Metabolomic Analysis Reveals the Association of Severe Bronchopulmonary Dysplasia with Gut Microbiota and Oxidative Response in Extremely Preterm Infants.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease mainly affecting premature infants needing ventilation or oxygen for respiratory distress. This study aimed to evaluate the molecular linkages for BPD in very and extremely preterm infants using a metabolomics-based approach. A case-control study of enrolling preterm infants born before 32 weeks gestational age (GA) was prospectively performed. These preterm infants were subsequently stratified into the following two groups for further analysis: no or mild BPD, and moderate or severe BPD based on the 2019 NICHD criteria. Urinary metabolomic profiling was performed using 1H-Nuclear magnetic resonance (NMR) spectroscopy coupled with partial least squares discriminant analysis (PLS-DA) at a corrected age of 6 months. Metabolites significantly differentially related to GA and BPD severity were performed between groups, and their roles in functional metabolic pathways were also assessed. A total of 89 preterm infants born before 32 weeks gestation and 50 infants born at term age (above 37 completed weeks' gestation) served as controls and were enrolled into the study. There were 21 and 24 urinary metabolites identified to be significantly associated with GA and BPD severity, respectively (p < 0.05). Among them, N-phenylacetylglycine, hippurate, acetylsalicylate, gluconate, and indoxyl sulfate were five metabolites that were significantly higher, with the highest importance in both infants with GA < 28 weeks and those with moderate to severe BPD, whereas betaine and N,N-dimethylglycine were significantly lower (p < 0.05). Furthermore, ribose and a gluconate related pentose phosphate pathway were strongly associated with these infants (p < 0.01). In conclusion, urinary metabolomic analysis highlights the crucial role of gut microbiota dysbiosis in the pathogenesis of BPD in preterm infants, accompanied by metabolites related to diminished antioxidative capacity, prompting an aggressive antioxidation response in extremely preterm infants with severe BPD.

The Clinical Characteristics, Microbiology and Risk Factors for Adverse Outcomes in Neonates with Gram-Negative Bacillary Meningitis.

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.

Invasive Candida parapsilosis Bloodstream Infections in Children: The Antifungal Susceptibility, Clinical Characteristics and Impacts on Outcomes.

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.

Influences of Initial Empiric Antibiotics with Ampicillin plus Cefotaxime on the Outcomes of Neonates with Respiratory Failure: A Propensity Score Matched Analysis.

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.

Pediatric Candida Bloodstream Infections Complicated with Mixed and Subsequent Bacteremia: The Clinical Characteristics and Impacts on 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.

Complicated Streptococcus agalactiae Sepsis with/without Meningitis in Young Infants and Newborns: The Clinical and Molecular Characteristics and Outcomes.

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.

Clinical characteristics and outcomes of neonates with polymicrobial ventilator-associated pneumonia in the intensive care unit.

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 < 0.001). None of any specific pathogens was significantly associated with worse outcomes. Instead, it is the severity of illness, including presence of concurrent bacteremia, septic shock, and requirement of high-frequency oscillatory ventilator and underlying neurological sequelae that are independently associated with treatment failure. CONCLUSIONS: Polymicrobial VAP accounted for 25.4% of all neonatal VAP in the NICU, and frequently occurred in neonates with prolonged intubation and underlying bronchopulmonary dysplasia. In our cohort, most clinical features, therapeutic responses and final outcomes of neonates with monomicrobial and polymicrobial VAP did not differ significantly.

Therapeutic effects and outcomes of rescue high-frequency oscillatory ventilation for premature infants with severe refractory respiratory failure.

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 < 0.001), and can be decreased within 24-48 h (all p < 0.001) after use of HFOV. 375 (56.1%) patients had a good response to HFOV within 3 days. The final in-hospital mortality rate was 34.7%. No association was found between specific primary pulmonary disease and survival in multivariate analysis. We found preterm neonates with gestational age < 28 weeks, occurrences of sepsis, severe hypotension, multiple organ dysfunctions, initial higher severity of respiratory failure and response to HFOV within the first 72 h were independently associated with final in-hospital mortality. The mortality rate of preterm neonates with severe respiratory failure remains high after rescue HFOV treatment. Aggressive therapeutic interventions to treat sepsis and prevent organ dysfunctions are the suggested strategies to optimize outcomes.

Multidrug-Resistant Healthcare-Associated Infections in Neonates with Severe Respiratory Failure and the Impacts of Inappropriate Initial Antibiotic Therap.

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.

Prognostic Factors and Clinical Features of Neonatal Splenic Rupture/Hemorrhage: Two Cases Reports and Literature Review.

Background: Neonatal splenic rupture/hemorrhage (SRH), an extremely rare and potentially fatal presentation, can spontaneously resolve without surgical treatment; However, treatment approaches remain controversial. The present study aimed to describe and analyze the clinical features and therapies of neonatal SRH and therapeutic approaches. Methods: We present the cases of two patients and review another 37 cases reported in English-literature. The literature search included all articles published in PUBMED from inception between January 1968 and December 2019. Demographic data, precipitating factors, clinical characteristics including presenting symptoms and signs, presenting time, age at SRH presentation, imaging findings, as well as treatments and outcomes were analyzed. Results: In addition to the two cases treated at our hospital, 37 neonates with SRH were reported during the study period. The rate of full-term neonates was 72% (28/39). The cause was idiopathic in most cases, and congenital coagulation disorders were underlying causes in 13% (5/39) of the cases. The most common presenting symptom and sign of neonatal SRH were pallor or anemia, followed by abdominal discoloration/distension. Additionally, 18% (7/39) of the cases presented with scrotal hematoma or swelling. The age at SRH presentation ranged between 3 h and 5 days of age. Abdominal ultrasonography or computed tomography was used as the diagnostic tool. Twenty-seven cases (69%) received surgical management. The prognosis was comparable between the neonates treated with splenectomy and those treated with non-surgical approaches. The mortality rate was 18% (7/39) in the study cohort. SRH presentation at ≤12 h of age was associated with higher mortality compared to SRH presenting time at >12 h of age (odds ratio 25.0, 95% CI 2.514-248.575, p = 0.001). Conclusion: Our literature review revealed that the mortality rate of neonatal SRH was 18% and that the mortality risk was higher in neonates presenting with SRH symptoms and signs at ≤12 h of age.

Safety and clinical application of nonbronchoscopic bronchoalveolar lavage in preterm neonates with clinical ventilator-associated pneumonia.

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.

Comparing learning outcomes among postgraduate year trainee groups.

BACKGROUND: The objective of postgraduate year (PGY) training programs is to inculcate in medical graduates the expected levels of skills in patient care. This study compared the core clinical competencies of trainees who received PGY training at Chang Gung Memorial Hospital by attending the pilot training program in different groups. METHODS: We used six 10-min test stations for clinical performance evaluation, which comprised four and two test stations designed for objective structured clinical examination and procedural skill, respectively, to evaluate the learning outcomes of the trainees. The trainees were divided into three groups according to the training programs that they had attended. RESULTS: The aspects of clinical performance included history taking, physical examination, medical communication, logical thinking, and problem-solving abilities. The trainees who selected the surgery-based training program exhibited a higher performance at the station for aseptic surgical preparation than the other two groups (p = 0.0261). The trainees who selected the internal medical training program (p = 0.0020) exhibited a higher performance at the station for abdominal pain in children. CONCLUSIONS: A well-designed postgraduate training program should develop trainees' competencies, particularly clinical operational skills. The results of this study may provide useful insight into methods for improving the design of training programs. Additional investigation is necessary for understanding the effects of different programs on the clinical performance of trainees.

Impacts of Multidrug-Resistant Pathogens and Inappropriate Initial Antibiotic Therapy on the Outcomes of Neonates with Ventilator-Associated Pneumonia.

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.

Use of high frequency oscillatory ventilator in neonates with respiratory failure: the clinical practice in Taiwan and early multimodal outcome prediction.

High-frequency oscillatory ventilation (HFOV) can be a rescue for neonates with refractory respiratory failure or an early elective therapy for preterm infants with severe respiratory distress syndrome (RDS). However, little is known about the current evolution and therapeutic limitations of HFOV. We therefore aimed to describe its use in clinical practice and predict the risk of mortality for neonates receiving HFOV. A retrospective observational study of all neonates treated with HFOV in a quaternary referral NICU between January 2007 and December 2016 was conducted. We classified these patients into five subgroups based on primary respiratory diagnoses. We performed the logistic regression and decision tree regression analyses to identify independent factors of 30-day mortality following HFOV. A total of 1125 patients who were ever supported on HFOV were enrolled, of whom 64.1% received HFOV as a rescue therapy, 27.2% received it as an elective therapy, and 8.7% received it for air leak. An average oxygenation index (OI) greater than 25 in the first 24 hours after the initiation of HFOV and patients with secondary pulmonary hypertension were found to have the greatest risk of in-hospital mortality (p < 0.0001). The overall in-hospital mortality rate was 25.8% (290/1125). Decision tree regression analysis revealed that neonates with refractory respiratory failure who had a pre-HFOV OI value higher than 20.5 and OI values higher than 21.5, 23.5 and 34 at 2 hours, 6 hours, and 12 hours after the use of HFOV, respectively, had a significantly increased risk of 30-day mortality. We identified the predictors and cutoff points of OI before and after the initiation of HFOV in neonates with respiratory failure, which can be clinically used as a reference for 30-day mortality. Further efforts are still needed to optimize the outcomes.

Risk Factors of Initial Inappropriate Antibiotic Therapy and the Impacts on Outcomes of Neonates with Gram-Negative Bacteremia.

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 ß-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.

Childhood otitis media: Relationship with daycare attendance, harsh parenting, and maternal mental health.

Psychological stress has been linked to developmental problems and poor health in children, but it is unclear whether it is also related to otitis media (OM). As part of a long-term study surveying the characteristics of childcare and development in Taiwan, we analyzed the relationship between OM and sources of psychological stress in children, such as poor maternal mental health and harsh parental discipline. We analyzed the data of 1998 children from the "Kids in Taiwan: National Longitudinal Study of Child Development & Care (KIT) Project" at the age of 3 years. Using bivariate and multivariate logistic regression models, we tested several risk factors as potential independent predictors of two outcomes: parent-reported incidence of OM and child health. The proportion of children who had developed OM in the first 3 years of their life was 12.5%. Daycare attendance (odds ratio [OR]: 1.475; 95% confidence interval [CI]: 1.063-2.046), poor maternal mental health (OR: 1.913; 95% CI: 1.315-2.784), and harsh parental discipline (OR: 1.091; 95% CI: 1.025-1.161) correlated with parent-reported occurrence of OM. These findings suggest that providing psychosocial support to both parents and children might be a novel strategy for preventing OM.

The Off-Label Use of Inhaled Nitric Oxide as a Rescue Therapy in Neonates with Refractory Hypoxemic Respiratory Failure: Therapeutic Response and Risk Factors for Mortality.

OBJECTIVES: The indication of inhaled nitric oxide (iNO) used in preterm infants has not been well defined. Neonates with refractory hypoxemia may benefit from the pulmonary vasodilatory effects of iNO. The aim of this study was to investigate the off-label use of iNO as a rescue therapy. METHODS: Between January 2010 and December 2017, all neonates who received iNO as a rescue therapy from a tertiary-level medical center were enrolled, and those who were not diagnosed with persistent pulmonary hypertension of newborn (PPHN) were defined as having received off-label use of iNO. The controls were 636 neonates with severe respiratory failure requiring high-frequency oscillatory ventilation but no iNO. RESULTS: A total of 206 neonates who received iNO as a rescue therapy were identified, and 84 (40.8%) had off-label use. The median (interquartile) gestational age was 30.5 (26.3-37.0) weeks. Neonates receiving iNO had significantly more severe respiratory failure and a higher oxygenation index than the controls (p < 0.001). Respiratory distress syndrome and secondary pulmonary hypertension after severe bronchopulmonary dysplasia (BPD) were the most common causes of the off-label iNO prescription. Of the 84 neonates with off-label use of iNO, 53 (63.1%) had initial improvement in oxygenation, but 44 (52.4%) eventually died. The overall mortality rate was 41.7% (86/206). After multivariate logistic regression, extremely preterm (odds ratio [OR] 5.51; p < 0.001), presence of pulmonary hemorrhage (OR 2.51; p = 0.036) and severe hypotension (OR 2.78; p = 0.008) were the independent risk factors for final mortality. CONCLUSIONS: iNO is applicable to be an off-label rescue therapy for premature neonates with refractory hypoxemia due to severe pulmonary hypertension and bronchopulmonary dysplasia.

Emerging serotype III sequence type 17 group B streptococcus invasive infection in infants: the clinical characteristics and impacts on outcomes.

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.

Understanding how to enhance efficacy and effectiveness of feedback via e-portfolio: a realist synthesis protocol.

INTRODUCTION: The validity of feedback as one of the defining components for electronic portfolios (e-portfolios) to be effective and efficacious has yet to be demonstrated. While the literature has shown individual beneficial features of e-portfolios and feedback per se, evidence of feedback as mediated through technology directly resulting in improved educational practice is scarce. The explanation of how feedback via e-portfolio improves educational practice is particularly vague. METHODS AND ANALYSIS: The aim of this research is to unpack how and why feedback via e-portfolio is likely to flourish or wither in its path. Given the complexity of intervention, we will apply a theory-driven approach for evidence synthesis called realist synthesis. Informed by realist philosophy of science, it seems the most appropriate method because it explores observed outcomes (O) in terms of causal relationship between relevant contexts (C) and generating mechanisms (M). Initial programme theory will be developed through literature scoping. Later on it will be tested against purposively gathered evidence (through database and journal search), which simultaneously will be evaluated for rigour and relevance (whether method used are trustworthy and whether data contributes to theory building). We strive to (1) uncover 'context sensitive' mechanisms that generate feedback via e-portfolio to be (in) effective and (2) define in what circumstances is this mostly likely to occur. ETHICS AND DISSEMINATION: The synthesis report will be written according to the RAMESES guidelines and its findings will be published in peer reviewed articles and presented at relevant conferences. The aim is to inform: (1) policy and decision makers for future-course design; (2) medical educators/clinical supervisors and learners for improved educational use. No formal ethical approval is required. PROSPERO REGISTRATION NUMBER: 120863.