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Purpose Rapid drug desensitization is known to be a good strategy in patients with drug hypersensitivity to chemotherapy. However, changes in maximal drug concentration and exposure time in blood through desensitization may alter other adverse reactions and efficacy of the drug. We investigated rapid desensitization for carboplatin in terms of severe adverse drug reactions (ADRs) and efficacy compared with the standard infusion. Methods A retrospective cohort study was conducted on patients with recurrent ovarian cancer who received carboplatin chemotherapy from 2017 to 2019. We compared serious adverse events (SAEs), ADRs according to organ classes, time to progression (TTP), and overall survival (OS). Results Of 108 desensitization procedures performed in 21 patients, 104 were successfully accomplished (96.3%). There were compared with 271 procedures in 41 patients who received the standard infusion method. There were 8 (7.7%) SAEs in the rapid desensitization group and 34 (12.5%) in the control group. One drug-related death occurred in the rapid desensitization group. In the rapid desensitized group, except for neutropenia, there was no statistically significant increase in SAEs and over grade 3 of ADRs according to organ classes compared with the control group. In the efficacy analysis, TTP and OS were similar in the 2 groups. Conclusions Rapid desensitization of carboplatin can lower the risk of immediate hypersensitivity reactions without changing the inherent effect and severe ADRs.

Neuropathic pain is a chronic pain state characterized by nerve damage, inflammation, and nociceptive neuron hyperactivity. As the underlying pathophysiology is complex, a more effective therapy for neuropathic pain would be one that targets multiple elements. Here, we generated recombinant adeno-associated viruses (AAVs) encoding three therapeutic genes, namely, glutamate decarboxylase 65, glial cell-derived neurotrophic factor, and interleukin-10, with various combinations. The efficacy for pain relief was evaluated in a rat spared nerve injury model of neuropathic pain. The maximal analgesic effect was achieved when the AAVs expressing all three genes were administered to rats with neuropathic pain. The combination of two virus constructs expressing the three genes was named KLS-2031 and evaluated as a potential novel therapeutic for neuropathic pain. Single transforaminal epidural injections of KLS-2031 into the intervertebral foramen to target the appropriate dorsal root ganglion produced notable long-term analgesic effects in female and male rats. Furthermore, KLS-2031 mitigated the neuroinflammation, neuronal cell death, and dorsal root ganglion hyperexcitability induced by the spared nerve injury. These results suggest that KLS-2031 represents a promising therapeutic option for refractory neuropathic pain., Graphical Abstract, Kim and colleagues demonstrated that single transforaminal injection of KLS-2031 (AAV vectors containing GAD65, GDNF, and IL-10) could produce long-term analgesic effects in rats with neuropathic pain by diminishing the neuroinflammation, neuronal cell death, and hyperexcitability. These observations suggest that KLS-2031 could be a promising treatment option for neuropathic pain.

Background: Vancomycin-resistant Enterococcus (VRE) has become more common in nosocomial infections, especially in urine samples. However, until now, no treatment regimen has been prov en to effectively eradicate urine VRE colonization. Therefore, to evaluate the efficacy of doxycy cline in eradicating urine VRE and shortening VRE isolation period, we compared VRE colony de tection period between doxycycline-treated and untreated patients. Methods: A retrospective cohort study of 83 patients with VRE colonization in urine cultures was conducted at a tertiary academic hospital from January 2011 to February 2018. Kaplan-Meier survival analysis was used to evaluate eradication rates in the treatment and non-treatment groups. Factors affecting urine VRE colonization persistence were analyzed by multiple logistic regression analysis. Results: The overall rate of VRE eradication during the entire hospital stay was higher in the dox ycycline treatment group (90.5%) than in the non-treatment group (58.1%, p=0.014). Survival analysis showed that the 5-, 10-, and 20-day cumulative eradication rates were 78.3%, 100%, and 100% in the doxycycline treatment group, and 18.5%, 45.7%, and 67.8% in the non-treat ment group, respectively, thereby indicating that eradication rates were higher in the doxycycline treatment group than in the non-treatment group (p

Kyoung-Hee Sohn,1 Myung-Nam Lee,2 Da Woon Sim,3 Sujeong Kim,4 You Sook Cho,5 Hyouk-Soo Kwon,5 Sang-Heon Kim6 1Division of Pulmonology and Allergy, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, South Korea; 2Department of Nursing, College of Health Science, Kangwon National University Samcheok, Samcheok-si, Gangwon-do, South Korea; 3Department of Allergy and Clinical Immunology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, South Korea; 4Division of Allergy and Clinical Immunology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea; 5Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 6Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South KoreaCorrespondence: Hyouk-Soo Kwon, Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea, Email kwonhs21@naver.com Sang-Heon Kim, Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea, Email sangheonkim@hanyang.ac.kr

Osthenol, a prenylated coumarin, is a C8-prenylated derivative of umbelliferone isolated from the root of Angelica koreana and Angelica dahurica, an intermediate and is known as a major metabolite ...

This paper reports a simple method of designing and synthesizing magnetic iron oxide (IO) integrated locust bean gum-cl-polyacrylonitrile hydrogel nanocomposites (LBG-cl-PAN/IONP) by in situ mineralization of iron ions in a hydrogel matrix. A two-step gel crosslink method followed by co-precipitation method was used to prepare these novel hydrogels embedded with magnetic iron oxide nanoparticles. The LBG-cl-PAN/IONP hydrogel nanocomposite (HNC) were tested in batch adsorption experiments for their ability to remove a cationic dyes, methylene blue (MB)Methyl violet (MV), from aqueous solution. In order to analyze the LBG-cl-PAN/IONP HNC, FTIR, XRD, XPS, VSM, TEM, and EDX techniques were applied. Numerous operating parameters were studied, including the amount of adsorbent, the contact time, pH, temperature, the dye concentration, and the coexisting ion concentration. According to the Langmuir isotherm model, MB and MV had maximum monolayer adsorptive capacities of 1250 and 1111 mg/g, respectively. LBG-cl-PAN/IONP HNC controlled IONP oxidation as well as sustained adsorptive removal over a wide pH range (7-10). The key mechanism of adsorption consisted of electrostatic interaction and ion exchange. For successful use in successive cycles after regeneration using HNO

Some reports have suggested that the clinical and economic burdens of asthma are associated with blood eosinophil levels. The association between clinical burden and blood eosinophil counts were evaluated in a Korean adult asthma cohort.Clinical information including blood eosinophil counts that were not affected by systemic corticosteroids were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea database. Clinical burden was defined as 1) asthma control status, 2) medication demand and 3) acute exacerbation (AE) events during 1 consecutive year after enrollment. All patients were divided into atopic and non-atopic asthmatics. The associations between asthma outcomes and the blood eosinophil count were evaluated.In total, 302 patients (124 atopic and 178 non-atopic asthmatics) were enrolled. In all asthmatics, the risk of severe AE was higher in patients with blood eosinophil levels100 cells/µL than in patients with levels ≥ 100 cells/µL (odds ratio [OR], 5.406; 95% confidence interval [CI], 1.266-23.078; adjustedThe baseline blood eosinophil count may predict the future clinical burden of asthma.

Background: Asthma is a heterogeneous inflammatory airway disorder with various phenotypes. Quantitative computed tomography (QCT) methods can differentiate among lung diseases through accurate assessment of the location, extent, and severity of the disease. The purpose of this study was to identify asthma clusters using QCT metrics of airway and parenchymal structure, and to identify associations with visual analyses conducted by radiologists. Methods: This prospective study used input from QCT-based metrics including hydraulic diameter (Dh), luminal wall thickness (WT), functional small airway disease (fSAD), and emphysematous lung (Emph) to perform a cluster analysis and made comparisons with the visual grouping analysis conducted by radiologists based on site of airway involvement and remodeling evaluated. Results: A total of 61 asthmatics of varying severities were grouped into 4 clusters. From C1 to C4, more severe lung function deterioration, higher fixed obstruction rate, and more frequent asthma exacerbations were observed in the 5-year follow-up period. C1 presented non-severe asthma with increased WT, Dh of proximal airways, and fSAD. C2 was mixed with non-severe and severe asthmatics, and showed bronchodilator responses limited to the proximal airways. C3 and C4 included severe asthmatics that showed a reduced Dh of the proximal airway and diminished bronchodilator responses. While C3 was characterized by severe allergic asthma without fSAD, C4 included ex-smokers with high fSAD% and Emph%. These clusters correlated well with the grouping done by radiologists and clinical outcomes. Conclusions: Four QCT imaging-based clusters with distinct structural and functional changes in proximal and small airways can stratify heterogeneous asthmatics and can be a complementary tool to predict clinical outcomes.

Resultative constructions show a wide range of cross-linguistic variation, which may pose nontrivial challenges to L2 learners. This study investigates how syntactic and semantic differences betwee...

Background: End-of-life (EOL) care in neonatal intensive care units (NICUs) can vary depending on religious beliefs of health care providers and families as well as the sociocultural environment. Although guidelines exist for EOL care in NICUs, most are based on Western studies, and little is known about such care in Asian countries, which have different religious and social background. Objective: This review synthesized empirical research to reveal the state of the science on infant EOL care in Asian countries. Design: This was an integrative review. Setting/Subjects: Data were collected from studies identified in CINAHL, Embase, PsycINFO, and PubMed. The search was limited to current empirical studies involving infant EOL care in Asian countries and published in English between 2007 and 2016. Results: Of 286 studies initially identified, 11 empirical studies conducted in Hong Kong, India, Israel, Japan, Mongolia, Taiwan, and Turkey were included in the review. Four themes were captured: factors influencing decision making, trends in decision making, practical aspects of EOL care, and health care providers' preparation. In most NICUs, health care providers controlled decisions regarding use of life-sustaining treatment, with parents participating in decision making no more than 60% of the time. Although care decisions were gradually changing from "do everything" for patient survival to a more palliative approach, comfort care at the EOL was chosen no more than 63% of the time. Conclusion: While infant EOL care practice and research vary by country, few articles address these matters in Asia. This integrative review characterizes infant EOL care in Asia and explores cultural influences on such care.

이 글은 최근 유치원 회계비리사태에서 제기된 정책 쟁점들을 공공성 강화라는 관점에서 분석하고, 회계투명성을 넘어서 돌봄 공공성 확충이라는 관점에서 필요한 정책 방향들을 논의하였다. 공공성은 공과 사, 정부와 이익집단의 이원적 대립으로 모두 포착될 수 없는 다차원적 개념으로 재정의할 수 있으며, 이 글에서는 소유권(설립주체), 재정, 통제의 세 가지 차원을 중심으로 사립유치원의 공공성 좌표를 진단하였다. 사립유치원 비리사태는 유치원시장에서 개인사업자가 지배적인 상황에서 비용지원에만 주력하고 관리감독 등의 통제적 공공성을 포기한 정부정책의 결과이다. 현재 사립유치원 공공성 강화방안의 핵심인 에듀파인 도입은 필수적이지만, 통제적 공공성의 확보가 자동적으로 고품질의 서비스를 적절하고 충분하게 보장하는 것은 아니다. 또 대안으로 주장되는 국공립유치원 40% 달성은 사립지배적인 생태계를 변화시키는 효과가 있겠지만 돌봄을 부차적인 기능으로 수행하고 있는 현재 국공립유치원의 관행이 변화되지 않는다면 돌봄공공성의 관점에서는 만족스러운 결과를 낳지 못할 것이다. 젠더 관점의 연구들은 돌봄이 사회정책 및 복지국가 재편의 중심 가치가 되어야 하며, 적절하고 충분한 수준의 돌봄의 사회화와 돌봄노동자의 처우와 노동권을 보장함으로써 돌봄을 저평가하는 사회적 인식과 관행이 해소되어야 한다고 주장해왔다. 이 글은 소유권, 재정, 통제 차원에서의 공공성 강화뿐 아니라 유치원(유아교육)서비스의 정체성에서 돌봄이 더 강화되고 사립유치원 교사의 근로조건과 처우를 개선하는 등 “돌봄적” 차원의 공공성이 강화될 필요가 있음을 주장하였다.

본 연구는 ‘개인화’라는 사회구조적 변동의 현실에서 개인주의에 대한 이해를 넓히고 현대사회의 가치와 도덕적 원리로서 개인주의의 가능성을 탐색하려는 목적 아래, 서구 개인주의에 대한 개념적 탐구를 시도한다. 먼저 개인주의 개념의 모호성을 짚어내며 그 근원이 되는 개인주의 개념의 복잡성과 다차원성을 서구의 개인주의 사상사를 통해 조명했다. 둘째, ‘개인주의’의 핵심 가치인 평등과 자유를 구체화하는 가치들로서 존엄성, 자율성, 사생활, 자기발전의 개념들을 소개하였다. 셋째, 개인주의가 무엇이고 어떻게 이해되었는지 살피기 위해 개인주의를 둘러싼 갈등과 대립을 검토하였다. 넷째, ‘칸트 대 괴테/니체’로 변별되는 게오르크 짐멜의 ‘개인주의 두 형식’을 비판적으로 논의했다. 마지막으로 한국의 사회문화 연구에서 개인주의와 관련하여 탐구되어야 할 주제와 쟁점을 논의하며 본 연구의 함의를 구체화 했다.

Background Thus far, human leukocyte antigen (HLA)-B∗58:01 has been recognized as the most important risk factor for allopurinol induced severe cutaneous adverse reactions (SCARs). Objective To determine the usefulness of prospective screening for the HLA-B∗58:01 allele to identify Korean individuals at risk for SCARs induced by allopurinol treatment. Methods We prospectively enrolled 542 patients with chronic renal insufficiency (CRI) from 10 hospitals nationwide and performed DNA genotyping to determine whether they carried the HLA-B∗58:01 allele. Of these, 503 HLA-B∗58:01-negative patients (92.8% of total) were treated with allopurinol, and 39 HLA-B∗58:01-positive patients (7.2%) were treated with febuxostat, an alternative drug. The patients then were followed up biweekly for 90 days using a telephone survey to monitor symptoms of adverse drug reactions, including SCARs. As a control, we used the historical incidence rate of allopurinol-induced SCARs in 4002 patients with CRI from the same hospitals who were enrolled retrospectively. Results Nineteen patients in the prospective cohort developed mild and transient adverse reactions but none showed allopurinol-induced SCARs. By contrast, we identified 38 patients with allopurinol-induced SCARs (0.95%) in the historical control. The difference in the incidence of allopurinol-induced SCARs between the prospective cohort and historical control was statistically significant (0% vs 0.95%, respectively; P = .029). Conclusions The present study demonstrated the clinical usefulness of the HLA-B∗58:01 screening test before allopurinol administration to prevent allopurinol-induced SCARs in patients with CRI.

To remove Cr(VI) from aqueous solution, a macroporous poly glycidyl methacrylate-co- ethylene glycol dimethacrylate (poly(GMA-co-EGDMA)) adsorbent was synthesized by radical suspension copolymerization. Allylamine was used to open the epoxy ring of the prepared copolymer, then the radical polymerization of the grafted allylamine was performed, and as the last step, methyl isothiocyanate (MITC) was reacted with the crosslinked graft copolymers to introduce the thiourea groups. The introduced amine and thiourea functional groups enabled the effective removal of Cr(VI). The polymer was analyzed by FT-IR spectroscopy, FE-SEM, and mercury porosimetry, and the chemical structure, surface morphology and pore characteristics of the polymer were confirmed. The pH of the Cr(VI) solution strongly affected the performance of the adsorbent, and the best removal efficiency was obtained at pH 2. In the kinetic studies, the qe value determined from the pseudo-second-order model was similar to the experimental qe value, and this model showed the best correlation. The isotherm data were better fit by the Langmuir adsorption isotherm model than the Freundlich isotherm model, and the maximum adsorption capacity was 166.24 mg/g.

The outbreak of infectious severe and acute respiratory syndrome (SARS)-CoV-2 which induces coronavirus disease 19 (COVID-19) causes patients to develop acute respiratory distress syndrome (ARDS) and death by triggering uncontrolled immune responses. Dysregulated immune responses impair healthy organs by over-production of pro-inflammatory cytokines, which are called “cytokine storm”. In this study, an improved cell-permeable nuclear import inhibitor (iCP-NI) has been developed by fusing sequence-optimized advanced macromolecule transduction domains (aMTDs) and nuclear localization sequence (NLS) originated from human NF-κB to treat the cytokine storm mediated organ failure and death in COVID-19. Intracellularly delivered NLS inhibits the transport of various inflammation-associated transcription factors (IATFs) such as NF-κB, NFAT, AP-1 and STAT1/3 which results in suppressed expression of pro-inflammatory cytokines. In brief, iCP-NI decreased the lethality of RNA virus infection mimetic pneumonitis animals by protecting the lung structure from inflammation-mediated destruction via reduction of the inflammatory cytokines in the lung. Continuously, iCP-NI significantly attenuates the severity of the SARS-CoV-2 infected syrian hamster model. The inhibition of viral replication is proved with quantitative PCR by reducing the level of RdRp gene (log7.04 vs log5.79). Likewise, the levels of inflammatory cytokines such as TNF-α and IL-17A in the lungs are significantly decreased and thereby, the lung structures are protected from inflammation-mediated damages. As a result, the iCP-NI could be developed as a novel medicine to cure various inflammatory diseases including COVID-19.

Purpose Nonsteroidal anti-inflammatory drugs (NSAIDs) are common cause of severe cutaneous adverse reactions (SCARs). The present study aimed to investigate the characteristics of SCARs induced by NSAIDs in the Korean SCAR registry. Methods A retrospective survey of NSAID-induced SCARs recorded between 2010 and 2015 at 27 university hospitals in Korea was conducted. Clinical phenotypes of SCARs were classified into Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Causative NSAIDs were classified into 7 groups according to their chemical properties: acetaminophen, and propionic, acetic, salicylic, fenamic and enolic acids. Results A total of 170 SCARs, consisting of 85 SJS, 32 TEN, 17 SJS-TEN overlap syndrome and 36 DRESS reactions, were induced by NSAIDs: propionic acids (n=68), acetaminophen (n=38), acetic acids (n=23), salicylic acids (n=16), coxibs (n=8), fenamic acids (n=7), enolic acids (n=5) and unclassified (n=5). Acetic acids (22%) and coxibs (14%) accounted for higher portions of DRESS than other SCARs. The phenotypes of SCARs induced by both propionic and salicylic acids were similar (SJS, TEN and DRESS, in order). Acetaminophen was primarily associated with SJS (27%) and was less involved in TEN (10%). DRESS occurred more readily among subjects experiencing coxib-induced SCARs than other NSAID-induced SCARs (62.5% vs. 19.7%, P = 0.013). The mean time to symptom onset was longer in DRESS than in SJS or TEN (19.1 ± 4.1 vs. 6.8 ±1.5 vs. 12.1 ± 3.8 days). SCARs caused by propionic salicylic acids showed longer latency, whereas acetaminophen- and acetic acid-induced SCARs appeared within shorter intervals. Conclusions The present study indicates that the phenotypes of SCARs may differ according to the chemical classifications of NSAIDs. To establish the mechanisms and incidences of NSAID-induced SCARs, further prospective studies are needed.

We aimed to determine the upper and lower cutoff values to simplify the diagnosis of gestational diabetes mellitus (GDM). We investigated the 50-g oral glucose tolerance test (OGTT) results from 1441 pregnancies and identified 423 gravidas who underwent the 100-g OGTT from 2011 to 2019. We collected the results of 50- and 100-g OGTTs. Moreover, we obtained the sum of the 50-g OGTT and 0-hour values, and the sum of those levels and 1-hour values. We determined the upper cutoff at 50-g OGTT, 0-, 1-hour, sum of 50-g OGTT and 0-hour results, and sum of those levels and 1-hour results for the confirmation of GDM. Also, we determined the lower cutoff at these tests for the exclusion of GDM. The upper cutoffs in 50-g OGTT, 0-, 1-hour, the sum of 50-g OGTT and 0-hour were 222, 115, 212, and 315 mg/dL, respectively. The lower cutoffs in 50-g OGTT, 0-, 1-hour, the sum of 50-g OGTT and 0-hour were 131, 65, 151, and 208 mg/dL, respectively. In addition, we discovered that the upper and lower cutoffs in the sum of 50-g OGTT, 0- and 1-hour values were516 and373 mg/dL, respectively. We implemented these cutoffs to our study group at 50-g OGTT and 0-, 1-hour of 100-g OGTT. It could omit 2- and 3-hour sampling in 216 gravidas (51.1%). Our approach was able to simplify GDM diagnostic steps in half of our study group.

An unbalanced microbial ecosystem on the human skin is closely related to skin diseases and has been associated with inflammation and immune responses. However, little is known about the role of the skin microbiome on skin aging. Here, we report that the Streptococcus species improved the skin structure and barrier function, thereby contributing to anti-aging. Metagenomic analyses showed the abundance of Streptococcus in younger individuals or those having more elastic skin. Particularly, we isolated Streptococcus pneumoniae, Streptococcus infantis, and Streptococcus thermophilus from face of young individuals. Treatment with secretions of S. pneumoniae and S. infantis induced the expression of genes associated with the formation of skin structure and the skin barrier function in human skin cells. The application of culture supernatant including Streptococcal secretions on human skin showed marked improvements on skin phenotypes such as elasticity, hydration, and desquamation. Gene Ontology analysis revealed overlaps in spermidine biosynthetic and glycogen biosynthetic processes. Streptococcus-secreted spermidine contributed to the recovery of skin structure and barrier function through the upregulation of collagen and lipid synthesis in aged cells. Overall, our data suggest the role of skin microbiome into anti-aging and clinical applications., Kim et al. show that several Streptococcus species improve the structure and barrier function of human skin. They find that Streptococcus-secreted spermidine accelerates the recovery of skin structure and barrier function by increasing collagen and lipid synthesis in aged cells. This study suggests the role of skin microbiome for anti-aging.

Stereotypic neutralizing antibody clonotypes specific for SARS-CoV-2 receptor binding domain in patients with COVID-19 and healthy individuals., Neutralizing antibodies on hand Stereotypic antibodies (Abs) are produced in healthy individuals by preexisting naïve B cells that have not undergone somatic hypermutation or class switching. Kim et al. have identified stereotypic neutralizing Abs (nAbs) against SARS-CoV-2 spike protein receptor binding domain (RBD) in healthy individuals and patients with COVID-19. They detected RBD-specific stereotypic variable heavy chain (VH) Ab clonotypes composed of Ig heavy variable 3-53 (IGHV3-53) or IGHV3-66 and Ig heavy joining 6 (IGHJ6) genes in 13 of 17 patients with COVID-19. One stereotypic nAb could inhibit in vitro replication of a clinical isolate of SARS-CoV-2. These VH clonotypes were also found in 6 of 10 healthy individuals with no evidence of exposure to SARS-CoV-2, and together, these findings provide evidence of the presence of preexisting nAbs to SARS-CoV-2., Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were composed of immunoglobulin heavy variable 3-53 (IGHV3-53) or IGHV3-66 and immunoglobulin heavy joining 6 (IGHJ6) genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching after SARS-CoV-2 infection. The different IGHV chains were paired with diverse light chains resulting in binding to the RBD of SARS-CoV-2 spike protein. Human antibodies specific for the RBD can neutralize SARS-CoV-2 by inhibiting entry into host cells. We observed that one of these stereotypic neutralizing antibodies could inhibit viral replication in vitro using a clinical isolate of SARS-CoV-2. We also found that these VH clonotypes existed in 6 of 10 healthy individuals, with IgM isotypes predominating. These findings suggest that stereotypic clonotypes can develop de novo from naïve B cells and not from memory B cells established from prior exposure to similar viruses. The expeditious and stereotypic expansion of these clonotypes may have occurred in patients infected with SARS-CoV-2 because they were already present.

Background In the past, general surgeons (GSs) without a pediatric surgical subspecialty often performed surgery on children and, even now, GSs are performing many pediatric surgeries. We aimed to investigate the involvement of pediatric surgeons (PSs) and GSs in pediatric surgery, compare the outcomes of surgery in the neonatal intensive care unit (NICU), and estimate the appropriate PS workforce in Korea. Methods We used surgical data from the National Health Insurance Service database that was collected from patients under the age of 19 years in hospitals nationwide from January 2002 to December 2017. In this database, we found 37 hospitals where PSs worked by using the index operation (congenital diaphragmatic hernia, esophageal atresia, hypertrophic pyloric stenosis, Hirschsprung's disease, abdominal wall defect, jejunoileal atresia, malrotation, anorectal malformation, and biliary atresia). It was assumed that the surgery in the 37 hospitals was performed by PS and that the surgery in other hospitals was performed by GS. Mortality was analyzed to compare the outcomes of acute abdominal surgery in the NICU. We estimated the number of PS currently needed in Korea for each situation under the assumption that PS would perform all operations for the index operation, main pediatric diseases (index operation + gastroesophageal reflux disease, choledochal cyst, inguinal hernia, and appendicitis), acute abdominal surgery in the NICU, and all pediatric surgeries. Additionally, we estimated the appropriate number of PS required for more advanced pediatric surgery in the future. Results The number of pediatric surgeries from 2002 to 2017 increased by 124%. Approximately 10.25% of the total pediatric surgeries were performed by PSs, and the percentage of the surgery performed by PSs increased from 8.32% in 2002 to 15.92% in 2017. The percentage of index operations performed by PSs annually was 62.44% in average. It was only 47.81% in 2002, and increased to 88.79% in 2017. During the last 5 years of the study period, the average annual number of surgeries for main pediatric diseases was approximately 33,228. The ratio of the number of surgeries performed by PS vs. GS steadily increased in main pediatric diseases, however, the ratio of the number of surgery performed by PS for inguinal hernia and appendicitis remained low in the most recent years. The percentage of the number of acute abdominal surgery performed by PS in the NICU was 44% in 2002, but it had recently risen to 89.7%. After 30 days of birth, mortality was significantly lower in all groups that were operated on by PS, rather than GS, during the last 5 years. In 2019, 49 PSs who were under the age of 65 years were actively working in Korea. Assuming that all pediatric surgeries of the patients under the age of 19 years should be performed by PS, the minimum number of PS currently required was about 63 if they perform all of the index operations, the main pediatric surgery was about 209, the NICU operation was about 63, and the all pediatric surgeries was about 366. Additionally, it was determined that approximately 165 to 206 PS will be appropriate for Korea to implement more advanced pediatric surgery in the future. Conclusion The proportion of the pediatric surgery performed by PS rather than GS is increasing in Korea, but it is still widely performed by GS. PSs have better operative outcomes for acute abdominal surgery in the NICU than GSs. We believe that at least the index operation or the NICU operation should be performed by PS for better outcome, and that a minimum of 63 PSs are needed in Korea to do so. In addition, approximately 200 PSs will be required in Korea in order to manage main pediatric diseases and to achieve more advanced pediatric surgery in the future., Graphical Abstract

We propose a method to generate optimal natural language for block placement directives generated by a machine’s planner during human-agent interactions in the blocks world. A non user-friendly machine directive, e.g., move(ObjId, toPos), is transformed into visually and contextually grounded referring expressions that are much easier for the user to comprehend. We describe an algorithm that progressively and generatively transforms the machine’s directive in ECI (Elementary Composable Ideas)-space, generating many alternative versions of the directive. We then define a cost function to evaluate the ease of comprehension of these alternatives and select the best option. The parameters for this cost function were derived empirically from a user study that measured utterance-to-action timings.

Zika virus (ZIKV) infection in both infants and adults is associated with neurological complications including, but not limited to, microcephaly and Guillain-Barre syndrome. Antibody therapy can be effective against virus infection. We isolated ZIKV envelope domain III-specific neutralizing antibodies (nAbs) from two convalescent patients with ZIKV infection. One antibody, 2F-8, exhibited potent in vitro neutralizing activity against Asian and American strains of ZIKV. To prevent FcγR-mediated antibody-dependent enhancement, we prepared IgG1 with LALA variation. A single dose of 2F–8 in the context of IgG1 or IgG1-LALA prior to or post lethal ZIKV challenge conferred complete protection in mice.

Current asthma guidelines recommend stepping down controller treatment when the condition is well-controlled for a certain time. However, the optimal step-down strategy for well-controlled patients receiving a low-dose inhaled corticosteroid (ICS) with a long-acting βThis study was a randomized, open-label, three-arm, parallel pragmatic trial comparing two kinds of step-down approaches for maintaining treatment.Adults with asthma who were aged 18 years or older, and who had been stable with low-dose ICS/LABA for at least 3 months, were enrolled. Subjects (n = 225) were randomly allocated into one of three groups (maintaining low-dose ICS/LABA [G1], discontinuing LABA [G2], and reducing ICS/LABA to once daily [G3]), and were observed for 6 months. The primary end point was a change in Asthma Control Test (ACT) scores between randomization and the final 6-month follow-up.The change in ACT was analyzed in the per-protocol population; noninferiority was not demonstrated in either step-down group compared with the maintenance group (95% confidence interval of the difference, G2 vs G1 = -1.40-0.55; G3 vs G1 = -1.19-0.77). Although over 90% of patients were fine, higher rates of treatment failure were observed in step-down groups (G1: 0%; G2: 9.46%; and G3: 9.09%; P = .027). There were no significant differences between step-down approaches in terms of ACT change or treatment failure.Both step-down methods were not noninferior to maintenance of treatment. Step-down therapy can be attempted when patients are stable, but appropriate monitoring and supervision are necessary with precautions regarding loss of disease control.

Background Although some respiratory virus infections are known to contribute to the development and exacerbation of asthma, commensal viromes in airway have not been extensively studied due to technical challenges. Objectives This study investigated the characteristics of the virome in asthmatic airways. Methods Both the bacteriome and virome profiles in sputum from 12 healthy individuals, 15 patients with nonsevere asthma, and 15 patients with severe asthma were analyzed and assessed for the association with clinical characteristics such as severity, exacerbation, Asthma Control Test (ACT), and lung function. Results While analysis of the 16S ribosomal RNA bacteriome in the airway showed no differences, clear contrasts in the diversity and composition of airway viromes were observed between healthy controls and patients with asthma. Herpesviruses were the most abundant type of virus in the asthma group (44.6 ± 4.6%), mainly with cytomegalovirus (CMV) and EBV accounting for 24.5 ± 3.3% and 16.9 ± 3.5%, respectively, in contrast to those in the healthy controls (5.4 ± 2.5% and 7.1 ± 3.0%, respectively). CMV and EBV were more abundant in patients with asthma who experienced exacerbation, and their abundance showed correlation with more severe asthma, lower ACT score, and lower lung function. On the contrary, bacteriophage that is abundant in healthy controls was severely reduced in patients with asthma in the order of nonsevere and severe asthma and presented significant positive correlation with ACT and FEV1/forced vital capacity. Conclusions Lung viromes, especially, CMV, EBV, and bacteriophage may be potential biomarkers of asthma severity and exacerbation.

ObjectiveTo evaluate the performance of the Patient Clinical Complexity Level (PCCL) mechanism, which is the patient level complexity adjustment factor within the Korean Diagnosis-Related Groups (KDRG) patient classification system, for explaining the variation of resource consumption within Age Adjacent Diagnosis-related groups (AADRGs).MethodsWe used the inpatient claims data from a public hospital in Korea from January 1, 2017 to June 30, 2019, with 18,846 claims and 138 Age Adjacent Diagnosis-related groups (AADRGs). The differences in the total average payment between the four PCCL levels for each AADRG was tested using ANOVA and Duncan’s post-hoc test. The three patterns of the differences with R-squared were: the PCCL reflected the complexity well (Valid); the average payment of PCCL 2, 3, 4 was greater than PCCL 0 (Partially Valid); the PCCL did not reflect the complexity (Not Valid).ResultsThere were 9 (6.52%), 26 (18.84%), and 103 (74.64%) ADRGs included in VALID, PARTIALLY VALID and NOT VALID, respectively. The average R-squared in VALID, PARTIALLY VALID, and NOT VALID was 32.18%, 40.81%, and 35.41% respectively, with the average R-squared for all patterns of 36.21%.ConclusionsAdjusting using PCCL in the KDRG classification system exhibited low performance to explain the variation of resource consumption within Age Adjacent Diagnosis-related groups (AADRGs). As the KDRG classification system is used for reimbursement under the New DRG-based PPS pilot project with plans for expansion, there should be an overall review of the validity of the complexity and rationality of using the KDRG classification system.

To the Editor: The spread of the coronavirus disease-2019 (COVID-19) remains a worsening global health crisis. Although many studies have reported risk factors for severe COVID-19, asthma characterization in COVID-19 is still controversial, with different early reports from China and recent reports from the Europe and United States.1 Prolonged viral shedding is not only a risk factor for poor outcome of COVID-19, but also clues to host immune response against the virus. However, there is limited data on this except for results from relative small group studies.2 In this study, 2 200 adult patients hospitalized for COVID-19 in Daegu were evaluated for prevalence of asthma and clinical outcomes with COVID-19 according to asthma. In addition, the risk factors for delayed viral clearance were evaluated.The prevalence of asthma in patients with COVID-19 was 3.2% which was not different from its prevalence in the Korea National Health and Nutrition Examination Survey (KNHANES) (Figure 1A and Table S1). By age group, the prevalence of asthma showed a similar U-shaped pattern as the general prevalence pattern in Korea. However, the prevalence of asthma in the 19–29-year age group (2.1%) was lower than that of KNHANES (Figure 1B).Table S2 compares the characteristics between the asthma group and the non-asthma group. Older age, overweight, and comorbidity of chronic obstructive pulmonary disease, and initial symptoms of dyspnea and nausea/vomiting were more common in the asthma group. Compared with the non-asthma group, the asthma group had a greater risk of death (13.6%vs. 6.4%, P = 0.02) and a greater need for high-flow oxygen therapy (18.2% vs . 10.5%, P = 0.048) (Figure 1C and Table S3). The higher mortality rate in asthma patients compared with non-asthmatic patients was particularly noticeable in female and overweight patients. Older patients (> 65 years) with asthma tended to have a higher mortality rate than those without asthma (Figure 1D). After adjusting for potential confounders, asthma had no significant association with clinical outcomes of COVID-19 (Figure 1E and Table S4). Meanwhile, older age, male gender, and comorbid diseases including overweight, diabetes, chronic kidney disease, cancer, autoimmune disease, dementia, and other psychological disorder were significant risk factors for mortality (Tables S5 and S6).Asthma is considered to have a lower risk of death than other well-known risk factors.3, 4 However, asthma is a heterogeneous disease and is often associated with atopic and eosinophilic asthma in younger patients. Meanwhile, obese asthma and elderly asthma are known to have common neutrophilic phenotypes.5, 6 The recent results of higher expression of COVID-19 receptors in respiratory specimens with neutrophilic asthma phenotype compared with the eosinophilic asthma phenotype.7 Considering prevalence and clinical outcome results, it is possible that neutrophilic asthma is a risk factor for infection and poor prognosis of COVID-19 rather than eosinophilic asthma.When delayed viral clearance was divided into two groups based on 30 days, 906 patients were included in the non-delayed viral clearance group and 415 patients in the delayed viral clearance group. After adjusting for potential confounders, delayed viral clearance was not significantly associated with asthma (Figure 1E and Table S4). However, older age >65 years (Odds ratio (OR) 2.002, 95% Confidence interval (CI) 1.292–3.101; P = 0.002), comorbid diseases including dementia (OR 3.123, 95% CI 1.833–5.321; P

In six of seven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, VH clonotypes, encoded by either immunoglobin heavy variable (IGHV)3-53 or IGHV3-66 and immunoglobin heavy joining (IGHJ)6, were identified in IgG1, IgA1, and IgA2 subtypes, with minimal mutations, and could be paired with diverse light chains, resulting in binding to the SARS-CoV-2 receptor-binding domain (RBD). Because most human antibodies against the RBD neutralized the virus by inhibiting host cell entry, we selected one of these clonotypes and demonstrated that it could potently inhibit viral replication. Interestingly, these VH clonotypes pre-existed in six of 10 healthy individuals, predominantly as IgM isotypes, which could explain the expeditious and stereotypic development of these clonotypes among SARS-CoV-2 patients.

According to a study by Cybersecurity Ventures, cybercrime is expected to cost $6 trillion annually by 2021. Most cybersecurity threats access internal networks through infected endpoints. Recently, various endpoint environments such as smartphones, tablets, and Internet of things (IoT) devices have been configured, and security issues caused by malware targeting them are intensifying. Event logs-based detection technology for endpoint security is detected using rules or patterns. Therefore, known attacks can respond, but unknown attacks can be difficult to respond to immediately. To solve this problem, in this paper, local outlier factor (LOF) and Autoencoder detect suspicious behavior that deviates from normal behavior. It also detects threats and shows the corresponding threats when suspicious events corresponding to the rules created through the attack profile are constantly occurring. Experimental results detected eight new suspicious processes that were not previously detected, and four malicious processes and one suspicious process were judged using Hybrid Analysis and VirusTotal. Based on the experiment results, it is expected that the use of operational policies such as allowlists in the proposed model will significantly improve performance by minimizing false positives.

Background Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators. Objective To clarify which therapeutic effect is better between the ICS + long-acting β2 agonist (LABA) and ICS + LABA + long-acting muscarinic antagonist (LAMA) treatment in patients with ACO. Methods We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS + LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS + LABA + LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV1, forced vital capacity, FEV1/forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide. Results In the ICS + LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS + LABA + LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV1 and forced vital capacity (P Conclusions Although this study was unable to conclude that ICS + LABA treatment is not inferior to ICS + LABA + LAMA in terms of exacerbation, it is obvious that the ICS + LABA + LAMA treatment group had improved lung function in ACO.

Background Patients who suffered drug reaction with eosinophilia and systemic symptom (DRESS) during the treatment of tuberculosis (TB) commonly experience multidrug hypersensitivity reactions resulting in limited anti-TB drug choices. Therefore, reintroduction based on a desensitization protocol may be an option to resume anti-TB medication. Objective To evaluate the outcomes and safety of resuming anti-TB drugs according to reintroduction methods in patients with anti-TB drug-related DRESS. Methods A retrospective cohort of patients who had experienced anti-TB drug-related severe cutaneous adverse reactions from 2011 to 2017 was established from separate 5 institutions. Results Anti-TB medication was resumed in 27 of 29 patients with anti-TB drug-related DRESS through complete changing regimen (n = 9), reintroduction by a graded challenge (n = 5), or reintroduction using a desensitization protocol (n = 13). Nine patients completely changed their anti-TB regimen to second-line TB drugs, but only 1 (11.1%) succeeded in maintaining new anti-TB drugs. The other 8 failed to take drugs due to the occurrence of hypersensitivity reactions to the newly introduced anti-TB drugs. Two (40.0%) of 5 patients who underwent graded rechallenges successfully completed anti-TB drugs, whereas 3 (60%) failed to resume anti-TB drugs due to the recurrence of hypersensitivity reactions. In 13 patients who resumed anti-TB drugs using a desensitization protocol, no one who underwent desensitization developed recurrence of DRESS; 11 (84.6%) eventually completed anti-TB treatment and 2 eventually failed to complete anti-TB treatment due to late-onset itching and drug-induced liver injury. Conclusions Resuming anti-TB medication based on desensitization protocols may be a safe and effective option for those with anti-TB drug-related DRESS.

Quite a few patients with chronic spontaneous urticaria (CSU) are refractory to H₁-antihistamines, even though the dose of H₁-antihistamines is increased up to 4-fold. CSU that is not controlled with H₁-antihistamines results in increased disease burden. Several immunomodulators have been used to manage these patients. The guidelines reported herein are connected to Part 1 of the KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children, and aimed to provide evidence-based recommendations for the management of H₁-antihistamine-refractory CSU. Part 2 focuses on the more commonly used additional treatment options for refractory CSU, including omalizumab, cyclosporine, leukotriene receptor antagonist, dapsone, methotrexate, and phototherapy. The evidence to support their efficacy, dosing, safety, and selection of these agents is systematically reviewed. To date, for patients with refractory CSU, the methodologically sound data to evaluate the use of omalizumab has been growing; however, the evidence of other immunomodulators and phototherapy is still insufficient. Therefore, an individualized stepwise approach with a goal of achieving complete symptom control and minimizing side effects can be recommended. Larger controlled studies are needed to elevate the level of evidence to select a rational therapeutic agent for patients with refractory CSU.

BACKGROUND The incidence of severe reaction induced by iodinated contrast media (ICM) has increased over the years with an increasing use of imaging modalities. Although ICM anaphylaxis is rare, it can be life-threatening, but currently, there is no biomarker that can identify individuals at risk of ICM anaphylaxis. OBJECTIVE The aim of this study is to investigate the genetic susceptibility of ICM anaphylaxis. METHODS Patients who had ICM anaphylaxis were enrolled in the study, and their blood samples were collected for genotyping of human leukocyte antigen (HLA)-A, -B, -C, and -DR. The results were compared with those of healthy Korean general population. MRGPRX2 gene in ICM anaphylaxis group was also sequenced and compared with the Korean standard database of genetic polymorphism. RESULTS The frequencies of 3 HLA alleles (B*52:01, C*12:02, and DRB1*15:02) were significantly higher in 47 patients with ICM anaphylaxis. In particular, HLA-DRB1*15:02 was 5 times more frequent in the ICM anaphylaxis group than the Korean general population (34.0% vs 6.6%; odds ratio, 7.306; 95% confidence interval, 3.622-14.740), and this difference was most pronounced in subjects with iohexol-induced anaphylaxis (odds ratio, 16.516; 95% CI, 5.241-52.047; P < 0.0001). Eight single nucleotide polymorphisms were identified in MRGPRX2 gene, but their frequencies were not different in those with ICM anaphylaxis compared with the general Korean population. CONCLUSIONS HLA-DRB1*15:02 is associated with ICM anaphylaxis in the Korean population.

The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics

K-12 classrooms consistently integrate collaboration as part of their learning experiences. However, owing to large classroom sizes, teachers do not have the time to properly assess each student and give them feedback. In this paper we propose using simple deep-learning-based machine learning models to automatically determine the overall collaboration quality of a group based on annotations of individual roles and individual level behavior of all the students in the group. We come across the following challenges when building these models: (1) Limited training data, (2) Severe class label imbalance. We address these challenges by using a controlled variant of Mixup data augmentation, a method for generating additional data samples by linearly combining different pairs of data samples and their corresponding class labels. Additionally, the label space for our problem exhibits an ordered structure. We take advantage of this fact and also explore using an ordinal-cross-entropy loss function and study its effects with and without Mixup.