A 3-month feeding trial with tongue sole Cynoglossus semilaevis broodstock was conducted before and during the spawning season to investigate the effects of dietary arachidonic acid (ARA) on the ...production of sex steroid hormones and gonadal gene expression of key proteins in steroidogenesis. Three isonitrogenous and isolipidic experimental diets were formulated to contain different ARA levels: the control diet without ARA supplementation (C, 0.58% ARA of total fatty acids (TFA)) and two diets with low (5.14% of TFA, ARA-L) or high ARA (15.44% of TFA, ARA-H) supplementation. The diets were randomly assigned to 9 tanks of 3-year-old tongue sole (10 females and 15 males in each tank). Fish were reared in a flowing seawater system and fed to apparent satiation twice daily. At the end of the feeding trial, tissue samples from mature females (MF, with spontaneous ovulation), immature females (IMF, early vitellogenesis), and mature males (MM, expressing milt) were collected to assay the production of sex steroid hormones, gonadal gene expression of sex steroid-synthesizing proteins, as well as the fatty acid profiles of gonad, liver and muscle lipids. Results showed that ARA supplementation significantly reduced the estradiol production in females, but stimulated the testosterone production in males. ARA supplementation significantly reduced the mRNA expression of aromatase in ovaries but significantly increased the gene expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) in testes. In mature ovaries, diet ARA-L significantly reduced the gene expression of follicle stimulating hormone receptor (FSHR), 3β-HSD, and 17β-HSD; however, in immature ovaries, it significantly increased the gene expression of FSHR, steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450ssc), 3β-HSD, and 17β-HSD. In all gonads, 17α-hydroxylase (P450c17) responded to dietary ARA differently from other sex steroid-synthesizing proteins. ARA was preferentially accumulated in tongue sole gonad lipids. ARA concentrations were highest in gonad, liver and muscle lipids of MM fish and lowest in MF fish. Compared to female tongue sole, males had higher DHA concentrations in gonad lipids, but lower concentrations in liver lipids. In conclusion, results suggest dietary ARA regulates sex steroid hormone synthesis in tongue sole broodstock, and accumulates in gonad lipids, depending on both fish gender and maturation stage. Dietary ARA supplementation appears more important for male fish than for female fish, and more important for immature females than for mature females.
This study is beneficial to the broodstock diet formulation.
•Dietary ARA enhanced the testosterone production in mature tongue sole testis but reduced the estradiol production in ovary.•Dietary ARA regulated gene expressions of sex steroid-synthesizing proteins depending on fish gender and maturation stage.•ARA is preferentially accumulated in gonads, and testes showed higher ARA contents than ovaries.•This is the first study observing the effects of fish gender and maturation stage on regulation of steroidogenesis by ARA.
The purpose of this study was to determine whether the addition of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) to standard ...first-line gemcitabine and cisplatin provides clinical benefit over gemcitabine and cisplatin alone in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). Gefitinib has demonstrated encouraging efficacy in advanced NSCLC in phase II trials in pretreated patients, and a phase I trial of gefitinib in combination with gemcitabine and cisplatin showed favorable tolerability.
This was a phase III randomized, double-blind, placebo-controlled, multicenter trial in chemotherapy-naive patients with unresectable stage III or IV NSCLC. All patients received up to six cycles of chemotherapy (cisplatin 80 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 of the 3-week cycle) plus either gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. Daily gefitinib or placebo was continued until disease progression. End points included overall survival (primary), time to progression, response rates, and safety evaluation.
A total of 1,093 patients were enrolled. There was no difference in efficacy end points between the treatment groups: for the gefitinib 500 mg/d, gefitinib 250 mg/d, and placebo groups, respectively, median survival times were 9.9, 9.9, and 10.9 months (global ordered log-rank GOLrank P =.4560), median times to progression were 5.5, 5.8, and 6.0 months (GOLrank; P =.7633), and response rates were 49.7%, 50.3%, and 44.8%. No significant unexpected adverse events were seen.
Gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efficacy over gemcitabine and cisplatin alone. The reasons for this remain obscure and require further preclinical testing.
Interpretation: Participants detailed barriers to accessing care, struggled to participate in shared decision-making, and desired trauma-informed care principles; they described strength in community ...and positive interactions with health care professionals, although barriers to accessing gender-affirming care often overshadowed other aspects of the perioperative experience. Additional research, increased education for health care professionals, and policy changes are necessary to improve access to competent care for TNB people.
To identify disciplinary alternatives to replace spanking, this study investigated ethnic differences in the associations of five disciplinary techniques with subsequent externalizing behavior ...problems in a national sample of 7- to 11-year-olds with ANCOVAs and difference-score analyses. Most techniques led to significant reductions in externalizing problems for African-Americans or Hispanics, but only after overcoming known biases in ANCOVA and not for other European-Americans. Privilege removal had the most significantly effective results, followed by grounding. Sending children to their room and spanking significantly reduced externalizing problems only in one or two analyses for African-Americans, whereas removing children's allowance was significantly effective in one overall analysis. Parenting research needs to distinguish between more vs. less effective use of all disciplinary techniques across multiple situational and cultural contexts.
Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy ...of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC.
Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect.
Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.
For the last seven years, our institution has repaired infants with CDH that require ECMO early after cannulation. Prior to that, we attempted to decannulate before repair, but repaired on ECMO if we ...were unable to wean after two weeks. This study compares those strategies.
From 2002 to 2016, 65 infants with CDH required ECMO. 67.7% were repaired on ECMO, and 27.7% were repaired after decannulation. Data were compared between patients repaired ≤5days after cannulation (“early protocol”, n=30) and >5days after cannulation or after de-cannulation (“late protocol”, n=35). We used Cox regression to assess differences in outcomes between groups.
Survival for the early and late protocol groups was 43.3% and 68.8%, respectively (p=0.0485). For patients that were successfully decannulated before repair, survival was 94.4%. Moreover, the early repair protocol was associated with prolongation of ECMO (16.8±7.4 vs. 12.6±6.8days, p=0.0216).
After multivariate regression, the early repair protocol was an independent predictor of both mortality (HR=3.48, 95% CI=1.28–9.45, p=0.015) and days on ECMO (IRR=1.39, 95% CI=1.07–1.79, p=0.012). All bleeding occurred in patients repaired on ECMO (29.5%, 13/44).
Our data suggest that protocolized CDH repair early after ECMO cannulation may be associated with increased mortality and prolongation of ECMO. However, early repair is not necessarily harmful for those patients who would otherwise be unable to wean from ECMO before repair. Further work is needed to better move towards individualized patient care.
Treatment Study.
Level III.
This study aimed to evaluate postoperative outcomes after minimally invasive repair of pectus excavatum (Nuss procedure) using video-assisted intercostal nerve cryoablation (INC) compared to thoracic ...epidural (TE).
We performed a single center retrospective review of pediatric patients who underwent Nuss procedure with INC (n = 19) or TE (n = 13) from April 2015 to August 2017. Preoperative, intraoperative, and postoperative characteristics were collected. The primary outcome was length of stay (LOS) and secondary outcomes were intravenous and oral opioid use, pain scores, and complications. Opioids were converted to oral morphine milligram equivalents per kilogram (oral morphine equivalent OME/kg). Mann–Whitney U test was used for continuous and chi-squared analysis for categorical variables.
There were no significant differences in patient characteristics, except Haller Index (INC: median interquartile range 4.3 3.6-4.9; TE: 3.2 2.8-4.0; P = 0.03). LOS was shorter with INC (INC: 3 3-4 days; TE: 6 5-7 days; P < 0.001). Opioid use was higher intraoperatively (INC: 1.08 0.87-1.37 OME/kg; TE: 0.46 0.37-0.67 OME/kg; P = 0.002) and unchanged postoperatively (INC: 1.78 1.26-3.77 OME/kg; TE: 1.82 1.05-3.37 OME/kg; P = 0.80), and prescription doses were lower at discharge in INC (INC: 30 30-40 doses; TE: 42 40-60 doses; P = 0.005). There was no significant difference in postoperative complications (INC: 42.1%; TE: 53.9%; P = 0.51).
INC during Nuss procedure reduced LOS, shifting postoperative opioid use earlier during admission. This may reflect the need for improved early pain control until INC takes effect. Prospective evaluation after INC is needed to characterize long-term pain medication requirements.
Recent advances in ECLS technology have led to the adoption of centrifugal pumps for the majority of patients worldwide. Despite several advantages of centrifugal pumps, they remain controversial ...because a number of studies have shown increased rates of hemolysis. The aim of this study was to assess the impact of transitioning from roller to centrifugal pumps on hemolysis rates at our center. A retrospective analysis of all pediatric ECMO patients at a single center between 2005 and 2017 was undertaken. Hemolysis was defined as a plasma free hemoglobin >50 mg/dL. Multivariable logistic regression was performed correcting for several factors to determine risk factors for hemolysis and analyze outcomes among patients with hemolysis. Significant findings were those with p < 0.05. A total of 590 patients were identified during the study period. Multivariable logistic regression for risk factors for hemolysis showed roller pumps (OR 1.92, CI 1.11–3.33) and ECMO duration (OR 1.002 per hour, CI 1.00–1.01) to be significant factors. Rates of hemolysis significantly improved following conversion from roller to centrifugal pumps, with significantly lower rates of hemolysis in 2012, 2015, 2016, and 2017 when compared to the historical average with roller pumps from 2005 to 2009 (34.7%). Additionally, hemolysis was associated with an increased risk of death (OR 3.59, CI 2.05–6.29) when correcting for other factors. These data suggest decreasing rates of hemolysis with centrifugal pumps compared to roller pumps. Since hemolysis was also associated with increased risk of death, these data support the switch from roller to centrifugal pumps at ECMO centers.
Sablefish (Anoplopoma fimbria) is a highly desired seafood product, which encourages development of sustainable aquaculture methods for this marine fish. Conventional marine fish-based feeds provide ...essential nutrients including long chain fatty acids for piscivorous species such as sablefish. Alternative terrestrial ingredients could reduce fishing pressures on pelagic species that are the source of fish meal and fish oil, and improve source sustainability. Using juvenile sablefish, we compared the effects of a standard fish-based diet to two diets that contained primarily terrestrial plant ingredients with flaxseed or corn oil replacing the added fish oil. After an 8-week trial feeding period, there were striking differences attributable to diet. Fish receiving the alternative feeds had lower weight gain and shorter length than fish receiving the fish-based feed, suggesting sablefish obtained lower nutrients from the alternative feeds. Among the histological differences, the intestinal mucosa was significantly less vacuolated and the frequency of intestinal mucous cells was reduced in alternative feed fish. The most dramatic lesions were observed in the liver, where severe bile duct hyperplasia (53%, flaxseed oil diet; 33%, corn oil diet), and hepatocellular lesions (nuclear pleomorphism/megalocytosis, regeneration, hypertrophy, clear cell foci) occurred in only alternative feed fish. The hepatic and biliary lesions indicate the alternative diets may be deficient or possibly harmful to sablefish. The bacterial community structures from corn oil fish showed much less diversity than those for the other diets, and the microbiome structures from the three diets were distinctly different from each other. The intestinal microbiome for the fish-based diet included the largest number of families (68), and these fish also had the largest number of unique bacterial families (11) compared to those for corn oil (two) or flaxseed oil (one) fish. Regardless of diet, the stomach and intestinal microbiomes differed significantly from each other, and the feed microbiome differed from all gastrointestinal communities, suggesting that feed is not a significant source of gut bacterial diversity. Similar to other teleosts, the sablefish gastrointestinal microbiome is dominated by Bacteroidetes, Firmicutes, and Proteobacteria. These results suggest that diet-induced shifts in microbiome can occur relatively quickly in sablefish, but the shifts may not be sufficiently adaptive or cannot overcome nutrient deficiencies. This multidisciplinary study demonstrates the utility of histology and microbiology in characterizing dietary effects for novel aquaculture species.
Physiological assessments such as gastrointestinal microbiomes and histopathology can provide a near-term evaluation of the nutritional adequacy of alternative feeds, such as plant-based lipid diets for marine carnivorous finfish. This is the first examination of the microbiome of sablefish, a marine species under development for sustainable aquaculture.
•The conventional fish-based feed produced better growth in sablefish than alternative plant-based feeds.•Liver pathology was observed only in sablefish receiving plant-based feeds.•Gut microbiome was more diverse in fish receiving fish-based diet.•Multidisciplinary evaluation of alternative feeds is important for new aquaculture species.
Juvenile sablefish were fed a low taurine, basal feed with seven graded levels of supplemental taurine to determine taurine requirements for growth and feed efficiency. The basal feed was plant ...based, formulated primarily with soy and corn proteins with a minimal (9%) amount of fishmeal. The unsupplemented, basal feed contained 0.14% taurine. Experimental feeds were supplemented with 0, 0.25, 0.50, 1.0, 1.5, 3.0, and 6.0% taurine. Using the five parameter, saturated kinetic model (5 SKM), peak weight gain was predicted at 1.5% dietary taurine. Optimum weight gain, as defined as the region of the 5 SKM curve corresponding to at least 95% of peak, was predicted between 0.4% and 5.8% dietary taurine. Peak feed efficiency was predicted at 1.1% dietary taurine with optimum weight gain predicted between 0.4% and 4.2%. Whole body and muscle tissue protein and lipid content were not affected by taurine supplementation. Tissue taurine content increased asymptotically with increasing dietary taurine supplementation. Whole body tissue became saturated at 0.25±0.02% taurine, expressed on a wet weight basis. Muscle tissue became saturated at 0.34±0.02% taurine. Results from this study should increase the performance of alternative, plant based feeds formulated for sablefish and enable regulatory agencies better estimate the potential human exposure to taurine from the consumption of sablefish receiving these feeds.
•Dietary taurine requirements were determined for optimum growth and feed efficiency of sablefish, a cold water marine fish.•Tissue taurine saturation is reported for whole body and muscle tissue of sablefish fed taurine supplemented feeds.•Human consumption of sablefish fed taurine supplemented feeds would result in low taurine exposure with minimal health risks.
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