Predictive Monitoring for Respiratory Decompensation Leading to Urgent Unplanned Intubation in the Neonatal Intensive Care Unit

Background: Infants admitted to the neonatal intensive care unit (NICU), and especially those born with very low birth weight (VLBW; \u3c 1,500 g), are at risk for respiratory decompensation requiring endotracheal intubation and mechanical ventilation. I ntubation and mechanical ventilation are associated with increased morbidity, particularly in urgent unplanned cases. Methods: We tested the hypothesis that the systemic response associated with respiratory decombensation can be detected from physiological monitoring and that statistical models of bedside monitoring data can identify infants at increased risk of urgent unplanned intubation. We studied 287 VLBW infants consecutively admitted to our NICU and found 96 events in 51 patients, excluding intUbations occurring within. 12h of a previous extubation. Results: In order of importance in a multivariable statistical model, we found that the characteristics of reduced O-2 satura, tion, especially as heart rate was falling; increased heart rate correlation with respiratory rate; and the amount of apnea were aIF significant independent pr,edictors.\u27 The predictive model, validated internally by bootStrap, had a receiver-operating characteristic area of 0.84 + / - 0.04. Conclusion: We propose that predictive monitoring in the NICU for urgent unplanned intubation may improve outcomes by allowing clinicians to intervene noninvasively before intubation is required

SOST Inhibits Prostate Cancer Invasion.

Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings

Breath-by-Breath Analysis of Cardiorespiratory Interaction for Quantifying Developmental Maturity in Premature Infants

Breath-by-breath analysis of cardiorespiratory interaction for quantifying developmental maturity in premature infants. J Appl Physiol 112: 859-867, 2012. First published December 15, 2011; doi:10.1152/japplphysiol.01152.2011.-In healthy neonates, connections between the heart and lungs through brain stem chemosensory pathways and the autonomic nervous system result in cardiorespiratory synchronization. This interdependence between cardiac and respiratory dynamics can be difficult to measure because of intermittent signal quality in intensive care settings and variability of heart and breathing rates. We employed a phase-based measure suggested by Sch fer and coworkers (Sch fer C, Rosenblum MG, Kurths J, Abel HH. Nature 392: 239-240, 1998) to obtain a breath-by-breath analysis of cardiorespiratory interaction. This measure of cardiorespiratory interaction does not distinguish between cardiac control of respiration associated with cardioventilatory coupling and respiratory influences on the heart rate associated with respiratory sinus arrhythmia. We calculated, in sliding 4-min windows, the probability density of heartbeats as a function of the concurrent phase of the respiratory cycle. Probability density functions whose Shannon entropy had a \u3c 0.1% chance of occurring from random numbers were classified as exhibiting interaction. In this way, we analyzed 18 infant-years of data from 1,202 patients in the Neonatal Intensive Care Unit at University of Virginia. We found evidence of interaction in 3.3 patient-years of data (18%). Cardiorespiratory interaction increased several-fold with postnatal development, but, surprisingly, the rate of increase was not affected by gestational age at birth. We find evidence for moderate correspondence between this measure of cardiorespiratory interaction and cardioventilatory coupling and no evidence for respiratory sinus arrhythmia, leading to the need for further investigation of the underlying mechanism. Such continuous measures of physiological interaction may serve to gauge developmental maturity in neonatal intensive care patients and prove useful in decisions about incipient illness and about hospital discharge

Ingestion of 10 grams of whey protein prior to a single bout of resistance exercise does not augment Akt/mTOR pathway signaling compared to carbohydrate

Background: This study examined the effects of a whey protein supplement in conjunction with an acute bout of lower body resistance exercise, in recreationally-active males, on serum insulin and insulin like growth factor 1 (IGF-1) and Akt/mTOR signaling markers indicative of muscle protein synthesis: insulin receptor substrate 1 (IRS-1), AKT, mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K) and 4E-binding protein 1 (4E-BP1).Methods: In a randomized, double-blind, cross-over design, 10 males ingested 1 week apart, either 10 g of whey protein (5.25 g EAAs) or carbohydrate (maltodextrose), 30 min prior to a lower-body resistance exercise bout. The resistance exercise bout consisted of 4 sets of 8-10 reps at 80% of the one repetition maximum (RM) on the angled leg press and knee extension exercises. Blood and muscle samples were obtained prior to, and 30 min following supplement ingestion and 15 min and 120 min post-exercise. Serum and muscle data were analyzed using two-way ANOVA.Results: No significant differences were observed for IGF-1 (p > 0.05). A significant main effect for Test was observed for serum insulin (p 0.05). For the Akt/MTOR signaling intermediates, no significant Supplement × Test interactions were observed (p > 0.05). However, significant main effects for Test were observed for phosphorylated concentrations of IRS, mTOR, and p70S6K, as all were elevated at 15 min post-exercise (p < 0.05). Additionally, a significant main effect for Test was noted for 4E-BP1 (p < 0.05), as it was decreased at 15 min post-exercise.Conclusion: Ingestion of 10 g of whey protein prior to an acute bout of lower body resistance exercise had no significant preferential effect compared to carbohydrate on systemic and cellular signaling markers indicative of muscle protein synthesis in untrained individuals

Docosahexaenoic acid counteracts palmitate-induced endoplasmic reticulum stress in C2C12 myotubes: Impact on muscle atrophy

Lipid accumulation in skeletal muscle results in dysregulation of protein meta- bolism and muscle atrophy. We previously reported that treating C2C12 myo- tubes with palmitate (PA), a saturated fatty acid, increases the overall rate of proteolysis via activation of the ubiquitin-proteasome and autophagy systems; co-treatment with the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents the PA-induced responses. Others have reported that PA induces endoplasmic reticulum (ER) stress which initiates the unfolded pro- tein response (UPR), a collective group of responses that can lead to activa- tion of caspase-mediated proteolysis and autophagy. Presently, we tested the hypothesis that DHA protects against PA-induced ER stress/UPR and its atro- phy-related responses in muscle cells. C2C12 myotubes were treated with 500 lmol/L PA and/or 100 lmol/L DHA for 24 h. Proteins and mRNA asso- ciated with ER stress/UPR, autophagy, and caspase-3 activation were evalu- ated. PA robustly increased the phosphorylation of protein kinase R (PKR)- like ER kinase (PERK) and eukaryotic initiation factor 2a (eIF2a). It also increased the mRNAs encoding activating transcription factor 4 (ATF4), spliced X-box binding protein 1 (XBP1s), C/EBP homologous protein (CHOP), and autophagy-related 5 (Atg5) as well as the protein levels of the PERK target nuclear factor erythroid 2-related factor (Nrf2), CHOP, and cleaved (i.e., activated) caspase-3. Co-treatment with DHA prevented all of the PA-induced responses. Our results indicate that DHA prevents PA- induced muscle cell atrophy, in part, by preventing ER stress/UPR, a process that leads to activation of caspase-mediated proteolysis and an increase in expression of autophagy-related genes

Creatine supplementation post-exercise does not enhance training-induced adaptations in middle to older aged males

PURPOSE: The present study evaluated the effects of creatine monohydrate (CrM) consumption post-exercise on body composition and muscle strength in middle to older males following a 12-week resistance training program. METHODS: In a double-blind, randomized trial, 20 males aged between 55 and 70 years were randomly assigned to consume either CrM-carbohydrate (CHO) [20 g days(−1) CrM + 5 g days(−1) CHO × 7 days, then 0.1 g kg(−1) CrM + 5 g CHO on training days (average dosage of ~8.8 g)] or placebo CHO (20 g days(−1) CHO × 7 days, then 5 g CHO on training days) while participating in a high intensity resistance training program [3 sets × 10 repetitions at 75 % of 1 repetition maximum (1RM)], 3 days weeks(−1) for 12 weeks. Following the initial 7-day “loading” phase, participants were instructed to ingest their supplement within 60 min post-exercise. Body composition and muscle strength measurements, blood collection and vastus lateralis muscle biopsy were completed at 0, 4, 8 and 12 weeks of the supplement and resistance training program. RESULTS: A significant time effect was observed for 1RM bench press (p = 0.016), leg press (p = 0.012), body mass (p = 0.03), fat-free mass (p = 0.005) and total myofibrillar protein (p = 0.005). A trend for larger muscle fiber cross-sectional area in the type II fibers compared to type I fibers was observed following the 12-week resistance training (p = 0.08). No supplement interaction effects were observed. CONCLUSION: Post-exercise ingestion of creatine monohydrate does not provide greater enhancement of body composition and muscle strength compared to resistance training alone in middle to older males

Original Research Oral Quercetin Supplementation and Blood Oxidative Capacity in Response to Ultramarathon Competition

Previous research indicates that ultramarathon exercise can result in blood oxidative stress. The purpose of this investigation was to examine the efficacy of oral supplementation with quercetin, a naturally occurring compound with known antioxidant properties, as a potential countermeasure against blood oxidative stress during an ultramarathon competition. In double-blind fashion, 63 participants received either oral quercetin (250 mg, 4×/day; 1,000 mg/day total) or quercetin-free supplements 3 weeks before and during the 160-km Western States Endurance Run. Blood drawn before and immediately after (quercetin finishers n = 18, quercetin-free finishers n = 21) the event was analyzed for changes in blood redox status and oxidative damage. Results show that quercetin supplementation did not affect race performance. In response to the ultramarathon challenge, aqueous-phase antioxidant capacity (ferric-reducing ability of plasma) was similarly elevated in athletes in both quercetin and quercetin-free treatments and likely reflects significant increases in plasma urate levels. Alternatively, trolox-equivalent antioxidant capacity was not altered by exercise or quercetin. Accordingly, neither F2-isoprostances nor protein carbonyls were influenced by either exercise or quercetin supplementation. In the absence of postrace blood oxidative damage, these findings suggest that oral quercetin supplementation does not alter blood plasma lipid or aqueous-phase antioxidant capacity or oxidative damage during an ultramarathon challenge

Liquefaction and Related Ground Failure from July 2019 Ridgecrest Earthquake Sequence

The 2019 Ridgecrest earthquake sequence produced a 4 July M 6.5 foreshock and a 5 July M 7.1 mainshock, along with 23 events with magnitudes greater than 4.5 in the 24 hr period following the mainshock. The epicenters of the two principal events were located in the Indian Wells Valley, northwest of Searles Valley near the towns of Ridgecrest, Trona, and Argus. We describe observed liquefaction manifestations including sand boils, fissures, and lateral spreading features, as well as proximate non‐ground failure zones that resulted from the sequence. Expanding upon results initially presented in a report of the Geotechnical Extreme Events Reconnaissance Association, we synthesize results of field mapping, aerial imagery, and inferences of ground deformations from Synthetic Aperture Radar‐based damage proxy maps (DPMs). We document incidents of liquefaction, settlement, and lateral spreading in the Naval Air Weapons Station China Lake US military base and compare locations of these observations to pre‐ and postevent mapping of liquefaction hazards. We describe liquefaction and ground‐failure features in Trona and Argus, which produced lateral deformations and impacts on several single‐story masonry and wood frame buildings. Detailed maps showing zones with and without ground failure are provided for these towns, along with mapped ground deformations along transects. Finally, we describe incidents of massive liquefaction with related ground failures and proximate areas of similar geologic origin without ground failure in the Searles Lakebed. Observations in this region are consistent with surface change predicted by the DPM. In the same region, geospatial liquefaction hazard maps are effective at identifying broad percentages of land with liquefaction‐related damage. We anticipate that data presented in this article will be useful for future liquefaction susceptibility, triggering, and consequence studies being undertaken as part of the Next Generation Liquefaction project

Liquefaction and Related Ground Failure from July 2019 Ridgecrest Earthquake Sequence

The 2019 Ridgecrest earthquake sequence produced a 4 July M 6.5 foreshock and a 5 July M 7.1 mainshock, along with 23 events with magnitudes greater than 4.5 in the 24 hr period following the mainshock. The epicenters of the two principal events were located in the Indian Wells Valley, northwest of Searles Valley near the towns of Ridgecrest, Trona, and Argus. We describe observed liquefaction manifestations including sand boils, fissures, and lateral spreading features, as well as proximate non‐ground failure zones that resulted from the sequence. Expanding upon results initially presented in a report of the Geotechnical Extreme Events Reconnaissance Association, we synthesize results of field mapping, aerial imagery, and inferences of ground deformations from Synthetic Aperture Radar‐based damage proxy maps (DPMs). We document incidents of liquefaction, settlement, and lateral spreading in the Naval Air Weapons Station China Lake US military base and compare locations of these observations to pre‐ and postevent mapping of liquefaction hazards. We describe liquefaction and ground‐failure features in Trona and Argus, which produced lateral deformations and impacts on several single‐story masonry and wood frame buildings. Detailed maps showing zones with and without ground failure are provided for these towns, along with mapped ground deformations along transects. Finally, we describe incidents of massive liquefaction with related ground failures and proximate areas of similar geologic origin without ground failure in the Searles Lakebed. Observations in this region are consistent with surface change predicted by the DPM. In the same region, geospatial liquefaction hazard maps are effective at identifying broad percentages of land with liquefaction‐related damage. We anticipate that data presented in this article will be useful for future liquefaction susceptibility, triggering, and consequence studies being undertaken as part of the Next Generation Liquefaction project

Comparative analysis of the complete genome sequence of the California MSW strain of myxoma virus reveals potential host adaptations

Myxomatosis is a rapidly lethal disease of European rabbits that is caused by myxoma virus (MYXV). The introduction of a South American strain of MYXV into the European rabbit population of Australia is the classic case of host-pathogen coevolution following cross-species transmission. The most virulent strains of MYXV for European rabbits are the Californian viruses, found in the Pacific states of the United States and the Baja Peninsula, Mexico. The natural host of Californian MYXV is the brush rabbit, Sylvilagus bachmani. We determined the complete sequence of the MSW strain of Californian MYXV and performed a comparative analysis with other MYXV genomes. The MSW genome is larger than that of the South American Lausanne (type) strain of MYXV due to an expansion of the terminal inverted repeats (TIRs) of the genome, with duplication of the M156R, M154L, M153R, M152R, and M151R genes and part of the M150R gene from the right-hand (RH) end of the genome at the left-hand (LH) TIR. Despite the extreme virulence of MSW, no novel genes were identified; five genes were disrupted by multiple indels or mutations to the ATG start codon, including two genes, M008.1L/R and M152R, with major virulence functions in European rabbits, and a sixth gene, M000.5L/R, was absent. The loss of these gene functions suggests that S. bachmani is a relatively recent host for MYXV and that duplication of virulence genes in the TIRs, gene loss, or sequence variation in other genes can compensate for the loss of M008.1L/R and M152R in infections of European rabbits.This work was funded in part by grant R01 AI093804 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. E.C.H. was supported by an NHMRC Australia Fellowship, and D.C.T. was supported by an ARC Future Fellowship