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Objective: The nucleoside diphosphate linked moiety X (Nudix)-Type motif 15 (NUDT15) enzyme is involved in thiopurine metabolism. Genetic variants in the NUDT15 gene result in decreased NUDT15 activity, which in addition to decreased thiopurine S-methyltransferase (TPMT) activity, contributes to thiopurine toxicity. Current standard approaches of NUDT15 genetic analysis have mainly been targeting several common variants. We aimed to develop a clinical-grade DNA-based assay for genetic analysis of the NUDT15 gene using Sanger di-deoxy sequencing., Results: Sanger sequencing results were fully concordant with the expected NUDT15 genotype in all 17 cell line samples with known NUDT15 variants (accuracy = 100%; 95% CI 80.49 to 100.00%). Precision studies showed 100% intra-run repeatability and 100% inter-run reproducibility, respectively. Genetic analysis of the NUDT15 gene was performed for 80 patients of Asian ethnicity with wildtype TPMT. 76% (N = 61) of the studied individuals had NUDT15 *1/*1 diplotype. 25% (N = 14) of Chinese and 36% (N = 5) of Malays were found to carry at least 1 non-functional NUDT15 allele. Our study confirmed a high frequency of NUDT15 c.415C>T and c.55_56insGAGTCG variants in the Chinese and Malay ethnic groups in Singapore, highlighting the importance of determining NUDT15 genotype prior to thiopurine dosing., (© 2022. The Author(s).)

Background: Chaihu-Shugan-San (CSS, named Shihosogansan in Korean), a Chinese traditional medicine, is frequently used to treat anxiety and depression. Psychiatric disorders including depression are associated with gut dysbiosis. Therefore, to comprehend gut microbiota-involved anti-depressive effect of CSS, we examined its effect on restraint stress (RS)-induced depression and gut dysbiosis in mice METHODS: CSS was extracted with water in boiling water bath and freeze-dried. Anxiety and depression was induced in C57BL/6 mice by exposure to RS. Anxiety- and depression-like behaviors were measured in the light/dark transition and elevated plus maze tasks, forced swimming test, and tail suspension test. Biomarkers were assayed by using the enzyme-linked immunosorbent assay and immunoblotting. The gut microbiota composition was analyzed by Illumina iSeq sequencer., Results: CSS significantly reduced the RS-induced anxiety- and depression-like behaviors in mice. CSS suppressed the RS-induced activation of NF-κB and expression of interleukin (IL)-6 and increased the RS-suppressed expression of brain-derived neurotrophic factor (BDNF). Furthermore, CSS suppressed the RS-induced IL-6 and corticosterone level in the blood and IL-6 expression and myeloperoxidase activity in the colon. CSS decreased the RS-induced γ-Proteobacteria population in gut microbiota, while the RS-suppressed Lactobacillaceae, Prevotellaceae, and AC160630_f populations increased. Fecal transplantation of vehicle-treated control or RS/CSS-treated mice into RS-exposed mice significantly mitigated RS-induced anxity- and depression-like behaviors, suppressed the NF-κB activation in the hippocampus and colon, and reduced the IL-6 and corticosterone levels in the blood. These fecal microbiota transplantations suppressed RS-induced Desulfovibrionaceae and γ-Proteobacteria populations and increased RS-suppressed Lactobacillaceae and Prevotellaceae poulation in the gut microbiota., Conclusions: CSS alleviated anxiety and depression by inducing NF-κB-involved BDNF expression through the regulation of gut inflammation and microbiota., (© 2021. The Author(s).)

Background: Gut microbiota closely communicate in the immune system to maintain a balanced immune homeostasis in the gastrointestinal tract of the host. Oral administration of probiotics modulates gut microbiota composition. In the present study, we isolated Lactobacillus rhamnosus HDB1258, which induced tumor necrosis factor (TNF)-α and interleukin (IL)-10 expression in macrophages, from the feces of breastfeeding infants and examined how HDB1258 could regulate the homeostatic immune response in mice with or without lipopolysaccharide (LPS)-induced systemic inflammation., Results: Oral administration of HDB1258 significantly increased splenic NK cell cytotoxicity, peritoneal macrophage phagocytosis, splenic and colonic TNF-α expression, TNF-α to IL-10 expression ratio, and fecal IgA level in control mice, while Th1 and Treg cell differentiation was not affected in the spleen. However, HDB1258 treatment significantly suppressed peritoneal macrophage phagocytosis and blood prostaglandin E2 level in mice with LPS-induced systemic inflammation. Its treatment increased LPS-suppressed ratios of Treg to Th1 cell population, Foxp3 to T-bet expression, and IL-10 to TNF-α expression. Oral administration of HDB1258 significantly decreased LPS-induced colon shortening, myeloperoxidase activity and NF-κB + /CD11c + cell population in the colon, while the ratio of IL-10 to TNF-α expression increased. Moreover, HDB1258 treatment shifted gut microbiota composition in mice with and without LPS-induced systemic inflammation: it increased the Cyanobacteria and PAC000664_g (belonging to Bacteroidetes) populations and reduced Deferribacteres and EU622763_s group (belonging to Bacteroidetes) populations. In particular, PAC001066_g and PAC001072_s populations were negatively correlated with the ratio of IL-10 to TNF-α expression in the colon, while the PAC001070_s group population was positively correlated., Conclusions: Oral administered HDB1258 may enhance the immune response by activating innate immunity including to macrophage phagocytosis and NK cell cytotoxicity in the healthy host and suppress systemic inflammation in the host with inflammation by the modulation of gut microbiota and IL-10 to TNF-α expression ratio in immune cells.

Background: In a pilot study, we found that feces transplantation from elderly individuals to mice significantly caused cognitive impairment. Paenalcaligenes hominis and Escherichia coli are increasingly detected in the feces of elderly adults and aged mice. Therefore, we isolated Paenalcaligenes hominis and Escherichia coli from the feces of elderly individuals and aged mice and examined their effects on the occurrence of age-related degenerative cognitive impairment and colonic inflammation in mice., Results: The transplantation of feces collected from elderly people and aged mice caused significantly more severe cognitive impairment in transplanted young mice than those from young adults and mice. Oral gavage of Paenalcaligenes hominis caused strong cognitive impairment and colitis in specific pathogen-free (SPF) and germ-free mice. Escherichia coli also induced cognitive impairment and colitis in SPF mice. Oral gavage of Paenalcaligenes hominis, its extracellular vesicles (EVs), and/or lipopolysaccharide caused cognitive impairment and colitis in mice. However, celiac vagotomy significantly inhibited the occurrence of cognitive impairment, but not colitis, in mice exposed to Paenalcaligenes hominis or its EVs, whereas its lipopolysaccharide or Escherichia coli had no such effects. Vagotomy also inhibited the infiltration of EVs into the hippocampus., Conclusions: Paenalcaligenes hominis, particularly its EVs, can cause cognitive function-impaired disorders, such as Alzheimer's disease, and its EVs may penetrate the brain through the blood as well as the vagus nerve. Video Abstract.

Background: A three-drug regimen (macrolide, ethambutol, and rifampicin) is recommended for the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). Although macrolide has proven efficacy, the role of ethambutol and rifampicin in patients without acquired immune deficiency syndrome is not proven with clinical studies. We aimed to clarify the roles of ethambutol and rifampicin in the treatment of MAC-PD., Methods: Patients treated for MAC-PD between March 1st, 2009 and October 31st, 2018 were reviewed retrospectively. Rates of culture conversion, microbiological cure, treatment failure, and recurrence were compared according to the maintenance (≥6 months) of ethambutol or rifampicin with macrolide., Results: Among the 237 patients, 122 (51.5%) maintained ethambutol and rifampicin with macrolide, 58 (24.5%) maintained ethambutol and macrolide, 32 (13.5%) maintained rifampicin and macrolide, and 25 (10.6%) maintained macrolide only. Culture conversion was reached for 190/237 (80.2%) patients and microbiological cure was achieved for 129/177 (72.9%) who completed the treatment. Treatment failure despite ≥12 months of treatment was observed in 66/204 (32.4%), and recurrence was identified in 16/129 (12.4%) who achieved microbiological cure. Compared with maintenance of macrolide only, maintenance of ethambutol, rifampicin or both with macrolide were associated with higher odds of culture conversion [odds ratio (OR), 95% confidence interval (CI): 18.06, 3.67-88.92; 15.82, 2.38-105.33; and 17.12, 3.93-74.60, respectively]. Higher odds of microbiological cure were associated with maintenance of both ethambutol and rifampicin with macrolide (OR, 95% CI: 5.74, 1.54-21.42) and macrolide and ethambutol (OR, 95% CI: 5.12, 1.72-15.24) but not macrolide and rifampicin. Maintenance of both ethambutol and rifampicin with macrolide was associated with lower odds of treatment failure (OR, 95% CI: 0.09, 0.01-0.53) compared with macrolide only, while maintenance of one of these with macrolide was not. Maintenance of both ethambutol and rifampicin or one of these with macrolide did not decrease the probability of recurrence when compared with macrolide only., Conclusions: Maintenance (≥6 months) of ethambutol and rifampicin with macrolide was associated with the most favorable treatment outcomes among patients with MAC-PD. Given the association between ongoing ethambutol use and microbiological cure, clinicians should maintain ethambutol unless definite adverse events develop.

Background: In 2015, South Korea experienced an outbreak of Middle East respiratory syndrome (MERS), and our hospital experienced a nosocomial MERS infection. We performed a comprehensive analysis to identify the MERS transmission route and the ability of our routine infection-prevention policy to control this outbreak., Methods: This is a case-cohort study of retrospectively analysed data from medical charts, closed-circuit television, personal interviews and a national database. We analysed data of people at risk of MERS transmission including 228 in the emergency department (ED) and 218 in general wards (GW). Data of personnel location and movement, personal protection equipment and hand hygiene was recorded. Transmission risk was determined as the extent of exposure to the index patient: 1) high risk: staying within 2 m; 2) intermediate risk: staying in the same room at same time; and 3) low risk: only staying in the same department without contact., Results: The index patient was an old patient admitted to our hospital. 11 transmissions from the index patient were identified; 4 were infected in our hospital. Personnel in the ED exhibited higher rates of compliance with routine infection-prevention methods as observed objectively: 93% wore a surgical mask and 95.6% washed their hands. Only 1.8% of personnel were observed to wear a surgical mask in the GW. ED had a higher percentage of high-risk individuals compared with the GW (14.5% vs. 2.8%), but the attack rate was higher in the GW (16.7%; l/6) than in the ED (3%; 1/33). There were no transmissions in the intermediate- and low-risk groups in the ED. Otherwise 2 patients were infected in the GW among the low-risk group. MERS were transmitted to them indirectly by staff who cared for the index patient., Conclusions: Our study provide compelling evidence that routine infection-prevention policies can greatly reduce nosocomial transmission of MERS. Conventional isolation is established mainly from contact tracing of patients during a MERS outbreak. But it should be extended to all people treated by any medical employee who has contact with MERS patients., Trial Registration: NCT02605109 , date of registration: 11th November 2015.

Background: We aimed to evaluate whether serum activin-A levels are elevated and have any value in predicting severity and prognosis in acute respiratory distress syndrome (ARDS)., Methods: Retrospective cohort study was performed with patients who were admitted to MICU with diagnosis of ARDS and have serum samples stored within 48 h of Intensive care unit (ICU) admission between March 2013 and December 2016 at a single tertiary referral hospital. Serum activin-A levels were measured with ELISA kit, and were compared with those of normal healthy control and non-ARDS sepsis patients., Results: Total 97 ARDS patients were included for the study. Levels of Activin-A were elevated in ARDS patients compared to those of healthy controls (Log-transformed activin-A levels 2.89 ± 0.36 vs. 2.34 ± 0.11, p < 0.001, absolute activin-A levels 1525.6 ± 1060.98 vs. 225.9 ± 30.1, p = 0.016) and non-ARDS sepsis patients (Log-transformed activin-A levels 2.89 ± 0.36 vs. 2.73 ± 0.34, p = 0.002, Absolute activin-A levels 1525.6 ± 1060.98 vs. 754.8 ± 123.5 pg/mL, p = 0.036). When excluding five outliers with extremely high activin-A levels, activin-A showed statistically significant correlation with in-hospital mortalities (In-hospital survivors 676.2 ± 407 vs. non-survivors 897.9 ± 561.9 pg/mL, p = 0.047). In predicting in-hospital mortality, serum activin-A concentrations showed superior area under curve compared to that of Acute physiologic and chronic health evaluation II scores (0.653; 95% CI [0541, 0.765] vs. 0.591, 95% CI [0.471, 0.710]). With cut-off level of 708 pg/mL, those with high serum activin-A levels had more than twofold increased risk of in-hospital mortalities. However, those relations were missing when outliers were in., Conclusions: Serum activin-A levels in ARDS patients are elevated. However, its levels are weakly associated with ARDS outcomes.

Background: Microbiological criteria for diagnosing nontuberculous mycobacterial pulmonary disease (NTM-PD) include positive culture results from at least two separately expectorated sputum specimens or one bronchial washing or lavage. However, the clinical similarities and differences between patients diagnosed by these two methods remain unclear. We compared clinical features and prognoses of patients with NTM-PD diagnosed from both specimen types., Methods: We analysed data from patients who participated in the Seoul National University Hospital NTM-PD cohort ( ClinicalTrials.gov identifier: NCT01616745). Baseline demographics, symptoms, radiographic findings, disease progression, and treatment responses were summarized and compared between patients diagnosed from sputum specimens and patients diagnosed from bronchoscopic specimens., Results: Three hundred forty-seven patients were included in the analyses. Of these, 279 (80.4%) were diagnosed from two separately expectorated sputum specimens, and 68 (19.6%) were diagnosed from bronchoscopic specimens. Patients diagnosed from sputum specimens had more frequent and severe cough, sputum, postnasal drip, and high St. George's Respiratory Questionnaire scores. However, the extent and severity of the radiographic lesions, disease progression, and treatment responses were similar for both groups. Further analysis based on the following three groups (sputum culture positive, sputum culture negative/bronchoscopy, and scanty sputum/bronchoscopy groups) suggested that the scanty sputum/bronchoscopy group appeared to have the worst prognosis in terms of both time to progression and time to culture conversion., Conclusions: Although some symptoms and quality of life were worse in patients with NTM-PD diagnosed from sputum specimens, their prognoses were similar to those of patients diagnosed by bronchoscopic specimen. We recommend bronchoscopic sampling for patients in whom NTM-PD is suspected clinically or radiographically, especially those who have no or scanty sputum.

Background: Co-existence or subsequent isolation of multiple nontuberculous mycobacteria (NTM) species in same patient has been reported. However, clinical significance of these observations is unclear. The aim of this study was to determine clinical implications of changes of NTM species during or after treatment in patients with NTM lung disease., Methods: Patients with NTM lung disease, who experienced changes of NTM species during treatment or within 2 years of treatment completion between January 1, 2009 and December 31, 2015, were included in the analysis. Demographic, clinical, microbiological, and radiographic data were reviewed and analyzed., Results: During the study period, 473 patients were newly diagnosed with NTM lung disease. Treatment was started in 164 patients (34.6%). Among these 164 patients, 16 experienced changes of NTM species during or within 2 years of treatment completion. Seven showed changes from M. avium complex (MAC) to M. abscessus subspecies abscessus (MAA) and five patients displayed changes from M. abscessus subspecies massiliense (MAM) to MAC. With isolation of new NTM species, 6 out of 7 patients with change from MAC to MAA reported worsening of symptoms, whereas none of the five patients with change from MAM to MAC reported worsening of symptoms. All MAA isolated during or after treatment for MAC lung diseases showed inducible resistance to clarithromycin., Conclusions: Change of NTM species may occur during or after treatment for NTM lung disease. Especially, changes from MAC to MAA is accompanied by symptomatic and radiographic worsening as well as inducible resistance to clarithromycin.

Background: The proportion of never-smokers with non-small cell lung cancer (NSCLC) is increasing, but that in Korea has not been well addressed in a large population. We aimed to evaluate the proportion and clinical features of never-smokers with NSCLC in a large single institution., Methods: We analyzed clinical data of 1860 consecutive patients who were newly diagnosed with NSCLC between June 2011 and December 2014., Results: Of the 1860 NSCLC patients, 707 (38.0%) were never-smokers. The proportions of women (83.7% vs. 5.6%) and adenocarcinoma (89.8% vs. 44.9%) were higher among never-smokers than among ever-smokers. Significantly more never-smokers were diagnosed at a younger median age (65 vs. 68 years, P < 0.001) and earlier stage (stage I-II, 44.5% vs. 38.9%, P = 0.015) compared with ever-smokers. Epidermal growth factor receptor mutations (57.8% vs. 24.4%, P < 0.001) and anaplastic lymphoma kinase rearrangements (7.8% vs. 2.8%, P < 0.001) were more common in never-smokers, whereas Kirsten rat sarcoma viral oncogene homolog mutations (5.8% vs. 9.6%, P = 0.021) were less frequently encountered in never-smokers than in ever-smokers. Never-smokers showed longer survival after adjusting for the favorable effects of younger age, female sex, adenocarcinoma histology, better performance status, early stage disease, being asymptomatic at diagnosis, received antitumor treatment, and the presence of driver mutations (hazard ratio, 0.624; 95% confidence interval, 0.460-0.848; P = 0.003)., Conclusions: More than one-third of the Korean patients with NSCLC were never-smokers. NSCLC in never-smokers had different clinical characteristics and major driver mutations and resulted in longer overall survival compared with NSCLC in ever-smokers.

Background: Patients with distinctive morphotype were more susceptible to nontuberculous mycobacterial lung disease (NTM-LD). However, little is known about the association between body morphotype and progression of NTM-LD. The aim of this study was to elucidate predictors of NTM-LD progression, focusing on body morphotype and composition., Methods: Data from patients with NTM-LD who participated in NTM cohort which started in 1 July 2011 were analyzed. Patients with more than 6 months of follow up were included for analysis. NTM-LD progression was defined as clinician-initiated anti-NTM treatment, based on symptomatic and radiologic aggravation. Body morphotype and composition was measured at entry to the cohort using bioelectrical impedance analysis., Results: NTM-LD progressed in 47 out of 150 patients with more than 6 months of follow up. Patients with middle (adjusted hazard ratio [aHR], 2.758; 95% confidence interval [CI], 1.112-6.843) or lowest tertile (aHR, 3.084; 95% CI, 1.241-7.668) of abdominal fat ratio had a higher risk of disease progression compared with the highest tertile. Other predictors for disease progression were presence of cavity on chest computed tomography (aHR, 4.577; 95% CI, 2.364-8.861), and serum albumin level <3.5 g/dL (aHR, 12.943; 95% CI, 2.588-64.718)., Conclusions: Progression of NTM-LD is associated with body composition. Lower abdominal fat ratio is an independent predictor of NTM-LD progression., Trial Registration: ClinicalTrials.gov, NCT01616745 Registered 25 March 2012.

Background: To date, more than 125 species of nontuberculous mycobacteria (NTM) have been identified. In this study, we investigated the frequency and clinical implication of the rarely isolated NTM from respiratory specimens., Methods: Patients with NTM isolated from their respiratory specimens between July 1, 2010 and June 31, 2012 were screened for inclusion. Rare NTM were defined as those NTM not falling within the group of eight NTM species commonly identified at our institution: Mycobacterium avium, M. intracellulare, M. abscessus, M. massiliense, M. fortuitum, M. kansasii, M. gordonae, and M. peregrinum. Clinical, radiographic and microbiological data from patients with rare NTM were reviewed and analyzed., Results: During the study period, 73 rare NTM were isolated from the respiratory specimens of 68 patients. Among these, M. conceptionense was the most common (nine patients, 12.3%). The median age of the 68 patients with rare NTM was 68 years, while 39 of the patients were male. Rare NTM were isolated only once in majority of patient (64 patients, 94.1%). Among the four patients from whom rare NTM were isolated two or more times, only two showed radiographic aggravation caused by rare NTM during the follow-up period., Conclusions: Most of the rarely identified NTM species were isolated from respiratory specimens only once per patient, without concomitant clinical aggravation. Clinicians could therefore observe such patients closely without invasive work-ups or treatment, provided the patients do not have decreased host immunity towards mycobacteria.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown causes. Three proteins (mammalian target of rapamycin, mTOR; zinc finger E-box-binding homeobox 1, ZEB1; Rho-associated, coiled-coil containing protein kinase 1, ROCK1) may be related to pulmonary fibrosis. However, they have not been assessed in human pulmonary fibrosis. We assessed the clinical significance of mTOR, ZEB1, and ROCK1 expression in human pulmonary fibrosis of usual interstitial pneumonia (UIP) pattern., Methods: The mTOR, ZEB1, and ROCK1 expression was evaluated by immunohistochemical staining of 30 surgical lung biopsy tissues from 26 IPF and 4 UIP pattern connective tissue disease related interstitial lung disease (CTD-ILD) patients. The expression scores correlated with the clinical features., Results: The mTOR, ZEB1 and ROCK1 mainly expressed in alveolar epithelial cells of UIP lungs. The histological fibrosis scores and lung function decline in the strong mTOR expression group were higher than those in the weak and intermediate expression group. Patients with positive ZEB1 expression had higher fibrosis scores and greater decline in carbon monoxide diffusion capacity (DLCO) than patients with negative ZEB1 expression. Patients with positive mTOR or ZEB1 expression had poorer prognosis than that of patients with negative mTOR or ZEB1 expression, although it was not statistically significant. ROCK1 was not associated with the studied clinicopathological features., Conclusions: The mTOR and ZEB1 expression in pulmonary fibrosis patients significantly correlated with the fibrosis score and lung function decline, indicating that it may be related to the prognosis of pulmonary fibrosis. Further studies involving large numbers of homogeneous IPF patients are warranted.

Background: There have been few studies of pulmonary actinomycosis, which is an uncommon anaerobic infection. Consequently, the optimal therapeutic regimen, appropriate duration of treatment, long-term prognosis, and factors predicting prognosis are not well established., Methods: We retrospectively reviewed the medical records of histopathologically confirmed cases of pulmonary actinomycosis seen between November 2003 and December 2012., Results: The study included 68 patients with a mean age of 58.4 ± 11.6 years. Of the 68, initial surgery was performed in 15 patients (22.1%), while the remaining 53 (77.9%) received antibiotic therapy initially. In the initial antibiotic group, 45/53 (84.9%) were cured without relapse (median antibiotic duration 5.3 months). 5/53 (9.4%) patients were refractory medically (median antibiotic duration 9.7 months), and 3/53 (5.7%) experienced a recurrence (median time to relapse 35.3 months). In the initial surgery group, 14/15 (93.3%) were cured and treatment failure occurred in one (6.7%). In the multivariate analysis, the absence of an antibiotic response at 1 month was the only independent factor associated with a poor treatment outcome, with an adjusted odds ratio of 49.2 (95% CI, 3.34-724.30). There was no significant difference in treatment outcome based on the size of the parenchymal lesion, comorbidities, whether intravenous antibiotics were used, antibiotic therapy duration, or whether the initial treatment was surgical., Conclusions: Antibiotic treatment with or without surgery was effective for treatment of pulmonary actinomycosis. Nevertheless, treatment failure or recurrence occurred in a considerable proportion of patients, especially those resistant to the initial antibiotic treatment.

Background: Delirium is a common problem and associated with poor outcomes in intensive care unit (ICU) patients. Diagnosis of delirium in ICU patients is limited and usually underdiagnosed by physicians. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is one of the most widely used screening methods for detection of ICU delirium. Our goal was to translate and validate the CAM-ICU for use in the Korean ICU setting., Methods: Translation of the CAM-ICU was done according to the guidelines suggested by the Translation and Cultural Adaptation Group. For validation and interrater reliability assessment of the Korean CAM-ICU, two nurses independently assessed delirium in ICU patients and the results were compared with the reference evaluation, which was done by a psychiatrist using the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV)., Results: Twenty-two patients were evaluated by two nurses and one psychiatrist expert independently. During the study period, we have continuously educated study nurses. Based on DSM-IV criteria, 16 out of 22 (72.7%) patients developed delirium. The sensitivities of the two nurses' evaluations using the Korean CAM-ICU were 89.80% for nurse 1 and 77.40% for nurse 2. Their specificities were 72.40% and 75.80% and their overall accuracy was 83.33% and 88.37% respectively. The Korean CAM-ICU was done with reasonable interrater reliability between nurse 1 and nurse 2 (κ = 0.81, p < 0.001)., Conclusions: The Korean CAM-ICU showed good validity and could be incorporated into clinical practice in Korean ICUs., Trial Registration: ISRCTN: ISRCTN50265663.

Background: Carcinoma of unknown primary tumors (CUP) is present in 0.5%-9% of all patients with malignant neoplasms; only 20%-27% of primary sites are identified before the patients die. Currently, 18F-fluorodeoxy-glucose positron-emission tomography (18F-FDG PET) or PET combined with computed tomography (PET/CT) is widely used for the diagnosis of CUP. However, the diagnostic yield of the primary site varies. The aim of this study was to determine whether PET or PET/CT has additional advantages over the conventional diagnostic workup in detecting the primary origin of CUP., Findings: Twenty patients with unknown primary tumors that underwent PET or PET/CT were included in this study. For all patients, the conventional diagnostic workup was unsuccessful in detecting the primary sites. Among 20 patients, 11 had PET scans. The remaining nine patients had PET/CT. In all 20 patients, neither the PET nor PET/CT identified the primary site of the tumor, including six cases with cervical lymph node metastases. The PET and PET/CT revealed sites of FDG uptake other than those associated with known metastases in seven patients, but these findings did not influence patient management or therapy. Two patients had unnecessary invasive diagnostic procedures due to false positive results on the PET or PET/CT., Conclusions: Although it is inconclusive because of small sample size of the study, the additional value of PET or PET/CT for the detection of primary sites in patients with CUP might be less than expected; especially in patients that have already had extensive conventional diagnostic workups. Further study is needed to confirm this finding.

Background: Biological networks, such as protein-protein interactions, metabolic, signalling, transcription-regulatory networks and neural synapses, are representations of large-scale dynamic systems. The relationship between the network structure and functions remains one of the central problems in current multidisciplinary research. Significant progress has been made toward understanding the implication of topological features for the network dynamics and functions, especially in biological networks. Given observations of a network system's behaviours or measurements of its functional dynamics, what can we conclude of the details of physical connectivity of the underlying structure?, Results: We modelled the network system by employing a scale-free network of coupled phase oscillators. Pairwise phase coherence (PPC) was calculated for all the pairs of oscillators to present functional dynamics induced by the system. At the regime of global incoherence, we observed a Significant pairwise synchronization only between two nodes that are physically connected. Right after the onset of global synchronization, disconnected nodes begin to oscillate in a correlated fashion and the PPC of two nodes, either connected or disconnected, depends on their degrees.Based on the observation of PPCs, we built a weighted network of synchronization (WNS), an all-to-all functionally connected network where each link is weighted by the PPC of two oscillators at the ends of the link. In the regime of strong coupling, we observed a Significant similarity in the organization of WNSs induced by systems sharing the same substrate network but different configurations of initial phases and intrinsic frequencies of oscillators.We reconstruct physical network from the WNS by choosing the links whose weights are higher than a given threshold. We observed an optimal reconstruction just before the onset of global synchronization.Finally, we correlated the topology of the background network to the observed change of the functional activities in the system., Conclusions: The results presented in this study indicate a strong relationship between the structure and dynamics of complex network systems. As coupling strength increases, synchronization emerges among hub nodes and recruits small-degree nodes. The results show that the onset of global synchronization in the system hinders the reconstruction of an underlying complex structure. Our analysis helps to clarify how the synchronization is achieved in systems of different network topologies.

Background: We performed a multicenter, open, randomized, clinical study of autologous cultured osteoblast injection for long-bone fracture, to evaluate the fracture healing acceleration effect and the safety of autologous cultured osteoblasts., Methods: Sixty-four patients with long-bone fractures were randomly divided into two groups, i.e. those who received autologous cultured osteoblast injection and those who received no treatment. The sum of the difference in the callus formation scores after four and eight weeks, was used as the first efficacy variable., Results: The autologous cultured osteoblast injection group showed fracture healing acceleration of statistical significance, and there were no specific patient complications when using this treatment., Conclusion: Autologous cultured osteoblast injection should therefore be considered as a successful treatment option for treating long-bone fracture.

Background: Miliary pulmonary nodules are commonly caused by various infections and cancers. We sought to identify the relative frequencies of various aetiologies and the clinical and radiographic predictors of miliary tuberculosis (TB) in patients with miliary pulmonary nodules., Methods: We performed a retrospective cohort study of patients who presented with micronodules occupying more than two-thirds of the lung volume, based on computed tomography (CT) of the chest, between November 2001 and April 2007, in a tertiary referral hospital in South Korea., Results: We analyzed 76 patients with miliary pulmonary nodules. Their median age was 52 years and 38 (50%) were males; 18 patients (24%) had a previous or current malignancy and five (7%) had a history of TB. The most common diagnoses of miliary nodules were miliary TB (41 patients, 54%) and miliary metastasis of malignancies (20 patients, 26%). Multivariate analysis revealed that age 25% of total lung volume increased the probability of miliary TB. However, a history of malignancy decreased the probability of miliary TB., Conclusion: Miliary TB accounted for approximately half of all causes of miliary pulmonary nodules. Young age, an immune-compromised state, and several clinical and radiographic characteristics increased the probability of miliary TB.