Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen.

BACKGROUND: The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial evaluating early treatment (≤72 hours after birth) with ibuprofen for a large PDA (diameter of ≥1.5 mm with pulsatile flow) in extremely preterm infants (born between 23 weeks 0 days' and 28 weeks 6 days' gestation). The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks of postmenstrual age. RESULTS: A total of 326 infants were assigned to receive ibuprofen and 327 to receive placebo; 324 and 322, respectively, had data available for outcome analyses. A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group (adjusted risk ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died (adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90). Among the infants who survived to 36 weeks of postmenstrual age, moderate or severe bronchopulmonary dysplasia occurred in 176 of 274 (64.2%) in the ibuprofen group and 169 of 285 (59.3%) in the placebo group (adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen. CONCLUSIONS: The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with ibuprofen than among those who received placebo. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977.).

Singularity in polarization: rewiring yeast cells to make two buds.

For budding yeast to ensure formation of only one bud, cells must polarize toward one, and only one, site. Polarity establishment involves the Rho family GTPase Cdc42, which concentrates at polarization sites via a positive feedback loop. To assess whether singularity is linked to the specific Cdc42 feedback loop, we disabled the yeast cell's endogenous amplification mechanism and synthetically rewired the cells to employ a different positive feedback loop. Rewired cells violated singularity, occasionally making two buds. Even cells that made only one bud sometimes initiated two clusters of Cdc42, but then one cluster became dominant. Mathematical modeling indicated that, given sufficient time, competition between clusters would promote singularity. In rewired cells, competition occurred slowly and sometimes failed to develop a single "winning" cluster before budding. Slowing competition in normal cells also allowed occasional formation of two buds, suggesting that singularity is enforced by rapid competition between Cdc42 clusters.

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity.

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE-/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE-/- deletion, and many were absent in Alox-/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial.

BACKGROUND: The question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks' gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic. METHODS: This is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0-28+ 6 weeks' gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0-28+ 6 weeks' gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks' postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. DISCUSSION: Prophylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done. Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks' postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age. TRIAL REGISTRATION: ISRCTN84264977 . Date assigned: 15/09/2010.

MEG Adaptation Resolves the Spatiotemporal Characteristics of Face-Sensitive Brain Responses.

An unresolved goal in face perception is to identify brain areas involved in face processing and simultaneously understand the timing of their involvement. Currently, high spatial resolution imaging techniques identify the fusiform gyrus as subserving processing of invariant face features relating to identity. High temporal resolution imaging techniques localize an early latency evoked component-the N/M170-as having a major generator in the fusiform region; however, this evoked component is not believed to be associated with the processing of identity. To resolve this, we used novel magnetoencephalographic beamformer analyses to localize cortical regions in humans spatially with trial-by-trial activity that differentiated faces and objects and to interrogate their functional sensitivity by analyzing the effects of stimulus repetition. This demonstrated a temporal sequence of processing that provides category-level and then item-level invariance. The right fusiform gyrus showed adaptation to faces (not objects) at ∼150 ms after stimulus onset regardless of face identity; however, at the later latency of ∼200-300 ms, this area showed greater adaptation to repeated identity faces than to novel identities. This is consistent with an involvement of the fusiform region in both early and midlatency face-processing operations, with only the latter showing sensitivity to invariant face features relating to identity. SIGNIFICANCE STATEMENT: Neuroimaging techniques with high spatial-resolution have identified brain structures that are reliably activated when viewing faces and techniques with high temporal resolution have identified the time-varying temporal signature of the brain's response to faces. However, until now, colocalizing face-specific mechanisms in both time and space has proven notoriously difficult. Here, we used novel magnetoencephalographic analysis techniques to spatially localize cortical regions with trial-by-trial temporal activity that differentiates between faces and objects and to interrogate their functional sensitivity by analyzing effects of stimulus repetition on the time-locked signal. These analyses confirm a role for the right fusiform region in early to midlatency responses consistent with face identity processing and convincingly deliver upon magnetoencephalography's promise to resolve brain signals in time and space simultaneously.

The role of phase-locking to the temporal envelope of speech in auditory perception and speech intelligibility.

The temporal envelope of speech is important for speech intelligibility. Entrainment of cortical oscillations to the speech temporal envelope is a putative mechanism underlying speech intelligibility. Here we used magnetoencephalography (MEG) to test the hypothesis that phase-locking to the speech temporal envelope is enhanced for intelligible compared with unintelligible speech sentences. Perceptual "pop-out" was used to change the percept of physically identical tone-vocoded speech sentences from unintelligible to intelligible. The use of pop-out dissociates changes in phase-locking to the speech temporal envelope arising from acoustical differences between un/intelligible speech from changes in speech intelligibility itself. Novel and bespoke whole-head beamforming analyses, based on significant cross-correlation between the temporal envelopes of the speech stimuli and phase-locked neural activity, were used to localize neural sources that track the speech temporal envelope of both intelligible and unintelligible speech. Location-of-interest analyses were carried out in a priori defined locations to measure the representation of the speech temporal envelope for both un/intelligible speech in both the time domain (cross-correlation) and frequency domain (coherence). Whole-brain beamforming analyses identified neural sources phase-locked to the temporal envelopes of both unintelligible and intelligible speech sentences. Crucially there was no difference in phase-locking to the temporal envelope of speech in the pop-out condition in either the whole-brain or location-of-interest analyses, demonstrating that phase-locking to the speech temporal envelope is not enhanced by linguistic information.

Coxiella burnetii exposure in northern sea otters Enhydra lutris kenyoni.

Valvular endocarditis has been well described in northern sea otters Enhydra lutris kenyoni of Alaska and in many cases no cause has been identified. It is also one of the most common conditions observed in people with chronic Coxiella burnetii infection. Given the high levels of C. burnetii exposure in marine mammals distributed throughout the same geographic range as the northern sea otter, and the presence of valvular lesions seen in otters, the objective of this study was to determine the level of C. burnetii exposure in otters and investigate any association between exposure, infection and valvular disease in this species. Archived serum from 75 live captured, apparently healthy otters (25 from each of 3 stocks) and 30 dead otters were tested for C. burnetii antibodies by indirect florescent antibody assay (IFA). Archived bone marrow and heart valves were tested for C. burnetii DNA by real-time PCR (qPCR). Overall, the seroprevalence in live otters was 17%, with significantly more exposed animals in the south central (40%) stock relative to the southwest (8%) and southeast (4%). The seroprevalence of animals sampled post mortem was 27%, although none of the bone marrow or heart valve samples were positive by qPCR. Results of this study failed to demonstrate a significant association between C. burnetii infection and valvular endocarditis in sea otters; however, the differing seroprevalence suggests that exposure opportunities vary geographically.

Relationships between explosive and maximal triple extensor muscle performance and vertical jump height.

The purpose of this study was to examine the relationships between maximum vertical jump height and (a) rate of torque development (RTD) calculated during 2 time intervals, 0-50 milliseconds (RTD50) and 0-200 milliseconds (RTD200) after torque onset and (b) peak torque (PT) for each of the triple extensor muscle groups. Thirty recreationally active individuals performed maximal isometric voluntary contractions (MVIC) of the hip, knee and ankle extensors, and a countermovement vertical jump. Rate of torque development was calculated from 0 to 50 (RTD50) and 0 to 200 (RTD200) milliseconds after the onset of joint torque. Peak torque was identified and defined as the maximum torque value during each MVIC trial. Greater vertical jump height was associated with greater knee and ankle extension RTD50, RTD200, and PT (p ≤ 0.05). However, hip extension RTD50, RTD200, and PT were not significantly related to maximal vertical jump height (p > 0.05). The results indicate that 47.6 and 32.5% of the variability in vertical jump height was explained by knee and ankle extensor RTD50, respectively. Knee and ankle extensor RTD50 also seemed to be more closely related to vertical jump performance than RTD200 (knee extensor: 28.1% and ankle extensor: 28.1%) and PT (knee extensor: 31.4% and ankle extensor: 13.7%). Overall, these results suggest that training specifically targeted to improve knee and ankle extension RTD, especially during the early phases of muscle contraction, may be effective for increasing maximal vertical jump performance.

Association Between Vitamin D Status and Maximal-Intensity Exercise Performance in Junior and Collegiate Hockey Players.

Recent evidence suggests that athletes are at risk for poor vitamin D status. This study used a cross-sectional design to investigate the strength of association between 25-hydroxyvitamin D (25(OH)D) concentration and measures of maximal-intensity exercise performance in competitive hockey players. Fifty-three collegiate and junior male ice hockey players training near Minneapolis, MN (44.9° N latitude) participated in the study during the off-season (May 16-June 28). Circulating 25(OH)D concentration, grip strength, vertical jump performance, and power production during the Wingate Anaerobic Test (WAnT) were evaluated. Despite no athletes with 25(OH)D concentration indicative of deficiency (<20 ng·mL), positive bivariate correlations were detected between vitamin D status, relative grip strength (p = 0.024), and peak power during the WAnT (p = 0.035). Only for relative grip strength (p = 0.043), did 25(OH)D concentration predict performance after adjusting for level of play, fat-free mass, fat mass, and self-reported total physical activity in sequential linear regression. Vitamin D status was positively associated with starting gradient (p = 0.020) during the squat jump, with higher concentrations associated with increased rate of force development in the initial portion of the jump. Interventional trials should investigate the impact of vitamin D supplementation on maximal-intensity exercise performance outcomes and rate of force development in large samples of vitamin D-deficient athletes while controlling for training exposure. Our data indicate that if vitamin D status is causally related to maximal-intensity exercise performance in athletes, the effect size is likely small.

Rapid activation of ATM on DNA flanking double-strand breaks.

The tumour-suppressor gene ATM, mutations in which cause the human genetic disease ataxia telangiectasia (A-T), encodes a key protein kinase that controls the cellular response to DNA double-strand breaks (DSBs). DNA DSBs caused by ionizing radiation or chemicals result in rapid ATM autophosphorylation, leading to checkpoint activation and phosphorylation of substrates that regulate cell-cycle progression, DNA repair, transcription and cell death. However, the precise mechanism by which damaged DNA induces ATM and checkpoint activation remains unclear. Here, we demonstrate that linear DNA fragments added to Xenopus egg extracts mimic DSBs in genomic DNA and provide a platform for ATM autophosphorylation and activation. ATM autophosphorylation and phosphorylation of its substrate NBS1 are dependent on DNA fragment length and the concentration of DNA ends. The minimal DNA length required for efficient ATM autophosphorylation is approximately 200 base pairs, with cooperative autophosphorylation induced by DNA fragments of at least 400 base pairs. Importantly, full ATM activation requires it to bind to DNA regions flanking DSB ends. These findings reveal a direct role for DNA flanking DSB ends in ATM activation.

A comparative study of accuracy in major adaptive filters for motion artifact removal in sleep apnea tests.

Sleep apnea is probably the most common respiratory disorder; respiration and blood oxygen saturation (SpO2) are major concerns in sleep apnea and are also the two main parameters checked by polysomnography (PSG, the gold standard for diagnosing sleep apnea). In this study, we used a simple, non-invasive monitoring system based on photoplethysmography (PPG) to continuously monitor SpO2 and heart rate (HR) for individuals at home. Various breathing experiments were conducted to investigate the relationship between SpO2, HR, and apnea under different conditions, where two techniques (empirical formula and customized formula) for calculating SpO2 and two methods (resting HR and instantaneous HR) for assessing HR were compared. Various adaptive filters were implemented to compare the effectiveness in removing motion artifacts (MAs) during the tests. This study fills the gap in the literature by comparing the performance of different adaptive filters on estimating SpO2 and HR during apnea. The results showed that up-down finger motion introduced more MA than left-right motion, and the errors in SpO2 estimation were increased as the frequency of movement was increased; due to the low sampling frequency features of these tests, the insertion of adaptive filter increased the noise in the data instead of eliminating the MA for SpO2 estimation; the normal least mean squares (NLMS) filter is more effective in removing MA in HR estimation than other filters.

Self-relevance and the activation of attentional networks.

Recent theoretical accounts maintain that core components of attentional functioning are preferentially tuned to self-relevant information. Evidence in support of this viewpoint is equivocal, however, with research overly reliant on personally significant (i.e., familiar) stimulus inputs (e.g., faces, forenames) and a diverse range of methodologies. Addressing these limitations, here we utilised arbitrary items (i.e., geometric shapes) and administered the Attention Network Test (ANT) to establish the extent to which self-relevance (vs friend-relevance) moderates the three subsystems of attentional functioning-alerting, orienting, and executive control. The results revealed that only executive control was sensitive to the meaning of the stimuli, such that conflict resolution was enhanced following the presentation of self-associated compared with friend-associated shapes (i.e., cues). Probing the origin of this effect, a further computational analysis (i.e., Shrinking Spotlight Diffusion Model analysis) indicated that self-relevance facilitated the narrowing of visual attention. These findings highlight when and how the personal significance of otherwise trivial material modulates attentional processing.

MEG demonstrates a supra-additive response to facial and vocal emotion in the right superior temporal sulcus.

An influential neural model of face perception suggests that the posterior superior temporal sulcus (STS) is sensitive to those aspects of faces that produce transient visual changes, including facial expression. Other researchers note that recognition of expression involves multiple sensory modalities and suggest that the STS also may respond to crossmodal facial signals that change transiently. Indeed, many studies of audiovisual (AV) speech perception show STS involvement in AV speech integration. Here we examine whether these findings extend to AV emotion. We used magnetoencephalography to measure the neural responses of participants as they viewed and heard emotionally congruent fear and minimally congruent neutral face and voice stimuli. We demonstrate significant supra-additive responses (i.e., where AV > [unimodal auditory + unimodal visual]) in the posterior STS within the first 250 ms for emotionally congruent AV stimuli. These findings show a role for the STS in processing crossmodal emotive signals.

Spectral properties of H-reflex recordings after an acute bout of whole-body vibration.

Although research supports the use of whole-body vibration (WBV) to improve neuromuscular performance, the mechanisms for these improvements remain unclear. The purpose of this study was to identify the effect of WBV on the spectral properties of electrically evoked H-reflex recordings in the soleus (SOL) muscle. The H-reflex recordings were measured in the SOL muscle of 20 participants before and after a bout of WBV. The H-reflexes were evoked every 15 seconds for 150 seconds after WBV. A wavelet procedure was used to extract spectral data, which were then quantified with a principle components analysis. Resultant principle component scores were used for statistical analysis. The analysis extracted 1 principle component associated with the intensity of the myoelectric spectra and 1 principle component associated with the frequency. The scores of the principle component that were related to the myoelectric intensity were smaller at 30 and 60 milliseconds after WBV than before WBV. The WBV transiently decreased the intensity of myoelectric spectra during electrically evoked contractions, but it did not influence the frequency of the spectra. The decrease in intensity likely indicates a smaller electrically evoked muscle twitch response, whereas the lack of change in frequency would indicate a similar recruitment pattern of motor units before and after WBV.

"A shovel or a shopping cart": lessons from ten years of disaster response by a student-led volunteer group.

Recent years have seen growing interest in enabling volunteers to play a more pronounced role in disaster response, and yet efforts to systematically analyse this crisis volunteer action, particularly among young people, have been surprisingly limited. This study examines the case of the Student Volunteer Army (SVA) in Aotearoa New Zealand, a student-led group which over the space of a decade has responded to multiple disasters, including earthquakes, floods, fires, a terrorist attack and the Covid-19 pandemic. Drawing on in-depth interviews, our analysis compares the practices adopted by the SVA in response to these different crises and identifies how members and supporters of the group have come to understand its capabilities, limitations, and conditions for effective operation. We present a framework of cross-cutting lessons of "why", "who", "when", "what" and "how" and demonstrate the ways they have been built upon for each new disaster mobilisation. In distilling, the key lessons of a youth-led crisis volunteer group that has mobilised for a spectrum of disasters, this paper contributes to theoretical understandings of how groups at a local level learn after sequential disasters, and the conditions and considerations that enable such groups to effectively-and repeatedly-"meet a need" in disaster response.

Use of Lifesaving Medications by Athletic Trainers.

The athletic trainer's (AT's) emergency management skillset requires competency in the delivery of basic lifesaving medications. Some lifesaving medications have been a part of athletic training practice for decades, but that list has grown as ATs' practice settings have expanded, increasing the types of emergent conditions that the AT may have to treat. The 2020 Commission on Accreditation of Athletic Training Education (CAATE) curricular standards require that athletic training students be trained to administer the following: supplemental oxygen, nitroglycerine, low-dose aspirin, bronchodilators, epinephrine using an automated injection device, glucagon, and naloxone. Clinically, the conditions treated by these medications can be categorized as cardiac, respiratory, hypoglycemia, and anaphylaxis. All ATs should know the indications, contraindications, administration methods, and details of patient monitoring for each medication. Generally, these medications are safe and have clear indications for use and few contraindications. Although ATs are trained to administer these medications, they must consider state laws and local policies governing administration.

Non-parametric statistical thresholding of baseline free MEG beamformer images.

Magnetoencephalography (MEG) provides excellent temporal resolution when examining cortical activity in humans. Inverse methods such as beamforming (a spatial filtering approach) provide the means by which activity at cortical locations can be estimated. To date, the majority of work in this field has been based upon power changes between active and baseline conditions. Recent work, however, has focused upon other properties of the time series data reconstructed by these methods. One such metric, the Source Stability Index (SSI), relates to the consistency of the time series calculated only over an active period without the use of a baseline condition. In this paper we apply non-parametric statistics to SSI volumetric maps of simulation, auditory and somatosensory data in order to provide a robust and principled method of statistical inference in the absence of a baseline condition.

Effects of morphine on histamine release from two cell lines of canine mast cell tumor and on plasma histamine concentrations in dogs with cutaneous mast cell tumor.

OBJECTIVE: To determine the effects of morphine on histamine release from 2 canine mast cell tumor (MCT) cell lines and on plasma histamine concentrations in dogs with cutaneous MCTs. ANIMALS: 10 dogs with cutaneous MCT and 10 dogs with soft tissue sarcoma (STS). PROCEDURES: The study consisted of 2 phases. First, 2 canine MCT cell lines were exposed to 3 pharmacologically relevant morphine concentrations, and histamine concentrations were determined by an ELISA. Second, dogs with MCT or STS received 0.5 mg of morphine/kg, IM, before surgery for tumor excision. Clinical signs, respiratory rate, heart rate, arterial blood pressure, rectal temperature, and plasma histamine concentrations were recorded before and 5, 15, 30, and 60 minutes after morphine administration but prior to surgery. Data were compared by use of a 2-way ANOVA with the Sidak multiple comparisons test. RESULTS: In the first phase, canine MCT cell lines did not release histamine when exposed to pharmacologically relevant morphine concentrations. In the second phase, no differences were noted for heart rate, arterial blood pressure, and rectal temperature between MCT and STS groups. Plasma histamine concentrations did not significantly differ over time within groups and between groups. CONCLUSIONS AND CLINICAL RELEVANCE: No significant changes in histamine concentrations were noted for both in vitro and in vivo study phases, and no hemodynamic changes were noted for the in vivo study phase. These preliminary results suggested that morphine may be used safely in some dogs with MCT.