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Patients diagnosed with glioblastoma (GBM) are treated with surgery followed by fractionated radiotherapy with concurrent and adjuvant temozolomide. Patients are monitored with serial magnetic resonance imaging (MRI). However, treatment-related changes frequently mimic disease progression. We reviewed a series of patients undergoing surgery for presumed first-recurrence GBM, where pathology reports were available for tissue diagnosis, in order to better understand factors associated with a diagnosis of treatment-related changes on final pathology.
Patient records at a single institution between 2005 and 2015 were retrospectively reviewed. Pathology reports were reviewed to determine diagnosis of recurrent GBM or treatment effect. Survival analysis was performed interrogating overall survival (OS) and progression-free survival (PFS). Correlation with radiation treatment plans was also examined.
One-hundred-twenty-three patients were identified. One-hundred-sixteen patients (94%) underwent resection and seven underwent biopsy. Treatment-related changes were reported in 20 cases (16%). These patients had longer median OS and PFS from the time of recurrence than patients with true disease progression. However, there was no significant difference in OS from the time of initial diagnosis. Treatment effect was associated with surgery within 90 days of completing radiation. In patients receiving radiation at our institution (n = 53), larger radiation target volume and a higher maximum dose were associated with treatment effect.
Treatment effect was associated with surgery nearer to completion of radiation, a larger radiation target volume, and a higher maximum point dose. Treatment effect was associated with longer PFS and OS from the time of recurrence, but not from the time of initial diagnosis.
Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
Growth rates in pre-weaned calves influence their health, age at first calving and lifetime productivity. Many farms restrict milk rations to encourage solid feed intake and facilitate early weaning, but this can compromise growth. This study determined the milk feeding policies and associated growth rates on 11 commercial dairy farms in South East England, each following their normal management regime. Between 26 and 54 heifers were recruited per farm, providing a final cohort of 492, of which 71% were pure Holstein. Information on calf rearing practices (feeding, weaning, housing) and health was collected via questionnaires and weekly observations. Estimates of actual milk fed (kg solids) between 1 and 63 days were calculated for individual calves. Morphometric data (weight, height, length) were taken at weeks 1, 5 and 9 and at a median age of 7.5 months and growth rates were calculated. Most calves were fed milk replacer via automated feeders (four farms), teat feeder (one) or buckets (four) whereas two farms provided drums of acidified waste milk. Farms fed between 4 and 6 l/day of milk at mixing rates of 10% to 15%, providing 400 to 900 g/day of milk solids. Both skeletal growth rates and average daily weight gain (ADG) increased in the second month of life compared with the first: height growth from 0.17±0.14 to 0.25±0.16 cm/day and ADG from 0.48±0.25 to 0.71±0.28 kg/day. Post-weaning heifers up to 7.5 months had height increases of 0.16±0.035 cm/day and ADG of 0.83±0.16 kg/day. From 1 to 63 days 70% of calves had growth rates <0.7 kg/day and of these 19.6% gained <0.5 kg/day. Mean ADG before 9 weeks varied between farms from 0.52±0.30 to 0.75±0.20 kg/day. This was related to the amount of milk fed at both a farm and individual calf level. Increasing the total milk solids fed between 1 and 63 days from 20.4 to 46.3 kg (the 10th to 90th percentile observed) was associated with an increase of 0.11 kg/day ADG. All farms had a wide variation in growth rates despite single feeding policies. Higher circulating immunoglobulin G and IGF1 concentrations were associated with better growth, whereas low temperatures in month of birth, high scores for diarrhoea, respiratory and umbilical disease and large birth size reduced growth. Many commercially grown dairy heifers therefore experienced growth restriction in the pre-weaned period, potentially reducing their health, welfare and productivity.
There is limited evidence on the acceptability, feasibility and cost-effectiveness of task-sharing interventions to narrow the treatment gap for mental disorders in sub-Saharan Africa. The purpose of this article is to describe the rationale, aims and methods of the Africa Focus on Intervention Research for Mental health (AFFIRM) collaborative research hub. AFFIRM is investigating strategies for narrowing the treatment gap for mental disorders in sub-Saharan Africa in four areas. First, it is assessing the feasibility, acceptability and cost-effectiveness of task-sharing interventions by conducting randomised controlled trials in Ethiopia and South Africa. The AFFIRM Task-sharing for the Care of Severe mental disorders (TaSCS) trial in Ethiopia aims to determine the acceptability, affordability, effectiveness and sustainability of mental health care for people with severe mental disorder delivered by trained and supervised non-specialist, primary health care workers compared with an existing psychiatric nurse-led service. The AFFIRM trial in South Africa aims to determine the cost-effectiveness of a task-sharing counselling intervention for maternal depression, delivered by non-specialist community health workers, and to examine factors influencing the implementation of the intervention and future scale up. Second, AFFIRM is building individual and institutional capacity for intervention research in sub-Saharan Africa by providing fellowship and mentorship programmes for candidates in Ethiopia, Ghana, Malawi, Uganda and Zimbabwe. Each year five Fellowships are awarded (one to each country) to attend the MPhil in Public Mental Health, a joint postgraduate programme at the University of Cape Town and Stellenbosch University. AFFIRM also offers short courses in intervention research, and supports PhD students attached to the trials in Ethiopia and South Africa. Third, AFFIRM is collaborating with other regional National Institute of Mental Health funded hubs in Latin America, sub-Saharan Africa and south Asia, by designing and executing shared research projects related to task-sharing and narrowing the treatment gap. Finally, it is establishing a network of collaboration between researchers, non-governmental organisations and government agencies that facilitates the translation of research knowledge into policy and practice. This article describes the developmental process of this multi-site approach, and provides a narrative of challenges and opportunities that have arisen during the early phases. Crucial to the long-term sustainability of this work is the nurturing and sustaining of partnerships between African mental health researchers, policy makers, practitioners and international collaborators.
The Murchison Widefield Array (MWA) is one of three Square Kilometre Array Precursor telescopes and is located at the Murchison Radio-astronomy Observatory in the Murchison Shire of the mid-west of Western Australia, a location chosen for its extremely low levels of radio frequency interference. The MWA operates at low radio frequencies, 80–300 MHz, with a processed bandwidth of 30.72 MHz for both linear polarisations, and consists of 128 aperture arrays (known as tiles) distributed over a ~3-km diameter area. Novel hybrid hardware/software correlation and a real-time imaging and calibration systems comprise the MWA signal processing backend. In this paper, the as-built MWA is described both at a system and sub-system level, the expected performance of the array is presented, and the science goals of the instrument are summarised.
The Carnegie Hubble Program (CHP) is a Warm Spitzer program with the aim of reducing the uncertainty in the Hubble constant to below 3%. The program is calibrated using Galactic Cepheids with precise parallax distances from the Hubble Space Telescope (HST), combined with a large sample of Cepheids in the Large Magellanic Cloud. We extend the Cepheid distance scale to the Local Group and beyond, into the regime probed by the Tully–Fisher relation. The entire program—from Galactic Cepheids to the most distant galaxies—uses the Spitzer/IRAC instrument. Completing the entire program with a single instrument on a single telescope virtually eliminates instrumental effects, whilst moving to the mid-infrared drastically reduces the reddening and metallicity effects that trouble the optical Cepheid distance scale. Our first measurement of the Hubble constant, using only two CHP galaxies tied into the HST Key Project results has produced a measurement of H0 = 74.3 ± 2.1 (systematic) km s−1 Mpc−1, which corresponds to a systematic uncertainty of 2.8%.
The electronic structure of delta plutonium (δ-Pu) and plutonium compounds is investigated using photoelectron spectroscopy (PES). Results for δ-Pu show a small component of the valence electronic structure which might reasonably be associated with a 5f6 configuration. PES results for PuTe are used as an indication for the 5f6 configuration due to the presence of atomic multiplet structure. Temperature dependent PES data on δ-Pu indicate a narrow peak centered 20 meV below the Fermi energy and 100 meV wide. The first PES data for PuCoIn5 indicate a 5f electronic structure more localized than the 5fs in the closely related PuCoGa5. There is support from the PES data for a description of Pu materials with an electronic configuration of 5f5 with some admixture of 5f6 as well as a localized/delocalized 5f5 description.
We have developed a three-dimensional (3D) circuit integration technology that exploits the advantages of silicon-on-insulator (SOI) technology to enable wafer-level stacking and micrometer-scale electrical interconnection of fully fabricated circuit wafers. This paper describes the 3D technology and discusses some of the advanced focal plane arrays that have been built using it.
The development of native language phonetic representations in bilingual infants was compared to that of monolingual infants. Infants (ages 6–8, 10–12, and 14–20 months) from English–French or English-only environments were tested on their ability to discriminate a French and an English voice onset time distinction. Although 6- to 8-month-olds responded similarly irrespective of language environment, by 10–12 months both groups of infants displayed language-specific perceptual abilities: the monolinguals demonstrated realignment to the native English boundary whereas the bilinguals began discriminating both native boundaries. This suggests that infants exposed to two languages from birth are equipped to phonetically process each as a native language and the development of phonetic representation is neither delayed nor compromised by additional languages.
Femtosecond modelocked lasers using new ytterbium-doped borate crystals (Yb:Sr3Y(BO3)3,
Yb:Ca4GdO(BO3)3 and Yb:Ca4YO(BO3)3) are demonstrated. Pulse duration as short as 69 fs
has been obtained. To modelock such lasers, fast saturable absorbers need to be used. Two
different types of fast saturable absorbers have been studied: low-temperature-grown
semiconductor mirrors (SESAM) and high-energy-ion-implanted semiconductor Bragg
reflectors (SBR). We demonstrated, for the first time to our knowledge, that ion-implanted
SBR can be used to modelock oscillators using Yb-doped materials.
Laser-induced-surface-flaw experiments on fused silica at 351 nm and 500 ps pulse duration are reported here. Specimens with surface flaws produced at a measured exit-surface damage threshold fluence of Fexit/th = 10 J/cm2 were irradiated at a constant fluence of FL = 1.8 × Fexit/th by different numbers of laser pulses, N = 110 to 520. Micrograph observations show that (i) the produced cracks have a semielliptical shape and (ii) the material strength predictions based on the radial crack depth (normal to the surface) instead of the crack surface length (parallel to the surface) are in good agreement with measured strengths obtained using a four-point bending fixture. The underlying basis of conventional crack analysis is first examined critically and is argued to be deficient in the way the failure strength for the cracks is related to the characteristic parameters of crack geometry. In general, it is necessary to incorporate a residual term into the failure strength formulation. The crack depth and the failure strength are found to increase and decrease with the number of laser pulses, respectively.
Clues regarding candidate genes which influence susceptibility
to spina bifida and anencephaly
come from the identification of folate-associated risk factors and from
studies of mouse mutants
showing neural tube anomalies. On this basis we selected five candidate
genes; CBS, MS, MTHFR,
T (Brachyury) and BRCA1 for genetic analysis
in 31 Dutch and 48 British NTD families. Ten
polymorphisms, two for each gene, were used in transmission tests for disequilibrium
(TDT). In six
instances more than 50 transmissions from heterozygous parents could be
examined. Using TDT we
find evidence for an association between an allele at the T gene
and liability to NTD in the embryo.
Data from British and Dutch populations showed the same trend and in combination
χ2TDT=4.89, P=0.03 (OR 2.39, CI 95%
1.02–5.61). No association, in either population group, was
found for CBS, MS and MTHFR, the enzymes most
directly associated with the known risk factors
in folate metabolism. The possibility of complex genetic interactions was
explored; the data show
that a Gly919 MS variant occurs more frequently in combination
with the MTHFR thermolabile
variant in mothers of NTD offspring (OR 3.94, CI 95% 1.0–16.3).
Titanium silicide films grown on silicon were analyzed by transmission electron microscopy (TEM), electron diffraction, scanning transmission electron microscopy (STEM), and energy dispersive x-ray spectroscopy. The films were prepared by sequential rapid thermal annealing (RTA) at 675 °C and 850 °C of 16-nm-thick sputtered Ti on Si (001) wafers. In some cases, a 20-nm-thick TiN capping layer was deposited on the Ti film before the RTA procedure and was removed after annealing. TEM and STEM analyses showed that the silicide films were less than 0.1 μm thick; the capped film was more uniform, ranging in thickness from ∼ 25 – 45 nm, while the uncapped film ranged in thickness from ∼ 15 – 75 nm. Electron diffraction was used to determine that the capped film contained C54-TiSi2, C49-TiSi2, Ti5Si3, and possibly TiSi, and that the uncapped film contained C49-TiSi2, TiSi, Ti5Si3, unreacted Ti, and possibly C54-TiSi2.
Barium titanate ultrafine particles are prepared by hydrothermal method at low temperature. Their phase structures and photoluminescence (PL) properties are examined by X-ray diffraction and Raman spectroscopy. The critical size of the cubic-tetragonal phase transition is about 48 nm and the lattice parameter ratio c/a equals 1.003. Strong photoluminescence is observed with central frequency located at 695 nm. The spectral behaviors at different annealing times and temperatures are studied. We attribute them to the semiconducting hexagonal phase embeded in the nanophase cubic BaTiO3to form trap centers and cause PL process.
The crystal structure, including hydrogen positions, of borcarite, Ca4Mg[B4O6(OH)6](CO3)2, monoclinic, a = 17.840(4), b = 8.380(2), c = 4.445(1) Å, β = 102.04(3)°, V = 649.9(3) Å3, space group C2/m, has been refined by full-matrix least-squares methods to R = 2.5% and wR = 3.0% for 1020 unique observed [|F| ≥ 5σ(F)] reflections collected using Mo-Kα X-radiation. The H positions were located on difference-Fourier maps and were refined using the ‘soft’ constraint that O-H distances are ∼ 0.96 Å. The 4:4T FBB (fundamental building block) of the borcarite structure contains four Bϕ4 tetrahedra (ϕ = unspecified ligand) which share corners to form a four-membered polyhedral ring. Borcarite is the only mineral known to contain this FBB. The FBBs do not polymerize, but each shares three anions with an Mgϕ6 octahedron on either side, forming rods of composition [MgB4O6(OH)6]4- along the c-axis. The rigidity of these rods is enhanced by hydrogen bonding, and individual rods are connected through Caϕ8 polyhedra, Cϕ3 triangles and hydrogen bonds.