Scanning transmission X-ray microscopy study of subcellular granules in human platelets at the carbon K- and calcium L2,3-edges.

Platelets and their subcellular components (e.g., dense granules) are essential components in hemostasis. Understanding their chemical heterogeneities at the sub-micrometer scale, particularly their activation during hemostasis and production of platelet-derived extracellular vesicles, may provide important insights into their mechanisms; however, this has rarely been investigated, mainly owing to the lack of appropriate chemical characterization tools at nanometer scale. Here, the use of scanning transmission X-ray microscopy (STXM) combined with X-ray absorption near edge structure (XANES) to characterize human platelets and their subcellular components at the carbon K-edge and calcium L2,3-edge, is reported. STXM images can identify not only the spatial distribution of subcellular components in human platelets, such as dense granules (DGs) with sizes of ~200 nm, but also their granule-to-granule chemical heterogeneities on the sub-micrometer scale, based on their XANES spectra. The calcium distribution map as well as the principal component analysis of the STXM image stacks clearly identified the numbers and locations of the calcium-rich DGs within human platelets. Deconvolution of the carbon K-edge XANES spectra, extracted from various locations in the platelets, showed that amide carbonyl and carboxylic acid functional groups were mainly found in the cytoplasm, while ketone-phenol-nitrile-imine, aliphatic, and carbonate functional groups were dominant in the platelet DGs. These observations suggest that platelet DGs are most likely composed of calcium polyphosphate associated with adenosine triphosphate (ATP) and adenosine diphosphate (ADP), with significant granule-to-granule variations in their compositions, while the cytoplasm regions of platelets contain significant amounts of proteins.

Conservative Treatment Without Any Intervention Compared With Other Therapeutic Strategies for Symptomatic Patent Ductus Arteriosus in Extremely Preterm Infants: A Nationwide Cohort Study in Korea.

Objective: Although symptomatic treatment is the most preferred treatment strategy for proven symptomatic patent ductus arteriosus (PDA), a considerable number of infants only received conservative treatment without any pharmacological or surgical interventions in the lower gestational age and lower birth weight group in Korea. We compared in-hospital outcomes of infants treated conservatively without any intervention and those of infants managed by other therapeutic strategies in extremely preterm infants with symptomatic PDA. Methods: A prospectively collected cohort study for 2,303 infants with gestational ages <28 weeks from the Korean Neonatal Network database. These infants were classified into four groups according to the presence of PDA-related symptoms and therapeutic treatment strategy: prophylactic treatment group, pre-symptomatic treatment (PST) group, symptomatic treatment (ST) group, and conservative treatment (CT) without any intervention group. Results: In multivariable logistic regression analysis, the risk of death was significantly decreased in the PST group (adjusted odds ratio [aOR] = 0.507; 95% confidence interval [CI] 0.311-0.826) and ST group (aOR = 0.349; 95% CI: 0.230-0.529) compared with the CT group. However, the risk of composite outcome of severe bronchopulmonary dysplasia or death had not increased in the PST group and ST group. Neonatal death due to pulmonary hemorrhage or neurological disease was significantly higher in the CT group than in the PST group or ST group. Conclusion: In extremely preterm infants, who are at highest risk of PDA-related morbidities and mortality, even less interventional approach for PDA can be allowed; the rescued pharmacological or surgical interventions are necessary if they met the criteria for hemodynamically significant PDA.

Hemodynamics of different volumes of red blood cell transfusion in preterm infants.

BACKGROUND: Although many controversies exist regarding the risk of red blood cell (RBC) transfusions, half of preterm infants born at <32 weeks of gestational age receive such transfusions because of anemia of prematurity. Because of the costs and risks associated with multiple transfusions, it has been suggested that a large transfusion volume reduces the number of transfusions. However, there have been persistent concerns that RBC transfusion might lead to volume overload. METHODS: We examined the impacts of large (20 mL/kg) compared to standard volume (15 mL/kg) transfusions on the hemodynamic variables of stable, electively transfused, preterm infants, by serially measuring echocardiographic parameters and plasma B-type natriuretic peptide levels. RESULTS: A total of 39 infants born at <34 weeks of gestation and aged >2 weeks at the time of enrollment were randomly allocated to either a standard volume (15 mL/kg) or a large volume (20 mL/kg) group. Significant reductions in cardiac output and transient increases in plasma B-type natriuretic peptide levels were found after RBC transfusion in both the standard and large volume (20 mL/kg) groups. However, these changes were not significantly different between the two groups. CONCLUSIONS: Large-volume transfusions could be tolerable in stable preterm infants with anemia.

Illnesses Encountered During Medical Volunteering in Takeo Province, Cambodia.

Background and Objectives: Medical volunteering seeks to meet the clinical needs of underserved areas, but has been criticized for difficulties in addressing local health issues and resultant lack of sustainability. Our team has visited rural Cambodia annually since 2012. This study reports the illnesses encountered during the recent mission and share our experiences to improve the efficiency of medical volunteering. Materials and Methods: Infrastructure, such as public electricity or water, was unavailable, hence most medical care and records were hand-performed. We categorized (1) primary diagnoses (chief complaints) by duration of symptoms, and (2) primary and secondary diagnoses (illnesses that were not related to the chief complaint) by severity of illness since patients commonly reported multiple symptoms. Blood pressure and anthropometric values were also checked and analyzed. Results: We encountered 317 adult and 141 pediatric patients. Among adults, 61.3% had persistent chronic (>6 month) symptoms of their chief complaints. The commonest diagnoses of chronic symptoms were musculoarthritis (31.5%) and gastroesophageal reflux disease and/or gastritis (21.7%). Hypertension and/or cardiac problems were relatively common among males (13.6%). The most common diagnosis among the severest cases (specialized or intensive care recommended) was cardiac problems (14.8%), often with abnormalities in sonography or electrocardiogram. For children, the overwhelming majority of diagnoses were related to acute symptoms and low severity, and approximately half were cases of the common cold. Commonly prescribed drugs were antacids or mucosal protectors (31.3%), Non-steroidal anti-inflammatory drugs (NSAIDs) or other painkillers (27.6%), and antiparasites (17.7%) in adults, and NSAIDs (44.7%) and antiparasites (23.2%) in children. Among adults, 32.7% were diagnosed with hypertension, and body mass index (p = 0.003) and age (p < 0.001) were both correlated with hypertension and its grade. Conclusion: Our study offers practical help to volunteer health workers planning to visit Southeast Asia.

Risk factors for treatment failure of heated humidified high-flow nasal cannula as an initial respiratory support in newborn infants with respiratory distress.

BACKGROUND: Humidified high-flow nasal cannula (HHFNC) has gained popularity because it is easier to use, more comfortable for babies, and advantageous for mother-infant bonding. HHFNC is not inferior to other non-invasive ventilators for preventing adverse outcomes, but more studies are needed to ensure the safe use of HHFNC as an initial respiratory support for newborns. The aim of this study was to investigate risk factors for treatment failure of HHFNC as an initial respiratory support in newborns with respiratory distress after birth. METHODS: We included 97 newborns who required non-invasive respiratory support within 24 h after birth. The success group included 68 infants who were successfully managed only on HHFNC, and 29 infants were the failure group who required other respiratory support because of respiratory acidosis, hypoxia, or apnea. RESULTS: Compared with the success group, the failure group had lower GA, a higher rate of antenatal steroid use, prolonged rupture of membrane, lower pH, higher pCO2 on blood-gas analysis after HHFNC application and higher incidence of respiratory distress syndrome of newborn (RDS). After adjusting for GA, higher FiO2 settings during acidosis, hypercarbia after the application of HHFNC shown on blood-gas analysis and the presence of RDS remained significant. The rate of treatment failure was 16.2% for ≥36 weeks, 19.3% for ≥34 weeks, and 22.1% for ≥33 weeks. CONCLUSION: Treatment failure of HHFNC should be considered a risk for newborns of less than 34 weeks and infants with respiratory distress from RDS. Higher FiO2 settings during HHFNC, and acidosis and hypercarbia after the application of HHFNC shown on blood-gas analysis may help identify high-risk newborns for other non-invasive ventilators or intubation.

Effectiveness of nCPAP for moderate preterm infants compared to BiPAP: A Randomized, Controlled Non-Inferiority Trial.

BACKGROUND: Bilevel positive airway pressure (BiPAP) has recently been used in preterm infants with respiratory distress as an alternative to nasal continuous positive airway pressure (nCPAP) because, theoretically, BiPAP is thought to be more effective than nCPAP. However, the results of some studies comparing nCPAP with BiPAP as the initial respiratory support were controversial. The aim of this study is to compare the clinical effectiveness and safety of nCPAP with BiPAP at gestational ages of 30+0 to 34+6  weeks. METHODS: A total of 93 infants with gestational ages of 30+0 to 34+6  weeks, who presented with respiratory distress within 24 h after birth, were randomized to the nCPAP group or the BiPAP group. The primary outcome was the incidence of treatment failure with these two non-invasive respiratory support devices. Criteria for treatment failure included any of the following: respiratory acidosis (PaCO2 >65 mmHg with pH <7.2), hypoxia (FiO2 >0.4), or apnea (>2-3 episodes of apnea/h). RESULTS: There was no statistically significant difference in treatment failure between the two groups (P = 0.576). The risk difference comparing treatment failure rate between nCPAP and BiPAP groups was -4.7% (95% CI: -21.5-11.9). CONCLUSIONS: Nasal continuous positive airway pressure is not inferior to BiPAP as an initial management of respiratory distress in these premature infants. We therefore conclude that nCPAP can be used as an initial management for preterm infants at gestational age of between 30 and 35 weeks as a substitute for BiPAP.

Chronological Echocardiographic Changes in Healthy Term Neonates within Postnatal 72 Hours Using Doppler Studies.

BACKGROUND: This study evaluated echocardiographic changes in full-term healthy neonates during early transitional period from postnatal 0-72 hours at 12-hour intervals by echocardiography. METHODS: This was a prospective, observational, and longitudinal single-center cohort study. Morphometric, functional, systolic, diastolic, and tissue Doppler imaging (TDI) parameters (patent ductus arteriosus [PDA], aorta, superior vena cava [SVC], stroke volume [SV], cardiac output [CO], cardiac index [CI], early diastolic flow velocity [E], late diastolic flow velocity [A], early filling in TDI [E'], peak systolic annular velocity in TDI [S'], late velocity peak in TDI [A'], and myocardial performance index [MPI]) were evaluated in left ventricle (LV) and right ventricle (RV) with 56 newborns. RESULTS: Sizes and peak velocities of PDA before postnatal 24 hours were significantly changed than those after postnatal 24 hours. Aortic velocity time integral (VTI), systolic blood pressure (BP), LV SV/kg, LV CO/kg, LV CI, and SVC flow/LV CO before 24 hours showed significantly changes than those after 24 hours. Also, LV and RV MPI before 24 hours were significantly higher than those after 24 hours. LV E/E' was significantly higher than RV E/E'. CONCLUSION: Postnatal 24 hours is critical time for hemodynamic closure of PDA because aortic VTI, systolic BP, LV SV, LV CO, LV CI, and SVC flow/LV CO showed simultaneously significant changes after 24 hours at the same time as 24 hours of physiological closure of PDA. Chronological and dramatic changes of systolic, diastolic, and TDI parameters during early postnatal period can be used to compile normal baseline data of healthy full-term neonates.

Individualized ibuprofen treatment using serial B-type natriuretic peptide measurement for symptomatic patent ductus arteriosus in very preterm infants.

PURPOSE: Plasma level of B-type natriuretic peptide (BNP), an emerging, sensitive, and specific biomarker of hemodynamically significant patent ductus arteriosus (PDA), rapidly decreases in infants receiving cyclooxygenase inhibitors for ductal closure. We investigated the usefulness of serial BNP measurement as a guide for individual identification of early constrictive responses to ibuprofen in preterm infants with symptomatic PDA (sPDA). METHODS: Before March 2010, the standard course of pharmacological treatment was initiated with indomethacin (or ibuprofen) and routinely followed by 2 additional doses at intervals of 24 hours. After April 2010, individualized pharmacological treatment was used, starting with the first dose of ibuprofen and withholding additional ibuprofen doses if the BNP concentration was <600 pg/mL and clinical symptoms of PDA improved. RESULTS: The BNP-guided group received significantly fewer doses of ibuprofen than the standard group did during the first course of treatment and the entire study period. The need for further doses of cyclooxygenase inhibitors and for surgical ligation was not significantly different between the 2 groups. No significant differences were seen in clinical outcomes and/or complications related to sPDA and/or pharmacological treatment. CONCLUSION: Individualized BNP-guided pharmacological treatment may be used clinically to avoid unnecessary doses of cyclooxygenase inhibitors without increasing the ductal closure failure and the short-term morbidity related to sPDA.

Humidified High Flow Nasal Cannula versus Nasal Continuous Positive Airway Pressure as an Initial Respiratory Support in Preterm Infants with Respiratory Distress: a Randomized, Controlled Non-Inferiority Trial.

Heated, humidified, high-flow nasal cannula (HHFNC) is frequently used as a noninvasive respiratory support for preterm infants with respiratory distress. But there are limited studies that compares HHFNC with nasal continuous positive airway pressure (nCPAP) only as the initial treatment of respiratory distress in preterm infants immediately after birth. The aim of this study is to assess the effectiveness and safety of HHFNC compared to nCPAP for the initial treatment of preterm infants with respiratory distress. Preterm infants at between 30 and 35 weeks of gestational age were randomized to HHFNC or nCPAP when they showed respiratory distress in less than 24 hours of age postnatally. Preterm infants who needed invasive respiratory supports were excluded. Primary outcome was the incidence of treatment failure (defined as need for the intubation or mechanical ventilation). Eighty-five infants were analyzed. Sixteen of 42 infants randomized to HHFNC showed treatment failure compared to 9 of 43 infants using nCPAP (Risk difference 17.17 [-1.90-36.23]; P = 0.099). In terms of the reason for treatment failure, the frequency of hypoxia was significantly higher in the HHFNC group than in the nCPAP group (P = 0.020). There was no difference between the 2 groups in terms of respiratory and clinical outcomes and complications. Although HHFNC is safe compared to nCPAP, it is not certain that HHFNC is effective compared to nCPAP non-inferiorly as an initial respiratory support in preterm infants with respiratory distress.

Correlation of B-type natriuretic peptide levels and echocardiographic parameters in preterm infants with patent ductus arteriosus.

PURPOSE: This study aimed to evaluate the correlation, according to postnatal age, between plasma B-type natriuretic peptide (BNP) levels and echocardiographic parameters for the assessment of patent ductus arteriosus (PDA) in preterm infants with respiratory distress. METHODS: We enrolled 42 preterm infants with respiratory distress who underwent serial echocardiographic evaluation with simultaneous plasma BNP measurements until ductal closure. The correlations between BNP levels and the following 4 representative echocardiographic parameters were studied: diameter of the ductus arteriosus (DA), ratio of the left atrial diameter to the aortic diameter (LA/Ao), ratio of the PDA diameter to the infant's left pulmonary artery diameter (PDA/LPA), and the antegrade diastolic flow of LPA (DFLPA). RESULTS: BNP levels were significantly correlated to the magnitude of the ductal shunt, comprising the DA diameter, PDA/LPA ratio, LA/Ao ratio, and antegrade DFLPA for the overall study period. The earliest significant correlation, starting from postnatal day 2, was observed between the LA/Ao ratio and BNP levels. The PDA/LPA ratio and the antegrade DFLPA showed significant correlations with BNP levels postnatal day 3 onward, and with the DA diameter, postnatal day 5 onward. CONCLUSION: BNP levels and echocardiographic parameters showed a positive correlation, but the significance of the correlations differed according to the postnatal age, especially during the first few days of life.

Initial Resuscitation at Delivery and Short Term Neonatal Outcomes in Very-Low-Birth-Weight Infants.

Survival of very-low-birth-weight infants (VLBWI) depends on professional perinatal management that begins at delivery. Korean Neonatal Network data on neonatal resuscitation management and initial care of VLBWI of less than 33 weeks gestation born from January 2013 to June 2014 were reviewed to investigate the current practice of neonatal resuscitation in Korea. Antenatal data, perinatal data, and short-term morbidities were analyzed. Out of 2,132 neonates, 91.7% needed resuscitation at birth, chest compression was performed on only 104 infants (5.4%) and epinephrine was administered to 80 infants (4.1%). Infants who received cardiac compression and/or epinephrine administration at birth (DR-CPR) were significantly more acidotic (P < 0.001) and hypothermic (P < 0.001) than those who only needed positive pressure ventilation (PPV). On logistic regression, DR-CPR resulted in greater early mortality of less than 7 days (OR, 5.64; 95% CI 3.25-9.77) increased intraventricular hemorrhage ≥ grade 3 (OR, 2.71; 95% CI 1.57-4.68), periventricular leukomalacia (OR, 2.94; 95% CI 1.72-5.01), and necrotizing enterocolitis (OR, 2.12; 95% CI 1.15-3.91) compared with those infants who needed only PPV. Meticulous and aggressive management of infants who needed DR-CPR at birth and quality improvement of the delivery room management will result in reduced morbidities and early death for the vulnerable VLBWI.