The Telescope Array (TA) observatory utilizes fluorescence detectors and surface detectors (SDs) to observe air showers produced by ultra high energy cosmic rays in Earth's atmosphere. Cosmic-ray ...events observed in this way are termed hybrid data. The depth of air shower maximum is related to the mass of the primary particle that generates the shower. This paper reports on shower maxima data collected over 8.5 yr using the Black Rock Mesa and Long Ridge fluorescence detectors in conjunction with the array of SDs. We compare the means and standard deviations of the observed X max distributions with Monte Carlo X max distributions of unmixed protons, helium, nitrogen, and iron, all generated using the QGSJet II-04 hadronic model. We also perform an unbinned maximum likelihood test of the observed data, which is subjected to variable systematic shifting of the data X max distributions to allow us to test the full distributions, and compare them to the Monte Carlo to see which elements are not compatible with the observed data. For all energy bins, QGSJet II-04 protons are found to be compatible with TA hybrid data at the 95% confidence level after some systematic X max shifting of the data. Three other QGSJet II-04 elements are found to be compatible using the same test procedure in an energy range limited to the highest energies where data statistics are sparse.
Abstract Objective To evaluate the effectiveness of the Shaping Healthy Choices Program (SHCP). Design A clustered, randomized, controlled intervention lasting 1 school year. Setting Schools in ...northern and central California. Participants Fourth-graders (aged 9–10 years) at 2 control schools (n = 179) and 2 intervention schools (n = 230). Intervention Garden-enhanced education, family, and community partnerships; increased regionally procured produce in the lunchroom; and school-site wellness committees. Main Outcome Measures Changes in body mass index (BMI) percentiles/Z-scores; nutrition knowledge, science process skills, and vegetable identification and preferences; and reported fruit and vegetable intake. Analysis Student t test, chi-square, ANOVA of change, and multilevel regression mixed model to evaluate change in outcomes with school as a random effect to account for cluster design effects. Statistical significance was set at P < .05. Results There was a greater improvement in BMI percentile (−6.08; P < 0.01), BMI Z-score (−0.28; P < .001), and waist-to-height ratio (−0.02; P < .001) in the intervention compared with the control schools. Conclusions and Implications The SHCP resulted in improvements in nutrition knowledge, vegetable identification, and a significant decrease in BMI percentiles. This supports the concept that the SHCP can be used to improve the health of upper elementary school students.
Abiraterone acetate is an oral 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCPRC) patients. Previously, a prospective ...observational trial demonstrated a relationship between abiraterone trough concentrations (C
) in plasma and treatment efficacy. The aim of our study was to investigate the exposure-response relationship of abiraterone and its metabolites, and to study if the proposed target for abiraterone of 8.4 ng/mL is feasible in a "real-world" patient cohort.
mCRPC patients who had at least one abiraterone plasma concentration at steady-state were included in this study. Plasma abiraterone and its metabolites levels were analyzed using a validated liquid chromatography-mass spectrometry method. Using calculated C
values of abiraterone and its active metabolite Δ(4)-abiraterone (D4A), univariate, and multivariable Cox regression analyses were performed.
Sixty-two patients were included in this retrospective analysis, of which 42% were underexposed (mean abiraterone C
≤ 8.4 ng/mL). In multivariable analysis, C
≥ 8.4 ng/mL was associated with longer prostate-specific antigen (PSA) independent progression-free survival (16.9 vs 6.1 months; p = 0.033), which resulted in a hazard ratio of 0.44 (95% confidence interval: 0.23-0.82, p = 0.01). D4A C
did not show a relationship with treatment efficacy.
Our study shows that mCRPC patients with an abiraterone C
≥ 8.4 ng/mL have a better prognosis compared with patients with low C
. Monitoring C
of abiraterone can help to identify those patients at risk of suboptimal treatment for whom treatment optimization may be appropriate.
Background
Abiraterone acetate is an irreversible 17α-hydroxylase/C17, 20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. ...Inhibition of this enzyme leads to low testosterone and cortisol levels in blood. There is growing evidence that clinical efficacy of abiraterone is related to the rate of suppression of serum testosterone. However, quantification of very low levels of circulating testosterone is challenging. We therefore aimed to investigate whether circulating cortisol levels could be used as a surrogate biomarker for CYP17 inhibition in patients with mCRPC treated with abiraterone acetate.
Patients and methods
mCRPC patients treated with abiraterone acetate were included. Abiraterone and cortisol levels were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). On treatment cortisol and abiraterone concentrations were related to treatment response and progression free survival.
Results
In total 117 patients were included with a median cortisol concentration of 1.13 ng/ml (range: 0.03 – 82.2) and median abiraterone trough concentration (C
min
) of 10.2 ng/ml (range: 0.58 – 92.1). In the survival analyses, abiraterone C
min
≥ 8.4 ng/mL and cortisol < 2.24 ng/mL were associated with a longer prostate-specific antigen (PSA) independent progression-free survival than patients with an abiraterone concentration ≥ 8.4 ng/mL and a cortisol concentration ≥ 2.24 ng/mL (13.8 months
vs
. 3.7 months).
Conclusion
Our study shows that cortisol is not an independent predictor of abiraterone response in patients with mCRPC, but it is of added value in combination with abiraterone levels, to predict a response on abiraterone.
Objective.
To formulate recommendations for health care professionals about the diagnosis, treatment, and evaluation of an initial urinary tract infection (UTI) in febrile infants and young children ...(ages 2 months to 2 years).
Design.
Comprehensive search and analysis of the medical literature, supplemented with consensus opinion of Subcommittee members.
Participants.
The American Academy of Pediatrics (AAP) Committee on Quality Improvement selected a Subcommittee composed of pediatricians with expertise in the fields of epidemiology and informatics, infectious diseases, nephrology, pediatric practice, radiology, and urology to draft the parameter. The Subcommittee, the AAP Committee on Quality Improvement, a review panel of office-based practitioners, and other groups within and outside the AAP reviewed and revised the parameter.
Methods.
The Subcommittee identified the population at highest risk of incurring renal damage from UTI—infants and young children with UTI and fever. A comprehensive bibliography on UTI in infants and young children was compiled. Literature was abstracted in a formal manner, and evidence tables were constructed. Decision analysis and cost-effectiveness analyses were performed to assess various strategies for diagnosis, treatment, and evaluation.
Technical Report.
The overall problem of managing UTI in children between 2 months and 2 years of age was conceptualized as an evidence model. The model depicts the relationship between the steps in diagnosis and management of UTI. The steps are divided into the following four phases: 1) recognizing the child at risk for UTI, 2) making the diagnosis of UTI, 3) short-term treatment of UTI, and 4) evaluation of the child with UTI for possible urinary tract abnormality.
Phase 1 represents the recognition of the child at risk for UTI. Age and other clinical features define a prevalence or a prior probability of UTI, determining whether the diagnosis should be pursued.
Phase 2 depicts the diagnosis of UTI. Alternative diagnostic strategies may be characterized by their cost, sensitivity, and specificity. The result of testing is the division of patients into groups according to a relatively higher or lower probability of having a UTI. The probability of UTI in each of these groups depends not only on the sensitivity and specificity of the test, but also on the prior probability of the UTI among the children being tested. In this way, the usefulness of a diagnostic test depends on the prior probability of UTI established in Phase 1.
Phase 3 represents the short-term treatment of UTI. Alternatives for treatment of UTI may be compared, based on their likelihood of clearing the initial UTI.
Phase 4 depicts the imaging evaluation of infants with the diagnosis of UTI to identify those with urinary tract abnormalities such as vesicoureteral reflux (VUR). Children with VUR are believed to be at risk for ongoing renal damage with subsequent infections, resulting in hypertension and renal failure. Prophylactic antibiotic therapy or surgical procedures such as ureteral reimplantation may prevent progressive renal damage. Therefore, identifying urinary abnormalities may offer the benefit of preventing hypertension and renal failure.
Because the consequences of detection and early management of UTI are affected by subsequent evaluation and long-term management and, likewise, long-term management of patients with UTI depends on how they are detected at the outset, the Subcommittee elected to analyze the entire process from detection of UTI to the evaluation for, and consequences of, urinary tract abnormalities. The full analysis of these data can be found in the technical report. History of the literature review along with evidence-tables and a comprehensive bibliography also are available in the report. This report is published in Pediatrics electronic pages and can be accessed at the following URL:http://www.pediatrics.org/cgi/content/full/103/4/e54.
Results.
Eleven recommendations are proposed for the diagnosis, management, and follow-up evaluation of infants and young children with unexplained fever who are later found to have a diagnosed UTI. Infants and young children are of particular concern because UTI in this age group (approximately 5%) may cause few recognizable signs or symptoms other than fever and has a higher potential for renal damage than in older children. Strategies for diagnosis and treatment depend on the clinician's assessment of the illness in the infant or young child. Diagnosis is based on the culture of a properly collected specimen of urine; urinalysis can only suggest the diagnosis. A sonogram should be performed on all infants and young children with fever and their first documented UTI; voiding cystourethrography or radionuclide cystography should be strongly considered.
The Pierre Auger Collaboration (Auger) recently reported a correlation between the arrival directions of cosmic rays with energies above 39 EeV and the flux pattern of 23 nearby starburst galaxies ...(SBGs). In this Letter, we tested the same hypothesis using cosmic rays detected by the Telescope Array experiment (TA) in the 9 yr period from 2008 May to 2017 May. Unlike the Auger analysis, we did not optimize the parameter values but kept them fixed to the best-fit values found by Auger, namely 9.7% for the anisotropic fraction of cosmic rays assumed to originate from the SBGs in the list and 12 9 for the angular scale of the correlations. The energy threshold that we adopted is 43 EeV, corresponding to 39 EeV in Auger when taking into account the energy-scale difference between two experiments. We find that the TA data is compatible with isotropy to within 1.1 and with the Auger result to within 1.4 , meaning that it is not capable to discriminate between these two hypotheses.
Abiraterone acetate is approved for the treatment of metastatic prostate cancer. At the currently used fixed dose of 1000 mg once daily in modified fasting state, 40% of patients do not reach the ...efficacy threshold of a minimum plasma concentration (Cmin) ≥ 8.4 ng/mL and are thereby at risk of decreased treatment efficacy. This study aims to evaluate whether pharmacokinetically (PK) guided abiraterone acetate dosing with a food intervention is feasible and results in an increased percentage of patients with concentrations above the target.
Patients starting regular treatment with abiraterone acetate in modified fasting state were included. Pharmacokinetic analysis was performed 4, 8 and 12 weeks after start of treatment and every 12 weeks thereafter. In case of Cmin < 8.4 ng/mL and acceptable toxicity, a PK-guided intervention was recommended. The first step was concomitant intake of abiraterone acetate with a light meal or a snack.
In total, 32 evaluable patients were included, of which 20 patients (63%) had a Cmin < 8.4 ng/mL at a certain time point during treatment. These patients were recommended to take abiraterone acetate concomitantly with food, after which Cmin increased from 6.9 ng/mL to 27 ng/mL (p < 0.001) without additional toxicities. This intervention led to adequate exposure in 28 patients (87.5%).
Therapeutic drug monitoring of abiraterone was applied in clinical practice and proved to be feasible. Concomitant intake with food resulted in a significant increase in Cmin and offers a cost-neutral opportunity to optimise exposure in patients with low Cmin.
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•Prospective study on therapeutic drug monitoring (TDM) of abiraterone.•Concomitant intake with food resulted in a significant increase in Cmin.•Cost-neutral opportunity to optimise exposure in patients with low Cmin.•Pharmacokinetically guided dosing led to target attainment without extra toxicity.•The effect of TDM on efficacy will be evaluated in a larger patient cohort.
The composition of ultra-high-energy cosmic rays is measured with the High Resolution Fly's Eye cosmic-ray observatory data using the X sub(max) technique. Data were collected in stereo between 1999 ...November and 2001 September. The data are reconstructed with well-determined geometry. Measurements of the atmospheric transmission are incorporated in the reconstruction. The detector resolution is found to be 30 g cm super(-2) in X sub(max) and 13% in energy. The X sub(max) elongation rate between 10 super(18.0) and 10 super(19.4) eV is measured to be 54.5 c 6.5 (stat) c 4.5 (sys) g cm super(-2) per decade. This is compared with predictions using the QGSJet01 and SIBYLL 2.1 hadronic interaction models for both protons and iron nuclei. CORSIKA-generated extensive air showers are incorporated directly into a detailed detector Monte Carlo program. The elongation rate and the X sub(max) distribution widths are consistent with a constant or slowly changing and predominantly light composition. A simple model containing only protons and iron nuclei is compared with QGSJet and SIBYLL. The best agreement between the model and the data is for 80% protons for QGSJet and 60% protons for SIBYLL.
Evidence for a large-scale supergalactic cosmic-ray multiplet (arrival directions correlated with energy) structure is reported for ultra-high-energy cosmic-ray (UHECR) energies above 1019 eV using 7 ...years of data from the Telescope Array (TA) surface detector and updated to 10 years. Previous energy-position correlation studies have made assumptions regarding magnetic field shapes and strength, and UHECR composition. Here the assumption tested is that, because the supergalactic plane is a fit to the average matter density of the local large-scale structure, UHECR sources and intervening extragalactic magnetic fields are correlated with this plane. This supergalactic deflection hypothesis is tested by the entire field-of-view (FOV) behavior of the strength of intermediate-scale energy-angle correlations. These multiplets are measured in spherical cap section bins (wedges) of the FOV to account for coherent and random magnetic fields. The structure found is consistent with supergalactic deflection, the previously published energy spectrum anisotropy results of the TA (the Hotspot and Coldspot), and toy-model simulations of a supergalactic magnetic sheet. The seven year data posttrial significance of this supergalactic structure of multiplets appearing by chance, on an isotropic sky, is found by Monte Carlo simulation to be 4.2 . The 10 years of data posttrial significance is 4.1 . Furthermore, the starburst galaxy M82 is shown to be a possible source of the TA Hotspot, and an estimate of the supergalactic magnetic field using UHECR measurements is presented.