Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Evaluation of Implementation of Early-Onset Sepsis Calculator in Newborns in Israel.

OBJECTIVE: To evaluate the recommendations based on the early-onset sepsis (EOS) calculator in the first 2 years of its implementation in Israel. STUDY DESIGN: Prospective 2-year surveillance of a cohort of infants born at gestational age of ≥34 weeks in Bnai Zion Medical Center, who were evaluated using the EOS calculator because of peripartum risk factors. RESULTS: We evaluate 1146 newborns with peripartum risk factors using the EOS calculator. The percentage of infants who had laboratory evaluation decreased to 4.6%, and the EOS calculator recommended empiric antibiotic therapy in only 2.2%. During the study period, there were 4 early-onset infections (EOS incidence of 0.6 in 1000 live births). Three had group B streptococcus (GBS) and one had Escherichia coli infection. Only 2 of these infants had perinatal risk factors and the EOS calculator identified them and recommended laboratory evaluation and empiric antibiotics. However, 2 infants with GBS EOS had no perinatal risk factors or clinical symptoms at delivery, and were discovered clinically at older ages. CONCLUSIONS: The Israeli EOS calculator-based guidelines seem to be appropriate and are associated with less laboratory evaluations, and little use of empiric antibiotics. Concerns are related to the current recommendation of no GBS universal screening in Israel, and the inability of the calculator-based approach to identify GBS EOS in infants born to mothers with unknown GBS who have no peripartum risk factors before presentation of clinical symptoms.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Perinatal Outcomes in Infants of Mothers with Diabetes in Pregnancy.

BACKGROUND: The incidence of gestational diabetes mellitus (GDM) is increasing in parallel to the worldwide obesity and type 2 diabetes pandemic. Both GDM and pre-gestational diabetes mellitus (PGDM) are associated with short- and long-term consequences in the offspring. There are few recent studies addressing outcomes of newborns born to women diagnosed with GDM and PGDM in Israel. OBJECTIVES: To assess perinatal complications in offspring of women with GDM and PGDM. METHODS: The authors conducted a single-center retrospective case-control study of outcomes of all newborns whose mothers had been diagnosed with diabetes in pregnancy compared to randomly assigned controls born on the same date, whose mothers had no diabetes. RESULTS: In the study period 2015-2017, 526 mothers diagnosed with GDM or PGDM and their newborn infants were identified. The authors randomly assigned 526 control infants. The rate of women with diabetes in pregnancy was 5.0%. Mothers with GDM and PGDM had higher rates of pre-eclampsia, multiple pregnancies, and preterm deliveries. Mothers with PGDM had significantly higher rates of intrauterine fetal demise (4.3%), congenital anomalies (12.8%), and small-for-gestational-age neonates (10.6%) compared to controls (0%, 3.2%, and 4.2%, respectively, P < 0.001). The risks for preterm or cesarean delivery, large-for-gestational-age neonate, respiratory morbidity, hypoglycemia, and polycythemia were increased in offspring of mothers with diabetes, especially PGDM. CONCLUSIONS: Despite all the advancements in prenatal care, diabetes in pregnancy, both PGDM and GDM, is still associated with significant morbidities and complications in offspring. Better preconception and inter-pregnancy care might reduce these risks.

[ALTERATIONS IN SENSITIVE MEASURES OF CARDIAC FUNCTION IN HEALTHY NEONATES DURING PHOTOTHERAPY].

OBJECTIVES: Phototherapy has been reported to reduce coronary blood flow in neonates but without affecting gross measures of cardiac function. The aim of our current study was to evaluate earlier, more sensitive changes in cardiac function during phototherapy. METHODS: Nineteen neonates with jaundice treated with phototherapy had Doppler echocardiographic evaluation, before, during and after phototherapy and were compared to 25 matched controls. Sensitive measures for cardiac performance in this study included left ventricular dimension, ventricular Doppler parameters and regional function assessment. RESULTS: Phototherapy was associated with a significant increase in heart rate. In addition, atrioventricular valve closure to opening interval decreased significantly during phototherapy while ventricular ejection times tended to decrease. However, left and right ventricular filling parameters and outflow velocity parameters, longitudinal tissue-Doppler annular velocities and myocardial performance indices were not affected by phototherapy and were similar to those in controls. Coronary blood velocities and integrals decreased significantly during phototherapy. CONCLUSIONS: Our study found no differences in early and sensitive measures of cardiac performance including the diastolic and systolic function, despite modestly lower flow in coronary arteries among healthy neonates during phototherapy.

Prostate Cancer Energetics and Biosynthesis.

Cancers must alter their metabolism to satisfy the increased demand for energy and to produce building blocks that are required to create a rapidly growing tumor. Further, for cancer cells to thrive, they must also adapt to an often changing tumor microenvironment, which can present new metabolic challenges (ex. hypoxia) that are unfavorable for most other cells. As such, altered metabolism is now considered an emerging hallmark of cancer. Like many other malignancies, the metabolism of prostate cancer is considerably different compared to matched benign tissue. However, prostate cancers exhibit distinct metabolic characteristics that set them apart from many other tumor types. In this chapter, we will describe the known alterations in prostate cancer metabolism that occur during initial tumorigenesis and throughout disease progression. In addition, we will highlight upstream regulators that control these metabolic changes. Finally, we will discuss how this new knowledge is being leveraged to improve patient care through the development of novel biomarkers and metabolically targeted therapies.

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.

OBJECTIVE: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. DESIGN: We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves-/- and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. RESULTS: BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves-/- mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. CONCLUSION: Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.

Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis.

The acquisition of beige adipocyte features by white fat cells corresponds to protection against obesity-induced metabolic diseases in humans and animal models of type 2 diabetes. In adipose tissue, expression of the E2 small ubiquitin-like modifier ligase ubiquitin carrier protein 9 (Ubc9) is positively correlated with markers of insulin resistance and corresponds with impaired browning of human white adipocytes. However, the molecular regulation of Ubc9 expression in adipocytes and other cells remains unclear. In this study, we demonstrate that the mRNA and protein expression of Ubc9 are regulated by the microRNA miRNA-30a (miR-30a) in human subcutaneous adipocytes. Ubc9 and miR-30a exhibit inverse expression in adipose tissue, with miR-30a robustly elevated in brown fat. Depletion of Ubc9 by siRNA or enforced expression of a miR-30a mimic augments mitochondrial volume and respiration in human white adipocytes, reflecting features of brown fat cells. Furthermore, Ubc9 depletion induces a brown fat gene program in human subcutaneous adipocytes. Induction of the beige-selective gene program corresponds to stabilization of the PR domain-containing 16 (PRDM16) protein, an obligate transcriptional regulator of the brown/beige fat metabolic program in white adipocytes that interacts with Ubc9. Taken together, our data demonstrate a previously unappreciated molecular axis that controls browning of human white adipocytes.

The Impact of Routine Evaluation of Gastric Residual Volumes on the Time to Achieve Full Enteral Feeding in Preterm Infants.

OBJECTIVE: To evaluate the time to full enteral feedings in preterm infants after a practice change from routine evaluation of gastric residual volume before each feeding to selective evaluation of gastric residual volume , and to evaluate the impact of this change on the incidence of necrotizing enterocolitis (NEC). STUDY DESIGN: Data were collected on all gavage-fed infants born at ≤34 weeks gestational age (GA) for 2 years before (n = 239) and 2 years after the change (n = 233). RESULTS: The median GA was 32.0 (IQR: 29.7-33.0) weeks before and 32.4 (30.4-33.4) weeks after the change (P = .02). Compared with historic controls, infants with selective evaluations of gastric residual volumes weaned from parenteral nutrition 1 day earlier (P < .001) and achieved full enteral feedings (150 cc/kg/day) 1 day earlier (P = .002). The time to full oral feedings and lengths of stay were similar. The rate of NEC (stage ≥ 2) was 1.7% in the selective gastric residual volume evaluation group compared with 3.3% in the historic control group (P = .4). Multiple regression analyses showed that the strongest predictor of time to full enteral feedings was GA. Routine evaluation of gastric residual volume and increasing time on noninvasive ventilation both prolonged the attainment of full enteral feedings. Findings were consistent in the subgroup with birth weights of <1500 g. Increased weight at discharge was most strongly associated with advancing postmenstrual, age but avoidance of routine evaluations of gastric residual volume also was a significant factor. CONCLUSIONS: Avoiding routine evaluation of gastric residual volume before every feeding was associated with earlier attainment of full enteral feedings without increasing risk for NEC.

BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.

Blood vessel epicardial substance (BVES/Popdc1) is a junctional-associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial-to-mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves(-/-) mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5 compared to wild-type (WT) mice. Intercross with Lgr5-EGFP reporter mice confirmed expansion of the stem cell compartment in Bves(-/-) mice. To examine stem cell function after BVES deletion, we used ex vivo 3D-enteroid cultures. Bves(-/-) enteroids demonstrated increased stemness compared to WT, when examining parameters such as plating efficiency, stem spheroid formation, and retention of peripheral cystic structures. Furthermore, we observed increased proliferation, expression of crypt-base columnar "CBC" and "+4" stem cell markers, amplified Wnt signaling, and responsiveness to Wnt activation in the Bves(-/-) enteroids. Bves expression was downregulated after radiation in WT mice. Moreover, after radiation, Bves(-/-) mice demonstrated significantly greater SI crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves(-/-) mice also demonstrated elevations in Lgr5 and Ascl2 expression, and putative damage-responsive stem cell populations marked by Bmi1 and TERT. Therefore, BVES is a key regulator of intestinal stem cell programs and mucosal homeostasis. Stem Cells 2016;34:1626-1636.

Evaluation and Management of Newborns with Suspected Early-Onset Sepsis: Comparison of Two Approaches and Suggestion for Guidelines.

Objective Although its incidence is declining with the widespread use of intrapartum antibiotics, early-onset sepsis (EOS) continues to be associated with high morbidity and mortality. Maternal, infant, and peripartum risk factors, as well as infant's laboratory tests, have been used to try and identify asymptomatic newborns at risk. In this study, we reevaluate the management of newborns at risk for EOS by comparing our outcomes using two different approaches. Study Design Comparison of clinical data and outcomes of newborns at risk for EOS between two study periods, in which we have used two different protocols for their evaluation and management. Results Although outcomes were not different, adoption of the criteria suggested in the 2012 American Academy of Pediatrics guidelines in the second era resulted in increased utilization of diagnostic laboratory tests and increased use of empiric antibiotic treatments with less yield in a population with a low incidence of EOS (< 0.3/1,000 live births), such as ours. Conclusion In asymptomatic newborns at risk for EOS, careful assessment of a set of maternal, infant, and peripartum risk factors and their severity combined with careful clinical observation, judicious use of laboratory evaluations, and empiric antibiotic treatment only in selected cases seem to be appropriate.

Impact of Continuous Capnography in Ventilated Neonates: A Randomized, Multicenter Study.

OBJECTIVE: To compare the time spent within a predefined safe range of CO2 (30-60 mmHg) during conventional ventilation between infants who were monitored with distal end-tidal CO2 (dETCO2, or capnography) and those who were not. STUDY DESIGN: For this randomized, controlled multicenter study, ventilated infants with a double-lumen endotracheal tube were randomized to 1 of 2 groups: the open (monitored) group, in which data from the capnograph were recorded, displayed to the medical team, and used for patient care, and the masked group, in which data from the capnograph were recorded. However, the measurements were masked and not available for patient care. dETCO2 was compared with PaCO2 measurements recorded for patient care. RESULTS: Fifty-five infants (25 open, 30 masked) participated in the study (median gestational age, 28.6 weeks; range, 23.5-39.0 weeks). The 2 groups were comparable. dETCO2 was in good correlation (r = 0.73; P < .001) and adequate agreement (mean ± SD of the difference, 3.0 ± 8.5 mmHg) with PaCO2. Compared with infants in the masked group, those in the monitored group had significantly (P = .03) less time with an unsafe dETCO2 level (high: 3.8% vs 8.8% or low: 3.8% vs 8.9%). The prevalence of intraventricular hemorrhage or periventricular leukomalacia rate was lower in the monitored group (P = .02) and was significantly (P < .05) associated with the independent factors dETCO2 monitoring and gestational age. CONCLUSION: Continuous dETCO2 monitoring improved control of CO2 levels within a safe range during conventional ventilation in a neonatal intensive care unit. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01572272.

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.

BACKGROUND: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. METHODS AND RESULTS: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F. CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-ß signaling.

Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGFß receptor 2 (Tgfbr2) in the stromal fibroblasts (Tgfbr2(fspKO)) induces inflammation and significant DNA damage in the neighboring epithelia of the forestomach. This results in loss or down-regulation of cyclin-dependent kinase inhibitors p15, p16, and p21, which contribute to the development of invasive squamous cell carcinoma (SCC). Anti-inflammation treatment restored p21 expression, delayed tumorigenesis, and increased survival of Tgfbr2(fspKO) mice. Our data demonstrate for the first time that inflammation is a critical player in the epigenetic silencing of p21 in tumor progression. Examination of human esophageal SCC showed a down-regulation of TGFß receptor 2 (TßRII) in the stromal fibroblasts, as well as increased inflammation, DNA damage, and loss or decreased p15/p16 expression. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TßRII in the stroma.

Heterogeneity in vascular smooth muscle cell embryonic origin in relation to adult structure, physiology, and disease.

Regional differences in vascular physiology and disease response exist throughout the vascular tree. While these differences in physiology and disease correspond to regional vascular environmental conditions, there is also compelling evidence that the embryonic origins of the smooth muscle inherent to the vessels may play a role. Here, we review what is known regarding the role of embryonic origin of vascular smooth muscle cells during vascular development. The focus of this review is to highlight the heterogeneity in the origins of vascular smooth muscle cells and the resulting regional physiologies of the vessels. Our goal is to stimulate future investigation into this area and provide a better understanding of vascular organogenesis and disease. .

Resident progenitors, not exogenous migratory cells, generate the majority of visceral mesothelium in organogenesis.

Historically, analyses of mesothelial differentiation have focused on the heart where a highly migratory population of progenitors originating from a localized "extrinsic" source moves to and over the developing organ. This model long stood alone as the paradigm for generation of this cell type. Here, using chick/quail chimeric grafting and subsequent identification of mesothelial cell populations, we demonstrate that a different mechanism for the generation of mesothelia exists in vertebrate organogenesis. In this newly discovered model, mesothelial progenitors are intrinsic to organs of the developing digestive and respiratory systems. Additionally, we demonstrate that the early heart stands alone in its ability to recruit an entirely exogenous mesothelial cell layer during development. Thus, the newly identified "organ intrinsic" model of mesotheliogenesis appears to predominate while the long-studied cardiac model of mesothelial development may be the outlier.

Identification of a novel developmental mechanism in the generation of mesothelia.

Mesothelium is the surface layer of all coelomic organs and is crucial for the generation of their vasculature. Still, our understanding of the genesis of this essential cell type is restricted to the heart where a localized exogenous population of cells, the proepicardium, migrates to and envelops the myocardium supplying mesothelial, vascular and stromal cell lineages. Currently it is not known whether this pattern of development is specific to the heart or applies broadly to other coelomic organs. Using two independent long-term lineage-tracing studies, we demonstrate that mesothelial progenitors of the intestine are intrinsic to the gut tube anlage. Furthermore, a novel chick-quail chimera model of gut morphogenesis reveals these mesothelial progenitors are broadly distributed throughout the gut primordium and are not derived from a localized and exogenous proepicardium-like source of cells. These data demonstrate an intrinsic origin of mesothelial cells to a coelomic organ and provide a novel mechanism for the generation of mesothelial cells.

Pilot study of a new mathematical algorithm for early detection of late-onset sepsis in very low-birth-weight infants.

BACKGROUND: Diagnosis of late onset sepsis (LOS) in very low birth weight (VLBW) preterm infants relies mainly on clinical suspicion, whereas prognosis depends on early initiation of antibiotic treatment. RALIS is a mathematical algorithm for early detection of LOS incorporating six vital signs measured every 2 hours. OBJECTIVE: The aim of this study is to study RALIS ability to detect LOS before clinical suspicion. STUDY DESIGN: A total of 118 VLBW preterm infants (gestational age < 33 weeks, birth weight < 1,500 g) were enrolled in a prospective multicentered study. Vital signs were recorded prospectively up to day 21 of life in a blinded manner, with no effect on standard care. The primary end point was comparison of the rates and timing of detection of LOS between RALIS and clinical/culture evidence of LOS. RESULTS: Of the 2,174 monitoring days, RALIS indicated sepsis in 590 days, and LOS was positively diagnosed in 229 days. Sensitivity, specificity, positive, and negative predictive values were 74.6, 80.7, 38.8, and 95.1%, respectively. RALIS provided an indication for sepsis 3 days on the average before clinical suspicion. CONCLUSION: RALIS has a promising potential as an easy to implement noninvasive early indicator of LOS, especially for ruling out LOS in VLBW high-risk infants.

Association Between Intermittent Hypoxemia or Bradycardia and Late Death or Disability in Extremely Preterm Infants.

IMPORTANCE: Extremely preterm infants may experience intermittent hypoxemia or bradycardia for many weeks after birth. The prognosis of these events is uncertain. OBJECTIVE: To determine the association between intermittent hypoxemia or bradycardia and late death or disability. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of data from the inception cohort assembled for the Canadian Oxygen Trial in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel, including 1019 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days who were born between December 2006 and August 2010 and survived to a postmenstrual age of 36 weeks. Follow-up assessments occurred between October 2008 and August 2012. EXPOSURES: Episodes of hypoxemia (pulse oximeter oxygen saturation <80%) or bradycardia (pulse rate <80/min) for 10 seconds or longer. Values were sampled every 10 seconds within 24 hours after birth until at least 36 weeks' postmenstrual age. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death after 36 weeks' postmenstrual age, motor impairment, cognitive or language delay, severe hearing loss, or bilateral blindness at 18 months' corrected age. Secondary outcomes were motor impairment, cognitive or language delay, and severe retinopathy of prematurity. RESULTS: Downloaded saturation and pulse rate data were available for a median of 68.3 days (interquartile range, 56.8-86.0 days). Mean percentages of recorded time with hypoxemia for the least and most affected 10% of infants were 0.4% and 13.5%, respectively. Corresponding values for bradycardia were 0.1% and 0.3%. The primary outcome was ascertained for 972 infants and present in 414 (42.6%). Hypoxemic episodes were associated with an estimated increased risk of late death or disability at 18 months of 56.5% in the highest decile of hypoxemic exposure vs 36.9% in the lowest decile (modeled relative risk, 1.53; 95% CI, 1.21-1.94). This association was significant only for prolonged hypoxemic episodes lasting at least 1 minute (relative risk, 1.66; 95% CI, 1.35-2.05 vs for shorter episodes, relative risk, 1.01; 95% CI, 0.77-1.32). Relative risks for all secondary outcomes were similarly increased after prolonged hypoxemia. Bradycardia did not alter the prognostic value of hypoxemia. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants who survived to 36 weeks' postmenstrual age, prolonged hypoxemic episodes during the first 2 to 3 months after birth were associated with adverse 18-month outcomes. If confirmed in future studies, further research on the prevention of such episodes is needed.

The chick embryo as an expanding experimental model for cancer and cardiovascular research.

A long and productive history in biomedical research defines the chick as a model for human biology. Fundamental discoveries, including the description of directional circulation propelled by the heart and the link between oncogenes and the formation of cancer, indicate its utility in cardiac biology and cancer. Despite the more recent arrival of several vertebrate and invertebrate animal models during the last century, the chick embryo remains a commonly used model for vertebrate biology and provides a tractable biological template. With new molecular and genetic tools applied to the avian genome, the chick embryo is accelerating the discovery of normal development and elusive disease processes. Moreover, progress in imaging and chick culture technologies is advancing real-time visualization of dynamic biological events, such as tissue morphogenesis, angiogenesis, and cancer metastasis. A rich background of information, coupled with new technologies and relative ease of maintenance, suggest an expanding utility for the chick embryo in cardiac biology and cancer research.