Changes in tuberculosis risk after transplantation in the setting of decreased community tuberculosis incidence: a national population-based study, 2008-2020.

BACKGROUND: Transplant recipients are immunocompromised and vulnerable to developing tuberculosis. However, active tuberculosis incidence is rapidly declining in South Korea, but the trend of tuberculosis infection among transplant recipients has not been elucidated. This study aimed to evaluate the risk of active tuberculosis after transplantation, including risk factors for tuberculosis and standardized incidence ratios, compared with that in the general population. METHODS: This retrospective study was conducted based on the South Korean health insurance review and assessment database among those who underwent transplantation (62,484 recipients) between 2008 and 2020. Tuberculosis incidence was compared in recipients treated during higher- (2010-2012) and lower-disease burden (2016-2018) periods. Standardized incidence ratios were analyzed using the Korean Tuberculosis Surveillance System. The primary outcome was the number of new tuberculosis cases after transplantation. RESULTS: Of 57,103 recipients analyzed, the overall cumulative incidence rate 1 year after transplantation was 0.8% (95% confidence interval [CI]: 0.7-0.8), significantly higher in the higher-burden period than in the lower-burden period (1.7% vs. 1.0% 3 years after transplantation, P < 0.001). Individuals who underwent allogeneic hematopoietic stem cell transplantation had the highest tuberculosis incidence, followed by those who underwent solid organ transplantation and autologous hematopoietic stem cell transplantation (P < 0.001). The overall standardized incidence ratio was 3.9 (95% CI 3.7-4.2) and was the highest in children aged 0-19 years, at 9.0 (95% CI 5.7-13.5). Male sex, older age, tuberculosis history, liver transplantation, and allogeneic hematopoietic stem cell transplantation were risk factors for tuberculosis. CONCLUSIONS: Transplant recipients are vulnerable to developing tuberculosis, possibly influenced by their immunocompromised status, solid organ transplant type, age, and community prevalence of tuberculosis. Tuberculosis prevalence by country, transplant type, and age should be considered to establish an appropriate tuberculosis prevention strategy for high-risk groups.

Haplotype diversity of Heterodera koreana (Tylenchida: Heteroderidae), affecting bamboo in Korea.

In a survey of plant-parasitic nematodes in agricultural fields, cyst-forming nematodes were found in soil planted bamboo in Korea. The aim of this study was to identify the cyst nematodes based on morphological and molecular characteristics. As the results, the morphology and morphometrics of cysts and second-stage juveniles (J2s) were consistent with those of previous descriptions of Heterodera koreana. In phylogenetic analyses based on DNA sequences, these cyst nematodes were clustered together with clade of H. koreana in internal transcribed spacer (ITS) region, and large subunit D2-D3 segments (LSU D2-D3). These nematodes were clustered together with clade of H. koreana in cytochrome c oxidase subunit I (COI) gene, but a haplotype was different when compared with previous reported haplotypes (haplotype A-C) in Japan. This study showed these cyst nematodes were identified as H. koreana, and a new haplotype of H. koreana is distributed in Korea. We suggest that the new haplotype of H. koreana name as haplotype D.

Outcomes in Patients with Pulmonary Arterial Hypertension Underwent Transcatheter Closure of an Atrial Septal Defect.

Pulmonary arterial hypertension (PAH) related to an atrial septal defect (ASD) poses a challenge to transcatheter closure of an ASD (tcASD). We aimed to determine the predictors for remaining PAH (rPAH) post-tcASD. This retrospective study was conducted at a single tertiary university hospital. Adult patients with an ASD and PAH were divided into three groups according to pulmonary vascular resistance (PVR). Normalization of pulmonary atrial systolic pressure (PASP) was defined as an estimated right ventricular systolic pressure < 40 mmHg and was determined using transthoracic echocardiography. Among 119 patients, 80% showed PAH normalization post-tcASD. Normalization of PAH post-tcASD was observed in 100%, 56.2%, and 28.6% of patients in mild, moderate, and severe PVR groups, respectively. The patients' New York Heart Association functional class improved. Multivariate logistic regression analysis showed that age and high PVR were significant risk factors for rPAH. A receiving operator curve analysis showed a PASP cutoff value > 67.5 mmHg to be predictive of rPAH post-tcASD, with an area under the curve value of 0.944 (sensitivity, 0.922; specificity 0.933). Most patients, including moderate-to-severe PAH patients, improved hemodynamically and clinically with tcASD. Since patients with severe PAH are at a risk of rPAH, tcASD should be performed by selecting the patient carefully based on pre-procedure medication, a vasoreactivity test, and a balloon occlusion test.

Impact of thyroid cancer on the cancer risk in patients with non-alcoholic fatty liver disease or dyslipidemia.

The raised prevalence of obesity has increased the incidence of obesity-related metabolic diseases such as dyslipidemia (DL) and non-alcoholic fatty liver disease (NAFLD), along with the development and progression of various types of cancer, including thyroid cancer. In this study, we investigated whether thyroid cancer in patients with DL and NAFLD could be a risk factor for other cancers. To achieve our goal, we generated two independent cohorts from our institution and from the National Health Insurance System in South Korea. Based on the ICD-10 code, we conducted exact matching (1:5 matching) and estimated the overall risk of thyroid cancer for other cancers in patients with DL or NAFLD. Univariate and multivariate analyses showed that the hazard ratio (HR) of thyroid cancer was 2.007 (95% Confidence Interval [CI], 1.597-2.522) and 2.092 (95% CI, 1.546-2.829), respectively in the institutional cohort and 1.329 (95% CI, 1.153-1.533) and 1.301 (95% CI, 1.115-1.517), respectively in the nationwide cohort. Risk analysis revealed a significant increase in the HR in lip, tongue, mouth, lung, bone, joint, soft tissue, skin, brain, male cancers and lymphoma after thyroid cancer occurred. Thyroid cancer in patients with DL or NAFLD might be a valuable factor for predicting the development of other cancers.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of Prasugrel in Healthy Male Volunteers.

This study evaluated the pharmacokinetics and pharmacodynamics of the antiplatelet agent prasugrel, and explored its optimal dose regimens via modeling and simulation using NONMEM. We measured platelet aggregation and the serial plasma concentrations of the inactive (R-95913) and active metabolites (R-138727) of prasugrel after a single oral dose of 10-60 mg in 20 healthy adult male volunteers. A pharmacokinetic model for R-95913 and R-138727, and a pharmacodynamic model between the concentration of R-138727 and maximal platelet aggregation measured by light transmittance were constructed. The predictability of the model for platelet aggregation was evaluated by comparing the model prediction values with the observed ones not used in the construction of the model. Pharmacokinetic data were best described by a 3-compartment models for R-95913, a 1-compartment model for R-138727 with transit compartment model for absorption delay, and first-pass metabolic conversion of R-95913 into R-138727 during absorption. The association-dissociation model between R-138727 and its receptor in platelets was applied for the inhibitory effect of prasugrel on platelet aggregation. Prasugrel rapidly inhibited platelet aggregation after oral administration, with a prolonged duration of action; however, the concentration of the active metabolite decreased rapidly, which may have been due to the slow dissociation rate of R-138727 from its target receptor in platelets. The external validation suggests that our model could be used to individualize prasugrel treatment in various clinical situations. Simulation showed rapid onset of inhibitory effect with great magnitude and consistent inhibition after therapeutic dose of prasugrel.

First Report of Pratylenchoides leiocauda parasitic on Perilla frutescenes in the Republic of Korea.

Perilla (Perilla frutescens (L.) Britton var. japonica) is an annual herbaceous crop belonging to Lamiaceae. It is one of the most important crops in Korea. A survey of plant parasitic nematodes was carried out in 70 perilla fields in Geumsan and Miryang, Korea in 2020. Migratory endo-parasitic nematodes were extracted from the perilla roots using modified root incubation methods (Mountain and Patrick, 1959). False root-lesion nematodes (Pratylenchoides) were recovered from 41.4% of the fields. They were identified using morphological and molecular analyses. Among the Pratylenchoides species, Pratylenchoides leiocauda was described in France from soil around non-identified grass and weeds. P. leiocauda is reported to weaken the root systems of tomato, potato and strawberry (Sher, 1970; Li et al., 2020). The morphological characteristics of males and females from the 2020 survey were very similar to P. leiocauda. The lateral field contained six incisures and the pharyngeal glands overlapped the intestine dorsally for 1-2 times the body width. Additionally, they had a second nucleus near the pharyngeal intestine valve, female tails with incisures, and a smooth conical tail with 18-23 annules. Measurements and micrographs with the light-microscope (DM5000, Leica, Germany) and camera (DFC450, Leica, Germany) were taken from females (n=23) for mean, standard deviation and range of body length: 824.5 ± 71.0 (657.7-993.8) µm, maximum body width: 28.4 ± 2.7 (24.8-36.2) µm, stylet length: 22.8 ± 0.7 (21.4-24.0) µm and percent of distance from anterior end to vulva / body length: 57.7 ± 1.4 (54.0-60.3). Males (n=5) were characterized by a body length: 653.5 ± 64.3 (555.3-714.7) µm, a stylet length: 20.9 ± 1.0 (19.7-22.0) µm and a spicule length: 26.1 ± 2.5 (22.3-28.5) µm. Morphological measurements and characteristics (Fig. 1A-F) were compared to previous descriptions of P. leiocauda. As a result, the Korean population was larger than that of the originally described population from France, and was more similar to the Chinese population (Sher, 1970; Azizi et al., 2016; Li et al., 2020). In addition, PCR was performed for the COⅠ, LSU rRNA D2-D3 and ITS region using the primers (Mwesige et al., 2020). The sequenced COⅠ, LSU rRNA D2-D3 segments and ITS region are 447, 776 and 777 bp, respectively. The newly obtained sequences were submitted to GenBank database under accession numbers MZ418130, MZ414163 and MZ418133 of ITS region. A BLASTn search of the LSU rRNA D2-D3 sequence was most similar to P. leiocauda (MN539650), which is the species isolated from tomato in China (Li et al., 2020). The identities of these two sequences were 99.9% (775/776), with no insertions/deletions. The phylogenetic relationships strongly support P. leiocauda (Fig. 1G). Symptoms of perilla associated with P. leiocauda under field conditions included small and curled leaves, chlorosis of leaf edges, dark brown root epidermis and root necrosis (Fig. 2A, B). Koch's postulates were completed by inoculating 100 P. leiocauda into ten 45-cm-in-diameter pots filled with sterilized sandy loam soil and planted with perilla cultivar 'Ipdeulkkae 1-ho'. The potted plants were maintained for 50 days at 25℃ under greenhouse conditions. A P. leiocauda reproduction factor was 1.45 ± 0.20 was observed at the end of the trial, with 106 ± 21.6 recovered from soil and 39 ± 6.7 from root tissue. The root and shoot symptoms in the greenhouse trial were the same as those observed under field conditions (Fig. 2C, D). This, therefore, is the first record of P. leiocauda associated with perilla in Korea and management is warranted.

Impact of Dyslipidemia on the Risk of Second Cancer in Thyroid Cancer Patients: A Korean National Cohort Study.

BACKGROUND: Studies have shown that radioactive iodine therapy (RAIT) affects the development of second cancer in thyroid cancer patients. The impact of other factors, such as dyslipidemia are not clear. METHODS: A retrospective analysis of thyroid cancer patients with a 1,251,913 person-year follow-up was conducted using data from the Health Insurance Review and Assessment database in South Korea from January 2008 to December 2018. We investigated factors related to second cancer development using a nested case-control analysis to avoid length bias. RESULTS: The overall risk of developing second cancer was higher in thyroid cancer patients than in the general population [standardized incidence ratio, 3.34; 95% confidence interval (CI) 3.30-3.39]. Second cancer incidence was higher in patients who received RAIT than in those who did not [odds ratio (OR) 1.130; 95% CI 1.094-1.169]. Moreover, the risk of second cancer was higher in patients with dyslipidemia than in those without dyslipidemia (OR 1.265; 95% CI 1.223-1.309). After adjustment for RAIT, the incidence of a second cancer was higher in patients with dyslipidemia than in those without dyslipidemia (OR 1.262; 95% CI 1.221-1.306). CONCLUSIONS: The risk of second cancer development in patients with thyroid cancer appears to be high. Dyslipidemia may be associated with an increased risk of several types of second cancers.

Morphological and molecular characterizations of Heterodera oryzae in Korea.

Rice is one of the most important staple grains in Korea and the largest starch source in addition to its usefulness in the production of beverages. Under different areas and environments of production, various pests and diseases including soil-borne plant pathogens such as plant-parasitic nematodes can compromise rice productivity. In a survey to identify plant parasitic nematodes on rice, cyst nematodes were encountered in rice fields that required characterization and identification. Phylogenetic analysis of the LSU D2-D3 region and ITS region could not separate the studied species from Heterodera elachista. However, phylogenetic analysis of the COI gene of the mitochondrial DNA clearly separated H. elachista from the new species into two different clusters. Combining morphology and molecular diagnostics, the species was identified as Heterodera oryzae belonging to the 'Cyperi' group whose cysts are characterized by vulval cones that are ambifenestrate, underbridge present with bullae. Second-stage juveniles have three incisors in the lateral field with long tails and long hyaline region.

Identification of Heterodera glycines (Tylenchida; Heteroderidae) Using qPCR.

The soybean cyst nematode, Heterodera glycines, is a major plant-parasitic nematode that has caused important economic losses to Korea's soybean production. Four species of cyst nematodes, H. schachtii, H. glycines, H. trifolii, and H. sojae, all belong to schachtii group are coexist in field soil in Korea. The rapid identification of the nematode is crucial for preventing crop damage and in decision making for controlling this nematode. This study aimed to develop a species-specific primer set for quantitative PCR (qPCR) assay of H. glycines. The specific primer set (HGF1 and HGR1) for H. glycines was designed based on the cytochrome c oxidase subunit I (COI) sequence of mitochondrial DNA. After optimization, it is possible to identify the H. glycines using a qPCR assay with DNA extracted from a single cyst and single second-stage juvenile (J2). The specificity was confirmed by the absence of SYBR fluorescent signals of three other Heterodera species. A serial dilution of DNA extracted from a single cyst was obtained for the sensitivity test. The result showed that the standard curve of the test had a highly significant linearity between DNA concentration and Ct value (R 2 = 0.996, slope = -3.49) and that the detection limit concentration of DNA of the primer set was 10 pg of DNA per reaction. Our findings suggested that H. glycines could be distinguished from H. sojae and other Heterodera species when a qPCR assay is used with a specific primer set.

Pharmacokinetics and pharmacodynamics of ticagrelor and prasugrel in healthy male Korean volunteers.

PURPOSE: A combination of clopidogrel and aspirin is the standard treatment for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Two novel antiplatelet agents, ticagrelor and prasugrel, have been shown to rapidly and more effectively inhibit the P2Y12 receptor compared with clopidogrel. The aim of this study was to evaluate and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor and prasugrel in healthy male Korean volunteers. METHODS: Two separate studies were conducted. One study was performed by using a single-sequence, open-label, crossover design in 12 volunteers who received a single oral dose of ticagrelor (180 mg) and then a single oral dose of prasugrel (60 mg for 4 volunteers and 30 mg for 8 volunteers) with a 7-day washout period. The other study was a randomized, open-label, parallel-group investigation in which 8 volunteers received a single oral dose of prasugrel (10 mg for 4 volunteers and 30 mg for 4 volunteers). In each study, blood samples for PK and platelet aggregation inhibition analysis were serially collected after the administration of each dose. Plasma concentrations of ticagrelor, AR-C124910XX (the active metabolite of ticagrelor), R-95913 (the inactive metabolite of prasugrel), and R-138727 (the active metabolite of prasugrel) were measured by using a validated LC-MS/MS method. PK was analyzed by using a noncompartmental method. Maximal platelet aggregations were assessed with light transmission aggregometry after induction with 20 µmol/L of adenosine diphosphate. FINDINGS: Twenty healthy male Korean volunteers participated in the 2 studies. Plasma concentrations of ticagrelor and AR-C124910XX were obtained from 12 subjects, R-95913 from 20 subjects, and R-138727 from 8 subjects. Both ticagrelor and prasugrel were rapidly absorbed, with the shortest median Tmax of 2.0 and 2.25 hours for ticagrelor and AR-C124910XX, respectively, and a Tmax of 0.5 hour for both R-95913 and R-138727. Strong inhibition of platelet aggregation was shown after administration of both ticagrelor and prasugrel, with slightly stronger and more rapid inhibition with prasugrel in the tested doses. Inhibitory activities of prasugrel lasted longer than those of ticagrelor, reflecting the difference in binding kinetics between the 2 drugs. IMPLICATIONS: Prasugrel 30 and 60 mg exhibited slightly stronger, more rapid, and sustainable platelet inhibitory effects compared with ticagrelor 180 mg. These differing effects should be considered when determining the efficacy and adverse effects of ticagrelor and prasugrel. ClinicalTrials.gov identifier: NCT01876797 and NCT02075268.

Comment on "Mode conversion of waves in the ion-cyclotron frequency range in magnetospheric plasmas".

A Comment on the Letter by Y. O. Kazakov and T. Fülöp, Phys. Rev. Lett. 111, 125002 (2013). The authors of the Letter offer a Reply.

Extraordinary-mode radiation produced by linear-mode conversion of langmuir waves.

Linear-mode conversion (LMC) of Langmuir waves to radiation near the plasma frequency at density gradients is important for space and astrophysical phenomena. We study LMC in warm magnetized plasmas using numerical electron fluid simulations when the density gradient is parallel to the ambient magnetic field (B0). We demonstrate that LMC can produce extraordinary- (x-) as well as ordinary- (o-) mode radiation from Langmuir waves, contrary to earlier expectations of o mode only. Equal amounts of o- and x-mode radiation are produced in the unmagnetized limit. The x-mode efficiency decreases as B0 increases, while the o-mode efficiency oscillates due to interference between incoming and reflected Langmuir waves. Both x and o modes should be produced for typical coronal and interplanetary parameters, alleviating the depolarization problem for type III solar radio bursts.

In vivo ligation of glucocorticoid-induced TNF receptor enhances the T-cell immunity to herpes simplex virus type 1.

GITR (glucocorticoid-induced TNF receptor) is a recently identified member of the TNF receptor superfamily. The receptor is preferentially expressed on CD4(+)CD25(+) regulatory T cells and GITR signals break the suppressive activity of the subset. In this study, we wanted to reveal the in vivo function of GITR in herpes simplex virus type 1 (HSV-1) infection. A single injection of anti-GITR mAb (DTA-1) immediately after viral infection significantly increased the number of CD4(+) and CD8(+) T cells expressing CD25, an activation surface marker, and secreting IFN-gamma. We confirmed these in vivo observations by showing ex vivo that re-stimulation of CD4(+) or CD8(+) T cells with a CD4(+) or CD8(+) T-cell-specific HSV-1 peptide, respectively, induced a significant elevation in cell proliferation and in IFN-gamma secretion. Our results indicate that GITR signals play a critical role in the T-cell immunity to HSV-1.