Overview and Current Advances in Dapsone Hypersensitivity Syndrome.

PURPOSE OF REVIEW: As a sulfone antibacterial agent, dapsone has been widely used to treat leprosy. Moreover, dapsone is also used in many immune diseases such as herpetic dermatitis because of its anti-inflammatory and immunomodulatory effects. However, dapsone can cause several adverse effects, the most serious being dapsone hypersensitivity syndrome. Dapsone hypersensitivity syndrome is characterized by a triad of eruptions, fever, and organ involvement, which limits the application of dapsone to some extent. RECENT FINDINGS: In this article, we review current research about the interaction model between HLA-B*13:01, dapsone, and specific TCR in dapsone-induced drug hypersensitivity. In addition to the proposed mechanisms, we also discussed clinical features, treatment progress, prevalence, and prevention of dapsone hypersensitivity syndrome. These studies reveal the pathogenesis, clinical features, and prevalence from the perspectives of genetic susceptibility and innate and adaptive immunity in dapsone hypersensitivity syndrome, thereby guiding clinicians on how to diagnose, prevent, and treat dapsone hypersensitivity syndrome.

Single-Nucleotide Polymorphisms Related to Leprosy Risk and Clinical Phenotypes Among Chinese Population.

BACKGROUND: Genome-wide association studies (GWASs) have identified some immune-related single-nucleotide polymorphisms (SNPs) to be associated with leprosy. METHODS: This study investigated the association of 17 SNPs based on previously published GWAS studies with susceptibility to leprosy, different polar forms and immune states of leprosy in a case-control study from southwestern China, including 1344 leprosy patients and 2732 household contacts (HHCs) (1908 relatives and 824 genetically unrelated contact individuals). The differences of allele distributions were analyzed using chi-squared analysis and logistic regression. RESULTS: After adjusting covariate factors, rs780668 and rs3764147 polymorphisms influenced susceptibilities to genetically related or unrelated leprosy contact individuals. rs142179458 was associated with onset early cases, rs73058713 A allele and rs3764147 A allele increased the risk of reversal reaction, while rs3764147 G allele had higher risk to present lepromatous leprosy and erythema nodosum leprosum. CONCLUSION: Our results demonstrated that genetic variants in the LACC1, HIF1A, SLC29A3 and CDH18 genes were positively correlated with the occurrence of leprosy and leprosy clinical phenotypes, providing new insights into the immunogenetics of the disease.

Predictive nomogram for leprosy using genetic and epidemiological risk factors in Southwestern China: Case-control and prospective analyses.

BACKGROUND: There is a high incidence of leprosy among house-contacts compared with the general population. We aimed to establish a predictive model using these genetic factors along with epidemiological factors to predict leprosy risk of leprosy household contacts (HHCs). METHODS: Weighted genetic risk score (wGRS) encompassing genome wide association studies (GWAS) variants and five non-genetic factors were examined in a case-control design associated with leprosy risk including 589 cases and 647 controls from leprosy HHCs. We constructed a risk prediction nomogram and evaluated its performance by concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling with 1000 resamples and a prospective design including 1100 HHCs of leprosy patients. FINDING: The C-index for the risk model was 0·792 (95% confidence interval [CI] 0·768-0·817), and was confirmed to be 0·780 through bootstrapping validation. The calibration curve for the probability of leprosy showed good agreement between the prediction of the nomogram and actual observation. HHCs were then divided into the low-risk group (nomogram score ≤ 81) and the high-risk group (nomogram score > 81). In prospective analysis, 12 of 1100 participants had leprosy during 63 months' follow-up. We generated the nomogram for leprosy in the validation cohort (C-index 0·773 [95%CI 0·658-0·888], sensitivity75·0%, specificity 66·8%). Interpretation The nomogram achieved an effective prediction of leprosy in HHCs. Using the model, the risk of an individual contact developing leprosy can be determined, which can lead to a rational preventive choice for tracing higher-risk leprosy contacts. FUNDING: The ministry of health of China, ministry of science and technology of China, Chinese academy of medical sciences, Jiangsu provincial department of science and technology, Nanjing municipal science and technology bureau.

Single-Nucleotide Polymorphisms in Genes Predisposing to Leprosy in Leprosy Household Contacts in Zhejiang Province, China.

PURPOSE: Genome-wide association studies (GWAS) have identified multiple genetic variants associated with leprosy. To investigate the single and combined associations between single-nucleotide polymorphisms (SNPs) and the development of leprosy, we therefore performed generalized multi-analytical (GMDR) analysis in Chinese leprosy household contacts and constructed a risk prediction model. PATIENTS AND METHODS: This case-control study included 229 leprosy cases and 233 healthy household contacts in Zhejiang province, China. Participants were genotyped for 17 polymorphisms selected from GWAS. The Pearson χ2 test, logistic regression and GMDR analysis were performed to investigate gene-gene interactions and construct a risk prediction model for leprosy. RESULTS: The genotype and the allele distributions of rs142179458, rs2275606, rs663743 and rs73058713 were significantly different between patients and controls. rs2275606, rs6478108, rs663743 and rs73058713 showed an association after adjusting for sex and age in the logistic regression. A five-way interaction model consisting of rs2058660, rs2275606, rs4720118, rs6478108 and rs780668 was chosen as the optimal model for determining leprosy susceptibility. The model classified 237 (51.3%) into the low-risk group and 225 (48.7%) individuals into the high-risk group. The area under the curve (AUC) of this model was 0.757 (95% CI: 0.712-0.803), and the odds ratio for leprosy between the high- and low-risk groups was 9.733 (95% CI: 6.384-14.960; P<0.001). The sensitivity and specificity of the model were observed to be 74.7% and 76.8%, respectively. CONCLUSION: Our results suggest that rs2058660, rs2275606, rs4720118, rs6478108 and rs780668, five SNPs with a significant sole effect on leprosy, interact to confer a higher risk for the disease in leprosy household contacts (HHCs).

Retraction Note to: Ambient air pollution and adverse birth outcomes: a systematic review and meta-analysis.

Retraction Note to: J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2019 20(3):238-252. https://doi.org/10.1631/jzus.B1800122. The authors have retracted this article (Guo et al., 2019) because some data from the original literature had not been converted to appropriate units in the paper, which resulted in deviation of the meta-analysis results. For example, for the forest plot used to examine associations between PM10 exposure and the risk of adverse birth outcomes, the estimates from Brauer et al. (2008), Pedersen et al. (2013), Zhao et al. (2015), and Hansen et al. (2006) were on the originally reported scales of 1 µg/m3, 10 µg/m3, 10 µg/m3, and Inter Quartile Range, respectively. None of these estimates had been converted to 20 µg/m3 increase scale that was stated in the article. Similar problem exists in the analysis on associations between NO2 exposure and risk of adverse birth outcomes. Therefore, the results of the meta-analysis are misleading. All authors have agreed to this retraction and express their deepest apologies to the original authors, publishers, and readers.

Evaluation of Prospective HLA-B*13:01 Screening to Prevent Dapsone Hypersensitivity Syndrome in Patients With Leprosy.

Importance: Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone. Objective: To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy. Design, Setting, and Participants: A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events. Exposures: Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT. Main Outcomes and Measures: The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control. Results: Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status. Conclusions and Relevance: Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

The Effects of Multi-Day vs. Single Pre-exercise Nitrate Supplement Dosing on Simulated Cycling Time Trial Performance and Skeletal Muscle Oxygenation.

Jo, E, Fischer, M, Auslander, AT, Beigarten, A, Daggy, B, Hansen, K, Kessler, L, Osmond, A, Wang, H, and Wes, R. The effects of multiday vs. single pre-exercise nitrate supplement dosing on simulated cycling time trial performance and skeletal muscle oxygenation. J Strength Cond Res 33(1): 217-224, 2019-A transient augmentation in the metabolic efficiency of skeletal muscle is the purported basis for dietary nitrate supplementation amongst competitive and recreational athletes alike. Previous studies support the ergogenic effects of nitrate supplementation, as findings indicated improved microvascular blood flow, exercise economy, and performance with relatively short-term supplementation. As with most ergogenic aids, the optimum duration of supplementation before performance or competition, i.e., loading phase, is a critical determinant for efficacy. Therefore, the purpose of this study was to investigate the effects of long-term vs. single dosing nitrate supplementation on skeletal muscle oxygenation and cycling performance. In a randomized, placebo controlled, double blind, parallel design study, healthy, recreationally active men (n = 15) and women (n = 14) subjects (age = 18-29 years) completed an 8 km (5 mi) simulated cycling time trial before and after a 14-day supplementation period with either a nitrate supplement (Multi-Day Dosing Group) (n = 14) or placebo (Single Pre-Exercise Dosing Group; SD) (n = 15). Both groups consumed a single dose of the nitrate supplement 2 hours before the post-treatment time trial. In addition, skeletal muscle oxygenation was measured via near-infrared spectroscopy during each time trial. Multiday nitrate supplementation significantly decreased time to completion (p = 0.01) and increased average power (p = 0.04) and speed (p = 0.02) from pre-to post-treatment, while a single dosing produced no significant changes to these measures. There were no significant differences over time and across treatments for any other measures including muscle oxygenation variables. Overall, long-term nitrate supplementation appears to have an advantage over a single pre-exercise dosing on cycling performance and metabolic efficiency as indicated by an increase in power output with no change in oxygenation.

Evaluating the Reliability and Reproducibility of the AO and Lauge-Hansen Classification Systems for Ankle Injuries.

Ankle injuries are responsible for more than 5 million emergency department visits each year. The AO and Lauge-Hansen classification systems are widely used in the clinical diagnosis of ankle injuries. This study aimed to analyze the intraobserver reliability and interobserver reproducibility of the AO and Lauge-Hansen classification systems. In addition, the authors explored the differences among physicians' classification responses and evaluated the clinical value for diagnosis. Fifty-six patients with an ankle injury with complete clinical and radiologic data were enrolled. The definition of injury type, the index score typing methods, and the specific study criteria were explained in detail. Five observers, who were orthopedic surgeons, determined the classifications according to both the AO and Lauge-Hansen systems. The classification was repeated 1 month later. Cronbach's alpha and Cohen's kappa test were used to determine interobserver reliability and intraobserver reproducibility. The physicians conducted 560 classifications (56 cases × 5 physicians × 2 times per patient). Average inter- and intraobserver kappa values for the AO system were 0.708 and 0.608, respectively. Average inter- and intraobserver kappa values for the Lauge-Hansen system were 0.402 and 0.398, respectively. Cronbach's alpha coefficient was 96.7% for the AO system and 76.0% for the Lauge-Hansen system. The Lauge-Hansen classification system is a comprehensive yet cumbersome system. Comparatively, the AO classification system is easier to understand. This study shows that the AO classification system has more reliability and reproducibility, and thus has more value in clinical practice, than the Lauge-Hansen classification system.

[Preliminary study on the genotyping of Mycobacterium leprae on 50 isolates from China].

OBJECTIVE: To understand the genotypic mapping of Mycobacterium leprae identified in China and to compare with those from other countries to select suitable alleles for epidemiological investigation in the transmission chain of leprosy. METHODS: Various number of tandem repeat(VNTR) in genomic DNA of Mycobacterium leprae was used in the present genotyping study. 33 skin biopsies from Wenshan prefecture,Yunnan province and 17 from other parts of China were studied. DNA extracted from skin biopsies of leprosy patients was subjected to PCR followed by agarose gel analysis and DNA sequencing to determine the number of repeats. RESULTS: Loci GGT-5,12-5,21-3 and 23-3 were as highly homogenous as 100%; The homogeneity of loci AC-8, 18-8, 27-5 and rpoT were 97%, 94%, 97% and 85% respectively. Loci GTA-9, AC-9 and 6-7 showed significant allelic diversity in isolates and the diversity of GTA-9 in Mycobacterium leprae isolated from China was also different from those identified other countries. We had subjected loci GTA-9 and the ten loci to phylogenetic tree analysis respectively. CONCLUSION: The present study revealed that the genotype of Mycobacterium leprae identified from China was close to the strains from the Philippines and India although a few loci were somehow differentiate. Locus 12-5 manifested as only 3 copies in China whereas 4-5 copies predominating in other countries. 12-5 locus might serve as a useful marker to diffrentiate Chinese strains from those in other countries. However, further study on the diversity of GTA-9 was needed in China. The molecular typing of Mycobacterium leprae from different geographic areas might be useful in studying the transmission of leprosy.