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.

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.

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.

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.

[Free trajectory cone beam computed tomography reconstruction method for synchronous scanning of geometric calibration phantom and imaging object].

In order to suppress the geometrical artifacts caused by random jitter in ray source scanning, and to achieve flexible ray source scanning trajectory and meet the requirements of task-driven scanning imaging, a method of free trajectory cone-beam computed tomography (CBCT) reconstruction is proposed in this paper. This method proposed a geometric calibration method of two-dimensional plane. Based on this method, the geometric calibration phantom and the imaging object could be simultaneously imaged. Then, the geometric parameters could be obtained by online calibration method, and then combined with the geometric parameters, the alternating direction multiplier method (ADMM) was used for image iterative reconstruction. Experimental results showed that this method obtained high quality reconstruction image with high contrast and clear feature edge. The root mean square errors (RMSE) of the simulation results were rather small, and the structural similarity (SSIM) values were all above 0.99. The experimental results showed that it had lower image information entropy (IE) and higher contrast noise ratio (CNR). This method provides some practical value for CBCT to realize trajectory freedom and obtain high quality reconstructed image.

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.

Postoperative glioma segmentation in CT image using deep feature fusion model guided by multi-sequence MRIs.

OBJECTIVES: Computed tomography (CT) and magnetic resonance imaging (MRI) are the most commonly selected methods for imaging gliomas. Clinically, radiotherapists always delineate the CT glioma region with reference to multi-modal MR image information. On this basis, we develop a deep feature fusion model (DFFM) guided by multi-sequence MRIs for postoperative glioma segmentation in CT images. METHODS: DFFM is a multi-sequence MRI-guided convolutional neural network (CNN) that iteratively learns the deep features from CT images and multi-sequence MR images simultaneously by utilizing a multi-channel CNN architecture, and then combines these two deep features together to produce the segmentation result. The whole network is optimized together via a standard back-propagation. A total of 59 CT and MRI datasets (T1/T2-weighted FLAIR, T1-weighted contrast-enhanced, T2-weighted) of postoperative gliomas as tumor grade II (n = 24), grade III (n = 18), or grade IV (n = 17) were included. Dice coefficient (DSC), precision, and recall were used to measure the overlap between automated segmentation results and manual segmentation. The Wilcoxon signed-rank test was used for statistical analysis. RESULTS: DFFM showed a significantly (p < 0.01) higher DSC of 0.836 than U-Net trained by single CT images and U-Net trained by stacking the CT and multi-sequence MR images, which yielded 0.713 DSC and 0.818 DSC, respectively. The precision values showed similar behavior as DSC. Moreover, DSC and precision values have no significant statistical difference (p > 0.01) with difference grades. CONCLUSIONS: DFFM enables the accurate automated segmentation of CT postoperative gliomas of profit guided by multi-sequence MR images and may thus improve and facilitate radiotherapy planning. KEY POINTS: • A fully automated deep learning method was developed to segment postoperative gliomas on CT images guided by multi-sequence MRIs. • CT and multi-sequence MR image integration allows for improvements in deep learning postoperative glioma segmentation method. • This deep feature fusion model produces reliable segmentation results and could be useful in delineating GTV in postoperative glioma radiotherapy planning.

Digital breast tomosynthesis versus digital mammography: integration of image modalities enhances deep learning-based breast mass classification.

OBJECTIVE: To evaluate the impact of utilizing digital breast tomosynthesis (DBT) or/and full-field digital mammography (FFDM), and different transfer learning strategies on deep convolutional neural network (DCNN)-based mass classification for breast cancer. METHODS: We retrospectively collected 441 patients with both DBT and FFDM on which regions of interest (ROIs) covering the malignant, benign and normal tissues were extracted for DCNN training and validation. Experiments were conducted for tasks in distinguishing malignant/benign/normal: (1) classification capabilities of DBT vs FFDM and the role of transfer learning were validated on 2D-DCNN; (2) different strategies of combining DBT and FFDM and the associated impacts on classification were explored; (3) 2D-DCNN and 3D-DCNN trained from scratch with volumetric DBT were compared. RESULTS: 2D-DCNN with transfer learning outperformed that without for DBT in distinguishing malignant (ΔAUC = 0.059 ± 0.009, p < 0.001), benign (ΔAUC = 0.095 ± 0.010, p < 0.001) and normal tissue (ΔAUC = 0.042 ± 0.004, p < 0.001) (paired samples t test). 2D-DCNN trained on DBT (with transfer learning) achieved higher accuracy than those on FFDM (malignant: ΔAUC = 0.014 ± 0.014, p = 0.037; benign: ΔAUC = 0.031 ± 0.006, p < 0.001; normal: ΔAUC = 0.017 ± 0.004, p < 0.001) (independent samples t test). The 2D-DCNN employing both DBT and FFDM for training achieved better performances in benign (FFDM: ΔAUC = 0.010 ± 0.008, p < 0.001; DBT: ΔAUC = 0.009 ± 0.005, p < 0.001) and normal (FFDM: ΔAUC = 0.005 ± 0.003, p < 0.001; DBT: ΔAUC = 0.002 ± 0.002, p < 0.001) (related samples Friedman test). The 3D-DCNN and 2D-DCNN trained from scratch with DBT only produced moderate classification. CONCLUSIONS: Transfer learning facilitates mass classification for both DBT and FFDM, and DBT outperforms FFDM when equipped with transfer learning. Integrating DBT and FFDM in DCNN training enhances mass classification accuracy for breast cancer. KEY POINTS: • Transfer learning facilitates mass classification for both DBT and FFDM, and the DBT-based DCNN outperforms the FFDM-based DCNN when equipped with transfer learning. • Integrating DBT and FFDM in DCNN training enhances breast mass classification accuracy. • 3D-DCNN/2D-DCNN trained from scratch with volumetric DBT but without transfer learning only produce moderate mass classification result.

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.

The Canadian Dermatology Association's Top Five Choosing Wisely Canada Recommendations.

INTRODUCTION: In this article, we present the Canadian Dermatology Association's (CDA) Choosing Wisely Canada (CWC) list of top "Five Things Physicians and Patients Should Question in Dermatology" and the evidence in support of each recommendation. METHODS: Using a nominal technique, the CDA Working Group and Task Force generated an initial list based on literature review and expert consultation. After several rounds of list refinement via a modified Delphi process, a final list of recommendations was generated. These were approved by the CDA Board of Directors, presented at the CDA 93rd Annual Conference in 2018, and published by CWC in 2019. RESULTS: The top five recommendations are as follows: (1) Don't routinely prescribe antibiotics for bilateral lower leg redness and swelling; (2) Don't routinely prescribe topical combination corticosteroid/antifungal products; (3) Don't routinely use topical antibiotics on a surgical wound; (4) Don't prescribe systemic antifungals without mycological confirmation of dermatophyte infection; and (5) Don't use oral antibiotics for acne vulgaris for more than 3 months without assessing efficacy. DISCUSSION: This list of recommendations aims to encourage both physicians and patients to reevaluate ineffective, yet common, practices in treating dermatologic conditions. These recommendations represent actionable changes in practice, and therefore have considerable potential to enhance value-based care in dermatology. CONCLUSIONS: This list was developed to identify tangible changes in practice within dermatology that may reduce inefficiencies, prevent potential patient harm, and improve care. Future advocacy work may include updates, feedback obtainment, and patient care handouts, to continue to promote value-based healthcare and best practices.

Metropolis Monte Carlo simulation scheme for fast scattered X-ray photon calculation in CT.

Monte Carlo (MC) method is commonly considered as the most accurate approach for particle transport simulation because of its capability to precisely model physics interactions and simulation geometry. Conventionally, MC simulation is performed in a particle-by-particle fashion. In certain problems such as computing scattered X-ray photon signal at a detector of CT, the conventional simulation scheme suffers from low efficiency mainly due to the fact that abundant photons are simulated but do not reach the detector. The computational resources spent on those photons are therefore wasted. To solve this problem, this study develops a novel GPU-based Metropolis MC (gMMC) with a novel path-by-path simulation scheme and demonstrates its effectiveness in an example problem of scattered X-ray photon calculation in CT. In contrast to the conventional MC approach, gMMC samples an entire photon path extending from the X-ray source to the detector using Metropolis-Hasting algorithm. The path-by-path simulation scheme ensures contribution of every sampled event to the signal of interest, improving overall efficiency. We benchmark gMMC against an in-house developed GPU-based MC tool, gMCDRR, which performs simulations in the conventional particle-by-particle fashion. gMMC reaches speed up factors of 37~48 times in simple phantom cases and 20-34 times in real patient cases. The results calculated by gMCDRR and gMMC agree well with average differences < 3%.

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.

Case-Based Learning in Dermatology.

IMPORTANCE: The instruction of dermatology can be challenging due to its large scope, heavy clinical nature, and limited curriculum space. Case-based learning (CBL) is an emerging education paradigm and has no current literature on its use in dermatology. OBJECTIVES: Assess CBL in undergraduate dermatology medical education. METHODS: Case-based learning was implemented in the preclerkship dermatology curriculum at the University of Toronto to 3 student cohorts (totaling 710 students and 93 tutors) between May 2016 and April 2017. We analyzed assignment performance, pre- and post-CBL knowledge test scores, and experience surveys on students and tutors. Surveys were evaluated using aggregate descriptive statistics for quantitative data and thematic data analysis for qualitative data. All assessments were anonymous and voluntary. RESULTS: We received strong positive feedback on the CBL experience, with no score less than 3.8 on a 5-point scale (where 5 indicated strongly agree with a positively phrased question). Thematic data analysis revealed several key themes, including positive comments for a specialist tutor, the use of visual media, and the "mini-cases" style of CBL, while challenges included a lack of motivation. Group assignments scored high, ranging from 88.9% to 99.3%. Tracked pre- and post-CBL knowledge test scores showed a 32% (from 42% to 74%) increase in scores after the CBL experience. Conclusion and Relevance: CBL in dermatology medical education was well received by students and tutors, with high scores in content evaluation and knowledge assessment. Future studies should examine optimal delivery methods and its long-term effects on knowledge retention.

Systemic Monotherapy Treatments for Generalized Pustular Psoriasis: A Systematic Review.

Generalized pustular psoriasis (GPP) is a rare but serious and difficult to treat cutaneous disease, with high morbidity and mortality rates. Despite the numerous treatment regimens available, the overall quality of evidence-based research is limited with a lack of an algorithmic approach available. In this review, we aim to evaluate the current level of evidence regarding the efficacy and safety/tolerability of systemic monotherapies available in the treatment of GPP. A comprehensive MEDLINE, EMBASE, and PubMed search of clinical studies examining systemic monotherapy treatment options for GPP was conducted. In total, 31 studies met eligibility criteria. Described treatment modalities included retinoids, cyclosporine, biologics, and dapsone. Despite the lack of high-quality evidence or a well-accepted treatment algorithm for GPP, systemic retinoids, cyclosporine, biologics, and dapsone are all possible first-line agents, with retinoids being one of the best-supported treatment options and biologics as an emerging therapeutic field with great potential requiring additional data. However, the final choice of treatment should be considered within the unique context of each patient.

SPARSE: Seed Point Auto-Generation for Random Walks Segmentation Enhancement in medical inhomogeneous targets delineation of morphological MR and CT images.

In medical image processing, robust segmentation of inhomogeneous targets is a challenging problem. Because of the complexity and diversity in medical images, the commonly used semiautomatic segmentation algorithms usually fail in the segmentation of inhomogeneous objects. In this study, we propose a novel algorithm imbedded with a seed point autogeneration for random walks segmentation enhancement, namely SPARSE, for better segmentation of inhomogeneous objects. With a few user-labeled points, SPARSE is able to generate extended seed points by estimating the probability of each voxel with respect to the labels. The random walks algorithm is then applied upon the extended seed points to achieve improved segmentation result. SPARSE is implemented under the compute unified device architecture (CUDA) programming environment on graphic processing unit (GPU) hardware platform. Quantitative evaluations are performed using clinical homogeneous and inhomogeneous cases. It is found that the SPARSE can greatly decrease the sensitiveness to initial seed points in terms of location and quantity, as well as the freedom of selecting parameters in edge weighting function. The evaluation results of SPARSE also demonstrate substantial improvements in accuracy and robustness to inhomogeneous target segmentation over the original random walks algorithm.

[A fast iterative reconstruction algorithm of sparse angular CT based on the selective total variation].

Aiming at the problem of high-quality image reconstruction from projection data at sparse angular views, we proposed an improved fast iterative reconstruction algorithm based on the minimization of selective image total variation (TV). The new reconstruction scheme consists of two components. Firstly, the algebraic reconstruction technique (ART) algorithm was adopted to reconstruct image that met the identity and non-negativity of projection data, and then, secondly, the selective TV minimization was used to modify the above image. Two phases were alternated until it met the convergence criteria. In order to further speed up the convergence of the algorithm, we applied a fast convergence technology in the iterative process. Experiments on simulated Shepp-Logan phantom were carried out. The results demonstrated that the new method not only improved image reconstruction quality and protected the edge of the image characteristics, but also improved the convergence speed of the iterative reconstruction significantly.

[Design and validation of synchronous exposure control system of dental cone beam CT].

In the design of oral cone beam CT, cooperation between synergic control of X-ray source, real-time acquisition of flat detector and motion of mechanical structure affects the CT image quality. Based on the full analysis of the flat detector's timing signal characteristics, this research was carried out with microprocessor controller (MCU), complex programmable logic device (CPLD), and light couplings to design and realize synchronous exposure control system. To evaluate whether the design of the synchronous exposure control system in this project could reach the required imaging accuracy, we employed the projected images in the system to analyze its stability, linear consistency, signal to noise ratio and precede the FDK construction.