Mechanosensing by ß1 integrin induces angiocrine signals for liver growth and survival.

Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1-4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1-4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates ß1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both ß1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.

Early changes in hepatic energy metabolism and lipid content in recent-onset type 1 and 2 diabetes mellitus.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with abnormal mitochondrial capacity. While oxidative capacity can be increased in steatosis, hepatic ATP decreases in long-standing diabetes. However, longitudinal studies on diabetes-related NAFLD and its relationship to hepatic energy metabolism are lacking. METHODS: This prospective study comprised volunteers with type 1 (T1DM, n = 30) and type 2 (T2DM, n = 37) diabetes. At diagnosis and 5 years later, we used 1H/31P magnetic resonance spectroscopy to measure hepatocellular lipid (HCL), γATP and inorganic phosphate (Pi) concentrations, and to assess adipose tissue volumes. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps. RESULTS: At diagnosis, individuals with T2DM had higher HCL and adipose tissue volumes, but lower whole-body insulin sensitivity than those with T1DM, despite comparable glycemic control. NAFLD was present in 38% of individuals with T2DM and 7% with T1DM. After 5 years, visceral adipose tissue only increased in individuals with T2DM, while HCL almost doubled in this group (p <0.001), resulting in a 70% prevalence of NAFLD (independent of diabetes treatment). Changes in HCL correlated with adipose tissue volume and insulin resistance (r = 0.50 and r = 0.44, both p <0.05). Pi decreased by 17% and 10% in individuals with T2DM and T1DM (p <0.05), respectively. In T1DM, HCL did not change, whereas γATP decreased by 10% and correlated negatively with glycated hemoglobin (r = -0.56, p <0.05). CONCLUSIONS: The rapid increase in HCL during the early course of T2DM likely results from enlarging adipose tissue volume and insulin resistance in response to impaired hepatic mitochondrial adaptation. The decrease of phosphorus metabolites in T1DM may be due to pharmacological insulin supply. LAY SUMMARY: Previous studies suggested that the impaired function of mitochondria, the power plants of cells, can promote fatty liver and type 2 diabetes mellitus. This study now shows that during the first 5 years of type 2 diabetes the increase in body fat content rapidly leads to a doubling of liver fat content, whereas the energy metabolism of the patients' livers progressively declines. These data suggest that fat tissue mass and liver mitochondria have an important role in the development of fatty liver disease in humans with diabetes. CLINICAL TRIAL NUMBER: NCT01055093.

In vivo absolute quantification of hepatic γ-ATP concentration in mice using 31 P MRS at 11.7 T.

Measurement of ATP concentrations and synthesis in humans indicated abnormal hepatic energy metabolism in obesity, non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes. Further mechanistic studies on energy metabolism require the detailed phenotyping of specific mouse models. Thus, this study aimed to establish and evaluate a robust and fast single voxel 31 P MRS method to quantify hepatic γ-ATP concentrations at 11.7 T in three mouse models with different insulin sensitivities and liver fat contents (72-week-old C57BL/6 control mice, 72-week-old insulin resistant sterol regulatory-element binding protein-1c overexpressing (SREBP-1c+ ) mice and 10-12-week-old prediabetic non-obese diabetic (NOD) mice). Absolute quantification was performed by employing an external reference and a matching replacement ATP phantom with 3D image selected in vivo spectroscopy 31 P MRS. This single voxel 31 P MRS method non-invasively quantified hepatic γ-ATP within 17 min and the repeatability tests provided a coefficient of variation of 7.8 ± 1.1%. The mean hepatic γ-ATP concentrations were markedly lower in SREBP-1c+ mice (1.14 ± 0.10 mM) than in C57BL/6 mice (2.15 ± 0.13 mM; p < 0.0002) and NOD mice (1.78 ± 0.13 mM; p < 0.006, one-way ANOVA test). In conclusion, this method allows us to rapidly and precisely measure hepatic γ-ATP concentrations, and thereby to non-invasively detect abnormal hepatic energy metabolism in mice with different degrees of insulin resistance and NAFLD. Thus, this 31 P MRS will also be useful for future mechanistic as well as therapeutic translational studies in other murine models.

Improving insulin sensitivity, liver steatosis and fibrosis in type 2 diabetes by a food-based digital education-assisted lifestyle intervention program: a feasibility study.

PURPOSE: Recent trials demonstrated remission of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) following formula diet-induced weight loss. To improve the outreach for populations in need, many mobile health apps targeting weight loss have been developed with limited scientific evaluation of these apps. The present feasibility study investigated the effects of a novel approach incorporating a regular 'whole food-based' low-calorie diet combined with app-based digital education and behavioral change program on glucose metabolism and disease management. METHODS: Twenty-four individuals with type 2 diabetes followed this approach supported by weekly coaching calls for 12 weeks. Phenotyping included bioimpedance analysis, mixed-meal tolerance test, magnetic resonance spectroscopy and transient elastography for assessing liver fat content and liver stiffness. RESULTS: Over 12 weeks, participants reduced their body weight by 9% (97 ± 13 to 88 ± 12 kg), body mass index (BMI; 33 ± 5 to 29 ± 4 kg/m2), total fat mass (31 ± 10 to 27 ± 10%) (all p < 0.01) and liver fat by 50% alongside with decreased liver stiffness. Target HbA1c (< 6.5%) was achieved by 38% and resolution of NAFLD (liver fat content < 5.6%) was observed in 30% of the participants. CONCLUSION: This novel approach combining digital education with a low-calorie diet results in effective improvements of body weight, glycemic control and NAFLD and could complement existing care for patients with type 2 diabetes. TRIAL REGISTRATION: NCT04509245.

Cardiometabolic risk factor clustering in patients with deficient branched-chain amino acid catabolism: A case-control study.

Classical organic acidemias (OAs) result from defective mitochondrial catabolism of branched-chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case-control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31 P/1 H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA.

1H-MRS of femoral red and yellow bone marrow fat composition and water content in healthy young men and women at 3 T.

OBJECTIVES: There is a discrepancy between studies suggesting that higher bone marrow fat saturation is associated with impaired health, and studies suggesting that erythropoiesis increases red bone marrow (RBM) fat saturation in young healthy individuals. Here, we seeked to elucidate these discrepancies by using long TE magnetic resonance spectroscopy (MRS) to study both yellow bone marrow (YBM) and RBM in the femur of healthy volunteers. MATERIALS AND METHODS: Thirty-three young healthy volunteers (17 females), age range 20-31 years, underwent long TE 1H MRS at 3.0 T of RBM and YBM fat composition in the left femur. The water content of the bone marrow depots was measured using short TE MRS. RESULTS: The female participants displayed a lower unsaturation in the sampled RBM volume (RBMV) than the males (P < 0.01) without displaying a concomitant difference in YBM (P = 0.42). They also showed a higher water content and broader spectral linewidths in RBM (P = 0.04). The water content in RBM strongly associated with broader spectral linewidths (R = 0.887, P ≪ 0.01) and inversely with RBMV fat unsaturation (R = - 0.365, P = 0.04). DISCUSSION: These results partly support the notion that females display higher rate of erythropoiesis and lower fat unsaturation in RBM.

In vivo 19F MR inflammation imaging after myocardial infarction in a large animal model at 3 T.

OBJECTIVES: Fluorine-19 (19F) MRI with intravenously applied perfluorocarbons allows the in vivo monitoring of infiltrating immune cells as demonstrated in small animal models at high field. Here, we aimed to transfer this approach to a clinical scanner for detection of inflammatory processes in the heart after acute myocardial infarction (AMI) in a large animal model. MATERIALS AND METHODS: Optimization of coil and sequence performance was carried out on phantoms and in vivo at a 3 T Philips Achieva. AMI was induced in Munich mini pigs by 90-min occlusion of the left anterior descending artery. At day 3 after AMI, pigs received a body weight-adjusted intravenous dose of a perfluorooctyl bromide nanoemulsion followed by 1H/19F MRI at day 6 after AMI. RESULTS: A balanced steady-state free precession turbo gradient echo sequence using an ellipsoidal 19F/1H surface coil provided the best signal-to-noise ratio and a superior localization of 19F patterns in vivo. This approach allowed the reliable detection of 19F signals in the injured myocardium within less than 20 min. The 19F signal magnitude correlated significantly with the functional impairment after AMI. CONCLUSION: This study demonstrates the feasibility of in vivo 19F MR inflammation imaging after AMI at 3 T within a clinically acceptable acquisition time.

National Registry Data from Korean Neonatal Network: Two-Year Outcomes of Korean Very Low Birth Weight Infants Born in 2013-2014.

BACKGROUND: The aim of this study was to observe long-term outcomes of very low birth weight infants (VLBWIs) born between 2013 and 2014 in Korea, especially focusing on neurodevelopmental outcomes. METHODS: The data were collected from Korean Neonatal Network (KNN) registry from 43 and 54 participating units in 2013 and 2014, respectively. A standardized electronic case report form containing 30 items related to long-term follow up was used after data validation. RESULTS: Of 2,660 VLBWI, the mean gestational age and birth weight were 291/7 ± 26/7 weeks and 1,093 ± 268 g in 2013 and 292/7 ± 26/7 weeks and 1,125 ± 261 g in 2014, respectively. The post-discharge mortality rate was 1.2%-1.5%. Weight < 50th percentile was 46.5% in 2013 and 66.1% in 2014. The overall prevalence of cerebral palsy among the follow up infants was 6.2% in 2013 and 6.6% in 2014. The Bayley Scales of Infant Developmental Outcomes version II showed 14%-25% of infants had developmental delay and 3%-8% of infants in Bayley version III. For the Korean developmental screening test for infants and children, the area "Further evaluation needed" was 5%-12%. Blindness in both eyes was reported to be 0.2%-0.3%. For hearing impairment, 0.8%-1.9% showed bilateral hearing loss. Almost 50% were readmitted to hospital with respiratory illness as a leading cause. CONCLUSION: The overall prevalence of long-term outcomes was not largely different among the VLBWI born between 2013 and 2014. This study is the first large national data study of long-term outcomes.

Funisitis is more common in cervical insufficiency than in preterm labor and preterm premature rupture of membranes.

OBJECTIVE: To compare the frequency of histologic chorioamnionitis and funisitis among women experiencing preterm labor, preterm premature rupture of membranes (PROM) and cervical insufficiency. METHODS: This retrospective cohort study included singleton pregnant women who delivered at ≤36 weeks of gestation. The patients with preterm birth were subdivided into preterm labor (n=117), preterm PROM (n=153), and cervical insufficiency (n=20). All placentas were examined for pathology, according to the criteria of Salafia with minor modification. Frequencies of histologic chorioamnionitis and funisitis were evaluated according to the causes of preterm birth. RESULTS: 1) Histologic chorioamnionitis was diagnosed in 48.7% (57/117) of cases with preterm labor, 47.4% (73/153) with preterm PROM, and 75.0% (15/20) with cervical insufficiency. Funisitis was detected in 11.1% (13/117) of cases with preterm labor, 15.7% (24/153) with preterm PROM, and 40.0% (8/20) with cervical insufficiency. 2) Frequency of histologic chorioamnionitis was higher in cases with cervical insufficiency compared to preterm PROM. Frequency of funisitis was higher in cases with cervical insufficiency compared to both preterm labor and preterm PROM (P<0.05). The difference in frequency of funisitis remained significant after adjustment for gestational age at delivery and cervical dilatation at diagnosis. 3) Frequency of grade 2 funisitis was higher in cases with cervical insufficiency (35.0%, 7/20) compared to both preterm labor (6.8%, 8/117) and preterm PROM (9.8%, 15/153) (P=0.001). And the difference remained significant after adjustment for gestational age at delivery and cervical dilatation at diagnosis. CONCLUSION: The highest frequency of funisitis was observed in cervical insufficiency among cases with spontaneous preterm birth.

Polyphenol-Rich Fraction of Ecklonia cava Improves Nonalcoholic Fatty Liver Disease in High Fat Diet-Fed Mice.

Ecklonia cava (E. cava; CA) is an edible brown alga with beneficial effects in diabetes via regulation of various metabolic processes such as lipogenesis, lipolysis, inflammation, and the antioxidant defense system in liver and adipose tissue. We investigated the effect of the polyphenol-rich fraction of E. cava produced from Gijang (G-CA) on nonalcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-fed mice. C57BL6 mice were fed a HFD for six weeks and then the HFD group was administered 300 mg/kg of G-CA extracts by oral intubation for 10 weeks. Body weight, fat mass, and serum biochemical parameters were reduced by G-CA extract treatment. MRI/MRS analysis showed that liver fat and liver volume in HFD-induced obese mice were reduced by G-CA extract treatment. Further, we analyzed hepatic gene expression related to inflammation and lipid metabolism. The mRNA expression levels of inflammatory cytokines and hepatic lipogenesis-related genes were decreased in G-CA-treated HFD mice. The mRNA expression levels of cholesterol 7 alpha-hydroxylase 1 (CYP7A1), the key enzyme in bile acid synthesis, were dramatically increased by G-CA treatment in HFD mice. We suggest that G-CA treatment ameliorated hepatic steatosis by inhibiting inflammation and improving lipid metabolism.

Retinopathy of Prematurity among Very-Low-Birth-Weight Infants in Korea: Incidence, Treatment, and Risk Factors.

This study was conducted to describe the incidence, risk factors, and current treatment status of retinopathy of prematurity (ROP) in very-low-birth-weight (VLBW) infants registered in the Korean Neonatal Network database. Medical records of 2,009 VLBW infants born between January 2013 and June 2014 who underwent examination by an ophthalmologist were reviewed. The total incidence of ROP was 34.1%. Of the patients, 11.6% showed ROP stage ≥ 3 and 11.5% received treatment of VLBW. Among all infants who received treatment of ROP, 63.6% underwent operation only; 16.9%, anti-vascular endothelial growth factor (anti-VEGF) treatment only; and 19.5%, both operation and anti-VEGF treatment. The mean gestational age (GA) and birth weight (BW) were significantly lower and the prevalence rates of respiratory distress syndrome, patent ductus arteriosus (PDA), invasive ventilator duration, and sepsis were significantly higher in the VLBW infants with ROP than in those without ROP. In the multivariable logistic regression analysis, PDA (odd ratio [OR], 2.1; 95% confidence interval [CI], 1.11-3.79) and invasive ventilator duration (OR, 1.0; 95% CI, 1.00-1.02) were significant risk factors of ROP and ROP stage ≥ 3. In conclusion, the high incidence of ROP is associated with low GA and BW, and attempt to reduce the aforementioned risk factors could reduce the incidence of ROP stage ≥ 3 in VLBW infants.

Effect of Prophylactic Palivizumab on Admission Due to Respiratory Syncytial Virus Infection in Former Very Low Birth Weight Infants with Bronchopulmonary Dysplasia.

The aim of this study was to observe the effects of prophylactic palivizumab on hospitalization secondary to respiratory syncytial virus (RSV) infection (RSVhospitalization) in former very low birth weight infants (VLBWI) with bronchopulmonary dysplasia (BPD). This study also sought to identify the risk factors of RSVhospitalizationin this particular infant population. A prospective observational study was conducted between September 2007 and April 2008 in seven Korean hospitals. Children with a history of very low birth weight, a diagnosis of BPD and who were <2 yr old at the onset of the RSV season were included in this study. Palivizumab injections were administered monthly for a maximum of five months during the RSV season. RSVhospitalization rates were reviewed, and RSVhospitalization rates between subgroups were categorized by gestational age, birth weight, and duration of ventilator care. A total of 90 subjects completed the follow-up interviews. The mean gestational age at birth was 26.1±1.7 weeks, and the mean birth weight was 889.4±222.2 g. The incidence of RSVhospitalization in the study population was 8.9% (8/90), and the mean hospital stay was 11.0±5.5 days, including one death. There were no statistically significant differences in the patients' demographic characteristics or risk factors for RSV hospitalization. When subgroup analyses were conducted, there were still no statistically significant differences. The administration of palivizumab prophylaxis during the entire RSV season is important in VLBWI with BPD, regardless of their gestational age and birth weight, or previous ventilator dependency.

Quantitative liver 31P magnetic resonance spectroscopy at 3T on a clinical scanner.

PURPOSE: The aims of this study were (i) to establish a robust and fast method to quantify hepatocellular phosphorus compounds in molar concentration on a 3T clinical scanner, (ii) to evaluate its reproducibility, and (iii) to test its feasibility for a use in large cohort studies. METHOD: Proton-decoupled (31) P magnetic resonance spectroscopy of liver (31) P compounds were acquired on 85 healthy subjects employing image selected in-vivo spectroscopy localization in 13 min of acquisition at 3T. Absolute quantification was achieved using an external reference and double-matching phantoms (inorganic phosphates and adenosine triphosphate (ATP) solutions). Reproducibility of the method was also examined. RESULTS: This method showed a high intra- and interday as well as inter- and intraobserver reproducibility (r > 0.98; P < 0.001), with a high signal to noise ratio (SNR) (i.e., mean SNR of γ-ATP: 16). The mean liver concentrations of 85 healthy subjects were assessed to be 1.99 ± 0.51 and 2.74 ± 0.55 mmol/l of wet tissue volume for Pi and γ-ATP, respectively. CONCLUSION: This method reliably quantified molar concentrations of liver (31) P compounds on 85 subjects with a short total examination time (∼25 min) on a 3T clinical scanner. Thus, the current method can be readily utilized for a clinical study, such as a large cohort study.

Initial clinical application of modified Dixon with flexible echo times: hepatic and pancreatic fat assessments in comparison with (1)H MRS.

OBJECTS: Hepatic and pancreatic fat content become increasingly important for phenotyping of individuals with metabolic diseases. This study aimed to (1) evaluate hepatic fat fractions (HFF) and pancreatic fat fractions (PFF) using (1)H magnetic resonance spectroscopy (MRS) and the recently introduced fast mDixon method, and to examine body fat effects on HFF and PFF, (2) investigate regional differences in HFF and PFF by mDixon. MATERIALS AND METHODS: HFF and PFF were quantified by mDixon with two flexible echo times and by single voxel (1)H MRS in 24 healthy subjects. The regional differences of PFF within the pancreas were assessed with mDixon. Abdominal visceral and subcutaneous fat was assessed by T1-weighted MRI at 3T. RESULTS: Both methods correlated well for quantification of HFF (r = 0.98, p < 0.0001) and PFF (r = 0.80, p < 0.0001). However, mDixon showed a higher low limit in HFF and PFF. PFF showed no regional differences using mDixon. In addition, both visceral and subcutaneous fat correlated with pancreatic fat, while only visceral fat correlated with liver fat, employing both (1)H MRS and mDixon. CONCLUSION: The novel and fast two-point mDixon exhibits a good correlation with the gold-standard (1)H MRS for assessment of HFF and PFF, with limited sensitivity for assessing lower fat content.

Delayed symptomatic TFV in neonatal posthemorrhagic hydrocephalus-pathophysiology and therapeutic strategy: A case report and review of the literature.

INTRODUCTION: Trapped fourth ventricle (TFV), which is a rare neurosurgical condition with multifactorial etiology, requires a prompt diagnosis and appropriate therapeutic method selection. We report a case of post-hemorrhagic hydrocephalus and TFV incited/worsened by prematurity, sepsis, acute respiratory distress syndrome (ARDS), mechanical ventilation, and concomitant fourth ventricle outlets stenosis; which displayed a delayed onset. This article addresses the proposed pathophysiology and the clinical importance of appropriate therapeutic strategies with a mini-review of the literature. CASE PRESENTATION: We encountered a case involving a premature Asian male newborn with sepsis and posthemorrhagic hydrocephalus who required ventriculoperitoneal shunt surgery. However, after three years, the baby was diagnosed with a trapped fourth ventricle and subsequently underwent retrograde endoscopic surgery with stent insertion. DISCUSSION: TFV is traditionally known as a complication of lateral ventricle shunting. However, in rare cases such as our neonate patient, it develops as a consequence of multiple pathophysiological processes including ventricular system inflammation along with associated anatomic and physiologic alterations, which necessitates prompt diagnosis and a case-specific therapeutic strategy. CONCLUSION: Understanding the multifactorial pathophysiological mechanisms leading to the development of TFV is crucial. The presence of comorbidities such as prematurity, neonatal sepsis, and ARDS increased the risk of intraventricular hemorrhage and subsequent inflammation and further exacerbated obstructions in cerebrospinal fluid pathways. When posthemorrhagic TFV is accompanied by collapsed lateral ventricles, the optimal treatment approach is retrograde endoscopic fenestration with stent insertion. This treatment option has proven effective in alleviating the condition and restoring proper cerebrospinal fluid flow.

Antenatal betamethasone attenuates intrauterine infection-aggravated hyperoxia-induced lung injury in neonatal rats.

BACKGROUND: Intrauterine infection can exacerbate postnatal hyperoxic lung injury. We hypothesized that antenatal betamethasone treatment attenuates hyperoxic lung injury aggravated by intrauterine infection in neonatal rats. METHODS: Newborn Sprague-Dawley rats were divided into eight experimental groups according to (i) whether rats were exposed to normoxia (N) or hyperoxia (H, 85% oxygen) from postnatal day (P)1 to P14, (ii) whether antenatal betamethasone (0.2 mg/dose) or vehicle was administered to pregnant rats at gestation days (E)19 and E20, and (iii) whether intrauterine infection was induced or not antenatally. Intrauterine infection was induced by intracervical inoculation of Escherichia coli into pregnant rats on E19. We measured cytokine levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß in P1 rat lungs and performed morphometric analyses and assessed inflammatory responses in lung tissue and bronchoalveolar lavage (BAL) at P14 by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining and measurement of myeloperoxidase activity, collagen, and cytokine levels. RESULTS: Cytokine levels in P1 rat lungs were increased by intrauterine infection, and these increases were attenuated by antenatal betamethasone. Hyperoxic lung injuries, indicated by morphometric changes and an inflammatory response in the lung and BAL fluid, were aggravated by intrauterine infection at P14. This aggravation was significantly attenuated by antenatal betamethasone. CONCLUSION: Antenatal betamethasone attenuated aggravated hyperoxic lung injuries induced by intrauterine infection in neonatal rats via its anti-inflammatory actions.

Comparison of neonatal outcomes between multiples and singletons among very low birth weight infants: the Korean Neonatal Network cohort study.

OBJECTIVE: To compare neonatal outcomes between multiples and singletons among very low birth weight infants, this was a prospective cohort study that was conducted by collecting data registered in the Korean Neonatal Network database. METHODS: From January 2013 to December 2016, there were 8265 infants in the Korean Neonatal Network database, and 2958 of them were from multiples. Among them, 2636 infants were twins, 308 infants were triplets, and 14 infants were quadruplets. Maternal and neonatal variables including and mortality major morbidity were compared. Finally, the predicted rates of major morbidity between singletons and multiples. RESULTS: Multiples had higher gestational age, birth weight, Apgar score at 5 min, rates of cesarean section and artificial reproductive technology but lower maternal hypertension, oligohydramnios, chorioamnionitis rates and Clinical Risk Index for Babies scores II without base excess than the singletons. In univariate analysis, multiples had a lower incidence of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis. The mortality rate was not significantly different for overall gestational ages except for those born at ≤26 weeks of gestation. In multivariate logistic analysis, the incidences of intraventricular hemorrhage (grade ≥3), and retinopathy of prematurity requiring treatment were significantly higher than the singletons. CONCLUSIONS: Mortality was not significantly different between multiples and singletons according to overall gestational age, except for multiples born at ≤26 weeks. A significant higher risk of intraventricular hemorrhage and retinopathy of prematurity requiring treatment was found in multiples. A new strategy to improve the mortality of immature multiples born at ≤26 weeks of gestation should be developed.

Ritodrine in external cephalic version: is it effective and safe?

OBJECTIVE: The external cephalic version (ECV) has been shown to lower the likelihood of cesarean section requirements among pregnant women with breech presentations. In the current study, we investigated the effectiveness and safety of ritodrine as a tocolytic for ECV. METHODS: A total of 407 pregnant women with breech presentations, who had no contraindications for ECV, were enrolled in this study. Multivariable logistic regression analyses were used to assess the impact of ritodrine use on the safety and efficacy of ECV. RESULTS: The overall success rate was 67.6%, and ritodrine use was associated with significantly higher odds of successful ECV after adjusting for confounders. Moreover, using ritodrine did not increase the risk of adverse effects, including temporary changes in fetal heart rate, need for elective or emergency cesarean section due to fetal distress during ECV, low Apgar scores, and perinatal mortality. CONCLUSION: Our results suggest that using ritodrine as a tocolytic during ECV may increase the likelihood of ECV success and may not increase adverse perinatal outcomes.

Pregnancy and Neonatal Outcomes After Exposure to Alprazolam in Pregnancy.

Alprazolam is a commonly prescribed benzodiazepine for anxiety or panic disorder, even in pregnant women. Information on the safety of alprazolam during pregnancy is insufficient. We aimed to evaluate pregnancy and neonatal outcomes after exposure to alprazolam during pregnancy. A prospective study was conducted on 725 pregnancies from January 2000 to December 2019. Participants were recruited through the Korean Mother-Safe Program, a service providing information on drug-induced teratogenic risk during pregnancy and breastfeeding. Exposed (N = 96) and non-exposed (N = 629) women to alprazolam during pregnancy were selected and followed-up until delivery. Pregnancy outcomes, including spontaneous abortion, still birth, low birth weight (LBW), preterm birth, Apgar score (at 1 and 5 min), and malformations were measured and compared. Multivariable logistic regression was performed to examine the association between alprazolam exposure and outcomes. The mean age was 32.9 (SD 4.0) years in the alprazolam-exposed group and 31.8 (SD 3.8) years in the unexposed group (p = 0.008). The alprazolam exposure group demonstrated a significantly higher likelihood of pregnancy and neonatal outcomes: spontaneous abortion (OR = 2.38; 95% CI 1.20-4.69), LBW (OR = 3.65; 95% CI 1.22-11.00), and Apgar score at 1 min ≤ 7 (OR = 2.19; 95% CI 1.02-4.67). There was no significant difference in congenital abnormalities between the exposure and non-exposure groups. Our findings confirmed that alprazolam exposure during pregnancy was significantly associated with adverse pregnancy and neonatal outcomes, including spontaneous abortion, low birth weight, and Apgar score at 1 min ≤ 7. Alprazolam during pregnancy should be appropriately regulated and monitored.

Corrigendum: Pregnancy and Neonatal Outcomes After Exposure to Alprazolam in Pregnancy.

[This corrects the article DOI: 10.3389/fphar.2022.854562.].