NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation.

NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target.

NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs.

Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor NLRP12 is associated with infectious and inflammatory diseases, but its activating triggers and roles in cell death and inflammation remain unclear. Here, we discovered that NLRP12 drives inflammasome and PANoptosome activation, cell death, and inflammation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induced Nlrp12 expression, which led to inflammasome formation to induce maturation of IL-1ß and IL-18. The inflammasome also served as an integral component of a larger NLRP12-PANoptosome that drove inflammatory cell death through caspase-8/RIPK3. Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model. Overall, we identified NLRP12 as an essential cytosolic sensor for heme plus PAMPs-mediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.

Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Progranulin haploinsufficiency mediates cytoplasmic TDP-43 aggregation with lysosomal abnormalities in human microglia.

BACKGROUND: Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency. METHODS: To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls. RESULTS: iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines. CONCLUSIONS: Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.

Ameliorating effects of Acanthopanax koreanum extract and components on nicotine dependence and withdrawal symptoms.

Tobacco smoking is a serious health problem in society. While smoking rates are declining, smoking remains a serious risk to national health. Currently, there are several medications available to aid in smoking cessation. However, these medications have the disadvantages of low success rates in smoking cessation and various side effects. Therefore, natural-based smoking cessation aids are being suggested as a good alternative due to their accessibility and minimal side effects. The roots and stems of Acanthopanax koreanum (AK) Nakai, a plant that is native to Jeju Island, South Korea, have traditionally been used as tonic and sedatives. Moreover, eleutheroside B and chlorogenic acid are the main components of AK stem extract. In the present study, we investigated the effect of 70% ethanol AK extract and its components on ameliorating nicotine dependence and withdrawal symptoms by using behavioural tests in mice. In addition, alterations in the dopaminergic and DRD1-EPAC-ERK-CREB pathways were observed using dopamine ELISA and western blotting using mouse brains. Our findings demonstrate that the AK extract and its components effectively mitigated the effects of nicotine treatment in behavioural tests. Furthermore, it normalized the dopamine concentration and the expression level of nicotine acetylcholine receptor α7. Additionally, it was observed that AK extract and its components led to the normalization of DRD1, ERK and CREB expression levels. These results indicate that AK extract exhibits effects in ameliorating nicotine dependence behaviour and alleviating withdrawal symptoms. Moreover, EB and CGA are considered potential marker components of AK extract.

Ultrasonographic Study of the Submandibular Gland for Botulinum Neurotoxin Injection.

BACKGROUND: Hypertrophied submandibular glands provide a bulky contour to the lower face. Botulinum neurotoxin injection methods are commonly used for facial contouring; however, no studies have suggested injection points because of the lack of delicate anatomical information on the submandibular gland. OBJECTIVE: The aim of this study was to determine the optimal injection site for botulinum neurotoxin injections in the submandibular gland. MATERIALS AND METHODS: Anatomical considerations when injecting botulinum neurotoxin into the submandibular gland were determined using ultrasonography. The thickness of the submandibular gland, its depth from the skin surface, and the location of the vascular bundle were observed bilaterally in 42 participants. Two cadavers were dissected to measure the location of the submandibular gland corresponding to the ultrasonographic observation. RESULTS: The thickest part of the submandibular gland measured 11.12 ± 2.46 in width with a depth of 4.63 ± 0.76. At the point where it crosses the line of the lateral canthus, it measured 5.53 ± 1.83 in width and 8.73 ± 1.64 in depth. CONCLUSION: The authors suggest optimal injection sites based on external anatomical landmarks. These guidelines aim to maximize the effects of botulinum neurotoxin therapy by minimizing its deleterious effects, which can be useful in clinical settings.

Posttranscriptional modulation of KCNQ2 gene expression by the miR-106b microRNA family.

MicroRNAs (miRNAs) have recently emerged as important regulators of ion channel expression. We show here that select miR-106b family members repress the expression of the KCNQ2 K+ channel protein by binding to the 3'-untranslated region of KCNQ2 messenger RNA. During the first few weeks after birth, the expression of miR-106b family members rapidly decreases, whereas KCNQ2 protein level inversely increases. Overexpression of miR-106b mimics resulted in a reduction in KCNQ2 protein levels. Conversely, KCNQ2 levels were up-regulated in neurons transfected with antisense miRNA inhibitors. By constructing more specific and stable forms of miR-106b controlling systems, we further confirmed that overexpression of precursor-miR-106b-5p led to a decrease in KCNQ current density and an increase in firing frequency of hippocampal neurons, while tough decoy miR-106b-5p dramatically increased current density and decreased neuronal excitability. These results unmask a regulatory mechanism of KCNQ2 channel expression in early postnatal development and hint at a role for miR-106b up-regulation in the pathophysiology of epilepsy.

Fourier Transform Infrared (FT-IR) Spectroscopy and Simple Algorithm Analysis for Rapid and Non-Destructive Assessment of Cotton Fiber Maturity and Crystallinity for Plant Mapping.

Information on boll distribution within a cotton plant is critical to evaluate the adaptation and response of cotton plants to environmental and biotic stress in cotton production. Cotton researchers have applied available conventional fiber measurements, such as the high volume instrument (HVI) and advanced fiber information system (AFIS), to map the location and the timing of boll development and distribution within plants and further to determine within-plant variability of cotton fiber properties. Both HVI and AFIS require numerous cotton bolls combined for the measurement. As an alternative approach, attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy was proposed to measure fiber maturity (MIR) and crystallinity (CIIR) of a sample as little as 0.5 mg lint. Extending fiber maturity and crystallinity measurement into a single boll for node-by-node mapping, FT-IR method might be advantageous due to less sampling amount compared with HVI and AFIS methods. Results showed that FT-IR technique enabled the evaluation of fiber MIR and CIIR at a boll level, which resulted in average MIR and CIIR values highly correlated with HVI micronaire (MIC) and AFIS maturity ratio (M). Hence, FT-IR technique possesses a good potential for a rapid and non-destructive node-by-node mapping of cotton boll maturity and crystallinity distribution.

Sihler's staining technique: How to and guidance for botulinum neurotoxin injection in human muscles.

The Sihler's stain is a whole-mount nerve staining technique that allows visualization of the nerve distribution and permits mapping of the entire nerve supply patterns of the organs, skeletal muscles, mucosa, skin, and other structures that contain myelinated nerve fibers. Unlike conventional approaches, this technique does not require extensive dissection or slide preparation. To date, the Sihler's stain is the best tool for demonstrating the precise intramuscular branching and distribution patterns of skeletal muscles. The intramuscular neural distribution is used as a guidance tool for the application of botulinum neurotoxin injections. In this review, we have identified and summarized the ideal botulinum neurotoxin injection points for several human tissues.

Comparison between botulinum toxin type A injection on masseter muscle only and additional injection on anterior belly of digastric muscle in sleep bruxism patients: A clinical trial.

OBJECTIVE: This study aims to evaluate the effects on bite force and muscle thickness of the botulinum toxin (BoNT) injection for patients with sleep bruxism (SB) by comparing injections into the masseter muscle only and both the masseter and the anterior belly of the digastric muscle (ABDM) in a clinical trial. METHODS: Twelve SB patients received BoNT-A injections using US-guided techniques into the masseter muscle only (Group A), while the remaining 12 SB patients received injections into both the masseter and ABDM (Group B). Bite force and muscle thickness were measured before injection, as well as 1 and 2 months after injection. RESULTS: The bite force and masseter muscle thickness decreased in both Group A and Group B before injection, and at 1 and 2 months after injection. However, there was no significant difference (p > .05, repeated measures analysis of variance) between the two groups, and there was also no significant difference in ABDM thickness (p > .05, repeated measures analysis of variance). CONCLUSION: This study is the first to assess the short-term effects of BoNT injected into ABDM for SB control. Results show no influence on SB reduction, suggesting the need for further research on BoNT's effectiveness in controlling intense ABDM contractions during sleep and assessing suprahyoid muscle potential impact on rhythmic masticatory muscle activity occurrence.

Effect of Copper Antifouling Paint on Marine Degradation of Polypropylene: Uneven Distribution of Microdebris between Nagasaki Port and Goto Island, Japan.

Microplastics (MP) encompass not only plastic products but also paint particles. Marine microdebris, including MP, was retrieved from five sampling stations spanning Nagasaki-Goto island and was classified into six types, primarily consisting of MP (A), Si-based (B), and Cu-based (C) paint particles. Type-A particles, i.e., MP, were exceedingly small, with 74% of them having a long diameter of 25 µm or less. The vertical distribution of type C, containing cuprous oxide, exhibited no depth dependence, with its dominant size being less than 7 µm. It was considered that the presence of type C was associated with a natural phenomenon of MP loss. To clarify this, polypropylene (PP) samples containing cuprous oxide were prepared, and their accelerated degradation behavior was studied using a novel enhanced degradation method employing a sulfate ion radical as an initiator. Infrared spectroscopy revealed the formation of a copper soap compound in seawater. Scanning electron microscopy/energy-dispersive X-ray spectroscopy analysis indicated that the chemical reactions between Cl- and cuprous oxide produced Cu+ ions. The acceleration of degradation induced by the copper soap formed was studied through the changes in the number of PP chain scissions, revealing that the presence of type-C accelerated MP degradation.

Sihler's staining of the anterior belly of digastric muscle for botulinum toxin injection.

PURPOSE: The anterior belly of the digastric muscle (ABDM) is the target of botulinum toxin injection; however, anatomical considerations related to the injection point are absent. This study used Sihler's staining to analyze the intramuscular nerve distribution of ABDM to identify the most effective botulinum toxin injection points. METHODS: We used 12 specimens from 6 embalmed cadavers in this study. The specimens were manually dissected to preserve the mylohyoid nerve and subjected to Sihler's staining. From the gnathion to and hyoid bone, the ABDM was divided into three equal parts, distinguishing the anterior, middle, and posterior thirds. RESULTS: Only a branch of the mylohyoid nerve entered the ABDM, and its entry point was located in the middle-third region in all cases. The nerve endings were concentrated in the middle third (100%), followed by the anterior third (58.3%) and were not observed in the posterior third. CONCLUSION: The landmarks used in this study (gnathion and hyoid bone) are easily palpable on the skin surface, allowing clinicians to target the most effective injection site (middle third of ABDM). These results provide scientific and anatomic evidence for injection points, and will aid in the management of ABDM injection procedures in clinical practice.

A novel description of the supporting system of the orbicularis oculi muscle in the infraorbital area: Tear trough muscle fiber.

BACKGROUND: The aim of this study was to elucidate the anatomical structures of supporting system of the infraorbital area. MATERIALS AND METHODS: Forty-four hemifaces from eleven Korean and eleven Thai cadavers were used to dissect the infraorbital area. Based on the dissection and previous histologic results, they were analyzed. RESULTS: The orbicularis oculi muscle (OOc) had two portions (palpebral and orbital portion) and four subparts (pretarsal, preseptal, prezygomatic, and premaxillary part). The elliptical muscle fiber of OOc was supported by circumferential connective tissue including skin ligament, orbicularis retaining ligament, zygomatic ligament, and zygomatic cutaneous ligament. The vertical muscle fiber, the tear trough muscle fiber, and medial muscular band directly attached to the skin. CONCLUSION: Full of subcutaneous tissue in the tear trough groove, strong attachment to the bone by tear trough ligament and to the skin by tear trough muscle fiber would multiply result in the tear trough on the face.

Anatomical Considerations for the Injection of Botulinum Neurotoxin in Shoulder and Arm Contouring.

The utilization of botulinum neurotoxin in the field of body contouring is on the rise. Body contouring procedures typically focus on specific muscle groups such as the superior trapezius, deltoid, and lateral head of the triceps brachii. The authors propose identifying optimal injection sites for botulinum neurotoxin to achieve desired aesthetic contouring of the shoulders and arms. The authors conducted a modified Sihler's staining method on specimens of the superior trapezius, deltoid, and lateral head of the triceps brachii muscles, totaling 16, 14, and 16 specimens, respectively. The neural distribution exhibited the most extensive branching patterns within the horizontal section (between 1/5 and 2/5) and the vertical section (between 2/4 and 4/4) of the superior trapezius muscle. In the deltoid muscle, the areas between the anterior and posterior deltoid bellies, specifically within the range of the horizontal 1/3 to 2/3 lines, showed significant intramuscular arborization. Furthermore, the middle deltoid muscle displayed arborization patterns between 2/3 and the axillary line. Regarding the triceps brachii muscle, the lateral heads demonstrated arborization between 4/10 and 7/10. The authors recommend targeting these regions, where maximum arborization occurs, as the optimal and safest points for injecting botulinum toxin.

Cholesterol sulfate inhibits osteoclast differentiation and survival by regulating the AMPK-Sirt1-NF-κB pathway.

Cholesterol sulfate (CS) is an activator of retinoic acid-related orphan receptor α (RORα). CS treatment or RORα overexpression attenuates osteoclastogenesis in a collagen-induced arthritis mouse model. However, the mechanism by which CS and RORα regulate osteoclast differentiation remains largely unknown. Thus, we aimed to investigate the role of CS and RORα in osteoclastogenesis and their underlying mechanism. CS inhibited osteoclast differentiation, but RORα deficiency did not affect osteoclast differentiation and CS-mediated inhibition of osteoclastogenesis. CS enhanced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and sirtuin1 (Sirt1) activity, leading to nuclear factor-κB (NF-κB) inhibition by decreasing acetylation at Lys310 of p65. The NF-κB inhibition was restored by AMPK inhibitor, but the effects of CS on AMPK and NF-κB were not altered by RORα deficiency. CS also induced osteoclast apoptosis, which may be due to sustained AMPK activation and consequent NF-κB inhibition, and the effects of CS were significantly reversed by interleukin-1ß treatment. Collectively, these results indicate that CS inhibits osteoclast differentiation and survival by suppressing NF-κB via the AMPK-Sirt1 axis in a RORα-independent manner. Furthermore, CS protects against bone destruction in lipopolysaccharide- and ovariectomy-mediated bone loss mouse models, suggesting that CS is a useful therapeutic candidate for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

Anatomical analysis of the motor endplate zones of the suprascapular nerve to the infraspinatus muscle and its clinical significance in managing pain disorder.

Myofascial pain syndrome caused by myofascial trigger points is a musculoskeletal disorder commonly encountered in clinical practice. The infraspinatus muscle is the region most frequently involved in the myofascial pain syndrome in the scapular region. The characteristics of the myofascial trigger points are that they can be found constantly in the motor endplate zone. However, localizing myofascial trigger points within the motor endplate zone and establishing an accurate injection site of the infraspinatus muscle has been challenging because the anatomical position of the motor endplate zone of the infraspinatus muscle is yet to be described. Therefore, this cadaveric study aimed to scrutinize the motor endplate zone of the infraspinatus muscle, propose potential myofascial trigger points within the muscle, and recommend therapeutic injection sites. Twenty specimens of the infraspinatus muscle for nerve staining and 10 fresh frozen cadavers for evaluation of the injection were used in this study. The number of nerve branches penetrating the infraspinatus muscle and their entry locations were analyzed and photographed. Modified Sihler's staining was performed to examine the motor endplate regions of the infraspinatus muscle. The nerve entry points were mostly observed in the center of the muscle belly. The motor endplate was distributed equally throughout the infraspinatus muscle, but the motor endplate zone was primarily identified in the B area, which is approximately 20-40% proximal to the infraspinatus muscle. The second-most common occurrence of the motor endplate zone was observed in the center of the muscle. These detailed anatomical data would be very helpful in predicting potential pain sites and establishing safe and effective injection treatment using botulinum neurotoxin, steroids, or lidocaine to alleviate the pain disorder of the infraspinatus muscle.

Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer's and concomitant cerebrovascular burdens.

OBJECTIVES: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. METHODS: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. RESULTS: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. CONCLUSION: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.

Effect of psychological factors on COVID-19 vaccine hesitancy.

BACKGROUND: Vaccine hesitancy can prevent full immunization against coronavirus infectious disease-19 (COVID-19). We hypothesized that multiple factors, including an individual's personality and psychological factors, are associated with vaccine hesitancy. METHODS: A total of 275 non-vaccinated individuals were recruited for this study. Participants completed a self-report questionnaire including sociodemographic factors, health status, COVID-19 literacy and psychological factors (depressive symptoms, generalized anxiety, somatization, illness anxiety, temperament and character). In a hierarchical logistic regression analysis, a discrete set of hierarchical variables with vaccine acceptance or hesitancy as the dependent variable was added to the demographic factors for Model 1; Model 1 + health status for Model 2; Model 2 + COVID-19 literacy for Model 3 and Model 3 + psychological factors for Model 4. RESULTS: Models 3 and 4 could predict vaccine hesitancy. High scores on the Generalized Anxiety Disorder-7 and the Illness Attitude Scale, low confidence, low collective responsibility and low reward dependence were risk factors for vaccine hesitancy. CONCLUSIONS: The present study demonstrates that psychological factors play critical roles in vaccine hesitancy. In addition to conventional policies that emphasize COVID-19 vaccines' safety and efficacy and the collective benefits of vaccination, a more individualized approach that considers an individual's emotions and personality is necessary.

Ultrasound-guided thread lifting for the prevention of parotid gland and diagnosing parotid duct complications.

BACKGROUND: Thread lifting is a common minimally invasive plastic surgery procedure. Parotid gland injury caused by thread lifting is a known complication; however, visual evidence of this complication is lacking. OBJECTIVES: This study aimed to present cases of parotid gland injury by thread lifting shown using ultrasound and to discuss the importance of ultrasound detection of the location of the parotid gland before thread insertion. METHODS: This study included eight patients diagnosed with parotid gland perforation and one with parotid duct injury due to threads from November 2020 to October 2022. RESULTS: Six patients showed tenderness and swelling, three were asymptomatic, and one with duct injury showed severe swelling and pain. Although the severity and duration of symptoms have differed, we confirmed the progress of improvement with conservative treatment and confirmed ultrasound findings progressed. CONCLUSIONS: Using ultrasound to detect the parotid gland's location before thread lifting might reduce the chance of parotid duct injury. Identifying immediate parotid duct or gland injury with ultrasound can help to act quickly for delayed pain or swelling and reduce the likelihood of additional complications.

Nationwide Treatment Outcomes of Patients With Multidrug/Rifampin-Resistant Tuberculosis in Korea, 2011-2017: A Retrospective Cohort Study (Korean TB-POST).

BACKGROUND: The treatment outcomes of patients with multidrug/rifampin-resistant (MDR/RR) tuberculosis (TB) are important indicators that reflect the current status of TB management and identify the key challenges encountered by TB control programs in a country. METHODS: We retrospectively evaluated the treatment outcomes as well as predictors of unfavorable outcomes in patients with MDR/RR-TB notified from 2011 to 2017, using an integrated TB database. RESULTS: A total of 7,226 patients with MDR/RR-TB were included. The treatment success rate had significantly increased from 63.9% in 2011 to 75.1% in 2017 (P < 0.001). Among unfavorable outcomes, the proportion of patients who failed, were lost to follow up, and were not evaluated had gradually decreased (P < 0.001). In contrast, TB-related death rate was not significantly changed (P = 0.513), while the non-TB related death rate had increased from 3.2% in 2011 to 11.1% in 2017 (P < 0.001). Older age, male sex, immigrants, low household income, previous history of TB treatment, and comorbidities were independent predictors of unfavorable outcomes. Of the 5,308 patients who were successfully treated, recurrence occurred in 241 patients (4.5%) at a median 18.4 months (interquartile range, 9.2-32.4) after completion treatment. CONCLUSION: The treatment outcomes of patients with MDR/RR-TB has gradually improved but increasing deaths during treatment is an emerging challenge for MDR-TB control in Korea. Targeted and comprehensive care is needed for vulnerable patients such as the elderly, patients with comorbidities, and those with low household incomes.