Prominent transcriptomic changes in Mycobacterium intracellulare under acidic and oxidative stress.

BACKGROUND: Mycobacterium avium complex (MAC), including Mycobacterium intracellulare is a member of slow-growing mycobacteria and contributes to a substantial proportion of nontuberculous mycobacterial lung disease in humans affecting immunocompromised and elderly populations. Adaptation of pathogens in hostile environments is crucial in establishing infection and persistence within the host. However, the sophisticated cellular and molecular mechanisms of stress response in M. intracellulare still need to be fully explored. We aimed to elucidate the transcriptional response of M. intracellulare under acidic and oxidative stress conditions. RESULTS: At the transcriptome level, 80 genes were shown [FC] ≥ 2.0 and p < 0.05 under oxidative stress with 10 mM hydrogen peroxide. Specifically, 77 genes were upregulated, while 3 genes were downregulated. In functional analysis, oxidative stress conditions activate DNA replication, nucleotide excision repair, mismatch repair, homologous recombination, and tuberculosis pathways. Additionally, our results demonstrate that DNA replication and repair system genes, such as dnaB, dinG, urvB, uvrD2, and recA, are indispensable for resistance to oxidative stress. On the contrary, 878 genes were shown [FC] ≥ 2.0 and p < 0.05 under acidic stress with pH 4.5. Among these genes, 339 were upregulated, while 539 were downregulated. Functional analysis highlighted nitrogen and sulfur metabolism pathways as the primary responses to acidic stress. Our findings provide evidence of the critical role played by nitrogen and sulfur metabolism genes in the response to acidic stress, including narGHIJ, nirBD, narU, narK3, cysND, cysC, cysH, ferredoxin 1 and 2, and formate dehydrogenase. CONCLUSION: Our results suggest the activation of several pathways potentially critical for the survival of M. intracellulare under a hostile microenvironment within the host. This study indicates the importance of stress responses in M. intracellulare infection and identifies promising therapeutic targets.

Cumulative sum analysis of the learning curve for retrograde intrarenal stone surgery in newbie surgeons.

INTRODUCTION: This study investigated the learning curve of retrograde intrarenal surgery (RIRS) in patients with medium-sized stones using cumulative sum analysis (CUSUM) to evaluate the competence and proficiency of three new surgeons during their first RIRS procedures. MATERIALS AND METHODS: We conducted a retrospective review of 227 patients from 2019 to 2022 at a single institution. The patients were divided into four groups based on the operating surgeon: tutor surgeon (85 patients), newbie surgeon A (21 patients), newbie surgeon B (85 patients), and newbie surgeon C (36 patients). Patients had one or multiple stones with the largest stone diameter fell within the range of 10-30 mm. Fragmentation efficacy was calculated as "removed stone volume (mm3) divided by operative time (minutes)." CUSUM analysis monitored changes in fragmentation efficacy and validated surgical outcomes. RESULTS: No statistically significant differences were observed in the total stone volume, maximum stone size, or total operation time between the three newbie surgeons and the tutor surgeon. The mean fragmentation efficacy value was comparable among the newbie surgeons, but significantly different from that of the tutor surgeon. The minimum acceptable fragmentation efficacy level was set at 25.12 mL/min, based on the tutor's average value. The CUSUM curves for the three surgeons initially remained relatively flat until Cases 12-15, after which they increased and eventually plateaued. Stone-free rates and postoperative complications did not differ significantly among the surgeons. CONCLUSION: Learning curve analysis for the three newbie surgeons indicated that approximately 12-15 cases were required to reach a plateau.

Bigger problems from smaller colonies: emergence of antibiotic-tolerant small colony variants of Mycobacterium avium complex in MAC-pulmonary disease patients.

BACKGROUND: Mycobacterium avium complex (MAC) is a group of slow-growing mycobacteria that includes Mycobacterium avium and Mycobacterium intracellulare. MAC pulmonary disease (MAC-PD) poses a threat to immunocompromised individuals and those with structural pulmonary diseases worldwide. The standard treatment regimen for MAC-PD includes a macrolide in combination with rifampicin and ethambutol. However, the treatment failure and disease recurrence rates after successful treatment remain high. RESULTS: In the present study, we investigated the unique characteristics of small colony variants (SCVs) isolated from patients with MAC-PD. Furthermore, revertant (RVT) phenotype, emerged from the SCVs after prolonged incubation on 7H10 agar. We observed that SCVs exhibited slower growth rates than wild-type (WT) strains but had higher minimum inhibitory concentrations (MICs) against multiple antibiotics. However, some antibiotics showed low MICs for the WT, SCVs, and RVT phenotypes. Additionally, the genotypes were identical among SCVs, WT, and RVT. Based on the MIC data, we conducted time-kill kinetic experiments using various antibiotic combinations. The response to antibiotics varied among the phenotypes, with RVT being the most susceptible, WT showing intermediate susceptibility, and SCVs displaying the lowest susceptibility. CONCLUSIONS: In conclusion, the emergence of the SCVs phenotype represents a survival strategy adopted by MAC to adapt to hostile environments and persist during infection within the host. Additionally, combining the current drugs in the treatment regimen with additional drugs that promote the conversion of SCVs to RVT may offer a promising strategy to improve the clinical outcomes of patients with refractory MAC-PD.

Risk Factors for the Mortality of Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation in a Non-Centralized Setting: A Nationwide Study.

BACKGROUND: Limited data are available on the mortality rates of patients receiving extracorporeal membrane oxygenation (ECMO) support for coronavirus disease 2019 (COVID-19). We aimed to analyze the relationship between COVID-19 and clinical outcomes for patients receiving ECMO. METHODS: We retrospectively investigated patients with COVID-19 pneumonia requiring ECMO in 19 hospitals across Korea from January 1, 2020 to August 31, 2021. The primary outcome was the 90-day mortality after ECMO initiation. We performed multivariate analysis using a logistic regression model to estimate the odds ratio (OR) of 90-day mortality. Survival differences were analyzed using the Kaplan-Meier (KM) method. RESULTS: Of 127 patients with COVID-19 pneumonia who received ECMO, 70 patients (55.1%) died within 90 days of ECMO initiation. The median age was 64 years, and 63% of patients were male. The incidence of ECMO was increased with age but was decreased after 70 years of age. However, the survival rate was decreased linearly with age. In multivariate analysis, age (OR, 1.048; 95% confidence interval [CI], 1.010-1.089; P = 0.014) and receipt of continuous renal replacement therapy (CRRT) (OR, 3.069; 95% CI, 1.312-7.180; P = 0.010) were significantly associated with an increased risk of 90-day mortality. KM curves showed significant differences in survival between groups according to age (65 years) (log-rank P = 0.021) and receipt of CRRT (log-rank P = 0.004). CONCLUSION: Older age and receipt of CRRT were associated with higher mortality rates among patients with COVID-19 who received ECMO.

Lack of Association between Inhaled Corticosteroid Use Based on the Exhaled Nitric Oxide and Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is known to useful biomarker for detecting eosinophilic airway inflammation. However, there is a lack of evidence regarding the role of FeNO in chronic obstructive pulmonary disease (COPD). We aimed to assess whether elevated FeNO and its impact on treatment change into an inhaled corticosteroid (ICS)-containing regimen and association with acute exacerbation (AE) in patients with COPD. METHODS: We retrospectively analyzed 107 COPD patients without a history of asthma from March 2016 to December 2019. The patients whose FeNO value was more than 50 parts per billion (ppb) were defined into the high FeNO group. Multivariable analysis with logistic regression was used to identify factors associated with AE in COPD. RESULTS: The median FeNO value was 32 ppb (interquartile range, 19 to 45) and 34 (20.0%) patients were classified as high FeNO group (median 74 ppb). In the high FeNO group, changes in inhaler treatment into an ICS-containing regimen occurred in 23 of 34 patients after the measurement of FeNO. In multivariate analysis, high FeNO was not a contributing factor for AE, but only the high blood eosinophil count (≥300 cells/µL) was associated with AE (adjusted odds ratio, 2.63; 95% confidence interval, 1.01 to 6.91; p=0.049). CONCLUSION: High FeNO value had a significant impact on the prescription of ICSs in COPD patients, but it did not show a significant association with AE either on its own or with changes in treatment.

Is There a Difference in the Incidence of Depression between Radiation and Surgical Treatments in Patients with Prostate Cancer?

PURPOSE: Patients with cancer have a high risk of depression. However, a few studies have assessed differences in the incidence of depression among patients with prostate cancer (PC) based on whether they received radiotherapy (RTx) or surgical treatment. MATERIALS AND METHODS: We analyzed data from the National Health Insurance Sharing Service database regarding the entire Korean adult population with PC (n=210,924) between 2007 and 2017. The adjusted hazard ratios (HRs) of depression associated with treatment were estimated using propensity score-matched Cox proportional hazards models and Kaplan-Meier survival analyses. RESULTS: Our final cohort comprised 9,456 patients with PC; of which, 8,050 men underwent surgery. During a mean follow-up duration of 7.1 years, 503 (5.3%) patients were newly diagnosed with depression. A significant difference in the incidence of depression was noted between the RTx and surgery groups (RTx vs. surgery: 5.55% vs. 5.28%; p=0.011) in the unmatched cohort. In the matched cohort, older age (≥70 years, HR: 1.596, p<0.001) and poor Charlson comorbidity index scores (HR: 1.232, p=0.039) were correlated with the risk of depression. In addition, the adjusted HR for depression in the surgery group was 0.843 (p=0.221) compared with that in the RTx group. Kaplan-Meier analyses revealed that no significant difference in the cumulative probability of persistent depression was detected between the RTx and surgery groups in matched cohort (p=0.3386). CONCLUSIONS: In this nationwide population-based study, no significant differences in the risk of depression were observed between the surgical and RTx groups.

Association between age-adjusted Endothelial Activation and Stress Index and ICU mortality in patients with severe coronavirus disease-2019.

BACKGROUND: Endothelial Activation and Stress Index (EASIX) reflects endothelial dysfunction or damage. Because endothelial dysfunction is one of the key mechanisms, a few studies have shown the clinical usefulness of original and age-adjusted EASIX (age-EASIX) in patients with coronavirus disease-19 (COVID-19). We aimed to evaluate the clinical utility of age-EASIX in predicting ICU mortality in critically ill patients with COVID-19 in South Korea. METHODS: Secondary analysis was performed using clinical data retrospectively collected from 22 nationwide hospitals in South Korea between January 1, 2020, and August 31, 2021. Patients were at least 19 years old and admitted to the ICU for severe COVID-19, demanding at least high-flow nasal cannula oxygen therapy. EASIX [lactate dehydrogenase (U/L) × creatinine (mg/dl) /platelet count (109 cells/L)] and age-EASIX (EASIX × age) were calculated and log2-transformed. RESULTS: The mean age of 908 critically ill patients with COVID-19 was 67.4 years with 59.7% male sex. The mean log2 age-EASIX was 7.38 ± 1.45. Non-survivors (n=222, 24.4%) in the ICU had a significantly higher log2 age-EASIX than of survivors (8.2 ± 1.52 vs 7.1 ± 1.32, P<0.001). Log2 age-EASIX was significantly associated with ICU mortality (odds ratio, 1.541; 95% confidence interval, 1.322-1.796, P<0.001) and had a better area under the receiver operating characteristic curve than of the sequential organ failure assessment (SOFA) score in predicting ICU mortality (0.730 vs 0.660, P=0.001). CONCLUSION: Age-EASIX is significantly associated with ICU mortality and has better discriminatory ability than the SOFA score in predicting ICU mortality.