Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants.

BACKGROUND: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).

The Prowess of Photogenerated Amine Radical Cations in Cascade Reactions: From Carbocycles to Heterocycles.

Cascade reactions represent a class of ideal organic reactions because they empower efficiency, elegance, and novelty. However, development of cascade reactions remains a daunting task for synthetic chemists. Radicals are known to be well suited for cascade reactions. Compared with widely used carbon-based radicals, nitrogen-based radicals, such as neutral aminyl radicals and protonated aminyl radicals (amine radical cations), are underutilized, although they are behind some notable synthetic methods such as the Hofmann-Löffler-Freytag reaction. The constraint on their usage is generally attributed to the limited number of available stable precursors. Since amine radical cations offer increased reactivity and selectivity in chemical transformations compared with neutral aminyl radicals, their generation is of utmost importance. Recently, a surge of reports has been revealed using visible light photoredox catalysis. It has been demonstrated that amines can act as an electron donor in a reductive quenching cycle while the amine itself is oxidized to the amine radical cation. Although a number of methods exist to generate amine radical cations, the photochemical formation of these species offers many practical advantages. In this Account, we discuss our journey to the development of annulation reactions with various π-bonds and electrophilic addition reactions to alkenes using photogenerated amine radical cations. Various carbocycles and heterocycles are produced by these reactions. In our annulation work, we first show that single electron photooxidation of cyclopropylanilines to the amine radical cations triggers ring opening of the strained carbocycle, producing distonic radical cations. These odd-electron species are shown to react with alkenes and alkynes to yield the corresponding cyclopentanes and cyclopentenes in an overall redox neutral process. Further development of this annulation reaction allows us to achieve the [4 + 2] annulation of cyclobutylanilines with alkynes. In our work on electrophilic addition reactions to alkenes, we reveal that photogenerated amine radical cations are capable of undergoing the electrophilic addition reactions to alkenes to form a variety of indoles and indolines. This chemistry represents a rare oxidative C-N bond-forming reaction using visible light. Conclusions drawn from observational results and proposed mechanisms are outlined in this Account. Additionally, open discussion of our successes and deficiencies in our experiences will give readers helpful insights as to how these species tend to react. The overall utility of photogenerated amine radical cations has yet to reach its full potential. With our current results, we anticipate more new transformations can still be derived from the ring opening processes of cyclopropylanilines and cyclobutylanilines under visible light photocatalysis. Additionally, since utilizing photogenerated amine radical cations in C-N bond-forming reactions has practically been absent in literature, we are confident more new reactions have yet been exploited.

Diastereoselective Oxidative C-N/C-O and C-N/C-N Bond Formation Tandems Initiated by Visible Light: Synthesis of Fused N-Arylindolines.

The synthesis of fused N-arylindolines using visible light photoredox catalysis has been developed. We previously described that photogenerated amine radical cations generate substituted indoles through an intermediate benzylic carbocation. Herein, we expand the application of this chemistry by trapping the benzylic carbocation with tethered heteronucleophiles. The reactivity of the photogenerated benzylic carbocation is explored and applied to a range of substrates with various electronic characters and ring constraints. The method described provides C2 and C3 fused indolines bearing a tetrasubstituted carbon stereocenter with greater than 99:1 diastereoselectivity in moderate to good yields.

Intermolecular [3+2] Annulation of Cyclopropylanilines with Alkynes, Enynes, and Diynes via Visible Light Photocatalysis.

One-step synthesis of carbocycles substituted with amines from simple starting materials remains rare. We recently developed intermolecular [3+2] annulation of cyclopropylanilines with alkenes and alkynes that enable this one-step synthesis. Herein, we report our findings for a fullscale study of the annulation. Significant expansion of the substrate scope for both cyclopropylanilines and alkynes is achieved. A range of structurally diverse carbocycles substituted with amines is prepared.

Apnoea after the 2-month immunisation in extremely preterm infants: what happens with the 4-month immunisation?

AIM: To describe the outcome of the 4-month immunisation in a cohort of extremely preterm babies who had clinically significant apnoea after their 2-month immunisation. METHOD: A retrospective audit was conducted from January 2001 to January 2011 at Flinders Medical Centre (FMC). Suspected apnoeic reactions to the 2-month immunisation in preterm infants ≤28 weeks + 6 days gestation were identified from the Neonatal Unit database. The medical records of babies with reactions then reviewed. We classified apnoeic reactions using predefined criteria into likely, possible or unlikely. The outcomes for subsequent immunisations were determined either when babies were specifically readmitted to FMC for immunisation and cardiorespiratory monitoring, or from the SA Health Immunisation Unit database. RESULTS: There were 203 extremely preterm babies at FMC over the study period who received their 2-month immunisation as inpatients. Clinically significant apnoea post immunisation occurred in 17 (8.4%) babies (likely in 12 and possible 5). The subsequent (4-month) immunisation was given with inpatient cardiorespiratory monitoring in nine babies (seven with likely and two with possible reactions), and no instability was identified. There were eight babies not readmitted to FMC for the subsequent immunisation. No reported adverse events were recorded on the SA Health Immunisation Unit database for these babies. CONCLUSIONS: Apnoea following the 2-month immunisation in extremely preterm infants is not likely to be repeated with the subsequent immunisation. Prospective surveillance using standardised case definitions and monitoring protocols in this population are required to guide uniform practice.

Optical flow sensor for continuous invasive measurement of blood flow velocity.

Continuous monitoring of intrapulse measurement of blood flow in humans is currently not achievable with clinically available instruments. In this paper, we demonstrate a method of measuring the instantaneous variations in flow during pulsatile blood flow with an optical flow sensor comprising a fiber Bragg grating sensor and illumination from a 565 nm Light-Emitting-Diode. The LED illumination heats the blood and fluctuations in temperature, due to variations in flow, are detected by the fiber sensor. A set of experiments at different flow rates (20 to 900 mL/min) are performed in a simulated cardiac circulation setup with pulsatile flow. Data are compared with an in-line time of flight ultrasound flow sensor. Our results show that the optical and ultrasonic signals correlate with Pearson coefficients ranging from -0.83 to -0.98, dependent on the pulsatile frequency. Average flow determined by ultrasound and the optical fiber sensor showed a parabolic relationship with R2 = 0.99. An abrupt step change in flow induced by occlusion and release of the circuit tubing demonstrated that the optical fiber and ultrasound sensor had similar response. The method described is capable of intrapulse blood flow measurement under pulsatile flow conditions, with potential applications in medicine where continuous blood flow sensing is desired.

Docosahexaenoic acid supplementation of preterm infants and parent-reported symptoms of allergic disease at 7 years corrected age: follow-up of a randomized controlled trial.

BACKGROUND: Docosahexaenoic acid (DHA, 22:6n-3) supplementation in the prenatal period is associated with a reduction in the incidence of some symptoms of allergic disease. Infants born preterm are at increased risk of allergic disease, but it is unknown if DHA supplementation reduces the risk of childhood allergies. OBJECTIVES: The aim of this study was to determine if supplementation of infants born at <33 wk gestation with high-DHA compared with standard-DHA enteral feeds decreases the incidence and severity of parent-reported allergic disease symptoms at a corrected age (CA) of 7 y. METHODS: This study was a follow-up of an Australian multicenter randomized controlled trial. Infants were given high-DHA (∼1% total fatty acids) or standard-DHA (∼0.3% total fatty acids) enteral feeds from 2-4 d of postnatal age until 40 wk postmenstrual age. Parent-reported incidence of respiratory allergic disease symptoms including wheeze and rhinitis at 7 y CA were the main outcomes. Other outcomes included the incidence of eczema symptoms; severity of any symptoms; and the incidence of wheeze, rhinitis, rhinoconjunctivitis, and eczema from birth to 7 y CA. RESULTS: Data were available for 569 of 657 (87%) children originally randomized. Symptoms of wheeze or rhinitis at 7 y CA did not differ between high- and standard-DHA groups [wheeze: RR: 1.10; 95% CI: 0.73, 1.65; P = 0.66; rhinitis: RR: 1.09; 95% CI: 0.81, 1.46; P = 0.59]. There was no difference in other allergic disease symptoms at 7 y CA or in the severity of symptoms. Parent-reported symptoms of wheeze, rhinitis, rhinoconjunctivitis, or eczema from birth to 7 y CA did not differ between the groups. CONCLUSIONS: High-dose DHA supplementation of infants born at <33 wk gestation did not alter allergic disease symptoms or severity at 7 y CA, or from birth to 7 y CA compared with standard-dose DHA. This trial was registered with the Australian New Zealand Clinical Trials Registry as ANZCTR 12606000327583 (http://www.anzctr.org.au).

Dietary Protein Intake, Breast Feeding and Growth in Human Milk Fed Preterm Infants.

Protein intakes of preterm infants are frequently below recommendations, but few studies report accurate intakes due to the difficulty of analysing human milk clinically. This observational analysis from a randomised trial of infants born.

Detection and Characterization of Package Defects and Integrity Failure using Dynamic Scanning Infrared Thermography (DSIRT).

A dynamic scanning infrared thermography (DSIRT) system developed at the Univ. of Illinois Urbana-Champaign (UIUC) Packaging Lab relies on variation in transient thermal artifacts to indicate defects, and offers the possibility of characterization of many types of materials and structures. These include newer polymer and laminate-based structures for shelf-stable foods that lack a reliable, nondestructive method for inspection, which is a continuing safety issue. Preliminary trials were conducted on a polyester/aluminum foil/polypropylene retort pouch laminate containing artificially-induced failed seal and insulating inclusion defects ranging from 1 to 10 mm wide in the plane of the seal. The samples were placed in relative motion to a laterally positioned infrared laser, inducing heating through the plane of the seal. The emergent thermal artifact on the obverse side was sensed using either a bolometer camera or a thermopile sensor, with thermal anomalies indicating potential defects and the results of each sensors were compared. The bolometer camera detected defects to the limit of its measured optical resolution-approximately 1 mm at 20 cm-although the lower-resolution thermopile sensors were only capable of detecting 5 mm defects even at closer distances of approximately 5 mm. In addition, a supplementary magnification system was fitted to the bolometer camera which increased resolution but reduced field of view and would require a much higher frame rate to be useful. Automatic processing of the image data rapidly detected the model defects and can lead to development of an automated inspection system.  Much higher material throughput speeds are feasible using faster instruments, and the system is scalable.

Neurodevelopmental outcomes at 7†years' corrected age in preterm infants who were fed high-dose docosahexaenoic acid to term equivalent: a follow-up of a randomised controlled trial.

OBJECTIVE: To determine if improvements in cognitive outcome detected at 18 months' corrected age (CA) in infants born <33 weeks' gestation receiving a high-docosahexaenoic acid (DHA) compared with standard-DHA diet were sustained in early childhood. DESIGN: Follow-up of a multicentre randomised controlled trial. Randomisation was stratified for sex, birth weight (<1250 vs ≥1250 g) and hospital. SETTING: Five Australian tertiary hospitals from 2008 to 2013. PARTICIPANTS: 626 of the 657 participants randomised between 2001 and 2005 were eligible to participate. INTERVENTIONS: High-DHA (≈1% total fatty acids) enteral feeds compared with standard-DHA (≈0.3% total fatty acids) from age 2-4 days until term CA. PRIMARY OUTCOME: Full Scale IQ of the Wechsler Abbreviated Scale of Intelligence (WASI) at 7 years CA. Prespecified subgroup analyses based on the randomisation strata (sex, birth weight) were conducted. RESULTS: 604 (92% of the 657 originally randomised) consented to participate (291 high-DHA, 313 standard-DHA). To address missing data in the 604 consenting participants (22 for primary outcome), multiple imputation was performed. The Full Scale IQ was not significantly different between groups (high-DHA 98.3, SD 14.0, standard-DHA 98.5, SD 14.9; mean difference adjusted for sex, birthweight strata and hospital -0.3, 95% CI -2.9 to 2.2; p=0.79). There were no significant differences in any secondary outcomes. In prespecified subgroup analyses, there was a significant sex by treatment interaction on measures of parent-reported executive function and behaviour. Scores were within the normal range but girls receiving the high-DHA diet scored significantly higher (poorer outcome) compared with girls receiving the standard-DHA diet. CONCLUSIONS: Supplementing the diets of preterm infants with a DHA dose of approximately 1% total fatty acids from days 2-4 until term CA showed no evidence of benefit at 7 years' CA. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12606000327583.

Experimental spatial sampling study of the real-time ultrasonic pulse-echo BAI-mode imaging technique.

The ultrasonic pulse-echo backscattered amplitude integral (BAI)-mode imaging technique has been developed to inspect the seal integrity of hermetically sealed, flexible food packages. With a focused 17.3-MHz transducer acquiring radio frequency (RF) echo data in a static rectilinear stop-and-go pattern, this technique was able to reliably detect channel defects as small as 38 microm in diameter and occasionally detect 6-microm-diameter channels. This contribution presents our experimental spatial sampling study of the BAI-mode imaging technique with a continuous zigzag scanning protocol that simulates a real-time production line inspection method in continuous motion. Two transducers (f/2 17.3 MHz and f/3 20.3 MHz) were used to acquire RF echo data in a zigzag raster pattern from plastic film samples bearing rectilinear point reflector arrays of varying grid spacings. The average BAI-value difference (deltaBAI) between defective and intact regions and the contrast-to-noise ratio (CNR) were used to assess image quality as a function of three spatial sampling variables: transducer spatial scanning step size, array sample grid spacing, and transducer -6-dB pulse-echo focal beam spot size. For a given grid size, the deltaBAI and CNR degraded as scanning step size in each spatial dimension increased. There is an engineering trade-off between the BAI-mode image quality and the transducer spatial sampling. The optimal spatial sampling step size has been identified to be between one and two times the -6-dB pulse-echo focal beam lateral diameter.

Acoustic Imaging of Defects in Flexible Food Packages.

A study was conducted using a high-frequency acoustic imaging system: the scanning laser acoustic microscope (SLAM), operating at 100 MHz, to detect packaging defects to within the system's resolution limit of 20 µm. The purpose of the study was to assess the feasibility of high-frequency acoustic imaging to detect and classify channel defects that would have the potential for microbial contamination through visually undetected defects. The SLAM can characterize and image various materials and defects by exploiting the differences in acoustic (mechanical) transmission properties within different materials. Channel defects transverse to the heat-seal major axis were fabricated by sandwiching 10-, 16-, 25-, and 37-µm wire between two layers of either polyethylene or plastic retort-pouch laminate film which were then heat sealed. The wire was then pulled out, leaving a channel filled variously with saline solution, air, or both. The channel defects were then assessed using the SLAM and validated with confocal microscopy. The results indicate that the SLAM technology can readily detect channel defects as small as 10 µm, the smallest channel defects examined, which is one-half the imaging system stated resolution specification. This study has clearly demonstrated that acoustic microscopy can nondestructively image micrometer-scale channel defects in heat seals at and smaller than the SLAM's resolution limit.