Effects of Real-Time Feedback Methods on Static Balance Training in Stroke Patients: A Randomized Controlled Trial.

BACKGROUND: The purpose of this study was to investigate the effects of real-time feedback methods on static balance training in stroke patients. There are two types of real-time feedback methods, as follows: one is Knowledge of Result (KR), and the other is Knowledge of Performance (KP). METHOD: Thirty stroke patients participated in this study and were randomly assigned to the KR group (n = 15) or the KP group (n = 15). All of the groups underwent real-time feedback training for four weeks (30 min per session, five sessions per week). The primary outcomes were sway length, sway velocity, and area 95%, which were assessed before and after the intervention. The secondary outcomes included the Berg Balance Scale, the Fugl Meyer Assessment for Lower Extremity, the Postural Assessment Scale for Stroke Trunk Impairment Scale, and the Fall Efficacy Scale. A group × time interaction was assessed using two-way ANOVA with repeated measures. RESULT: There was a significant increase over time in all outcomes (p < 0.05). Significant differences were observed for a group × time interaction in sway length and area 95% (p < 0.05). CONCLUSIONS: Real-time feedback training for static balance enhanced stroke patients' static balance abilities, clinical outcome assessments, and promoted self-efficacy against falls.

Effect of characteristics on the clinical course at the initiation of treatment for human immunodeficiency virus infection using dimensionality reduction.

The beginning of human immunodeficiency virus (HIV) infection treatment depends on various factors, which are significantly correlated with the initial CD4 cell number. However, a covariate correlation between these factors may not reflect the correct outcome variable. Thus, we evaluated the effects of a combination of fixed factors (reduced dimensions), which determine when to start treatment for the first time, on short-term outcome, long-term outcome, and survival, considering correlations between factors. Multiple correspondence analysis was performed on variables obtained from 925 patients who participated in a Korean HIV/acquired immunodeficiency syndrome cohort study (2006-2017). Five reduced dimension groups were derived according to clinical data, viral load, CD4 cell count at diagnosis, initial antiretroviral therapy, and others. The dimension group with high initial viral loads (55,000 copies/mL) and low CD4 cell counts (< 200 cells/mm3) should start treatment promptly after diagnosis. Groups with high initial CD4 cell counts (> 350 cells/mm3) that did not require immediate treatment according to previous guidelines had a higher failure rate for long-term relative CD4 recovery. Our results highlight the importance of early diagnosis and treatment to positively influence long-term disease outcomes, even if the initial immune status is poor, given the patient's combination of early diagnostic symptoms.

9 months of delamanid, linezolid, levofloxacin, and pyrazinamide versus conventional therapy for treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-END): a multicentre, randomised, open-label phase 2/3 non-inferiority trial in South Korea.

BACKGROUND: With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We aimed to investigate whether a new all-oral regimen was non-inferior to the conventional regimen including second-line anti-tuberculosis drugs for 20-24 months in the treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis. METHODS: In this multicentre, randomised, open-label phase 2/3 non-inferiority trial, we enrolled men and women aged 19-85 years with multidrug-resistant tuberculosis confirmed by phenotypic or genotypic drug susceptibility tests or rifampicin-resistant tuberculosis by genotypic tests at 12 participating hospitals throughout South Korea. Participants with fluoroquinolone-resistant multidrug-resistant tuberculosis were excluded. Participants were randomly assigned (1:1) to two groups using a block randomisation, stratified by the presence of diabetes and cavitation on baseline chest radiographs. The investigational group received delamanid, linezolid, levofloxacin, and pyrazinamide for 9 months, and the control group received a conventional 20-24-month regimen, according to the 2014 WHO guidelines. The primary outcome was the treatment success rate at 24 months after treatment initiation in the modified intention-to-treat population and the per-protocol population. Participants who were "cured" and "treatment completed" were defined as treatment success following the 2014 WHO guidelines. Non-inferiority was confirmed if the lower limit of a 97·5% one-sided CI of the difference between the groups was greater than -10%. Safety data were collected for 24 months in participants who received a predefined regimen at least once. This study is registered with ClinicalTrials.gov, NCT02619994. FINDINGS: Between March 4, 2016, and Sept 14, 2019, 214 participants were enrolled, 168 (78·5%) of whom were included in the modified intention-to-treat population. At 24 months after treatment initiation, 60 (70·6%) of 85 participants in the control group had treatment success, as did 54 (75·0%) of 72 participants in the shorter-regimen group (between-group difference 4·4% [97·5% one-sided CI -9·5% to ∞]), satisfying the predefined non-inferiority margin. No difference in safety outcomes was identified between the control group and the shorter-regimen group. INTERPRETATION: 9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis. FUNDING: Korea Disease Control and Prevention Agency, South Korea.

Can nirmatrelvir/ritonavir treatment shorten the duration of COVID-19 isolation?

Background: The impact of nirmatrelvir/ritonavir treatment on shedding of viable virus in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Methods: A prospective cohort study evaluating mildly ill COVID-19 patients was conducted. Virologic responses were compared between nirmatrelvir/ritonavir-treatment and supportive care groups. Risk factors and relevant clinical factors for shedding of viable virus were investigated. Results: A total of 80 COVID-19 patients were enrolled and 222 sputum specimens were collected. Ten patients were dropped during follow-up, and 33 patients in the nirmatrelvir/ritonavir and 37 in the supportive care groups were compared. The median age was 67 years, and 67% were male. Clinical characteristics were similar between groups. Viral loads decreased significantly faster in the nirmatrelvir/ritonavir group compared with the supportive care group (P < 0.001), and the slope was significantly steeper (-2.99 ± 1.54 vs. -1.44 ± 1.52; P < 0.001). The duration of viable virus shedding was not statistically different between groups. In the multivariable analyses evaluating all collected specimens, male gender (OR 2.51, 95% CI 1.25-5.03, P = 0.010), symptom score (OR 1.41, 95% CI 1.07-1.87, P = 0.015), days from symptom onset (OR 0.72, 95% CI 0.59-0.88, P = 0.002), complete vaccination (OR 0.09, 95% CI 0.01-0.87, P = 0.038), and BA.2 subtype (OR 0.49, 95% CI 0.26-0.91, P = 0.025) were independently associated with viable viral shedding, while nirmatrelvir/ritonavir treatment was not. Conclusion: Nirmatrelvir/ritonavir treatment effectively reduced viral loads of SARS-CoV-2 Omicron variants but did not decrease the duration of viable virus shedding.

Mortality and Causes of Death among Individuals Diagnosed with Human Immunodeficiency Virus in Korea, 2004-2018: An Analysis of a Nationwide Population-Based Claims Database.

The mortality rate and causes of death among individuals diagnosed with human immunodeficiency virus (HIV) infection in Korea were described and compared to those of the general population of Korea using a nationwide population-based claims database. We included 13,919 individuals aged 20-79 years newly diagnosed with HIV between 2004 and 2018. The patients' vital status and cause of death were linked until 31 December 2019. Standardized mortality ratios (SMRs) for all-cause death and specific causes of death were calculated. By the end of 2019, 1669 (12.0%) of the 13,919 HIV-infected participants had died. The survival probabilities of HIV-infected individuals at 1, 5, 10, and 15 years after diagnosis in Korea were 96.2%, 91.6%, 85.9%, and 79.6%, respectively. The main causes of death during the study period were acquired immunodeficiency syndrome (AIDS; 59.0%), non-AIDS-defining cancer (8.2%), suicide (7.4%), cardiovascular disease (4.9%), and liver disease (2.7%). The mortality rate of men and women infected with HIV was 5.60-fold (95% CI = 5.32-5.89) and 6.18-fold (95% CI = 5.30-7.09) that of men and women in the general population, respectively. After excluding deaths due to HIV, the mortality remained significantly higher, with an SMR of 2.16 (95% CI = 1.99-3.24) in men and 3.77 (95% CI = 3.06-4.48) in women. HIV-infected individuals had a higher overall mortality than the general population, with AIDS the leading cause of mortality. Additionally, mortality due to non-AIDS-related causes was higher in HIV-infected individuals.

Cancer Incidence Among Adults With HIV in a Population-Based Cohort in Korea.

Importance: In combination with a decreased risk of AIDS-defining cancers and improved survival of people infected with HIV, the burden of non-AIDS-defining cancer has increased markedly. Although a substantial number of studies have measured the cancer risk among people with HIV in developed countries, little research has been conducted on the risk of cancer in HIV-infected people in Asia. Objective: To examine the cancer incidence and the estimated risk of cancer among people in Korea infected with HIV compared with the general population. Design, Setting, and Participants: This retrospective cohort study evaluated patients without cancer newly diagnosed with HIV from January 1, 2006, to December 31, 2018, using a nationwide population-based claims database embedded in the National Health Insurance Service database. Data were analyzed between December 6, 2021, and February 28, 2022. Exposures: Infection with HIV. Main Outcomes and Measures: Cancer incidence and standardized incidence rate (SIR) through indirect standardization. Results: A total of 11 552 individuals without cancer (10 444 male [90.4%]; mean [SD] age, 39.9 [11.2] years) diagnosed with HIV were identified. The SIR for all cancers was 1.68 (95% CI, 1.50-1.87) in men and 1.26 (95% CI, 0.89-1.64) in women. In men, the highest SIRs were for Kaposi sarcoma (SIR, 349.10; 95% CI, 196.10-502.20) and anal cancer (SIR, 104.20; 95% CI, 55.56-149.90). The incidence of non-Hodgkin lymphoma (SIR, 15.62; 95% CI, 11.85-19.39), Hodgkin lymphoma (SIR, 16.67; 95% CI, 4.32-29.02), and oropharyngeal cancer (SIR, 2.97; 95% CI, 1.36-4.58) in men infected with HIV was higher than in the general population. In women infected with HIV, an increased incidence of cervical cancer (SIR, 4.98; 95% CI, 1.29-8.66) and non-Hodgkin lymphoma (SIR, 11.78; 95% CI, 2.35-21.21) compared with the general population was observed. The SIR of thyroid cancer in patients with HIV was lower than in the general population in both men (SIR, 0.63; 95% CI, 0.27-0.99) and women (SIR, 0.48; 95% CI, 0.06-0.90). Conclusions and Relevance: In this cohort study, cancer risks, especially AIDS-defining cancer and virus-related cancer, were elevated in people with HIV. Efforts for cancer prevention, screening, and better accessibility to medical care in HIV-infected people are warranted.

Eribulin Mesylate Improves Cisplatin-Induced Cytotoxicity of Triple-Negative Breast Cancer by Extracellular Signal-Regulated Kinase 1/2 Activation.

Background and Objectives; Triple-negative breast cancer (TNBC) is associated with poor patient prognosis because of its multiple molecular features. Thus, more effective treatment for TNBC is urgently needed. This study determined the possible involvement of ERK1/2 activation in cisplatin-induced cytotoxicity in TNBC by providing additional eribulin treatment. Materials and Methods; We investigated cell viability and apoptosis caused by eribulin, cisplatin, or co-treatment in HCC38, MDA-MB-231, and SKBR3 human breast cancer cells. Results; Cisplatin significantly lowered cell viability and caused high apoptotic cell death in all breast cancer cell lines. The viability of TNBC cells was significantly lower in the group co-treated with cisplatin and eribulin than in the cisplatin-only treatment group. Additional eribulin treatment significantly enhanced PARP cleavage and caspase-3 activity in cisplatin-treated TNBC cells. Moreover, cisplatin treatment activated ERK1/2 in all breast cancer cell lines. The cisplatin and eribulin combination synergistically activated ERK1/2 in TNBC cells compared with the cisplatin-only treatment. Administration of the ERK1/2 inhibitor PD98059 increased the viability of TNBC cells treated with cisplatin plus eribulin. Conclusions; Eribulin could synergize the cytotoxic and apoptotic activities of cisplatin and increase ERK1/2 activation, thus enhancing anti-cancer effects against TNBC cells.

Clinical Characteristics of 40 Patients Infected With the SARS-CoV-2 Omicron Variant in Korea.

Since severe acute respiratory syndrome-coronavirus-2 variant B.1.1.529 (omicron) was first reported to the World Health Organization on November 24, 2021, the cases of the omicron variant have been detected in more than 90 countries over the last month. We investigated the clinical and epidemiological characteristics of the first 40 patients with the omicron variant who had been isolated at the National Medical Center in South Korea during December 4-17, 2021. The median age of the patients was 39.5 years. Twenty-two patients (55%) were women. Seventeen patients (42.5%) were fully vaccinated, and none were reinfected with the omicron. Eighteen (45%) had recent international travel history. Half of the patients (19, 47.5%) were asymptomatic, while the others had mild symptoms. Six patients (15%) showed lung infiltrations on chest image; however, none required supplemental oxygen. These mild clinical features are consistent with recent case reports on the omicron variant from other countries.

A forebrain neural substrate for behavioral thermoregulation.

Thermoregulatory behavior is a basic motivated behavior for body temperature homeostasis. Despite its fundamental importance, a forebrain region or defined neural population required for this process has yet to be established. Here, we show that Vgat-expressing neurons in the lateral hypothalamus (LHVgat neurons) are required for diverse thermoregulatory behaviors. The population activity of LHVgat neurons is increased during thermoregulatory behavior and bidirectionally encodes thermal punishment and reward (P&R). Although this population also regulates feeding and caloric reward, inhibition of parabrachial inputs selectively impaired thermoregulatory behaviors and encoding of thermal stimulus by LHVgat neurons. Furthermore, two-photon calcium imaging revealed a subpopulation of LHVgat neurons bidirectionally encoding thermal P&R, which is engaged during thermoregulatory behavior, but is largely distinct from caloric reward-encoding LHVgat neurons. Our data establish LHVgat neurons as a required neural substrate for behavioral thermoregulation and point to the key role of the thermal P&R-encoding LHVgat subpopulation in thermoregulatory behavior.

Changes in treatment for multidrug-resistant tuberculosis according to national income.

The aim of this study was to analyse temporal changes in treatments for and outcomes of multidrug-resistant (MDR)/rifampin-resistant (RR)-tuberculosis (TB) in the context of national economic status.We analysed data collected by the Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB Treatment on MDR/RR-TB patients from 37 countries. The data were stratified by three national income levels (low-/lower-middle, upper-middle and high) and grouped by time of treatment initiation (2001-2003, 2004-2006, 2007-2009, 2010-2012 and 2013-2015). Temporal trends over the study period were analysed. The probability of treatment success in different income groups over time was calculated using generalised linear mixed models with random effects.In total, 9036 patients were included in the analysis. Over the study period, use of group A drugs (levofloxacin/moxifloxacin, bedaquiline and linezolid) recommended by the World Health Organization increased and treatment outcomes improved in all income groups. Between 2001-2003 and 2013-2015, treatment success rates increased from 60% to 78% in low-/lower-middle-income countries, from 40% to 67% in upper-middle-income countries, and from 73% to 81% in high-income countries. In earlier years, the probability of treatment success in upper-middle-income countries was lower than that in low-/lower-middle-income countries, but no difference was observed after 2010. However, high-income countries had persistently higher probability of treatment success compared to upper-middle income countries.Improved treatment outcomes and greater uptake of group A drugs were observed over time for patients with MDR/RR-TB at all income levels. However, treatment outcomes are still unsatisfactory, especially in upper-middle-income countries.

A neural circuit mechanism for mechanosensory feedback control of ingestion.

Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood1-12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract.

Occupational Health Injuries by Job Characteristics and Working Environment among Street Cleaners in South Korea.

In 2018, 1822 incidents relating to death or injury occurred among street cleaners in South Korea. However, South Korea currently lacks comprehensive studies on related injuries based on street cleaners' job characteristics and environments in the country. This study analyzed injuries according to the job characteristics and environment through a survey of 150 Korean street cleaners working in the Seoul and Gyeonggi-do areas. This study assessed three category measures-demographic, job characteristics, and environments-to determine the effects of injuries. The demographic measures consisted of age, gender, and education level. Job characteristic variables consisted of length of time on the job, job contract, monthly income, working hours per day, working start time, overtime per month, and days off per month. For job environments, this survey included job duty, classification, main tasks, work intensity, and safety equipment. The data were analyzed according to descriptive statistics, injury ratio, and Probit regression analysis. The results of the analysis demonstrated that the participants with the highest risk of injury were mostly males with less than a middle school education. Assessment of the job characteristics showed that the most prevalent length of working experience was less than 5 years, with most engaging in contract/day work. A share of 36.67% of the participants reported injuries. The most prevalent reason for injury was overwork (32.73%), and the most frequent injury area was the lower back (49.09%). In summary, injuries among street cleaners were associated with education level, job experience, days off from work, and work intensity. As such, street cleaners should receive more education to decrease the risk of injuries, regardless of the number of employees or their contract status.

Protocol of a Nationwide Observational Study among Patients with Nontuberculous Mycobacterium Pulmonary Disease in South Korea (NTM-KOREA).

BACKGROUND: The burden of nontuberculous mycobacterial (NTM) pulmonary disease (PD) is increasing globally. To understand the treatment outcomes and prognosis of NTM-PD, a unified registry is needed. In this project, we aim to construct a multicenter prospective observational cohort with NTM-PD in South Korea (NTM-KOREA). METHODS: The primary objective of this study is to analyze treatment outcomes according to the species. In addition, recurrence rate, adverse events, the impact of each drug on treatment outcomes as well as the impact of characteristics of mycobacteriology will be analyzed. The inclusion criteria for the study are as follows: fulfilling the criteria for NTM-PD having one of the following etiologic organisms: Mycobacterium avium complex, M. abscessus subspecies abscessus, M. abscessus subspecies massiliense, or M. kansasii; receiving the first treatment for NTM-PD after enrollment; age >20 years; and consenting to participate in the study. Seven institutions will participate in patient enrollment and about 500 patients are expected to be enrolled. Participants will be recruited from 1 March 2020 until 19 March 2024 and will be observed through 19 March 2029. During the follow-up period, participants' clinical course will be tracked and their clinical data as well as NTM isolates will be collected. CONCLUSION: NTM-KOREA will be the first nationwide observational cohort for NTM-PD in South Korea. It will provide the information to optimize treatment modalities and will contribute to deeper understanding of the treatment outcomes and long-term prognosis of patients with NTM-PD in South Korea.

Scalable and Isotropic Expansion of Tissues with Simply Tunable Expansion Ratio.

Tissue expansion techniques physically expand swellable gel-embedded biological specimens to overcome the resolution limit of light microscopy. As the benefits of expansion come at the expense of signal concentration, imaging volume and time, and mechanical integrity of the sample, the optimal expansion ratio may widely differ depending on the experiment. However, existing expansion methods offer only fixed expansion ratios that cannot be easily adjusted to balance the gain and loss associated with expansion. Here, a hydrogel conversion-based expansion method is presented, that enables easy adjustment of the expansion ratio for individual needs, simply by changing the duration of a heating step. This method, termed ZOOM, isotropically expands samples up to eightfold in a single expansion process. ZOOM preserves biomolecules for post-processing labelings and supports multi-round expansion for the imaging of a single sample at multiple zoom factors. ZOOM can be flexibly and scalably applied to nanoscale imaging of diverse samples, ranging from cultured cells to thick tissues, as well as bacteria, exoskeletal Caenorhabditis elegans, and human brain samples.

Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.

BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END): study protocol for a phase II/III, multicenter, randomized, open-label clinical trial.

BACKGROUND: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. METHODS: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80%, and a < 10% difference in treatment success rate between the control and investigational arms (80% vs. 70%) when the anticipated actual success rate in the treatment group is assumed to be 90%, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50%, and 5% loss to follow-up, the number of participants is calculated as N/( 0.50 × 0.95), resulting in 102 persons per group (204 in total). DISCUSSION: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB. TRIAL REGISTRATION: ClincalTrials.gov, NCT02619994 . Registered on 2 December 2015.

Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis. METHODS: We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul-Seongnam, South Korea). Patients, aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460. FINDINGS: Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1% (-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62·8%] of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75 [62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient. INTERPRETATION: Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis. FUNDING: Ministry of Health and Welfare, South Korea.

Corrigendum: Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure.

This corrects the article DOI: 10.1038/nm.4177.

Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis.

BACKGROUND: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid. METHODS: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M. tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions. RESULTS: Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 µg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 µg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 µg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater. CONCLUSIONS: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; ClinicalTrials.gov number, NCT02251327 .).