Abstract Background Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB). Evidence has linked the DM-related dysbiosis of gut microbiota to modifiable host immunity to Mycobacterium tuberculosis infection. However, the crosslinks between gut microbiota composition and immunological effects on the development of latent TB infection (LTBI) in DM patients remain uncertain. Methods We prospectively obtained stool, blood, and medical records from 130 patients with poorly-controlled DM (pDM), defined as ever having an HbA1c > 9.0% within previous 1 year. Among them, 43 had LTBI, as determined by QuantiFERON-TB Gold in-Tube assay. The differences in the taxonomic diversity of gut microbiota between LTBI and non-LTBI groups were investigated using 16S ribosomal RNA sequencing, and a predictive algorithm was established using a random forest model. Serum cytokine levels were measured to determine their correlations with gut microbiota. Results Compared with non-LTBI group, the microbiota in LTBI group displayed a similar alpha-diversity but different beta-diversity, featuring decrease of Prevotella_9, Streptococcus , and Actinomyces and increase of Bacteroides, Alistipes , and Blautia at the genus level. The accuracy was 0.872 for the LTBI prediction model using the aforementioned 6 microbiome-based biomarkers. Compared with the non-LTBI group, the LTBI group had a significantly lower serum levels of IL-17F (p = 0.025) and TNF-α (p = 0.038), which were correlated with the abundance of the aforementioned 6 taxa. Conclusions The study results suggest that gut microbiome composition may modulate host immunity relevant to TB susceptibility, and microbial signature might be a potential diagnostic biomarker and therapeutic target for LTBI in pDM patients.
Incidentally discovered solitary pulmonary nodules (SPN) caused by nontuberculous mycobacteria (NTM) is uncommon, and its optimal treatment strategy remains uncertain. This cohort study determined the clinical characteristics and outcome of asymptomatic patients with NTM-SPN after surgical resection. Resected SPNs with culture-positive for NTM in six hospitals in Taiwan during January, 2010 to January, 2017 were identified. Asymptomatic patients without a history of NTM-pulmonary disease (PD) or same NTM species isolated from the respiratory samples were selected. All were followed until May 1, 2019. A total of 43 patients with NTM-SPN were enrolled. Mycobacterium avium complex (60%) and M. kansasii (19%) were the most common species. The mean age was 61.7 ± 13.4. Of them, 60% were female and 4% had history of pulmonary tuberculosis. The NTM-SPN was removed by wedge resection in 38 (88%), lobectomy in 3 (7%) and segmentectomy in 2 (5%). Caseating granuloma was the most common histologic feature (58%), while chronic inflammation accounts for 23%. Mean duration of the follow-up was 5.2 ± 2.8 years (median: 4.2 years [2.5–7.0]), there were no mycobacteriology recurrence or NTM-PD development. In conclusion, surgical resection is likely to curative for incidentally discovered NTM-SPN in asymptomatic patients without culture evidence of the same NTM species from respiratory specimens, and routine mycobacterium culture for resected SPN might be necessary for differentiating pulmonary tuberculosis and NTM because further treatment differs.
Aim A population pharmacokinetic (PPK) study of the correlation of adverse drug reactions (ADRs) with the 3HP regimen (weekly high‐dose rifapentine plus isoniazid for 12 doses) for latent tuberculosis infection (LTBI) remains lacking. The purpose of this study is to determine the association of rifapentine or isoniazid concentration and ADRs. Methods This prospective, multicentre, observational study enrolled LTBI contacts receiving 3HP treatment between January 2017 and August 2020. The concentrations of rifapentine, isoniazid and their metabolites (25‐desacetyl‐rifapentine and acetyl‐isoniazid) in plasma samples collected monthly after 3HP treatment were determined. A PPK model was constructed to predict the maximum concentration ( C max ) and area under the concentration–time curve from 0 to 24 h (AUC). Their association with ADRs was evaluated by applying three multivariate logistic regression models with adjustment for various covariates. Results A total of 415 LTBI cases were ultimately enrolled; 355 (85.5%) completed the 3HP treatment. Among them, 47 (11.3%) experienced systemic drug reactions and 291 (70.0%) experienced one or more flu‐like symptom. The plasma concentration–time profiles of isoniazid, rifapentine and their metabolites were adequately described by the developed models. A higher C max of isoniazid was significantly correlated with a higher risk of any ADR (adjusted odds ratio and 95% confidence interval: 3.04 [1.07–8.65]) and any or at least two flu‐like symptoms (all severity grades) (2.76 [1.06–7.17]). Conclusions Isoniazid may be responsible for ADRs, especially flu‐like symptoms, during 3HP treatment.
ObjectivesPredicting progression of nontuberculous mycobacterial lung disease (NTM-LD) remains challenging. This study evaluated whether sputum bacterial microbiome diversity can be the biomarker and provide novel insights into related phenotypes and treatment timing.MethodsWe analyzed 126 sputum microbiomes of 126 patients with newly diagnosed NTM-LD due to Mycobacterium avium complex, M. abscessus complex, and M. kansasii between May 2020 and December 2021. Patients were followed for 2 years to determine their disease progression status. We identified consistently representative genera that differentiated the progressor and nonprogressor by using six methodologies. These genera were used to construct a prediction model using random forest with 5-fold cross validation.ResultsDisease progression occurred in 49 (38.6%) patients. Compared with nonprogressors, α-diversity was lower in the progressors. Significant compositional differences existed in the β-diversity between groups (p=0.001). The prediction model for NTM-LD progression constructed using seven genera (Burkholderia, Pseudomonas, Sphingomonas, Candidatus Saccharibacteria, Phocaeicola, Pelomonas, and Phascolarctobacterium) with significantly differential abundance achieved an area under curve of 0.871.ConclusionsIdentification of the composition of sputum bacterial microbiome facilitates prediction of the course of NTM-LD, and maybe used to develop precision treatment involving modulating the respiratory microbiome composition to ameliorate NTM-LD.
Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.
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