A novel inherited CARD9 deficiency in an otherwise healthy woman with CNS candidiasis.

Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.

DIMOND: DIffusion Model OptimizatioN with Deep Learning.

Diffusion magnetic resonance imaging is an important tool for mapping tissue microstructure and structural connectivity non-invasively in the in vivo human brain. Numerous diffusion signal models are proposed to quantify microstructural properties. Nonetheless, accurate estimation of model parameters is computationally expensive and impeded by image noise. Supervised deep learning-based estimation approaches exhibit efficiency and superior performance but require additional training data and may be not generalizable. A new DIffusion Model OptimizatioN framework using physics-informed and self-supervised Deep learning entitled "DIMOND" is proposed to address this problem. DIMOND employs a neural network to map input image data to model parameters and optimizes the network by minimizing the difference between the input acquired data and synthetic data generated via the diffusion model parametrized by network outputs. DIMOND produces accurate diffusion tensor imaging results and is generalizable across subjects and datasets. Moreover, DIMOND outperforms conventional methods for fitting sophisticated microstructural models including the kurtosis and NODDI model. Importantly, DIMOND reduces NODDI model fitting time from hours to minutes, or seconds by leveraging transfer learning. In summary, the self-supervised manner, high efficacy, and efficiency of DIMOND increase the practical feasibility and adoption of microstructure and connectivity mapping in clinical and neuroscientific applications.

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.

Prevalence and adverse perinatal outcomes of anaemia in the third trimester of pregnancy in Hebei Province, China.

BACKGROUND: Anaemia in pregnancy is one of the most frequent complications related to pregnancy and is a public health concern. This article examines the prevalence of anaemia in the third trimester of pregnancy and the associations between anaemia and adverse perinatal outcomes in Hebei Province, China. METHODS: We used SPSS software to describe the incidence of anaemia in the third trimester of pregnancy in Hebei Province and analysed the clinical characteristics in anaemic patients and the relationship between anaemia and adverse pregnancy outcomes. RESULTS: The overall prevalence of anaemia in the third trimester of pregnancy was 35.0% in Hebei Province. The prevalence of anaemia in the population with a high education level was lower than that in the population with a low education level. The incidence rate in rural areas was higher than that in urban areas. After adjustment for confounding factors, anaemia in the third trimester of pregnancy is an independent risk factor in terms of placenta previa, placental abruption, uterine atony, pre-eclampsia, gestational diabetes mellitus, heart disease, postpartum haemorrhage, premature birth, laceration of birth canal, puerperal infection, caesarean section and large for gestational age. CONCLUSIONS: The prevalence of anaemia in the third trimester of pregnancy is associated with an increased risk of adverse perinatal outcomes. A comprehensive approach to prevent anaemia is needed to improve maternal and child health outcomes.

Activation and Denitrosylation of Procaspase-3 in KA-induced Excitotoxicity.

BACKGROUND: It has been reported that activation of glutamate kainate receptor subunit 2 (GluK2) subunit-containing glutamate receptors and the following Fas ligand(FasL) up-regulation, caspase-3 activation, result in delayed apoptosis-like neuronal death in hippocampus CA1 subfield after cerebral ischemia and reperfusion. Nitric oxide-mediated S-nitrosylation might inhibit the procaspase activation, whereas denitrosylation might contribute to cleavage and activation of procaspases. OBJECTIVES: The study aimed to elucidate the molecular mechanisms underlying procaspase-3 denitrosylation and activation following kainic acid (KA)-induced excitotoxicity in rat hippocampus. METHODS: S-nitrosylation of procaspase-3 was detected by biotin-switch method. Activation of procaspase-3 was shown as cleavage of procaspase-3 detected by immunoblotting. FasL expression was detected by immunoblotting. Cresyl violets and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining were used to detect apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields. RESULTS: KA led to the activation of procaspase-3 in a dose- and time-dependent manner, and the activation was inhibited by KA receptor antagonist NS102. Procaspase-3 was denitrosylated at 3 h after kainic acid administration, and the denitrosylation was reversed by SNP and GSNO. FasL ASODNs inhibited the procaspase-3 denitrosylation and activation. Moreover, thioredoxin reductase (TrxR) inhibitor auranofin prevented the denitrosylation and activation of procaspase-3 in rat hippocampal CA1 and CA3 subfields. NS102, FasL AS-ODNs, and auranofin reversed the KAinduced apoptosis and cell death in hippocampal CA1 and CA3 subfields. CONCLUSIONS: KA led to denitrosylation and activation of procaspase-3 via FasL and TrxR. Inhibition of procaspase-3 denitrosylation by auranofin, SNP, and GSNO played protective effects against KA-induced apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields. These investigations revealed that the procaspase-3 undergoes an initial denitrosylation process before becoming activated, providing valuable insights into the underlying mechanisms and possible treatment of excitotoxicity.

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.

Preoperative computed tomography enterography-based radiomics signature: A potential predictor of postoperative anastomotic recurrence in patients with Crohn's disease.

BACKGROUND: More than half of patients with Crohn's disease (CD) require at least one surgery for symptom management; however, approximately half of the patients may experience postoperative anastomotic recurrence (PAR). OBJECTIVES: This study aims to develop and validate a preoperative computed tomography enterography (CTE)-based radiomics signature to predict early PAR in CD. DESIGN: A total of 186 patients with CD (training cohort, n = 134; test cohort, n = 52) who underwent preoperative CTE and surgery between January 2014 and June 2020 were included in this retrospective multi-centre study. METHODS: 106 radiomic features were initially extracted from intestinal lesions and peri-intestinal mesenteric fat, respectively; significant radiomic features were selected from them and then used to develop intestinal or mesenteric radiomics signatures, using the least absolute shrinkage and selection operator and a Cox regression model. A radiomics-based nomogram incorporating these signatures with clinical-radiological factors was created for comparison with a model based on clinical-radiological features alone. RESULTS: 68 of 134 patients in training cohort and 16 of 52 patients in test cohort suffered from PAR. The intestinal radiomic signature (hazard ratio [HR]: 2.17; 95% confidence interval [CI]: 1.32-3.58; P = 0.002) and mesenteric radiomic signature (HR: 2.19; 95% CI: 1.14-4.19; P = 0.018) were independent risk factors for PAR in the training cohort as per a multivariate analysis. The radiomics-based nomogram (C-index: 0.710; 95% CI: 0.672-0.748) yielded superior predictive performance than the clinical-radiological model (C-index, 0.607; 95% CI: 0.582-0.632) in the test cohort. Decision curve analysis demonstrated that the radiomics-based nomogram outperformed the clinical-radiological model in terms of clinical usefulness. CONCLUSIONS: Preoperative mesenteric and intestinal CTE radiomics signatures are potential non-invasive predictors of PAR in postoperative patients with CD.

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.

Neuroprotective effect of meglumine cyclic adenylate against ischemia/reperfusion injury via STAT3-Ser727 phosphorylation.

OBJECTIVES: Ischemia/reperfusion can induce neuronal apoptosis in the brain and lead to function deficits. The activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is neuroprotective against transient cerebral ischemia. The neuroprotective mechanisms of PKA mainly involve the regulation of gene transcription via the PKA/CREB pathway. The present study aims to investigate the neuroprotective effect of meglumine cyclic adenylate, an activator of PKA, under a rat model of global cerebral ischemia/reperfusion and to reveal the underlying mechanism involving signal transducer and activator of transcription 3 (STAT3)-Ser727 phosphorylation and mitochondrion modulation. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to 15 min global cerebral ischemia, and meglumine cyclic adenylate was treated through tail intravenous injection 30 min before ischemia. Cresyl violet staining was used to evaluate neuron injury at 5 d of reperfusion. Western blotting was used to detect p-Ser727-STAT3, total STAT3, cytochrome c (Cyt c) and active caspase-3 in the tissues of hippocampal CA1 region at 6 h of reperfusion. STAT3-S727A was overexpressed in HT22 cells to reveal the significance of STAT3-Ser727 phosphorylation in the neuroprotective effect of meglumine cyclic adenylate. RESULTS: Pretreatment with meglumine cyclic adenylate not only significantly ameliorated neuron loss in CA1 region after global cerebral ischemia but also enhanced STAT3-Ser727 phosphorylation, increased mitochondrial STAT3, and decreased cytosolic Cyt c and active caspase-3. Overexpression of STAT3-S727A in HT22 cells eliminated meglumine cyclic adenylate-induced increase of p-Ser727-STAT3, mitochondrial STAT3, cytosolic Cyt c and active caspase-3. CONCLUSION: Meglumine cyclic adenylate protects neurons against ischemia/reperfusion injury via promoting p-Ser727-STAT3-associated mitochondrion modulation and inhibiting apoptosis pathway.

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.

Evaluating breast ultrasound S-detect image analysis for small focal breast lesions.

Background: S-Detect is a computer-assisted, artificial intelligence-based system of image analysis that has been integrated into the software of ultrasound (US) equipment and has the capacity to independently differentiate between benign and malignant focal breast lesions. Since the revision and upgrade in both the breast imaging-reporting and data system (BI-RADS) US lexicon and the S-Detect software in 2013, evidence that supports improved accuracy and specificity of radiologists' assessment of breast lesions has accumulated. However, such assessment using S-Detect technology to distinguish malignant from breast lesions with a diameter no greater than 2 cm requires further investigation. Methods: The US images of focal breast lesions from 295 patients in our hospital from January 2019 to June 2022 were collected. The BI-RADS data were evaluated by the embedded program and as manually modified prior to the determination of a pathological diagnosis. The receiver operator characteristic (ROC) curves were constructed to compare the diagnostic accuracy between the assessments of the conventional US images, the S-Detect classification, and the combination of the two. Results: There were 326 lesions identified in 295 patients, of which pathological confirmation demonstrated that 239 were benign and 87 were malignant. The sensitivity, specificity, and accuracy of the conventional imaging group were 75.86%, 93.31%, and 88.65%. The sensitivity, specificity, and accuracy of the S-Detect classification group were 87.36%, 88.28%, and 88.04%, respectively. The assessment of the amended combination of S-Detect with US image analysis (Co-Detect group) was improved with a sensitivity, specificity, and accuracy of 90.80%, 94.56%, and 93.56%, respectively. The diagnostic accuracy of the conventional US group, the S-Detect group, and the Co-Detect group using area under curves was 0.85, 0.88 and 0.93, respectively. The Co-Detect group had a better diagnostic efficiency compared with the conventional US group (Z = 3.882, p = 0.0001) and the S-Detect group (Z = 3.861, p = 0.0001). There was no significant difference in distinguishing benign from malignant small breast lesions when comparing conventional US and S-Detect techniques. Conclusions: The addition of S-Detect technology to conventional US imaging provided a novel and feasible method to differentiate benign from malignant small breast nodules.

Secular increase in the prevalence of gestational diabetes and its associated adverse pregnancy outcomes from 2014 to 2021 in Hebei province, China.

Objective: We aimed to investigate the secular prevalence of gestational diabetes mellitus (GDM) and evaluate its adverse pregnancy outcomes among pregnant women in Hebei province, China. Methods: We analyzed the data from the monitoring information management system for pregnant women in 22 hospitals of Hebei province, China. In this study, 366,212 individuals with singleton live births from 2014 to 2021 were included, of whom 25,995 were diagnosed with gestational diabetes. We described the incidence of common complications and further analyzed the clinical characteristics in GDM patients and the relationship between GDM and adverse pregnancy outcomes. Results: The top 3 pregnancy complications in Hebei province are anemia, gestational hypertension, and GDM. The average incidence of GDM was 7.10% (25,995/366,212). The incidence rate of GDM significantly increased from 2014 to 2021 (χ2 trend = 7,140.663, P < 0.001). The top 3 regions with GDM incidence were Baoding (16.60%), Shijiazhuang (8.00%), and Tangshan (3.80%). The incidence of GDM in urban pregnant women (10.6%) is higher than that in rural areas (3.7%).The difference between the GDM and Non-GDM groups was statistically significant in terms of maternal age, gravidity, parity, education level, and incidence of pregnancy complications (gestational hypertension, heart diseases, and anemia) (P < 0.05). GDM individuals were at significantly increased risk of most assessed adverse pregnancy outcomes, including premature delivery, Cesarean delivery, uterine inertia, neonatal intensive care unit (NICU) admission, Apgar (activity-pulse-grimace-appearance-respiration) score at 1 min, and macrosomia (P < 0.05). The multivariate logistic regression analysis showed that GDM was an independent risk factor in terms of premature birth, Cesarean delivery, uterine inertia, placental abruption, NICU admission, and macrosomia. Conclusion: The risk of adverse pregnancy outcome in pregnant women with GDM is significantly increased. In order to reduce the occurrence of adverse pregnancy outcomes, effective interventions are needed.

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.

Deep Fungal Infections Among General Hospital Inpatients in Southwestern China: A 5-Year Retrospective Study.

Background: Deep fungal infection is a type of life-threatening opportunistic infection. Its incidence has been increasing in recent years. This infection can affect the prognosis of patients, prolong hospital stays and raise costs for patients and their families. Objective: We aimed to understand the current situation of deep fungal infections in the First Affiliated Hospital of Kunming Medical University and to provide a basis for the clinical diagnosis and treatment of deep fungal infections. Methods: This was a retrospective analysis of 528,743 cases in the hospital from 2015 to 2019, including the epidemiological characteristics, treatment and prognosis of deep fungal infections. Results: A total of 274 cases (0.05%) with deep fungal infections were identified, accounting for 0.05% of the total number of hospitalizations. The incidence of deep fungal infections in the hospital showed an increasing trend from 2015 to 2019. The most commonly infected site was the respiratory tract (93.07%). Among patients with deep fungal infections, 266 specimens were positive for fungal culture, by which 161 cultured Candida albicans (C. albicans), accounting for 60.53%, the main pathogen causing deep fungal infection. From 2015 to 2019, the percentage of C. albicans cases showed a downward trend, while that of non-C. albicans showed an opposite trend. Antibiotics were the most common predisposing factor for deep fungal infections (97.45%). Among the underlying diseases of patients with deep fungal infections, infectious diseases (59.49%) were the most common. Those with underlying diseases such as renal insufficiency and neurological diseases had a worse prognosis. Indwelling catheters, nervous system disease and tumors were risk factors for a poor prognosis. Conclusions: We report for the first time the epidemiological data of deep fungal infections in a general hospital in southwestern China from 2015 to 2019. In the past 5 years, the number of patients with deep fungal infections in the First Affiliated Hospital of Kunming Medical University has been increasing. Although the clinical data are limited, these results can provide references for the diagnosis and treatment of deep fungal infections.

High-fidelity fast volumetric brain MRI using synergistic wave-controlled aliasing in parallel imaging and a hybrid denoising generative adversarial network (HDnGAN).

PURPOSE: The goal of this study is to leverage an advanced fast imaging technique, wave-controlled aliasing in parallel imaging (Wave-CAIPI), and a generative adversarial network (GAN) for denoising to achieve accelerated high-quality high-signal-to-noise-ratio (SNR) volumetric magnetic resonance imaging (MRI). METHODS: Three-dimensional (3D) T2 -weighted fluid-attenuated inversion recovery (FLAIR) image data were acquired on 33 multiple sclerosis (MS) patients using a prototype Wave-CAIPI sequence (acceleration factor R = 3 × 2, 2.75 min) and a standard T2 -sampling perfection with application-optimized contrasts by using flip angle evolution (SPACE) FLAIR sequence (R = 2, 7.25 min). A hybrid denoising GAN entitled "HDnGAN" consisting of a 3D generator and a 2D discriminator was proposed to denoise highly accelerated Wave-CAIPI images. HDnGAN benefits from the improved image synthesis performance provided by the 3D generator and increased training samples from a limited number of patients for training the 2D discriminator. HDnGAN was trained and validated on data from 25 MS patients with the standard FLAIR images as the target and evaluated on data from eight MS patients not seen during training. HDnGAN was compared to other denoising methods including adaptive optimized nonlocal means (AONLM), block matching with 4D filtering (BM4D), modified U-Net (MU-Net), and 3D GAN in qualitative and quantitative analysis of output images using the mean squared error (MSE) and Visual Geometry Group (VGG) perceptual loss compared to standard FLAIR images, and a reader assessment by two neuroradiologists regarding sharpness, SNR, lesion conspicuity, and overall quality. Finally, the performance of these denoising methods was compared at higher noise levels using simulated data with added Rician noise. RESULTS: HDnGAN effectively denoised low-SNR Wave-CAIPI images with sharpness and rich textural details, which could be adjusted by controlling the contribution of the adversarial loss to the total loss when training the generator. Quantitatively, HDnGAN (λ = 10-3 ) achieved low MSE and the lowest VGG perceptual loss. The reader study showed that HDnGAN (λ = 10-3 ) significantly improved the SNR of Wave-CAIPI images (p < 0.001), outperformed AONLM (p = 0.015), BM4D (p < 0.001), MU-Net (p < 0.001), and 3D GAN (λ = 10-3 ) (p < 0.001) regarding image sharpness, and outperformed MU-Net (p < 0.001) and 3D GAN (λ = 10-3 ) (p = 0.001) regarding lesion conspicuity. The overall quality score of HDnGAN (λ = 10-3 ) (4.25 ± 0.43) was significantly higher than those from Wave-CAIPI (3.69 ± 0.46, p = 0.003), BM4D (3.50 ± 0.71, p = 0.001), MU-Net (3.25 ± 0.75, p < 0.001), and 3D GAN (λ = 10-3 ) (3.50 ± 0.50, p < 0.001), with no significant difference compared to standard FLAIR images (4.38 ± 0.48, p = 0.333). The advantages of HDnGAN over other methods were more obvious at higher noise levels. CONCLUSION: HDnGAN provides robust and feasible denoising while preserving rich textural detail in empirical volumetric MRI data. Our study using empirical patient data and systematic evaluation supports the use of HDnGAN in combination with modern fast imaging techniques such as Wave-CAIPI to achieve high-fidelity fast volumetric MRI and represents an important step to the clinical translation of GANs.

Factors associated with treatment response to CD19 CAR-T therapy among a large cohort of B cell acute lymphoblastic leukemia.

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has demonstrated striking responses among B cell acute lymphoblastic leukemia (B-ALL), but analyses of potential factors associated with poor response and relapse are lacking. Here, we summarize the long-term follow-up of 254 B-ALL treated with CD19 CAR-T cells from 5 clinical trials (NCT03173417, NCT02546739, and NCT03671460 retrospectively registered on May 23, 2017, March 1, 2018, and September 7, 2018, respectively, at www.clinicaltrials.gov ; ChiCTR-ONC-17012829, and ChiCTR1800016541 retrospectively registered on September 28, 2017, and June 7, 2018, at www.chictr.org.cn ). Our data showed that TP53 mutation, bone marrow blasts > 20%, prior CAR-T/blinatumomab treatment, and severe cytokine release syndrome (CRS) were associated with a lower complete remission (CR) rate while age, extramedullary disease, complex cytogenetics, history of prior transplant, prior courses of chemotherapy, CAR-T cell dose, and manufacturing source of the cellular product did not affect patients' CR rate. Risk factors related to leukemia-free survival (LFS) and overall survival (OS) were history of prior transplant, complex cytogenetics, TP53 mutation, severe CRS, neurotoxicity, and CAR-T therapy without consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Age and CAR-T cell dose did not influence LFS and OS. Patients with consolidative allo-HSCT after CAR-T therapy had a superior OS and LFS compared to those who did not. This benefit was also observed in both pediatric and adult patients as well as in patients either in high- or low-risk groups. This large study to identify risk factors of CR, LFS, and OS may help to maximize clinical outcomes of CAR-T therapy. Précis TP53 mutation and BM blasts > 20% are two independent factors associated with the CR rate. Patients with high tumor burden as well as those with bone marrow blasts < 5% can benefit from consolidative allo-HSCT post-CAR-T therapy.

[Review of Computer Modeling and Simulation of Spinal Thermal Ablation].

Thermal ablation surgery can effectively eliminate bone tumors in the spine and meanwhile reduce damage to the human body. To realize the computer modeling and simulation of spine thermal ablation surgery, it is necessary to ensure the accuracy of both spine modeling and simulation temperature. This review summarizes the research progress of this field and analyzes the prospects from two aspects: computer modeling based on spine segmentation from medical images and simulation calculation of temperature field in ablation surgery. The research on spine segmentation has made great progress, but there are still some problems that prevent it from being applied in clinical simulation. Related research has been trying to solve the problems. For the ablation surgery of the spine, some researchers have tried ablation simulation and obtained simulation results that are relatively consistent with the actual temperature value.

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.