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1.
Biomaterials ; 267: 120454, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33160122

RESUMO

The development of tumor acidic microenvironment-responsive theranostic agents is a research hotspot. Herein, we developed highly photostable amphiphilic croconium dye-anchored red blood cell membrane vesicle (denoted as LET-5) for tumor pH-responsive near-infrared fluorescence (NIRF) and photoacoustic (PA) duplex imaging-guided photothermal therapy. In tumor acidic microenvironment, both NIRF and PA signals of LET-5 were significantly enhanced and the photothermal effect of LET-5 was activated. Notably, cell membrane-based vesicle with enhanced stability and long blood circulation significantly improved the tumor accumulation of croconium dye, thus achieving better therapeutic effect than free croconium dye. These findings provide a promising approach to construct amphiphilic dye-anchored cell membrane vesicle for cancer theranostics.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33146858

RESUMO

PURPOSE: This study aimed to (1) explore the prevalence and relevant influencing factors of different mental disorders 5 years after the Lushan earthquake in Ya'an, China. METHODS: An epidemiological mental health survey was conducted to identify the prevalence of mental disorders in general population in Ya'an. A multi-stage, group-matching random sampling method was adopted. Face-to-face interviews were done with a two-stage design by trained interviewers and psychiatrists. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) was used for the diagnosis. RESULTS: There were 8876 participants who were interviewed in this study. The total 12-month and lifetime prevalence of all mental disorders were 12.5% and 14.7%, respectively. There was a significant difference between males and females in the prevalence patterns of several mental disorders. Han ethnic group had higher prevalence of anxiety disorders (2.7%), and the Tibetan group had higher prevalence of alcohol-related disorders (5.0%). Logistic regression analysis showed that the areas severely affected by the earthquake had significantly higher prevalence of depressive disorders, and the extremely severe affected areas had significantly higher prevalence of trauma- and stressor-related disorders. CONCLUSION: Our findings show that the prevalence of a range of mental disorders 5 years after the earthquake in Ya'an are high, and the prevalence of depressive and trauma- and stressor-related disorders may be influenced differently by the various severity of earthquake impact. This study may be crucial for the health policy-making, cultural-specific mental health services and long-term mental recovery after the earthquake.

3.
J Neuroinflammation ; 17(1): 337, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176803

RESUMO

BACKGROUND: Intermittent hypoxia (IH) caused by obstructive sleep apnea (OSA) leads to neuroinflammation. Pinocembrin has been shown to have neuroprotective effects, while the therapeutic functions under IH condition are still unknown. METHODS: An OSA model was established by CIH exposure inside custom-made chambers. C57BL/6 mice were intraperitoneally injected with pinocembrin (40 mg/kg, i.p.) or vehicle (PBS containing 5% povidone; i.p.), and the changes of behavior on mice were detected by the Morris water maze test. Immunohistochemical staining, western blotting, immunofluorescence assays, and immunoprecipitation were used to investigate the association between NLRP3 inflammasome and BNIP3-dependent mitophagy. The mitochondrial morphology and mitophagosomes were detected under a transmission electron microscope. The detrimental effects of IH were tested by annexin V-FITC/PI staining, Mito SOX Red staining, and JC-1 mitochondrial membrane potential assay. RESULTS: In this study, our observations in vivo indicated that the administration of pinocembrin can restore spatial learning and memory ability and reduce neuronal apoptosis and hippocampal inflammation. Pinocembrin treatment significantly inhibited the formation of NLRP3 inflammasome and infiltration of microglia and enhanced BNIP3-mediated mitophagy in the hippocampus of IH mice. Additionally, our in vitro results show that pinocembrin protects microglial cells against IH-induced cytotoxicity by activating BNIP3-dependent mitophagy through the JNK-ERK signaling pathway. CONCLUSIONS: In summary, our findings demonstrated that pinocembrin can act as a potential therapeutic strategy for IH-induced neuroinflammation.

4.
Eur J Clin Pharmacol ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188451

RESUMO

AIMS: Chloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure-efficacy/safety relationship and provide a basis for a possible dosing regimen optimization. SUBJECT AND METHODS: In this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications. RESULTS: A two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h-1, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml). CONCLUSION: Model-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics-pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19.

5.
Sci Rep ; 10(1): 19890, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199785

RESUMO

Carcinoma in situ (CIS) of the uterine cervix is a precursor to cervical carcinoma. However, hysterectomy can be avoided in patients who can be treated by cone biopsy. Previous studies have shown that imaging-based approaches allow for the noninvasive visualization of cervical cancer, and radiomics has high accuracy in classifying cancer and predicting treatment outcome for different cancer types. To develop a magnetic resonance (MR)-based radiomics model for identifying residual disease in patients with CIS after cervical conization. Patients who had CIS after conization and finally underwent hysterectomy were collected to comprise a database to establish an imaging model for predicting the residual status after conization. Then, patients who opted for uterine preservation were classified as high-risk or low-risk patients according to the model. The disease-free survival was compared between the different risk groups using the Kaplan-Meier curve. The model built with the Boruta features outperformed the random forest model. Further validation with patients with uterine preservation showed that the patients classified as high risk were more likely to have tumor recurrence/residual disease in the follow-up period. In conclusion, radiomics can be used to identify residual disease in patients with CIS after cervical conization and could have the potential to predict recurrence in patients who opt for uterine preservation.

6.
J Pak Med Assoc ; 70 [Special Issue](9): 45-50, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33177727

RESUMO

OBJECTIVE: To study the application of ultrasound-guided indwelling epidural catheter in painless labour. METHODS: A total of 300 single-foetus cephalic position and full-term primipara who did not implement labour analgesia under the same conditions were randomly selected. According to the principle of random grouping, 150 pregnant women who requested and signed the informed consent for labour analgesia were selected as the analgesic group (group A). The other 150 pregnant women who experienced natural delivery without any analgesic measures were categorised as the control group. In the analgesic group, epidural anaesthesia was used when the uterine orifice reached 2.5 cm. The pain grade, motor nerve block, uterine contraction, foetal heart rate and the time of the first stage of labuor were recorded. RESULTS: The results showed that the group receiving epidural block had lesser pain compared to the control group. The duration of first stage of labour of the analgesic group was significantly shorter than the group without analgesia.. There were no significant differences in the degree of motor nerve block, uterine contractions and foetal heart rate between the analgesic group and the control group. CONCLUSIONS: The use of ultrasound-guided first stage indwelling epidural catheter had a significant effect in causing painless labour in the parturient.

7.
ACS Nano ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206522

RESUMO

Nanotheranostics based on tumor-selective small molecular prodrugs could be more advantageous in clinical translation for cancer treatment, given its defined chemical structure, high drug loading efficiency, controlled drug release, and reduced side effects. To this end, we have designed and synthesized a reactive oxygen species (ROS)-activatable heterodimeric prodrug, namely, HRC, and nanoformulated it for tumor-selective imaging and synergistic chemo- and photodynamic therapy. The prodrug consists of the chemodrug camptothecin (CPT), the photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), and a thioketal linker. Compared to CPT- or HPPH-loaded polymeric nanoparticles (NPs), HRC-loaded NPs possess higher drug loading capacity, better colloidal stability, and less premature drug leakage. Interestingly, HRC NPs were almost nonfluorescent due to the strong π-π stacking and could be effectively activated by endogenous ROS once entering cells. Thanks to the higher ROS levels in cancer cells than normal cells, HRC NPs could selectively light up the cancer cells and exhibit much more potent cytotoxicity to cancer cells. Moreover, HRC NPs demonstrated highly effective tumor accumulation and synergistic tumor inhibition with reduced side effects on mice.

8.
Sci Data ; 7(1): 376, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168820

RESUMO

Both poly(A) enrichment and ribosomal RNA depletion are commonly used for RNA sequencing. Either has its advantages and disadvantages that may lead to biases in the downstream analyses. To better access these effects, we carried out both ribosomal RNA-depleted and poly(A)-selected RNA-seq for CD4+ T naive cells isolated from 40 healthy individuals from the Blueprint Project. For these 40 individuals, the genomic and epigenetic data were also available. This dataset offers a unique opportunity to understand how library construction influences differential gene expression, alternative splicing and molecular QTL (quantitative loci) analyses for human primary cells.

9.
Int Immunopharmacol ; 88: 107021, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33182037

RESUMO

Mammalian Ste20-like kinase 4 (MST4), a new member of the germinal-center kinase STE20 family, was recently demonstrated to be a negative regulator of inflammation. However, whether MST4 participates in the inflammatory response to fungal infection remains unknown. Our study investigated the role and molecular mechanisms of MST4 in mice cornea and corneal epithelial cells exposed to Aspergillus fumigatus (A. fumigatus). Protein level of MST4 was detected in mice corneas and human corneal epithelial cells (HCECs) by Western blot analysis. The MST4 protein level was significantly elevated in mice corneas infected with A. fumigatus and HCECs exposed to A. fumigatus. MST4 expression was also detected in mice corneas by immunofluorescence staining. Furthermore, we found recombinant MST4 inhibited proinflammatory cytokines expressions induced by A. fumigatus at both the mRNA and protein levels in mice corneas and HCECs. To further investigate the mechanism of MST4's anti-inflammatory effect in A. fumigatus keratitis, we verified recombinant MST4 can inhibit curdlan-mediated proinflammatory cytokines production in HCECs. Surprisingly, recombinant MST4 protein downregulated A. fumigatus-induced Dectin-1 expression in both mRNA and protein levels in mice corneas. Recombinant MST4 can inhibit the mRNA expression level of Dectin-1 which was induced by curdlan in HCECs. MST4 can also inhibit the expression of Dectin-1 in mRNA levels increased by Dectin-1 overexpression plasmid in HCECs. Moreover, A. fumigatus or curdlan significantly induced the phosphorylation of Syk, which was consequently suppressed by recombinant MST4. Finally, recombinant MST4 promotes HCECs proliferation, which contribute to cornea wound healing. Taken together, our results provide evidences that MST4 inhibits inflammatory signaling response in A. fumigatus keratitis by downregulating Dectin-1/p-Syk pathway and simultaneously promotes HCECs proliferation.

10.
Phys Chem Chem Phys ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33057548

RESUMO

Carbon nanotubes (CNT)-cerium oxide (CeO2) nanocomposites were fabricated successfully by one-pot microwave hydrothermal growth of regular CeO2 nanoparticles with a size of 8 nm on hydroxyl-functionalized multi-walled CNTs. These nanocomposite photocatalysts demonstrated an acid orange (AO7) photocatalytic degradation efficiency of above 90% under solar-simulated light irradiation for 3 h, which was much higher than that of the pure CeO2 nanoparticles. The enhanced photocatalytic activity was observed to mainly originate from the ˙O2- and hole traps, while the hydroxyl radical ˙OH played a secondary role.

11.
Eur Spine J ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33098009

RESUMO

OBJECTIVE: The objective of the study was to compare the safety, efficacy, and accuracy of the pedicle screws with the three-dimensional (3D) printed navigation template to the free-hand screws for type II odontoid fractures. PATIENTS AND METHODS: A total of 60 patients with type II odontoid fractures, treated with either template guiding pedicle screws or free-hand screws, were retrospectively assessed. The guiding group was treated with pedicle screws with the assistance of a virtual reality (VR) software-designed, 3D printed navigation template with two guide tubes. The safety rate and treatment efficacy of the screw placement, as well as the trajectory accuracy, were evaluated by respective measures and compared between two surgical groups. RESULTS: There were reduced surgical time (P < 0.05), blood loss (P < 0.01), and C-arm shots (P < 0.01) with 3D printed template guiding screws. The rates of safe pedicle screws in both C1 and C2 were significantly higher in 3D guiding group (P < 0.01) compared to the free-hand group, and the scores of visual analogue scale (VAS) and impairment scale (ASIA) were improved in guiding group at 1 week post-surgery (P < 0.01 and P < 0.05, respectively). Postoperative CT and image reconstruction showed the 3D guiding group had better horizontal screw accuracy on both sides of C1 (L: P < 0.001, R: P < 0.01) and C2 (L: P < 0.001, R: P < 0.01) than free-hand group. CONCLUSION: The herein screw technique using 3D printed navigation template leads to greater improvement in the screw safety, efficacy, and accuracy, which may be a promising alternative to free-hand surgery for the treatment of odontoid fractures.

13.
Nucleic Acids Res ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084905

RESUMO

Alternative splicing is widespread throughout eukaryotic genomes and greatly increases transcriptomic diversity. Many alternative isoforms have functional roles in developmental processes and are precisely temporally regulated. To facilitate the study of alternative splicing in a developmental context, we created MeDAS, a Metazoan Developmental Alternative Splicing database. MeDAS is an added-value resource that re-analyses publicly archived RNA-seq libraries to provide quantitative data on alternative splicing events as they vary across the time course of development. It has broad temporal and taxonomic scope and is intended to assist the user in identifying trends in alternative splicing throughout development. To create MeDAS, we re-analysed a curated set of 2232 Illumina polyA+ RNA-seq libraries that chart detailed time courses of embryonic and post-natal development across 18 species with a taxonomic range spanning the major metazoan lineages from Caenorhabditis elegans to human. MeDAS is freely available at https://das.chenlulab.com both as raw data tables and as an interactive browser allowing searches by species, tissue, or genomic feature (gene, transcript or exon ID and sequence). Results will provide details on alternative splicing events identified for the queried feature and can be visualised at the gene-, transcript- and exon-level as time courses of expression and inclusion levels, respectively.

14.
Ann Palliat Med ; 9(5): 3288-3292, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33065784

RESUMO

BACKGROUND: Dysmenorrhea is one of the most common symptoms in gynecology. It refers to people who experience lower abdominal pain, swelling, backache, or another discomfort before and after menstruation or during menstruation, which seriously affects the quality of life and work. Clinically, there are many methods to treat primary dysmenorrhea, among which acupuncture and traditional Chinese medicine (TCM) are beneficial. This work aimed to test the efficacy of acupuncture and TCM in the treatment of primary dysmenorrhea and hope to supply more reliable evidence for clinical treatment. METHODS: We searched articles from the Wanfang database and China National Knowledge Infrastructure and collected the clinical, randomized, or quasi-randomized controlled trials of acupuncture compared with TCM for primary dysmenorrhea. We tested the quality and data of the included studies according to the Cochrane criteria and compiled detailed systematic reviews and meta-analysis. RESULTS: Seven articles (including 492 patients) on acupuncture and TCM for primary dysmenorrhea were included in the systematic review. Seven studies were included in the final analysis, and there was no heterogeneity among the studies (P=0.98, I2=0%). The results showed that the clinical effectiveness of acupuncture was better than TCM (OR: 4.86, 95% CI: 2.84-8.33, Z =5.75, P<0.00001). CONCLUSIONS: The efficacy of acupuncture is superior to TCM in the treatment of primary dysmenorrhea.

15.
Adv Mater ; : e2004481, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33015905

RESUMO

Simultaneous photodynamic therapy (PDT) and photothermal therapy (PTT) can reduce the risks of drug leakage, body burden, and preparation complexity in traditional combination PDT/PTT. Here, a versatile nanoporphyrin (Pp18-lipos) self-assembled from lipid-purpurin 18 conjugates (Pp18-lipids) and pure lipids is presented. The as-prepared Pp18-lipos with 2 mol% Pp18-lipids can perform effective PDT and fluorescence imaging. The Pp18-lipos with 65 mol% Pp18 can perform potent PTT and photoacoustic imaging. The chelation of Mn2+ endows the Pp18-lipids-Mn2+ a high T1 -weighted magnetic resonance imaging contrast. Notably, pretreatment of low-dose PDT facilitates the endocytosis and tumor accumulation of Pp18-lipos, thus achieving synergistic PDT/PTT. Upon exposure to a single 705 nm-laser, the combination of PDT/PTT achieves a significantly higher tumor growth inhibition rate than PDT or PTT alone. In addition, it is found that the synergistic PDT/PTT triggers more potent anti-tumor immune response including tumor infiltration of immune cells and release of related cytokines.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33115254

RESUMO

SIGNIFICANCE: To improve the outcome of in vitro culture of human oocytes and embryos, the dynamic balance and roles of reactive oxygen species (ROS) in folliculogenesis and embryo development merit further consideration. Recent Advances: ROS have been demonstrated to participate in various signaling processes and act as mediators in various physiological events in germ cells. An imbalance between prooxidants and antioxidants seems to explain the high failure rate of assisted reproduction. CRITICAL ISSUES: Oxidative stress induced by excessive ROS or insufficient antioxidant protection can cause detrimental effects on both male and female reproduction. In this study, the oxidative stress in folliculogenesis and embryo development are summarized and the multiple modifiable factors of the in vitro culture systems in relation to the ROS are discussed. FUTURE DIRECTIONS: More studies are needed to establish an optimal redox state in the in vitro culture systems for human oocytes and embryos.

18.
Sleep Breath ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001351

RESUMO

PURPOSE: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with alterations in glucose metabolism. The Berlin questionnaire (BQ) is effective in identifying subjects with high risk of OSAHS. However, its validity in patients with glucose metabolic dysfunction remains unclear. Our study aims to examine the diagnostic efficacy of the BQ in detecting OSAHS in patients with glucose metabolic dysfunction and to explore the effect of nasal CPAP on glucose metabolism. METHODS: Patients with glucose metabolic dysregulation were first asked to complete the BQ and then recruited for polysomnogram (PSG). The diagnostic accuracy of the BQ and the relationships between groups with normal glucose tolerance (NGT), elevated fasting blood glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM) were analyzed. Subjects with both OSAHS and glucose dysregulation received CPAP treatment and underwent an oral glucose tolerance test. Changes in apnea-hypopnea indices (AHI) and glycemic parameters were calculated to determine the efficacy of CPAP. RESULTS: Glycosylated hemoglobin and insulin levels were statistically different between the high-risk and low-risk groups according to the BQ. For diagnosis of subjects with OSAHS who also had glucose metabolic dysfunction, the sensitivity and specificity of the BQ using AHI cut-off values at 5 events per hour were 73% and 67%. CPAP therapy effectively reduced the blood glucose, HOMA-IR, and insulin levels. CONCLUSIONS: The BQ can be considered to be an effective and economical screening tool for patieints with OSAHS who also have glucose metabolic dysfunction. Treatment with CPAP may improve glycemic parameters.

19.
Cell ; 183(4): 875-889.e17, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33035453

RESUMO

Banyan trees are distinguished by their extraordinary aerial roots. The Ficus genus includes species that have evolved a species-specific mutualism system with wasp pollinators. We sequenced genomes of the Chinese banyan tree, F. microcarpa, and a species lacking aerial roots, F. hispida, and one wasp genome coevolving with F. microcarpa, Eupristina verticillata. Comparative analysis of the two Ficus genomes revealed dynamic karyotype variation associated with adaptive evolution. Copy number expansion of auxin-related genes from duplications and elevated auxin production are associated with aerial root development in F. microcarpa. A male-specific AGAMOUS paralog, FhAG2, was identified as a candidate gene for sex determination in F. hispida. Population genomic analyses of Ficus species revealed genomic signatures of morphological and physiological coadaptation with their pollinators involving terpenoid- and benzenoid-derived compounds. These three genomes offer insights into and genomic resources for investigating the geneses of aerial roots, monoecy and dioecy, and codiversification in a symbiotic system.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33039642

RESUMO

BACKGROUND: Bullous skin disorders are induced by different pathomechanisms and several are emergent, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Rapid diagnostic methods for SJS/TEN or cytotoxic T-lymphocyte (CTL)-mediated bullous disorders are crucial for early treatment. Granulysin, primarily expressed by CTLs, is a specific cytotoxic protein responsible for SJS/TEN and similar skin reactions. OBJECTIVE: To assess granulysin levels in blister fluids to differentiate SJS/TEN and similar CTL-mediated bullous reactions from other autoimmune bullous disorders. METHODS: Using ELISA, we measured granulysin in blister fluids from patients with bullous skin disorders, including SJS/TEN, erythema multiforme major, bullous fixed-drug eruption, bullous lupus erythematosus, paraneoplastic pemphigus, pemphigus vulgaris, bullous pemphigoid, purpura fulminans-related bullae, and hand-foot syndrome/hand-foot-skin reactions. We compared serum and blister granulysin levels in patients with SJS/TEN presenting varying severity, monitoring serial granulysin levels from acute to late stages. RESULTS: Overall, 144 patients presenting with bullous skin disorders were enrolled. Blister granulysin levels (mean ± SD) in CTL-mediated disorders, including TEN (n = 28; 3938.7 ± 3475.7), SJS-TEN overlapping (n = 22; 1440.4 ± 1179.6), SJS (n = 14; 542.0 ± 503.2), erythema multiforme major (n = 7; 766.3 ± 1073.7), generalized bullous fixed-drug eruption (n = 10; 720.4 ± 858.3), and localized bullous fixed-drug eruption (n = 16; 69.0 ± 56.4), were significantly higher than in non-CTL-mediated bullous disorders (P < .0001), including bullous lupus erythematosus (n = 3; 22.7 ± 20.1), paraneoplastic pemphigus (n = 3; 20.3 ± 8.6), pemphigus vulgaris (n = 3; 4.4 ± 2.8), bullous pemphigoid (n = 18; 4.0 ± 2.7), purpura fulminans (n = 4; 5.9 ± 5.5), and hand-foot syndrome/hand-foot-skin reactions (n = 6; 4.6 ± 3.5). Blister granulysin levels correlated with clinical severity of SJS/TEN (P < .0001). CONCLUSIONS: Determination of blister granulysin levels is a noninvasive and useful tool for rapid differential diagnosis of SJS/TEN and other similar CTL-mediated bullous skin disorders for treatment selection.

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