Molecular biology of glucose-6-phosphate dehydrogenase and UDP-glucuronosyltransferase 1A1 in the development of neonatal unconjugated hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and variants of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are the most common genetic causes of neonatal unconjugated hyperbilirubinemia (NUH). In this review, we searched PubMed for articles on the genetic causes of NUH published before December 31, 2022, and analyzed the data. On the basis of the results, we reached eight conclusions: (1) 37 mutations of the G6PD gene are associated with NUH; (2) the clinical manifestation of G6PD deficiency depends not only on ethnicity but also on the molecular mechanisms underlying the deficiency (and thus its severity); (3) of mutations in the UGT1A1 gene, homozygous c.-53A(TA)6TAA > A(TA)7TAA is the main cause of NUH in Caucasians and Africans, whereas homozygous c.211G > A is the main genetic cause of NUH in East Asians; (4) in Indonesian neonates, homozygous c.-3279T > G is the most common cause of NUH development, and neither c.-53 A(TA)6TAA > A(TA)7TAA nor c.211G > A causes it; (5) in breast-fed East Asian neonates, the TA7 repeat variant of the UGT1A1 gene protects against the development of NUH; (6) G6PD deficiency combined with homozygous c.211G > A variation of the UGT1A1 gene increases the risk of severe NUH; (7) in Pakistani and Caucasian patients with Crigler-Najjar syndrome type 2 (CN-2), point mutations of the UGT1A1 gene are widely distributed and frequently occur with variation at nucleotide -53, whereas in Asian patients with CN-2, compound homozygous variations in the coding region are frequently observed; and (8) records of G6PD deficiency and UGT1A1 variation status for a neonate offer useful pharmacogenomic information that can aid long-term care. These results indicate that timely diagnosis of NUH through molecular tests is crucial and that early initiation of treatment for the neonates and educational programs for their parents improves outcomes.

Reappraisal of therapeutic vancomycin trough concentrations with empirical dosing in neonatal infections.

BACKGROUND: Vancomycin is commonly used for neonatal sepsis. However, consensus on an empirical neonatal vancomycin regimen remains uncertain. We aimed to reappraise the therapeutic optimum concerning vancomycin trough concentrations with empirical dosing and to evaluate the relationship between trough concentrations and predicted 24-h area under the curve (AUC24). METHODS: This was a 3-year retrospective study. Neonates who were admitted to the neonatal intensive care unit with available vancomycin trough concentrations were enrolled. Trough levels were obtained before the fourth dose. Achievement of goal trough after implementing the vancomycin dosing regimen was based on the Practical Neonatology Medical Manual, published by the National Taiwan University College of Medicine. RESULTS: A total of 46 neonates were included for analysis. Coagulase-negative staphylococci were the most commonly identified pathogens of sepsis. Among these patients, 22 achieved goal trough levels of 10-20 mcg/mL. Trough levels of 5-10 or >20 mcg/mL occurred in 13 and 11 patients, respectively. A moderately positive correlation between trough and predicted AUC24 was found in all patients (Spearman's rho = 0.676, p < 0.001). In patients with body weight 1200-2000 g and postnatal age >7 days, the serum creatinine of those with trough levels >20 mcg/mL was significantly higher than those with goal trough levels (0.61 vs. 0.45 mg/dL, p = 0.01). Among those with trough levels >20 mcg/mL, 5 patients received ibuprofen for patent ductus arteriosus closing prior to vancomycin treatment (45%, 5/11), compared to only 3 patients with trough levels <20 mcg/mL (9%, 3/35) (p = 0.013). CONCLUSION: Only half of the neonates receiving empirical vancomycin regimen achieved goal trough levels of 10-20 mcg/mL. Higher serum creatinine or ibuprofen treatment may increase the risk of overly high trough levels. The vancomycin regimen needs further validation and modification to provide adequate dosing for optimal use in neonates.

Can NT-proBNP Levels Be an Early Biomarker of Reduced Left Ventricular Ejection Fraction in Preterm Infants?

Background/Objective: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a cardiac natriuretic hormone that cardiomyocytes release in response to ventricular stretch. It helps with the diagnosis of heart failure in adults, but this application in preterm infants has rarely been reported. This study aimed to evaluate whether NT-proBNP could be used for the early detection of reduced cardiac ejection fraction in preterm infants and the optimal timing for NT-proBNP assessment. Design/Methods: This prospective, single-center, observational study enrolled all preterm infants with NT-proBNP measurements from October 2014 to February 2022. They underwent echocardiographic examinations within 48 h of the NT-proBNP measurements. Reduced left ventricular ejection fraction was defined as below 60%. Receiver operator characteristic (ROC) curves were generated to assess the optimal NT-proBNP cutoff point for the early prediction of reduced cardiac ejection fraction. Results: A total of 68 preterm infants were enrolled, with a total of 134 NT-proBNP measurements being available for analysis. Reduced left ventricular ejection fraction was present in seven infants (10.3%) due to various underlying diseases. The NT-proBNP cutoff level for detecting reduced left ventricular ejection fraction was 9248 pg/mL, with 71.4% sensitivity and 60.8% specificity; the area under the curve was 0.623 (95% CI: 0.487~0.760). The threshold for the optimal postnatal age for applying NT-proBNP to detect reduced left ventricular ejection fraction was >2 days of life (AUC: 0.682; 95% CI: 0.518~0.845), with 70% sensitivity and 67.1% specificity. Conclusions: Although the NT-proBNP levels declined dramatically after birth, a NT-proBNP serum level of 9248 pg/mL might be helpful for the early detection of reduced ejection fraction in preterm infants, and the optimal age for detection was after 2 days of life.

Case report: The art of anesthesiology-Approaching a minor procedure in a child with MPI-CDG.

Background: Protein glycosylation plays an important role in post-translational modification, which defines a broad spectrum of protein functions. Accordingly, infants with a congenital disorder of glycosylation (CDG) can have N-glycosylation, O-glycosylation, or combined N- and O-glycosylation defects, resulting in similar but different multisystem involvement. CDGs can present notable gastrointestinal and neurologic symptoms. Both protein-losing enteropathy and hypotonia affect the decision of using anesthetics. We reported a case of MPI-CDG with protein-losing enteropathy and muscular hypotonia that underwent different anesthesia approach strategies of vascular access. Here, we highlight why intubation with sevoflurane anesthesia and sparing use of muscle relaxants is the optimal strategy for such a condition. Case presentation: A 25-month-old girl, weighing 6.6 kg and 64 cm tall, suffered chronic diarrhea, hypoalbuminemia, and hypotonia since birth. Protein-losing enteropathy due to MPI-CDG was documented by whole-exome sequencing. She underwent three sedated surgical procedures in our hospital. The sedation was administered twice by pediatricians with oral chloral hydrate, intravenous midazolam, and ketamine, to which the patient showed moderate to late recovery from sedation and irritability the following night. The most recent one was administered by an anesthesiologist, where endotracheal intubation was performed with sevoflurane as the main anesthetic. The patient regained consciousness immediately after the operation. She had no complications after all three sedation/anesthesia interventions and was discharged 7 days later, uneventful after the third general anesthesia procedure. Conclusion: We performed safe anesthetic management in a 25-month-old girl with MPI-CDG using sevoflurane under controlled ventilation. She awoke immediately after the procedure. Due to the disease entity, we suggested bypassing the intravenous route to avoid excess volume for drug administration and that muscle relaxant may not be necessary for endotracheal intubation and patient immobilization when performing procedures under general anesthesia in CDG patients.

Fresh Frozen Plasma Transfusion: An Independent Risk Factor for Hemodynamically Significant Patent Ductus Arteriosus in Premature Infants.

OBJECTIVE: The incidence of patent ductus arteriosus (PDA), a major complication of prematurity, may be reduced by restricting fluid administration. Prophylactic fresh frozen plasma (FFP) transfusion may reduce the incidence of intraventricular hemorrhage in these infants, but risks transfusion-related volume overload. We conducted a retrospective study to investigate whether FFP transfusion is a risk factor for hemodynamically significant PDA (hsPDA) in very low birth weight (BW) premature infants. STUDY DESIGN: From January 2009 to December 2014, 102 premature infants with gestational age (GA) less than or equal to 30 weeks were admitted to a level III neonatal intensive care unit, and 88 patients were enrolled. Patients were further divided into non-hsPDA (n = 29) and hsPDA groups (n = 59). We retrospectively reviewed demographic characteristics and various perinatal and postnatal variables. Univariate and multivariable analyses were performed to identify risk factors for hsPDA. RESULTS: Compared with non-hsPDA patients, hsPDA patients had lower mean BW and GA, a higher incidence of severe respiratory distress symptoms, perinatal infection, use of surfactant, and need for FFP transfusion. However, multivariable logistic regression analysis showed that only FFP transfusion remained an independent risk factor for hsPDA (adjusted odds ratio = 3.880, 95% confidence interval: 1.214-12.402, p = 0.022) after adjusting for confounding factors. CONCLUSION: FFP transfusion is a significant risk factor for the subsequent development of hsPDA in our study population. FFP transfusion may complicate the fluid management of premature infants and increase the risk of hsPDA. KEY POINTS: · Hemodynamic significant PDA is an important complication of preterm infant.. · FFP transfusion may complicate the fluid management of premature infants.. · FFP transfusion is an independent risk factor for hsPDA in very low birth weight premature infants..

Lenticulostriate Vasculopathy in Very-Low-Birth-Weight Preterm Infants: A Longitudinal Cohort Study.

BACKGROUND: The pathogenesis and clinical significance of lenticulostriate vasculopathy (LSV) are unclear. Our study aimed to determine the prevalence, presentation, and evolution of LSV, and the perinatal risk factors associated with LSV among very-low-birth-weight (VLBW) preterm infants. METHODS: One-hundred-and-thirty VLBW preterm infants were retrospectively enrolled in this study. Serial cranial ultrasound examinations were performed regularly from birth until a corrected age of 1 year. Infants with LSV were assigned to early-onset (≤10 postnatal days) and late-onset (>10 postnatal days) groups. Data describing the infants' perinatal characteristics, placental histopathology, and neonatal morbidities were collected, and the groups were compared. RESULTS: Of the VLBW infants, 39.2% had LSV before they were 1 year old. Linear-type LSV was the most common presentation, and >50% of the infants had bilateral involvement. LSV was first detected at 112 ± 83 postnatal days, and its detection timing correlated negatively with gestational age (GA) (R2 = 0.153, p = 0.005) and persisted for 6 months on average. The infants with and without LSV had similar perinatal characteristics, placental pathologies, cytomegalovirus infection rates, and clinical morbidities. The late-onset LSV group comprised 45 (88.2%) infants who had a significantly higher rate of being small for gestational age (SGA) and used oxygen for longer than the infants without LSV. After adjusting a multivariable regression model for GA and SGA, analysis showed that the duration of oxygen usage was an independent risk factor for late-onset LSV development in VLBW infants (odds ratio: 1.030, p = 0.032). CONCLUSION: LSV may be a nonspecific marker of perinatal insult to the developing brains of preterm infants. Prolonged postnatal oxygen usage may predispose VLBW preterm infants to late-onset LSV development. The long-term clinical impacts of LSV should be clarified.

Histological chorioamnionitis and its impact on respiratory outcome in very-low-birth-weight preterm infants.

BACKGROUND: The role of intrauterine infection in the development of neonatal pulmonary disease is unclear and the impact of histological chorioamnionitis (HCAM) on respiratory outcomes in preterm infants remains controversial. The aim of this study was to explore the association between HCAM and neonatal respiratory outcomes in very-low-birth-weight (VLBW) preterm infants and evaluate the stepwise difference in the stage and severity of HCAM among neonatal respiratory outcomes. METHODS: We retrospectively enrolled 129 VLBW preterm infants with placenta histopathology examinations in this study. HCAM was subdivided into 3 stages (early, intermediate, and advanced) according to the progression of the maternal inflammatory response. The perinatal characteristics, placental histopathology, and neonatal morbidities, including respiratory outcomes (respiratory distress syndrome (RDS), Wilson-Mikity syndrome (WMS) and bronchopulmonary dysplasia (BPD)), were collected for comparison. RESULTS: A total of 52.7% (68/129) of the infants had HCAM, including 23 early (stage 1), 30 intermediate (stage 2), and 15 advanced (stage 3) stage. There was no significant difference in the gestational age, birth body weight or mortality rate between the HCAM and non-HCAM groups. Mothers with HCAM had a significantly lower incidence of pre-eclampsia but a higher rate of premature rupture of membrane. They also had higher WBC counts and C-reactive protein levels before delivery. Neonates with HCAM had a lower incidence of RDS but were at a higher risk for developing WMS and BPD. After multivariate analysis adjustment, HCAM was still negatively associated with RDS (aOR = .069, p < .001) but without correlation with BPD. However, neonates with intermediate to advanced-stage HCAM had a higher risk of developing WMS and increased home oxygen usage rate compared to those with early-stage HCAM. CONCLUSION: HCAM has a protective effect from RDS in preterm neonates. Additionally, VLBW neonates with intermediate to advanced-stage HCAM are at risk for WMS.

Effects of Stepwise Lung Recruitment Maneuvers in Patients with Early Acute Respiratory Distress Syndrome: A Prospective, Randomized, Controlled Trial.

Since the clinical benefit of lung recruitment maneuvers (LRMs) is still conflicting, we performed this prospective, randomized, controlled study to investigate whether LRMs should be used in the routine management of acute respiratory distress syndrome (ARDS). This trial was conducted in four intensive care units (ICUs) to compare application of a modified stepwise LRMs with solely lung-protective ventilation in patients with moderate to severe ARDS within 72 h from the onset. The primary outcome was 28-day mortality, and the secondary outcomes were ventilator-free days and ICU-free days. We collected data on 120 ARDS patients from 2009 to 2012, and there was no difference in 28-day mortality between the two groups (28.3% vs. 30.0%, p = 0.84). However, among survivors, patients in the LRM group had a significant longer median duration of ventilator-free days (18 vs. 13 days; p = 0.04) and ICU-free days (16 vs. 11 days; p = 0.03) at 28 days than in the control group. The respiratory system compliance was significantly higher in the LRM group from day 1 to day 7. The occurrence rate of barotrauma was similar in both groups. We concluded that LRMs combined with lung-protective ventilation in early ARDS may improve patient outcomes.

Clinical manifestations of candidemia caused by uncommon Candida species and antifungal susceptibility of the isolates in a regional hospital in Taiwan, 2007-2014.

OBJECTIVE: This retrospective study investigated clinical manifestations of candidemia caused by uncommon Candida species and antifungal susceptibility of the isolates in a regional hospital in Taiwan. METHODS: The uncommon Candida species was initially defined as Candida species other than C. albicans, C. tropicalis, C. glabrata complex, C. parapsilosis complex and C. krusei. All uncommon Candida isolates were identified and confirmed by molecular methods. In vitro susceptibility testing of the uncommon Candida species to nine antifungal agents was conducted using the broth microdilution method with the Sensititre YeastOne (SYO) system (Trek Diagnostic Systems, Ltd., East Grimstead, UK). RESULTS: Twenty-one patients, comprising 11 males and 10 females with a median age of 69 years, were recruited. Cancer (n = 11) was the most common underlying disease, 19 (90.5%) cases had prior antibiotic exposure, and only two patients had prior antifungal use. The overall in-hospital mortality rate was 38.1% (n = 8). C. guilliermondii (n = 11) was the most common pathogen, followed by C. curvata (n = 3). C. guilliermondii isolates exhibited relatively high rates of azole minimum inhibitory concentrations (MICs) above epidemiological cut-off values (ECVs), whereas C. pelliculosa and C. lusitaniae isolates all remained susceptible to azoles. All three C. curvata isolates had high caspofungin (>8 mg/L) and fluconazole MICs (8 mg/L) and could be defined as multidrug-resistant. CONCLUSIONS: Uncommon Candida species frequently exhibit high rates of non-susceptibility to antifungals. Identification of all Candida isolates at the species level from blood samples is of value for treatment.

Curcumin Inhibits LIN-28A through the Activation of miRNA-98 in the Lung Cancer Cell Line A549.

Metastasis is common in lung cancer and is associated with poor clinical outcomes and increased mortality. Curcumin is a natural anti-cancer agent that inhibits the metastasis of various cancers by modulating the expression of micro (mi) RNAs such as miR-98, which acts as a tumor suppressor. This study investigated the effect of curcumin on miR-98 expression and in vitro cell line growth and invasiveness in lung cancer. Curcumin treatment enhanced the expression of miR-98 and reduced that of the miR-98 target gene LIN28A as well as matrix metalloproteinase (MMP) 2 and MMP9 in vitro and in vivo. MiR-98 overexpression suppressed lung cancer cell migration and invasion by inhibiting LIN28A-induced MMP2 and MMP9 expression. Meanwhile, LIN28A level was downregulated by overexpression of miR-98 mimic. Induction of miR-98 by curcumin treatment suppressed MMP2 and MMP9 by targeting LIN28A. These findings provide insight into the mechanisms by which curcumin suppresses lung cancer cell line growth in vitro and in vivo and invasiveness in vitro.

Serial measurements of serum alkaline phosphatase for early prediction of osteopaenia in preterm infants.

AIM: Osteopaenia commonly occurs in preterm infants; however, its diagnosis is often delayed when based on radiological findings. The aim of this study was to examine whether serial measurements of bone turnover markers are useful for early prediction of osteopaenia in preterm infants. METHODS: Premature infants of ≤ 34 weeks gestation were enrolled. Serum alkaline phosphatase (ALP), bone form ALP (BALP), calcium and inorganic phosphate were concurrently measured biweekly from 3 weeks post-natal age until 40 weeks post-conceptional age. Radiographic examination of the forearm was performed at term age. Osteopaenia was defined as positive radiographic findings according to Koo's criteria. RESULTS: Of the 46 premature infants completing the follow-up study at term age, 18 showed osteopaenia in radiographic examination. Serum ALP was highly correlated with BALP (R(2) = 0.93, P < 0.001). Infants who had osteopaenia showed a higher level of ALP and BALP after 3 weeks post-natal age than those who had no osteopaenia. ALP concentration exceeding 700 IU/L at 3 weeks post-natal age was predictive of osteopaenia at term age (sensitivity 73% and specificity 73%) and so did for the predictive value of BALP concentration exceeding 95 ug/L (sensitivity 73% and specificity 80%). BALP measures provided no greater benefit of diagnostic performance than ALP in early detection of osteopaenia. Furthermore, premature infants with osteopaenia showed similar levels of calcium and inorganic phosphatase concentration compared with those without. CONCLUSION: Serum ALP concentration exceeding 700 IU/L at 3 weeks post-natal age can predict the risk of osteopaenia in preterm infants.

Antenatal steroid treatment reduces childhood asthma risk in very low birth weight infants without bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) and very low birth weight (VLBW) are associated with increased incidences of asthma and pulmonary dysfunction in childhood. However, no studies exist which examine asthma risk factors in children who were VLBW infants and did not have BPD. To address this issue, we assessed the asthma incidence and risk factors for asthma in 117 children (approximate mean age of 5 years) who were VLBW [<1500 g, mean gestational age (GA): 30 weeks] infants without BPD. The risk factors were both perinatal (such as steroid treatment, mechanical ventilation, surfactant treatment) and environmental (parental smoking, pet adoption, etc). The asthma incidence was 18.8%. Following multivariate analysis, it was determined that a family history of atopy was a strong risk factor for childhood asthma. Maternal antenatal steroid treatment was associated with a significantly reduced risk for asthma. GA and birth weight were not predictive of childhood asthma. These findings indicate that a history of familial atopy and antenatal steroid treatment are positively and negatively associated (independent of BPD) with childhood asthma in VLBW infants. The finding regarding antenatal steroid treatment warrants more extensive investigations.

Outcome and hospital cost for infants weighing less than 500 grams: a tertiary centre experience in Taiwan.

AIM: To determine the outcome and hospital cost for infants weighing < or =500 g at a tertiary centre in Taiwan. METHODS: We retrospectively reviewed the medical records of infants who were born alive with birthweight < or =500 g at the National Taiwan University Hospital from 1997 to 2004. Their outcome and hospital cost were analysed. RESULTS: A total of 168 infants were included for analysis that 146 of them died after compassionate care in the delivery room and 22 received postnatal resuscitation. The infants who received resuscitation were more likely to have higher birthweights, older gestational ages and multiple births compared with those who received compassionate care. After resuscitation, five of the infants died and 17 were admitted to neonatal intensive care unit (NICU) for further management. Subsequently, 12 infants died and five infants survived to discharge. Two infants were discharged against advice and died within days. After exclusion of those receiving compassionate care, the NICU survival rate was 22.7% and the long-term survival rate was 13.6%. The most common early morbidities were respiratory distress syndrome, intraventricular haemorrhage and patent ductus arteriosus, whereas the late morbidities included cholestatic jaundice, retinopathy of prematurity and chronic lung disease. The average total hospital costs for the NICU survivors with birthweight < or =500 g was US $42,411 and the average hospital cost per day was US $350. CONCLUSION: Exclusive compassionate care was given to the majority of the infants weighing < or =500 g in Taiwan. The survival rate remained low in these marginally viable infants.