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IntroductionAtherosclerotic cardiovascular disease is associated with a high mortality rate due to vascular calcification. The role of fetuin-A in aortic arch calcification (AAC) is less well understood.MethodsAn analysis of secondary biomarkers was performed on 800 individuals from the biobank using the community database. AAC was defined by radiologists based on imaging. Multiple variables logical analysis was used for risk analysis.ResultsA total of 736 individual samples were collected based on age and gender. The average age is 65 ± 10 years, and half the population comprises men. In spite of similar body weight, renal function, and hepatic function, the AAC group had higher blood pressure and fetuin-A levels independently: systolic blood pressure (SBP) index ≥130 mmHg [adjusted odds ratio (aOR) 1.85, 95% confidence interval (CI) 1.34–2.57, p = 0.002] and fetuin-A (aOR 0.62, 95% CI 0.50–0.76, p

Abstract Background Little research has been done on ischemic outcomes related to left ventricular ejection fraction (EF) in acute decompensated heart failure (ADHF). Methods A retrospective cohort study was conducted between 2001 and 2021 using the Chang Gung Research Database. ADHF Patients discharged from hospitals between January 1, 2005, and December 31, 2019. Cardiovascular (CV) mortality and heart failure (HF) rehospitalization are the primary outcome components, along with all-cause mortality, acute myocardial infarction (AMI) and stroke. Results A total of 12,852 ADHF patients were identified, of whom 2,222 (17.3%) had HFmrEF, the mean (SD) age was 68.5 (14.6) years, and 1,327 (59.7%) were males. In comparison with HFrEF and HFpEF patients, HFmrEF patients had a significant phenotype comorbid with diabetes, dyslipidemia, and ischemic heart disease. Patients with HFmrEF were more likely to experience renal failure, dialysis, and replacement. Both HFmrEF and HFrEF had similar rates of cardioversion and coronary interventions. There was an intermediate clinical outcome between HFpEF and HFrEF, but HFmrEF had the highest rate of AMI (HFpEF, 9.3%; HFmrEF, 13.6%; HFrEF, 9.9%). The AMI rates in HFmrEF were higher than those in HFpEF (AHR, 1.15; 95% Confidence Interval, 0.99 to 1.32) but not in HFrEF (AHR, 0.99; 95% Confidence Interval, 0.87 to 1.13). Conclusion Acute decompression in patients with HFmrEF increases the risk of myocardial infarction. The relationship between HFmrEF and ischemic cardiomyopathy, as well as optimal anti-ischemic treatment, requires further research on a large scale.

Background: Subdural empyema is one of the more serious complications of bacterial meningitis and therapeutic challenges to clinicians. We aimed to evaluate the clinical characteristics, treatment, and outcome of subdural empyema in neonates with bacterial meningitis. Methods: A retrospective cohort study was conducted in two medical centers in Taiwan that enrolled all cases of neonates with subdural empyema after bacterial meningitis between 2003 and 2020. Results: Subdural empyema was diagnosed in 27 of 153 (17.6%) neonates with acute bacterial meningitis compared with cases of meningitis without subdural empyema. The demographics and pathogen distributions were comparable between the study group and the controls, but neonates with subdural empyema were significantly more likely to have clinical manifestations of fever (85.2%) and seizure (81.5%) (both p values < 0.05). The cerebrospinal fluid results of neonates with subdural empyema showed significantly higher white blood cell counts, lower glucose levels and higher protein levels (p = 0.011, 0.003 and 0.006, respectively). Neonates with subdural empyema had a significantly higher rate of neurological complications, especially subdural effusions and periventricular leukomalacia. Although the final mortality rate was not increased in neonates with subdural empyema when compared with the controls, they were often treated much longer and had a high rate of long-term neurological sequelae. Conclusions: Subdural empyema is not uncommon in neonates with acute bacterial meningitis and was associated with a high risk of neurological complications, although it does not significantly increase the final mortality rate. Close monitoring of the occurrence of subdural empyema is required, and appropriate long-term antibiotic treatment after surgical intervention may lead to optimized outcomes.

ABSTRACT Streptococcus agalactiae (group B Streptococcus [GBS]) is well known to cause serious diseases in infants. A serotype Ib GBS strain has recently emerged and become prevalent in Southeast Asia. We aimed to investigate the clinical and genetic characteristics of this strain. All neonates with invasive GBS diseases from a tertiary-level medical center in Taiwan between 2003 and 2020 were analyzed. The capsule serotyping, multilocus sequence typing, and antimicrobial resistance analyses were performed on all the invasive GBS isolates, and whole-genome sequencing (WGS) was performed specifically on the type Ib GBS strain. A total of 188 neonates with invasive GBS disease during the study period were identified. The type Ib GBS strain accounted for 7.4% (n = 14) of neonatal GBS invasive diseases. Almost all type Ib GBS isolates belonged to sequence type 12 (13/14, 92.9%) and clonal complex 12. Neonates with type Ib GBS disease had a significantly higher rate of complicated sepsis (10/14, 71.4%; P

Streptococcus agalactiae (Group B Streptococcus, GBS) is an important pathogen of bacterial meningitis in neonates. We aimed to investigate the clinical and genetic characteristics of neonatal GBS meningitis. All neonates with GBS meningitis at a tertiary level medical center in Taiwan between 2003 and 2020 were analyzed. Capsule serotyping, multilocus sequence typing, antimicrobial resistance, and whole-genome sequencing (WGS) were performed on the GBS isolates. We identified 48 neonates with GBS meningitis and 140 neonates with GBS sepsis. Neonates with GBS meningitis had significantly more severe clinical symptoms; thirty-seven neonates (77.8%) had neurological complications; seven (14.6%) neonates died; and 17 (41.5%) survivors had neurological sequelae at discharge. The most common serotypes that caused meningitis in neonates were type III (68.8%), Ia (20.8%), and Ib (8.3%). Sequence type (ST) is highly correlated with serotypes, and ST17/III GBS accounted for more than half of GBS meningitis cases (56.3%, n = 27), followed by ST19/Ia, ST23/Ia, and ST12/Ib. All GBS isolates were sensitive to ampicillin, but a high resistance rates of 72.3% and 70.7% to erythromycin and clindamycin, respectively, were noted in the cohort. The virulence and pilus genes varied greatly between different GBS serotypes. WGS analyses showed that the presence of PezT; BspC; and ICESag37 was likely associated with the occurrence of meningitis and was documented in 60.4%, 77.1%, and 52.1% of the GBS isolates that caused neonatal meningitis. We concluded that GBS meningitis can cause serious morbidity in neonates. Further experimental models are warranted to investigate the clinical and genetic relevance of GBS meningitis. Specific GBS strains that likely cause meningitis requires further investigation and clinical attention.

Abstract Background Ventilator associated pneumonia (VAP) caused by more than one microorganisms is not uncommon and may be potentially challenging, but the relevant data is scarce in ventilated neonates. We aimed to investigate the clinical characteristics and outcomes of polymicrobial VAP in the neonatal intensive care unit (NICU). Methods All neonates with definite diagnosis of VAP from a tertiary level neonatal intensive care unit (NICU) in Taiwan between October 2017 and September 2020 were prospectively observed and enrolled for analyses. All clinical features, therapeutic interventions and outcomes were compared between the polymicrobial VAP and monomicrobial VAP episodes. Multivariate regression analyses were used to find the independent risk factors for treatment failure. Results Among 236 episodes of neonatal VAP, 60 (25.4%) were caused by more than one microorganisms. Polymicrobial VAP episodes were more likely to be associated with multidrug-resistant pathogens (53.3% versus 34.7%, P = 0.014), more often occurred in later days of life and in neonates with prolonged intubation and underlying bronchopulmonary dysplasia. Otherwise most clinical characteristics of polymicrobial VAP were similar to those of monomicrobial VAP. The therapeutic responses and treatment outcomes were also comparable between these two groups, although modification of therapeutic antibiotics were significantly more common in polymicrobial VAP episodes than monomicrobial VAP episodes (63.3% versus 46.2%; P

Background: We aimed to describe the clinical features of Gram-negative bacillary (GNB) meningitis in neonates and investigate the risk factors associated with final adverse outcomes of neonatal GNB meningitis. Methods: From 2003 to 2020, all neonates (aged ≤ 90 days old) with bacterial meningitis who were hospitalized in four tertiary-level neonatal intensive care units (NICUs) of two medical centers in Taiwan were enrolled. Neonates with GNB meningitis were compared with those with Streptococcus agalactiae (group B streptococcus, GBS) meningitis. Results: During the study period, a total of 153 neonates with bacterial meningitis were identified and enrolled. GNB and GBS accounted for 40.5% (n = 62) and 35.3% (n = 54) of all neonatal bacterial meningitis, respectively. In neonates with GNB meningitis, the final mortality rate was 6.5% (4 neonates died); 48 (77.4%) had neurological complications, and 26 (44.8%) of 58 survivors had neurological sequelae at discharge. Although the final outcomes were comparable between neonates with GNB meningitis and those with GBS meningitis, neonates with GNB meningitis were more likely to have more severe clinical manifestations initially and have ventriculomegaly at follow-up. After multivariate logistic regression analysis, neonates with seizure at onset, early onset sepsis, and requirement of surgical intervention for neurological complications were independently associated with final adverse outcomes. Conclusions: GNB meningitis was associated with a high risk of neurological complications and sequelae, although it did not significantly increase the final mortality rate. Close monitoring of the occurrence of neurological complications and advanced therapeutic strategies to optimize the outcomes are urgently needed in the future.

BackgroundThe serum aminotransferase elevation in metabolic syndrome (MetS) reflected hepatosteatosis, but there is a conflict with the coexistence of viral hepatitis, especially for the hepatitis B virus (HBV). Thus, this study aimed to investigate the relationship between the alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio, MetS, and HBV infection in a rural Taiwanese population.MethodsWe conducted a cross-sectional analysis in southern Taiwan between March and December 2019. Multivariable logistic regression analyses adjusted for demographics, education, dietary behaviors, irregular exercise, substance use, and viral markers were performed to investigate the association between the ALT/AST ratio and MetS.ResultsAltogether, 2,416 participants (891 men and 1,525 women; mean age, 64.1 ± 14.9 years) were enrolled. Of the participants, 22.7% (n = 519) were seropositive for viral hepatitis. In the multivariable analysis, age [odds ratio (OR) 1.02, 95% CI 1.01–1.03, p 1 (OR 2.63, 95% CI 2.15–3.21, p 0.852 for the Youden index.ConclusionAn ALT/AST ratio >1 could be a simple index for MetS prediction during community checkups. In contrast to age and betel nut chewing, HBV seropositivity and higher education might be inversely associated with MetS. Aggressive health promotion for MetS prevention has emerged as essential in participants without HBV and with lower education levels. Further large-scale, longitudinal studies are needed to unlink these correlations.

Abstract Despite wide application of high frequency oscillatory ventilation (HFOV) in neonates with respiratory distress, little has been reported about its rescue use in preterm infants. We aimed to evaluate the therapeutic effects of HFOV in preterm neonates with refractory respiratory failure and investigate the independent risk factors of in-hospital mortality. We retrospectively analyzed data collected prospectively (January 2011–December 2018) in four neonatal intensive care units of two tertiary-level medical centers in Taiwan. All premature infants (gestational age 24–34 weeks) receiving HFOV as rescue therapy for refractory respiratory failure were included. A total of 668 preterm neonates with refractory respiratory failure were enrolled. The median (IQR) gestational age and birth weight were 27.3 (25.3–31.0) weeks and 915.0 (710.0–1380.0) g, respectively. Pre-HFOV use of cardiac inotropic agents and inhaled nitric oxide were 70.5% and 23.4%, respectively. The oxygenation index (OI), FiO2, and AaDO2 were markedly increased after HFOV initiation (all p

Background: The safety and clinical application of nonbronchoscopic bronchoalveolar lavage (NB-BAL) in preterm neonates with ventilator-associated pneumonia (VAP) have not been fully investigated, and limited data on the feasibility of this method are available. Methods: Premature infants with clinically suspected VAP between October 2017 and June 2019 were enrolled, and NB-BAL was performed. The tolerance and safety of NB-BAL were prospectively recorded during the procedure, and the clinical applications of NB-BAL were observed. Results: A total of 46 NB-BAL procedures were performed in 31 neonates with clinically suspected VAP. The median (interquartile range) gestational age and birth body weight were 28.7 (26.7–31.3) weeks and 1055.0 (817.0–1475.0) grams, respectively. Overall, all episodes of the procedure were well tolerated, with only 9 (19.5%) episodes showing transient desaturation and one patient (2.2%) showing bradycardia during the NB-BAL procedure. There were no impairments in arterial blood gas, cardiopulmonary parameters or respiratory severity scores after NB-BAL. No significant complications occurred in any of the patients who received NB-BAL. No chronic comorbidities affected the safety and clinical application of NB-BAL in these mechanically ventilated preterm neonates. NB-BAL yielded a diagnosis in 32 (69.6%) of these VAP episodes. Staphylococcus aureus was the most common isolated bacterium and accounted for 7 (15.2%) confirmed cases of VAP in our study, followed by polymicrobial microorganisms (n = 6, 13.0%). The appropriate antibiotics were prescribed and modified according to the NB-BAL results in 25 (54.3%) cases of VAP. Conclusions: NB-BAL is a safe and clinically applicable method for determining the etiology and diagnosis of VAP in the NICU, even in extremely preterm neonates with major chronic comorbidities. Further studies to investigate the diagnostic accuracy and impact of NB-BAL on VAP treatment in neonates are warranted in the future.

Background: Candida parapsilosis is the most common non-albicans candida species that causes invasive candidiasis, but little is known about its impacts on the outcomes of pediatric patients. We aimed to characterize the clinical characteristics, risk factors and outcomes of C. parapsilosis bloodstream infections (BSIs) in children. Methods: All pediatric patients with Candida parapsilosis BSIs between 2005 and 2020 from a medical center in Taiwan were enrolled and analyzed. The antifungal susceptibility, clinical manifestations, management and outcomes were investigated. Cases of Candida parapsilosis BSIs were compared between patients with C. albicans BSIs and other Candida spp. BSIs. Results: During the study period, 95 episodes (26.0% of total cases) of Candida parapsilosis BSIs were identified and analyzed. No significant difference was found between pediatric patients with C. parapsilosis BSIs and those with C. albicans BSIs in terms of patients’ demographics, most chronic comorbidities or risk factors. Pediatric patients with C. parapsilosis BSIs were significantly more likely to have previous azole exposure and be on total parenteral nutrition than those with C. albicans BSIs (17.9 vs. 7.6% and 76.8 vs. 63.7%, p = 0.015 and 0.029, respectively). The duration of C. parapsilosis candidemia was relatively longer, and therefore patients often required a longer duration of antifungal treatment when compared with those of C. albicans candidemia, although the candidemia-attributable mortality rates were comparable. Of the C. parapsilosis isolates, 93.7% were susceptible to all antifungal agents, and delayed appropriate antifungal treatment was an independent factor in treatment failure. Conclusions: Pediatric patients with C. parapsilosis BSIs were more likely to have previous azole exposure and be on total parenteral nutrition, and the clinical significances included a longer duration of candidemia and patients often required a longer duration of antifungal treatment.

Background: Empiric antibiotics are often prescribed in critically ill and preterm neonates at birth until sepsis can be ruled out. Although the current guideline suggests narrow-spectrum antibiotics, an upgrade in antibiotics is common in the neonatal intensive care unit. The impacts of initial broad-spectrum antibiotics on the outcomes of critically ill neonates with respiratory failure requiring mechanical intubation have not been well studied. Methods: A total of 1162 neonates from a tertiary level neonatal intensive care unit (NICU) in Taiwan who were on mechanical ventilation for respiratory distress/failure at birth were enrolled, and neonates receiving ampicillin plus cefotaxime were compared with those receiving ampicillin plus gentamicin. Propensity score-matched analysis was used to investigate the effects of ampicillin plus cefotaxime on the outcomes of critically ill neonates. Results: Ampicillin plus cefotaxime was more frequently prescribed for intubated neonates with lower birth weight, higher severity of illness, and those with a high risk of early-onset sepsis. Only 11.1% of these neonates had blood culture-confirmed early-onset sepsis and/or congenital pneumonia. The use of ampicillin plus cefotaxime did not significantly contribute to improved outcomes among neonates with early-onset sepsis. After propensity score-matched analyses, the critically ill neonates receiving ampicillin plus cefotaxime had significantly worse outcomes than those receiving ampicillin plus gentamicin, including a higher risk of late-onset sepsis caused by multidrug-resistant pathogens (11.2% versus 7.1%, p = 0.027), longer duration of hospitalization (median [IQR], 86.5 [47–118.8] days versus 78 [45.0–106.0] days, p = 0.002), and a significantly higher risk of in-hospital mortality (14.2% versus 9.6%, p = 0.023). Conclusions: Ampicillin plus cefotaxime should not be routinely prescribed as the empiric antibiotics for critically ill neonates at birth because they were associated with a higher risk of infections caused by multidrug-resistant pathogens and final worse outcomes.

Background: Pediatricians face a therapeutic challenge when patients with Candida bloodstream infections (BSIs) simultaneously have positive bacterial culture. We aim to characterize the clinical characteristics of pediatric Candida BSIs complicated with mixed bacteremia and subsequent bacterial infections, risk factors and impacts on outcomes. Methods: All episodes of pediatric Candida BSIs between 2005 and 2020 from a medical center in Taiwan were reviewed. Mixed Candida/bacterial BSIs were defined as isolation of a bacterial pathogen from blood cultures obtained within 48 h before or after the onset of Candida BSI. The clinical features and impacts of mixed Candida/bacterial BSIs were investigated. Results: During the study period, 320 patients with a total of 365 episodes of Candida BSIs were identified and analyzed. Mixed Candida/bacterial BSIs were 35 episodes (9.6%). No significant difference was found between mixed Candida/bacterial BSIs and monomicrobial Candida BSIs in terms of patient demographics, Candida species distributions, most chronic comorbidities or risk factors. Patients with mixed Candida/bacterial BSIs were associated with a significantly higher risk of subsequent bacteremia (51.4% vs. 21.2%, p < 0.001) and a relatively higher candidemia-attributable mortality rate (37.2% vs. 22.4%, p = 0.061) than those with monomicrobial Candida BSIs. Mixed Candida/bacterial BSIs were not an independent risk factor of treatment failure or final mortality according to multivariate logistic regression analyses. Conclusions: The clinical significance of mixed Candida/bacterial BSIs in children included a longer duration of septic symptoms, significantly higher likelihood to have subsequent bacteremia, and relatively higher risk of candidemia attributable mortality.

Background: Probiotics have been previously reported to reduce the incidence of necrotizing enterocolitis (NEC) in extremely preterm infants, but the mechanisms by which the probiotics work remain unknown. We aimed to investigate the effects of probiotics on the gut microbiota of extremely preterm infants. Methods: A prospective cohort study was conducted on 120 extremely preterm neonates (gestational age ≤ 28 weeks) between August 2019 and December 2021. All neonates were divided into the study (receiving probiotics) and the control (no probiotics) groups. Multivariate logistic regression analysis was performed to investigate the significantly different compositions of gut microbiota between these two groups. The effects of probiotics on the occurrence of NEC and late-onset sepsis were also investigated. Results: An increased abundance of Lactobacillus was noted in neonates who received the probiotics (AOR 4.33; 95% CI, 1.89–9.96, p = 0.009) when compared with the control group. Subjects in the probiotic group had significantly fewer days of total parenteral nutrition (median [interquartile range, IQR]) 29.0 (26.8–35.0) versus 35.5 (27.8–45.0), p = 0.004) than those in the control group. The probiotic group had a significantly lower rate of late-onset sepsis than the control group (47.1% versus 70.0%, p = 0.015), but the rate of NEC, duration of hospitalization and the final in-hospital mortality rates were comparable between these two groups. Conclusions: Probiotic supplementation of extremely preterm infants soon after the initiation of feeding increased the abundance of Lactobacillus. Probiotics may reduce the risk of late-onset sepsis, but further randomized controlled trials are warranted in the future.

Backgound: Conventional diagnosis of invasive fungal disease from blood cultures is often notoriously delayed and inadequately sensitive. We aimed to develop a universal primers-based polymerase chain reaction (PCR) assay and restriction fragment length polymorphisms (RFLP) for rapid identification of invasive fungal disease (IFD). Methods: We evaluated 16 clinical fungal species using a combination of PCR assays with 3 different restriction endonucleases targeting various internal transcribed spacer (ITS) regions and high resolution melting analysis (HRMA). Serial samples from 75 patients suspected to have IFD were analyzed for clinical verification. Results: We have designed a universal PCR capable of amplifying a portion of the 18S rRNA gene of 16 clinically important fungal species. The restriction patterns of most PCR products generated by EcoRI or double digested by ClaI and AvaI were different, except Aspergillus niger and Aspergillus flavus had a similar pattern, and Aspergillus fumigatus and Aspergillus terreus had a similar pattern. All these species had a unique melting curve shape using the HRMA. Both HRMA and universal PCR had adequate sensitivity, and all sixteen reference fungal species can be clearly distinguished by the universal PCR-RFLP-HRMA assay. With a reference library of 176 clinically relevant fungal strains, and 75 clinical samples from patients with suspicious IFD were tested, our assay identified 100% and 61.1% of isolates from the reference library and clinical samples, respectively. Conclusions: Universal PCR and RFLP coupled with HRMA could be a highly discriminative and useful molecular diagnostic that could enhance the current diagnostic, treatment, and surveillance methods of invasive fungal disease.

Abstract Background Group B Streptococcus (GBS) is an important pathogen that causes high mortality and morbidity in young infants. However, data on clinical manifestations between different GBS serotypes and correlation with molecular epidemiology are largely incomplete. The aim of this study was to determine the serotype distribution, antimicrobial resistance, clinical features and molecular characteristics of invasive GBS isolates recovered from Taiwanese infants. Methods From 2003 to 2017, 182 non-duplicate GBS isolates that caused invasive disease in infants less than one year of age underwent serotyping, multilocus sequence typing (MLST) and antibiotic susceptibility testing. The clinical features of these infants with GBS disease were also reviewed. Results Of the 182 patients with invasive GBS disease, 41 (22.5%) were early-onset disease, 121 (66.5%) were late-onset disease and 20 (11.0%) were late late-onset disease (> 90 days of age). All these patients were treated with effective antibiotics on time. Among them, 51 (28.0%) had meningitis, 29 (16.0%) had neurological complications, 12 (6.6%) died during hospitalization, and 15 (8.8%) out of 170 patients who survived had long-term neurological sequelae at discharge. Serotype III GBS strains accounted for 64.8%, followed by serotype Ia (18.1%) and Ib (8.2%). MLST analysis revealed 11 different sequence types among the 182 isolates and ST-17 was the most dominant sequence type (56.6%). The correlation between serotype III and ST17 was evident, as ST17 accounted for 87.3% of all serotype III isolates. There was an obvious increasing trend of type III/ST-17 GBS that caused invasive disease in infants. All isolates were susceptible to penicillin, cefotaxime, and vancomycin, while 68.1 and 65.9% were resistant to erythromycin and clindamycin, respectively. Conclusions Despite timely and appropriate antibiotic treatment, a significant proportion of invasive GBS disease still inevitably causes adverse outcomes. Further study to explore preventive strategies and development of serotype-based vaccines will be necessary in the future.

Abstract Background High-dose steroids and intravenous immunoglobulin (IVIG) are controversial treatments for pediatric patients with acute myocarditis. This study aimed to investigate their efficacies in the Taiwanese pediatric population. Methods This study evaluated 5563 acute myocarditis patients from the Taiwan’s National Health Insurance Research Database and identified 1542 pediatric patients hospitalized for acute myocarditis between January 1, 2001 and December 31, 2011. The exclusion criteria were age of > 11 years, associated cardiovascular comorbidities, autoimmune disease, malignancy before the index hospitalization, extracorporeal membrane oxygenation, intra-aortic balloon pumping, and dual therapy using IVIG and high-dose steroids. Results After 2:1 propensity score matching, we identified 208 subjects without steroid therapy and 104 subjects who received high-dose steroids. The mean age in that cohort was 2.6 ± 2.9 years, and high-dose steroid therapy had no significant effects on major in-hospital complications and post-discharge outcomes. After 2:1 propensity score matching, we identified 178 subjects without IVIG therapy and 89 subjects who received IVIG. The mean age in that cohort was 2.0 ± 2.1 years, and IVIG had no significant effects on the major outcomes. Conclusions The present study revealed that high-dose steroid or IVIG therapy had no significant effects on major in-hospital complications, late heart failure hospitalization, and long-term mortality.

Neonatal candidemia is associated with significant morbidities and a high mortality rate. We aimed to investigate the clinical characteristics of Candida bloodstream infections in neonates and the impact of therapeutic strategies on the outcomes. We identified all the neonates with candidemia from a medical center in Taiwan over an 18-year period (2003–2021) and analyzed them. Clinical isolates were confirmed by DNA sequencing, and antifungal susceptibility testing was performed. The prognostic factors associated with clinical treatment failure (30-day, all-cause mortality and persistent candidemia > 72 h after antifungal agents) and in-hospital mortality were analyzed using logistic regression modeling. A total of 123 neonates with 139 episodes of candidemia were included in the study. The median (IQR) gestational age and birth weight of the neonates with candidemia were 29.0 (26.0–35.0) weeks and 1104.0 (762.0–2055) g, respectively. The most common Candida spp. was Candida albicans (n = 57, 41.0%), followed by C. parapsilosis (n = 44, 31.7%), Candida guilliermondii (n = 12, 8.6%), and C. glabrata (n = 11, 7.9%). The overall susceptibility to fluconazole was 81.3%, and the resistant rates against other antifungal agents were less than 3%. The cumulative mortality rate at 7 and 30 days after the first episode of candidemia was 11.3% and 32.3%, respectively. The overall in-hospital mortality rate was 42.3%. The treatment outcomes did not change over the study period and were not affected by delayed initiation of antifungal agents. Multivariate analysis showed that delayed catheter removal (odds ratio [OR], 5.54; 95% confidence interval [CI]: 1.93–15.86, p = 0.001), septic shock (OR, 7.88; 95% CI: 2.83–21.93, p < 0.001), and multiple chronic comorbidities (OR, 8.71; 95% CI: 1.82–41.81, p = 0.007) were independently associated with the final in-hospital mortality. We concluded that the overall mortality of neonatal candidemia has remained consistently high over the past decade. Prompt early catheter removal and an aggressive treatment strategy for neonatal candidemia with septic shock would be critical to improving patient outcomes.

Abstract Many uncommon Candida spp. (species other than C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, and C. krusei) have been shown to emerge in tertiary care facilities. We aimed to investigate these uncommon candidemia in children. Forty-six cases of candidemia caused by uncommon Candida spp. were identified during 2003–2015 from a medical center in Taiwan. The most common specie was C. guilliermondii (31.2%), followed by C. lusitaniae (18.8%) and C. metapsilosis (18.8%). These cases were analyzed and compared with 148 episodes of C. albicans candidemia. The incidence density of uncommon Candida spp. candidemia and the proportion to all candidemia episodes increased substantively during the study period. Prior exposure to azoles was uncommon in the 30 days prior to infection, but fluconazole resistant strains were significantly more common (n = 19, 41.3%). The increased incidence density of uncommon Candida spp. candidemia was associated with increasing use of antifungal agents. No differences in demographics, underlying comorbidities, risk factors, clinical features, dissemination, and 30-day mortality were found between uncommon Candida spp. and C. albicans candidemia. Patients with uncommon Candida spp. candidemia were more likely to require modifications in antifungal treatment and receive echinocandin drugs (43.5% vs 21.6%, p = 0.007). Candidemia caused by uncommon Candida spp. had poorer response to antifungal treatment, led to longer duration of candidemia (median 4.0 versus 2.5 days, p = 0.008), and had a higher treatment failure rate (56.5% vs 38.5%, p = 0.040).

Abstract Background Invasive candidiasis differs greatly between children and neonates. We aimed to investigate the different therapeutic approaches and their effects on treatment outcomes of these two groups. Methods Episodes of neonatal invasive candidiasis were compared with non-neonatal pediatric episodes during a 12-year cohort study. Clinical isolates were documented by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and DNA sequencing, and antifungal susceptibility testing was performed. Results A total of 342 episodes of invasive candidiasis (113 neonatal and 229 non-neonatal pediatric episodes) in 281 pediatric patients (96 neonates and 185 children) were identified. Candida albicans was the most common pathogen causing invasive candidiasis in neonates and children (47.8% vs. 44.1%). The antifungal susceptibility profiles were not significantly different between neonates and children. More neonates received amphotericin B as therapy, whereas more children received fluconazole or caspofungin. Compared with children, neonates had a significantly longer duration of fungemia, higher rates of septic shock (34.5% vs. 21.8%; P = 0.013), sepsis-attributable mortality (28.3% vs. 17.5%; P = 0.024) and in-hospital mortality (42.7% vs. 25.4%; P = 0.004) than children. Independent risk factors for treatment failure of invasive candidiasis were septic shock (odds ration [OR] 16.01; 95% confidence interval [CI] 7.64–33.56; P

Background: Early identification of critically ill neonates with poor outcomes can optimize therapeutic strategies. We aimed to examine whether machine learning (ML) methods can improve mortality prediction for neonatal intensive care unit (NICU) patients on intubation for respiratory failure. Methods: A total of 1734 neonates with respiratory failure were randomly divided into training (70%, n = 1214) and test (30%, n = 520) sets. The primary outcome was the probability of NICU mortality. The areas under the receiver operating characteristic curves (AUCs) of several ML algorithms were compared with those of the conventional neonatal illness severity scoring systems including the NTISS and SNAPPE-II. Results: For NICU mortality, the random forest (RF) model showed the highest AUC (0.939 (0.921–0.958)) for the prediction of neonates with respiratory failure, and the bagged classification and regression tree model demonstrated the next best results (0.915 (0.891–0.939)). The AUCs of both models were significantly better than the traditional NTISS (0.836 (0.800–0.871)) and SNAPPE-II scores (0.805 (0.766–0.843)). The superior performances were confirmed by higher accuracy and F1 score and better calibration, and the superior and net benefit was confirmed by decision curve analysis. In addition, Shapley additive explanation (SHAP) values were utilized to explain the RF prediction model. Conclusions: Machine learning algorithms increase the accuracy and predictive ability for mortality of neonates with respiratory failure compared with conventional neonatal illness severity scores. The RF model is suitable for clinical use in the NICU, and clinicians can gain insights and have better communication with families in advance.

Background: Antibiotic-resistant type III/ST-17 Streptococcus agalactiae (group B Streptococcus, GBS) strain is predominant in neonatal invasive GBS diseases. We aimed to investigate the antibiotic resistance profiles and genetic characteristics of type III/ST-17 GBS strains. Methods: A total of 681 non-duplicate GBS isolates were typed (MLST, capsular types) and their antibiotic resistances were performed. Several molecular methods (WGS, PCR, sequencing and sequence analysis) were used to determine the genetic context of antibiotic resistant genes and pili genes. Results: The antibiotic resistant rates were significantly higher in type Ib (90.1%) and type III (71.1%) GBS isolates. WGS revealed that the loss of PI-1 genes and absence of ISSag5 was found in antibiotic-resistant III/ST-17 GBS isolates, which is replaced by a ~75-kb integrative and conjugative element, ICESag37, comprising multiple antibiotic resistance and virulence genes. Among 190 serotype III GBS isolates, the most common pilus island was PI-2b (58.4%) alone, which was found in 81.3% of the III/ST-17 GBS isolates. Loss of PI-1 and ISSag5 was significantly associated with antibiotic resistance (95.5% vs. 27.8%, p < 0.001). The presence of ICESag37 was found in 83.6% of all III/ST-17 GBS isolates and 99.1% (105/106) of the antibiotic-resistant III/ST-17 GBS isolates. Conclusions: Loss of PI-1 and ISSag5, which is replaced by ICESag37 carrying multiple antibiotic resistance genes, accounts for the high antibiotic resistance rate in III/ST-17 GBS isolates. The emerging clonal expansion of this hypervirulent strain with antibiotic resistance after acquisition of ICESag37 highlights the urgent need for continuous surveillance of GBS infections.

Background: Streptococcus agalactiae (also known as group B streptococcus, GBS) is associated with high mortality and morbidity rates in infants, especially those with complicated GBS sepsis, defined as those with meningitis, severe sepsis and/or septic shock. We aimed to characterize the clinical and molecular characteristics and risk factors for adverse outcomes of neonates with invasive GBS diseases. Methods: From 2003 to 2020, all neonates with invasive GBS diseases who were hospitalized in a tertiary-level neonatal intensive care unit (NICU) were enrolled. The GBS isolates underwent serotyping, multilocus sequence typing (MLST) and antibiotic susceptibility testing. We compared cases of complicated GBS sepsis with uncomplicated GBS bacteremia. Results: During the study period, a total of 188 neonates (aged less than 6 months old) with invasive GBS diseases were identified and enrolled. Among them, 119 (63.3%) had uncomplicated GBS bacteremia and 69 (36.7%) neonates had complicated GBS sepsis, including meningitis (25.5%, n = 48) and severe sepsis or septic shock. Among neonates with complicated GBS sepsis, 45 (65.2%) had neurological complications, and 21 (42.0%) of 50 survivors had neurological sequelae at discharge. The overall final mortality rate was 10.1% (19 neonates died). Type III/ST-17 GBS isolates accounted for 56.5% of all complicated GBS sepsis and 68.8% of all GBS meningitis, but this strain was not significantly associated with worse outcomes. The antimicrobial resistance rate among the invasive GBS isolates was obviously increasing in the past two decades. After multivariate logistic regression analysis, neonates with thrombocytopenia and respiratory failure were independently associated with final adverse outcomes. Conclusions: a total of 36.7% of all neonatal invasive GBS diseases were associated with complicated sepsis with/without meningitis. Given the high mortality and morbidity rates in neonates with complicated GBS sepsis, further studies for early identification of specific strains, risk factors or genetic mechanisms that will cause complicated GBS sepsis are urgently needed in the future.

Group B Streptococcus (GBS) is an important pathogen of neonatal infections, and the clonal complex (CC)-17/serotype III GBS strain has emerged as the dominant strain. The clinical manifestations of CC17/III GBS sepsis may vary greatly but have not been well-investigated. A total of 103 CC17/III GBS isolates that caused neonatal invasive diseases were studied using a new approach based on clustered regularly interspaced short palindromic repeats (CRISPR) loci and restriction fragment length polymorphism (RFLP) analyses. All spacers of CRISPR loci were sequenced and analyzed with the clinical presentations. After CRISPR-RFLP analyses, a total of 11 different patterns were observed among the 103 CRISPR-positive GBS isolates. GBS isolates with the same RFLP patterns were found to have highly comparable spacer contents. Comparative sequence analysis of the CRISPR1 spacer content revealed that it is highly diverse and consistent with the dynamics of this system. A total of 29 of 43 (67.4%) spacers displayed homology to reported phage and plasmid DNA sequences. In addition, all CC17/III GBS isolates could be categorized into three subgroups based on the CRISPR-RFLP patterns and eBURST analysis. The CC17/III GBS isolates with a specific CRISPR-RFLP pattern were more significantly associated with occurrences of severe sepsis (57.1% vs. 29.3%, p = 0.012) and meningitis (50.0% vs. 20.8%, p = 0.009) than GBS isolates with RFLP lengths between 1000 and 1300 bp. Whole-genome sequencing was also performed to verify the differences between CC17/III GBS isolates with different CRISPR-RFLP patterns. We concluded that the CRISPR-RFLP analysis is potentially applicable to categorizing CC17/III GBS isolates, and a specific CRISPR-RFLP pattern could be used as a new biomarker to predict meningitis and illness severity after further verification.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a global problem and pediatric obesity has risen dramatically. Early NAFLD might progress to nonalcoholic steatohepatitis (NASH) or liver cirrhosis and significantly increase liver disease-related mortality. We looked for NAFLD predictors in children and adolescents. Methods This community-based, cross-sectional study ran from December 2012 to September 2013 in southwestern Taiwan. Children 19 years old, with detected hepatic diseases, or who drank alcohol were excluded. The diagnosis of NAFLD was based on ultrasound: age, sex, anthropometric measurements, and laboratory data were evaluated for associated risks by using logistic regression analysis. Receiver operating characteristic (ROC) curves were used to determine cutoff values. Results We enrolled one thousand, two hundred and ten children (594 males; 616 females; mean age: 15.5 ± 2.8 years). Age, anthropometric measurements, and laboratory data were significantly higher in children with NAFLD. The association between NAFLD and the waist-to-height ratio (WHtR) was significant (adjusted odds ratio: 2.6; 95% confidence interval: 1.909-3.549; P

Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed. Keywords: Angiotensin II, Carbon monoxide, Human aortic smooth muscle cell, Inflammation, Matrix metallopeptidase-9

Abstract Background Neonatal bloodstream infection (BSI) is the most important cause of morbidity and mortality in the neonatal intensive care unit (NICU). Although most neonatal BSIs are primary bacteremia, some are associated with a focus of infection. This distinction is not well characterized. Methods All patients with neonatal late-onset sepsis (LOS) between January 2006 and December 2013 were enrolled. LOS was categorized as a BSI with a concurrent focus of infection if LOS occurred before or within 24 h after the diagnosis of a specific infectious entity, and as “primary bacteremia” if no concurrent focus of infection was identified. Data concerning demographics, hospital course, microbiology, and outcomes were compared via univariate and multivariate analyses. Results Of 948 episodes of neonatal LOS, 781 (82.4%) were primary bacteremia, whereas 167 (17.6%) were associated with a known focus of infection, including meningitis (n = 51, 5.4%), ventilator-associated pneumonia (VAP) (n = 36, 3.8%), catheter-related bloodstream infections (n = 57, 6.0%), and necrotizing enterocolitis (NEC) (n = 21, 2.2%). The majority of NEC-associated BSIs were caused by gram-negative bacilli (85.7%). Group B streptococcus accounted for nearly one-third of all meningitis cases (29.4%). Although sepsis-attributable mortality was comparable between primary bacteremia and neonatal BSIs with a focus of infection, neonatal BSIs with meningitis, VAP, and NEC had significantly higher rates of infectious complications. The independent risk factors of sepsis-attributable mortality were infectious complications (Odds ratio [OR] 6.98; 95% confidence interval [CI] 3.64–13.39, P

Abstract We aimed to determine the clinical and microbiological characteristics of Candida bloodstream infections in children and the impact of therapeutic strategies on outcomes. All pediatric patients with candidemia from a medical center in Taiwan over a 13-year period (2003–2015) were included and a total of 262 patients with 319 episodes of candidemia were analyzed. Overall susceptibility to fluconazole was 86.1%. Cumulative mortality at 7 and 30 days after the first episode of candidemia was 13.4% and 25.2%, respectively. The overall in-hospital mortality rate was 35.1%. The treatment outcomes did not change over the study period. Multivariate analysis showed that delayed catheter removal (odds ratio [OR], 5.52; 95% confidence interval [CI]: 2.97–10.25), septic shock (OR, 5.49; 95% CI: 2.85–10.57), and breakthrough candidemia (OR, 3.66; 95% CI: 1.43–9.35) were independently associated with clinical treatment failure. In children with candidemia, underlying renal insufficiency and hematological/oncological malignancy, delayed catheter removal, and septic shock at onset were independently associated final in-hospital mortality. Analyzing the subgroup of non-neonatal children did not change the findings. We concluded overall mortality of pediatric candidemia remains high during the past decade. Prompt early catheter removal and aggressive treatment strategy in patients with septic shock would be critical to improve outcomes.

We aimed to analyze the molecular characteristics, clonality and antimicrobial resistance profiles of group B streptococcus (GBS) isolates collected in Taiwan from invasive diseases and carriage. Multilocus sequence typing (MLST) was used to assess the genetic diversity of 225 GBS strains from neonates and adults with invasive GBS diseases. 100 GBS strains collected from colonized pregnant women during the same period were compared, and all strains were characterized for one of nine capsule genotypes. We also determined the susceptibilities of all GBS isolates to various antimicrobial agents. The most frequently identified serotypes that caused invasive disease in neonates were III (60.6%) and Ia (17.3%), whereas type VI (32.7%), Ib (19.4%), and V (19.4%) were the most common to cause invasive disease in adults. Serotype VI was the leading type that colonized pregnant women (35.0%). Twenty-six sequence types (STs) were identified, and 90.5% of GBS strains were represented by 6 STs. ST-17 and ST-1 were more prevalent in invasive diseases in neonates and adults, respectively. The majority of serotype III and VI isolates belonged to clonal complex (CC)-17 and CC-1, respectively. ST-17 strains were more likely to cause meningitis and late-onset disease than other strains. In addition, ST-12 and ST-17 GBS strains showed the highest rate of resistance to erythromycin and clindamycin (range: 75.8–100%). In conclusion, CC-17/type III and CC-1/type VI are the most important invasive pathogens in infants and non-pregnant adults in Taiwan, respectively. GBS genotypes vary between different age groups and geographical areas and should be considered during GBS vaccine development.

Background: Multidrug-resistant (MDR) pathogens have emerged as an important issue in neonatal intensive care units (NICUs), especially in critically ill neonates with severe respiratory failure. We aimed to investigate neonatal healthcare-associated infections (HAIs) caused by MDR pathogens and the impacts of inappropriate initial antibiotic therapy on the outcomes. Methods: We retrospectively analyzed all cases of HAIs in neonates with severe respiratory failure in a tertiary-level NICU in Taiwan between January 2014 and May 2020. All clinical features, microbiology, therapeutic interventions, and outcomes were compared between the MDR-HAI and non-MDR HAI groups. Multivariate regression analyses were used to investigate independent risk factors for sepsis-attributable mortality. Results: A total of 275 critically ill neonates with severe respiratory failure who had HAIs were enrolled. Ninety-five cases (34.5%) were caused by MDR pathogens, and 141 (51.3%) cases had positive bacterial cultures from multiple sterile sites. In this cohort, the MDR-HAI group was more likely to receive inappropriate initial antibiotic therapy (51.0% versus 4.7%, respectively; p < 0.001) and exhibit delayed control of the infectious focus (52.6% versus 37.8%, respectively; p = 0.021) compared with the non-MDR HAI group. The sepsis-attributable and final in-hospital rates were 21.8% and 37.1%, respectively, and they were comparable between the MDR-HAI and non-MDR HAI groups. Empirically broad-spectrum antibiotics were prescribed in 76.7% of cases, and inappropriate initial antibiotic treatment was not significantly associated with worse outcomes. Independent risk factors for sepsis-attributable mortality in neonates with severe respiratory failure included the presence of septic shock (OR: 3.61; 95% CI: 1.54–8.46; p = 0.003), higher illness severity (OR: 1.33; 95% CI: 1.04–1.72; p = 0.026), and neonates with bronchopulmonary dysplasia (OR: 2.99; 95% CI: 1.47–6.09; p = 0.003). Conclusions: MDR pathogens accounted for 34.5% of all neonatal HAIs in the NICU, but neither MDR pathogens nor inappropriate initial antibiotics were associated with final adverse outcomes. Because the overuse of broad-spectrum antibiotics has emerged as an important issue in critically ill neonates, the implementation of antimicrobial stewardship to promote the appropriate use of antimicrobials is urgently needed.

Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a rapid and accurate method to identify microorganisms in clinical laboratories. This study isolates yeast-like microorganisms in the oral washes that are collected from non-bedridden nursing home residents, using CHROMagar Candida plates, and identifies them using Bruker MALDI-TOF MS. The ribosomal DNA sequences of the isolates are then examined. Three hundred and twenty yeast isolates are isolated from the oral washes. Candida species form the majority (78.1%), followed by Trichosporon/Cutaneotrichosporon species (8.8%). Bruker MALDI-TOF MS gives a high-level confidence, with a log(score) value of ≥1.8, and identifies 96.9% of the isolates. There are six inconclusive results (1.9%), and those sequences are verified as rare clinical species, including Candida ethanolica, Cutaneotrichosporon jirovecii, Exophiala dermatitidis, and Fereydounia khargensis. Almost all of the isolates have a regular color on the CHROMagar Candida plates. If the colonies are grouped by color on the plates, a specific dominant yeast species is present in each color group, except for purple or orange isolates. In conclusion, MALDI-TOF MS is verified as a fast, accurate and practical method to analyze oral yeasts in elderly subjects.

It is unknown whether neonatal ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) pathogens and inappropriate initial antibiotic treatment is associated with poor outcomes after adjusting for confounders. Methods: We prospectively observed all neonates with a definite diagnosis of VAP from a tertiary level neonatal intensive care unit (NICU) in Taiwan between October 2017 and March 2020. All clinical features, therapeutic interventions, and outcomes were compared between the MDR–VAP and non-MDR–VAP groups. Multivariate regression analyses were used to investigate independent risk factors for treatment failure. Results: Of 720 neonates who were intubated for more than 2 days, 184 had a total of 245 VAP episodes. The incidence rate of neonatal VAP was 10.1 episodes/per 1000 ventilator days. Ninety-six cases (39.2%) were caused by MDR pathogens. Neonates with MDR–VAP were more likely to receive inadequate initial antibiotic therapy (51.0% versus 4.7%; p < 0.001) and had delayed resolution of clinical symptoms (38.5% versus 25.5%; p = 0.034), although final treatment outcomes were comparable with the non-MDR–VAP group. Inappropriate initial antibiotic treatment was not significantly associated with worse outcomes. The VAP-attributable mortality rate and overall mortality rate of this cohort were 3.7% and 12.0%, respectively. Independent risk factors for treatment failure included presence of concurrent bacteremia (OR 4.83; 95% CI 2.03–11.51; p < 0.001), septic shock (OR 3.06; 95% CI 1.07–8.72; p = 0.037), neonates on high-frequency oscillatory ventilator (OR 4.10; 95% CI 1.70–9.88; p = 0.002), and underlying neurological sequelae (OR 3.35; 95% CI 1.47–7.67; p = 0.004). Conclusions: MDR–VAP accounted for 39.2% of all neonatal VAP in the neonatal intensive care unit (NICU), but neither inappropriate initial antibiotics nor MDR pathogens were associated with treatment failure. Neonatal VAP with concurrent bacteremia, septic shock, and underlying neurological sequelae were independently associated with final worse outcomes.

Background: Rheumatoid arthritis (RA) has been associated with air pollution, possibly due to the augmentation of inflammatory effects. In this study, we aimed to determine the roles of inflammatory pathways and microRNA involved in the pathogenesis of RA fibroblast-like synoviocytes (FLS) inflammation induced by particulate matter. Methods: The inflammatory mediators, messenger RNAs, microRNAs and their interrelationships were investigated using western blotting, QPCR, ELISA and immunohistochemistry. Results: Particulate matter (PMs) induced an increase in the expression of interleukin-6 (IL-6) and cyclooxygenase-II (COX-II) in RA-FLS and microRNA-137 was found definitely to mediate the inflammatory pathways. PMs-induced generation of reactive oxygen species (ROS) in RA-FLS was attenuated by pretreatment with antioxidants. Nox-dependent ROS generation led to phosphorylation of ERK1/2, p38 and JNK, followed by downregulation of microRNA-137. In vivo studies, the joints of rats exposed to PMs revealed synovial fibroblast inflammation under pathologic examination and the expressions of IL-6 and COX-II were obviously increased. PMs exposure results in activated ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways and cause increased IL-6 and COX-II through downregulation of hsa-miRNA-137, which lead to inflammation and RA exacerbation. Conclusions: microRNA-137 plays an important role in PMs-induced RA acute exacerbation through MAPK signaling pathways and IL-6/COX-II activation. Targeting these mechanisms can potentially be used to develop new therapeutic strategies and prevention of RA inflammation in the future.

Background: Timely appropriate empirical antibiotic plays an important role in critically ill patients with gram-negative bacteremia. However, the relevant data and significant impacts have not been well studied in the neonatal intensive care unit (NICU). Methods: An 8-year (1 January 2007–31 December 2014) cohort study of all NICU patients with gram-negative bacteremia (GNB) in a tertiary-care medical center was performed. Inadequate empirical antibiotic therapy was defined when a patient did not receive any antimicrobial agent to which the causative microorganisms were susceptible within 24 h of blood culture sampling. Neonates with GNB treated with inadequate antibiotics were compared with those who received initial adequate antibiotics. Results: Among 376 episodes of Gram-negative bacteremia, 75 (19.9%) received inadequate empirical antibiotic therapy. The cause of inadequate treatment was mostly due to the pathogen resistance to prescribed antibiotics (88.0%). Bacteremia caused by Pseudomonas aeruginosa (Odds ratio [OR]: 20.8, P < 0.001) and extended spectrum β-lactamase (ESBL)-producing bacteria (OR: 18.4, P < 0.001) had the highest risk of inadequate treatment. Previous exposure with third generation cephalosporin was identified as the only independent risk factor (OR: 2.52, 95% CI: 1.18–5.37, P = 0.018). Empirically inadequately treated bacteremias were significantly more likely to have worse outcomes than those with adequate therapy, including a higher risk of major organ damage (20.0% versus 6.6%, P < 0.001) and infectious complications (25.3% versus 9.3%, P < 0.001), and overall mortality (22.7% versus 11.0%, P = 0.013). Conclusions: Inadequate empirical antibiotic therapy occurs in one-fifth of Gram-negative bacteremias in the NICU, and is associated with worse outcomes. Additional prospective studies are needed to elucidate the optimal timing and aggressive antibiotic regimen for neonates who are at risk of antibiotic-resistant Gram-negative bacteremia.

We aimed to evaluate the occurrence, treatment, and outcomes of neurological complications after bacterial meningitis in young infants. A case series study from a retrospective cohort from two tertiary-level medical centers in Taiwan between 2007 and 2016 was conducted. Eighty-five young infants aged < 90 days with bacterial meningitis were identified. 25 (29.4%) were born at preterm. Group B Streptococcus (GBS) and Escherichia coli caused 74.1% of identified cases. Despite the majority (90.6%) initially received microbiologically appropriate antibiotics, 65 (76.5%) had experienced at least one neurological complication identified at a median of 6 days (range: 1–173) after onset of bacterial meningitis. The most common neurological complication was seizure (58.8%), followed by subdural effusion (47.1%), ventriculomegaly (41.2%), subdural empyema (21.2%), hydrocephalus (18.8%), ventriculitis (15.3%), periventricular leukomalacia (11.8%), and encephalomalacia (10.6%). Nine patients (10.6%) died (including 4 had critical discharge on request) and 29/76 (38.2%) of the survivors had major neurological sequelae at discharge. Nighteen (22.4%) received surgical intervention due to these complications. After multivariate logistic regression, initial seizure (adjusted odds ratio [aOR]: 4.76, 95% confidence interval [CI]: 1.7–13.0, P = 0.002) and septic shock (aOR: 6.04; 95% CI: 1.35–27.0, P = 0.019) were independent predictors for final unfavorable outcomes.Conclusions: Neurological complications and sequelae are common in young infants after bacterial meningitis. Patients presented with early seizure or septic shock can be an early predictor of final unfavorable outcomes and require close monitoring. Further research regarding how to improve clinical management and outcomes is warranted.

Glioblastoma multiforme (GBM) is an extremely aggressive and devastating malignant tumor in the central nervous system. Its incidence is increasing and the prognosis is poor. Artocarpin is a natural prenylated flavonoid with various anti-inflammatory and anti-tumor properties. Studies have shown that artocarpin is associated with cell death of primary glioblastoma cells. However, the in vivo effects and the cellular and molecular mechanisms modulating the anticancer activities of artocarpin remain unknown. In this study, we demonstrated that treating the glioblastoma cell lines U87 and U118 cells with artocarpin induced apoptosis. Artocarpin-induced apoptosis is associated with caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage and is mediated by the mitochondrial pathway. This is associated with mitochondrial depolarization, mitochondrial-derived reactive oxidative species (ROS) production, cytochrome c release, Bad and Bax upregulations, and Bcl-2 downregulation. Artocarpin induced NADPH oxidase/ROS generation plays an important role in the mitochondrial pathway activation. Furthermore, we found artocarpin-induced ROS production in mitochondria is associated with Akt- and ERK1/2 activation. After treatment with artocarpin, ROS causes PI3K/Akt/ERK1/2-induced cell death of these tumor cells. These observations were further verified by the results from the implantation of both U87 and U118 cells into in vivo mouse. In conclusion, our findings suggest that artocarpin induces mitochondria-associated apoptosis of glioma cells, suggesting that artocarpine can be a potential chemotherapeutic agent for future GBM treatment.

Extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteremia (GNB) in the neonatal intensive care unit was characterized by comparison with two control groups: a susceptible control group and a general base population group over 2001 to 2012. The influence of ESBL production on mortality was studied in all study subjects and ESBL-GNB isolates were microbiologically characterized. We identified 77 episodes of ESBL-GNB (14.2% of all neonatal late-onset GNB), which were caused by Klebsiella spp. (62.3%), E. coli (20.8%) and Enterobacter spp. (16.9%). Most ESBL-GNB strains were genetically unrelated and the SHV-type ESBLs were the most prevalent (67% of isolates). Comparison with both control groups disclosed previous usage of 3rd generation cephalosporin (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.03-10.97; P < 0.001), and underlying renal disease (OR, 4.07; 95% CI, 1.10-15.08; P = 0.035) as independent risk factors for ESBL-GNB. Inadequate empiric antibiotics, a higher illness severity, higher rates of infectious complications and sepsis-attributable mortality were more frequently seen in neonates with ESBL-GNB than those with non-ESBL GNB (20.8% and 15.6% vs. 9.2% and 7.9%, respectively; P = 0.008 and 0.049, respectively). Neonates with underlying secondary hypertension (OR, 7.22; 95% CI, 2.17-24.06) and infectious complications after bacteremia (OR, 6.66; 95% CI, 1.81-19.31) were identified as independent risk factor for in-hospital mortality. ESBL-GNB accounted for one-seventh of all neonatal gram-negative bacteremia, especially in neonates exposed to broad-spectrum cephalosporins. Neonates with ESBL-GNB bacteremia more frequently received inadequate empirical antibiotic therapy, which were associated with a higher rate of infectious complications and an adverse outcome.

Late-onset sepsis (LOS) in neonates with patent ductus arteriosus (PDA) may predispose them to more complicated hospital courses. The objective of this study was to determine the incidence, the distribution of pathogens, and the clinical features of LOS in neonates with PDA and analyze their outcomes. Methods: The medical records were reviewed retrospectively of infants with PDA and LOS who were hospitalized in NICUs of Chang Gung Children’s Hospital between January 2003 and December 2009. The clinical features of these infants were compared with a group of gestational age and birth body weight-matched neonates with LOS during the same period. Results: During this period, 224 neonates were found to have at least one event of blood-culture proven LOS and 79 (35.3%) were documented to have PDA. Although most LOS episodes (85/104, 81.7%) in neonates with PDA occurred after closure of PDA, neonates with PDA had a significantly higher rate of bronchopulmonary dysplasia (81.0% vs. 61.0%, p = 0.002) and a relatively higher rate of recurrent sepsis (25.3% vs. 15.2%, p = 0.079) than those without PDA. Longer durations of ventilator support and hospital stay were also noted in neonates with PDA as compared to those without (p = 0.001 and 0.005, respectively). Conclusion: In neonates with LOS, the presence of PDA, even though it is aggressively treated with indomethacin or surgical intervention, may still contribute to the complexity of hospitalization. Close monitoring and aggressive treatments are warranted in these neonates with PDA.

Hepatoblastoma is the most common malignant liver tumor in children. Comparative studies have elucidated the optimal pre- or postoperative chemotherapeutic regimens. The aim of this study was to investigate the prognostic significance of baseline tumor characteristics for overall survival and disease-free survival in children with hepatoblastoma. Methods: There were 19 male and 16 female children with a median age of 19 months at diagnosis (range: 1–169 months) in our institution between February 1990 and June 2009. We reviewed the clinical presentation, serum α-fetoprotein level at diagnosis, histological subtype, treatment, and outcomes. Results: Twenty-seven patients (78%) underwent neoadjuvant chemotherapy. The majority of patients subsequently underwent either hemihepatectomy (56%) or bisegmentectomy (16%). Only six patients underwent extended hepatic resection, and one of them required rescue liver transplantation. During follow-up, six patients died of progressive disease and two of perioperative mortality. Four of the six who died had pulmonary metastases at the time of diagnosis or follow-up. The median survival time was 28 months (range: 1–181 months). Five-year overall survival was 67.7% (95% confidence interval: 52.0–87.8%) and disease-free survival was 60.2% (95% confidence interval: 41.9–86.5%). Conclusion: The potential down-staging effect of neoadjuvant chemotherapy on hepatoblastoma might facilitate remission and convert unresectable tumors into operable ones.

Infected percutaneously inserted central venous catheters (PICCs) are a problem in hospitalized patients, especially in the neonatal intensive care unit. The objective of this study was to assess the risk of infection and other PICC-associated complications in very low birth weight infants. Methods: Between January 2005 and December 2006, we studied 412 PICCs inserted in 267 neonates with a birth body weight ≤ 1500g. PICC-related bloodstream infections and other complications were recorded and analyzed. Results: These 412 PICCs were inserted for a mean duration of 16.6 ± 9.9 (SD) days. The most common catheter-related complications were catheter-related blood-stream infection (CRBSI; incidence: 8.3 per 1000 catheter days), followed by catheter occlusion (4.0 per 1000 catheter days), catheter site inflammation (3.5 per 1000 catheter days), and phlebitis (3.1 per 1000 catheter days). The most common pathogen of CRBSI was coagulase-negative staphylococcus (40.1%). Significant risk factors of CRBSI included catheters inserted at femoral sites (increased risk of CRBSI compared with nonfemoral catheters: 1.76; 95% confidence interval, 1.01–3.07, p = 0.045) and a longer duration of PICC placement (p < 0.001). A low birth body weight and gestational age were not found to significantly affect the risk of CRBSI. Conclusion: It is important to avoid inserting a PICC at the femoral site. Strict catheter care protocol should also be applied to reduce local site bacterial colonization and removal of PICCs as soon as they are no longer essential for patient care to reduce the incidence of infection.

Gastroschisis requires surgical management soon after birth. Few publications have reached conclusion regarding the differences of outcomes between primary closure (PC) and a staged repair with silo pouch reduction (SR); as the initial management of gastroschisis. Methods: A retrospective review was conducted in 44 newborns with gastroschisis between 1996 and 2007 at Chang Gung Children's Hospital. We recorded and analyzed basic demographic data, including birth body weight, gestational age, size of the wall defect, initial operative procedure, outcomes, and mortality. Results: The male-to-female ratio was 21:23. Patients had a low birth body weight (2263 ± 539g, mean ± SD) and were borderline premature (gestational age = 36.3 ± 1.86 weeks). Thirty-two patients received PC and 12 received SR as the initial treatment. Seven of the newborn infants died because of delayed initial surgical intervention (n = 2), operation-related complications (n = 4), or underlying multiple congenital anomalies (n = 1). The mortality rate was 16%. When comparing PC and SR (excluding “complicated” gastroschisis), there were no significant differences in survival, days of ventilator use, days to reach full enteral feeding, and hospitalization. Conclusion: PC and SR are comparable as initial treatment modalities for gastroschisis. In addition to underlying gastrointestinal anomalies, the factors that led to significant morbidity in our study were bowel gangrene or perforation resulting from postponed surgical management and the development of abdominal compartment syndrome.

Meconium peritonitis (MP) develops when bowel perforation occurs in utero or soon after birth, resulting in leakage of meconium into the peritoneal cavity. The clinical features are often variable and prenatal ultrasonography plays an important role in prenatal diagnosis. Methods: We conducted a retrospective review of neonates diagnosed with MP in our hospital from January 1998 to December 2007. Prenatal examinations, postnatal presentations, investigations, management, patient outcomes, and possible causes were analyzed. Results: Ten patients (five boys, five girls) diagnosed with MP were studied. The most common prenatal ultrasonographic finding was fetal ascites (7/10, 70%), followed by polyhydramnios (3/10, 30%), bowel dilatation (3/10, 30%), intra-abdominal calcification (1/10, 10%), and hydrops fetalis (1/10, 10%). Two of our patients were completely normal on prenatal ultrasonography. Only one MP diagnosis (1/10, 10%) was definitely confirmed by prenatal ultrasonography due to the presence of ascites, bowel perforation and intra-abdominal calcification. Nine patients (90%) required surgical intervention because of bowel perforation (5), bowel atresia (2), obstruction due to ileus (1), and intussusception (1). Peritonitis was of cystic type in one case (10%), fibroadhesive in five cases (50%), and generalized in four cases (40%). All 10 patients survived without long-term gastrointestinal complications. Conclusion: Prenatal ultrasonography can be diagnostic for MP, which should be con sidered in the differential diagnosis of patients presenting with ascites or ab dominal distension at birth. Close observation of postnatal clinical manifestations and timely surgical intervention resulted in a high survival rate and favorable outcome in these patients at our hospital.

BACKGROUND:An atypical pattern of neonatal sepsis, characterized by persistent positive blood culture despite effective antimicrobial therapy, has been correlated with adverse outcomes. However, previous studies focused only on coagulate-negative staphylococcus infection. METHODS:All episodes of persistent bloodstream infection (BSI), defined as 3 or more consecutive positive blood cultures with the same bacterial species, at least two of them 48 hours apart, during a single sepsis episode, were enrolled over an 8-year period in a tertiary level neonatal intensive care unit. These cases were compared with all non-persistent BSI during the same period. RESULTS:We identified 81 episodes of persistent BSI (8.5% of all neonatal late-onset sepsis) in 74 infants, caused by gram-positive pathogens (n=38, 46.9%), gram-negative pathogens (n=21, 25.9%), fungus (n=20, 24.7%) and polymicrobial bacteremia (n=2, 2.5%). Persistent BSI does not differ from non-persistent BSI in most clinical characteristics and patient demographics, but tends to have a prolonged septic course, longer duration of feeding intolerance and more frequent requirement of blood transfusions. No difference was observed for death attributable to infection (9.8% vs. 6.5%), but neonates with persistent BSI had significantly higher rates of infectious complications (29.6% vs. 9.2%, P < 0.001), death from all causes (21.6% vs. 11.7%, P = 0.025), and duration of hospitalization among survivors [median (interquartile range): 80.0 (52.5-117.5) vs. 64.0 (40.0-96.0) days, P = 0.005] than those without persistent BSI. CONCLUSIONS:Although persistent BSI does not contribute directly to increased mortality, the associated morbidities, infectious complications and prolonged septic courses highlight the importance of aggressive treatment to optimize outcomes.

Melanoma is the most malignant form of skin cancer and is associated with a very poor prognosis. The aim of this study was to evaluate the apoptotic effects of cudraflavone C on A375.S2 melanoma cells and to determine the underlying mechanisms involved in apoptosis. Cell viability was determined using the MTT and real-time cytotoxicity assays. Flow cytometric evaluation of apoptosis was performed after staining the cells with Annexin V-FITC and propidium iodide. The mitochondrial membrane potential was evaluated using the JC-1 assay. Cellular ROS production was measured using the CellROX assay, while mitochondrial ROS production was evaluated using the MitoSOX assay. It was observed that cudraflavone C inhibited growth in A375.S2 melanoma cells, and promoted apoptosis via the mitochondrial pathway mediated by increased mitochondrial ROS production. In addition, cudraflavone C induced phosphorylation of MAPKs (p38, ERK, and JNK) and up-regulated the expression of apoptotic proteins (Puma, Bax, Bad, Bid, Apaf-1, cytochrome C, caspase-9, and caspase-3/7) in A375.S2 cells. Pretreatment of A375.S2 cells with MitoTEMPOL (a mitochondria-targeted antioxidant) attenuated the phosphorylation of MAPKs, expression of apoptotic proteins, and the overall progression of apoptosis. In summary, cudraflavone C induced apoptosis in A375.S2 melanoma cells by increasing mitochondrial ROS production; thus, activating p38, ERK, and JNK; and increasing the expression of apoptotic proteins. Therefore, cudraflavone C may be regarded as a potential form of treatment for malignant melanoma.

BACKGROUND: Neonates with bacteremia are at risk of neurologic complications. Relevant information warrants further elucidation. STUDY DESIGN: This was a retrospective cohort study of neonates with bacteremia-related neurologic complications (BNCs) in a tertiary-level neonatal intensive care unit (NICU). A systemic chart review was performed conducted to identify clinical characteristics and outcomes. A cohort of related conditions was constructed as the control group. Logistic regression analysis was used to identify independent risk factors for BNC. RESULTS: Of 1037 bacteremia episodes, 36 (3.5%) had BNCs. Twenty-four cases of BNCs were related to meningitis, five were presumed meningitis, and seven occurred after septic shock. The most common causative pathogens were Group B streptococcus (41.7%) and E. coli (16.7%). The major BNCs consisted of seizures (28), hydrocephalus (20), encephalomalacia (11), cerebral infarction (7), subdural empyema (6), ventriculitis (8), and abscess (4). Eight (22.8%) neonates died and six (16.7%) were discharged in critical condition when the family withdrew life-sustaining treatment. Among the 22 survivors, eight had neurologic sequelae upon discharge. After multivariate logistic regression analysis, neonates with meningitis caused by Group B streptococcus (adjusted odds ratio [OR]: 8.90, 95% confidence interval [CI]: 2.20-36.08; p = 0.002) and combined meningitis and septic shock (OR, 5.94; 95% CI: 1.53-23.15; p = 0.010) were independently associated with BNCs. CONCLUSIONS: Neonates with bacteremia-related neurologic complications are associated with adverse outcomes or sequelae. Better strategies aimed at early detection and reducing the emergence of neurologic complications and aggressive treatment of Group B streptococcus sepsis are needed in neonates with meningitis and septic shock.

BACKGROUND: Polymicrobial bloodstream infections (PBSIs) have been associated with complex underlying medical conditions and a high incidence of specific microorganisms in several settings, but the relevant data are scarce in neonates. METHODS: Positive blood cultures from January 2004 to December 2011 in the neonatal intensive care unit (NICU) of Chang Gung Memorial Hospital (CGMH) were reviewed. Each neonate with PBSI (case episode) was matched to two episodes of monomicrobial BSI (control episode) by birth weight, gestational age and gender. Records were reviewed to compare their underlying medical conditions, organisms isolated, adequacy of therapy, clinical characteristics and outcomes. RESULTS: Forty-five episodes of PBSI (4.4% of all neonatal BSIs) were identified in 43 neonates. Gram-negative organisms constituted 59.8% of all PBSI pathogens, and 33 (73.3%) of PBSIs were caused by at least one Gram-negative organism. PBSIs were significantly more likely to be the recurrent episode and have endotracheal tube in place. No significant difference was found between PBSIs and controls in terms of demographics and most chronic conditions. PBSIs were significantly associated with a higher severity of illness, a longer duration of septic symptoms, and a higher rate of modification of antimicrobial regimens than monomicrobial BSIs. However, the sepsis-attributable mortality rates were comparable between these two groups. CONCLUSIONS: In the NICU, PBSIs were more often caused by Gram-negative bacilli, and often occurred in neonates without any chronic conditions. The clinical significance of PBSIs included a more severe illness, longer duration of septic symptoms and a higher rate of modification of antimicrobial regimens.

Septic arthritis due to Salmonella has been reported frequently, but multiple joint involvements have rarely been reported in children. A 3-year-old girl presented with Salmonella arthritis involving multiple joints. Laboratory investigations revealed pancytopenia inconsistent with diagnosis of juvenile rheumatoid arthritis or septic arthritis. Bone marrow examination 2 weeks later confirmed the diagnosis of acute lymphoblastic leukemia (ALL). Immunophenotyping studies were consistent with a diagnosis of pre-B ALL. This case illustrates that a delay in the diagnosis may occur when there is an apparent infection focus without classic features of leukemia. Multiple joints involvement of septic arthritis associated with pancytopenia should highlight the possibility of underlying hematologic disorders.

Upregulation of intercellular adhesion molecule-1 (ICAM-1) involves adhesions between both circulating and resident leukocytes and the human lung epithelial cells during lung inflammatory reactions. We have previously demonstrated that curcumin-loaded polyvinylpyrrolidone nanoparticles (CURN) improve the anti-inflammatory and anti-oxidative properties of curcumin in hepatocytes. In this study, we focused on the effects of CURN on the expression of ICAM-1 in TNF-α-treated lung epithelial cells and compared these to the effects of curcumin water preparation (CURH). TNF-αinduced ICAM-1 expression, ROS production, and cell-cell adhesion were significantly attenuated by the pretreatment with antioxidants (DPI, APO, or NAC) and CURN, but not by CURH, as revealed by western blot analysis, RT-PCR, promoter assay, and ROS detection and adhesion assay. In addition, treatment of TNF-α-treated cells with CURN and antioxidants also resulted in an inhibition of activation of p47 (phox) and phosphorylation of MAPKs, as compared to that using CURH. Our findings also suggest that phosphorylation of MAPKs may eventually lead to the activation of transcription factors. We also observed that the effects of TNF-α treatment for 30 min, which includes a significant increase in the binding activity of AP-1 and phosphorylation of c-jun and c-fos genes, were reduced by CURN treatment. In vivo studies have revealed that CURN improved the anti-inflammation activities of CURH in the lung epithelial cells of TNF-α-treated mice. Our results indicate that curcumin-loaded polyvinylpyrrolidone nanoparticles may potentially serve as an anti-inflammatory drug for the treatment of respiratory diseases.