Implementation of a Bayesian based advisory tool for target-controlled infusion of propofol using qCON as control variable.

This single blinded randomized controlled trial aims to assess whether the application of a Bayesian-adjusted CePROP (effect-site of propofol) advisory tool leads towards a more stringent control of the cerebral drug effect during anaesthesia, using qCON as control variable. 100 patients scheduled for elective surgery were included and randomized into a control or intervention group (1:1 ratio). In the intervention group the advisory screen was made available to the clinician, whereas it was blinded in the control group. The settings of the target-controlled infusion pumps could be adjusted at any time by the clinician. Cerebral drug effect was quantified using processed EEG (CONOX monitor, Fresenius Kabi, Bad Homburg, Germany). The time of qCON between the desired range (35-55) during anaesthesia maintenance was defined as our primary end point. Induction parameters and recovery times were considered secondary end points and coefficient of variance of qCON and CePROP was calculated in order to survey the extent of control towards the mean of the population. The desired range of qCON between 35 and 55 was maintained in 84% vs. 90% (p = 0.15) of the case time in the control versus intervention group, respectively. Secondary endpoints showed similar results in both groups. The coefficient of variation for CePROP was higher in the intervention group. The application of the Bayesian-based CePROP advisory system in this trial did not result in a different time of qCON between 35 and 55 (84 [21] vs. 90 [18] percent of the case time). Significant differences between groups were hard to establish, most likely due to a very high performance level in the control group. More extensive control efforts were found in the intervention group. We believe that this advisory tool could be a useful educational tool for novices to titrate propofol effect-site concentrations.

Racing against time: leveraging preclinical models to understand pulmonary susceptibility to perinatal acetaminophen exposures.

Over the past decade, clinicians have increasingly prescribed acetaminophen (APAP) for patients in the neonatal intensive care unit (NICU). Acetaminophen has been shown to reduce postoperative opiate burden, and may provide similar efficacy for closure of the patent ductus arteriosus (PDA) as nonsteroidal anti-inflammatory drugs (NSAIDs). Despite these potential benefits, APAP exposures have spread to increasingly less mature infants, a highly vulnerable population for whom robust pharmacokinetic and pharmacodynamic data for APAP are lacking. Concerningly, preclinical studies suggest that perinatal APAP exposures may result in unanticipated adverse effects that are unique to the developing lung. In this review, we discuss the clinical observations linking APAP exposures to adverse respiratory outcomes and the preclinical data demonstrating a developmental susceptibility to APAP-induced lung injury. We show how clinical observations linking perinatal APAP exposures to pulmonary injury have been taken to the bench to produce important insights into the potential mechanisms underlying these findings. We argue that the available data support a more cautious approach to APAP use in the NICU until large randomized controlled trials provide appropriate safety and efficacy data.

Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants.

Rationale: Bronchopulmonary dysplasia increases the risk of disability in extremely preterm infants. Although the pathophysiology remains uncertain, prior exposure to intermittent hypoxemia may play a role in this relationship. Objectives: To determine the association between prolonged episodes of intermittent hypoxemia and severe bronchopulmonary dysplasia. Methods: A post hoc analysis of extremely preterm infants in the Canadian Oxygen Trial who survived to 36 weeks' postmenstrual age was performed. Oxygen saturations <80% for ⩾1 minute and the proportion of time per day with hypoxemia were quantified using continuous pulse oximetry data that had been sampled every 10 seconds from within 24 hours of birth until 36 weeks' postmenstrual age. The study outcome was severe bronchopulmonary dysplasia as defined in the 2001 NIH Workshop Summary. Measurements and Main Results: Of 1,018 infants, 332 (32.6%) developed severe bronchopulmonary dysplasia. The median number of hypoxemic episodes ranged from 0.8/day (interquartile range, 0.2-1.1) to 60.2/day (interquartile range, 51.4-70.3) among the least and most affected 10% of infants. Compared with the lowest decile of exposure to hypoxemic episodes, the adjusted relative risk of severe bronchopulmonary dysplasia increased progressively from 1.72 (95% confidence interval, 1.55-1.90) at the 2nd decile to 20.40 (95% confidence interval, 12.88-32.32) at the 10th decile. Similar risk gradients were observed for time in hypoxemia. Significant differences in the rates of hypoxemia between infants with and without severe bronchopulmonary dysplasia emerged within the first week after birth. Conclusions: Prolonged intermittent hypoxemia beginning in the first week after birth was associated with an increased risk of developing severe bronchopulmonary dysplasia among extremely preterm infants. Clinical trial registered with www.isrctn.com (ISRCTN62491227) and www.clinicaltrials.gov (NCT00637169).

Dietary supplementation with casein glycomacropeptide, leucine and tryptophan reduces plasma amino acid levels in men.

BACKGROUND: The treatment of mania in bipolar disorders needs to be more efficient, as the manic condition creates severe problems for the patient when it comes to work, finances, relationships and health. This proof-of-concept study examines to what extent casein glycomacropeptide (CGMP) may reduce the precursors of dopamine, phenylalanine and tyrosine, in plasma, and therefore be a potential new intervention to treat acute manic episodes. METHOD: The study was designed as a double-blind randomised dose-response study of CGMP (with added leucine and tryptophan) in 15 healthy men, receiving 3 different doses of CGMP with an interval of at least 14 days. RESULTS: Administration of CGMP produced a dose-dependent depletion of plasma aromatic amino acids. The total area under the curve of plasma ratios of phenylalanine-tyrosine compared to the level of leucine-isoleucine-valine--tryptophan was CGMP (20 g): 3.648 [SE:0.3281]; CGMP (40 g): 2.368 [SE:0.1858]; and CGMP (60 g)1.887 [SE:0.2591]. A comparison of the groups showed a dose-dependent statistical difference, with a one-way ANOVA summary (Dunnett) F = 11.87, p = 0.0003, CGMP 20 g versus CGMP 40 g, p = 0.0042, CGMP 20 g versus CGMP 60 g, p = 0.0002. No significant side effects were observed. CONCLUSIONS: This study demonstrate CGMP is a well-tolerated and effective mixture, and that 60 g of CGMP produced the highest depletion of plasma aromatic amino acids (phenylalanine and tyrosine). The effect seems to be highest after 3-4 h. We therefore conclude that this dose should be the one considered for future studies involving CGMP in humans.

Should Vitamin A Injections to Prevent Bronchopulmonary Dysplasia or Death Be Reserved for High-Risk Infants? Reanalysis of the National Institute of Child Health and Human Development Neonatal Research Network Randomized Trial.

OBJECTIVE: To determine whether infants at higher risk of bronchopulmonary dysplasia (BPD) or death benefit more from vitamin A therapy than those at lower risk. STUDY DESIGN: We conducted a post hoc reanalysis of a landmark phase III randomized controlled trial conducted from January 1996 to July 1997 at 14 university-affiliated neonatal intensive care units in the US. Data analysis was performed from October 2019 to October 2020. Infants born weighing 401-1000 g and receiving respiratory support at 24 hours of age were assigned to intramuscular vitamin A 5000 IU or sham procedure 3 times weekly for 4 weeks. The primary outcome was BPD, defined as use of supplemental oxygen, or death at 36 weeks postmenstrual age. An externally validated model for predicting BPD or death was used to estimate the risk of these outcomes for each infant. RESULTS: As previously reported, 222 of 405 infants (54.8%) assigned vitamin A therapy and 248 of 402 infants (61.7%) in the control group developed BPD or died (relative risk [RR], 0.89 [95% CI, 0.80-0.99]; risk difference [RD], -6.9% [95% CI, -13.0 to -0.7]). The predicted individual risks of BPD or death ranged from 7.1% to 98.6% (median, 61.5%; mean, 60.9%). The effect of vitamin A therapy on BPD or death depended on infants' risk of the primary outcome (P = .03 for interaction): for example, a RR of 0.73 (RD, -14.5%) for infants with a 25% predicted risk and a RR of 0.96 (RD, -1.0%) for infants with a 75% risk. There was no difference in the decrease in vitamin A deficiency across risk groups. CONCLUSIONS: Contrary to expectations, the effect of vitamin A therapy on BPD or death was greater for lower risk than higher risk infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT01203488.

Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge.

OBJECTIVES: To measure between-center variation in loop diuretic use in infants developing severe bronchopulmonary dysplasia (BPD) in US children's hospitals, and to compare mortality and age at discharge between infants from low-use centers and infants from high-use centers. STUDY DESIGN: We performed a retrospective cohort study of preterm infants at <32 weeks of gestational age with severe BPD. The primary outcome was cumulative loop diuretic use, defined as the proportion of days with exposure between admission and discharge. Infant characteristics associated with loop diuretic use at P < .10 were included in multivariable models to adjust for center differences in case mix. Hospitals were ranked from lowest to highest in adjusted use and dichotomized into low-use centers and high-use centers. We then compared mortality and postmenstrual age at discharge between the groups through multivariable analyses. RESULTS: We identified 3252 subjects from 43 centers. Significant variation between centers remained despite adjustment for infant characteristics, with use present in an adjusted mean range of 7.3% to 49.4% of days (P < .0001). Mortality did not differ significantly between the 2 groups (aOR, 0.98; 95% CI, 0.62-1.53; P = .92), nor did postmenstrual age at discharge (marginal mean, 47.3 weeks [95% CI, 46.8-47.9 weeks] in the low-use group vs 47.4 weeks [95% CI, 46.9-47.9 weeks] in the high-use group; P = .96). CONCLUSIONS: A marked variation in loop diuretic use for infants developing severe BPD exists among US children's hospitals, without an observed difference in mortality or age at discharge. More research is needed to provide evidence-based guidance for this common exposure.

Characterization of Disease Phenotype in Very Preterm Infants with Severe Bronchopulmonary Dysplasia.

Rationale: Bronchopulmonary dysplasia (BPD) is a heterogenous condition with poorly characterized disease subgroups.Objectives: To define the frequency of three disease components: moderate-severe parenchymal disease, pulmonary hypertension (PH), or large airway disease, in a referral cohort of preterm infants with severe BPD. The association between each component and a primary composite outcome of death before hospital discharge, tracheostomy, or home pulmonary vasodilator therapy was assessed.Methods: This was a retrospective, single-center cohort study of infants born at <32 weeks' gestation with severe BPD who underwent both chest computed tomography with angiography (CTA) and echocardiography between 40 and 50 weeks postmenstrual age between 2011 and 2015. Moderate-severe parenchymal lung disease was defined as an Ochiai score ≥8 on CTA. PH was diagnosed by echocardiogram using standard criteria. Large airway disease was defined as tracheomalacia or bronchomalacia on bronchoscopy and/or tracheoscopy or CTA.Measurements and Main Results: Of 76 evaluated infants, 73 (96%) were classifiable into phenotypic subgroups: 57 with moderate-severe parenchymal disease, 48 with PH, and 44 with large airway disease. The presence of all three disease components was most common (n = 23). Individually, PH and large airway disease, but not moderate-severe parenchymal disease, were associated with increased risk for the primary study outcome. Having more disease components was associated with an incremental increase in the risk for the primary outcome (2 vs. 1: odds ratio, 4.9; 95% confidence interval, 1.4-17.2 and 3 vs. 1: odds ratio, 12.8; 95% confidence interval, 2.4-70.0).Conclusions: Infants with severe BPD are variable in their predominant pathophysiology. Disease phenotyping may enable better risk stratification and targeted therapeutic intervention.

Structural Evolution of a Crustal-Scale Seismogenic Fault in a Magmatic Arc: The Bolfin Fault Zone (Atacama Fault System).

How major crustal-scale seismogenic faults nucleate and evolve in crystalline basements represents a long-standing, but poorly understood, issue in structural geology and fault mechanics. Here, we address the spatio-temporal evolution of the Bolfin Fault Zone (BFZ), a >40-km-long exhumed seismogenic splay fault of the 1000-km-long strike-slip Atacama Fault System. The BFZ has a sinuous fault trace across the Mesozoic magmatic arc of the Coastal Cordillera (Northern Chile) and formed during the oblique subduction of the Aluk plate beneath the South American plate. Seismic faulting occurred at 5-7 km depth and ≤ 300°C in a fluid-rich environment as recorded by extensive propylitic alteration and epidote-chlorite veining. Ancient (125-118 Ma) seismicity is attested by the widespread occurrence of pseudotachylytes. Field geologic surveys indicate nucleation of the BFZ on precursory geometrical anisotropies represented by magmatic foliation of plutons (northern and central segments) and andesitic dyke swarms (southern segment) within the heterogeneous crystalline basement. Seismic faulting exploited the segments of precursory anisotropies that were optimal to favorably oriented with respect to the long-term far-stress field associated with the oblique ancient subduction. The large-scale sinuous geometry of the BFZ resulted from the hard linkage of these anisotropy-pinned segments during fault growth.

Comparison of the Conox (qCON) and Sedline (PSI) depth of anaesthesia indices to predict the hypnotic effect during desflurane general anaesthesia with ketamine.

Comparison of two depth of anesthesia indices, qCON (Conox) and PSI (Sedline), during desflurane sedation and their sensitivity to random ketamine boluses in patients undergoing routine surgery. The performance of desflurane and ketamine on both indices was analyzed for 11 patients, and the ketamine sensitivity was compared with another group of 11 patients under sevoflurane and propofol.The MOAA/S was used to determine sedation level and pain. Different boluses of ketamine ranging from 10 to 30 mg where randomly administered in both groups and the effect on the indexes were measured after 4 min.The indices were recorded during the whole surgery, and their correlations with the desflurane concentration and the discrimination between awake and anesthetized states were evaluated with the prediction probability statistic (Pk). The Pk values, mean (se), discriminating between awake and anesthetized states were 0.974(0.016) for the qCON and 0.962(0.0123) for the PSI, while the 1-Pk statistic for the qCON and the PSI with respect to the desflurane concentration were 0.927(0.016) and 0.918(0.018), respectively, with no statistically significant differences.The agreement between both depth of hypnosis parameters was assessed under the Bland-Altman plot and the Spearman correlation, rs = 0.57(p < 0.001).During the sevoflurane-propofol anesthesia, which served as a control group, both indices experienced a similar behavior with a no significant change of their median values after ketamine. However, during desflurane anesthesia the qCON index did not change significantly after ketamine administration, qCON (before = 33 (4), after = 30 (17); Wilcoxon, p = 0.89), while the PSI experienced a significant increase, PSI (before = 31(6), after = 39(16) Wilcoxon, p = 0.013).This study shows that qCON and PSI have similar performance under desflurane with good discrimination between the awake and anesthetized states. While both indices exhibited similar behavior under ketamine boluses under a sevoflurane-propofol anesthesia, the qCON index had a better performance under ketamine during desflurane anesthesia.

Structural Contour Map of the Iota Carbonic Anhydrase from the Diatom Thalassiosira pseudonana Using a Multiprong Approach.

Carbonic anhydrases (CAs) are a family of ubiquitous enzymes that catalyze the interconversion of CO2 and HCO3-. The "iota" class (ι-CA) was first found in the marine diatom Thalassiosira pseudonana (tpι-CA) and is widespread among photosynthetic microalgae and prokaryotes. The ι-CA has a domain COG4875 (or COG4337) that can be repeated from one to several times and resembles a calcium-calmodulin protein kinase II association domain (CaMKII-AD). The crystal structure of this domain in the ι-CA from a cyanobacterium and a chlorarachniophyte has been recently determined. However, the three-dimensional organization of the four domain-containing tpι-CA is unknown. Using biophysical techniques and 3-D modeling, we show that the homotetrameric tpι-CA in solution has a flat "drone-like" shape with a core formed by the association of the first two domains of each monomer, and four protruding arms formed by domains 3 and 4. We also observe that the short linker between domains 3 and 4 in each monomer confers high flexibility, allowing for different conformations to be adopted. We propose the possible 3-D structure of a truncated tpι-CA containing fewer domain repeats using experimental data and discuss the implications of this atypical shape on the activity and metal coordination of the ι-CA.

Drugs to Prevent Bronchopulmonary Dysplasia: Effect of Baseline Risk on the Number Needed to Treat.

Infants born very preterm have a variable baseline risk of bronchopulmonary dysplasia (BPD). Using the example of evidence-based drug therapies to prevent BPD, we designed a visual aid that displays the "number needed to treat" with CIs for caffeine, vitamin A, and hydrocortisone over a range of baseline risks.

Host-specific competitiveness to form nodules in Rhizobium leguminosarum symbiovar viciae.

Fabeae legumes such as pea and faba bean form symbiotic nodules with a large diversity of soil Rhizobium leguminosarum symbiovar viciae (Rlv) bacteria. However, bacteria competitive to form root nodules (CFN) are generally not the most efficient to fix dinitrogen, resulting in a decrease in legume crop yields. Here, we investigate differential selection by host plants on the diversity of Rlv. A large collection of Rlv was collected by nodule trapping with pea and faba bean from soils at five European sites. Representative genomes were sequenced. In parallel, diversity and abundance of Rlv were estimated directly in these soils using metabarcoding. The CFN of isolates was measured with both legume hosts. Pea/faba bean CFN were associated to Rlv genomic regions. Variations of bacterial pea and/or faba bean CFN explained the differential abundance of Rlv genotypes in pea and faba bean nodules. No evidence was found for genetic association between CFN and variations in the core genome, but variations in specific regions of the nod locus, as well as in other plasmid loci, were associated with differences in CFN. These findings shed light on the genetic control of CFN in Rlv and emphasise the importance of host plants in controlling Rhizobium diversity.

Lifelong pulmonary sequelae of bronchopulmonary dysplasia.

PURPOSE OF REVIEW: To summarize the current literature evaluating long-term pulmonary morbidity among surviving very preterm infants with bronchopulmonary dysplasia (BPD). RECENT FINDINGS: BPD predisposes very preterm infants to adverse respiratory signs and symptoms, greater respiratory medication use, and more frequent need for rehospitalization throughout early childhood. Reassuringly, studies also indicate that older children and adolescents with BPD experience, on average, similar functional status and quality of life when compared to former very preterm infants without BPD. However, measured deficits in pulmonary function may persist in those with BPD and indicate an increased susceptibility to early-onset chronic obstructive pulmonary disease during adulthood. Moreover, subtle differences in exercise tolerance and activity may put survivors with BPD at further risk of future morbidity in later life. SUMMARY: Despite advances in neonatal respiratory care, a diagnosis of BPD continues to be associated with significant pulmonary morbidity over the first two decades of life. Long-term longitudinal studies are needed to determine if recent survivors of BPD will also be at increased risk of debilitating pulmonary disease in adulthood.

Influence of an "Electroencephalogram-Based" Monitor Choice on the Delay Between the Predicted Propofol Effect-Site Concentration and the Measured Drug Effect.

BACKGROUND: Clinicians can optimize propofol titration by using 2 sources of pharmacodynamic (PD) information: the predicted effect-site concentration for propofol (Ceprop) and the electroencephalographically (EEG) measured drug effect. Relation between these sources should be time independent, that is, perfectly synchronized. In reality, various issues corrupt time independency, leading to asynchrony or, in other words, hysteresis. This asynchrony can lead to conflicting information, making effective drug dosing challenging. In this study, we tried to quantify and minimize the hysteresis between the Ceprop (calculated using the Schnider model for propofol) and EEG measured drug effect, using nonlinear mixed-effects modeling (NONMEM). Further, we measured the influence of EEG-based monitor choice, namely Bispectral index (BIS) versus qCON index (qCON) monitor, on propofol PD hysteresis. METHODS: We analyzed the PD data from 165 patients undergoing propofol-remifentanil anesthesia for outpatient surgery. Drugs were administered using target-controlled infusion (TCI) pumps. Pumps were programmed with Schnider model for propofol and Minto model for remifentanil. We constructed 2 PD models (direct models) relating the Schnider Ceprop to the measured BIS and qCON monitor values. We quantified the models' misspecification due to hysteresis, on an individual level, using the root mean squared errors (RMSEs). Subsequently, we optimized the PD models' predictions by adding a lag term to both models (lag-time PD models) and quantified the optimization using the RMSE. RESULTS: There is a counterclockwise hysteresis between Ceprop and BIS/qCON values. Not accounting for this hysteresis results in a direct PD model with an effect-site concentration which produces 50% of the maximal drug effect (Ce50) of 6.24 and 8.62 µg/mL and RMSE (median and interquartile range [IQR]) of 9.38 (7.92-11.23) and 8.41(7.04-10.2) for BIS and qCON, respectively. Adding a modeled lag factor of 49 seconds to the BIS model and 53 seconds to the qCON model improved both models' prediction, resulting in similar Ce50 (3.66 and 3.62 µg/mL for BIS and qCON) and lower RMSE (median (IQR) of 7.87 (6.49-9.90) and 6.56 (5.28-8.57) for BIS and qCON. CONCLUSIONS: There is a significant "Ceprop versus EEG measured drug effect" hysteresis. Not accounting for it leads to conflicting PD information and false high Ce50 for propofol in both monitors. Adding a lag term improved the PD model performance, improved the "pump-monitor" synchrony, and made the estimates of Ce50 for propofol more realistic and less monitor dependent.

The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach.

Rationale: Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately predict childhood morbidity.Objectives: To determine which of 18 prespecified, revised definitions of bronchopulmonary dysplasia that variably define disease severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks' postmenstrual age best predicts death or serious respiratory morbidity through 18-26 months' corrected age.Methods: We assessed infants born at less than 32 weeks of gestation between 2011 and 2015 at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.Measurements and Main Results: Of 2,677 infants, 683 (26%) died or developed serious respiratory morbidity. The diagnostic criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks' postmenstrual age, regardless of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (n = 773); grade 1, nasal cannula ≤2 L/min (n = 1,038); grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure (n = 617); and grade 3, invasive mechanical ventilation (n = 249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33-79%) was observed for death or neurodevelopmental impairment.Conclusions: The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks' postmenstrual age, regardless of supplemental oxygen use.

Use of Point-of-Care Gastric pH Testing to Assess the Efficacy of Acid Suppression Therapy in the Neonatal Intensive Care Unit.

OBJECTIVE: The use of acid suppression therapies in newborns lacks efficacy and is associated with adverse effects. Point-of-care (POC) assessment of gastric aspirate pH may provide an objective, noninvasive measure of gastric acidity in tube fed infants. We conducted the present study to characterize the POC gastric pH levels in gastric tube fed infants before and after initiation of enteral omeprazole or ranitidine. STUDY DESIGN: Retrospective cohort study of infants with gastric aspirate pH levels determined by POC pH strips. Gastric pH levels recorded during 7 days before and 14 days after medication initiation were compared using Wilcoxon's sign-rank tests. RESULTS: Among 307 evaluated infants, 284 (92%) had a median gastric pH level ≥4 in 7 days prior to ranitidine or omeprazole. In 14 days after medication initiation, the median gastric pH of infants with pretreatment median gastric pH < 4 increased to 4.5 and 5 (p < 0.01) in the ranitidine and omeprazole groups, respectively. There was no change in infants with pretreatment median gastric pH ≥4. CONCLUSION: Among infants receiving gastric tube feedings and enteral omeprazole or ranitidine, only those with a pretreatment gastric pH level <4 demonstrated a significant increase in gastric pH. Validation of our findings against esophageal pH multichannel intraluminal impedance testing is needed.

Insights on the Functions and Ecophysiological Relevance of the Diverse Carbonic Anhydrases in Microalgae.

Carbonic anhydrases (CAs) exist in all kingdoms of life. They are metalloenzymes, often containing zinc, that catalyze the interconversion of bicarbonate and carbon dioxide-a ubiquitous reaction involved in a variety of cellular processes. So far, eight classes of apparently evolutionary unrelated CAs that are present in a large diversity of living organisms have been described. In this review, we focus on the diversity of CAs and their roles in photosynthetic microalgae. We describe their essential role in carbon dioxide-concentrating mechanisms and photosynthesis, their regulation, as well as their less studied roles in non-photosynthetic processes. We also discuss the presence in some microalgae, especially diatoms, of cambialistic CAs (i.e., CAs that can replace Zn by Co, Cd, or Fe) and, more recently, a CA that uses Mn as a metal cofactor, with potential ecological relevance in aquatic environments where trace metal concentrations are low. There has been a recent explosion of knowledge about this well-known enzyme with exciting future opportunities to answer outstanding questions using a range of different approaches.

Gastrostomy Tube Feeding in Extremely Low Birthweight Infants: Frequency, Associated Comorbidities, and Long-term Outcomes.

OBJECTIVE: To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes. STUDY DESIGN: Analysis of ELBW infants from 25 centers enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables. RESULTS: Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up. CONCLUSIONS: GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Relationship between pulmonary artery acceleration time and pulmonary artery pressures in infants.

BACKGROUND: Pulmonary artery acceleration time measured by echocardiography inversely correlates with pulmonary artery pressures in adults and children older than 1 year of age. There is a paucity of data investigating this relationship in young children, particularly among preterm infants. OBJECTIVE: To characterize the relationship between pulmonary artery acceleration time (PAAT) and pulmonary artery pressures in infants. DESIGN/METHODS: Patients ≤ 1 year of age at Children's Hospital of Philadelphia between 2011 and 2017 were reviewed. Infants with congenital heart disease were excluded, except those with a patent ductus arteriosus (PDA), atrial septal defect (ASD), or ventricular septal defect (VSD). Linear regression analysis was used to assess the correlation between PAAT measured by echocardiography and systolic pulmonary artery pressure, mean pulmonary artery pressure, and indexed pulmonary vascular resistance from cardiac catheterization. RESULTS: Fifty-seven infants were included, of which 61% were preterm and 49% had a diagnosis of bronchopulmonary dysplasia. The median postmenstrual age and weight at catheterization were 51.1 weeks (IQR 35.8-67.9 weeks) and 4400 g (IQR 3100-6500 g), respectively. Forty-four infants (77%) had a patent ductus arteriosus (PDA). There was a weak inverse correlation between PAAT with mPAP (r = -0.35, P = 0.01), sPAP (r = -0.29, P = 0.03), and PVRi (r = -0.29, P = 0.03). CONCLUSION: There is a weak inverse relationship between PAAT and pulmonary artery pressures. This relationship is less robust in our population of infants with a high incidence of PDAs compared to previous studies in older children. Thus, PAAT may be less clinically meaningful for diagnosing pulmonary arterial hypertension in infants, particularly those with PDAs.