Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial

Background : The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. Methods : This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. Discussion : This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. Trial registration : ClinicalTrials.gov NCT04485156.Registered on July 24, 2020.This work was supported by a grant from the Korea National Institute of Health (2020-ER5201-01), Republic of Korea. High-dose rifampicin tablets and capsules were donated from Yuhan (Seoul, Republic of Korea) for this study. The funder and donor had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

A logical network-based drug-screening platform for Alzheimer’s disease representing pathological features of human brain organoids

Developing effective drugs for Alzheimer’s disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood–brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs. © 2021, The Author(s).1

A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population

Despite substantial advances in disease genetics, studies to date have largely focused on individuals of European descent. This limits further discoveries of novel functional genetic variants in other ethnic groups. To alleviate the paucity of East Asian population genome resources, we established the Korean Variant Archive 2 (KOVA 2), which is composed of 1896 whole-genome sequences and 3409 whole-exome sequences from healthy individuals of Korean ethnicity. This is the largest genome database from the ethnic Korean population to date, surpassing the 1909 Korean individuals deposited in gnomAD. The variants in KOVA 2 displayed all the known genetic features of those from previous genome databases, and we compiled data from Korean-specific runs of homozygosity, positively selected intervals, and structural variants. In doing so, we found loci, such as the loci of ADH1A/1B and UHRF1BP1, that are strongly selected in the Korean population relative to other East Asian populations. Our analysis of allele ages revealed a correlation between variant functionality and evolutionary age. The data can be browsed and downloaded from a public website (https://www.kobic.re.kr/kova/). We anticipate that KOVA 2 will serve as a valuable resource for genetic studies involving East Asian populations

Evaluation of Four GLUE Likelihood Measures and Behavior of Large Parameter Samples in ISPSO-GLUE for TOPMODEL

We tested four likelihood measures including two limits of acceptability and two absolute model residual methods within the generalized likelihood uncertainty estimation (GLUE) framework using the topography model (TOPMODEL). All these methods take the worst performance of all time steps as the likelihood of a model and none of these methods were successful in finding any behavioral models. We believe that reporting this failure is important because it shifted our attention from which likelihood measure to choose to why these four methods failed and how to improve these methods. We also observed how large parameter samples impact the performance of a hybrid uncertainty estimation method, isolated-speciation-based particle swarm optimization (ISPSO)-GLUE using the Nash–Sutcliffe (NS) coefficient. Unlike GLUE with random sampling, ISPSO-GLUE provides traditional calibrated parameters as well as uncertainty analysis, so over-conditioning the model parameters on the calibration data can affect its uncertainty analysis results. ISPSO-GLUE showed similar performance to GLUE with a lot less model runs, but its uncertainty bounds enclosed less observed flows. However, both methods failed in validation. These findings suggest that ISPSO-GLUE can be affected by over-calibration after a long evolution of samples and imply that there is a need for a likelihood measure that can better explain uncertainties from different sources without making statistical assumptions

Factors Influencing the Accuracy of Shallow Snow Depth Measured Using UAV-Based Photogrammetry

Factors influencing the accuracy of UAV-photogrammetry-based snow depth distribution maps were investigated. First, UAV-based surveys were performed on the 0.04 km2 snow-covered study site in South Korea for 37 times over the period of 13 days under 16 prescribed conditions composed of various photographing times, flight altitudes, and photograph overlap ratios. Then, multi-temporal Digital Surface Models (DSMs) of the study area covered with shallow snow were obtained using digital photogrammetric techniques. Next, the multi-temporal snow depth distribution maps were created by subtracting the snow-free DSM from the multi-temporal DSMs of the study area. Then, snow depth in these UAV-Photogrammetry-based snow maps were compared to the in situ measurements at 21 locations. The accuracy of each of the multi-temporal snow maps were quantified in terms of bias (median of residuals, QΔD) and precision (the Normalized Median Absolute Deviation, NMAD). Lastly, various factors influencing these performance metrics were investigated. The results are as follows: (1) the QΔD and NMAD of the eight surveys performed at the optimal condition (50 m flight altitude and 80% overlap ratio) ranged from −2.30 cm to 5.90 cm and from 1.78 cm to 4.89 cm, respectively. The best survey case had −2.30 cm of QΔD and 1.78 cm of NMAD; (2) Lower UAV flight altitude and greater photograph overlap lower the NMAD and QΔD; (3) Greater number of Ground Control Points (GCPs) lowers the NMAD and QΔD; (4) Spatial configuration and accuracy of GCP coordinates influenced the accuracy of the snow depth distribution map; (5) Greater number of tie-points leads to higher accuracy; (6) Smooth fresh snow cover did not provide many tie-points, either resulting in a significant error or making the entire photogrammetry process impossible

The use of bedaquiline to treat patients with multidrug-resistant tuberculosis and end-stage renal disease: A case report

The use of bedaquiline to treat patients with multidrug-resistant tuberculosis (MDR-TB) and end-stage renal disease (ESRD) may raise safety concerns. Currently, no clinical information is available on the use of bedaquiline to treat MDR-TB patients with ESRD. We report the use of bedaquiline to treat two patients with MDR-TB and ESRD. This report highlights the safety and tolerability of bedaquiline as well as the treatment outcome. The use of bedaquiline in patients with ESRD is also discussed. Keywords: Bedaquiline, Tuberculosis, Multidrug resistance, End-stage renal diseas

자동 조립시스템의 제작/설치 시 발생하는 치수 편차 극복을 위한 신속 로봇 보정시스템 개발

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Time to appropriate treatment in patients with multidrug-resistant tuberculosis in South Korea: Are we still in 2010?

BackgroundThis study investigated the time to appropriate treatment and factors affecting late treatment initiation in patients with multidrug-resistant tuberculosis (MDR-TB) in South Korea.MethodsData from patients with culture-confirmed pulmonary MDR-TB who received treatment at Pusan National University Hospital (PNUH) between January 2010 and July 2018 were reviewed retrospectively. Patients were divided into two groups according to the first institution they visited [patients who were transferred to PNUH after diagnosis of MDR-TB (Group A) and patients who were initially diagnosed with TB at PNUH (Group B)].ResultsA total of 100 patients were included (53 in Group A and 47 in Group B). The percentage of patients in whom line probe assays (LPAs) for isoniazid and rifampin or Xpert MTB/RIF assays were performed was higher in Group B than in Group A [20.8 vs. 57.4% (P ConclusionsThe time to appropriate treatment in patients with MDR-TB in South Korea was not acceptable, particularly for patients diagnosed outside of PNUH and for patients with pre-XDR- or XDR-TB. The use of rapid molecular drug susceptibility tests in various healthcare settings and introduction of second-line LPAs are required