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Cough is the most common respiratory symptom that can have various causes. It is a major clinical problem that can reduce a patient’s quality of life. Thus, clinical guidelines for the treatment of cough were established in 2014 by the cough guideline committee under the Korean Academy of Tuberculosis and Respiratory Diseases. From October 2018 to July 2020, cough guidelines were revised by members of the committee based on the first guidelines. The purpose of these guidelines is to help clinicians efficiently diagnose and treat patients with cough. This article highlights the recommendations and summary of the revised Korean cough guidelines. It includes a revised algorithm for the evaluation of acute, subacute, and chronic cough. For a chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered in differential diagnoses. If UACS is suspected, first-generation antihistamines and nasal decongestants can be used empirically. In cases with CVA, inhaled corticosteroids are recommended to improve cough. In patients with suspected chronic cough due to symptomatic GERD, proton pump inhibitors are recommended. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, intake of angiotensin-converting enzyme inhibitor, intake of dipeptidyl peptidase-4 inhibitor, habitual cough, psychogenic cough, interstitial lung disease, environmental and occupational factors, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and unexplained cough can also be considered as causes of a chronic cough. Chronic cough due to laryngeal dysfunction syndrome has been newly added to the guidelines.

Background Pro-inflammatory cytokines are dysregulated in Crohn’s disease (CD) and could serve as surrogate markers to improve diagnostic and therapeutic approaches, potentially addressing an unmet need. We profiled circulating biomarkers and whole blood transcriptional pathway activity to identify those associated with CD using data from the phase 2 FITZROY study with filgotinib, an oral preferential janus kinase-1 inhibitor. Methods Patients with serum and whole blood samples taken from the induction period were included. Serum cytokines were measured (ELISA), whole blood RNA sequenced, and stool samples taken to measure fecal calprotectin (FC). Spearman’s Rank correlations were assessed between biomarkers and baseline disease activity; post-treatment endoscopic improvement was measured by the Simplified Endoscopy Score for CD (SES-CD), FC and the Crohn’s Disease Activity Index. Effect of filgotinib on circulating biomarkers was also evaluated. Results Serum biomarkers (n = 168) and whole blood RNA sequencing (n = 104) were assessed. Moderate correlation between serum analytes with SES-CD and FC was noted; most highly correlated were acute phase proteins CRP (rho = 0.35 [SES-CD] and 0.47 [FC]), serum amyloid A (rho = 0.40 and 0.39, respectively) and pro-inflammatory cytokines interleukin (IL)-6 (rho = 0.31 and 0.30, respectively), IL-22 (rho = 0.36 and 0.35, respectively), and oncostatin M (rho = 0.35 and 0.33, respectively). Filgotinib treatment was associated with reduction of many candidate biomarkers, particularly in patients with treatment response. Early changes in IL-6 and IL-10 may be prognostic for endoscopic response. Conclusions Several circulating factors with potential as CD activity biomarkers were identified. Larger studies are necessary to investigate the best utility of these markers for CD.

Dengue control approaches are best informed by granular spatial epidemiology of these viruses, yet reconstruction of inter- and intra-household transmissions is limited when analyzing case count, serologic, or genomic consensus sequence data. To determine viral spread on a finer spatial scale, we extended phylogenomic discrete trait analyses to reconstructions of house-to-house transmissions within a prospective cluster study in Kamphaeng Phet, Thailand. For additional resolution and transmission confirmation, we mapped dengue intra-host single nucleotide variants on the taxa of these time-scaled phylogenies. This approach confirmed 19 household transmissions and revealed that dengue disperses an average of 70 m per day between households in these communities. We describe an evolutionary biology framework for the resolution of dengue transmissions that cannot be differentiated based on epidemiologic and consensus genome data alone. This framework can be used as a public health tool to inform control approaches and enable precise tracing of dengue transmissions.

Finding etiology of chronic cough is an essential part of treatment. Although guidelines include many laboratory tests for diagnosis, these are not possible in many primary care centers. We aimed to identify the characteristics and the differences associated with its cause to develop a clinical prediction model. Adult subjects with chronic cough who completed both Korean version of the Leicester Cough Questionnaire (K-LCQ) and COugh Assessment Test (COAT) were enrolled. Clinical characteristics of each etiology were compared using features included in questionnaires. Decision tree models were built to classify the causes. A total of 246 subjects were included for analysis. Subjects with asthma including cough variant asthma (CVA) suffered from more severe cough in physical and psychological domains. Subjects with eosinophilic bronchitis (EB) presented less severe cough in physical domain. Those with gastro-esophageal reflux disease (GERD) displayed less severe cough in all 3 domains. In logistic regression, voice hoarseness was an independent feature of upper airway cough syndrome (UACS), whereas female sex, tiredness, and hypersensitivity to irritants were predictors of asthma/CVA; less hoarseness was a significant feature of EB, and feeling fed-up and hoarseness were less common characteristics of GERD. The decision tree was built to classify the causes and the accuracy was relatively high for both K-LCQ and COAT, except for UACS. Voice hoarseness, degree of tiredness, hypersensitivity to irritants and feeling fed-up are important features in determining the etiologies. The decision tree may further assists classifying the causes of chronic cough.

OBJECTIVEIn this double-blind randomized trial, the necessity of preoperative steroid administration in patients without adrenal insufficiency (AI) undergoing endoscopic transsphenoidal surgery (ETSS) for pituitary adenoma was evaluated.METHODSForty patients with and without AI, defined as a peak cortisol level > 18 µg/dl on the insulin tolerance test or rapid adrenocorticotropic hormone (ACTH) test, undergoing ETSS for nonfunctioning pituitary adenomas were randomly allocated to treatment with either 100 mg of preoperative hydrocortisone (group HC, n = 20) or normal saline (group C, n = 20). The patients with pituitary apoplexy, the use of a drug within the last 3 months that could affect the hypothalamic-pituitary-adrenal axis, or a previous history of brain or adrenal surgery were excluded. Intraoperative cortisol and ACTH levels were measured after anesthesia induction, dura incision, and tumor removal, and at the end of surgery. Intraoperative hypotension, early postoperative AI, and postoperative 3-month pituitary function were investigated.RESULTSIntraoperative serum cortisol levels were significantly higher in the HC group than in the C group after anesthesia induction (median 69.0 µg/dl [IQR 62.2–89.6 µg/dl] vs 12.7 µg/dl [IQR 8.4–18.2 µg/dl], median difference 57.5 µg/dl [95% CI 33.0–172.9 µg/dl]), after dura incision (median 53.2 µg/dl [IQR 44.9–63.8 µg/dl] vs 6.4 [IQR 4.8–9.2 µg/dl], median difference 46.6 µg/dl [95% CI 13.3–89.2 µg/dl]), after tumor removal (median 49.5 µg/dl [IQR 43.6–62.4 µg/dl] vs 9.2 µg/dl [IQR 5.75–16.7 µg/dl], median difference 39.4 µg/dl [95% CI 0.3–78.1 µg/dl]), and at the end of surgery (median 46.9 µg/dl [IQR 40.1–63.4 µg/dl] vs 16.9 µg/dl [IQR 12.1–23.2 µg/dl], median difference 32.2 µg/dl [95% CI −42.0 to 228.1 µg/dl]). Serum ACTH levels were significantly lower in group HC than in group C after anesthesia induction (median 3.9 pmol/L [IQR 1.7–5.2 pmol/L] vs 6.9 pmol/L [IQR 3.9–11.9 pmol/L], p = 0.007). No patient showed intraoperative hypotension due to AI. Early postoperative AI was observed in 3 and 5 patients in groups HC and C, respectively. The postoperative 3-month pituitary hormone outcomes including ACTH deficiency were not different between groups.CONCLUSIONSPreoperative steroid administration may be unnecessary in patients without AI undergoing ETSS for nonfunctioning pituitary adenomas. However, a further large-scale study is needed to determine whether preoperative steroid administration has a significant impact on clinically meaningful events such as perioperative AI and postoperative 3-month ACTH deficiency in these patients.Korean Clinical Trial Registry no.: KCT0002426 (https://cris.nih.go.kr/cris/).

Dengue seroprevalence data are useful for understanding epidemiologic trends and transmission dynamics, and for making decisions about implementation of dengue control programs. A logistical challenge to seroprevalence surveys is the collection and transport of serum samples. For conducting large and repeated dengue serosurveys, dried blood spots (DBS) would allow easier sample collection, shipment, transport, and storage than standard serum collection methods. Further evidence is needed to understand how well DBS performs compared with standard serum collection methods in laboratory assays. We evaluated the detection of anti-dengue antibodies by IgG indirect ELISA when using DBS compared with sera. Specimens were collected from healthy children in Cebu, Philippines, who would be 9–14 years of age at the time of a mass dengue vaccination program. Using an ELISA index value cutoff of 0.9, 1,285/1,488 (86.4%) of the DBS were seropositive and 203 (13.6%) were seronegative, compared with 1,292/1,488 (86.8%) seropositive and 196 (13.2%) seronegative serum samples. Compared with sera, the DBS method had a 98.3% sensitivity, 92.4% specificity, 98.9% positive predictive value, and 89.2% negative predictive value. Considering the advantages in terms of sample collection, shipment, and storage, DBS sampling may be appropriate for dengue population serosurveys.

BACKGROUND: Acute upper respiratory tract infection (AURI) together with acute bronchitis is the most common illness worldwide. Botanical medicines used as expectorants and antitussives have proven to be effective while also having excellent safety margins. We aimed at evaluating the efficacy and safety of a new botanical drug, CKD-497, in patients with AURI and acute bronchitis. METHODS: In this phase 2 study, 225 patients were enrolled and randomly assigned to one of four treatment groups: placebo (n=55), Synatura(®) (n=49), CKD-497 200 mg (n=68), or CKD-497 300 mg (n=53). The study drugs were administered three times daily over the course of 7 days. Primary endpoint was the change in the bronchitis severity score (BSS) from baseline to day 7. Secondary endpoint was evaluated based on clinical response rates on days 4 and 7. A safety analysis was also performed. RESULTS: Between baseline and day 7, the mean BSS scores decreased significantly in each group (P

Purpose The prevalence of chronic obstructive pulmonary disease (COPD) in females has increased, changing the concept of COPD as a disease mostly limited to males. In this study, the clinical characteristics of COPD in females were investigated. Patients and methods The study was based on a multicenter cohort of COPD patients recruited from 54 medical centers in South Korea. Sex-based differences in general characteristics, exposure risk factors, depression scores, results of pulmonary function tests, COPD exacerbation, symptom scores, and radiologic findings were evaluated. Sex-related differences in the annual FEV1 change over 5 years were analyzed in a linear mixed model. Results Of the 2515 patients enrolled in this study, 8.1% were female. Female patients who had a higher BMI and a lower level of education were less likely to be smokers, were more exposed to passive smoking/biomass, and were more depressed compared to males. The rates of bronchiectasis, previous childhood respiratory infection, and asthma were higher in females. Female patients also had more symptoms and a poorer exercise capacity than males, but no significant differences were observed in terms of exacerbations. Radiologic findings revealed that male patients had worse emphysema, and female patients had worse bronchiectasis, as determined based on chest X-ray and computed tomography findings. On pulmonary function tests, female patients had less obstruction and less annual FEV1 loss over 5 years. Conclusion This study revealed differences in the clinical parameters between male and female patients with COPD, including general characteristics, disease characteristics, and clinical outcomes.

This study describes the natural history of dengue virus (DENV) infection in rhesus monkeys exposed to the bites of DENV-infected Aedes aegypti mosquitoes. Dengue virus–infected mosquitoes were generated by either intrathoracic inoculation or by oral feeding on viremic blood meals. Each of the six rhesus monkeys that were fed upon by intrathoracically infected mosquitoes developed non-structural protein 1 (NS1) antigenemia and an IgM response; viremia was detected in 4/6 individuals. No virological or immunological evidence of DENV infection was detected in the three monkeys exposed to mosquitoes that had been orally infected with DENV. These results demonstrate the utility of mosquito-borne challenge of rhesus monkeys with DENV.

Perioperative cell count-associated predictors, including the neutrophil/lymphocyte ratio (N/LR) and platelet/lymphocyte ratio (P/LR), are associated with poor clinical outcomes including myocardial injury. Study investigators aimed to examine the association among the perioperative N/LR, P/LR, and postoperative major adverse cardiovascular and cerebral events (MACCE) after noncardiac surgery in patients with drug-eluting stent (DES) insertion.Retrospective and observational.Single university hospital.The study comprised 965 patients who underwent noncardiac surgery within 6 months after DES implantation.None.Baseline perioperative clinical parameters, including N/LR and P/LR measured before surgery, immediately after surgery, and on postoperative day (POD) 1, were obtained. MACCE was defined as a composite of nonfatal myocardial infarction, coronary revascularization, nonhemorrhagic stroke, and pulmonary embolism within 1 month after surgery. Multivariate logistic regression analysis and propensity score matching were used to identify predictors of MACCE after surgery. MACCE occurred in 67 patients (6.9%) and was more common in patients with N/LR on POD 14.3 (multivariable-adjusted odds ratio [OR] 2.03, 95% confidence interval [CI] 1.12-2.79; p = 0.040 and as a continuous N/LR [OR 1.17, 95% CI 1.08-1.27; p0.001]). This association was consistent after propensity score matching and was stronger when the antiplatelet agent was stopped before surgery (OR 3.02, 95% CI 2.14-4.48; p = 0.006 for stopping dual antiplatelet therapy).In patients undergoing noncardiac surgery within 6 months after DES implantation, elevated N/LR on POD 1 is independently associated with postoperative MACCE. Elevated postoperative N/LR as a marker of systemic inflammation may help to predict the development of MACCE in these high-risk patients.

Objective Various experimental studies have reported neuroprotective effects of sevoflurane postconditioning against cerebral ischemia-reperfusion injury. We therefore investigated its neuroprotective effects on hyperperfusion-related transient neurologic deterioration, called symptomatic cerebral hyperperfusion (SCH), and also identified predictive factors for SCH in patients with moyamoya disease after revascularization surgery. Methods A total of 152 adult patients with moyamoya disease undergoing anastomosis of the superficial temporal artery to middle cerebral artery were randomly allocated into 2 groups. The postconditioning group (group S, n = 76) inhaled sevoflurane of 1 minimum alveolar concentration for 15 minutes immediately after reperfusion and then washed it out slowly for 15 minutes. The control group (group C, n = 76) received no intervention. The incidence of SCH was compared between the 2 groups. Results The incidence of SCH was not significantly different between groups S and C (53.3% vs. 43.4%, respectively; P = 0.291). The incidence of postoperative complications and the Glasgow Outcome Scale score at hospital discharge also did not differ significantly. Predictive factors for SCH included a decreased vascular reserve in preoperative single-photon emission computed tomography scan (odds ratio [OR], 7.18; 95% confidence interval [CI], 1.78–29.02; P = 0.006), an operation performed on the dominant hemisphere (OR, 3.32; 95% CI, 1.57–6.98; P = 0.002), temporal occlusion time (OR, 1.06; 95% CI, 1.01–1.11; P = 0.017), and intraoperative minimum partial pressure of carbon dioxide (PaCO2) (OR, 0.86; 95% CI, 0.78–0.94; P = 0.001). Conclusions Sevoflurane postconditioning did not reduce the incidence of SCH after revascularization surgery in patients with moyamoya disease. Rather, a decreased vascular reserve, operation on the dominant hemisphere, increased temporal occlusion time, and decreased intraoperative minimum PaCO2 were associated with SCH in these patients.

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0–93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community.

Highlights • Data are lacking on dengue in Africa. • This surveillance covered the beginning of a dengue outbreak in April-May 2017. • 61% of 482 patients with non-malarial fever in Mombasa were dengue-positive. • Dengue cases presented with rash, retro-orbital pain, myalgia, arthralgia, etc. • Dengue cases were mostly mild with only two cases requiring observation, and no DHF., Objectives Information on dengue in Africa is limited. To estimate the proportion of dengue-positive cases among febrile patients and describe clinical indicators of dengue, we conducted passive health facility-based fever surveillance in Mombasa, Kenya. Methods Non-malarial febrile patients between one and 55 years were enrolled at three health facilities between March 2016 and May 2017. Acute and convalescent blood samples were collected with an interval of 10–21 days. Acute samples were tested with dengue RDT and a selected subset with RT-PCR, and acute/convalescent samples with IgM/IgG ELISA. Results Among 482 enrollees, 295 (61.2%) were dengue-positive based on laboratory results. The surveillance covered the beginning of a dengue outbreak in April-May 2017, during which 73.9% of enrollees were dengue-positive. By contrast, during the non-outbreak period, 54.6% were dengue-positive. Dengue case status was positively associated with rash, fatigue, headache, retro-orbital pain, nausea/vomiting, nose bleeding, gum bleeding, loss of appetite, myalgia, and arthralgia. Dengue-positive cases in our study had mostly mild disease, with only two requiring observation, and no DHF. Conclusions The clinical response was generally mild relative to what was observed in SE Asia and the Americas. Given the high level of DENV transmission in Mombasa, more data would be needed to further understand the disease burden and improve case detection for surveillance/monitoring of outbreaks.

We identified the predictive factors and prognostic significance of transarterial chemoembolization (TACE) for achieving pathologic complete response (pCR) before curative surgery for hepatocellular carcinoma (HCC) in hepatitis B-endemic areas.Among 753 HCC patients treated with surgery, 124 patients underwent preoperative TACE before liver resection (LR), and 166 before liver transplantation (LT) between 2005 and 2016. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. Pathologic response (PR) was defined as the mean percentage of necrotic area, and pCR was defined as the absence of viable tumor.A total of 34 (27%) and 38 (23%) patients had pCR before LR and LT, respectively. Alpha-fetoprotein (AFP) 100 ng/mL and single tumor were significant preoperative predictors of pCR. OS and RFS were significantly improved in patients with pCR or a PR ≥ 90%, but not in patients with PR ≥ 50% after LR and LT. On multivariate analyses, PR ≥ 90% remained an independent predictor of better OS and RFS in LR and LT groups.Overall, our data clearly demonstrate that pCR predicts favorable prognosis after curative surgery for HCC, and predictors of pCR are AFP100 ng/mL and single tumor.

Purpose Previous studies have used various definitions to classify chronic obstructive pulmonary disease (COPD) patients into chronic bronchitis (CB) and non-CB patients. This study was performed to identify differences among three definitions of CB based on the classical method, St. George's Respiratory Questionnaire (SGRQ), and the CAT (COPD Assessment Test) score. Patients and methods We extracted data from the multicenter Korea COPD Subgroup Study (KOCOSS) cohort, for which patients recruited from among 47 medical centers in South Korea beginning in April 2012. Patients were classified according to three different definitions of CB: 1) classical definition; 2) SGRQ (using questions regarding cough and sputum); and 3) CAT score (comprising cough [CAT1] and sputum [CAT2] subscale scores). Results A total of 2694 patients were enrolled in this study. The proportions of CB were 10.8%, 35.8%, and 24.0% according to the classical, SGRQ, and CAT definitions, respectively. The three definitions yielded consistently significant differences between CB and non-CB patients in modified Medical Research Council dyspnea scale CAT score, SGRQ score, number of moderate-to-severe exacerbations per year and forced expiratory volume in 1 second. By three definitions, CB consistently predicted future risk of exacerbation. The kappa coefficient of agreement between the classical definition and SGRQ definition was 0.29, that of the classical definition and CAT definition was 0.32, and that of the SGRQ definition and CAT definition was 0.44. Conclusion Patients with CB according to the new definitions based on SGRQ or CAT score showed similar clinical characteristics to those defined according to the classical definition. The new CB definitions may be used as alternatives to the classical definition.

Background: This study examined the differences in the prevalence and clinical features of asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO) with identical diagnostic criteria by race and ethnicity in two nationwide cohorts of COPD.Methods: We used data from the Korean COPD Subgroup Study (KOCOSS) and phase I of the US Genetic Epidemiology of COPD (COPDGene) study. We defined ACO by satisfying bronchodilator response (BDR) >15% and 400 ml and/or blood eosinophil count ≥300/μl.Results: The prevalences of ACO according to ethnicity were non-Hispanic white (NHW), 21.4%; African American (AA), 17.4%; and Asian, 23.8%. Asian patients with ACO were older, predominantly male, with fewer symptoms, more severe airflow limitation, and fewer comorbidities than NHW and AA patients. During 1-year follow-up, exacerbations occurred in 28.2, 22.0, and 48.4% of NHW, AA, and Asian patients with ACO, respectively. Compared to patients with non-ACO from the same racial group, the risk for exacerbation was significantly higher in NHW and Asian patients with ACO [adjusted incident rate ratio (aIRR), 1.17; 95% CI, 1.01–1.36, and aIRR, 1.37; 95% CI, 1.09–1.71 for NHW and Asian patients with ACO, respectively]. Inhaled corticosteroid (ICS) reduced the risk for future exacerbation in total patients with ACO but the effect was not significant in each racial group.Conclusions: The prevalence of ACO was similar in the two cohorts using the same diagnostic criteria. The risk for future exacerbation was significantly higher in ACO, and the use of ICS reduced the risk for exacerbation in total patients with ACO.

Infraclavicular and supraclavicular approaches are used for subclavian venous catheterisation. We hypothesised that the supraclavicular approach is non-inferior to the infraclavicular approach in terms of safety during ultrasound-guided right subclavian venous catheterisation. We randomly allocated 401 neurosurgical patients undergoing ultrasound-guided right subclavian venous catheterisation into supraclavicular (n = 200) and infraclavicular (n = 201) groups. We assessed catheterisation-related complications (primary outcome measure) including catheter misplacement and mechanical complications (arterial puncture, haematoma formation, pneumothorax and haemothorax). We also recorded catheterisation success rates and time required for venous puncture and catheterisation. The number (proportion) of patients with catheterisation-related complications was six (3.0%) in the supraclavicular group and 27 (13.4%) in the infraclavicular group, mean difference (95%CI) -10.4% (-15.7 to -5.1%), p

Dengue is the world’s most prevalent and important arboviral disease. More than 50% of the world’s population lives at daily risk of infection and it is estimated more than 95 million people a year seek medical care following infection. Severe disease can manifest as plasma leakage and potential for clinically significant hemorrhage, shock, and death. Treatment is supportive and there is currently no licensed anti-dengue virus prophylactic or therapeutic compound. A single dengue vaccine, Sanofi Pasteur’s Dengvaxia®, has been licensed in 20 countries but uptake has been poor. A safety signal in dengue seronegative vaccine recipients stimulated an international re-look at the vaccine performance profile, new World Health Organization recommendations for use, and controversy in the Philippines involving the government, regulatory agencies, Sanofi Pasteur, clinicians responsible for testing and administering the vaccine, and the parents of vaccinated children. In this review, we provide an overview of Dengvaxia’s® development and discuss what has been learned about product performance since its licensure.

Objectives Depression is a major comorbidity that affects clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). COPD patients with depression are hospitalized more frequently, and show more acute exacerbations, decreased physical and social activities, and higher mortality compared to their non-depressed counterparts. In the present study, we investigated the clinical impact of depressive symptoms and associated clinical factors in Korean patients with COPD by evaluating multicenter cohort data. Materials and methods Patients with COPD enrolled in the Korean COPD Subtype Study, a multicenter observational study, from December 2011 to October 2014 were selected for evaluation. The initial evaluation of all patients included pulmonary function tests, 6 min walk distance (6MWD), the COPD Assessment Test (CAT), and the COPD-specific version of the St. George's Respiratory Questionnaire (SGRQ-C). Significant depression was defined as a Beck Depression Inventory-II (BDI-II) score ≥17. Results Among the 270 study patients, 19.6% had significant depression. The depressed group showed a higher proportion of females (41.4%), lower body mass index (BMI), and lower education level compared to the non-depressed group (p = 0.002, p = 0.008, and p = 0.019, respectively). The depressed group had significantly higher CAT and SGRQ-C scores, as well as a lower 6MWD, compared to the non-depressed group based on 6 month-interval serial measurements over 3 years. The total SGRQ-C score and the symptoms, activity, and impact domain scores were significant predictors of depression (area under curves [AUCs] of 0.699 [0.613-0.786], 0.670 [0.581-0.758], 0.680 [0.589-0.770], and 0.689 [0.603-0.776], respectively). From CAT score domains, sleep and energy scores were significant predictors of depression (AUCs of 0.619 [0.522-0.715] and 0.595 [0.504-0.685], respectively). SGRQ-C score, low BMI, and decreased 6MWD were significantly associated with depression in a multivariable analysis. Conclusion A considerable proportion of patients with COPD had depression, and a high SGRQ-C score, low BMI, and low 6MWD were significantly associated with depression. As improving quality of life in this subgroup is difficult, physicians should be more active in screening patients with significant depression.

The first licensed dengue vaccine, CYD-TDV (Dengvaxia) is efficacious in seropositive individuals, but increases the risk for severe dengue in seronegative persons about two years after administration of the first dose. For countries considering the introduction of Dengvaxia, WHO recommends a pre-vaccination screening strategy whereby only persons with evidence of a past dengue infection would be vaccinated. Policy-makers need to consider the risk-benefit of vaccination strategies based on such screening tests, the optimal age to introduce the vaccine, communication and implementation strategies. To address these questions, the Global Dengue and Aedes-transmitted diseases Consortium (GDAC) organized a 3-day workshop in January 2019 with country representatives from Asia and Latin America. The meeting discussions highlighted many challenges in introducing Dengvaxia, in terms of screening test characteristics, costs of such tests combined with a 3-dose schedule, logistics, achieving high coverage rates, vaccine confidence and communication; more challenges than for any other vaccine introduction programme. A screening test would require a high specificity to minimize individual risk, and at the same time high sensitivity to maximize individual and population benefit. The underlying seroprevalence dependent positive predictive value is the best indicator for an acceptable safety profile of a pre-vaccination screening strategy. The working groups discussed many possible implementation strategies. Addressing the bottlenecks in school-based vaccine introduction for Dengvaxia will also benefit other vaccines such as HPV and booster doses for tetanus and pertussis. Levels of public trust are highly variable and context specific, and understanding of population perceptions and concerns is essential to tailor interventions, monitor and mitigate risks.

Jeong Uk Lim, Chang Dong Yeo, Chin Kook Rhee, Hye Seon Kang, Chan Kwon Park, Ju Sang Kim, Jin Woo Kim, Seung Joon Kim, Hyoung Kyu Yoon, Sang Haak LeeDivision of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaObjectives: A significant proportion of non-small cell lung cancer (NSCLC) patients are never-smokers. However, the clinical impact of spirometrically diagnosed chronic obstructive pulmonary disease (COPD) on the prognosis of never-smoking NSCLC has not been evaluated in the context of treatment modalities and other cancer-related factors. In the present study, we evaluated the clinical impact of COPD in non-smoking NSCLC patients, and correlations between COPD and other previously unevaluated clinical variables.Materials and methods: Lung cancer patients (stages I to IV) diagnosed with NSCLC between January 2008 and December 2015 at six university hospitals were enrolled in the study cohort and retrospectively evaluated. Clinical parameters were compared between spirometrically diagnosed COPD and non-COPD groups. Correlations between COPD status and other variables were evaluated. In order to reduce the effect of potential confounders and selection bias, we performed adjustment for differences in baseline parameters by using propensity score matching (PSM). After PSM, clinical variables were evaluated for their effects on overall survival (OS).Results: Of the 345 patients enrolled in the study, 277 were categorized as non-COPD and 68 as COPD. Old age, male gender, and wild-type EGFR were significantly correlated with COPD. By univariate analysis of 218 patients in a propensity score matched cohort, not receiving active anticancer treatment, advanced stage, and COPD were significantly associated with shorter OS. Multivariate analysis showed that not receiving active anticancer treatment, advanced cancer stage, and COPD (P=0.044, HR: 1.526, 95% CI: 1.012–2.300) were significant predictors of shorter OS.Conclusion: In the present study, never-smoker NSCLC patients with COPD had shorter OS times, compared to non-COPD never-smoker NSCLC patients.Keywords: never smoker, overall survival, risk factor &nbsp

Background and objective A cough-specific quality-of-life questionnaire is recommended to assess the impact of cough; however, a simple instrument to quantify cough is required for everyday clinical practice. This study was aimed to develop a short patient-completed questionnaire (COugh Assessment Test, COAT). Methods The COAT was developed and validated by comparison with the Korean version of Leicester Cough Questionnaire (K-LCQ) and cough numeric rating scale (NRS, 0-10, 11-point scale) for chronic cough patients. Results Item selection identified five items regarding cough frequency, daily activity, sleep disturbance, fatigue and cough hypersensitivity (0-4 scaling of items, 0-20 score range) through reliability test cohort (n = 78). Test-retest reliability was strong (intra-class correlation coefficient = 0.88). The final COAT was compared with K-LCQ and cough NRS in a validation cohort (n = 323). In Rasch analysis, COAT fitted well to a unidimensional model. Pearson correlations of COAT versus K-LCQ (i) before treatment, (ii) after treatment; COAT versus cough NRS (iii) before treatment, (iv) after treatment; (v) delta-COAT versus delta-cough NRS, (vi) delta-COAT versus delta-K-LCQ were (i) -0.71, (ii) -0.81, (iii) 0.69, (iv) 0.82, (v) -0.66 and (vi) 0.72, respectively. Conclusion The COAT is a useful, simple questionnaire for assessing and monitoring cough.

Background Smoking is a major risk factor for COPD. However, there is low COPD awareness among smokers. We conducted a field survey to investigate COPD awareness, optimistic bias associated with COPD, and COPD prevalence (using handheld spirometry) among current male smokers. Subjects and methods We enrolled currently smoking males aged over 40 years, who completed a self-administered questionnaire. The questionnaire consisted of six parts: 1) baseline demographics, 2) participants' awareness of COPD and pulmonary function tests, 3) presence of COPD-related respiratory symptoms and experience with pulmonary function testing, 4) optimistic bias about COPD, 5) willingness to change attitude toward respiratory health, and 6) preference of media for obtaining health-related information. Pulmonary function was assessed via handheld spirometry by two experienced pulmonary function laboratory technicians after completion of the questionnaire. Results We enrolled 105 participants. Only 24.8% knew of COPD. Awareness of pulmonary function testing was reported by 41.9% of participants, and 30.5% had previously undertaken pulmonary function tests. Among the subjects who had not previously undergone pulmonary function tests, 47% were not aware of their existence. The mean optimistic bias scores were 3.9 and 4.0, respectively, reflecting the general perception, among participants, that they were about as likely to develop COPD as similarly aged smokers and friends, respectively. A total of 40.0% of participants perceived personal COPD risk to be lower than COPD risk among their friends. Abnormal handheld spirometry results were observed in 28.6% of participants. Among the subjects with abnormal handheld spirometry results, 36.7% had FEV1 values

BACKGROUND The aim of the current study was to investigate the prevalence and clinicopathologic characteristics of ROS1-rearranged non-small cell lung cancer (NSCLC) in routine genotypic screening in conjunction with the study of PD-L1 expression, a biomarker for first-line treatment decisions. METHODS Reflex simultaneous genotypic screening for EGFR by peptide nucleic acid clamping, and ALK and ROS1 by fluorescence in situ hybridization (FISH) was performed on consecutive NSCLC cases at the time of initial pathologic diagnosis. We evaluated genetic aberrations, clinicopathologic characteristics, and PD-L1 tumor proportion score (TPS) using a PD-L1 22C3 assay kit. RESULTS In 407 consecutive NSCLC patients, simultaneous genotyping identified 14 (3.4%) ROS1 and 19 (4.7%) ALK rearrangements, as well as 106 (26%) EGFR mutations. These mutations were mutually exclusive and were found in patients with similar clinical features, including younger age, a prevalence in women, adenocarcinoma, and advanced stage. The PD-L1 assay was performed on 130 consecutive NSCLC samples. High PD-L1 expression (TPS ≥ 50%) was observed in 29 (22.3%) tumors. PD-L1 expression (TPS ≥ 1%) was significantly associated with wild type EGFR, while ROS1 rearrangement was associated with high PD-L1 expression. Of the 14 cases with ROS1 rearrangement, 12 (85.7%) showed PD-L1 expression and 5 (35.7%) showed high PD-L1 expression. CONCLUSION In the largest consecutive routine Asian NSCLC cohort analyzed to date, we found that high PD-L1 expression frequently overlapped with ROS1 rearrangement, while it negatively correlated with EGFR mutations.

Renal function declines after partial nephrectomy due to ischemic reperfusion injury induced by surgical insult or renal artery clamping. The effect of remote ischemic preconditioning (RIPC) on reducing renal injury after partial nephrectomy has not been studied regarding urinary biomarkers. Eighty-one patients undergoing partial nephrectomy were randomly assigned to either RIPC or the control group. RIPC protocol consisted of four cycles of five-min inflation and deflation of a blood pressure cuff to 250 mmHg. Serum creatinine levels were compared at the following time points: preoperative baseline, immediate postoperative, on the first and third days after surgery, and two weeks after surgery. The incidence of acute kidney injury, other surgical complication rates, and urinary biomarkers, including urine creatinine, β-2 microglobulin, microalbumin, and N-acetyl-beta-D-glucosaminidase were compared. Split renal functions measured by renal scan were compared up to 18 months after surgery. There was no significant difference in the serum creatinine level on the first postoperative day (median (interquartile range) 0.87 mg/dL (0.72–1.03) in the RIPC group vs. 0.92 mg/dL (0.71–1.12) in the control group, p = 0.728), nor at any other time point. There was no significant difference in the incidence of acute kidney injury. Secondary outcomes, including urinary biomarkers, were not significantly different between the groups. RIPC showed no significant effect on the postoperative serum creatinine level of the first postoperative day. We could not reveal any significant difference in the urinary biomarkers and clinical outcomes. However, further larger randomized trials are required, because our study was not sufficiently powered for the secondary outcomes.

We aimed to evaluate whether the duration and stage of acute kidney injury (AKI) are associated with the occurrence of chronic kidney disease (CKD) in patients undergoing cardiac or thoracic aortic surgery. A total of 2009 cases were reviewed. The patients with postoperative AKI stage 1 and higher stage were divided into transient (serum creatinine elevation ≤48 h) or persistent (&gt, 48 h) AKI, respectively. Estimated glomerular filtration rate (eGFR) values during three years after surgery were collected. Occurrence of new-onset CKD stage 3 or higher or all-cause mortality was determined as the primary outcome. Multivariable Cox regression and Kaplan–Meier survival analysis were performed. The Median follow-up of renal function after surgery was 32 months. The cumulative incidences of our primary outcome at one, two, and three years after surgery were 19.8, 23.7, and 26.1%. There was a graded significant association of AKI with new-onset CKD during three years after surgery, except for transient stage 1 AKI (persistent stage 1: HR 3.11, 95% CI 2.62–4.91, transient higher stage: HR 4.07, 95% CI 2.98–6.11, persistent higher stage: HR 13.36, 95% CI 8.22–18.72). There was a significant difference in survival between transient and persistent AKI at the same stage. During three years after cardiac surgery, there was a significant and graded association between AKI stages and the development of new-onset CKD, except for transient stage 1 AKI. This association was stronger when AKI lasted more than 48 h at the same stage. Both duration and severity of AKI provide prognostic value to predict the development of CKD.

Intra-host single nucleotide variants (iSNVs) have been increasingly used in genomic epidemiology to increase phylogenetic resolution and reconstruct fine-scale outbreak dynamics. These analyses are preferably done on sequence data from direct clinical samples, but in many cases due to low viral loads, there might not be enough genetic material for deep sequencing and iSNV determination. Isolation of the virus from clinical samples with low-passage number increases viral load, but few studies have investigated how dengue virus (DENV) culture isolation from a clinical sample impacts the consensus sequence and the intra-host virus population frequencies. In this study, we investigate consensus and iSNV frequency differences between DENV sequenced directly from clinical samples and their corresponding low-passage isolates. Twenty five DENV1 and DENV2 positive sera and their corresponding viral isolates (T. splendens inoculation and C6/36 passage) were obtained from a prospective cohort study in the Philippines. These were sequenced on MiSeq with minimum nucleotide depth of coverage of 500×, and iSNVs were detected using LoFreq. For both DENV1 and DENV2, we found a maximum of one consensus nucleotide difference between clinical sample and isolate. Interestingly, we found that iSNVs with frequencies ≥5 % were often preserved between the samples, and that the number of iSNV positions, and sample diversity, at this frequency cutoff did not differ significantly between the sample pairs (clinical sample and isolate) in either DENV1 or DENV2 data. Our results show that low-passage DENV isolate consensus genomes are largely representative of their direct sample parental viruses, and that low-passage isolates often mirror high frequency within-host variants from direct samples.

More than half of the world’s population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk. Multiyear analysis of antibody responses in recipients of the dengue vaccine Dengvaxia in the Philippines supports their utility as a predictor of protection against disease, and reveals that Dengvaxia efficacy declines 3 years after complete vaccination.

Because of limited data on dengue virus in Burkina Faso, we conducted 4 consecutive age-stratified longitudinal serologic surveys, ≈6 months apart, among persons 1-55 years of age, during June 2015-March 2017, which included a 2016 outbreak. The seroconversion rate before the serosurvey enrollment was estimated by binomial regression, taking age as the duration of exposure, and assuming constant force of infection (FOI) over age and calendar time. We calculated FOI between consecutive surveys and rate ratios for potentially associated characteristics based on seroconversion using the duration of intervals. Among 2,897 persons at enrollment, 66.3% were IgG-positive, and estimated annual FOI was 5.95%. Of 1,269 enrollees participating in all 4 serosurveys, 438 were IgG-negative at enrollment. The annualized FOI ranged from 10% to 20% (during the 2016 outbreak). Overall, we observed high FOI for dengue. These results could support decision-making about control and preventive measures for dengue

Introduction Filgotinib (FIL) is a JAK1 inhibitor under phase 3 clinical evaluation for treatment of IBD. We conducted a post hoc analysis in patients (pts) with moderately to severely active Crohn’s disease (CD) to assess the effect of FIL on markers of JAK1 signaling (STAT1/3 phosphorylation [pSTAT1/3]) within intestinal mucosa and their correlation to histologic/endoscopic indices (NCT02048618). Methods Baseline (BL) and Week 10 (W10) biopsies were collected from predefined bowel segments. Within-subject matched biopsies (FIL, n=42; placebo [PBO], n=18) were scored for histologic and endoscopic disease activity. Machine learning (Visiopharmv.2019.06) was used to quantify%pSTAT1 and%pSTAT3 positive nuclei within epithelium (Ep) and non-Ep regions. Basal pSTAT levels from 182 non-diseased segments were used to classify segments as low or high molecular disease activity (MDA). Agreement between endoscopy/histology and MDA was evaluated by Cohen’s kappa coefficient (κ) and% agreement. Results In segments with BL GHAS activity subscore ≥2, Ep (10–30%) and non-Ep (25–35%) MDA were elevated and correlated to histologic activity. Table 1 shows the effect of FIL on MDA in the intestinal mucosa: significantly fewer low BL MDA segments showed MDA worsening, and significantly more high BL MDA segments showed MDA improvement (pSTAT3 only) with FIL vs. PBO. Agreement for MDA and endoscopy was fair to moderate (κ 0.3–0.5), and for MDA and histology was moderate to good (κ 0.4–0.8). Conclusions FIL improved JAK1-related MDA within the mucosa of pts with CD. Agreement between MDA and clinical indices was highest with histology.

Background: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a condition characterized by the overlapping clinical features of asthma and COPD. To evaluate the appropriateness of different sets of ACO definition, we compared the clinical characteristics of the previously defined diagnostic criteria and the specialist opinion in this study. Methods: Patients enrolled in the KOrea COpd Subgroup Study (KOCOSS) were evaluated. Based on the questionnaire data, the patients were categorized into the ACO and non-ACO COPD groups according to the four sets of the diagnostic criteria. Results: In total 1,475 patients evaluated: 202 of 1,475 (13.6%), 32 of 1,475 (2.2%), 178 of 1,113 (16.0%), and 305 of 1,250 (24.4%) were categorized as ACO according to the modified Spanish Society of Pneumonology and Thoracic Surgery (SEPAR), American Thoracic Society (ATS) Roundtable, Global Initiative for Asthma (GINA)/Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, and the specialists diagnosis, respectively. The ACO group defined according to the GINA/GOLD criteria showed significantly higher St. George''s Respiratory Questionnaire and COPD Assessment Test scores than the non-ACO COPD group. When the modified SEPAR definition was applied, the ACO group showed a significantly larger decrease in the forced expiratory volume in 1 second (FEV1, %). The ACO group defined by the ATS Roundtable showed significantly larger decrease in the forced vital capacity values compared to the non-ACO COPD group (-18.9% vs. -2.2%, p=0.007 and -412 mL vs. -17 mL, p=0.036). The ACO group diagnosed by the specialists showed a significantly larger decrease in the FEV1 (%) compared to the non-ACO group (-5.4% vs. -0.2%, p=0.003). Conclusion: In this study, the prevalence and clinical characteristics of ACO varied depending on the diagnostic criteria applied. With the criteria which are relatively easy to use, defining ACO by the specialists diagnosis may be more practical in clinical applications.

Intra-host single nucleotide variants (iSNVs) have been increasingly used in genomic epidemiology to increase phylogenetic resolution and reconstruct fine-scale outbreak dynamics. These analyses are preferably done on sequence data from direct clinical samples, but in many cases due to low viral loads, there might not be enough genetic material for deep sequencing and iSNV determination. Isolation of the virus from clinical samples with low passage number increases viral load, but to date, no studies have investigated how dengue virus (DENV) culture isolation from a clinical sample impacts the consensus sequence, and there is no information on the intra-host virus population changes that may result from viral isolation. In this study, we investigate consensus and iSNV frequency differences between DENV sequenced directly from clinical samples and their corresponding low-passage isolates. Twenty five DENV1 and DENV2 positive sera and their corresponding viral isolates (T.splendens inoculation and C6/36 passage) were obtained from a prospective cohort study in the Philippines. These were sequenced on MiSeq with minimum nucleotide depth of coverage of 1000x, and iSNVs were detected using LoFreq. For both DENV1 and DENV2, we found that the nucleotide call concordance (including called iSNVs with variant cutoff at 5%) between direct sera sample and its cultured virus was on average 99.99%. There were a maximum of one consensus nucleotide difference between clinical sample and isolate. Interestingly, we found that iSNV frequencies were also largely preserved between the samples, with an average difference in minor variant frequency of 6.8% (95CI: 3.6%-10%) and 9.6% (95CI: 7%-12.2%) for DENV1 and DENV2, respectively. Furthermore, we found no significant differences in either DENV1 or DENV2 between the sample pairs (clinical sample and isolate) in their number of iSNV positions per genome, or in the difference in variant frequencies (p=0.36 and p=0.13, respectively, F-test). Our results show that low-passage DENV isolates may be used for identification of the majority of their human-derived within-host variant populations, which are increasingly being used for precision tracking of DENV and other RNA viruses.

Objective Platelets play a critical role in the inflammatory response, accompanied by microvascular endothelial dysfunction, underlying postoperative symptomatic cerebral hyperperfusion syndrome (PSCHS) after superficial temporal artery–middle cerebral artery (STA-MCA) anastomosis in moyamoya patients. We examined whether the preoperative platelet count can predict PSCHS after STA-MCA anastomosis in such patients. Methods In 160 adult moyamoya patients undergoing 186 STA-MCA anastomoses, preoperative (demographics, initial clinical manifestation, and Suzuki grade), intraoperative (surgical time, operative side, fluid balance, and maximum and minimum mean blood pressure before and after vessel anastomosis), immediate postoperative (APACHE 2 score), and laboratory (hemoglobin and C-reactive protein levels and white blood cell and platelet counts) data were collected retrospectively. Results 84 patients (90 sides, 48.4 %) developed PSCHS with a median(IQR) onset of postoperative day 1(0–3) and duration of 4(3–7) days. The preoperative (25.2[22.8–28.0] vs. 23.1[19.7–26.2] ×104/μL, p = 0.009) platelet count was significantly higher in patients with PSCHS than in those without. The preoperative platelet count (odds ratio[95 % confidence interval], 1.14[1.03–1.27], p = 0.011), operation on the dominant hemisphere (6.84 [3.26–14.36], p Conclusion A high preoperative platelet count may be associated with the development of PSCHS after STA-MCA anastomosis in adult moyamoya patients.

BACKGROUND: Lead exposure is a resurgent environmental issue globally. Smoking can be a source of lead exposure, although the majority of lead poisonings originate from workplace exposures. However, no study has been undertaken concerning the blood lead levels based on the chronic obstructive pulmonary disease (COPD), smoking status, and other risk factors of COPD. This cross-sectional study was conducted to investigate the blood lead levels according to COPD and clinical variables associated with COPD. METHODS: Data (total number =53,829) were collected from the Korean National Health and Nutrition Examination Survey (IV in 2008 and 2009, V in 2010–2012, and VI in 2013). Multivariable linear regression analyses were performed to determine variables associated with elevated blood lead levels. RESULTS: Univariate regression analysis showed that male sex, older age, smoking, occupation level, income level, education level, and presence of COPD were related to higher blood lead levels, whereas the other co-morbidities including diabetes, hypertension, cerebral stroke, osteoporosis, asthma, and depression were not related (P

Objective Vaccination with the first licensed dengue vaccine is recommended only for those who have had previous infection with dengue virus (DENV). A point-of-care test with the desired sensitivity of 95% and specificity of 98% could facilitate pre-vaccination screening. We evaluated a newly developed, automated dengue immunoglobulin fluorescence immunoassay for determining dengue serostatus. Methods We used serum samples collected just prior to a mass dengue vaccination in Cebu, Philippines. Healthy children residing in Bogo and Balamban who would be 9–14 years old at the time of the mass dengue vaccination were eligible to participate. We evaluated the ichroma™ II dengue fluorescence immunoassay (Boditech Med Incorporated, Gang-won-do, Republic of Korea) using a neutralization test (NT) as the reference assay. Results We enrolled 2996 children (mean age 10.39 years, 51.7% female) in the cohort and included a subsample of 1000 (mean age 10.56 years, 54.4% female) in this study. Of the 1000 children, 86/1000 (8.6%) tested seronegative and 914/1000 (91.4%) seropositive for DENV antibodies by neutralization testing. Compared with the NT, the dengue IgG fluorescence immunoassay had an overall specificity of 90.7% (95%CI: 82.5–95.9%) and a sensitivity of 91.8% (95%CI: 89.8–93.5%) for determining dengue seropositivity. The sensitivity declined to 51.2% (42.3–61.0%) for the detection of the subset with a monotypic dengue profile. Conclusion The insufficient specificity and sensitivity (particularly in the detection of a previous monotypic dengue infection) would render the test, in its current state, inadequate for pre-vaccination screening. Considering its user-friendly interphase and possibility of point-of-care use, the test could be further developed and validated to improve its performance characteristics.

Background Blood eosinophil count may predict treatment response in patients with chronic obstructive pulmonary disease (COPD) during acute exacerbations (AE). However, the ability and thresholds of blood eosinophil counts in stable status to predict eosinophilic AECOPD have not been completely investigated. Methods This was a retrospective multicenter study performed January 2010 to December 2014. COPD subjects hospitalized with exacerbations, were included. Blood samples were obtained at the time of AE and stable disease at outpatient clinic before or after admission. We identified a blood eosinophil count cut-off point at stable COPD, either taken as a percentage or as absolute value, for identification of predicting blood eosinophil count at AECOPD. Results There was significant positive correlation of eosinophil counts between stable COPD and AECOPD. The best cut-off value of blood eosinophil count in stable status for the prediction of eosinophilic COPD exacerbation based on blood eosinophil count ≥ 2% was 300 cells/µL (area under the ROC curve [AUC] 0.614, P = 0.001, 39% sensitivity, 83.8% specificity). When the eosinophilic COPD exacerbation was based on blood eosinophil count ≥ 300 cells/µL, the best cut-off value of blood eosinophil count in stable status for the prediction of eosinophilic COPD exacerbation was also 300 cells/uL (AUC 0.634, P = 0.046, 45.8% sensitivity, 80.9% specificity). Conclusions We demonstrated association between blood eosinophil counts at stable COPD and those with AECOPD. The thresholds of blood counts at stable COPD to predict eosinophilic exacerbations was 300 cells/µL. Further and prospective studies in other populations should validate our results.

Background Blood eosinophil count may predict treatment response in patients with chronic obstructive pulmonary disease (COPD) during acute exacerbations (AE). However, the ability and thresholds of blood eosinophil counts in stable status to predict eosinophilic AECOPD have not been completely investigated. Methods This was a retrospective multicenter study performed January 2010 to December 2014. COPD subjects hospitalized with exacerbations, were included. Blood samples were obtained at the time of AE and stable disease at outpatient clinic before or after admission. We identified a blood eosinophil count cut-off point at stable COPD, either taken as a percentage or as absolute value, for identification of eosinophilic exacerbation. Results There was significant positive correlation of eosinophil counts between stable COPD and AECOPD. The best cut-off value of blood eosinophil count in stable status for the prediction of eosinophilic COPD exacerbation based on blood eosinophil count ≥ 2% was 300 cells/µL (area under the ROC curve [AUC] 0.614, P = 0.001, 39% sensitivity, 83.8% specificity). When the eosinophilic COPD exacerbation was based on blood eosinophil count ≥ 300 cells/µL, the best cut-off value of blood eosinophil count in stable status for the prediction of eosinophilic COPD exacerbation was also 300 cells/uL (AUC 0.634, P = 0.046, 45.8% sensitivity, 80.9% specificity). Conclusions We demonstrated association between blood eosinophil counts at stable COPD and those with AECOPD. The thresholds of blood counts at stable COPD to predict eosinophilic exacerbations was 300 cells/µL. Further and prospective studies in other populations should validate our results.

Background Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD. Methods Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell-depleted bone marrow with or without spleen cells to generate Scl-GVHD. hMSCs were intravenously treated on days 3, 5, and 7 post-transplantation, and the control antibody or CCL1 blocking antibody was subcutaneously injected according to the same schedule as the hMSCs. Fourteen days after transplantation, the recipient mice were sacrificed, and their skin and lungs were analyzed. Results After the early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs had migrated into the lungs, but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently upregulated the expression of CCL1 in the lungs, but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with the preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and upregulation of chemokines were also decreased in lung tissues, along with the recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade. Conclusions These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 upregulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.

Summary Background Detection of dengue virus antibodies is important for understanding future dengue virus risk and for prevaccination screening. We aimed to evaluate the performance of a dengue IgG indirect ELISA in determining dengue seroprevalence in a cohort of children in the Philippines, using a focus reduction neutralisation test (FRNT) as the reference test. Methods In this prospective population-based cohort study, we enrolled healthy children residing in Bogo or Balamban, Cebu, Philippines, who were to be aged 9–14 years at the time of a mass dengue vaccination campaign. Sera were collected from participants and batch tested by indirect IgG ELISA and FRNT. The primary endpoint was dengue seroprevalence in the cohort, detected by ELISA, and validated by that detected by reference FRNT. This study is registered with ClinicalTrials.gov , NCT03465254 . Findings We collected 2996 serum samples between May 2, and June 2, 2017, and we tested each sample with IgG ELISA. Using 1961 samples (65·5%) that were tested with FRNT, and 1035 samples (34·5%) with imputed results, we found that 320 (10·7%) of 2996 children were dengue naive and 2676 (89·3%) were seropositive for previous dengue virus infection. Based on the 1961 non-imputed FRNT results classified as dengue seronegative or seropositive, the ELISA (with a 0·9 index value cutoff) showed 95·2% sensitivity, 93·4% specificity, 6·6% false positivity, and 4·8% false negativity. However, sensitivity of the ELISA was poor (77·1%) among children with immunity to just one dengue virus serotype. Of the 11 sera that were false positive with ELISA, seven samples (63·6%) were seropositive for Zika virus or Japanese encephalitis virus with FRNT. Interpretation Most children (89·3%) assessed in our study and eligible to participate in the mass dengue vaccination campaign were seropositive for previous dengue virus infection. Compared with FRNT, ELISA had high sensitivity and specificity (>90%), but the false-negative and false-positive rates makes the test suboptimal for prevaccination screening. Individuals who are falsely identified as seropositive by dengue IgG ELISA and then vaccinated might be at risk of developing severe disease during a subsequent exposure to wild-type dengue virus. Those with a monotypic profile would benefit the most from vaccination, but the sensitivity of the IgG ELISA was much lower in this group than in those with a multitypic profile. Funding Philippine Department of Health, Hanako Foundation, WHO, Swedish International Development Cooperation Agency through the International Vaccine Institute, and University of North Carolina, Chapel Hill, NC, USA.

Background The emergence of drug-resistant tuberculosis (DR-TB) is a major healthcare concern worldwide. Here, we analyzed age-related trends in DR-TB rates in South Korea. Methods Drug susceptibility test results were collected from patients with culture-confirmed TB between 2015 and 2018 from eight university-affiliated hospitals. Patients were divided into three subgroups: younger (15–34 years), middle (35–59 years), and older (≥60 years) to compare drug-resistance patterns. To evaluate trends in age-stratified drug-resistance, chi-square test for linear trends was performed. Results Among enrolled native patients aged ≥15 years, 4.1% (179/4417), 1.2% (53/4417) and 7.2% (316/4417) were multidrug-resistant TB (MDR-TB), rifampicin-mono-resistant TB (RR-TB), and isoniazid-mono-resistant TB (Hr-TB), respectively. Proportions of Hr-TB cases were 5.4% (40/734), 7.2% (114/1593), and 7.8% (162/2090) in the younger, middle and older age groups, respectively. MDR/RR-TB case rates decreased significantly with age from 8.6% (63/734) in younger age group to 3.3% (68/2090) in older age group. Fluoroquinolone resistance was highest among second-line drugs, and there were no differences in resistance to fluoroquinolones and second-line injectable drugs among the three age groups. Conclusions The number of MDR/RR-TB cases was highest in young patients. Effective public health interventions should include increased focus on rifampicin resistance in young patients.

Background: Low body mass index (BMI) is an important prognostic factor in chronic obstructive pulmonary disease (COPD). However, the prognostic value of longitudinal BMI change in COPD has not been well studied. Objective: We aimed to evaluate the association between longitudinal change of BMI and prognosis of COPD in Korean COPD cohort. Methods: This study was conducted in a prospective Korean Obstructive Lung Disease (KOLD) cohort where COPD patients were recruited on an outpatient basis at 17 hospitals in South Korea. Annual BMI was measured over a period of 3 years or more. All patients were categorized into underweight (UW), normal weight (NW), and overweight (OW) groups by BMI. Clinical characteristics and outcomes including exacerbation and mortality were compared based on initial BMI grade and longitudinal change of BMI. Results: This analysis included 537 COPD patients (mean age = 67.4 ± 7.9 years, male = 97.0%, mean BMI = 23.0 ± 3.1) of KOLD cohort. The proportions of UW, NW, and OW groups were 6.9% (n = 37), 68.9% (n = 370), and 24.2% (n = 130) respectively. The UW group showed lower forced expiratory volume in 1 s (FEV1) (p < 0.001), shorter 6-minute walk distance (p < 0.001), higher modified Medical Research Council score (p = 0.002), higher St. George Respiratory Questionnaire score (p < 0.001), higher emphysema index (p < 0.001) and air-trapping index (p < 0.001), and more frequent (p < 0.001) and severe exacerbations (p = 0.003). Multivariable analyses demonstrated that decrease of BMI (hazard ratio [HR] = 0.786, p = 0.038) and the descent of BMI group (HR = 3.167, p = 0.016) at 3-year follow-up along with age, initial BMI, post-bronchodilator FEV1, and severe exacerbations were significantly associated with mortality. Conclusions: This study demonstrated that BMI decrease during follow-up was independently associated with exacerbation and higher mortality of COPD, suggesting BMI reduction in COPD should be carefully managed.

Background: Detection of dengue virus (DENV) antibodies is important for understanding future dengue risk and for pre-vaccination screening. We assessed dengue seroprevalence in a cohort of Filipino children and compared a dengue immunoglobulin G indirect enzyme-linked immunosorbent assay (ELISA) with focus reduction neutralization test (FRNT). Methods: We collected 2,996 serum samples from 9 to 14 year old children, just prior to a mass dengue vaccination. Sera were batch tested by ELISA and FRNT. Findings: By FRNT, 320 (10.7%) of the 2,996 were dengue naive, 292 (9.7%) had past primary dengue infection and 2,384 (79.6%) had 2 or more (multitypic) infections. Compared with an FRNT seronegative or seropositive outcome, the ELISA with a 0.9OD cut-off showed 96.8% sensitivity, 96.6% specificity, 3.4% false positivity and 3.2% false negativity. The sensitivity of the IgG ELISA was especially poor (77.1%) among children with immunity to just one DENV serotype. Of the 11 sera that were false positive by ELISA, 7 (63.6%) were seropositive for Zika or Japanese Encephalitis viruses by FRNT. Interpretation: A majority of the cohort were not only DENV seropositive, but had a multitypic response by FRNT indicating past infection by two or more serotypes. While the ELISA had a high sensitivity and specificity, the false-negative and false-positive rates may render the test less than optimal for determining DENV serostatus prior to vaccination. Children with primary immunity to just one serotype would benefit the most from vaccination but the sensitivity of the IgG ELISA was much lower in this group. Trial Registration: ClinicalTrials.gov Identifier: NCT03465254 Funding Statement: Philippine Department of Health, Hanako Foundation, World Health Organization, Swedish International Development Cooperation Agency through the International Vaccine Institute, and University of North Carolina at Chapel Hill. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The protocol was reviewed and approved by the University of the Philippines – Manila Research Ethics Board (UPM-REB). A parent or legal guardian of the participants provided written informed consent.

Previous studies have found that the prescription rates of inhaled corticosteroid (ICS) were considerably low although it is recommended as the optimal asthma treatment. The aim of this study was to analyze the current status of ICS prescription for asthma patients in the South Korea.We evaluated quality assessment data based on nationwide Health Insurance Review and Service (HIRA) database from July 2013 to June 2014. ICS prescription rates in asthma patients were analyzed by types and specialty of medical institutions. Also, we graded medical institutions by their ICS prescription rate. In addition, ICS prescription rates were calculated by patient gender, age, and insurance type.This study included 831,613 patients and 16,804 institutions in the analysis. The overall mean ICS prescription rate was 22.58%. Tertiary hospitals had the highest mean prescription rate (84.16%) whereas primary healthcare clinics had the lowest (20.71%). By specialty, internal medicine physicians prescribed ICS more frequently compared to other specialists. Of all, 47.17% of medical institutions prescribed ICS to10% of asthma patients, while less than 6% of institutions prescribed ICS to80% of asthma patients. Also, we found that female and patients with age90 or20 years exhibited lower ICS prescription rate.The ICS prescription rate was found to be inadequate, given the importance of ICS as an asthma treatment. The prescription rates were especially low in primary healthcare clinics, and by specialists in fields other than internal medicine.

Background Anesthetic techniques can affect perioperative neuroendocrine function. The objective of this study was to compare 3-month post-operative neuroendocrine functional outcomes between sevoflurane and propofol anesthesia in patients undergoing endoscopic transsphenoidal surgery (ETS) for removal of non-functional pituitary adenomas (NFPAs) retrospectively. Methods Among 356 patients who underwent ETS for removal of NFPAs under sevoflurane-remifentanil anesthesia (sevoflurane group, n = 103) or propofol-remifentanil anesthesia (propofol group, n = 253), 92 patients in each group were selected and their 3-month post-operative neuroendocrine functional outcomes (primary outcome measure) were compared after propensity score matching. Results Overall changes in post-operative 3-month neuroendocrine function compared to pre-operative baseline did not differ between the sevoflurane and propofol groups (worsened: 32.6% vs 29.3%, persistently decreased: 9.8% vs 12.0%, improved: 12.0% vs 20.7%, normalized: 9.8% vs 12.0%, persistently normal: 18.5% vs 19.6%; P = .400). The incidence of pituitary hormone deficiency at 3 months post-operatively did not differ between the sevoflurane and propofol groups (adrenocorticotropic hormone deficiency: 18.5% vs 17.4%, P = 1.000; thyroid-stimulating hormone deficiency: 10.9% vs 3.3%, P = .081; gonadotropin deficiency: 54.3% vs 48.9%, P = .555; growth hormone deficiency: 45.7% vs 48.9%, P = .768; panhypopituitarism: 1.1% vs 1.1%, P = 1.000). Conclusion In patients undergoing ETS for removal of NFPAs, the effects of both sevoflurane-remifentanil and propofol-remifentanil anesthetic techniques on post-operative 3-month neuroendocrine functional outcomes were similar, suggesting that propofol and sevoflurane can be freely used in such patients in terms of post-operative intermediate-term neuroendocrine functional outcome.

Jeong Uk Lim, Chang Dong Yeo, Chin Kook Rhee, Yong Hyun Kim, Chan Kwon Park, Ju Sang Kim, Jin Woo Kim, Seung Joon Kim, Hyoung Kyu Yoon, Sang Haak Lee Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Objectives: Focusing on the advanced non-small cell lung cancer (NSCLC) patients without driver mutations can elucidate the clinical impact of COPD on treatment outcomes. The present study evaluated the effects of COPD on the overall survival of driver mutation-negative NSCLC patients undergoing conventional chemotherapy as the first-line treatment. Patients and methods: Medical records of stage IIIB and IV NSCLC patients from January 2008 to December 2015 from six university hospitals were reviewed. Results: The total study population consisted of 197 patients; 92 (46.7%) were COPD patients and 105 (53.3%) were non-COPD patients. The median survival in the non-COPD group was 11.5 months, compared to 9.2 months in the COPD group. Univariate analysis showed that old age (>70 years), high Eastern Cooperative Oncology Group status score (2–3), squamous cell histology, and COPD were risk factors for mortality. The presence of COPD was a significant prognostic factor in univariate analysis (hazard ratio [HR], 1.402; p=0.037), but not in multivariate analysis (HR, 1.275; p=0.144). Subgroup analysis of 143 smokers showed that COPD was a significant prognostic factor on multivariate analysis (HR, 1.726; p=0.006). In 154 stage IV patients, COPD was also a prognostic factor in multivariate analysis (HR, 1.479; p=0.039). Conclusion: COPD had a negative impact on overall survival in the stage IV NSCLC and smoker NSCLC patients who underwent conventional chemotherapy. Keywords: non-small cell lung cancer, chronic obstructive pulmonary disease, smoker, overall survival

Chronic obstructive pulmonary disease (COPD) results in high morbidity and mortality among patients nationally and globally. The Korean clinical practice guideline for COPD was revised in 2018. The guideline was drafted by the members of the Korean Academy of Tuberculosis and Respiratory Diseases as well as the participating members of the Health Insurance Review and Assessment Service, Korean Physicians' Association, and Korea Respiration Trouble Association. The revised guideline encompasses a wide range of topics, including the epidemiology, diagnosis, assessment, monitoring, management, exacerbation, and comorbidities of COPD in Korea. We performed systematic reviews assisted by an expert in meta-analysis to draft a guideline on COPD management. We expect this guideline to facilitate the treatment of patients with respiratory conditions by physicians as well other health care professionals and government personnel in South Korea.

To evaluate potential immunocompetent small animal models of Zika virus (ZIKV) infection, we inoculated Syrian golden hamsters (subcutaneously or intraperitoneally) and strain 13 guinea pigs (intraperitoneally) with Senegalese ZIKV strain ArD 41525 or Philippines ZIKV strain CPC-0740. We did not detect viremia in hamsters inoculated subcutaneously with either virus strain, although some hamsters developed virus neutralizing antibodies. However, we detected statistically significant higher viremias (P = 0.0285) and a higher median neutralization titer (P = 0.0163) in hamsters inoculated intraperitoneally with strain ArD 41525 compared with strain CPC-0740. Furthermore, some hamsters inoculated with strain ArD 41525 displayed mild signs of disease. By contrast, strain 13 guinea pigs inoculated intraperitoneally with either strain did not have detectable viremias and less than half developed virus neutralizing antibodies. Our results support the use of the Syrian golden hamster intraperitoneal model to explore phenotypic variation between ZIKV strains.