Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

Congenital Candidiasis

Congenital candidiasis presents with a variety of clinical features. We report two neonates with congenital candidiasis characterized by diffuse erythematous papules associated with pneumonia and respiratory distress. Candida pseudohyphae were identifiable in skin scrapings. Systemic cultures were negative, but urine and sputum cultures grew Candida albicans. After prompt systemic antifungal therapy, the infants were discharged from hospital with no overt complications. This report highlights the presence of characteristic skin lesions associated with candidal infection, occurring within 24 hours of birth. This is an important observation which could help in the early diagnosis of congenital candidal infection

Serum retinol levels and neonatal outcomes in preterm infants

Glucocorticoids are frequently administered to preterm infants, both antenatally and postnatally; however, the effect on serum retinol levels has not been determined. The risk of bronchopulmonary dysplasia is increased in premature infants with low retinol concentrations. Objectives: Our purpose was to determine the effect of glucocorticoid administration on serum retinol levels in preterm infants. Methods: All infants <1250 g or <29 weeks' gestation admitted to the neonatal intensive care unit within 48 h of birth were eligible for inclusion. A retinol concentration <20 μg/dL during the first 48 h of birth was defined as low serum retinol, and a level <10 μg/dL as retinol deficiency. Results: Data from 115 premature infants were collected during a 7-year period, from 2005 to 2012. Neither antenatal nor postnatal steroid administration affected retinol concentrations. Retinol deficiency was associated with an increased risk for severe respiratory distress syndrome and adverse pulmonary outcome (death during the first 28 days of life and long-term oxygen dependence >90 days); low retinol levels conferred an increased risk for bronchopulmonary dysplasia. Prolonged duration of total parenteral nutrition (>21 days) was associated with serum retinol deficiency during hospitalization (P < 0.05). Retinol deficiency was associated with an increased risk for delayed neurological development in 1-year-old and 2-year-old children. Conclusion: Glucocorticoids do not affect retinol levels in premature infants, but retinol concentrations are correlated with respiratory and neurological outcomes

Epidemiological and microbiological characteristics of culture-proven acute otitis media in Taiwanese children

Acute otitis media (AOM) is one of the most common diseases in children. Here, we describe the epidemiological and microbiological characteristics of AOM in Taiwanese children over a 10-year period. Methods: We retrospectively enrolled pediatric patients with culture-proven AOM who were treated at Mackay Memorial Hospital, Taipei between 1999–2008. The data include demographic characteristics, clinical history, and microbiological characteristics. Results: Six hundred and fourteen patients were included. The male:female ratio was 1.4 (p 5 years of age and was associated with spontaneous otorrhea (p<0.001). Conclusion: S. pneumoniae and NTHi are common causes of culture-confirmed AOM in Taiwanese children. Although S. pyogenes is not as common, it usually causes AOM in children > 5 years of age and is associated with spontaneous otorrhea

Outcomes and related factors in a cohort of infants born in Taiwan over a period of five years (2007–2011) with borderline viability

Background: Advances in perinatal and neonatal care have increased the survival of extremely preterm infants, but the viability limit is still debated. Here we assess the survival, neonatal morbidity, and neurodevelopmental outcomes at 2 years of age of infants born at 22–26 weeks of gestation in Taiwan between 2007 and 2011. Methods: This is a prospective longitudinal multicenter cohort study on extremely preterm infants registered in the Taiwan Premature Infant Developmental Collaborative Study Group from 2007 to 2011, including 22 neonatal care centers. We extracted demographic and clinical data of infants born at 22–26 weeks, and obtained growth and developmental outcome data from the follow-up clinic at 24 months of corrected age. Multivariate analyses using a logistic regression model identified factors significantly impacting survival. Results: 647 of the 1098 infants included in the study (58.9%) survived to discharge. Survival rates were 8% (4/50), 25% (27/108), 46.8% (117/250), 67.0% (211/315), and 76.8% (288/375) for infants born at 22, 23, 24, 25, and 26 weeks, respectively. Most survivors (567/647, 87.6%) had major morbidities during hospitalization, and we identified factors that positively and negatively affected survival. 514 (79.4%) patients received follow-up evaluation at 2 years, and 204 (39.7%) of them had neurodevelopmental impairment (NDI) with an incidence of 75%, 65.2%, 49.5%, 39.5%, and 32.8% for infants born at 22, 23, 24, 25, and 26 weeks, respectively. Conclusion: Infants born at 22 and 23 weeks have a very low likelihood of surviving with little or no impairment. These findings are valuable for parental counseling and perinatal care decisions. Keywords: Extremely preterm, Morbidity, Mortality, Outcome

Acute otitis media caused by Streptococcus pneumoniae serotype 19A ST320 clone: epidemiological and clinical characteristics

Background: Streptococcus pneumoniae serotype 19A ST320, a highly multiresistant and virulent clone, has emerged as a common pathogen causing acute otitis media (AOM) in children. Methods: Patients aged 0–18 years with AOM who presented at Mackay Memorial Hospital, Taipei, Taiwan were prospectively enrolled between December 1, 2009, and November 30, 2012. For each patient, a specimen of middle-ear fluid was obtained and cultured. S. pneumoniae isolates were tested by serotyping, antibiotic-resistance profiling, and multilocus sequence typing. Demographic characteristics and clinical history of patients with pneumococcal AOM were recorded. Results: Pneumococcal AOM was observed in 108 (24.8%) of 436 episodes. One hundred and four isolates of S. pneumoniae were available for study. The most common serotypes were 19A (67 isolates, 64.4%), followed by 19F (16 isolates, 15.4%), and 3 (7 isolates, 6.7%). Among the 85 sequence-typed isolates, Serotype 19A ST320 (50, 58.8%) was the most frequent. Children with AOM caused by Serotype 19A ST320 were younger (33.9 ± 21.4 months vs. 46.7 ± 35.9 months, p = 0.04) and had a higher rate of spontaneous rupture of the tympanic membrane (64.0% vs. 40%, p = 0.05) than those caused by isolates of other sequence types. Serotype 19A ST320 caused 90% of AOM episodes in children aged ≤ 12 months and had had higher resistance rates to penicillin according to meningeal breakpoints (p = 0.011), amoxicillin (p < 0.001) and trimethoprim/sulfamethoxazol (p < 0.001). Conclusions: It is better to use pneumococcal conjugate vaccine effective against Serotype 19A in early infancy to prevent the first and subsequent episodes of AOM in children in Taiwan

Prolonged seasonality of respiratory syncytial virus infection among preterm infants in a subtropical climate.

OBJECTIVE: There is limited epidemiological data on the seasonality of respiratory syncytial virus (RSV) infection in subtropical climates, such as in Taiwan. This study aimed to assess RSV seasonality among children ≤24 months of age in Taiwan. We also assessed factors (gestational age [GA], chronologic age [CA], and bronchopulmonary dysplasia [BPD]) associated with RSV-associated hospitalization in preterm infants to confirm the appropriateness of the novel Taiwanese RSV prophylactic policy. STUDY DESIGN: From January 2000 to August 2010, 3572 children aged ≤24-months were admitted to Taipei Mackay Memorial Hospital due to RSV infection. The monthly RSV-associated hospitalization rate among children aged ≤24 months was retrospectively reviewed. Among these children, 378 were born preterm. The associations between GA, CA, and BPD and the incidence of RSV-associated hospitalization in the preterm infants were assessed. RESULTS: In children aged ≤24 months, the monthly distribution of RSV-associated hospitalization rates revealed a prolonged RSV season with a duration of 10 months. Infants with GAs ≤32 weeks and those who had BPD had the highest rates of RSV hospitalization (P<0.001). Preterm infants were most vulnerable to RSV infection within CA 9 months. CONCLUSIONS: Given that Taiwan has a prolonged (10-month) RSV season, the American Academy of Pediatrics' recommendations for RSV prophylaxis are not directly applicable. The current Taiwanese guidelines for RSV prophylaxis, which specify palivizumab injection (a total six doses until CA 8-9 months) for preterm infants (those born before 28(6/7) weeks GA or before 35(6/7) weeks GA with BPD), are appropriate. This prophylaxis strategy may be applicable to other countries/regions with subtropical climates

Changing of bloodstream infections in a medical center neonatal intensive care unit

Background/Purpose: Bloodstream infections (BSIs) are associated with high mortality and morbidity in neonatal intensive care units (NICUs). The epidemiology of these infections may change after the application of new infection control policies. The aims of this study are to reveal the changing epidemiology of BSIs in our NICU and inspect the effects of infection control efforts. Methods: We reviewed and analyzed the clinical characteristics of culture-proven BSIs in our NICU from 2008 to 2013 and compared them with our two previously reported data (1992–2001 and 2002–2007). Results: The mortality rate decreased from 16.3% in 1992–2001 to 5.6% in 2008–2013. In the recent study period, Gram-positive infections became predominant (58.0%). Coagulase-negative staphylococci remained the most commonly isolated organisms (26.0%). Group B Streptococcus (GBS) BSIs had the highest mortality rate (30.0%). Most GBS-infected infants' mother did not perform prenatal GBS screening. There was a decrease in the total fungal infection rate after fluconazole prophylaxis for very-low-birth-weight (VLBW) neonates, but the infections of fluconazole-resistant Malassezia pachydermatis increased. The incidence of central line-associated BSI increased to 10.6% in 2011. After restricting the catheter duration to <21 days, the incidence decreased to 4.2% in 2013. Conclusion: Through the years, the overall mortality rate of BSIs in our NICU decreased. Maternal GBS screening is an important issue for avoiding early onset GBS mortality. Fungal infection rate decreased after antifungal prophylaxis policy for VLBW infants, but we should be aware of resistant strains. Restriction of the catheter duration may decrease the incidence of catheter-related BSI

Neonatal Outcomes of Extremely Preterm Infants from Taiwan: Comparison with Canada, Japan, and the USA

This study compared the current trend in survival rates and morbidity for very low birth weight (VLBW) infants in five Medical Training Centers of Prematurity for the Premature Baby Foundation of Taiwan (PBFT), with the outcomes from the USA, National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN), the Canadian Neonatal Network (CNN), and the Neonatal Research Network of Japan (NRNJ). Methods: The survival rates of VLBW infants according to gestational age (GA) and major morbidities were compared between networks (Taiwan, USA, Canada, and Japan). Taiwanese data for VLBW infants of GA ≤28 weeks between 2007 and 2012 were obtained from the “PBFT Annual Conferences of Premature Care” reports defining survival rate as neonates that survived to the time of discharge. Major morbidities included severe neurological injury (Grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia), bronchopulmonary dysplasia, severe retinopathy of prematurity, necrotizing enterocolitis, late-onset sepsis, and patent ductus arteriosus. Results: The survival rates of VLBW infants of GA ≤28 weeks from the PBFT (Taiwan), NICHD NRN (USA), CNN (Canada), and NRNJ (Japan) were 77% (1323/1718), 72% (6859/9575), 82% (2353/2872), and 89% (4489/5069), respectively. The annual survival rates in Taiwan from 2007 to 2012 were 72%, 76%, 76%, 74%, 77%, and 78%, respectively. When GA from ≤23 weeks to 28 weeks was assessed in Taiwan, the survival rates of VLBW infants according to each week were 22%, 50%, 70%, 80%, 88%, and 92%, respectively. The survival rate, especially at lower GAs, was highest in the NRNJ (Japan). The major difference between Taiwan and Japan was attributed to the lower survival rates at lower GA (≤26 weeks) in Taiwan. Japan had the lowest rates of major morbidities among the four countries. Conclusion: The survival rate of VLBW infants has improved over the past 6 years in Taiwan. It is higher than the USA, but lower than Canada and Japan. However, the results from Taiwan are from five Medical Training Centers for the PBFT rather than from a population-based study. It is crucial to have a nationwide neonatal research network to develop new practical approaches for VLBW infants in Taiwan