infection (LTBI) but not active diseases, creates an extensive reservoir at risk of developing active tuberculosis. Previously, we constructed a novel recombinant Sendai virus (SeV)-vectored vaccine encoding two dominant antigens of Mtb, which elicited immune protection against acute Mtb infection. In this study, nine Mtb latency-associated antigens were screened as potential supplementary vaccine candidate antigens, and three antigens (Rv2029c, Rv2028c, and Rv3126c) were selected based on their immune-therapeutic effect in mice, and their elevated immune responses in LTBI human populations. Then, a recombinant SeV-vectored vaccine, termed SeV986A, that expresses three latency-associated antigens and Ag85A was constructed. In murine models, the doses, titers, and inoculation sites of SeV986A were optimized, and its immunogenicity in BCG-primed and BCG-naive mice were determined. Enhanced immune protection against the Mtb challenge was shown in both acute-infection and latent-infection murine models. The expression levels of several T-cell exhaustion markers were significantly lower in the SeV986A-vaccinated group, suggesting that the expression of latency-associated antigens inhibited the T-cell exhaustion process in LTBI infection. Hence, the multistage quarter-antigenic SeV986A vaccine holds considerable promise as a novel post-exposure prophylaxis vaccine against tuberculosis.

Pathomorphological characteristics of tuberculous placenta and its clinical implication.

BACKGROUND: The study of pathologic diagnosis of placental TB is rare. The aim of this study is analyzing the pathomorphological characteristics of tuberculosis (TB) placenta during pregnancy and its clinical significance. METHODS: Nineteen cases of placental tissue specimens during pregnancy were collected from June 2015 to February 2022 at Shanghai Public Health Clinical Center, the only inpatient center for pregnant women with TB in Shanghai, China. Hematoxylin-eosin staining, acid-fast staining, and molecular testing were applied to analyze them comprehensively in combination with clinical information. RESULTS: Among the 19 cases, 7 cases caused intrauterine stillbirth, 3 cases received artificial abortion required by the pregnant woman, the other 9 cases received standard delivery and the infants survived, however, 3 of them were low-weight preterm infants, and another 1 case suffered mild intrauterine asphyxia. The 9 surviving infants were followed-up, of which 3 cases got congenital TB. For pathological characteristics of placental tissues under light microscopy, there were 3 cases of epithelioid granuloma formation, 13 cases of acute fetal membranitis, 4 cases of caseous necrosis, 7 cases of inflammatory necrosis, 10 cases of coagulative necrosis, and 6 cases with small focal calcifications. All placental tissues were positive for acid-fast staining and polymerase chain reaction (PCR). Molecular pathological diagnosis showed that 18 cases were positive for Mycobacterium tuberculosis, with 1 case not having received examination. CONCLUSIONS: Combining acid-fast staining and molecular pathological testing is helpful for accurately diagnosing placental TB.

Advances in protein subunit vaccines against tuberculosis.

Tuberculosis (TB), also known as the "White Plague", is caused by Mycobacterium tuberculosis (Mtb). Before the COVID-19 epidemic, TB had the highest mortality rate of any single infectious disease. Vaccination is considered one of the most effective strategies for controlling TB. Despite the limitations of the Bacille Calmette-Guérin (BCG) vaccine in terms of protection against TB among adults, it is currently the only licensed TB vaccine. Recently, with the evolution of bioinformatics and structural biology techniques to screen and optimize protective antigens of Mtb, the tremendous potential of protein subunit vaccines is being exploited. Multistage subunit vaccines obtained by fusing immunodominant antigens from different stages of TB infection are being used both to prevent and to treat TB. Additionally, the development of novel adjuvants is compensating for weaknesses of immunogenicity, which is conducive to the flourishing of subunit vaccines. With advances in the development of animal models, preclinical vaccine protection assessments are becoming increasingly accurate. This review summarizes progress in the research of protein subunit TB vaccines during the past decades to facilitate the further optimization of protein subunit vaccines that may eradicate TB.

Broad-spectrum vaccine via combined immunization routes triggers potent immunity to SARS-CoV-2 and its variants.

IMPORTANCE: The development of broad-spectrum SARS-CoV-2 vaccines will reduce the global economic and public health stress from the COVID-19 pandemic. The use of conserved T-cell epitopes in combination with spike antigen that induce humoral and cellular immune responses simultaneously may be a promising strategy to further enhance the broad spectrum of COVID-19 vaccine candidates. Moreover, this research suggests that the combined vaccination strategies have the ability to induce both effective systemic and mucosal immunity, which may represent promising strategies for maximizing the protective efficacy of respiratory virus vaccines.

Advancing Microbe Detection for Lower Respiratory Tract Infection Diagnosis and Management with Metagenomic Next-Generation Sequencing.

Background: Due to limitations of traditional microbiological methods and the presence of the oropharyngeal normal flora, there are still many pathogens that cause lower respiratory tract infections (LRTIs) cannot be detected. Metagenomic next-generation sequencing (mNGS) has the potential capacity to solve this problem. Methods: This retrospective study successively reviewed 77 patients with LRTI and 29 patients without LRTI admitted to Tianjin Medical University General Hospital, China from August 2020 to June 2021. Pathogens in bronchoalveolar lavage fluid (BALF) specimens were detected adopting mNGS and traditional microbiological assays. The diagnostic performance of pathogens was compared between mNGS and BALF culture. The value of mNGS for aetiological and clinical impact investigation in LRTI was also evaluated. Results: Among 77 patients with LRTI, 22.1%, 40.3%, and 65.0% of cases were detected as definite or probable pathogens by culture, all conventional microbiological tests, and mNGS, respectively. Using the final diagnosis as a gold standard, mNGS exhibited a sensitivity of 76.6% (95% confidence interval [CI], 65.6-85.5%), which was considerably superior to that of BALF culture (76.6% vs 18.2%; P < 0.01); specificity of 79.3% (95% CI, 60.3-92.0%), which was similar (79.3% vs 89.7%; P = 0.38); positive-predictive value of 90.8% (95% CI, 81.0-96.5%), and negative-predictive value of 56.1% (95% CI, 39.7-71.5%). According to our data, mNGS identified potential microorganisms in 66.7% (42/63) of culture-negative samples. Among 59 patients with pathogens identified by mNGS, conventional microbiological methods confirmed pathogenic infections in less than half (28/59) cases. Within the 77 patients, 34 (44.2%) patients received pathogen-directed therapy, 7 (9.1%) patients underwent antibiotic adjustment, and 3 (3.9%) patients stopped using antibiotics due to mNGS results. Conclusion: mNGS exhibits high accuracy in diagnosing LRTI, and combine with traditional microbiological tests, causative pathogens can be detected in approximately 70.0% of cases, thus yields a positive effect on antibiotic application.

Diagnostic performance of CA125, HE4, ROMA, and CPH-I in identifying primary ovarian cancer.

AIMS: To evaluate the ability of carbohydrate antigen 125 (CA125), human epididymis protein 4 (HE4), risk of ovarian malignancy algorithm (ROMA), and Copenhagen Index (CPH-I) to identify primary ovarian cancer (OC) from borderline and benign ovarian tumors (OTs) and explore ideal cutoff points. METHODS: A total of 684 OTs containing 276 OC patients, 116 ovarian borderline OTs and 292 benign OTs patients who underwent surgery in our hospital were included. We retrospectively searched the results of CA125 and HE4 before patients' surgery from the hospital's electronic medical records system. ROMA and CPH-I were calculated according to their menopausal status and age, respectively. Diagnostic performance of these four were assessed by drawing receiver operating characteristic (ROC) curves. RESULTS: CA125, HE4, ROMA, and CPH-I were all significantly higher in OC women compared with borderline OTs (p < 0.001), followed by benign OTs (p < 0.001). Area under the curves (AUCs) for distinguishing OC were 0.850 (0.818-0.882), 0.891 (0.865-0.916), 0.910 (0.888-0.933) and 0.906 (0.882-0.930), respectively, and the corresponding ideal cutoff values for CA125, HE4, ROMA, and CPH-I were 132.5, 68.6, 23.8, and 6.4, respectively. The difference between ROMA and CPH-I was not significant (p = 0.97), but both were higher than CA125 and HE4 (p < 0.05). HE4 showed a significantly higher AUC than CA125 (p < 0.05). For postmenopausal women, CA125 performed equivalently to ROMA (p = 0.73) and CPH-I (p = 0.91). CONCLUSIONS: In identifying patients with OC, ROMA and CPH-I outperformed single tumor marker. The diagnostic performance of HE4 was significantly higher than that of CA125. CA125 was more suitable for postmenopausal women.

Emergence of Antifungal Resistant Subclades in the Global Predominant Phylogenetic Population of Candida albicans.

Candida albicans remains the most common species causing invasive candidiasis. In this study, we present the population structure of 551 global C. albicans strains. Of these, the antifungal susceptibilities of 370 strains were tested. Specifically, 66.6% of the azole-nonsusceptible (NS)/non-wild-type (NWT) strains that were tested belonged to Clade 1. A phylogenetic analysis, a principal components analysis, the population structure, and a loss of heterozygosity events revealed two nested subclades in Clade 1, namely, Clade 1-R and Clade 1-R-α, that exhibited higher azole-NS/NWT rates (75.0% and 100%, respectively). In contrast, 6.4% (21/326) of the non-Clade 1-R isolates were NS/NWT to at least 1 of 4 azoles. Notably, all of the Clade 1-R-α isolates were pan-azole-NS/NWT that carried unique A114S and Y257H double substitutions in Erg11p and had the overexpression of ABC-type efflux pumps introduced by the substitution A736V in transcript factor Tac1p. It is worth noting that the Clade 1-R and Clade 1-R-α isolates were from different cities that are distributed over a large geographic span. Our study demonstrated the presence of specific phylogenetic subclades that are associated with antifungal resistance among C. albicans Clade 1, which calls for public attention on the monitoring of the future spread of these clones. IMPORTANCE Invasive candidiasis is the most common human fungal disease among hospitalized patients, and Candida albicans is the predominant pathogen. Considering the large number of infected cases and the limited alternative therapies, the azole-resistance of C. albicans brings a huge clinical threat. Here, our study suggested that antifungal resistance in C. albicans could also be associated with phylogenetic lineages. Specifically, it was revealed that more than half of the azole-resistant C. albicans strains belonged to the same clade. Furthermore, two nested subclades of the clade exhibited extremely high azole-resistance. It is worth noting that the isolates of two subclades were from different cities that are distributed over a large geographic span in China. This indicates that the azole-resistant C. albicans subclades may develop into serious public health concerns.

An Updated Review on MSMD Research Globally and A Literature Review on the Molecular Findings, Clinical Manifestations, and Treatment Approaches in China.

Mendelian susceptibility to mycobacterial disease (MSMD) arises from a group of rare inherited errors of immunity that result in selective susceptibility of otherwise healthy people to clinical disease caused by low virulence strains of mycobacteria, such as Mycobacterium bovis Bacille Calmette-Guérin (BCG) and environmental mycobacteria. Patients have normal resistance to other pathogens and no overt abnormalities in routine immunological and hematological evaluations for primary immunodeficiencies. At least 19 genes and 34 clinical phenotypes have been identified in MSMD. However, there have been no systematic reports on the clinical characteristics and genetic backgrounds of MSMD in China. In this review, on the one hand, we summarize an update findings on molecular defects and immunological mechanisms in the field of MSMD research globally. On the other hand, we undertook a systematic review of PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, EMBASE, CNKI, and Wanfang to identify articles published before Jan 23, 2022, to summarize the clinical characteristics, diagnosis, treatment, and prognosis of MSMD in China. All the English and Chinese publications were searched without any restriction on article types.

Association of in vitro fertilization with maternal and perinatal outcomes among pregnant women with active tuberculosis: A retrospective hospital-based cohort study.

Background: Study on effect of fertilization methods on maternal and perinatal outcomes with respect to TB during pregnancy was scarce. This study aimed to analyze maternal and perinatal outcomes in active TB cases after in vitro fertilization (IVF) treatment vs. normal pregnancy. Methods: Clinical data of 80 pregnant women with active TB hospitalized at Shanghai Public Health Clinical Center between June 1st, 2014 and November 30th, 2020 were extracted and retrospectively analyzed. History of receiving IVF was recorded at admission and its association with maternal and perinatal outcomes were assessed using multivariable logistic regression models with adjustment for potential confounders. Results: Of the 80 pregnant women with active TB, 28 (35.0%) received IVF treatment and 52 (65.0%) did not receive IVF treatment. After adjusting for potential confounders, receiving IVF was associated with worse maternal and perinatal outcomes, including maternal criticality (21.4 vs. 2.0%, adjusted OR = 28.3, P = 0.015), miliary TB (89.3 vs. 13.5%, adjusted OR = 75.4, P < 0.001), TB meningitis (32.1 vs. 7.7%, adjusted OR = 6.2, P = 0.010), and perinatal mortality (64.3 vs. 28.8%, adjusted OR = 9.8, P = 0.001). Conclusion: The additional risk of TB to women receiving IVF treatment is a public health challenge specific to countries with a high tuberculosis burden. Increased awareness of latent tuberculosis infection in women receiving IVF treatment is needed.

Heterologous prime-boost BCG with DNA vaccine expressing fusion antigens Rv2299c and Ag85A improves protective efficacy against Mycobacterium tuberculosis in mice.

The development of heterologous prime-boost regimens utilizing Bacille Calmette-Guerin (BCG) as the priming vaccine is a promising approach to improve the efficacy of vaccination against tuberculosis (TB). In this study, we examined the ability of a DNA vaccine that expressed a fusion of antigens Rv2299c and Ag85A to boost BCG immunity and protection against Mycobacterium tuberculosis (Mtb) in Balb/c mice. The fusion DNA vaccine was moderately immunogenic and afforded some protection when used on its own. After a priming BCG vaccination, the DNA boost significantly amplified Th1-type cell-mediated immunity compared to that resulting from either BCG or DNA immunization. In the DNA-boosted mice, Ag-specific CD4+ and CD8+ T cells that were mono-positive for IFN-γ alone were the most prominently expanded in infected lungs. The protective efficacy afforded by BCG against challenge infection was greatly improved by the DNA boost; bacterial loads were significantly reduced in both spleen and lung and histological damage in the lung was less. The use of a DNA vaccine containing the fusion antigens Rv2299c and Ag85A to boost BCG may be a good choice for the rational design of an efficient vaccination strategy against TB.