Development of a random forest model to classify sarcoidosis and tuberculosis.

OBJECTIVE: To identify significant diagnostic factors and establish a predictive model for diagnosis of sarcoidosis and tuberculosis. METHODS: This study included 252 patients (123 cases of lung sarcoidosis and 129 cases of lung tuberculosis) who underwent laboratory evaluation, including routine hematologic testing, serum immunology, blood coagulation, angiotensin-converting enzyme, and T lymphocyte subset. The factors that statistically different between the two groups were identified by an independent sample t test first, and then processed by the random forest model to distinguish two diseases with the classification function. Moreover, the diagnostic performance of the predictive random forest model was evaluated through the identification of individual contribution of various diagnostic factors conducted by the model. RESULTS: The random forest model revealed a classification error rate of 24.9%. Among all of the statistically significant diagnostic factors, the individual factors with the greatest and second contribution were angiotensin-converting enzyme and prothrombin time, respectively. The area under the receiver operating characteristic (ROC) curve of the random forest prediction model was 0.915. CONCLUSION: The random forest model can be used to distinguish between sarcoidosis and tuberculosis by incorporating statistically significant diagnostic factors, which is of potential clinical application value.

Treatment Outcome of a Shorter Regimen Containing Clofazimine for Multidrug-resistant Tuberculosis: A Randomized Control Trial in China.

BACKGROUND: The emergence of multidrug-resistant tuberculosis (MDR-TB) poses a serious obstacle to global TB control programs. METHODS: We carried out a prospective, randomized, multicenter study in China that was focused on the potential of a shorter regimen containing clofazimine (CFZ) for the treatment of MDR-TB. There were 135 MDR-TB cases that met eligibility requirements and were randomly stratified into either the control group or experimental group. Patients in the control group received an 18-month treatment regimen, whereas patients in the experimental group received a 12-month treatment regimen containing CFZ. RESULTS: At the completion of the treatment period, the difference in sputum-culture conversion rates between the experimental group and the control group was not significant. Notably, by the end of 3 months of treatment, 68.7% patients receiving the experimental regimen had sputum-culture conversion, as compared with 55.9% of those receiving the control regimen; this was a significant difference, suggesting an early sputum conversion (P = .04). There were 67 adverse events reported in 56 patients in this study, including 32 in the control group and 35 in the experimental group. No significant difference in the overall incidences of adverse events was observed between the 2 groups. CONCLUSIONS: The MDR-TB patients treated with the shorter regimen containing CFZ had a comparable successful outcome rate when compared to those with the standard regimen. The patients assigned to the experimental group achieved more rapid sputum-culture conversion, reflecting superior antimicrobial activity against MDR-TB. CLINICAL TRIALS REGISTRATION: Chinese Clinical Trial Registry ChiCTR 1800020391.

Sex Disparity in Severity of Lung Lesions in Newly Identified Tuberculosis Is Age-Associated.

Background: The age-associated characteristic of computed tomography (CT) images of tuberculosis (TB) and the reason for male bias in TB are still not clear. Methods: We compared the CT images, clinical inflammatory indices and sputum bacterial counts between 594 non-smoking men and women with newly diagnosed TB with matched large span of ages from 15 to 92 years old. Logistic regression analyses were used to identify the cavity-associated factors of men and women, separately and in combination. Results: Sputum bacterial counts, ratio of cavities, lung injury scores, and level of C reactive protein were significantly higher in men than in women with ages from 15 to 74, but not in cases older than 75. In CT images, thick walled cavity, cicatricial emphysema and parenchymal bands were present in men at ages of 15-74 more than matched women. Ratios of cases with lobular emphysema and pleural effusion were higher in men after age of 56. While ratios of cases with parenchymal bands, calcification, pleural effusion, pleural thickening, lobular emphysema and bronchovascular distortion increased with aging, those of centrilobular nodules, micronodules and tree in bud decreased with aging in men. Erythrocyte sedimentation rate (ESR) increased with aging, but no differences were found between men and women in ESR or T-SPOT TB tests. Higher complement C4 and lower body mass index in men and positive result in anti-TB antibody test in women were strongly associated with the presence of cavity. Conclusions: The sex bias in TB is age-associated. TB prevention, treatment and research should take differences of sex and age into account.

Critical role of molecular test in early diagnosis of gastric tuberculosis: a rare case report and review of literature.

BACKGROUD: Early diagnosis of gastric tuberculosis is often challenging because the disease is very rare and its clinical manifestation is nonspecific and misleading. To raise the awareness and emphasize early diagnosis of gastric tuberculosis, we present a case of gastric tuberculosis secondary to pleural and pulmonary tuberculosis. CASE PRESENTATION: A 26-year-old woman complained gastric pain for 1 month but showed no other symptoms, who had no previous exposure to tuberculosis.Gastric stromal tumor was originally suspected. However, the pathology of her gastroscopic biopsy of the gastric lesion showed granulomatous lesions and caseating necrosis. Gene sequencing of the biopsy specimen identified deoxyribonucleic acid fragment of Mycobacterium tuberculosis. Chest computed tomography scan revealed nodular shadows in the lesser curvature soft tissue of the stomach, patchy densities and calcified nodular shadows in the upper right lung, bilateral pleural thickening, and calcified pleural nodules. Thus, the diagnosis was gastric tuberculosis secondary to pulmonary and pleural tuberculosis. The patient was hospitalized and treated with the antituberculosis therapy for 1 week. After discharged from the hospital, the patient continued routine antituberculosis therapy for 18 months and was follow-up was normal.Literature search found 22 cases of gastric tuberculosis reported from 2000 to 2016. Review of the 22 cases suggested that polymerase chain reaction has been increasingly used in the recent years in addition to the conventional histopathological and bacteriological approaches. CONCLUSION: Clinical presentation of gastric tuberculosis is not specific.When granuloma or caseation is detected on biopsy in patients who are suspected of having gastric malignancy or acid peptic diseases, polymerase chain reaction for Mycobacterium tuberculosis could be used as an available and sensitive diagnostic test in addition to pathology, acid-fast bacilli smear staining and culture.

Clofazimine for Treatment of Extensively Drug-Resistant Pulmonary Tuberculosis in China.

We performed a multicenter, prospective, randomized study to investigate the efficacy and safety of clofazimine (CLO) for treatment of extensively drug-resistant tuberculosis (XDR-TB) in China. Forty-nine patients infected with XDR-TB were randomly assigned to either the control group or the CLO group, both of which received 36 months of individually customized treatment. The primary endpoint was the time to sputum culture conversion on solid medium. Clinical outcomes of patients were evaluated at the time of treatment completion. Of the 22 patients in the experimental group, 7 (31.8%) met the treatment criterion of "cure" and 1 (4.5%) "complete treatment," for a total of 8 (36.4%) exhibiting successful treatment outcomes without relapse. In the control group, 6 patients (22.2%) were cured and 6 (22.2%) completed treatment by the end of the study. Statistical analysis revealed no significant difference in successful outcome rates between the CLO group and the control group. The average sputum culture conversion time for the experimental group was 19.7 months, which was not statistically different from that for the control group (20.3 months; P = 0.57). Of the 22 patients in the CLO group, 12 (54.5%) experienced adverse events after starting CLO treatment. The most frequently observed adverse event was liver damage, with 31.8% of patients (7/22 patients) in the CLO group versus 11.1% (3/27 patients) in the control group exhibiting this adverse event. Our study demonstrates that inclusion of CLO in background treatment regimens for XDR-TB is of limited benefit, especially since hepatic disorders arise as major adverse events with CLO treatment. (This study is registered with the Chinese Clinical Trial Registry [ChiCTR, www.chictr.org.cn] under identifier ChiCTR1800014800.).

Hemostasis and Lipoprotein Indices Signify Exacerbated Lung Injury in TB With Diabetes Comorbidity.

BACKGROUND: Exacerbated immunopathology is a frequent consequence of TB that is complicated by diabetes mellitus (DM); however, the underlying mechanisms are still poorly defined. METHODS: In the two groups of age- and sex-matched patients with TB and DM (DM-TB) and with TB and without DM, we microscopically evaluated the areas of caseous necrosis and graded the extent of perinecrotic fibrosis in lung biopsies from the sputum smear-negative (SN) patients. We scored acid-fast bacilli in sputum smear-positive (SP) patients and compiled CT scan data from both the SN and SP patients. We compared inflammatory biomarkers and routine hematologic and biochemical parameters. Binary logistic regression analyses were applied to define the indices associated with the extent of lung injury. RESULTS: Enlarged caseous necrotic areas with exacerbated fibrotic encapsulations were found in SN patients with DM-TB, consistent with the higher ratio of thick-walled cavities and more bacilli in the sputum from SP patients with DM-TB. Larger necrotic foci were detected in men compared with women within the SN TB groups. Significantly higher fibrinogen and lower high-density lipoprotein cholesterol (HDL-C) were observed in SN patients with DM-TB. Regression analyses revealed that diabetes, activation of the coagulation pathway (shown by increased platelet distribution width, decreased mean platelet volume, and shortened prothrombin time), and dyslipidemia (shown by decreased low-density lipoprotein cholesterol, HDL-C, and apolipoprotein A) are risk factors for severe lung lesions in both SN and SP patients with TB. CONCLUSIONS: Hemostasis and dyslipidemia are associated with granuloma necrosis and fibroplasia leading to exacerbated lung damage in TB, especially in patients with DM-TB.

A Large Cohort Study on the Clinical Value of Simultaneous Amplification and Testing for the Diagnosis of Pulmonary Tuberculosis.

The AmpSure simultaneous amplification and testing method for the detection of Mycobacterium tuberculosis (SAT-TB assay) was designed to diagnose rapidly pulmonary tuberculosis (PTB). Unfortunately, the diagnostic advantage is unclear from previous small sample studies. In the current inquiry, a large sample size was used to reevaluate the clinical accuracy of the SAT-TB assay using sputum specimens. A total of 3608 patients with suspected PTB were enrolled prospectively for diagnosis from sputum specimens using the SAT-TB assay. Of these, 2457 had a definite diagnosis of PTB confirmed by positive microbiology, or pathologic findings of TB in the lung, or clinical diagnosis of active PTB following anti-TB treatment with a favorable response. The sensitivity, specificity and accuracy of the SAT-TB assay were 75.8%, 100%, and 80.2%, respectively. The sensitivity of SAT-TB was significantly higher than that of the sputum smear (23.8%) (X(2) = 1327.437; P = 0.000), wheresa significantly lower than that of sputum culture (89.0%) (X(2) = 148.197; P = 0.000). The specificity of SAT-TB was significantly higher than that of sputum smears (96.3%) (X(2) = 20.375, P = 0.000), whereas no significant difference was found compared with sputum cultures (99.6%) (X(2) = 2.004, P = 0.500). Positive results in the SAT-TB assay using sputum specimens indicates that active PTB is present and anti-TB treatment is strongly recommended regardless of smear and culture test results. Simultaneous amplification and testing method for detection of Mycobacterium tuberculosis is an accurate, cheap, and rapid method for PTB diagnosis.

Platelets direct monocyte differentiation into epithelioid-like multinucleated giant foam cells with suppressive capacity upon mycobacterial stimulation.

BACKGROUND: Epithelioid, foam, and multinucleated giant cells (MNGCs) are characteristics of tuberculosis granulomas, yet the precise genesis and functions of these transformed macrophages are unclear. We evaluated the role of platelets as drivers of macrophage transformation in mycobacterial infection. METHODS: We employed flow cytometry and microscopy to assess cellular phenotype and phagocytosis. Immune assays allowed quantification of cytokines and chemokines, whereas gene microarray technology was applied to estimate global transcriptome alterations. Immunohistochemical investigations of tuberculosis granulomas substantiated our findings at the site of infection. RESULTS: Monocytes differentiated in presence of platelets (MP-Macs) acquired a foamy, epithelioid appearance and gave rise to MNGCs (MP-MNGCs). MP-Macs up-regulated activation markers, phagocytosed mycobacteria, and released abundant interleukin 10. Upon extended culture, MP-Macs shared transcriptional features with epithelioid cells and M2 macrophages and up-regulated CXCL5 transcripts. In line with this, CXCL5 concentrations were significantly increased in airways of active tuberculosis patients. The platelet-specific CD42b antigen was detected in MP-Macs, likewise in macrophages, MNGCs, and epithelioid cells within tuberculosis granulomas, along with the platelet aggregation-inducing factor PDPN. CONCLUSIONS: Platelets drive macrophage differentiation into MNGCs with characteristics of epithelioid, foam, and giant cells observed in tuberculosis granulomas. Our data define platelets as novel participants in tuberculosis pathogenesis.

Hybrid quantum mechanical and molecular mechanics study of the S(N)2 Reaction of CCl4 + OH- in aqueous solution: the potential of mean force, reaction energetics, and rate constants.

The bimolecular nucleophilic substitution reaction of CCl(4) and OH(-) in aqueous solution was investigated on the basis of a combined quantum mechanical and molecular mechanics method. A multilayered representation approach is employed to achieve high accuracy results at the CCSD(T) level of theory. The potential of mean force calculations at the DFT level and CCSD(T) level of theory yield reaction barrier heights of 22.7 and 27.9 kcal/mol, respectively. Both the solvation effects and the solvent-induced polarization effect have significant contributions to the reaction energetics, for example, the solvation effect raises the saddle point by 10.6 kcal/mol. The calculated rate constant coefficient is 8.6 × 10(-28) cm(3) molecule(-1) s(-1) at the standard state condition, which is about 17 orders magnitude smaller than that in the gas phase. Among the four chloromethanes (CH(3)Cl, CH(2)Cl(2), CHCl(3), and CCl(4)), CCl(4) has the lowest free energy activation barrier for the reaction with OH(-) in aqueous solution, confirming the trend that substitution of Cl by H in chloromethanes diminishes the reactivity.

Hybrid quantum mechanical/molecular mechanics study of the S(N)2 reaction of CH3Cl+OH- in water.

The S(N)2 mechanism for the reaction of CH(3)Cl + OH(-) in aqueous solution was investigated using combined quantum mechanical and molecular mechanics methodology. We analyzed structures of reactant, transition, and product states along the reaction pathway. The free energy profile was calculated using the multilayered representation with the DFT and CCSD(T) level of theory for the quantum-mechanical description of the reactive region. Our results show that the aqueous environment has a significant impact on the reaction process. We find that solvation energy contribution raises the reaction barrier by ~18.9 kcal/mol and the reaction free energy by ~24.5 kcal/mol. The presence of the solvent also induces perturbations in the electronic structure of the solute leading to an increase of 3.5 kcal/mol for the reaction barrier and a decrease of 5.6 kcal/mol for the reaction free energy, respectively. Combining the results of two previous calculation results on CHCl(3) + OH(-) and CH(2)Cl(2) + OH(-) reactions in water, we demonstrate that increase in the chlorination of the methyl group (from CH(3)Cl to CHCl(3)) is accompanied by the decrease in the free energy reaction barrier, with the CH(3)Cl + OH(-) having the largest barrier among the three reactions.

[The effect of the regimen containing cefoxitin on highly drug-resistant rapidly growing nontuberculous mycobacterial pulmonary disease].

OBJECTIVE: To evaluate the therapeutic effect and safety of the regimen containing cefoxitin on highly drug-resistant rapidly growing nontuberculous mycobacterial (RGM) pulmonary disease. METHODS: From January to December 2007, 16 patients with RGM pulmonary disease, who had been treated for 6-48 months, average (15 ± 11) months but still sputum positive, were included in the study and treated with a new regimen containing cefoxitin, fluoroquinolone, macrolide, and SMZco. Cefoxitin was used in the first 3 months and the total duration of therapy was 18 months. Sputum conversion rate, radiology change and side effects were observed before and after the therapy. RESULTS: Underlying chronic diseases including COPD (n = 2), tuberculosis (n = 3), bone-marrow transplantation due to chronic leukemia (n = 1) and bronchiectasis (n = 5), were present in 11 patients. Main symptoms before therapy were cough and expectoration. There were multi-focal patchy, small nodular shadows with cavities on CT scans. The 16 clinical strains were highly resistant to anti-tuberculous drugs: 15/16 to streptomycin, 16/16 to isoniazid, 14/16 to rifampin, 13/16 to ethambutol, 14/15 to amikacin, 15/15 to capreomycin and 14/15 to ofloxacin. After treatment, the clinical symptoms improved in all patients. Eight of the 16 patients became sputum negative by 6 months which lasted to the end of the therapy, while another 8 patients remained sputum positive. Six patients showed radiological improvement. No one experienced side effects induced by cefoxitin. The total cure rate was 8/16. CONCLUSION: The regimen containing cefoxitin has certain effect on highly drug-resistant nontuberculous mycobacterial pulmonary disease, especially for RGM.

Elevated serum levels of CCL17 correlate with increased peripheral blood platelet count in patients with active tuberculosis in China.

The serum levels of Th2 markers, including CCL17 (thymus and activation-regulated chemokine [TARC]), CCL22 (macrophage-derived chemokine [MDC]), and soluble CD30, were measured in 101 HIV-negative tuberculosis patients, 103 healthy community controls, and 18 tuberculosis patients in recovery. The levels of CCL17/TARC (249.8 ± 19.91 versus 143.9 ± 10.54, P < 0.0001) and sCD30 (7.78 ± 0.44 versus 4.93 ± 0.23, P < 0.0001) were significantly higher in patients with active tuberculosis than in controls; however, the CCL22/MDC serum level had no statistical difference between the groups (579.9 ± 16.42 versus 556.5 ± 15.29, P = 0.298). The counts of platelet and eosinophil in the peripheral blood of patients with active tuberculosis are significantly increased as well (289.4 ± 8.14 versus 248.3 ± 5.34 [P < 0.0001] and 165.1 ± 14.33 versus 102.5 ± 10.72 [P = 0.0005], respectively), and the platelet counts were positively correlated with serum TARC levels (Pearson r = 0.456, P < 0.0001), which indicates a new source of Th2 bias showing in active TB patients.