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Between March and May 2012, three neonates born at a regional maternity hospital developed Elizabethkingia meningoseptica (previously Chryseobacterium meningosepticum) sepsis with meningitis aged

Metagenomic approaches to detect viral genomes and variants in clinical samples have various challenges, including low viral titers and bacterial and human genome contamination. To address these limitations, we examined a next-generation sequencing (NGS) and iterative mapping approach for virus detection in clinical samples. We analyzed 40 clinical specimens from hospitalized children diagnosed with acute bronchiolitis, croup, or respiratory tract infections in which virus identification by viral culture or polymerase chain reaction (PCR) was unsuccessful. For our NGS data analysis pipeline, clinical samples were pooled into two NGS groups to reduce sequencing costs, and the depth and coverage of assembled contigs were effectively increased using an iterative mapping approach. PCR was individually performed for each specimen according to the NGS-predicted viral type. We successfully detected previously unidentified respiratory viruses in 26 of 40 specimens using our proposed NGS pipeline. Two dominant populations within the detected viruses were human rhinoviruses (HRVs; n = 14) and human coronavirus NL63 (n = 8), followed by human parainfluenza virus (HPIV), human parechovirus, influenza A virus, respiratory syncytial virus (RSV), and human metapneumovirus. This is the first study reporting the complete genome sequences of HRV-A101, HRV-C3, HPIV-4a, and RSV, as well as an analysis of their genetic variants, in Taiwan. These results demonstrate that this NGS pipeline allows to detect viruses which were not identified by routine diagnostic assays, directly from clinical samples. Electronic supplementary material The online version of this article (doi:10.1007/s00705-017-3367-4) contains supplementary material, which is available to authorized users.

A comprehensive evaluation of associations between the susceptibility to norovirus infections and histo-blood group antigens is not available in the Taiwanese population, in which the nonsecretor phenotype is absent.A 1:1 matched case-control study was conducted in northern Taiwan from February 2013 to December 2014 when an epidemic of norovirus infection occurred. Cases were children18 years old who were hospitalized because of diarrhea and were found to have laboratory-confirmed norovirus infections. Controls were healthy children matched to the cases by age and gender. The norovirus genotype was determined by polymerase chain reaction sequencing of the VP1 gene. The secretor status, Lewis antigen and ABO type were determined by characterization of genetic polymorphisms in the FUT2, FUT3 and ABO genes, respectively.A total of 147 case-control pairs were included. GII.4 Sydney strain was the major genotype and identified in 78.3% of the cases. The weak-secretor and Lewis-positive genotypes were less commonly identified in cases than in controls (5.4% vs. 23.1% and 79.6% vs. 89.8%, respectively). Multivariate analysis revealed that the secretor and Lewis-negative genotypes were both independent factors associated with increased risk of norovirus infections [matched odds ratio: 6.766, 95% confidence interval (CI): 2.649-17.285, P0.0001 and matched odds ratio: 3.071, 95% confidence interval [CI]: 1.322-7.084, P = 0.0085, respectively]. The ABO types were not significantly related to norovirus infections (P0.05).The weak-secretor genotype and the Lewis antigen-positive genotype were both protective factors against severe norovirus gastroenteritis during the GII.4 Sydney strain epidemic in Taiwan.

Invasive fungal infections in children with acute lymphoblastic leukemia have been a major cause of mortality. Recent reports have described increasing incidence of invasive non-Aspergillus mold infections in patients with hematological malignancies. It is always challenging to treat invasive fungal infection and underlying hematological malignancies successfully. Here we report a girl with high-risk acute lymphoblastic leukemia who developed disseminated Cunninghamella bertholletiae infection during induction chemotherapy. This case illustrates the difficulties of diagnosis and treatment of invasive C. bertholletiae infection. It also highlights the necessity for physicians to keep high suspicion and awareness for this infrequent fungal infection.

Background A regional antibiotic susceptibility data of common pathogens is crucial to first-line physician for clinical judgment and appropriate selection of antimicrobial agents. The aim of this study is to update the epidemiology data of drug resistance of pneumococcus causing invasive pneumococcal disease (IPD) in adults. Methods From the logbooks of microbiology laboratories, we retrospectively retrieved Streptococcus pneumoniae isolates, collected from normally sterile sites in adult patients in three hospitals in Taiwan from July 2011 to June 2015. Antibiotic resistance and serotypes of the isolates and clinical manifestations were further analyzed. Results A total of 150 non-duplicated isolates were collected. According to CLSI meningitis breakpoint, the proportion of ceftriaxone non-susceptible pneumococcus (CNSP) showed an increasing trend from 4.5% in 2011 to > 40% in 2013–2015 (p = 0.007). Serotypes 19A and 23F were significantly associated with CNSP. Imipenem and meropenem had a relative low susceptible rate of 36.7% and 50.7%, respectively. Serotypes 6A, 14, 19A and 19F were significantly associated with the non-susceptibility to these carbepanems. Conclusion The increase in the prevalence of CNSP using meningitis breakpoint was observed. For treating pneumococcal meningitis, empirical monotherapy with ceftriaxone might not be adequate. Imipenem and meropenem might not be a good choice for empirical treatment of adult IPDs. Antibiotic resistance of pneumococcus to ceftriaxone, cefepime, imipenem and meropenem were associated with 13-velent pneumococcal conjugate vaccine serotypes.

During recent 20 years, enterovirus A71 (EV-A71) has emerged as a major concern among pediatric infectious diseases, particularly in the Asia-Pacific region. The clinical manifestations of EV-A71 include uncomplicated hand, foot, and mouth disease, herpanina or febrile illness and central nervous system (CNS) involvement such as aseptic meningitis, myoclonic jerk, polio-like syndrome, encephalitis, encephalomyelitis and cardiopulmonary failure due to severe rhombencephalitis. In follow-up studies of patients with EV-A 71 CNS infection, some still have hypoventilation and need tracheostomy with ventilator support, some have dysphagia and need nasogastric tube or gastrostomy feeding, some have limb weakness/astrophy, cerebellar dysfunction, neurodevelopmental delay, lower cognition, or attention deficiency hyperactivity disorder. Long term sequelae may be related to greater severity of CNS involvement or neuron damage, hypoxia and younger age of onset.

ObjectiveTo explored 6-month longitudinal changes in conjunctival colonisation and antibiotic resistance profiles of coagulase-negativeStaphylococcus(CNS) after cataract surgery with 1 month tobramycin treatment.DesignProspective cohort study between 1 August 2012, and 31 July 2013.SettingA single medical centre in Taiwan.ParticipantsA total of 128 Taiwanese patients with 46.9% of male participants.InterventionsSamples from the conjunctival sacs of both operation (OP) and non-OP eyes were obtained separately before cataract surgery and at 1, 3 and 6 months after surgery. Tobramycin (0.3%) treatment was applied four times daily for 1 month postoperatively.Main outcome measureIdentification of CNS isolates and their antibiotic susceptibility by using disk diffusion or E-test.ResultsCNS was detected in 24.2% of patients at baseline. During postoperative follow-up, the CNS colonisation rate did not decrease in either eye but showed an increasing trend in the OP eyes at 1 month (p=0.06). The colonisation rate showed no significant difference between the OP and non-OP eyes from baseline to a specific follow-up. We observed a significant increase (pConclusionsDuring the 6-month postoperative follow-up, 0.3% tobramycin administration failed to reduce CNS colonisation but increased resistance to several antibiotics. Postoperative antibiotic treatment may be replaced by other evidence-endorsed prophylactic routines.

Background There have been no reports regarding clinical features and molecular characteristics of childhood methicillin-susceptible Staphylococcus aureus (MSSA) infections in Taiwan. Methods We prospectively collected clinical S. aureus isolates from patients aged

Pediatric myocarditis symptoms can be mild or as extreme as sudden cardiac arrest. Early identification of the severity of illness and timely provision of critical care is helpful; however, the risk factors associated with mortality remain unclear and controversial. We undertook a retrospective review of the medical records of pediatric patients with myocarditis in a tertiary care referral hospital for over 12 years to identify the predictive factors of mortality. Demographics, presentation, laboratory test results, echocardiography findings, and treatment outcomes were obtained. Regression analyses revealed the clinical parameters for predicting mortality. During the 12-year period, 94 patients with myocarditis were included. Of these, 16 (17%) patients died, with 12 succumbing in the first 72 hours after admission. Fatal cases more commonly presented with arrhythmia, hypotension, acidosis, gastrointestinal symptoms, decreased left ventricular ejection fraction, and elevated isoenzyme of creatine kinase and troponin I levels than nonfatal cases. In multivariate analysis, troponin I > 45 ng/mL and left ventricular ejection fraction < 42% were significantly associated with mortality. Pediatric myocarditis had a high mortality rate, much of which was concentrated in the first 72 hours after hospitalization. Children with very high troponin levels or reduced ejection fraction in the first 24 hours were at higher risk of mortality, and targeting these individuals for more intensive therapies may be warranted.

Background Cervical lymphadenopathy is among the cardinal manifestations of Kikuchi disease (KD). The incidences and locations of extra-cervical lymph nodes (LNs) involvement in KD have not been comprehensively reported. Methods From 2003 to 2016, 60 patients with pathologically confirmed KD and with computed tomography and/or whole-body inflammation scans at diagnosis were retrospectively identified. The locations, sizes and characteristics of all affected LNs were analyzed by extensive review of the image studies. The clinical and laboratory parameters were abstracted from medical records and the associations with extra-cervical LNs involvement were identified. Results Female accounted for 35 (58.3%) patients and the median age of all patients was 21.3 years (ranges, 3–64 years). Of 59 patients with evaluable neck images, 42 (71.2%) and 16 (27.1%) patients presented with unilateral and bilateral nodal involvement, respectively, with the most common locations at level II, III and IV by Som's classification. The largest LNs appeared most commonly in level II. The incidences of extra-cervical lymphadenopathy in abdomen, pelvis, inguina, axilla and mediastinum with available images were respectively 52.9% (9/17), 47.1% (8/17), 41.2% (7/17), 30.6% (11/36) and 14.3% (8/56). When compared to cases with solitary cervical lymphadenopathy, the cases with extra-cervical lymphadenopathy had significantly greater incidences of bilateral cervical lymphadenopathy (P = .0379) and leukopenia (P = .0173). Conclusion Unilateral cervical lymphadenopathy was the most frequent form of LNs involvement of KD. Extra-cervical lymphadenopathy was not uncommon and was associated with the appearance of bilateral distribution of cervical LNs and leukopenia.

Enteroviruses generally cause mild and self-limited diseases, but they have been found to affect neonates much differently, and often more severely than older children. Clinical manifestations are difficult to differentiate from those of bacterial sepsis, such as fever, poor feeding, lethargy, respiratory distress and cardiovascular collapse. Severe life threatening complications, including hepatic necrosis with coagulopathy, meningoencephalitis and myocarditis, usually present during the first week of life. Factors affecting severity and outcome include virus serotype, mode of transmission, and presence or absence of passively acquired, serotype-specific maternal antibodies. Echoviruses and coxsackievirus B viruses are most common serotypes associated with the neonatal sepsis. An awareness of the clinical syndromes, recognition of the risk factors and monitoring parameters associated with severe cases and use of rapid reverse-transcriptase polymerase chain reaction test for viral load may help physicians in diagnosing severe cases in a timely manner. Prompt aggressive treatment including early intravenous immunoglobulin treatment may help in reducing morbidity and mortality. Enterovirus infections in neonates are common and should be routinely considered in the differential diagnosis of febrile neonates, particularly during enterovirus season. This article provides an overview of what is known about non-polio enteroviruses in neonates including epidemiology, transmission, clinical presentation, diagnosis, and treatment. Keywords: Enterovirus, Neonates, Intravenous immunoglobulin, Myocarditis, Coagulopathy

Flowchart of the next-generation sequencing (NGS) method. (PDF 85 kb)

Recombination analysis of MF422581_E9_TW_2008 using the RDP 4.0 program. The analyses were conducted via RDP 4.0 using the manual Bootscan method. Windows200 nt, step 20â nt. (PDF 194 kb)

Characteristics of enterovirus patients characterized using NGS in Taiwan, 2008. (DOCX 23 kb)

Analysis of enterovirus genomes sequenced using NGS in a pilot study. (DOCX 21 kb)

Objectives We studied paediatric patients with human adenovirus (HAdV) infection during the 2011 outbreak in northern Taiwan to define the clinical features of different HAdV genotypes in children. Methods Between January and December 2011, 637 patients 3 years; p 100 mg/L, whereas leucocytosis (white blood cell count >15 000/mm3) was more common in HAdV-2-infected patients (p 0.007). HAdV-7 infections were significantly associated with a longer duration of fever, leucopenia (white blood cell count

BackgroundTo establish the seroepidemiologic data of hepatitis A virus (HAV) vaccine-preventable HAV diseases among school children (7–12 years old) attending elementary schools in New Taipei City, Taiwan. This is a pilot study of an ongoing nationwide study, and will be the reference for a national immunization program.MethodsThe school children were selected for samplings, based on a multistage stratified sampling method that included 14 variables (4 socioeducational variables, 4 socioeducational variables, and 6 medical facilities' variables). The 29 administrative districts of New Taipei City were categorized into five strata. In total, 936 school children from 14 schools were recruited and bled for the serologic tests of HAV by enzyme-linked immunosorbent assay method.ResultsThe seropositive rate for HAV was 8.33% among the 936 children. From each school, the difference in the seropositive rate for HAV ranged 0–18.75%. There was no significant difference between each stratum (p = 0.059) or grade (p = 0.570); however, there was a difference between schools in the first stratum (p = 0.033) that was associated with different vaccination rates. This study also revealed a significantly greater seropositive rate in the vaccination group (p

Background Infants in a neonatal intensive care unit (NICU) have a higher incidence of bloodstream infections (BSIs) than any other pediatric or adult population. The predisposing factors have not been comprehensively evaluated in this population in Taiwan. Methods A retrospective matched case-control study was conducted in the NICUs of a teaching hospital in Taiwan. The case patients were identified from a staff-maintained electronic database containing the records of BSIs from July 2003 to June 2006. The case patients and the control patients (who did not develop BSI during their NICU stay) were 1:1 matched by birth weight, gestational age, gender, Apgar score, and date of birth. Results A total of 164 infants with culture-proven BSI were identified. Of these, 74 (45.1%) infants were female. The mean gestational age and birth weight were 30.7 ± 0.7 weeks and 1512 ± 804 g, respectively. The common etiologic pathogens included coagulase-negative staphylococci (28.7%), Staphylococcus aureus (16.5%), and Klebsiella pneumoniae (14.6%). Candida spp. accounted for 11 (6.7%) episodes. Two independent factors associated with BSIs in the neonates, as identified by multivariate analysis using conditional logistic regression, were the use of parenteral nutrition (matched odds ratio [mOR], 6.07; 95% confidence interval [CI], 1.14–32.32; p = 0.034) and intraventricular hemorrhage (mOR, 2.68; 95% CI, 1.20–5.99; p = 0.017). Conclusion Parenteral nutrition was a significant and independent risk of late-onset neonatal sepsis. This risk should be considered when implementing early parenteral nutrition in NICUs.

Background Gram-negative bacillary (GNB) bloodstream infections account for 20%-30% of neonatal late-onset sepsis (LOS). We aimed to identify the incidence, clinical characteristics, and risk factors for adverse outcomes in neonates with GNB LOS. Methods All patients with GNB LOS admitted to the neonatal intensive care units (NICUs) of a university-affiliated teaching hospital in Taiwan from January 1, 2004-December 31, 2011, were enrolled. A case-control-control study was performed to evaluate risk factors for acquisition of neonatal GNB LOS. Results Of the 5,010 neonates, 290 (5.8%) had a total of 346 episodes of GNB LOS (36.7% of total LOS), with an incidence rate of 13.6 per 10,000 neonate hospital days. The overall mortality rate was 17.6% (51/290), and the sepsis attributable mortality rate was 9.8% (34/346 episodes). After multivariate logistic regression analysis, neonates with prolonged use of total parenteral nutrition (adjusted odds ratio [OR] = 1.53; 95% confidence interval [CI], 1.02-2.29; P = .041) were independently associated with acquisition of GNB LOS. The independent predictors of in-hospital mortality were Pseudomonas aeruginosa etiology (OR = 11.45; 95% CI, 2.83-46.24) and underlying secondary pulmonary hypertension (OR = 18.02; 95% CI, 3.28-98.89), renal disease (OR = 17.16; 95% CI, 2.96-99.38), and neuromuscular comorbidities (OR = 2.72; 95% CI, 1.06-7.00). Conclusion Given the higher illness severity and sepsis-attributable mortality rate of neonatal GNB LOS in the NICU, strategies to reduce the incidence need to be addressed urgently.

A novel pandemic influenza A(H1N1)pdm09 virus emerged in 2009 globally, and it continues to circulate in humans. The National Influenza Surveillance Network in Taiwan identified five A(H1N1)pdm09-predominant seasons, representing the 2009/2010, 2010/2011, 2012/2013, 2013/2014, and 2015/2016 outbreaks from 2009 to 2016. Independently, a retrospective cohort study (which enrolled 639 infected patients during the five seasons) was conducted at Chang Gung Memorial Hospital to explore the risk factors associated with influenza A(H1N1)pdm09-related complications. A phylogenetic analysis of hemagglutinin (HA) sequences showed that the circulating A(H1N1)pdm09 virus belonged to clades 1, 2, and 8 in 2009/2010; clades 3, 4, 5, and 7 in 2010/2011; clades 7 and 6C in 2012/2013; clades 6B in 2013/2014; and 6B/6B.1/6B.2 in 2015/2016. Compared to individuals infected in non-6B/6B.1/6B.2 seasons (2009/2010, 2010/2011, and 2012/2013), those infected in 6B/6B.1/6B.2 seasons (2013/2014 and 2015/2016) were at higher risk for influenza-related complications (adjusted odds ratio [aOR]: 1.6, 95% confidence interval [CI]: 1.0–2.8), pneumonia (aOR: 1.78, 95% CI: 1.04–3.04), mechanical ventilation (aOR: 2.6, 95% CI: 1.2–5.6), and acute respiratory distress syndrome (aOR: 5.5, 95% CI: 1.9–15.9). For the increased severity of infection during the influenza A(H1N1)pdm09 clade 6B/6B.1/6B.2 seasons, aspects related to the antigenic change of A(H1N1)pdm09 virus, immune response of the host, and environmental factors required further investigation.

Bacteremia caused by MRSA with reduced vancomycin susceptibility (MRSA-RVS) frequently resulted in treatment failure and mortality. The relation of bacterial factors and unfavorable outcomes remains controversial. We retrospectively reviewed clinical data of patients with bacteremia caused by MRSA with vancomycin MIC = 2 mg/L from 2009 to 2012. The significance of bacterial genotypes, agr function and heterogeneous vancomycin-intermediate S. aureus (hIVSA) phenotype in predicting outcomes were determined after clinical covariates adjustment with multivariate analysis. A total of 147 patients with mean age of 63.5 (±18.1) years were included. Seventy-nine (53.7%) patients failed treatment. Forty-seven (31.9%) patients died within 30 days of onset of MRSA bacteremia. The Charlson index, Pitt bacteremia score and definitive antibiotic regimen were independent factors significantly associated with either treatment failure or mortality. The hVISA phenotype was a potential risk factor predicting treatment failure (adjusted odds ratio 2.420, 95% confidence interval 0.946–6.191, P = 0.0652). No bacterial factors were significantly associated with 30-day mortality. In conclusion, the comorbidities, disease severity and antibiotic regimen remained the most relevant factors predicting treatment failure and 30-day mortality in patients with MRSA-RVS bacteremia. hIVSA phenotype was the only bacterial factor potentially associated with unfavorable outcome in this cohort.

North America experienced life-threatening outbreaks of enterovirus D68 (EV-D68) in 2014. We retrospectively detected EV-D68 from a child with Wilson's disease in 2008 in Taiwan. After comparing this EV-D68/Taiwan/2008 strain with EV-D68 genomes obtained from the public domain, it was classified as genome type 1-B; it is phylogenetically related to the predominant EV-D68 viruses that circulated in 2009 in Vietnam. It is necessary to strengthen EV-D68 detection globally, including in children with acute liver failure. Moreover, harmonization of genomic analysis of EV-D68 is desirable to understand global evolution of EV-D68. Keywords: Enterovirus D68, Genome study, Molecular epidemiology, Next-generation sequencing

Background Despite the increasingly recognized role of norovirus in global acute gastroenteritis (AGE), specific estimates of the associated disease burden remain sparse, primarily due to limited availability of sensitive norovirus diagnostics in the clinical setting. We sought to estimate the incidence of norovirus-associated hospitalizations by age group in Taiwan using a previously developed indirect regression method. Methods AGE-related hospitalizations in Taiwan were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes abstracted from a national database; population data were provided from the Department of Household Registration Affairs. Population and hospitalizations were aggregated by month and year (July 2003-June 2013) and grouped by age

Although studies on skin microbiome of acute and chronic wounds abound, evidence on newly built microbial communities of subacute wounds remains scant. To characterize the skin microbiome of recently healed (scarred) burn wounds in relation to unaffected skin surfaces, we collected weekly swabs from patients with moderate to severe burns in the 3rd postburn month for 4 weeks in 2015. We performed skin type (moist, dry, and oily)-matched comparisons within six burn patients (43 pairs of swabs) and with 13 skin-healthy, control patients (22 pairs of samples) using 16S ribosomal RNA gene sequencing results. Results of comparative microbiome analysis showed that, there were no substantial variations in the microbial abundance (all p 0.05) or composition (all p 0.01, adjusted for multiple comparisons) between samples obtained from wound scars and those from unaffected surfaces of burn patients. Nor did we find significant temporal dynamics in microbial richness or diversity in burn samples (all p ≥ 0.05). However, samples from burn patients harbored more Firmicutes (median: 25.6%, interquartile range [IQR]: 14.3%-52.8%) than those of control patients (14.9%, IQR: 6.7%-27.0%; p: 0.016), even after adjusting for host age, sex, and skin type-matching (p: 0.026). The number of observed bacterial operational taxonomic units at the genus level was reduced in burn patients (median: 62, IRQ: 32-85) as compared to control patients (median: 128, IQR: 112-136; age-, skin type-adjusted p 0.01). Meanwhile, estimates of community diversity and evenness for surveyed body sites of burn patients were higher than those of control patients (all adjusted p ≤ 0.05). With a much-reduced bacterial burden and a relative overgrowth of Staphylococcus spp., the skin microbiota of burn patients remained dysbiotic in the subacute phase as compared to that of skin-normal patients.

BACKGROUND The development of non-susceptibility to glycopeptides and daptomycin in MRSA during persistent bacteraemia has become a significant therapeutic challenge. However, the in vivo evolution and mechanism of the dual resistance have remained incompletely understood. METHODS A series of MRSA blood isolates with incremental non-susceptibility to glycopeptides and daptomycin were consecutively recovered from a bacteraemic patient who was failing chemotherapy. The evolutionary pathways during conversion from a glycopeptide- and daptomycin-susceptible phenotype into a vancomycin-intermediate Staphylococcus aureus (VISA) and a daptomycin-resistant S. aureus (DRSA) phenotype were then traced by WGS of the isogenic strains. RESULTS A total of six non-synonymous mutations and three evolutionary pathways were identified during the development of the VISA/DRSA phenotype. The first pathway involved two steps of evolution, with an initial 1 bp insertion into yycH and a subsequent gain-in-function point mutation in mprF (S295L). The two mutations were correlated with heteroresistance to daptomycin/vancomycin and full development of the VISA/DRSA phenotype. The second pathway involved an 11 bp deletion mutation in yycH and point mutations at two genes, correlating with the development of the VISA phenotype and heteroresistance to daptomycin. Mutation in mprF (S295L) and a 5 bp deletion mutation in yycH were identified in the third pathway and corresponded to conversion into the full VISA/DRSA phenotype. The mutations in yycH resulted in premature terminations of YycH with variable lengths. CONCLUSIONS Multiple evolutionary pathways involving yycH and mprF can proceed simultaneously and may mediate cross-resistance to glycopeptides and daptomycin during persistent MRSA bacteraemia under antibiotic selective pressure.

BACKGROUND The incidence of necrotizing pneumococcal pneumonia has increased during the past 2 decades. We hypothesized that increased pneumococcal load or augmented inflammatory cytokine production might lead to destructive pneumococcal lung disease. METHODS This study enrolled prospectively 0- to 18-year-old children with a diagnosis of community-acquired pneumonia with pleural effusion admitted to 6 medical centers from March 2010 to April 2012. Children were diagnosed with pneumococcal empyema if the pleural fluid tested positive for quantitative pneumococcal (lytA) detection by real-time polymerase chain reaction. Pneumococcal empyema cases were further divided into 4 groups according to necrosis severity: (0) nonnecrosis, (1) mild necrosis, (2) cavitation and (3) bronchopleural fistula. Nasopharyngeal and pleural pneumococcal load, as well as levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8), Th1-(IL-2, IFN-γ), Th2-(IL-4, IL-10) and Th17-cytokines (IL-17), in the pleural fluid was measured. RESULTS Serotypes 19A and 3 accounted for 69.4% and 12.5%, respectively, of 72 cases of pneumococcal empyema. Pleural pneumococcal load was significantly higher in serotypes 19A and 3 infection than in the other strains causing infection (P = 0.006). There was a correlation between nasopharyngeal and pleural pneumococcal load (ρ = 0.35; P = 0.05). In multivariate ordinal logistic regression analysis, pleural pneumococcal load (adjusted odds ratio: 1.79; 95% confidence interval: 1.03-3.06) and IL-8 (adjusted odds ratio: 2.64; 95% confidence interval: 1.21-5.75) were independent factors associated with the severity of lung necrosis. CONCLUSIONS Evolution of Streptococcus pneumoniae toward increased fitness in their interaction with host and exaggerated IL-8 expression may be responsible for the increase of necrotizing pneumococcal pneumonia.

Human metapneumovirus (hMPV) is a common respiratory tract infection in children. However, conventional immunofluorescence assays (IFAs) for detecting hMPV in respiratory samples have limited reliability with a sensitivity and false-negative predictive value of 58.1% and approximately 17.8%, respectively. In this study, hMPV was measured in 91 clinical respiratory samples (55 sputum and 36 nasopharyngeal aspirate samples), which were obtained from children under three years of age, utilizing our previously developed high-throughput metal-enhanced fluorescence (MEF)-based biosensor (HT-MEFB). The sensitivity of HT-MEFB for hMPV detection in the 91 samples was improved by up to 77.4% compared with that obtained with IFAs, and the specificity of HT-MEFB for hMPV detection was 91.7%. In addition, the specificity and accuracy obtained after the selection of 55 sputum samples as the analyzed specimen reached 92.3% and 90.9%, respectively. Thus, in terms of accuracy, high throughput, and sensitivity, HT-MEFB exhibits considerable potential for hMPV detection in clinical settings.

The benefits of intravenous immunoglobulin (IVIG) therapy for severe neonatal enterovirus infections are still controversial.To evaluate whether timing of IVIG administration might affect clinical outcomes of neonates with severe enteroviral infections.We retrospectively analyzed 67 neonates with culture-confirmed severe enteroviral infection, defined as hepatitis with coagulopathy and thrombocytopenia. Clinical features, outcomes and the usage of IVIG therapy were collected and analyzed. IVIG administered within 3 days of illness onset was classified as early IVIG therapy.Of the 67 cases, 38 (57%) were male, 27 (40%) were premature, 57 (85%) had disease onset within 7 days of life and all but 2 cases were caused by coxsackievirus B group. Ten infants (15%) had clinically evident myocarditis. 41 infants (61%) received IVIG therapy and 29 were early IVIG therapy. Fifteen infants (22%) eventually died, without IVIG therapy for 7 infants. The deceased had a significantly higher peak serum aspartate aminotransferase (AST) level than the survivors (3539 vs. 866 IU/L, p0.01). The timing of IVIG therapy was highly correlated with the timing of peak AST level in patients with early IVIG therapy. Multiple logistic regression analysis showed that a higher nadir hemoglobin level (adjusted odds ratio 2.8, 95% confidence interval: 1.4-5.4), no concurrent myocarditis (42.6 [3.4-5289]) and early IVIG therapy (14.7 [1.3-163]) were independently associated with a favorable prognosis.In defined severe neonatal enterovirus infections, serum AST level correlated with the disease severity. Early IVIG therapy, if needed, may be beneficial for survival.

BACKGROUND Human enterovirus 71 (EV71) is the major causative agents of hand-foot-and-mouth disease and frequently associated with severe complications such as encephalitis and death. Understanding the host response following enteroviral infection may facilitate the development of biomarkers for EV71 infections. METHODS We implemented two-dimensional gel electrophoresis technology on proteins prepared from serum obtained from 4 mild and 4 severe cases of EV71 infections and 4 healthy control children, to investigate the differentially expressed proteins. The differential expressed proteins were further identified with liquid chromatography-mass spectrometry/mass spectrometry analysis and western blotting validation. RESULTS A total of 27 differentially expressed proteins were picked and identified with liquid chromatography-mass spectrometry/mass spectrometry. Of the 27 identified proteins, 6 proteins were up-regulated in the mild-infected and severe EV71-infected patients in comparison to the healthy control group. Two proteins, alpha-1-acid-glycoprotein (AGP1) and alpha-antichymotrypsin (AACT), were not detected in the EV71-infected patients, but appeared in the control patient. Western blotting analysis demonstrated that AGP1 and AACT proteins were negatively associated with the clinical severity of EV71 infection. Similarly, both of the proteins were not detected in the secretion medium from the EV71-infected neuroblastoma cells, but detected in the mock-infected cells, suggesting that differentially expressed AGP1/AACT protein levels are in response to EV71 infections. CONCLUSIONS Two candidate proteins AGP1 and AACT, whose expression levels were reduced under the EV71 infection pathological condition, provide useful source of information for potential diagnostic biomarkers of EV71 infection in children.

Background Enterovirus 71 (EV71) remains a leading pathogen for acute infectious diseases in children, especially in Asia. The cellular basis for establishing a virus-specific antibody response to acute EV71 infections is unclear in children. Methods We studied the magnitude of virus-specific antibody-secreting B cells (ASCs) and its relationship with serological response, clinical parameters, and virological parameters among children with laboratory-confirmed EV71 infection. Results A potent EV71 genogroup B- and virus-specific ASC response was detected in the first week of illness among genotype B5 EV71-infected children. The cross-reactive EV71-specific ASC response to genogroup C viral antigens composed about 10% of the response. The EV71-specific ASC response in children aged ≥3 years produced immunoglobulin G predominantly, but immunoglobulin M was predominant in younger children. Proliferation marker was expressed by the majority of circulating ASCs in the acute phase of EV71 infection. Virus-specific ASC responses significantly correlated with throat viral load, fever duration, and serological genogroup-specific neutralization titer. Conclusions The presence of a virus-specific ASC response serves an early cellular marker of an EV71-specific antibody response. Further detailed study of EV71-specific ASCs at the monoclonal level is crucial to delineate the specificity and function of antibody immunity in children.

Background Most reported studies of methicillin-resistant Staphylococcus aureus (MRSA) carriage have represented 1 time point. To better understand dynamic changes of nasal MRSA carriage, we conducted this longitudinal study in Taiwan. Methods We recruited 304 newborn babies and obtained samples from nares for detection of S. aureus within 3 days of life, and obtained further samples periodically up to 2 years of age. A total of 12 samplings were attempted to be obtained. Results Totally, 273 subjects with ≥9 samples were included for analysis. One hundred and ten subjects (40%) harbored MRSA, on one or more occasions; of these 82 (75%) had ≥2 positive specimens and 84 (76%) had colonization ≤4 months of age. Fourteen infants (5.1%) carried MRSA within 3 days of life, the rate peaked at the age of 2 months (21%) and it was lowest (3.1%) at the age of 18 months. All but 4 first MRSA isolates from the colonized subjects carried either staphylococcal cassette chromosome (SCCmec) IV or V(T). Of 32 subjects with ≥4 MRSA isolates, all isolates from the same subject were genetically indistinguishable in 17 (53%) and genetically related in an additional 9 (28%). Five episodes of skin and soft tissue infections (SSTIs) were identified in 4 subjects. Conclusion In Taiwan, during the first 2 years of life, two-fifths of the children ever harbored MRSA, whereas fewer than 2% of them had SSTIs. Three-fourths of the colonization occurred within the first 4 months and were persistent. More than half of the persistent colonizing isolates were genetically indistinguishable.

Background/PurposeCoinfection of Mycoplasma pneumoniae is not uncommon in children with respiratory syndromes. The purpose of this study was to investigate the impact of bacterial and viral coinfection on mycoplasmal pneumonia in hospitalized children with community-acquired pneumonia (CAP).MethodsChildren coinfected with M. pneumoniae in a prospective study of the etiology of CAP at a tertiary pediatric facility Children's Hospital were enrolled and retrospectively reviewed. The data of clinical characteristics, complications, and outcomes of these children were collected and analyzed.ResultsA total of 59 children were enrolled and stratified into three groups: M. pneumoniae infection alone (n = 31), M. pneumoniae with Streptococcus pneumoniae coinfection (n = 9), and M. pneumoniae with virus coinfection (n = 19). As compared with children infected with M. pneumoniae alone, coinfection of children with S. pneumoniae was more likely to occur under the age of 5 years with a longer duration of fever and hospital stay. Furthermore, total leukocyte count and serum C-reactive protein level were also significantly higher in these children (p

An episode of breakthrough bacteremia, which was defined as positive blood cultures despite appropriate antibiotic therapy, imposes a treatment challenge in the neonatal intensive care unit (NICU).All episodes of breakthrough bacteremia from a tertiary level NICU in Taiwan between 2004 and 2011 were analyzed and compared with nonbreakthrough bacteremia.Breakthrough bacteremia was identified in 7.6% (72/942) of neonatal bacteremia, and 43 (59.7%) occurred as recurrent episodes. Gram-negative organisms (41.7%) and fungi (15.3%) accounted for more than half of all microorganisms in breakthrough bacteremia. Compared with nonbreakthrough bacteremia, breakthrough bacteremia was significantly associated with more severe disease, was more likely to require aggressive therapies, and had a higher rate of infectious complications. Previous use of broad-spectrum antibiotics (odds ratio [OR], 7.54; P .001) and particular microbial etiologies (Pseudomonas aeruginosa: OR, 4.40; P = .025; fungi: OR, 2.70; P = .013) were independent risk factors for developing breakthrough bacteremia. The crude sepsis-attributable mortality rate was greater in breakthrough bacteremia episodes (16.7% vs 6.4%; P = .004), and this condition was independently associated with an increased risk of death (OR, 2.14; 95% confidence interval, 1.04-4.40; P = .040).Breakthrough bacteremia is not uncommon (7.6% of all bacteremia) in NICUs and represents a more severe form of neonatal bacteremia that is independently associated with an increased risk of death.

In 2006, two rotavirus vaccines (Rotarix and RotaTeq) became available on the private market in Taiwan. Although vaccine coverage is currently low, molecular surveillance of rotavirus strains can provide pertinent information for evaluation of the potential impact of vaccine introduction and infection control. During January 2008-December 2011, children aged5 years hospitalized with acute gastroenteritis were enrolled from sentinel surveillance hospitals in three geographic areas of Taiwan. Fecal specimens collected from enrolled patients were tested for rotavirus by enzyme immunoassay and reverse transcriptase-polymerase chain reaction. For genotyping, gene specific primer sets were used to amplify and sequence the genes encoding the neutralization antigens, VP7 and VP4. The resulting sequences were then subjected to phylogenetic analysis. In brief, a total of 4,052 fecal specimens were tested and 742 (18%) samples were positive for rotavirus. The annual range of rotavirus positive specimens varied between 16% and 20.7%. Of all specimens, genotype G1P[8] (63.3%) was the predominant strain, followed by G2P[4] (12.5%), G3P[8] (11.7%), and G9P[8] (5.1%). Uncommon strains were also detected in low percentages. We observed that the rotavirus positivity rate steadily decreased from 21% to 16% during 2008-2010, then slightly increased to 20% in 2011, when an increase in the number of G2P[4] cases was observed. Sequence and phylogenetic analysis was carried out to help understand any potential changes of G2P[4] rotaviruses over time. A number of G2P[4] strains collected between 2004 and 2011 were analyzed in detail and our analyses showed marked genetic and antigenic variability in the VP7 and VP4 genes. The Taiwanese strains could be classified into two major G2 VP7 lineages (IV and V) and two major P[4] VP4 lineages (IV and V) and several minor sublineages within lineage IV. Lineage V within both G2 and P[4] represented newly recognized genetic variants of the respective genotypes. The distribution of individual combinations of the G2 and P[4] (sub)lineages showed some temporal variations. This study provides further evidence for the great genetic diversity among G2P[4] strains and helps understand the epidemiological trends of these strains among children in Taiwan.

Cat scratch disease (CSD) can present as a systemic disease in 5-10% of cases and lead to various disease entities. A previously healthy 16-month-old boy presented with fever for 7 days without other obvious symptoms. Abdominal computed tomography scan demonstrated enlarged right inguinal lymph nodes and multiple small round hypodensities in the spleen. Despite antibiotic treatment for 1 week, the fever persisted and the intrasplenic lesions progressed. Inguinal lymph node biopsy confirmed CSD by immunohistochemistry staining. The diagnosis of CSD was also supported by a history of contact, imaging and serological findings. The patient recovered after treatment with azithromycin for a total of 5 weeks and, in serial follow-up, the hepatosplenic micro-abscesses resolved after 4th months.

Purpose: To evaluate the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage in patients with diabetic foot ulcer (DFU) in Taiwan, and to assess the concordance between colonizing and clinical MRSA isolates from the patients. Method: A total of 354 nasal specimens were collected from 112 to 242 diabetic patients with and without foot ulcer, respectively. MRSA clinical isolates from DFU wound cultures were collected for comparison. Results: Nasal carriage rate of S. aureus and MRSA was similar between diabetic patients with and without foot ulcer (15.2% vs. 16.9% for S. aureus and 5.4% vs. 1.7% for MRSA). Nasal S. aureus colonization was an independent predictor for wound S. aureus infection (Odds ratio [OR]: 5.33, 95% confidence interval [CI]: 1.61–17.59), so did nasal MRSA colonization (OR: 19.09, 95% CI: 2.12–171.91). The levels of glycated hemoglobin, and the usage with immunosuppressant agent were associated with S. aureus nasal colonization while oral hypoglycemic agent usage a protective factor. Sequence type 59/staphylococcal chromosome cassette mec IV or V, the local endemic community-associated clone, accounted for 42% and 70% of the clinical and colonizing isolates, respectively. Six of 10 patients with paired colonizing and clinical isolates, either MRSA or methicillin-sensitive S. aureus, had a genetically identical strain from a single patient. Conclusion: Less than one-fifth of patients with DFU have nasal S. aureus, including MRSA, colonization; however, the colonization is significantly associated with S. aureus diabetic foot infection. Screening for S. aureus colonizing status in DFU patients might have a potential clinical implication. Keywords: Methicillin-resistant Staphylococcus aureus, Diabetic mellitus, Diabetic foot ulcer, Colonization

ObjectiveTo investigate the conjunctival and nasal flora and the antibiotic susceptibility profiles of isolates from patients undergoing cataract surgery.DesignObservational and cross-sectional study.SettingA single-centre study in Taiwan.Participants128 consecutive patients precataract surgery.Primary and secondary outcome measures methodsConjunctival and nasal cultures were prospectively obtained from 128 patients on the day of cataract surgery before instillation of ophthalmic solutions in our hospital. Isolates and antibiotic susceptibility profiles were identified through standard microbiological techniques. Participants were asked to complete a questionnaire on healthcare-associated factors.ResultsThe positive culture rate from conjunctiva was 26.6%, yielding 84 isolates. Coagulase-negativeStaphylococciwere the most commonly isolated organisms (45.2%), and 35% of staphylococcal isolates were methicillin-resistant. Among staphylococcal isolates, all were susceptible to vancomycin, and 75%–82.5% were susceptible to fluoroquinolones. Methicillin-resistant isolates were significantly less susceptible than their methicillin-sensitive counterparts to tobramycin, the most commonly used prophylactic antibiotic in our hospital (28.6% vs 69.2%; p=0.005). The positive culture rate from nares forStaphylococcusaureuswas 21.9%, and six isolates were methicillin-resistant. No subjects hadS. aureuscolonisation on conjunctiva and nares simultaneously. There were no associated risk factors for colonisation of methicillin-resistantStaphylococci.ConclusionThe most common conjunctival bacterial isolate of patients undergoing cataract surgery was coagulase-negativeStaphylococciin Taiwan. Because of predominant antibiotic preferences and selective antibiotic pressures,Staphylococciwere more susceptible to fluoroquinolones but less to tobramycin than in other reports. Additionally, methicillin-resistantStaphylococciexhibited co-resistance to tobramycin but not to fluoroquinolones.

BACKGROUND In 2009, a booster dose of acellular pertussis vaccine for children at or before entry to elementary school was added to the national immunization program in Taiwan, which includes pertussis vaccination at 2, 4, 6 and 18 months of age. In 2013, a study to assess the level of humoral immunity against pertussis in elementary and junior high school children and adolescents was conducted. METHODS A multistage stratified systematic sampling method was applied to randomly selected grade 1 to 9 school children for testing. Serum samples were tested for IgG antibodies to Bordetella pertussis using commercial enzyme-linked immunosorbent assay kits. The study collected information on sociodemographic characteristics, vaccination history, sibling number and disease history of pertussis. RESULTS The study recruited 2782 school children from 58 schools around the country. By questionnaire, only 1% (28/2782) students had history of pertussis. The overall positivity rate of anti-B. pertussis IgG was 42.5%, and the rates were not different between the 5 geographical areas (range from 39.6% to 44.6%, P = 0.375). Age-stratified data showed that the positivity rates were 43.6-48.8% among grade 1-3 students, 26.6-28.7% in grade 4-5 students and increased progressively from 39.4% to 51.3% in grade 6-9 students. The overall positivity rate was significantly higher in the nonbooster group (46.4% versus 38.6%, P < 0.01). CONCLUSION The prevalence of anti-B. pertussis antibody was 42.5% in grade 1-9 students under the current vaccination program in Taiwan. Antibody induced by the booster vaccination before entry of primary school waned rapidly in 3-4 years. Rapid waning of anti-B. pertussis antibody may explain the resurgence of whooping cough in recent decades. Additional booster doses should be considered in adolescents and adults.

Background Since first reported in 2002, the rate of methicillin-resistant Staphylococcus aureus (MRSA) among childhood community-associated (CA) S. aureus infection in Taiwan increased significantly up to 2005. There have been no reports on this issue since then. Methods We prospectively collected clinical S. aureus isolates from the patients

Objectives Clonal complex (CC) 9 is a prevalent livestock-associated (LA) MRSA clone in Asia whose pathogenicity in humans remains unknown. Methods In 2012, we identified a patient with CC9-MRSA infection linked to livestock. After screening 3328 clinical MRSA isolates from a national database, eight isolates (0.24%) collected between 1998 and 2012 were further confirmed to be of CC9. The detailed molecular features of the nine human CC9 strains and phylogenetic relatedness to animal CC9 strains were characterized with WGS. The antibiotic susceptibilities were determined and the clinical information was abstracted from medical records. Results WGS grouped the CC9 strains into two clades, which were respectively associated with distinct toxome profiles, resistance gene profiles and staphylococcal cassette chromosomes (SCCmecXII for 7 isolates and SCCmecVT for 2 isolates). The SCCmecXII strains were phylogenetically related to animal CC9-MRSA strains, negative for Panton-Valentine leucocidin and 100% resistant to ciprofloxacin, erythromycin, clindamycin, gentamicin and tigecycline. Four of the seven SCCmecXII isolates were associated with invasive diseases including bacteraemia leading to death (2) and osteomyelitis (2). Two SCCmecXII isolates were from patients with exposure to pigs before development of the MRSA diseases. Conclusions The CC9-SCCmecXII MRSA prevailing in pigs in Asia is multidrug resistant and potentially pathogenic to humans. It is critical to continuously monitor the local epidemiology of MRSA and implement effective control measures to limit the spread of LA-MRSA between animals, to humans and in healthcare facilities.

BackgroundHow biologics affect psoriasis patients’ risks for SSTIs in a pragmatic clinical setting remains unclear.MethodsIn a cohort of adult psoriasis outpatients (aged 20 years or older) who visited the Dermatology Clinic in 2010-2015, we compared incident SSTI risks between patients using biologics (users) versus nonbiologics (nonusers). We also estimated SSTI risks in biologics-associated time-periods relative to nonbiologics only in users. We applied random effects Cox proportional hazard models with propensity score-stratification to account for differential baseline hazards.ResultsOver a median follow-up of 2.8 years (interquartile range: 1.5, 4.3), 172 of 922 patients ever received biologics (18.7%); 233 SSTI incidents occurred during 2518.3 person-years, with an overall incidence of 9.3/100 person-years (95% confidence interval [CI]: 8.1, 10.6). In univariate analysis, users showed an 89% lower risk for SSTIs than nonusers (hazard ratio [HR]: 0.11, 95%CI: 0.05, 0.26); the association persisted in a multivariable model (adjusted HR: 0.26, 95%CI: 0.12, 0.58). Among biologics users, biologics-exposed time-periods were associated with a nonsignificant 21% increased risk (adjusted HR: 1.21, 95%CI: 0.41, 3.59).ConclusionsDespite of adjusting for the underlying risk profiles, risk comparisons between biologics users and nonusers remained confounded by treatment selection. By comparing time-periods being exposed versus unexposed to biologics among users, the current analysis did not find evidence for an increased SSTI risk that was associated with biologics use in psoriasis patients.

The genetic susceptibility to and vaccine effectiveness against rotavirus gastroenteritis were different in distinct ethnic groups. The case-control study was aimed to evaluate the effectiveness of rotavirus vaccines and associations between the histo-blood group antigens and susceptibility to rotavirus infections in a Taiwanese population. Cases were children P = 0.003 and mOR 16.8, 95% CI 1.08–2601, P = 0.04, respectively). The distribution of ABO blood types did not differ significantly between cases and controls (P = 0.47). In conclusion, Taiwanese children with the secretor genotype and Lewis-positive genotype were at increased risk of moderate-to-severe rotavirus infections. The illness can be effectively prevented by immunization in this population.

Molecular epidemiologic studies collecting information of the spatiotemporal distribution of rotavirus VP7 (G) and VP4 (P) genotypes have shown evidence for the increasing global importance of genotype G9 rotaviruses in humans and pigs. Sequence comparison of the VP7 gene of G9 strains identified different lineages to prevail in the respective host species although some of these lineages appear to be shared among heterologous hosts providing evidence of interspecies transmission events. The majority of these events indicates the pig-to-human spillover, although a reverse route of transmission cannot be excluded either. In this study, new variants of G9 rotaviruses were identified in two children with diarrhea and numerous pigs in Taiwan. Whole genome sequence and phylogenetic analyses of selected strains showed close genetic relationship among porcine and human strains suggesting zoonotic origin of Taiwanese human G9 strains detected in 2014–2015. Although the identified human G9P[19] and G9P[13] rotaviruses represented minority strains, the repeated detection of porcine-like rotavirus strains in Taiwanese children over time justifies the continuation of synchronized strain surveillance in humans and domestic animals.

Inactivated influenza vaccination induces a hemagglutinin-specific antibody response to the strain used for immunization. Annual vaccination is strongly recommended for health care personnel. However, it is debatable if repeated vaccination would affect the antibody response to inactivated influenza vaccine through the time. We enrolled health care personnel who had repeated and first trivalent inactivated influenza vaccination in 2005–2008. Serological antibody responses were measured by hemagglutination-inhibition (HI) test. Subjects with repeated vaccination had higher pre-vaccination and lower post-vaccination HI titer than those with first vaccination, although serological responses between groups might vary with different antigen types and while the drifted strain was introduced in the vaccine. Higher fold rise in the HI titer was observed in the group with first than repeated vaccination and the fold increase in the HI titer was inversely correlated with pre-vaccination titer in 2007 and 2008. Nevertheless, no significant difference in the day 28 seroprotection rate was observed between groups with repeated and first vaccination in most circumstances. Further studies are needed to understand the long-term effect of repeated vaccination on the antibody response both at the serological and repertoire levels among health care personnel.

BACKGROUND The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-β, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors. CONCLUSIONS STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.)

Not only is Asia the most populous region in the world, but inappropriate therapy, including seif-medication with over-the-counter antimicrobial agents, is a common response to infectious diseases. The high antibiotic selective pressure among the overcrowded inhabitants creates an environment that is suitable for the rapid development and efficient spread of numerous multidrug-resistant pathogens. Indeed, Asia is among the regions with the highest prevalence rates of healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in the world. Most hospitals in Asia are endemic for multidrug-resistant methicillin-resistant S. aureus (MRSA), with an estimated proportion from 28% (in Hong Kong and Indonesia) to >70% (in Korea) among all clinical S. aureus isolates in the early 2010s. Isolates with reduced susceptibility or a high level of resistance to glycopeptides have also been increasingly identified in the past few years. In contrast, the proportion of MRSA among community-associated S. aureus infections in Asian countries varies markedly, from 35%. Two pandemic HA-MRSA clones, namely multilocus sequence type (ST) 239 and ST5, are disseminated internationally in Asia, whereas the molecular epidemiology of CA-MRSA in Asia is characterized by clonal heterogeneity, similar to that in Europe. In this review, the epidemiology of S. aureus in both healthcare facilities and communities in Asia is addressed, with an emphasis on the prevalence, clonal structure and antibiotic resistant profiles of the MRSA strains. The novel MRSA strains from livestock animals have been considered to constitute a public health threat in western countries. The emerging livestock-associated MRSA strains in Asia are also included in this review.

Purpose Viral etiology of bronchiolitis in children in Taiwan has been fragmentary. We conducted a prospective study to figure out the viral epidemiology of bronchiolitis in Taiwan. Materials and methods From January 2009 to March 2011, a total of 113 children with bronchiolitis, aged