Presence of Epstein-Barr virus in cerebrospinal fluid is associated with increased mortality in HIV-negative cryptococcal meningitis.

Cryptococcus neoformans is the most common cause of fungal meningitis and is associated with a high mortality. The clinical significance of concurrent Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM) remains unclear. A retrospective cohort study was performed by analyzing CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA in these patients by metagenomic next-generation sequencing (mNGS) and compared 10-week survival rates among those with and without EBV DNA in CSF. Of the 79 CSF samples tested, 44.3% (35/79) had detectable viral DNA in CSF, while 55.7% (44/79) were virus-negative. The most frequent viral pathogen was EBV, which was detected in 22.8% (18/79) patients. The median number of CSF-EBV DNA reads was 4 reads with a range from 1 to 149 reads. The 10-week mortality rates were 22.2% (4/18) in those with positive CSF-EBV and 2.3% (1/44) in those with negative CSF-virus (hazard ratio 8.20, 95% confidence interval [CI] 1.52-81.80; P = 0.014), which remained significant after a multivariate adjustment for the known risk factors of mortality (adjusted hazard ratio 8.15, 95% CI 1.14-92.87; P = 0.037). mNGS can identify viruses that coexist in CSF of HIV-negative patients with CM. EBV DNA is most commonly found together with C. neoformans in CSF and its presence is associated with increased mortality in HIV-negative CM patients.

We retrospectively analyzed CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA by mNGS and compared 10-week survival rates among those with and without EBV DNA. Positive CSF-EBV DNA is associated with the increased mortality in HIV-negative CM patients.

Rosmarinic acid ameliorates autoimmune responses through suppression of intracellular nucleic acid-mediated type I interferon expression.

Recognition of intracellular nucleic acids is a vital step for host to mount prompt immune responses against microbial pathogens. However, inappropriate response to self-nucleic acids leads to sustained type I interferon (IFN) production, which is implicated in the development of several autoimmune diseases, such as Aicardi-Goutières syndrome (AGS). Therefore, effective confinement of intracellular nucleic acid-induced IFN expression is a potential strategy for the treatment of such autoimmune diseases. In this study, we found that rosmarinic acid (RA), a natural compound isolated from rosemary, inhibits intracellular nucleic acid-stimulated IFN expression. Mechanistic investigation revealed that RA binds to both G3BP1 and cGAS, and impairs cGAS activation through disrupting the binding of DNA with cGAS. More importantly, we showed that RA could effectively attenuate the expression of IFN-stimulated genes (ISGs) in the well-established cell models for AGS. Thus, our study provides a promising compound for the treatment of autoimmune responses induced by aberrant nucleic acid-sensing.

The effect of serum uric acid, bilirubin, and albumin levels on antioxidant status in HIV-negative immunocompetent cryptococcal meningitis patients with post-infectious inflammatory response syndrome.

Oxidative imbalances have been observed in various neurological diseases. Despite the microbiological control in cryptococcal meningitis (CM), a proportion of previously healthy patients experience a clinical deterioration known as post-infectious inflammatory response syndrome (PIIRS). However, the antioxidant status in PIIRS remains unclear. In this study, we found that the serum antioxidant status of HIV-negative immunocompetent CM patients during PIIRS episodes was lower than that of healthy controls. There was a relationship between baseline serum indirect bilirubin levels and the development of PIIRS, and serum uric acid levels may indicate the severity of the disease during PIIRS episodes. Oxidative stress may play a role in the development of PIIRS.

This retrospective study on the serum antioxidant status in HIV-negative immunocompetent CM patients suggested that during PIIRS episodes, the serum antioxidant status in CM patients may be lower. CM patients with high baseline serum Ibil levels were more likely to develop PIIRS.

Clinical characteristics, treatment, and outcome of low-risk non-HIV-associated cryptococcal meningitis: A retrospective cohort study.

Although non-human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is a severe disease, there are still some non-HIV CM patients with a low risk of therapeutic failure. Recognizing clinical characteristics of low-risk non-HIV-associated CM may enable clinicians to treat non-HIV-associated CM more reasonably. According to the definition of low-risk non-HIV-associated CM in the 2010 Infectious Diseases Society of America guideline, a total of 220 non-HIV CM patients were divided into two groups (Group 1: 35 low-risk patients and Group 2: 185 non-low-risk patients). Clinical characteristics, treatment, and outcome were compared between the two groups. Compared with non-low-risk patients, low-risk patients had a lower rate of headache (82.9% vs. 95.7%, P = .012), cerebrospinal fluid (CSF) opening pressure (OP) at baseline (CSF OP < 250-mm H2O, 60.0% vs. 32.4%, P = .001), and baseline CSF cryptococcal count (median, 0 vs. 2376, P < .001), higher baseline CSF white blood cell (median, 130 vs. 90, P = .029) and CSF protein (median, 0.87 vs. 0.73, P = .011). Multivariate analysis showed that baseline CSF OP <250-mm H2O (OR: 2.545, 95% CI 1.168, 5.545, P = .019) was independently associated with low-risk for non-HIV-associated CM. The lengths of AMB-d-based induction therapy of low-risk patients (median, 20 days) were shorter (P < .001) than that of non-low-risk patients (median, 38 days). The successful outcome rate of low-risk patients was higher than non-low-risk patients (97.1% vs. 54.6%, P < .001). We demonstrated that non-HIV-associated CM patients with baseline CSF OP < 250-mm H2O were prone to the low-risk status.

This was a retrospective cohort study to find the features of low-risk non-human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM). We found that non-HIV-associated CM patients with baseline cerebrospinal fluid opening pressure <250-mm H2O were prone to low-risk status.

Exploring Shared Genetic Signatures of Alzheimer's Disease and Multiple Sclerosis: A Bioinformatic Analysis Study.

INTRODUCTION: Many clinical studies reported the coexistence of Alzheimer's disease (AD) and multiple sclerosis (MS), but the common molecular signature between AD and MS remains elusive. The purpose of our study was to explore the genetic linkage between AD and MS through bioinformatic analysis, providing new insights into the shared signatures and possible pathogenesis of two diseases. METHODS: The common differentially expressed genes (DEGs) were determined between AD and MS from datasets obtained from Gene Expression Omnibus (GEO) database. Further, functional and pathway enrichment analysis, protein-protein interaction network construction, and identification of hub genes were carried out. The expression level of hub genes was validated in two other external AD and MS datasets. Transcription factor (TF)-gene interactions and gene-miRNA interactions were performed in NetworkAnalyst. Finally, receiver operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of hub genes. RESULTS: A total of 75 common DEGs were identified between AD and MS. Functional and pathway enrichment analysis emphasized the importance of exocytosis and synaptic vesicle cycle, respectively. Six significant hub genes, including CCL2, CD44, GFAP, NEFM, STXBP1, and TCEAL6, were identified and verified as common hub genes shared by AD and MS. FOXC1 and hsa-mir-16-5p are the most common TF and miRNA in regulating hub genes, respectively. In the ROC curve analysis, all hub genes showed good efficiency in helping distinguish patients from controls. CONCLUSION: Our study first identified a common genetic signature between AD and MS, paving the road for investigating shared mechanism of AD and MS.

Seasonality and meteorological factors of HIV-negative cryptococcal meningitis in Guangdong Province, China.

OBJECTIVE: Information about the seasonal characteristics of human immunodeficiency virus (HIV)-negative cryptococcal meningitis (CM) is quite limited. The aim of this study was to explore the seasonality and meteorological factors of HIV-negative patients with CM. METHODS: We performed a retrospective study of 469 HIV-negative CM patients admitted to the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. Their initial onset symptoms of CM occurred from January 2011 to December 2020. The temperature, precipitation, sunlight, humidity and wind speed for the corresponding period and the associated topographic, ecological type and soil type parameters data were collected. The Poisson regression model was used to determine the meteorological factors associated with CM onset. The geographical detector method was used to detect other environmental factors associated with CM onset. RESULTS: CM onset did not showed a seasonal fluctuation, but was strongly associated with mean temperature (ß = .010, p = .028) and mean relative humidity (ß = -.011, p = .006). In the rainy season, only mean wind speed remained significantly associated with CM onset (ß = -.108, p = .041). In the dry season, mean temperature (ß = .014, p = .016), mean relative humidity (ß = -.016, p = .006) and hours of sunlight (ß = -.002, p = .016) were significantly associated with CM onset. Topographic, ecological type and soil type factors did not add explanatory power. CONCLUSIONS: Our findings add the knowledge about the environmental factors of HIV-negative CM. Meteorological factors, especially temperature and humidity, may be the main environmental factors affecting the onset of HIV-negative CM.

Protein Condensate Formation via Controlled Multimerization of Intrinsically Disordered Sequences.

Many proteins harboring low complexity or intrinsically disordered sequences (IDRs) are capable of undergoing liquid-liquid phase separation to form mesoscale condensates that function as biochemical niches with the ability to concentrate or sequester macromolecules and regulate cellular activity. Engineered disordered proteins have been used to generate programmable synthetic membraneless organelles in cells. Phase separation is governed by the strength of interactions among polypeptides with multivalency enhancing phase separation at lower concentrations. Previously, we and others demonstrated enzymatic control of IDR valency from multivalent precursors to dissolve condensed phases. Here, we develop noncovalent strategies to multimerize an individual IDR, the RGG domain of LAF-1, using protein interaction domains to regulate condensate formation in vitro and in living cells. First, we characterize modular dimerization of RGG domains at either terminus using cognate high-affinity coiled-coil pairs to form stable condensates in vitro. Second, we demonstrate temporal control over phase separation of RGG domains fused to FRB and FKBP in the presence of dimerizer. Further, using a photocaged dimerizer, we achieve optically induced condensation both in cell-sized emulsions and within live cells. Collectively, these modular tools allow multiple strategies to promote phase separation of a common core IDR for tunable control of condensate assembly.

Evolutionary history of carabid ground beetles with special reference to morphological variations of the hind-wings.

Most beetles belonging to the subfamily Carabinae of the family Carabidae (so-called carabid ground beetles) cannot fly, because their hind-wings are highly degenerated. However, about half of the species in the subtribe Calosomina within the same subfamily can fly. From extensive morphological examinations of the hind-wings of Carabinae species in conjunction with DNA molecular phylogenetic trees, the process and possible causes of hind-wing degeneration in the Carabinae are discussed.

Ceramide-Fabricated Co-Loaded Liposomes for the Synergistic Treatment of Hepatocellular Carcinoma.

Combination therapy is one of the important methods to improve therapeutic effect on the treatment of hepatocellular carcinoma (HCC). Sorafenib (SF) is a canonical US Food and Drug Administration-approved multikinase molecule inhibitor against HCC. However, therapeutic benefit with Sorafenib alone was usually unsatisfactory. Ceramide (CE) is an endogenous bioactive sphingolipid, which has a strong potential to suppress various tumors. The combination of SF and CE was hoping to exert maximum synergistic antitumor effect through different tumor-suppressible mechanisms. In this respect, SF and CE co-loaded liposomes (SF/CE-liposomes) were developed to verify synergistic antitumor efficacy. The optimal molar ratio of SF and CE was determined through combination index. SF/CE-liposomes were prepared by thin-film hydration method, which exhibited spherical or ellipsoidal shape. Particle size of SF/CE-liposomes was 174 ± 4 nm with homogeneous distribution. Release profile of SF demonstrated that addition of CE imposed no significant impact on the release of SF. SF/CE-liposomes exhibited acceptable stability in different media and desirable storage stability over 30 days at 4°C. In vitro cellular uptake confirmed that SF/CE-liposomes could be efficiently internalized into HepG2 cells. In vitro cytotoxicity evaluation indicated that SF/CE-liposomes exhibited higher cytotoxicity on HepG2 cells. IC50 value of SF/CE-liposomes was 11.5 ± 0.44 µM, which was significantly lower than that of SF-liposomes (**p < 0.01). Evaluation of in vivo synergistic effect on H22-bearing mice verified that SF/CE-liposomes achieved robust antitumor activity in preventing tumor growth. All results suggested that SF/CE-liposomes might be served as an efficient co-delivery system for improving therapeutic efficacy of HCC.

Genome-wide sequence data suggest the possibility of pollinator sharing by host shift in dioecious figs (Moraceae, Ficus).

The obligate mutualism of figs and fig-pollinating wasps has been one of the classic models used for testing theories of co-evolution and cospeciation due to the high species-specificity of these relationships. To investigate the species-specificity between figs and fig pollinators and to further understand the speciation process in obligate mutualisms, we examined the genetic differentiation and phylogenetic relationships of four closely related fig-pollinating wasp species (Blastophaga nipponica, Blastophaga taiwanensis, Blastophaga tannoensis and Blastophaga yeni) in Japan and Taiwan using genome-wide sequence data, including mitochondrial DNA sequences. In addition, population structure was analysed for the fig wasps and their host species using microsatellite data. The results suggest that the three Taiwanese fig wasp species are a single panmictic population that pollinates three dioecious fig species, which are sympatrically distributed, have large differences in morphology and ecology and are also genetically differentiated. Our results illustrate the first case of pollinator sharing by host shift in the subgenus Ficus. On the other hand, there are strict genetic codivergences between allopatric populations of the two host-pollinator pairs. The possible processes that produce these pollinator-sharing events are discussed based on the level and pattern of genetic differentiation in these figs and fig wasps.

Silent evolution.

Phylogenetic analyses using mitochondrial DNA sequences of several kinds of beetles have shown that their evolution included a silent stage in which no morphological changes took place. We thus propose a new category of evolutionary process called "silent evolution".

Relationship between tyrosine phosphorylation and protein expression of insulin receptor and insulin resistance in gestational diabetes mellitus.

The relationship between tyrosine phosphorylation (TP) and protein expression of insulin receptor (InsR) and insulin resistance (IR) in patients with gestational diabetes mellitus (GDM) was investigated. The InsR expression and TP in skeleton muscle tissue were determined by Western blotting and immunoprecipitation in women with GDM (GDM group, n=22), normal pregnant women (normal pregnancy group, n=22) and normal non-pregnant women (normal non-pregnant group, n=13). Fasting plasma glucose (FPG) and fasting insulin (FINS) were measured by oxidase assay and immunoradioassay. The results showed that the levels of FPG (5.61±0.78 mmol/L), FINS (15.42±5.13 mU/L) and Homeostasis model assessment-IR (HOMA-IR) (1.21±0.52) in GDM group were significantly higher than those in normal pregnancy group (4.43±0.46 mmol/L, 10.56±3.07 mU/L and 0.80±0.31 respectively) (P<0.01). The levels of FINS and HOMA-IR in normal pregnancy group were significantly higher than those in normal non-pregnant group (7.56±2.31 mU/L and 0.47±0.26 respectively) (P<0.01). There was no significant difference in the InsR expression level among the three groups (P>0.05). TP of InsR with insulin stimulation was significantly decreased in GDM group (0.20±0.05) as compared with normal pregnancy group (0.26±0.06) (P<0.01). TP of InsR with insulin stimulation in normal pregnancy group was lower than that in normal non-pregnant group (0.31±0.06) (P<0.01). TP of InsR with insulin stimulation was negatively related with HOMA-IR in GDM group (r=-0.525, P<0.01). There was no correlation between the protein expression of InsR and HOMA-IR in GDM group (r=-0.236, P>0.05). It was suggested that there is no significant correlation between the protein expression of InsR in skeletal muscle and IR in GDM, but changes in TP of InsR are associated with IR in GDM.

Analysis of the relationship between drug susceptibility of Cryptococcus neoformans isolates and mortality in HIV-negative cryptococcal meningitis.

OBJECTIVES: The relationship between antifungal susceptibility and mortality of cryptococcal meningitis (CM) in HIV-negative patients is poorly understood. METHODS: We conducted a retrospective analysis of 1-year follow-up of 200 HIV-negative CM patients with an initial cerebrospinal fluid (CSF) culture for Cryptococcus neoformans. According to the cut-off values of minimum inhibitory concentration (MIC), two groups of five antifungal agents were classified: amphotericin B (AmB), ≤0.5 µg/mL, >0.5 µg/mL; 5-flucytosine (5-FC), ≤4 µg/mL, >4 µg/mL; fluconazole (FLU), ≤4 µg/mL, >4 µg/mL; itraconazole (ITR), ≤0.125 µg/mL, >0.125 µg/mL; and voriconazole (VOR), <0.25 µg/mL, ≥0.25 µg/mL. Comparisons were performed to analyse clinical features, laboratory, modified Rankin Scale (mRS) scores, and CSF findings under different prognosis outcomes in 1-year. RESULTS: All of Cryptococcus neoformans isolates were sensitive to AmB and VOR, most of them were sensitive to 5-FC and FLU (95.5% and 90.5%, respectively) while only 55.0% of them were susceptible to ITR. Minimum inhibitory concentrations of ITR and VOR were significantly related to baseline mRS scores. All-cause mortality was not significantly related to MICs in Cryptococcus neoformans strains. The combination of actual antifungal agents and two groups of the MICs values for antifungal agents had no significant effects on all-cause mortality. CONCLUSION: Most Cryptococcus neoformans isolates were sensitive to AmB, VOR, 5-FC, and FLU. Because of the small number of deaths, we are not able to comment on whether MIC is associated with mortality of CM in HIV-negative patients.

The discrimination between autoimmune glial fibrillary acidic protein astrocytopathy and tuberculous meningitis.

OBJECTIVE: The differential diagnosis between autoimmune glial fibrillary acidic protein astrocytopathy (AGFAPA) mimicking tuberculous meningitis and tuberculous meningitis (TBM) remains challenging in clinical practice. This study aims to identify the clinical, laboratory parameters, and clinical score systems that may be helpful in differentiating AGFAPA from TBM. METHOD: Overall 22 AGFAPA patients who were initially misdiagnosed as TBM (AGFAPA-TBM) and 30 confirmed TBM patients were included. The clinical, laboratory, imaging parameters, Thwaites systems, and Lancet consensus scoring systems (LCSS) of all patients were reviewed. Logistic regression was employed to establish a diagnostic formula to differentiate AGFAPA-TBM from TBM. The receiver operating characteristic (ROC) curve was applied to determine the best diagnostic critical point of the formula. RESULTS: Urinary retention was more frequent in AGFAPA-TBM patients (72.7% vs 33.3%, p = 0.012). A significantly lower ratio of T-SPOT. TB was noted in AGFAPA-TBM patients (9.1% vs 82.1%, p < 0.001). We found the LCSS was able to differentiate AGFAPA-TBM from TBM (AUC value 0.918, 95% CI=0.897-0.924). Furthermore, we set up a new scoring system with three variables: urinary retention, T-SPOT. TB, and cerebral imaging criteria in LCSS. The proposed diagnostic score ranges from -8 to 2, and a score of ≥ 0 was suggestive of AGFAPA-TBM (AUC value 0.938, 95% CI=0.878-0.951). CONCLUSIONS: This study is the first to evaluate the Thwaites system and LCSS in AGFAPA-TBM and TBM. We provide an alternative diagnostic formula to differentiate AGFAPA-TBM from TBM and suggest testing for GFAP antibodies to avoid misdiagnosis when this scoring system meets AGFAPA-TBM.

Deficiency of Trex1 leads to spontaneous development of type 1 diabetes.

BACKGROUND: Type 1 diabetes is believed to be an autoimmune condition, characterized by destruction of insulin-producing cells, due to the detrimental inflammation in pancreas. Growing evidences have indicated the important role of type I interferon in the development of type 1 diabetes. METHODS: Trex1-deficient rats were generated by using CRISPR-Cas9. The fasting blood glucose level of rat was measured by a Roche Accuchek blood glucose monitor. The levels of insulin, islet autoantibodies, and interferon-ß were measured using enzyme-linked immunosorbent assay. The inflammatory genes were detected by quantitative PCR and RNA-seq. Hematein-eosin staining was used to detect the pathological changes in pancreas, eye and kidney. The pathological features of kidney were also detected by Masson trichrome and periodic acid-Schiff staining. The distribution of islet cells, immune cells or ssDNA in pancreas was analyzed by immunofluorescent staining. RESULTS: In this study, we established a Trex1-deletion Sprague Dawley rat model, and unexpectedly, we found that the Trex1-/- rats spontaneously develop type 1 diabetes. Similar to human diabetes, the hyperglycemia in rats is accompanied by diabetic complications such as diabetic nephropathy and cataract. Mechanistical investigation revealed the accumulation of ssDNA and the excessive production of proinflammatory cytokines, including IFN-ß, in Trex1 null pancreas. These are likely contributing to the inflammation in pancreas and eventually leading to the decline of pancreatic ß cells. CONCLUSIONS: Our study links the DNA-induced chronic inflammation to the pathogenesis of type 1 diabetes, and also provides an animal model for type 1 diabetes studies.

Molecular phylogenetic analyses support the monophyly of Hexapoda and suggest the paraphyly of Entognatha.

BACKGROUND: Molecular phylogenetic analyses have revealed that Hexapoda and Crustacea form a common clade (the Pancrustacea), which is now widely accepted among zoologists; however, the origin of Hexapoda remains unresolved. The main problems are the unclear relationships among the basal hexapod lineages, Protura (proturans), Collembola (springtails), Diplura (diplurans), and Ectognatha (bristletails, silverfishes, and all winged insects). Mitogenomic analyses have challenged hexapod monophyly and suggested the reciprocal paraphyly of Hexapoda and Crustacea, whereas studies based on nuclear molecular data support the monophyletic origin of hexapods. Additionally, there are significant discrepancies with respect to these issues between the results of morphological and molecular studies. To investigate these problems, we performed phylogenetic analyses of Pancrustacea based on the protein sequences of three orthologous nuclear genes encoding the catalytic subunit of DNA polymerase delta and the largest and second largest subunits of RNA polymerase II from 64 species of arthropods, including representatives of all hexapod orders. RESULTS: Phylogenetic analyses were conducted based on the inferred amino acid (aa) sequences (~3400 aa in total) of the three genes using the maximum likelihood (ML) method and Bayesian inference. Analyses were also performed with additional datasets generated by excluding long-branch taxa or by using different outgroups. These analyses all yielded essentially the same results. All hexapods were clustered into a common clade, with Branchiopoda as its sister lineage, whereas Crustacea was paraphyletic. Within Hexapoda, the lineages Ectognatha, Palaeoptera, Neoptera, Polyneoptera, and Holometabola were each confirmed to be monophyletic with robust support, but monophyly was not supported for Entognatha (Protura + Collembola + Diplura), Ellipura (Protura + Collembola), or Nonoculata (Protura + Diplura). Instead, our results showed that Protura is the sister lineage to all other hexapods and that Diplura or Diplura + Collembola is closely related to Ectognatha. CONCLUSION: This is the first study to include all hexapod orders in a phylogenetic analysis using multiple nuclear protein-coding genes to investigate the phylogeny of Hexapoda, with an emphasis on Entognatha. The results strongly support the monophyletic origin of hexapods but reject the monophyly of Entognatha, Ellipura, and Nonoculata. Our results provided the first molecular evidence in support of Protura as the sister group to other hexapods. These findings are expected to provide additional insights into the origin of hexapods and the processes involved in the adaptation of insects to life on land.

Neurological worsening during treatment of HIV-negative cryptococcal meningitis in a patient with Evans syndrome.

A 49-year-old woman with a rare autoimmune hematological disease, Evans syndrome, was admitted to the authors' hospital with immune reconstitution inflammatory syndrome-like reconstitution syndrome after effective antifungal therapy for cryptococcal meningitis. She initially improved after receiving corticosteroid treatment; after prednisone was tapered, her clinical presentation and brain imaging deteriorated but finally improved with the addition of thalidomide. Immune reconstitution inflammatory syndrome-like reconstitution syndrome is a rare complication in cryptococcal meningitis patients receiving immunosuppressive therapy. Thalidomide can be given in addition to corticosteroid therapy to effectively control the paradoxical inflammatory response and improve clinical outcomes.

Failure of Early Mycological Clearance in HIV-Negative Cryptococcal Meningitis.

Background: Negative cerebrospinal fluid (CSF) cultures at 2 weeks after antifungal treatment (early mycological clearance [EMC]) should be a treatment goal of cryptococcal meningitis (CM). However, EMC in human immunodeficiency virus (HIV)-negative patients with CM is poorly understood. Methods: We conducted a retrospective review of medical records and 1-year follow-up of 141 HIV-negative patients with CM with an initial positive CSF culture for Cryptococcus neoformans. Multivariate logistic regression was performed to analyze clinical features and laboratory and CSF findings of patients with CM with different EMC statuses. Random forest models were used to predict failure of EMC. All-cause mortality and clinical functional status were analyzed. Results: Of 141 patients, 28 (19.9%) had EMC failure. The 1-year mortality rate was 5.7% (8/141). Multivariate analysis showed that non-amphotericin B (AmB)-based regimens, baseline log10 Cryptococcus count/mL, baseline CSF opening pressure (CSF-OP) >30 cm H2O, and baseline serum creatinine were significantly associated with EMC failure. A parsimonious predictive rule given by the decision tree identified patients with CM with non-AmB-based therapy and baseline CSF-OP >30 cm H2O as being at high risk of EMC failure. Incidence of all-cause mortality, the follow-up modified Rankin Scale, and Karnofsky performance status scores were not significantly related to EMC. Conclusions: EMC failure in HIV-negative CM is attributed to non-AmB-based therapy and is associated with log10 Cryptococcus count/mL and CSF-OP >30 cm H2O at baseline. Because of the small number of deaths, we are not able to comment on whether or not EMC is associated with mortality.

Reversible deafness and blindness in Cryptococcus gattii meningitis with a ventriculoperitoneal shunt: A case report and literature review.

Cryptococcus gattii (C. gattii) has been considered a leading cause of meningitis in immunocompetent hosts in tropical and subtropical regions. Visual loss is common but hearing impairment is relatively infrequent in C. gattii meningitis. Notably, there have been limited studies on the etiology, and especially therapy of auditory and ocular complications associated with C. gattii meningitis. Here we report a case of reversible deafness and blindness treated with a ventriculoperitoneal shunt (VPS) surgery in C. gattii meningitis. This case indicated that elevated intracranial pressure (ICP) may play a role in the concurrent hearing and vision impairments associated with C. gattii meningitis and the early VPS surgery after the initiation of the antifungal therapy may effectively improve both hearing and vision in this condition.

Central nervous system nocardiosis diagnosed by metagenomic next-generation sequencing: A case series and literature review.

BACKGROUND: Central nervous system (CNS) nocardiosis is a rare suppurative disease caused by the genus Nocardia. It is found most frequently in immunocompromised individuals. OBJECTIVES: In this study, we retrospectively reviewed the clinical presentations, laboratory examination, therapy and outcomes of 9 patients with CNS nocardiosis diagnosed using metagenomic next-generation sequencing (mNGS) in our hospital. MATERIAL AND METHODS: We reviewed 9 patients with confirmed diagnosis of CNS Nocardia infection from January 2017 to December 2021 in the Department of Neurology at The Third Affiliated Hospital, Sun Yat-sen University (Guangzhou, China). In addition, we searched literature related to CNS Nocardia infection on PubMed and included all case reports with proven CNS nocardiosis since 2016. RESULTS: The metagenomic next-generation sequencing (mNGS) of CSF can be used for the rapid diagnosis of nocardiosis in CNS and N. farcinica are the most commonly isolated species. Underlying autoimmune diseases, immunosuppressive agents including corticosteroids and organ transplantation are predisposing factors of developing CNS nocardiosis. Single or multiple hyper-enhanced ring lesions indicative of cerebral abscesses are commonly presented in brain imaging. Trimethoprim-sulfamethoxazole (TMP-SMX) is used as the primary agent for the antibacterial therapy and in combination with other antibacterial agents. CONCLUSION: Our study demonstrated that mNGS of CSF can be conducted for definitive and rapid diagnosis for CNS nocardiosis.