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BACKGROUND: Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model. METHODS: In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically. RESULTS: In vitro, IL-1ß, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group. CONCLUSION: Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI.
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Lesión Pulmonar Aguda , Vesículas Extracelulares , Células Madre Mesenquimatosas , Ratones Endogámicos ICR , Trombina , Animales , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/microbiología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/terapia , Ratones , Células Madre Mesenquimatosas/metabolismo , Células RAW 264.7 , Trombina/metabolismo , Escherichia coli , Masculino , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Infecciones por Escherichia coli/terapia , Resultado del Tratamiento , Modelos Animales de Enfermedad , HumanosRESUMEN
Despite recent advances in neonatal intensive care medicine, neonatal disorders such as (bronchopulmonary dysplasia [BPD], intraventricular hemorrhage [IVH], and hypoxic ischemic encephalopathy [HIE]) remain major causes of death and morbidity in survivors, with few effective treatments being available. Recent preclinical studies have demonstrated the pleiotropic host injury-responsive paracrine protective effects of cell therapy especially with mesenchymal stromal cells (MSCs) against BPD, IVH, and HIE. These findings suggest that MSCs therapy might emerge as a novel therapeutic modality for these currently devastating neonatal disorders with complex multifactorial etiologies. Although early-phase clinical trials suggest their safety and feasibility, their clinical therapeutic benefits have not yet been proven. Therefore, based on currently available preclinical research and clinical trial data, we focus on critical issues that need to be addressed for future successful clinical trials and eventual clinical translation such as selecting the right patient and optimal cell type, route, dose, and timing of MSCs therapy for neonatal disorders such as BPD, HIE, and IVH.
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This study investigated the predictive factors for perinatal bacterial transmission in very-low-birth-weight infants (VLBWIs) born to mothers with a history of intrapartum colonization. We retrospectively reviewed the medical records of 173 VLBWIs, wherein pathogens were confirmed in maternal cultures obtained from the blood, urine, and vagina during the intrapartum period from 2013 to 2020. Newborns were categorized based on microbiological tests, including gastric aspirates, endotracheal aspirates, blood, and skin/nasal swab cultures collected immediately after birth. Infants whose cultures matched their maternal pathogens were categorized into the "transmission group" (n = 45), while those who tested negative were assigned to the "control group" (n = 128). The predominant maternal-colonizing pathogen observed was Escherichia coli (30.6%), which also emerged as the primary colonizing pathogen in neonates (35.6%). Transmission group had higher incidences of maternal leukocytosis, chorioamnionitis, and cervical cerclage. Regarding neonatal characteristics, the transmission group demonstrated lower initial base excesses (- 6.3 ± 3.9 vs. - 9.2 ± 4.9, P < 0.05) and higher C-reactive protein levels (0.1 ± 0.3 vs. 0.4 ± 0.8, P < 0.05). Notably, regarding major neonatal outcomes, transmission group had higher mortality rates and incidences of severe intraventricular hemorrhage. These findings may be useful for making decisions when considering antibiotic treatment for infants with a history of maternal colonization.
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Recién Nacido de muy Bajo Peso , Transmisión Vertical de Enfermedad Infecciosa , Humanos , Femenino , Recién Nacido , Estudios Retrospectivos , Embarazo , Masculino , Adulto , Complicaciones Infecciosas del Embarazo/microbiología , Madres , Factores de Riesgo , Escherichia coli/aislamiento & purificaciónRESUMEN
BACKGROUND: Post-hemorrhagic hydrocephalus (PHH), a common complication of severe intraventricular hemorrhage (IVH) in very low birth weight (BW) infants, is associated with significant morbidity and poor neurological outcomes. The objective of this study was to assess the current status of PHH and analyze the risk factors associated with the necessity of treatment for PHH in infants born between 22 and 28 weeks of gestation, specifically those with severe IVH (grade 3 or 4). METHODS: The analysis was conducted on 1,097 infants who were born between 22-28 gestational weeks and diagnosed with severe IVH, using data from the Korean Neonatal Network. We observed that the prevalence of PHH requiring treatment was 46.3% in infants with severe IVH. RESULTS: Higher rates of mortality, transfer during admission, cerebral palsy, and ventriculoperitoneal shunt after discharge were higher in infants with PHH than in those without PHH. PHH in severe IVH was associated with a higher rate of pulmonary hemorrhage, seizures, and IVH grade 4 in the entire cohort. In addition, it was associated with a lower rate of small for gestational age and chorioamnionitis. In the subgroup analysis, high BW, outborn status, pulmonary hemorrhage, seizure, sepsis, and IVH grade 4 were associated with a higher incidence of PHH between 22 and 25 gestational weeks (GW). In infants born between 26 and 28 GW, a higher incidence of PHH was associated with seizures and IVH grade 4. CONCLUSION: It is necessary to maintain meticulous monitoring and neurological intervention for infants with PHH not only during admission but also after discharge. In addition, identifying the clinical factors that increase the likelihood of developing PHH from severe IVH is crucial.
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Edad Gestacional , Hidrocefalia , Humanos , Hidrocefalia/complicaciones , República de Corea/epidemiología , Recién Nacido , Femenino , Masculino , Factores de Riesgo , Estudios de Cohortes , Hemorragia Cerebral/complicaciones , Índice de Severidad de la Enfermedad , Hemorragia Cerebral Intraventricular/complicaciones , Derivación Ventriculoperitoneal , Lactante , Recién Nacido de muy Bajo PesoRESUMEN
This study investigated whether late pulmonary hypertension (LPH) independently increases the risk of long-term mortality or neurodevelopmental delay (NDD) in extremely preterm infants (EPIs) with severe bronchopulmonary dysplasia (BPD). Using prospectively collected data from the Korean Neonatal Network, we included EPIs with severe BPD born at 22-27 weeks' gestation between 2013 and 2021. EPIs having severe BPD with LPH (LPH, n = 124) were matched 1:3 with those without pulmonary hypertension (PH) as controls (CON, n = 372), via propensity score matching. LPH was defined as PH with the initiation of medication after 36 weeks' corrected age (CA). Long-term mortality after 36 weeks' CA or NDD at 18-24 months' CA was analyzed. NDD was assessed using composite scores based on various neurodevelopmental assessment modalities. LPH had significantly higher long-term mortality or NDD (45.2% vs. 23.1%, P < 0.001), mortality (24.2% vs. 4.84%, P < 0.001), and NDD (68.4% vs. 37.8%, P = 0.001), respectively than CON, even after adjusting for different demographic factors. Multivariable regression demonstrated that LPH independently increased the risk of mortality or NDD (adjusted odds ratio, 1.95; 95% confidence intervals, 1.17-3.25). When LPH occurs in EPIs with severe BPD, special monitoring and meticulous care for long-term survival and neurodevelopment are continuously needed.
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Displasia Broncopulmonar , Hipertensión Pulmonar , Lactante , Humanos , Recién Nacido , Displasia Broncopulmonar/complicaciones , Displasia Broncopulmonar/tratamiento farmacológico , Recien Nacido Extremadamente Prematuro , Hipertensión Pulmonar/tratamiento farmacológico , Edad GestacionalRESUMEN
Objectives: The management of patent ductus arteriosus (PDA) is a critical concern in premature infants, and different hospitals may have varying treatment policies, fluid management strategies, and incubator humidity. The Asian Neonatal Network Collaboration (AsianNeo) collected data on prematurity care details from hospitals across Asian countries. The aim of this study was to provide a survey of the current practices in the management of PDA in premature infants in Asian countries. Methods: AsianNeo performed a cross-sectional international questionnaire survey in 2022 to assess the human and physical resources of hospitals and clinical management of very preterm infants. The survey covered various aspects of hospitals resources and clinical management, and data were collected from 337 hospitals across Asia. The data collected were used to compare hospitals resources and clinical management of preterm infants between areas and economic status. Results: The policy of PDA management for preterm infants varied across Asian countries in AsianNeo. Hospitals in Northeast Asia were more likely to perform PDA ligation (p < 0.001) than hospitals in Southeast Asia. Hospitals in Northeast Asia had stricter fluid restrictions in the first 24â h after birth for infants born at <29 weeks gestation (p < 0.001) and on day 14 after birth for infants born at <29 weeks gestation (p < 0.001) compared to hospitals in Southeast Asia. Hospitals in Northeast Asia also had a more humidified environment for infants born between 24 weeks gestation and 25 weeks gestation in the first 72â h after birth (p < 0.001). A logistic regression model predicted that hospitals were more likely to perform PDA ligation for PDA when the hospitals had a stricter fluid planning on day 14 after birth [Odds ratio (OR) of 1.70, p = 0.048], more incubator humidity settings (<80% vs. 80%-89%, OR of 3.35, p = 0.012 and <80% vs. 90%-100%, OR of 5.31, p < 0.001). Conclusions: In advanced economies and Northeast Asia, neonatologists tend to adopt a more conservative approach towards fluid management, maintain higher incubator humidity settings and inclined to perform surgical ligation for PDA.
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Mitochondrial DNA (mtDNA) released from dead or injured cells can activate inflammation, and mesenchymal stem cell (MSC) transplantation can reduce inflammation and injury. However, it has not been tested whether the release of mtDNA can be reduced by MSC transplantation. We hypothesized that the level of extracellular mtDNA would be increased after hyperoxia-induced lung injury but reduced after lung injury attenuation by MSC therapy in our newborn rat model. In an in vitro study using a rat lung epithelial L2 cell line, we found that the level of extracellular mtDNA was significantly increased with H2O2-induced cell death but reduced after MSC co-incubation. In an in vivo study, we confirmed that the levels of cell death, extracellular mtDNA, and inflammatory cytokines were significantly increased in hyperoxic newborn rat lungs but reduced after MSC transplantation. The levels of extracellular mtDNA were significantly and positively correlated with the levels of the inflammatory cytokines. The TLR9/MyD88/NF-κB pathway, which is activated by binding to mtDNA, was also significantly upregulated but downregulated after MSC transplantation. We found a significant positive correlation between inflammatory cytokines and extracellular mtDNA in intubated neonates. The levels of inflammatory cytokines and extracellular mtDNA changed over time in a similar pattern in transtracheal aspirate samples from intubated neonates. In conclusion, increased levels of extracellular mtDNA are associated with increased inflammation in hyperoxia-induced lung injury, and attenuation of lung inflammation by MSC therapy is associated with reduced levels of extracellular mtDNA.
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Blood culture proven sepsis is associated with increased mortality and morbidity. Given the extended hospitalization of very preterm infants, catheter-related blood stream infections (CRBSIs) play a substantial role in sepsis. The reported incidence of CRBSIs in neonates varies from 3.2 to 21.8 CRBSIs per 1000 catheter line days. Moreover, discrepancies in neonatal practices and potential neglect may lead to the unwarranted prolongation of central lines. This study aims to compare two distinct periods (Pre-QI vs. Post-QI) in relation to the central line insertion rate and duration, as well as blood culture proven sepsis, duration of total parenteral nutrition (TPN), and the progression of feeding. These factors are known to be associated with prolonged hospitalization and increased morbidities. A total of 210 very low birth weight infants (VLBWIs), defined as either less than 32 weeks of gestational age (GA) or weighing less than 1500 g, were admitted to the Neonatal Intensive Care Unit (NICU) at Seoul St. Mary's Hospital, The Catholic University of Korea, between January 2020 and June 2023. Fourteen infants were excluded from the study as they did not survive beyond 1 month of life, and one was excluded due to a congenital anomaly. Consequently, the analysis included 195 VLBWIs. The Quality Improvement (QI) initiative began in January 2022, marking the division into two distinct epochs: the Pre-QI period, encompassing the years 2020 to 2021, and the Post-QI period, spanning from 2022 to 2023. The primary outcome measures included PICC insertion rates, duration, and feeding advancement or feeding-related complications. The hospital outcome measures were also compared between the two periods. A total of 195 VLBWI were included in the analysis. The birth weight was significantly lower in the pre-QI period, with an average of 1023 g compared to 1218 g (P < 0.001). Severe BPD ≥ moderate was significantly lower in the post-QI period (36.2% vs. 53.9%) (P < 0.001) along with shorter mechanical ventilation days (12 ± 29 vs. 22 ± 27) (P = 0.046). The PICC insertion rate was significantly decreased from 95.6% in pre-QI period compared to 55.2% in post-QI period (P < 0.001) along with a notable reduction in blood culture-proven sepsis (25.6% vs. 10.5%, P = 0.008). CRBSI rate was reduced from 1.3 to 1.1 per 1000 catheter days in the post-QI period. Moreover, the time required to achieve full enteral feeding of 100 mL/kg/day was significantly shorter in the post-QI (24 ± 23 vs. 33 ± 25) (P = 0.006). Multivariable logistic regression analysis for sepsis revealed that both birth weight and pre/post QI consistently demonstrated an association with lower sepsis rates in the Post-QI period. QI has the potential to reduce the burden of unnecessary interventions and blood culture proven sepsis rate along with CRBSI rate, thereby, optimizing the better care of very preterm babies.
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Recien Nacido Prematuro , Sepsis , Lactante , Recién Nacido , Humanos , Peso al Nacer , Mejoramiento de la Calidad , Recién Nacido de muy Bajo Peso , Sepsis/epidemiología , Sepsis/prevención & controlRESUMEN
BACKGROUND: Infants with congenital anomalies of the digestive system and abdominal wall defects requiring surgery are at risk of growth and developmental delays. The aim of this study was to analyze long-term growth and developmental outcomes for infants with congenital anomalies of the digestive system and abdominal wall defects who underwent surgery in Korea. METHODS: We extracted data from the Korean National Health Insurance Service database for the years 2013-2019. Major congenital anomalies were defined according to the International Classification of Diseases-10 and surgery insurance claim codes. The χ² test and the Cochran-Armitage trend test were performed for data analysis. RESULTS: A total of 4,574 infants with major congenital anomalies in the digestive system and abodminal wall defects, who had undergone surgey, were reviewed. Anorectal obstruction/stenosis was the most prevalent anomaly (4.9 per 10,000 live births). The prevalence of congenital anomalies of the digestive system was 15.5 per 10,000 live births, and that of abdominal wall defects was 1.5 per 10,000 live births. Seven percent of infants with congenital anomalies in the digestive system died, of which those with diaphragmatic hernia had the highest mortality rate (18.8%). Among 12,336 examinations at 6, 12, 24, 36, 48, 60, and 72 months of age, 16.7% showed a weight below the 10th percentile, 15.8% had a height below the 10th percentile, and 13.2% had a head circumference below the 10th percentile. Abnormal developmental screening results were observed in 23.0% of infants. Infants with esophageal atresia with/without tracheoesophageal fistula most often had poor growth and development. Delayed development and cerebral palsy were observed in 490 (10.7%) and 130 (2.8%) infants respectively. Comparing the results of infants born in 2013 between their 24- and 72-month health examinations, the proportions of infants with poor height and head circumference growth increased by 6.5% and 5.3%, respectively, whereas those with poor weight growth and abnormal developmental results did not markedly change between the two examinations. CONCLUSION: Infants with congenital anomalies of the digestive system and abdominal wall defects exhibit poor growth and developmental outcomes until 72 months of age. Close monitoring and careful consideration of their growth and development after discharge are required.
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Pared Abdominal , Anomalías Congénitas , Lactante , Embarazo , Femenino , Humanos , Niño , Adolescente , Pared Abdominal/cirugía , Parto , Sistema Digestivo , República de Corea/epidemiología , Anomalías Congénitas/epidemiologíaRESUMEN
Although it has been suggested that toll-like receptor (TLR) 3 and TLR4 activation alters mesenchymal stromal cells (MSCs)' immunoregulatory function as anti- or pro-inflammatory phenotypes, we have previously confirmed that TLR4-primed hUCB-MSCs alleviate lung inflammation and tissue injury in an E. coli-induced acute lung injury (ALI) mouse model. Therefore, we hypothesized that strong stimulation of TLR3 or TLR4 prompts hUCB-MSCs to exhibit an anti-inflammatory phenotype mediated by extracellular vesicles (EVs). In this study, we compared the anti-inflammatory effect of TLR3-primed and TLR4-primed hUCB-MSCs against an LPS-induced ALI in vitro model by treating MSCs, MSC-derived conditioned medium (CM), and MSC-derived extracellular vesicles (EVs). LPS-induced rat primary alveolar macrophage and RAW 264.7 cells were treated with naïve, TLR3-, and TLR4-primed MSCs and their derived CM and EVs. Flow cytometry and ELISA were used to evaluate M1-M2 polarization of macrophages and pro-inflammatory cytokine levels, respectively. LPS-stimulated macrophages showed significantly increased pro-inflammatory cytokines compared to those of the normal control, and the percentage of M2 macrophage phenotype was predominantly low. In reducing the inflammatory cytokines and enhancing M2 polarization, TLR3- and TLR4-primed MSCs were significantly more effective than the naïve MSCs, and this finding was also observed with the treatment of MSC-derived CMs and EVs. No significant difference between the efficacy of TLR3- and TLR-primed MSCs was observed. Strong stimulation of TLR3- and TLR4-stimulated hUCB-MSCs significantly reduced pro-inflammatory cytokine secretion from LPS-induced macrophages and significantly enhanced the M2 polarization of macrophages. We further confirmed that TLR-primed MSC-derived EVs can exert anti-inflammatory and immunosuppressive effects alone comparable to MSC treatment. We hereby suggest that in the LPS-induced macrophage in vitro model, EVs derived from both TLR3 and TLR4-primed MSCs can be a therapeutic candidate by promoting the M2 phenotype.
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Lesión Pulmonar Aguda , Vesículas Extracelulares , Células Madre Mesenquimatosas , Ratones , Ratas , Animales , Receptor Toll-Like 3 , Lipopolisacáridos/toxicidad , Receptor Toll-Like 4 , Escherichia coli , Macrófagos , Citocinas , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/terapia , Antiinflamatorios/farmacología , Vesículas Extracelulares/fisiologíaRESUMEN
BACKGROUND: Though antenatal magnesium sulfate (MgSO4) is widely used for fetal neuroprotection, suspicions about the long-term neuroprotection of antenatal MgSO4 have been raised. METHODS: We investigated short- and long-term outcomes of antenatal MgSO4 use for 468 infants weighing < 1,500 g with a gestational age of 24-31 weeks. RESULTS: Short-term morbidities and the risk of developmental delay, hearing loss, and cerebral palsy at a corrected age of 18-24 months and 3 years of age did not decrease in the MgSO4 group (infants who were exposed to MgSO4 for any purpose) or neuroprotection group (infants who were exposed to MgSO4 for fetal neuroprotection) compared with the control group (infants who were not exposed to MgSO4). The z-scores of weight, height, and head circumference did not increase in the MgSO4 group or neuroprotection group compared with the control group. CONCLUSION: Antenatal MgSO4 including MgSO4 for neuroprotection did not have beneficial effects on long-term neurodevelopmental and growth outcomes.
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Fármacos Neuroprotectores , Nacimiento Prematuro , Lactante , Humanos , Embarazo , Femenino , Recién Nacido , Sulfato de Magnesio/uso terapéutico , Nacimiento Prematuro/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Atención Prenatal , Recién Nacido de muy Bajo PesoRESUMEN
BACKGROUND: In Korea, there have been no reports comparing the prevalence of major congenital anomalies with other countries and no reports on surgical treatment and long-term mortality. We investigated the prevalence of 67 major congenital anomalies in Korea and compared the prevalence with that of the European network of population-based registries for the epidemiological surveillance of congenital anomalies (EUROCAT). We also investigated the mortality and age at death, the proportion of preterm births, and the surgical rate for the 67 major congenital anomalies. METHODS: Korean National Health Insurance claim data were obtained for neonates born in 2013-2014 and admitted within one-year-old. Sixty-seven major congenital anomalies were defined by medical diagnoses classified by International Classification of Diseases-10 codes according to the EUROCAT definition version 2014. Mortality and surgery were defined if any death or surgery claim code was confirmed until 2020. Poisson distribution was used to calculate the 95% confidence interval of the congenital anomaly prevalence. RESULTS: The total prevalence of the 67 major anomalies was 433.5/10,000 livebirths. When compared with the prevalence of each major anomaly in EUROCAT, the prevalence of spina bifida, atrial septal defect (ASD), congenital megacolon, hip dislocation and/or dysplasia and skeletal dysplasia were more than five times higher in Korea. In contrast, the prevalence of aortic atresia/interrupted aortic arch and gastroschisis was less than one-fifth in Korea. The proportion of preterm births was 15.7%; however, more than 40% of infants with anencephaly, annular pancreas and gastroschisis were preterm infants. Additionally, 29.2% of the major anomalies were admitted to the neonatal intensive care units at birth, and 25.6% received surgical operation. The mortality rate was 1.7%, and 78.2% of the deaths occurred within the first year of life. However, in neonates with tricuspid valve atresia and stenosis, duodenal atresia or stenosis, and diaphragmatic hernia, more than half died within their first month of life. ASD and ventricular septal defect were the most common anomalies, and trisomy 18 and hypoplastic left heart syndrome were the most fatal anomalies. All infants with aortic atresia/interrupted aortic arch and conjoined twins received surgery. CONCLUSION: The proportion of surgeries, preterm births and mortality was high in infants with major congenital anomalies. The establishment of a national registry of congenital anomalies and systematic support by national medical policies are needed for infants with major congenital anomalies in Korea.
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Enfermedades de la Aorta , Anomalías Congénitas , Gastrosquisis , Nacimiento Prematuro , Lactante , Femenino , Recién Nacido , Humanos , Niño , Nacimiento Prematuro/epidemiología , Constricción Patológica , Recien Nacido Prematuro , República de Corea/epidemiología , Anomalías Congénitas/epidemiología , Sistema de Registros , PrevalenciaRESUMEN
Standardized protocols have been designed and developed specifically for clinical information collection and obtaining trio genomic information from infants affected with congenital anomalies (CA) and their parents, as well as securing human biological resources. The protocols include clinical and genomic information collection on multiple CA that were difficult to diagnose using pre-existing screening methods. We obtained human-derived resources and genomic information from 138 cases, including 45 families of infants with CA and their parent trios. For the clinical information collection protocol, criteria for target patient selection and a consent system for collecting and utilizing research resources are crucial. Whole genome sequencing data were generated for all participants, and standardized protocols were developed for resource collection and manufacturing. We recorded the phenotype information according to the Human Phenotype Ontology term, and epidemiological information was collected through an environmental factor questionnaire. Updating and recording of clinical symptoms and genetic information that have been newly added or changed over time are significant. The protocols enabled long-term tracking by including the growth and development status that reflect the important characteristics of newborns. Using these clinical and genetic information collection protocols for CA, an essential platform for early genetic diagnosis and diagnostic research can be established, and new genetic diagnostic guidelines can be presented in the near future.
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Advances in perinatal care have led to the increased survival of preterm infants with subsequent neonatal morbidities, such as retinopathy of prematurity (ROP). This study aims to compare the differences of neonatal healthcare systems, resources, and clinical practice concerning ROP in Asia with review of current literature. An on-line survey at the institutional level was sent to the directors of 336 neonatal intensive care units (NICU) in 8 collaborating national neonatal networks through the Asian Neonatal Network Collaboration (AsianNeo). ROP screening was performed in infants born at < 34 weeks in Indonesia and Japan. In South Korea, Malaysia, and Taiwan, most screened for ROP in infants born at < 32 weeks. In all networks, majority of NICUs conducted ROP screening to infants with birth weight < 1500 g. In most NICU's in-hospital ophthalmologists performed indirect ophthalmoscopy and some were supplemented with digital imaging. Both laser photocoagulation and anti-vascular endothelial growth factor injection are performed for treatment and, vitreous surgeries are conducted less frequently in all countries. Despite limited information collected by the survey, this first study to compare ROP practices implemented in eight Asian countries through AsianNeo will enable an understanding of the differences and facilitate quality improvement by sharing better practices.
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Retinopatía de la Prematuridad , Recién Nacido , Lactante , Femenino , Embarazo , Humanos , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/epidemiología , Recien Nacido Prematuro , Asia/epidemiología , Japón , Taiwán , Recién Nacido de muy Bajo PesoRESUMEN
Congenital cytomegalovirus (CMV) infection is a common cause of sensorineural hearing loss and neurodevelopmental impairment in newborns. However, congenital CMV infection cannot be diagnosed using samples collected more than 3 weeks after birth because testing after this time cannot distinguish between congenital infection and postnatal infection. Herein, we developed a robust loop-mediated isothermal amplification (LAMP) assay for the large-scale screening of newborns for congenital CMV infection. In contrast to conventional quantitative polymerase chain reaction (qPCR), which detects CMV within a dynamic range of 1.0 × 106 to 1.0 × 102 copies/µL, our quantitative LAMP assay (qLAMP) detects CMV within a dynamic range of 1.1 × 108 to 1.1 × 103 copies/µL. Moreover, the turnaround time for obtaining results following DNA extraction is 90 min in qPCR but only 15 min in qLamp. The colorimetric LAMP assay can also detect CMV down to 1.1 × 103 copies/µL within 30 min, irrespective of the type of heat source. Our LAMP assay can be utilized in central laboratories as an alternative to conventional qPCR for quantitative CMV detection, or for point-of-care testing in low-resource environments, such as developing countries, via colorimetric naked-eye detection. KEY POINTS: ⢠LAMP assay enables large-scale screening of newborns for congenital CMV infection. ⢠LAMP allows colorimetric or quantitative detection of congenital CMV infection. ⢠LAMP assay can be used as a point-of-care testing tool in low-resource environments.
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(1) Background: This study aimed to evaluate whether the implementation of a modified blood-sampling protocol, which focused on need-based laboratory testing and minimized venous sampling by replacing it with point-of-care testing (POCT) via capillary puncture, successfully reduced iatrogenic blood loss, incidence of anemia, and the frequency of blood transfusion among extremely low-birth-weight infants (ELBWIs) without negatively affecting neonatal outcomes. (2) Methods: A retrospective analysis was conducted on 313 ELBWIs with a gestational age (GA) of between 23 and 28 weeks and born between 2013 and 2019. The infants were divided into two groups corresponding to the periods before (period I) and after (period II) the implementation of the modified blood-sampling protocol in January 2016. Propensity score matching was conducted to minimize selection bias. Clinical data, including the frequency and amount of blood sampling, the frequency and volume of blood transfusion, and clinical characteristics, such as gestational age, birth weight, and neonatal outcome data, were collected and compared between the two groups. (3) Results: No significant differences in GA or birth weight between the two periods were observed. The total sampling volume a month after birth (16.7 ± 4.1 mL vs. 15.6 ± 4.4 mL, p = 0.03) and the total sampling volume during hospitalization days (51.4 ± 29.7 mL vs. 44.3 ± 27.5 mL, p = 0.04) in period II were significantly lower than those in period I. There were no differences in terms of anemia (hemoglobin 10.8 ± 2.2 vs. 11.0 ± 1.9, p = 0.43) and mortality or morbidity, such as intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, and sepsis, between the two periods. Although the transfusion frequency and amount did not present significant differences between the periods, we observed a positive correlation between the transfusion frequency and sampling volume (coefficient: 0.09, 95% CI: 0.08-0.11). (4) Conclusions: The modified blood-sampling protocol effectively reduced the level of iatrogenic blood loss without negatively affecting the neonatal outcomes.
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BACKGROUND: We previously performed a phase II randomised double-blind clinical trial of mesenchymal stromal cell (MSCs) transplantation to prevent bronchopulmonary dysplasia in extremely premature infants. Subsequently, we followed the infants enrolled in this clinical trial to determine the safety and effectiveness of MSCs against bronchopulmonary dysplasia at 5-year follow-up. METHODS: We evaluated infants at 5 years of age receiving placebo or MSCs in a prospective follow-up study. RESULTS: In terms of the primary end point of composite respiratory morbidities, including respiratory problem-related readmission, emergency department visits or oxygen therapy, the MSC group had a rate of 60.7% for composite morbidities, while the control group showed a tendency of higher rate of 83.9% for the same outcomes without statistical significance. In terms of the secondary outcomes, the MSC group infants showed a tendency of being less likely to visit emergency department (control 67.7% vs MSC 35.7%) and to receive oxygen therapy (control 29.0% vs MSC 3.6%). No difference was observed in the incidence of respiratory problem-related hospital readmission or wheezing episodes between the groups. CONCLUSION: Intratracheally instilled MSCs showed the possibility of potential to decrease respiratory symptom-related emergency department visits and oxygen therapy episodes in infants born extremely preterm during the 5 years after a phase II randomised controlled, double-blind trial of MSCs transplantation for bronchopulmonary dysplasia. This small size study suggests preliminary insights that can be further tested using larger sample sizes. TRIAL REGISTRATION NUMBER: NCT01897987.
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Displasia Broncopulmonar , Recién Nacido , Lactante , Humanos , Displasia Broncopulmonar/terapia , Estudios de Seguimiento , Estudios Prospectivos , Células del Estroma , Oxígeno/uso terapéuticoRESUMEN
BACKGROUND: The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a multidisciplinary approach including obstetrics, pediatrics, pathology, and otorhinolaryngology-head and neck surgery. METHODS: This is a retrospective study including 30 consecutive cases of congenital CMV infection that were diagnosed at a single tertiary hospital located in Seoul, Korea from January 2009 to December 2020. Congenital CMV infection was defined as a positive result by polymerase chain reaction from urine, saliva or cerebrospinal fluid or positive CMV IgM from neonatal blood sampled within 3 weeks after birth. All cases were analyzed with respect to whole clinical characteristics from diagnosis to treatment of congenital CMV by a multidisciplinary approach including prenatal sonographic findings, maternal immune status regarding CMV infection, detailed placental pathology, neonatal clinical manifestation, auditory brainstem response test, and antiviral treatment (ganciclovir or valganciclovir). Long-term outcomes including developmental delay and hearing loss were also investigated. RESULTS: The total number of births during the study period in our institution was 19,385, with the prevalence of congenital infection estimated to be 0.15%. Among 30 cases of congenital CMV, the median gestational age at delivery was 32.2 weeks [range, 22.6-40.0] and 66.7% of these infants were delivered preterm at less than 37 weeks. Suspected fetal growth restriction was the most common prenatal ultrasound finding (50%) followed by ventriculomegaly (17.9%) and abnormal placenta (17.9%), defined as thick placenta with calcification. No abnormal findings on ultrasound examination were observed in one-third of births. Maternal CMV serology tests were conducted in only 8 cases, and one case each of positive and equivocal IgM were found. The most common placental pathologic findings were chronic villitis (66.7%) and calcification (63.0%), whereas viral inclusions were identified in only 22.2%. The most common neonatal manifestations were jaundice (58.6%) followed by elevation of aspartate aminotransferase (55.2%) and thrombocytopenia (51.7%). After excluding cases for which long-term outcomes were unavailable due to death (n = 4) or subsequent follow up loss (n = 3), developmental delay was confirmed in 43.5% of infants (10/23), and hearing loss was confirmed in 42.9% (9/21) during the follow-up period. In our cohort, 56.7% (17/30) of neonates were treated for congenital CMV with ganciclovir or valganciclovir. CONCLUSION: Our data show that prenatal findings including maternal serologic tests and ultrasound have limited ability to detect congenital CMV in Korea. Given that CMV is associated with high rates of developmental delay and hearing loss in infants, there is an urgent need to develop specific strategies for the definite diagnosis of congenital CMV infection during the perinatal period by a multidisciplinary approach to decrease the risks of neurologic impairment and hearing loss through early antiviral treatment.
Asunto(s)
Infecciones por Citomegalovirus , Pérdida Auditiva , Lactante , Recién Nacido , Embarazo , Femenino , Humanos , Niño , Valganciclovir/uso terapéutico , Estudios Retrospectivos , Placenta , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/complicaciones , Ganciclovir/uso terapéutico , Antivirales/uso terapéutico , Retardo del Crecimiento Fetal , Parto , Inmunoglobulina MRESUMEN
Mesenchymal stem cells (MSCs) have been studied as novel therapeutic agents because of their immunomodulatory properties in inflammatory diseases. The suppressor of cytokine signaling (SOCS) proteins are key regulators of the immune response and macrophage modulation. In the present study, we hypothesized that SOCS in MCSs might mediate macrophage modulation and tested this in a bacteria-induced acute lung injury (ALI) mouse model. The macrophage phenotype was observed in RAW264.7 alveolar macrophages exposed to lipopolysaccharide (LPS) in an in vitro model, and in the ALI mouse model induced by tracheal administration of Escherichia coli (1 × 107 CFU in 0.05mL PBS). In LPS-exposed RAW264.7 cells, the levels of markers of M1 macrophages, such as CD86 and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6 and TNF-α), significantly increased, but they significantly reduced after MSC treatment. Meanwhile, the levels of markers of M2 macrophages, such as CD204 and anti-inflammatory cytokines (IL-4 and IL-10), increased after LPS exposure, and further significantly increased after MSC treatment. This regulatory effect of MSCs on M1/M2 macrophage polarization was significantly abolished by SOCS3 inhibition. In the E. coli-induced ALI model, tissue injury and inflammation in the mouse lung were significantly attenuated by the transplantation of MSCs, but not by SOCS3-inhibited MSCs. The regulatory effect of MSCs on M1/M2 macrophage polarization was observed in the lung injury model but was significantly abolished by SOCS3 inhibition. Taken together, our findings suggest that SOCS3 is an important mediator for macrophage modulation in anti-inflammatory properties of MSCs.
Asunto(s)
Lesión Pulmonar Aguda , Células Madre Mesenquimatosas , Ratones , Animales , Proteína 3 Supresora de la Señalización de Citocinas/genética , Lipopolisacáridos/toxicidad , Escherichia coli , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/terapia , Proteínas Supresoras de la Señalización de Citocinas/genética , Antiinflamatorios , Interleucina-1alfa , PulmónRESUMEN
Neonatal brain injury resulting from various intractable disorders including intraventricular hemorrhage and hypoxic ischemic encephalopathy still remains a major cause of mortality and morbidities with few effective treatments. Recent preclinical research results showing the pleiotropic neuroprotective effects of stem cell therapy, specifically mesenchymal stem cells (MSCs), suggest that MSCs transplantation might be a promising new therapeutic modality for neuroprotection against the currently intractable and devastating neonatal brain injury with complex multifactorial etiology. This review summarizes recent advances in preclinical stem cell research for treating neonatal brain injury with a focus on the important issues including the mechanism of neuroprotection, and determining the ideal cell source, route, timing and dose of MSCs transplantation.