A nursing report on a corneal contact lens wearer receiving keratoplasty due to corneal ulcer and perforation caused by Pythium insidiosum infection: A case report.

BACKGROUND: To report the nursing experience of a case of corneal contact lens wearer receiving the 2nd keratoplasty due to corneal ulcer and perforation caused by Pythium insidiosum infection. METHODS: A 30-year-old female patient had blurred vision after deep anterior lamellar keratoplasty for a right corneal ulcer. At the 5th week, the right eye appeared the symptoms, such as redness and pain. The anterior segment photography was performed on the eye, and the result showed that the epithelium was missing in the right eye lesion area, and a large number of longitudinal and transversal streaks were visible from the epithelium to the stroma, with fungus filaments to be discharged. Upon macro-genome sequencing of the corneal secretion, a P. insidiosum infection was observed. Then, the patient underwent the keratoplasty, and 3 weeks later, the corneal implant showed a tendency to dissolve, the sutures were partially loosened, and the eye was almost blind. Subsequently, the patient was admitted to our hospital and subject to the 2nd penetrating keratoplasty of the right eye (allograft). After surgery, linezolid and azithromycin injections were given through intravenous drip and local drip of the eye for anti-inflammation, and tacrolimus eye drops for antirejection. RESULTS: Postoperatively, the patient showed signs of recovery with slight corneal edema and visible pupil, leading to discharge with improved vision. The corneal implant was normal 1 week after surgery and the vision of the right eye was hand move/before eye at the 6th month of follow-up. Continuous care and removal of sutures 3 months post-surgery contributed to a successful outcome, with the patient achieving hand motion vision 6 months after the procedure. CONCLUSION: Corneal ulcer caused by P. insidiosum infection not only needs timely and effective keratoplasty intervention, but also requires perfect nursing measures.

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.

Acute ischemic stroke in tuberculous meningitis.

Background: The underlying mechanism for stroke in patients with tuberculous meningitis (TBM) remains unclear. This study aimed to investigate the predictors of acute ischemic stroke (AIS) in TBM and whether AIS mediates the relationship between inflammation markers and functional disability. Methods: TBM patients admitted to five hospitals between January 2011 and December 2021 were consecutively observed. Generalized linear mixed model and subgroup analyses were performed to investigate predictors of AIS in patients with and without vascular risk factors (VAFs). Mediation analyses were performed to explore the potential causal chain in which AIS may mediate the relationship between neuroimaging markers of inflammation and 90-day functional outcomes. Results: A total of 1,353 patients with TBM were included. The percentage rate of AIS within 30 days after admission was 20.4 (95% CI, 18.2-22.6). A multivariate analysis suggested that age ≥35 years (OR = 1.49; 95% CI, 1.06-2.09; P = 0.019), hypertension (OR = 3.56; 95% CI, 2.42-5.24; P < 0.001), diabetes (OR = 1.78; 95% CI, 1.11-2.86; P = 0.016), smoking (OR = 2.88; 95% CI, 1.68-4.95; P < 0.001), definite TBM (OR = 0.19; 95% CI, 0.06-0.42; P < 0.001), disease severity (OR = 2.11; 95% CI, 1.50-2.90; P = 0.056), meningeal enhancement (OR = 1.66; 95% CI, 1.19-2.31; P = 0.002), and hydrocephalus (OR = 2.98; 95% CI, 1.98-4.49; P < 0.001) were associated with AIS. Subgroup analyses indicated that disease severity (P for interaction = 0.003), tuberculoma (P for interaction = 0.008), and meningeal enhancement (P for interaction < 0.001) were significantly different in patients with and without VAFs. Mediation analyses revealed that the proportion of the association between neuroimaging markers of inflammation and functional disability mediated by AIS was 16.98% (95% CI, 7.82-35.12) for meningeal enhancement and 3.39% (95% CI, 1.22-6.91) for hydrocephalus. Conclusion: Neuroimaging markers of inflammation were predictors of AIS in TBM patients. AIS mediates < 20% of the association between inflammation and the functional outcome at 90 days. More attention should be paid to clinical therapies targeting inflammation and hydrocephalus to directly improve functional outcomes.

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.

Effect of Different Durations of Eye-Covering Pretreatment on Emergence Delirium after Ophthalmic Surgery in Preschool-Aged Children: A Randomized Controlled Study.

Background: Preoperative eye-covering training for 3 hours has been reported to effectively reduce the incidence of emergence delirium (ED) in preschool children. However, most children can only maintain the eye being covered for less than 60 min, and shortening eye-covering duration can also achieve similar clinical effects as long duration of eye-covering. This study was designed to compare the effects of 30-min and 60-min eye-covering pretreatment based on cartoon education only on preoperative anxiety, postoperative ED, and pain score after ophthalmic surgery with general anesthesia in preschool-aged children. Methods: Preschool-aged children (3-7 years) who were diagnosed with cataract, blepharoptosis, trichiasis, strabismus, eyelid tumor, and underwent ophthalmic surgery with general anesthesia from August 2021 to January 2022 were recruited. A total of 228 patients were randomly assigned at a 1 : 1:1 ratio to receive 30-min eye covering (30-min group), 60-min eye covering (60-min group) pretreatment, or programmed education only (C group). The preoperative anxiety, postoperative emergence delirium, and pain were compared between the groups. Results: The preoperative anxiety score, postoperative ED score, and incidence of ED in the 30-min group (n = 76) and 60-min group (n = 72) were significantly lower than those in the C group (n = 76), demonstrating a significant between-group difference (P < 0.001). However, the 30-min group and 60-min group had no significant difference in the abovementioned outcome measures (P > 0.05). Moreover, no significant difference was found in postoperative pain scores among the three groups (H = 0.274, P=0.872). Conclusion: Both 30-min and 60-min eye-covering pretreatments significantly reduce preoperative anxiety and postoperative ED after ophthalmic surgery with general anesthesia in preschool-aged children. The effects of the two groups show no intergroup difference, but the 30-min eye-covering pretreatment may be more convenient for practicing. Trial Registration. This study was registered with the No. NCT04973150.

Research Advances for Virus-vectored Tuberculosis Vaccines and Latest Findings on Tuberculosis Vaccine Development.

Tuberculosis (TB), caused by respiratory infection with Mycobacterium tuberculosis, remains a major global health threat. The only licensed TB vaccine, the one-hundred-year-old Bacille Calmette-Guérin has variable efficacy and often provides poor protection against adult pulmonary TB, the transmissible form of the disease. Thus, the lack of an optimal TB vaccine is one of the key barriers to TB control. Recently, the development of highly efficacious COVID-19 vaccines within one year accelerated the vaccine development process in human use, with the notable example of mRNA vaccines and adenovirus-vectored vaccines, and increased the public acceptance of the concept of the controlled human challenge model. In the TB vaccine field, recent progress also facilitated the deployment of an effective TB vaccine. In this review, we provide an update on the current virus-vectored TB vaccine pipeline and summarize the latest findings that might facilitate TB vaccine development. In detail, on the one hand, we provide a systematic literature review of the virus-vectored TB vaccines are in clinical trials, and other promising candidate vaccines at an earlier stage of development are being evaluated in preclinical animal models. These research sharply increase the likelihood of finding a more effective TB vaccine in the near future. On the other hand, we provide an update on the latest tools and concept that facilitating TB vaccine research development. We propose that a pre-requisite for successful development may be a better understanding of both the lung-resident memory T cell-mediated mucosal immunity and the trained immunity of phagocytic cells. Such knowledge could reveal novel targets and result in the innovative vaccine designs that may be needed for a quantum leap forward in vaccine efficacy. We also summarized the research on controlled human infection and ultra-low-dose aerosol infection murine models, which may provide more realistic assessments of vaccine utility at earlier stages. In addition, we believe that the success in the ongoing efforts to identify correlates of protection would be a game-changer for streamlining the triage of multiple next-generation TB vaccine candidates. Thus, with more advanced knowledge of TB vaccine research, we remain hopeful that a more effective TB vaccine will eventually be developed in the near future.

Trained immunity: A Yin-Yang balance.

Traditionally, immune memory is regarded as an exclusive hallmark of adaptive immunity. However, a growing body of evidence suggesting that innate immune cells show adaptive characteristics has challenged this dogma. In the past decade, trained immunity, a de facto innate immune memory, has been defined as a long-term functional reprogramming of cells of the innate immune system: the reprogramming is evoked by endogenous or exogenous insults, the cells return to a nonactivated state and subsequently show altered inflammatory responses against a second challenge. Trained immunity became regarded as a mechanism selected in evolution to protect against infection; however, a maladaptive effect might result in hyperinflammation. This dual effect is consistent with the Yin-Yang theory in traditional Chinese philosophy, in which Yang represents active, positive, and aggressive factors, whereas Yin represents passive, negative, and inhibitory factors. In this review, we give a brief overview of history and latest progress about trained immunity, including experimental models, inductors, molecular mechanisms, clinical application and so on. Moreover, this is the first time to put forward the theory of Yin-Yang balance to understand trained immunity. We envision that more efforts will be focused on developing novel immunotherapies targeting trained immunity in the coming years.

Mycobacterium tuberculosis Rv3628 isan effective adjuvant via activationof dendritic cells for cancer immunotherapy.

Tumor antigens (Ags) are weakly immunogenic and elicit inadequate immune responses, thus induction of antigen-specific immune activation via the maturation of dendritic cells (DCs) is a strategy used for cancer immunotherapy. In this study, we examined the effect of Rv3628 from Mycobacterium tuberculosis (Mtb) on activation of DCs and anti-tumor immunity in vivo. Intravenous injection of mice with Rv3628 promoted DC activation of spleen and lymph nodes. More importantly, Rv3628 also induced activation of DCs and enhanced Ag presentation in tumor-bearing mice. In mice bearing ovalbumin (OVA)-expressing tumors, combination treatment with Rv3628 and OVA peptide promoted OVA-specific T cell activation and accumulation of interferon (IFN)-γ and tumor necrosis factor (TNF)-α-producing OT-I and OT-II cells in tumor-draining lymph nodes. Moreover, three different tumor Ags in three different tumor models showed enhanced anti-tumor activity with Rv3628 as adjuvant, including inhibition of growth of OVA-expressing B16 melanoma, CT26 carcinoma, and B16 melanoma tumors, and a synergistic effect with anti-programmed cell death protein 1 (PD-1) antibody treatment. Additionally, potential application against human tumors was indicated by similar activation of human peripheral blood DCs by Rv3628. Taken together, these data demonstrate that Rv3628 could be an effective adjuvant in tumor immunotherapy via enhanced capacity of DC activation and Ag presentation.

High rate of completion for weekly rifapentine plus isoniazid treatment in Chinese children with latent tuberculosis infection-A single center study.

Three months of weekly rifapentine plus isoniazid (3HP) is a short course regimen for latent tuberculosis infection treatment with satisfied safety and efficacy. However, research on its use in children is limited. In this study, we evaluated the completion rate and safety of the 3HP regimen among children in China. Participants aged 1-14 years receiving 3HP for TB prevention at Shanghai Public Health Clinical Center were followed from December 2019 to November 2020 to evaluate the safety and completion rate of the treatment. Thirty-one children were eligible for inclusion, but five were excluded from the analysis (three were treated with a lower than recommended dose, and two were lost to follow-up). Of the 26 children included in the analysis, the treatment completion rate was 100%. Adverse drug reactions (ADRs) were reported in 38.5% (10/26) of the patients. The most common ADRs were gastrointestinal symptoms (19.2%,5/26), and all ADRs were rated as Grade 1. The 3HP regimen has a high completion rate, and it seems well tolerated in our study population. However, further randomized controlled clinical trial with larger sample size are warranted.

A Niemann-pick C1 disease child with BCG-itis: a case report and analysis.

BACKGROUND: Niemann-Pick C disease is a rare autosomal recessive lysosomal lipid storage disorder. Some primary immunodeficiency diseases patients developed regional disease or disseminated disease after vaccinating BCG. It is unclear whether NPC gene deficiency is associated with Mycobacteria infection. CASE PRESENTATION: We report and discuss a case of a child who presented at the age of 6 months with NPC1 and BCG-itis. The patient was treated with Miglustat and the symptom of lymphadenopathy was improved. CONCLUSIONS: We reasonably speculate that NPC1 is a susceptibility gene of Mtb infection and mainly affects innate immunity. Once diagnosed, the infant should not be vaccinated with BCG and early treated.

Safety Evaluation of Recombinant Fusion Protein RP22 as a Skin Test Reagent for Tuberculosis Diagnosis: A Phase I Clinical Trial.

INTRODUCTION: This phase I clinical trial was conducted to evaluate the safety of RP22 as a skin test reagent for tuberculosis (TB) diagnosis and to explore the appropriate dosage. METHODS: We used a randomized, double-blind, placebo-controlled identification allergen (IA) skin test. A total of 72 healthy adult volunteers with negative chest X-ray results were randomized into six groups and given a QuantiFERON-TB Gold (QFT) test. Of the 12 participants in each group, eight received RP22 and four received placebo. The doses of RP22 in the six experimental groups ranged from 0.1 to 4.0 µg in a single intradermal injection of 0.1 ml. Skin reactions and adverse events were recorded at intervals. RESULTS: All doses of RP22 except the highest were well tolerated and safe. No serious adverse events associated with the injection were observed in all groups. There were 11 participants who had positive QFT results, eight had a skin reaction with a redness or induration area diameter of greater than 10 mm at 48-72 h, one had no skin reaction. Among the 60 negative-QFT participants, none had a reaction area diameter of greater than 10 mm. CONCLUSION: The RP22 skin test was well tolerated and safe, it could play a key role in screening for latent tuberculosis infection (LTBI) by providing a much-wanted alternative to the tuberculin skin test (TST) and interferon-γ release assays (IGRAs).

Stool-based Xpert MTB/RIF Ultra assay as a tool for detecting pulmonary tuberculosis in children with abnormal chest imaging: A prospective cohort study.

OBJECTIVES: To evaluate the diagnostic efficacy of stool-based Xpert MTB/RIF Ultra assay versus other assays for the detection of paediatric pulmonary tuberculosis (PTB). METHODS: A prospective head-to-head comparative study was conducted from Dec 2017 to May 2019 in Shanghai Public Health Clinical Centre. Samples were collected from children (< 15 years) with abnormal chest imaging (X-ray or CT scan) results for the following tests: Ultra on stool sample (Ultra-Stool), Ultra on respiratory tract sample (Ultra-RTS), Xpert MTB/RIF assay (Xpert) on RTS (Xpert-RTS), acid-fast bacilli smear on RTS (AFB-RTS), and Mycobacterium tuberculosis (Mtb) culture on RTS (Culture-RTS). The results were compared with a composite reference standard. RESULTS: A total of 126 cases with paired results were analysed. Against a composite reference standard, Ultra-RTS demonstrated the highest sensitivity (52%) and specificity (100%). Ultra-Stool showed 84.1% concordance with Ultra-RTS, demonstrating 45.5% sensitivity and 94.7% specificity (kappa = 0.65, 95% CI= 0.51-0.79). The sensitivity of Ultra-Stool was similar to Mtb culture (45.5%, p = 1.000) and higher than AFB-RTS (27.3%, p < 0.05). Assay positivity was associated with age and infiltration range in chest imaging. CONCLUSIONS: When RTS is difficult to obtain, stool sample-based Ultra is a comparable alternative.

Heterologous prime-boost vaccination against tuberculosis with recombinant Sendai virus and DNA vaccines.

In an earlier study, a novel Sendai virus-vectored anti-tuberculosis vaccine encoding Ag85A and Ag85B (SeV85AB) was constructed and shown to elicit antigen-specific T cell responses and protection against Mycobacterium tuberculosis (Mtb) infection in a murine model. In this study, we evaluate whether the immune responses induced by this novel vaccine might be elevated by a recombinant DNA vaccine expressing the same antigen in a heterologous prime-boost vaccination strategy. The results showed that both SeV85AB prime-DNA boost (SeV85AB-DNA) and DNA prime-SeV85AB boost (DNA-SeV85AB) vaccination strategies significantly enhanced the antigen-specific T cell responses induced by the separate vaccines. The SeV85AB-DNA immunization regimen induced higher levels of recall T cell responses after Mtb infection and conferred better immune protection compared with DNA-SeV85AB or a single immunization. Collectively, our study lends strong evidence that a DNA vaccine boost might be included in a novel SeV85AB immunization strategy designed to enhance the immune protection against Mtb. KEY MESSAGES: A heterologous prime-boost regimen with a novel recombinant SeV85AB and a DNA vaccine increase the T cell responses above those from a single vaccine. The heterologous prime-boost regimen provided protection against Mtb infection. The DNA vaccine might be included in a novel SeV85AB immunization strategy designed to enhance the immune protection against Mtb.

Differential T cell responses against DosR-associated antigen Rv2028c in BCG-vaccinated populations with tuberculosis infection.

The IFN-γ release assays (IGRAs) based on region of difference 1 (RD1) antigens have improved diagnosis of Mycobacterium tuberculosis (Mtb) infection. However, IGRAs with these antigens could not distinguish latent tuberculosis infection (LTBI) from active tuberculosis (ATB). DosR regulon genes are thought to be important for Mtb dormancy, and their products have higher immunogenicity in LTBI than ATB individuals, suggesting protective immunity mediated by DosR regulon-encoded antigens and potential utility of them for differential diagnostics of Mtb-infected populations or development of therapeutic vaccines against tuberculosis (TB). Among them, Rv2028c is a dormancy-related antigen that has demonstrated potential use in TB control, but its immunological characteristics in the BCG-vaccinated Chinese population are unknown. In this study, a total of 148 individuals, including 98 patients with ATB, 20 cases with LTBI and 30 healthy controls, were tested for Rv2028c-specific T cell responses by using an IFN-γ ELISA assay. The results showed that the T-cell responses in LTBI individuals were almost always higher than those in ATB patients, regardless of the site of infection or the results of bacteriological examination in the patients. This allowed for good differentiation between these two groups of Mtb-infected individuals even in the BCG-vaccinated high TB-incidence setting that pertains in China. In addition, the diagnostic efficacy for ATB was enhanced by combining the results from Rv2028c and RD1 antigen-based IFN-γ ELISA assays. In conclusion, Rv2028c-specific T-cell responses might contribute to natural protection against dormant Mtb infection, and the determination of these responses can aid discrimination between healthy LTBI individuals and ATB patients in the Mtb-infected populations.