Anti-GM-CSF autoantibodies predict outcome of cryptococcal meningitis in patients not infected with HIV: A cohort study.

OBJECTIVES: To explore the seroprevalence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in non-HIV cryptococcal meningitis (CM) and assess its predictive value for survival. METHODS: This is a retrospective study of 12 years of non-HIV CM. We detected serum anti-GM-CSF autoantibodies, and evaluated the clinical features and outcomes, together with the exploration of prognostic factors for 2-week and 1-year survival. RESULTS: A total of 584 non-HIV CM cases were included. 301 of 584 patients (51.5%) were phenotypically healthy. 264 Cryptococcus isolates were obtained from cerebrospinal fluid (CSF) culture, of which 251 were identified as C. neoformans species complex and 13 as C. gattii species complex. Thirty-seven of 455 patients (8.1%) tested positive for serum anti-GM-CSF autoantibodies. Patients with anti-GM-CSF autoantibodies were more susceptible to C. gattii species complex infection (66.7% vs. 6.3%; p < 0.001) and more likely to develop pulmonary mass lesions with a diameter >3 centimetres (42.9% vs. 6.5%; p 0.001). Of 584 patients 16 (2.7%) died within 2 weeks, 77 of 563 patients (13.7%) died at 1 year, and 93 of 486 patients (19.1%) lived with disabilities at 1 year. Univariant Cox regression analysis found that anti-GM-CSF autoantibodies were associated with lower 1-year survival (HR, 2.66; 95% CI, 1.34-5.27; p 0.005). Multivariable Cox proportional hazards modelling revealed that CSF cryptococcal antigen titres ≥1:1280 were associated with both, reduced 2-week and 1-year survival rates (HR, 5.44; 95% CI, 1.23-24.10; p 0.026 and HR, 5.09; 95% CI, 1.95-13.26; p 0.001). DISCUSSION: Presence of serum anti-GM-CSF autoantibodies is predictive of poor outcomes, regardless of host immune status and the causative Cryptococcus species complex.

Diagnostic Laboratory Features and Performance of an Aspergillus IgG Lateral Flow Assay in a Chronic Pulmonary Aspergillosis Cohort.

Chronic pulmonary aspergillosis (CPA) is a chronic and progressive fungal disease with high morbidity and mortality. Avoiding diagnostic delay and misdiagnosis are concerns for CPA patients. However, diagnostic practice is poorly evaluated, especially in resource-constrained areas where Aspergillus antibody testing tools are lacking. This study aimed to investigate the diagnostic laboratory findings in a retrospective CPA cohort and to evaluate the performance of a novel Aspergillus IgG lateral flow assay (LFA; Era Biology, Tianjin, China). During January 2016 and December 2021, suspected CPA patients were screened at the Center for Infectious Diseases at Huashan Hospital. A total of 126 CPA patients were enrolled. Aspergillus IgG was positive in 72.1% with chronic cavitary pulmonary aspergillosis, 75.0% with chronic necrotizing pulmonary aspergillosis, 41.7% with simple aspergilloma, and 30.3% with Aspergillus nodule(s). The cavitary CPA subtypes had significantly higher levels of Aspergillus IgG. Aspergillus IgG was negative in 52 patients, who were finally diagnosed by histopathology, respiratory culture, and metagenomic next-generation sequencing (mNGS). Sputum culture was positive in 39.3% (42/107) of patients and Aspergillus fumigatus was the most common species (69.0%, 29/42). For CPA cohort versus controls, the sensitivity and specificity of the LFA were 55.6% and 92.7%, respectively. In a subgroup analysis, the LFA was highly sensitive for A. fumigatus-associated chronic cavitary pulmonary aspergillosis (CCPA; 96.2%, 26/27). Given the complexity of the disease, a combination of serological and non-serological tests should be considered to avoid misdiagnosis of CPA. The novel LFA has a satisfactory performance and allows earlier screening and diagnosis of CPA patients. IMPORTANCE There are concerns on avoiding diagnostic delay and misdiagnosis for chronic pulmonary aspergillosis due to its high morbidity and mortality. A proportion of CPA patients test negative for Aspergillus IgG. An optimal diagnostic strategy for CPA requires in-depth investigation based on real-world diagnostic practice, which has been rarely discussed. We summarized the clinical and diagnostic laboratory findings of 126 CPA patients with various CPA subtypes. Aspergillus IgG was the most sensitive test for diagnosing CPA. However, it was negative in 52 patients, who were finally diagnosed by non-serological tests, including biopsy, respiratory culture, and metagenomic next-generation sequencing. We also evaluated a novel Aspergillus IgG lateral flow assay, which showed a satisfactory performance in cavitary CPA patients and was highly specific to Aspergillus fumigatus. This study gives a full picture of the diagnostic practice for CPA patients in Chinese context and calls for early diagnosis of CPA with combined approaches.

Diagnostic performance of noncultural methods for central nervous system aspergillosis.

BACKGROUND: Central nervous system (CNS) aspergillosis is an uncommon but fatal disease, the diagnosis of which is still difficult. OBJECTIVES: We aim to explore the diagnositic performance of noncultural methods for CNS aspergillosis. METHODS: In this retrospective study, all pathologically confirmed rhinosinusitis patients in whom cerebrospinal fluid (CSF) galactomannan (GM) test and metagenomic next-generation sequencing (mNGS) had been performed were included. We evaluated the diagnostic performances of CSF GM optical density indexes (ODI) at different cut-off values and compared performance with mNGS in patients with and without CNS aspergillosis, as well as in patients with different manifestations of CNS aspergillosis. RESULTS: Of the 21 proven and probable cases, one had positive culture result, five had positive mNGS results and 10 had a CSF GM ODI of >0.7. Sample concordance between mNGS and GM test was poor, but best diagnostic performance was achieved by combination of GM test (ODI of >0.7) and mNGS, which generated a sensitivity of 61.9% and specificity of 82.6%. Further investigation of combination diagnostic performances in different kind of CNS aspergillosis was also conducted. Lowest sensitivity (42.9%) was identified in abscess group, while increased sensitivity (60.0%) was achieved in abscess with encephalitis groups. Combination test exhibited the best performance for encephalitis patients who had only CSF abnormalities, in whom the sensitivity and specificity were 77.8% and 82.6%, respectively. CONCLUSIONS: In conclusion, combination of these two tests might be useful for diagnosis of CNS aspergillosis associated with fungal rhinosinusitis, especially in encephalitis patients.

Induction therapy with high-dose fluconazole plus flucytosine for human immunodeficiency virus-uninfected cryptococcal meningitis patients: Feasible or not?

BACKGROUND: Cryptococcal meningitis (CM) is increasingly recognised in human immunodeficiency virus (HIV)-uninfected patients with high mortality. The efficacy and safety profiles of induction therapy with high-dose fluconazole plus flucytosine remain unclear. METHODS: HIV-uninfected CM patients who received high-dose fluconazole (800 mg/d) for initial therapy in Huashan Hospital were included in this retrospective study from January 2013 to December 2018. Efficacy and safety of initial therapy, clinical outcomes and risk factors were evaluated. RESULTS: Twenty-seven (71.1%) patients who received high-dose fluconazole with flucytosine combination therapy and 11 (28.9%) having fluconazole alone for induction therapy were included. With a median duration of 42 days (IQR, 28-86), the successful response rate of initial therapy was 76.3% (29/38), while adverse drug reactions occurred in 14 patients (36.8%). The rate of persistently positive cerebrospinal fluid (CSF) culture results was 30.6% at 2 weeks, which was significantly associated with CSF CrAg titre >1:1280 (OR 9.56; 95% CI 1.40-103.65; p = .010) and CSF culture of Cryptococcus >3.9 log10 CFU/ml (OR 19.20; 95% CI 1.60-920.54; p = .011), and decreased to 8.6% at 4 weeks. One-year mortality was 15.8% (6/38), and low serum albumin (35 g/L) was found as an independent risk factor for 1-year mortality (HR 6.31; 95% CI 1.150-34.632; p = .034). CONCLUSIONS: Induction therapy with high-dose fluconazole (800 mg/d), combined with flucytosine, effectively treated HIV-uninfected CM and was well tolerated. Long-term fluconazole treatment with continued monitoring is beneficial for patients with persistent infection.

Cerebrospinal fluid cytokine and chemokine patterns correlate with prognosis of HIV-uninfected cryptococcal meningitis: A prospective observational study.

The cerebrospinal fluid (CSF) immune responses in HIV-uninfected cryptococcal meningitis (CM) have not been well studied. In this study, we aimed to explore the phenotype of CSF immune response during the course of disease and to examine relationships between phenotypes and disease severity. We profiled the CSF immune response in 128 HIV-uninfected CM and 30 pulmonary cryptococcosis patients using a 27-plex Luminex cytokine kit. Principal component analyses (PCA) and logistic regression model were performed. Concentrations of 23 out of 27 cytokines and chemokines in baseline CSF were significantly elevated in CM patients compared with pulmonary cryptococcosis cases. In CM patients with Cryptococcus neoformans infection, IL-1ra, IL-9, and VEGF were significantly elevated in immunocompetent cases. Cytokine levels usually reached peaks within the first 2 weeks of antifungal treatment and gradually decreased over time. PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting of Th1, Th2, and Th17 type cytokines. Prognostic analysis showed that higher scores for the PCs loading pro-inflammatory cytokines, IFN-γ, TNF-α, and IL-12; and anti-inflammatory cytokine, IL-4; and chemokines, Eotaxin, FGF-basis, and PDGF-bb; as well as lower scores for the PCs loading RANTES were associated with disease severity, as defined by a Glasgow Coma Scale of <15 or death. In conclusion, combined inflammatory responses in CSF involving both pro- and anti-inflammatory cytokines and chemokines are upregulated in HIV-uninfected CM, and associated with disease severity.

Immune reconstitution inflammatory syndrome in non-HIV cryptococcal meningitis: Cross-talk between pathogen and host.

BACKGROUND: Cryptococcal meningitis (CM)-associated immune reconstitution inflammatory syndrome (IRIS) is associated with high mortality, the epidemiology and pathophysiology of which is poorly understood, especially in non-HIV populations. OBJECTIVES: We aim to explore the incidence, clinical risk factors, immunological profiles and potential influence of leukotriene A4 hydroxylase (LTA4H) on non-HIV CM IRIS populations. METHODS: In this observational cohort study, 101 previously untreated non-HIV CM patients were included. We obtained data for clinical variables, 27 cerebrospinal fluid (CSF) cytokines levels and LTA4H genotype frequencies. Changes of CSF cytokines levels before and at IRIS occurrence were compared. RESULTS: Immune reconstitution inflammatory syndrome was identified in 11 immunocompetent males, generating an incidence of 10.9% in non-HIV CM patients. Patients with higher CrAg titres (> 1:160) were more likely to develop IRIS, and titre of 1:1280 is the optimum level to predict IRIS occurrence. Baseline CSF cytokines were significantly higher in IRIS group, which indicated a severe host immune inflammation response. Four LTA4H SNPs (rs17525488, rs6538697, rs17525495 and rs1978331) exhibited significant genetic susceptibility to IRIS in overall non-HIV CM, while five cytokines were found to be associated with rs1978331, and baseline monocyte chemotactic protein 1 (MCP-1) became the only cytokine correlated with both IRIS and LTA4H SNPs. CONCLUSIONS: Our study suggested that non-HIV CM patients with high fungal burden and severe immune inflammation response were more likely to developed IRIS. LTA4H polymorphisms may affect the pathogenesis of IRIS by regulating the level of baseline CSF MCP-1.

Clinical Predictors Impacting Cryptococcal Dissemination and Poor Outcome in Patients With Cirrhosis.

BACKGROUND: Cirrhosis is an end-stage liver disease and is reported as an independent risk factor for cryptococcosis. Information about cryptococcosis in patients with cirrhosis remains sparse. METHODS: Human immunodeficiency virus-uninfected patients with cryptococcosis and cirrhosis admitted to Huashan Hospital from July 2005 to June 2020 were reviewed. Efficacy and safety of antifungal treatments, clinical outcome, and prognostic factors of mortality were evaluated. RESULTS: A total of 49 cryptococcosis patients with cirrhosis were included. Sites of infection involved central nervous system (n = 38), lung (n = 21), bloodstream (n = 11), skin (n = 1), and bone (n = 1). Nine patients (18.4%) had pulmonary cryptococcosis alone. Viral hepatitis B infection (57.1%) was the most common cause of cirrhosis. Patients with decompensated cirrhosis (Child-Pugh class B and C) were more likely to have extrapulmonary cryptococcosis than those with compensated cirrhosis (90.7% vs 64.7%; P = .049). In patients with cryptococcal meningitis (CM), 7 were treated with amphotericin B with/without flucytosine, 5 with amphotericin B plus fluconazole with/without flucytosine, and 12 with fluconazole with/without flucytosine. Fluconazole (>400 mg/day) was well tolerated and only 1 patient had a mild adverse drug reaction. At 1-year follow-up, all patients treated with fluconazole with or without flucytosine survived, whereas the mortality rate was 14.3%-20.0% in the remaining groups. In addition, Child-Pugh class C cirrhosis (hazard ratio [HR], 7.555 [95% confidence interval {CI}, 1.393-40.971]) and time to diagnosis >120 days (HR, 18.619 [95% CI, 2.117-163.745]) were independent factors for 1-year mortality in patients with CM. CONCLUSIONS: Severity of cirrhosis was associated with developing extrapulmonary cryptococcosis and mortality in CM. Early diagnosis and intervention of cryptococcosis are key for outcome.

Characterization of membrane-bound IL-22+ T cell subsets in HIV-1 patients coinfected with Mycobacterium tuberculosis.

BACKGROUND: Previously, we have found that IL-22 could be not only secreted outside of cells, but also highly expressed on the T cells membrane in HIV-1 negative patients with tuberculosis (TB). However, the study on membrane-bound IL-22+ cells of HIV-1 infected patients is rare. Therefore, we investigated antigen-specific membrane-bound IL-22+ T cell subsets in Mycobacterium tuberculosis (M.tb) coinfection of HIV-1 infected individuals. METHODS: A case-control study that enrolled 74 HIV-1 infected participants was carried out, including HIV-1 monoinfection (HIV+TB-, n = 43), HIV-1 infected patients with latent TB (HIV+LTB, n = 18) and HIV-1 coinfected patients with active TB (HIV+TB+, n = 13). We made use of an IFN-γ release assay (IGRA) to screen LTB individuals. Purified protein derivative (PPD) and phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) were used as specific-stimulators to detect the levels of peripheral blood membrane-bound IL-22+ T cell subsets via cell surface staining and flow cytometry among three groups. RESULTS: An approximate rate of 24.3% (n = 18 out of 74) of latent M.tb infection among HIV-1 positive population in Eastern China. Interestingly, HMBPP-specific CD3+Vγ2+ T cells were impaired in HIV+TB+patients compared with HIV+LTB patients (P < 0.05). Furthermore, increases of PPD-specific and HMBPP-specific membrane-bound IL-22+ T cell subsets including CD3+, CD3+CD4+ and CD3+Vγ2+ T cells were observed in HIV+TB+group rather than HIV+LTB groups (all P < 0.05). CONCLUSION: Antigen-specific membrane-bound IL-22+ T cells were highly expressed in M.tb coinfection of HIV-1 infected individuals, and may play an important role in anti-TB immune response during coinfection with HIV-1.

Association of cytokine gene polymorphisms with chronic hepatitis C virus genotype 1b infection in Chinese Han population: An observational study.

Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case-control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-ß (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69-11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08-10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49-10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25-1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25-1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01-13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14-82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00-18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.

Risk-Based Estimate of Human Fungal Disease Burden, China.

We conducted a systematic literature review to obtain risk population-based fungal disease incidence or prevalence data from China. Data were categorized by risk factors and extrapolated by using most recent demographic figures. A total of 71,316,101 cases (5.0% of the population) were attributed to 12 risk factors and 17 fungal diseases. Excluding recurrent Candida vaginitis (4,057/100,000 women) and onychomycosis (2,600/100,000 persons), aspergillosis (317/100,000 persons) was the most common problem; prevalence exceeded that in most other countries. Cryptococcal meningitis, an opportunistic infection, occurs in immunocompetent persons almost twice as often as AIDS. The pattern of fungal infections also varies geographically; Talaromyces marneffei is distributed mainly in the Pearl River Basin, and the Yangtze River bears the greatest histoplasmosis burden. New host populations, new endemic patterns, and high fungal burdens in China, which caused a huge impact on public health, underscore the urgent need for building diagnostic and therapeutic capacity.

Evaluation of low cryptococcal antigen titer as determined by the lateral flow assay in serum and cerebrospinal fluid among HIV-negative patients: a retrospective diagnostic accuracy study.

Cryptococcosis is one of the most common opportunistic infections in both immunocompetent and immunocompromised hosts. Although the cryptococcal antigen (CrAg) lateral flow assay (LFA) has been widely used in clinical settings due to its high sensitivity and specificity, the diagnostic value of a low CrAg LFA titers remains unclear. In this study, we performed a retrospective analysis of 149 HIV-negative patients with low CrAg LFA titers (≤1:10) in a Chinese tertiary hospital from January 2013 to December 2017, to evaluate the diagnostic value of low CrAg LFA titers in serum and cerebrospinal fluid (CSF) at different thresholds. Sensitivity and specificity of low CrAg LFA titers in patients with definitive diagnoses of cryptococcosis were 39.6% (95% CI, 29.7-50.1%) and 100% (95% CI, 69.2-100%), respectively, at a threshold of 1:10 in serum. A sensitivity of 72.9% (95% CI, 62.9-81.5%) and a decreased specificity of 70.0% (95% CI, 34.8-93.3%) were observed at a threshold of 1:5 in serum. No false-positive cases were identified in patients with low CrAg titers in CSF and all positive predictive values (PPVs) were 100%. Among the cases with low serum CrAg titers, lumbar puncture was performed in 97 patients and positive CSF CrAg titers were reported in 6 patients. In conclusion, the results of this study imply that low CrAg LFA titer, either in serum or CSF, is crucial for early diagnosis of cryptococcosis in HIV-negative patients, and lumbar puncture is recommended to be performed routinely for CSF testing when a positive low serum titer is reported. Cryptococcal meningitis should be considered seriously when the CSF CrAg titer is positive.

Genetic polymorphisms of transient receptor potential melastatin 1 correlate with voriconazole-related visual adverse events.

BACKGROUND: Causes of voriconazole-related visual adverse events (VVAE) remained controversial. OBJECTIVES: We aimed to explore the relationship between voriconazole serum concentrations and VVAE as well as the potential influence of transient receptor potential melastatin 1 (TRPM1) on VVAE. PATIENTS/METHODS: This prospective observational cohort study was done in two stages. Patients who received voriconazole for invasive fungal diseases were consecutively enrolled. Correlations between voriconazole trough levels and VVAE were explored in 76 patients. Genotyping was further conducted for 17 tag SNPs of TRPM1 in a larger population of 137 patients. Genotype distributions were compared between patients with and without VVAE. RESULT: Of the 76 patients, a total of 229 steady-state voriconazole trough levels were evaluated, 69.9% of which were within the target range (1-5.5 mg/L). No correlations were found between voriconazole trough levels and VVAE. Of the total 137 patients, VVAE occurred in 37 (27.0%) patients, including visual hallucination (13.9%, 19/137) and visual disturbances (19.0%, 26/137). Significant difference in TRPM1 genotype distribution was only observed in patients with visual hallucination but not with visual disturbances. We found that rs890160 G/T genotype was under-presented (OR, 0.11; 95% CI, 0.01-0.84; P = .011) and rs1378847 C/C genotype was more frequently detected (OR, 8.89; 95% CI, 1.14-69.02; P = .013) in patients with visual hallucination when compared with those without. CONCLUSION: Transient receptor potential melastatin 1 was genetically associated with voriconazole-related visual hallucination. The correlation was failed to found between voriconazole trough levels and VVAE.

High dose fluconazole in salvage therapy for HIV-uninfected cryptococcal meningitis.

BACKGROUND: The 2010 Infectious Diseases Society of America (IDSA) guidelines for management of cryptococcal diseases recommend high dose fluconazole (≥ 800 mg/day), either alone or with other antifungal drugs, as alternative anticryptococcal choices. But evidence for its use in the treatment of HIV-uninfected cryptococcal meningitis (CM) remains sparse. METHODS: A retrospective analysis of HIV-uninfected CM patients who received fluconazole 800 mg/day for salvage therapy from January 2011 to December 2016 at Huashan Hospital, Shanghai, China was performed. Efficacy and safety were assessed, and mortality and prognostic factors evaluated. RESULTS: A total of 44 patients were studied including 19 refractory to amphotericin B induction therapy, 8 refractory to fluconazole consolidation therapy (400 mg/d), and 17 intolerant of antifungal drugs. For salvage, 11 patients received triple therapy of high dose fluconazole, amphotericin B and flucytosine, 20 received dual therapy of high dose fluconazole and flucytosine, 13 received monotherapy of high dose fluconazole. Median duration of high dose fluconazole in salvage regimens was 136.5 days (range, 1-667 days). Clinical response rates were 72.1% (31/43) and 83.7% (36/43) when assessed at 2 weeks and the end of salvage therapy, respectively. Adverse events possibly related to high dose fluconazole occurred in 54.5% (24/44) of the patients, and all were mild or moderate. From the initiation of salvage therapy, 1-year all-cause mortality was 13.6% (6 of 44 patients) among the study population with no significant difference in refractory or intolerant patients. CONCLUSIONS: Adherence to guideline recommendations of high dose fluconazole, alone or in combination with other antifungals, was safe and often effective for salvage therapy of HIV-uninfected CM patients.

Genetic influence of Toll-like receptors on non-HIV cryptococcal meningitis: An observational cohort study.

BACKGROUND: Cryptococcal meningitis (CM) is a significant source of mortality, the pathogenesis of which has not been fully understood, especially in non-HIV infected populations. We aimed to explore the potential genetic influence of Toll-like receptor (TLR) on non-HIV CM. METHODS: This observational cohort study was done in two stages: a discovery stage and a validation stage. A case-control genetic association study was conducted between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility went further validation in a second cohort of 583 subjects from a certain district. Associations among TLR SNPs, cerebrospinal fluid (CSF) cytokine concentrations, and clinical severity were explored in a third cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity. FINDINGS: In the discovery stage, eight TLR SNPs exhibited significant genetic susceptibility to non-HIV CM, one of which was validated in a population validation of HIV-infected cases while none survived in non-HIV cases. CSF cytokine detections showed that 18 cytokines were significantly over-expressed in severely ill patients. Two of the 8 SNPs (rs5743604 and rs3804099) were also significantly associated with disease severity. Specifically, the rs3804099 C/T genotype was further found to be correlated to 12 of the 18 up-regulated cytokines in severe patients. In addition, high levels of interleukin (IL)-10 in CSF (OR 2·97, 95% CI 1·49-5·90; p = 0·002) was suggested as an independent predictor for severity after adjusted for possible confounders. INTERPRETATION: TLR participates in both the occurrence and the pathogenesis of non-HIV CM. The in situ immune responses of CM were under genetic influence of TLR and contributed to disease severity. FUND: National Natural Science Foundation of China and National Key Basic Research Program of China (973 Program).

Entities of Chronic and Granulomatous Invasive Fungal Rhinosinusitis: Separate or Not?

BACKGROUND: Chronic and granulomatous invasive fungal rhinosinusitis are important causes of blindness and craniocerebral complications. However, the classification of these 2 diseases remains controversial. METHODS: We retrospectively analyzed patients with chronic and granulomatous invasive fungal rhinosinusitus in a Chinese tertiary hospital from 2009 to 2017, with a focus on classification and comparisons. RESULTS: Among 55 patients enrolled in our study, 11 (11/55, 20%) had granulomatous invasive fungal rhinosinusitis (GIFRS) and 44 (44/55, 80%) had chronic invasive fungal rhinosinusitis (CIFRS). Aspergillus fumigatus and Dematiaceous hyphomycetes were identified in 2 patients with GIFRS. Compared with granulomatous type, CIFRS was more frequently encountered in immunocompromised patients (P = .022), and the time from onset to diagnosis was much shorter (P = .001). Proptosis and orbital apex syndrome showed no significant difference between granulomatous and CIFRS in our study. The treatment options and prognosis of both diseases also showed no significant difference. CONCLUSIONS: Despite the consensus on histopathology, the classification of the chronic and granulomatous types may need further evaluation in clinical considerations.

Combing δ15N and δ18O to identify the distribution and the potential sources of nitrate in human-impacted watersheds, Shandong, China.

Identifying the anthropogenic and natural sources of nitrate emissions contributing to surface water continues to be an enormous challenge. It is necessary to control the water quality in the watershed impacted by human disturbance. In this study, water chemical parameters including nitrate (NO3 -) concentrations, δ15N-NO3 -, δ18O-NO3 -, and δ18O-H2O were analyzed to investigate the contamination and sources of NO3 - in two watershed rivers (Jinyun, JYN and Jinyang, JYA), Jinan, Shandong, China. Results indicated NO3 - concentrations in the JYN were significantly higher than those in the JYA (P < 0.05), probably because of high N input of the extensive farmlands or orchards in the drainage basin. δ15N-NO3 - and δ18O-NO3 -, associated with Cl-, indicated that nitrate-nitrogen (NO3 --N) was not derived from atmospheric deposition but came principally from manure/sewage and soil organic matter in these two watersheds. The microbial nitrification took place in the nitrate of manure/sewage and soil nitrate. The combination of NO3 - concentration and nitrogen and oxygen isotope suggested that NO3 - had undergone microbial denitrification after entering the rivers. Furthermore, NO3 - concentrations had significant temporal and spatial variation highlighting differential sources and fates. These results expand our understanding of mechanisms driving NO3 - retention and transport and provide strategies in managing NO3 - contamination in different land use watersheds around the world.

The Value of GPC3 and GP73 in Clinical Diagnosis of Hepatocellular Carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has increased over the past decades in China. Current screening methods of HCC such as detection of α-fetoprotein (AFP) combined with liver ultrasonography remain unsatisfactory. Many HCC patients have already missed the optimal treatment period when diagnosed. Our study aimed to evaluate the value of Glypican 3 (GPC3) and Golgi protein 73 (GP73) in the detection of HCC. METHODS: Thirty-nine patients with HCC and 31 patients with liver cirrhosis were enrolled. The level of serum GPC3 and GP73 were determined by ELISA. The expression of GPC3 mRNA and GP73 mRNA in peripheral blood mononuclear cell (PBMC) and liver tissues were also measured with qRT-PCR. Then, receiving operating characteristic (ROC) curves were plotted to detect the sensitivity and specificity of serum GPC3 and GP73 in the diagnosis of HCC. RESULTS: The levels of serum GPC3 and GP73 in the HCC group were significantly higher than in the cirrhosis group (p < 0.0001). Patients with GPC3 > 9.3 µg/L and GP73 > 77.68 ng/mL had a risk of HCC of 92.31%. The HCC diagnosis ROC curve analysis indicated that when setting the GPC3 cutoff value > 9.3 µg/L, AUC = 0.956. The sensitivity and specificity of GPC3 were 89.74% and 96.77%, respectively, with a positive predictive value of 97.2%, negative predictive value of 88.2%, + LR of 27.82 and - LR of 0.11. When setting GP73 cutoff value > 77.68 ng/mL, AUC = 0.937. The sensitivity and specificity of GP73 were 92.31% and 83.87%, respectively, with positive predictive value of 87.8%, negative predictive value of 89.7%, + LR of 5.72 and - LR of 0.092. No significant difference (p > 0.05) was found between GPC3 and GP73 AUC in ROC curves, indicating that these two biomarkers were equivalent in the prediction of HCC. CONCLUSIONS: The expression of serum GPC3 and GP73 was significantly higher in the HCC patients compared with the cirrhosis patients. GPC3 and GP73 might be effective non-invasive diagnostic indicators of HCC.