Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).

BACKGROUND: Plaque psoriasis affects children and adults, but treatment options for paediatric psoriasis are limited. OBJECTIVES: To evaluate the efficacy and safety of ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, for moderate-to-severe paediatric psoriasis. METHODS: In a randomized, double-blind, placebo-controlled, phase III study (IXORA-PEDS), patients aged 6 to < 18 years with moderate-to-severe plaque psoriasis were randomized 2 : 1 to weight-based dosing of IXE every 4 weeks (IXE Q4W, n = 115) or placebo (n = 56) through week 12, followed by open-label IXE Q4W. Coprimary endpoints were the proportions of patients at week 12 achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and those achieving a static Physician's Global Assessment score of 0 or 1 (sPGA 0,1). RESULTS: IXE was superior (P < 0·001) to placebo for both coprimary endpoints of PASI 75 (IXE Q4W, 89%; placebo, 25%) and sPGA (0,1) (IXE Q4W, 81%; placebo, 11%). IXE was also superior for all gated secondary endpoints, including PASI 75 and sPGA (0,1) at week 4, improvement in itch, and complete skin clearance. IXE Q4W provided significant (P < 0·001) improvements vs. placebo in quality of life and clearance of scalp and genital psoriasis. Responses at week 12 were sustained or further improved through week 48. Through week 12, 45% (placebo) and 56% (IXE) of patients reported treatment-emergent adverse events. One serious adverse event was reported (IXE), one patient discontinued due to an adverse event (placebo) and no deaths were reported. CONCLUSIONS: IXE was superior to placebo in the treatment of moderate-to-severe paediatric psoriasis, and the safety profile was generally consistent with that observed in adults. What is already known about this topic? Paediatric psoriasis affects approximately 1% of children and can negatively impact health-related quality of life. Treatment options for paediatric psoriasis are typically limited to off-label treatments and approved systemic biologics. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for moderate-to-severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate-to-severe paediatric psoriasis. What does this study add? Ixekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health-related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate-to-severe plaque psoriasis. The safety profile of ixekizumab was generally consistent with that seen in adults. Ixekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin-17A antagonist) for the treatment of moderate-to-severe paediatric psoriasis. Plain language summary available online.

Complex arterial reconstruction in multivisceral transplantation.

We report the case of a successful multivisceral transplant in which both donor and recipient presented aberrant anatomy of the celiac-mesenteric axis requiring five separate arterial anastomoses to reconstruct the blood inflow to the graft.

Menstrual cycle stage and oral contraceptive effects on anterior tibial displacement in collegiate female athletes.

AIM: The aim of this study was to establish if differences in anterior tibial displacement exists in collegiate female student-athletes at different stages of the menstrual cycle. DESIGN AND SETTING: a 2 x 3 factorial design with repeated measures on the second factor guided this study. The first independent variable was group with 2 levels (control and oral contraceptive) and the second independent variable was menstrual cycle phase with 3 levels (follicular, ovulation, luteal). The single dependent variable was anterior tibial displacement. All data were collected in a research laboratory. SUBJECTS: 53 female student athletes (control: n=28; oral contraceptive: n=25) with no previous history of knee injury or anomalies with a normal 28-30 day menstrual cycle participated. MEASUREMENTS: anterior tibial displacement (mm) measurements were taken on days 1 (follicular phase), 13 (ovulation phase), and 23 (luteal phase) of each subject's menstrual cycle using a KT1000 knee arthrometer. RESULTS: For the entire group, statistically significant increases in anterior tibial laxity were found (F=4.49; df=52.1; P<0.05) between the follicular cycle (0+/-SD =5.14 mm) and ovulation cycle (0+/-SD=5.81 mm); and follicular cycle (0+/-SD=5.14 mm) and luteal cycle (0+/-SD=5.79 mm). A separate analysis of the non-birth control group revealed no significant difference in anterior tibial laxity throughout the stages of the menstrual cycle. CONCLUSION: The results of this study suggest that: 1) the menstrual cycle does have an influence on laxity of the anterior displacement of the knee; 2) significant increases in anterior displacement are shown during the ovulation and luteal phases of the menstrual cycle; and 3) birth control subjects tend to have increased laxity when compared to those subjects who are not on hormone therapy.

Modulation of soleus H-reflex by presynaptic spinal mechanisms during varying surface and ankle brace conditions.

AIMS: Reflex excitability is modulated in part by presynaptic spinal mechanisms. Presynaptic inhibition may prevent an over-response of the motoneuron pool to afferent information. A paired-reflex depression (PRD) conditioning protocol can be used to monitor reflex plasticity. Manipulation of stance, surface, and external bracing are common methods of rehabilitating and treating lower extremity musculoskeletal injuries. The intent of this study was to evaluate changes in PRD of the soleus H-reflex during single-leg stance under varying stability conditions. METHODS: Seven trials were completed for each condition in ten healthy volunteers (age=23+/-1.8 yr, weight 65.0+/-11.3 kg, height=168.7+/-28.0 cm). The conditioning stimuli were composed of soleus H-reflex pairs evoked 80 ms apart at an equal intensity. The mean percent decrease of the second H-reflex relative to the first represented PRD. RESULTS: A 2 x 2 repeated measures ANOVA (P<0.05) was used to evaluate influence of surface (foam, no foam) and support (semi-rigid ankle brace, no ankle brace) on PRD. Main effects testing revealed a significantly greater soleus PRD (P=.034) for the foam surface (62.5%) compared the flat surface (57.5%). Ankle brace application did not influence soleus PRD (P=0.63). CONCLUSION: The increase in soleus PRD during the foam condition suggests depression of the motoneuron pool. This may lessen postural over-corrections while maintaining upright stance during less stable conditions. No change in PRD during the ankle brace condition suggests that mechanical reinforcement provided an increase in ankle stability, decreasing the demand on the motoneuron pool.

Effect of inversion and ankle bracing on peroneus longus Hoffmann reflex.

This study examined peroneus longus (PL) Hoffmann reflex (H-reflex) during sudden inversion perturbation of the ankle/foot complex under an ankle brace and non-brace condition. Ten healthy subjects volunteered. H-reflexes were tested on the up-sloping portion of the recruitment curve, utilizing a control trial M-wave above motor threshold to maintain consistency between subjects and conditions. The PL H/maximum M-wave (M(max)) ratio was established using the PL H-reflex and PL M(max) peak-to-peak measures. The mean ratio across five trials for each subject under each ankle brace (brace, no brace) and surface (flat, inversion) conditions was utilized for analysis. The 1 x 4 repeated measures ANOVA revealed a significant main effect for treatment condition (P<0.0001). The PL H/M(max) ratio significantly increased during sudden inversion-no ankle brace condition compared with the flat surface no-ankle brace condition (P=0.04). Application of an ankle brace had no effect on PL H/M(max) ratio during inversion (P=0.78). During this study PL H/M(max) ratios increased during an inversion perturbation in healthy ankles. This is believed to occur due to heightened sensorimotor demand placed on the nervous system during this motion. Moreover, application of an ankle brace during inversion does not appear to affect PL H/M(max) ratio.

Control of the stereochemical impact of the lone pair in lead(II) tris(pyrazolyl)methane complexes. Improved preparation of Na[B[3,5-(CF3)2C6H3]4].

The reaction of Pb(acac)2 with 2 equiv of [H(Et2O)2][B[3,5-(CF3)2C6H3]4] (HBAr(f)) in CH2Cl2 followed by addition of 2 equiv of either HC(pz)3 or HC(3,5-Me2pz)3 (pz = pyrazolyl ring) leads to the formation of [Pb[HC(pz)3]2][B[3,5-(CF3)2C6H3]4]2 (1) and [Pb[HC(3,5-Me2pz)3]2][B[3,5-(CF3)2C6H3]4]2 (2), respectively. The cation in 1 has a distorted octahedral structure with a stereochemically active lone pair on lead(II). In contrast, the cation in 2 is trigonally distorted octahedral with the lone pair on the lead(II) clearly stereochemically inactive. The driving force for this cation to have a stereochemically inactive lone pair is that in this geometric arrangement the interligand distances between adjacent 3-position methyl groups are close to 4.0 A, the sum of the van der Waals radii of two methyl groups. To facilitate this chemistry, the synthesis of Na[B[3,5-(CF3)2C6H3]4], needed to prepare HBAr(f), has been dramatically improved. The main change is to add NaBF4 to the reaction mixture before forming the Grignard from the reaction of magnesium and 3,5-(CF3)2C6H3Br. The Grignard reacts with the NaBF4 as it forms, reducing the danger of explosion and leading to a higher isolated yield of the product. Crystallographic information: 1 is triclinic, P1, a = 13.0133(6) A, b = 17.2210(7) A, c = 24.7634(11) A, alpha = 71.7300(10) degrees, beta = 82.3630(10) degrees, gamma = 70.5120(10) degrees, Z = 2; 2 is triclinic, P1, a = 12.756(4) A, b = 13.469(4) A, c = 17.160(5) A, alpha = 82.454(7) degrees, beta = 89.904(8) degrees, gamma = 72.995(7) degrees, Z = 1.

Variable-temperature x-ray structural investigation of [Fe[HC(3,5-Me2pz)3]2](BF4)2 (pz= pyrazolyl ring): observation of a thermally induced spin state change from all high spin to an equal high spin-low spin mixture, concomitant with the onset of nonmerohedral twinning.

The complex [Fe[HC(3,5-Me(2)pz)(3)](2)](BF(4))(2) (pz = pyrazolyl ring) undergoes a phase transition that occurs concomitantly with a thermally induced spin conversion between the high-spin (HS, S = 2) and low-spin (LS, S = 0) states. Above 204 K the compound is completely HS with the structure in the C2/c space group with Z = 4. A crystal structure determination of this phase was performed at 220 K yielding the cell constants a = 20.338(2) A, b = 10.332(1) A, c = 19.644(2) A, beta = 111.097(2) degrees, and V = 3851.5(6) A(3). There is one unique iron(II) site at this temperature. Below 206 K the compound converts to a 50:50 mixture of HS and LS. The radical change in the coordination sphere for half of the iron(II) sites, most notably a shortening of the Fe-N bond distances by ca. 0.2 A, that accompanies this magnetic transition causes a phase transition. The crystal system changes from C-centered monoclinic to primitive triclinic with Z = 2 with two half-molecules on independent inversion centers. A crystal structure determination was performed at 173 K in space group P1 with a = 10.287(2) A, b = 11.355(3) A, c = 18.949(4) A, alpha = 90.852(4) degrees, beta = 105.245(4) degrees, gamma = 116.304(4) degrees, and V = 1892.3(8) A(3). All specimens investigated below the phase transition temperature were determined to be nonmerohedral twins. Temperature cycling between these two forms does not appear to degrade crystal quality. Previous magnetic susceptibility measurements indicate a second, irreversible increase in the magnetic moment the first time the crystals are cooled below 85 K. A crystal structure determination at 220 K of a specimen precooled to 78 K was not significantly different from those not cooled below 220 K.

A synthetic, structural, magnetic, and spectral study of several [Fe[tris(pyrazolyl)methane]2](BF4)2 complexes: observation of an unusual spin-state crossover.

The complexes [Fe[HC(3,5-Me2pz)3]2](BF4)2 (1), [Fe[HC(pz)3]2](BF4)2 (2), and [Fe[PhC(pz)2(py)]2](BF4)2 (3) (pz = 1-pyrazolyl ring, py = pyridyl ring) have been synthesized by the reaction of the appropriate ligand with Fe(BF4)2.6H2O. Complex 1 is high-spin in the solid state and in solution at 298 K. In the solid phase, it undergoes a decrease in magnetic moment at lower temperatures, changing at ca. 206 K to a mixture of high-spin and low-spin forms, a spin-state mixture that does not change upon subsequent cooling to 5 K. Crystallographically, there is only one iron(II) site in the ambient-temperature solid-state structure, a structure that clearly shows the complex is high-spin. Mössbauer spectral studies show conclusively that the magnetic moment change observed at lower temperatures arises from the complex changing from a high-spin state at higher temperatures to a 50:50 mixture of high-spin and low-spin states at lower temperatures. Complexes 2 and 3 are low-spin in the solid phase at room temperature. Complex 2 in the solid phase gradually changes over to the high-spin state upon heating above 295 K and is completely high-spin at ca. 470 K. In solution, variable-temperature 1H NMR spectra of 2 show both high-spin and low-spin forms are present, with the percentage of the paramagnetic form increasing as the temperature increases. Complex 3 is low-spin at all temperatures studied in both the solid phase and solution. An X-ray absorption spectral study has been undertaken to investigate the electronic spin states of [Fe[HC(3,5-Me2pz)3]2](BF4)2 and [Fe[HC(pz)3]2](BF4)2. Crystallographic information: 2 is monoclinic, P2(1)/n, a = 10.1891(2) A, b = 7.6223(2) A, c = 17.2411(4) A, beta = 100.7733(12) degrees, Z = 2; 3 is triclinic, P1, a = 12.4769(2) A, b = 12.7449(2) A, c = 13.0215(2) A, alpha = 83.0105(8) degrees, beta = 84.5554(7) degrees, gamma = 62.5797(2) degrees, Z = 2.

Plasmid pGW16, a derivative of pKM101, increases post-UV DNA synthesis, but sensitises some strains of Escherichia coli to UV.

Plasmid pKM101, which carries muc genes that are analogous in function to chromosomal umu genes, protected Escherichia coli strains AB1157 uvrB+ umuC+, JC3890 uvrB umuC+, TK702 uvrB+ umuC and TK501 uvrB umuC against ultraviolet irradiation (UV). Plasmid pGW16, a derivative of pKM101 selected for its increased spontaneous mutator effect, also gave some protection to the UmuC-deficient strains, TK702 and TK501. However, it sensitised the wild-type strain AB1157 to low, but protected against high doses of UV, whilst sensitising strain JC3890 to all UV doses tested. Even though its UV-protecting effects varied, pGW16 was shown to increase both spontaneous and UV-induced mutation in all strains. Another derivative of pKM101, plasmid pGW12, was shown to have lost all spontaneous and UV-induced mutator effects and did not affect post-UV survival. Plasmids pKM101 and pGW16 increased post-UV DNA synthesis in strains AB1157 and TK702, whereas pGW12 had no effect. Similarly, the wild-type UV-protecting plasmids R46, R446b and R124 increased post-UV DNA synthesis in strain TK501, but the non-UV-protecting plasmids R1, RP4 and R6K had no effect. These results accord with the model for error-prone DNA repair that requires umu or muc gene products for chain elongation after base insertion opposite non-coding lesions. They also suggest that the UV-sensitizing effects of pGW16 on umu+ strains can be explained in terms of overactive DNA repair resulting in lethal, rather than repaired UV-induced lesions.

A method to automate radiological surveys: the Ultrasonic Ranging and Data System.

The Ultrasonic Ranging and Data System (USRADS) was developed to allow radiation exposure rate data and positional information to be simultaneously collected, stored, and analyzed in a manner more efficient than conventional survey techniques. USRADS is field portable using ultrasonics to locate a field surveyor on a site and radiofrequency to transmit data. Surveyor position (e.g., measurement location within 10 cm) and an integrated instrument measurement are recorded and stored once each second in a microcomputer. Operational experience indicates that the system results in collection of greater quantity and higher quality of radiological data with less effort in data transcription and analysis and only slightly more field effort compared to conventional manual methods.

Relevance of plasmid pKM101-mediated mutagenicity in bacteria to genotoxicity in mammalian cells.

Three structurally related compounds, 4-acetoxy-3-acetoxy-methyl-acetophenone (AAMAP), 1-[4'-hydroxy-3'-hydroxy-methylphenyl]-2-[benzyl-t-butylamino] ethanone hydrochloride (HHBEH) and 1-[4'-hydroxy-3'-hydroxymethyl-phenyl]-2-[benzyl-t-butylamino] ethanol (HHBE), gave positive dose-related mutagenic responses in the Ames test when Salmonella typhimurium strain TA100 was used as the test organism. Strain TA100 carries the hisG46 allele, which is revertable by base changes, together with plasmid pKM101, which encodes mucAB genes that are analogous to umuDC, the chromosomal SOS-repair genes of Escherichia coli K-12. None of the compounds was mutagenic in Ames strain TA1535, which is the plasmid-free derivative of strain TA100. Only AAMAP, and that at only the highest concentration tested, was mutagenic in strain TA98, which detects frameshift mutations and carries plasmid pKM101. No compound was significantly mutagenic in strain TA1538, which is the plasmid-free derivative of strain TA98. When the three compounds were tested for the induction of sister-chromatid exchanges (SCEs) in Chinese hamster cells, the two more potent mutagens, AAMAP and HHBEH were found to increase SCEs, whereas HHBE did not give a significant response at any concentration tested. Ames test data showing plasmid pK101-dependent mutagenesis are therefore, at least for these compounds, relevant indicators of eukaryotic genotoxicity.

Studies of error-prone DNA repair in Escherichia coli K-12 and Ames Salmonella typhimurium strains using a model alkylating agent.

4-Acetoxy-3-acetoxymethyl acetophenone (AAMAP) is mutagenic in Ames Salmonella typhimurium tester strains TA100 and TA98, which carry plasmid pKM101, but not in the isogenic plasmid-less strains TA1535 and TA1538. Similarly, no AAMAP-induced reversion of the his-4 allele is detectable in Escherichia coli K-12 umuC strains in the absence of the plasmid, even when the strains are treated with ethylene-diaminetetraacetate to increase permeability, or when the uvrB allele is introduced to increase error-prone DNA repair. AAMAP is, however, mutagenic in umuC+ strains or in umuC strains in which plasmid pKM101 has been introduced, suggesting that the plasmid-encoded MucAB or the chromosomally determined UmuDC proteins are required for mutagenesis. Mutation frequencies are higher in E. coli umuC (pKM101) strains, which resemble Ames tester strains of S. typhimurium, than in E. coli umuC+ or even umuC+ (pKM101) strains. Therefore, providing that the recommended pKM101-containing tester strains are used, the apparent absence of Umu-like protein activity in S. typhimurium may actually increase the sensitivity of the Ames test for the detection of mutagens that require error-prone DNA repair for activity.

Optimization of sampling for the determination of mean radium-226 concentration in surface soil.

There are thousands of properties in the United States on which the soil has been contaminated to some degree with uranium mill tailings. An effort is now underway by the United States Department of Energy to identify sites contaminated with tailings and to perform remedial action when (226)Ra levels exceed current guidelines. Because of the large number of sites involved, it is imperative that sample collection be performed in a cost-effective manner. In this paper we describe the results of a study in which we compared the efficiencies of different methods of sample collection in order to determine an optimal method for estimating the mean (226)Ra concentration in soil. The study involved a field experiment in which extensive sampling was performed on sites known to be contaminated with uranium tailings. The experiment was designed to identify the advantages and limitations of composite sampling, the relative merits of random and uniformly spaced sample collection, the use of field gamma measurements for supplementing and reducing soil sample collection, and practical levels of accuracy and precision that can be obtained. Conclusions regarding gamma measurements are unique to (226)Ra contamination. On the other hand, conclusions concerning composite sampling and random versus uniformly spaced sampling may depend primarily on the way the contamination was spread by man and hence may not be unique to (226)Ra.

Comparison of observed and predicted air concentrations for 18.6 micron fluorescein particles.

From 1967 to 1973, numerous atmospheric dispersion experiments were conducted at Hanford, Washington, by the staff of Battelle Pacific Northwest Laboratories. We compared published data from those experiments to predictions made by the Gaussian plume atmospheric dispersion model for conditions similar to the field releases. The express purpose of the study was to consider the effects of non-zero dry deposition parameters on the accuracy of the model predictions of ground-level normalized air concentrations by comparing these predictions to the published Hanford field observations. Predictions were made consistent with existing dose assessment practices. We conclude that for the conditions tested, the predictive capability of the model was most improved when the deposition velocity parameters (vd) and the gravitational fall velocity (vg) were both set equal to 1.8 cm/s.