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Background and objectives Subclinical acute rejection is associated with poor outcomes in kidney transplant recipients. As an alternative to surveillance biopsies, noninvasive screening has been established with a blood gene expression profile. Donor-derived cellfree DNA (cfDNA) has been used to detect rejection in patients with allograft dysfunction but not tested extensively in stable patients. We hypothesized that we could complement noninvasive diagnostic performance for subclinical rejection by combining a donor-derived cfDNA and a gene expression profile assay. Design, setting, participants, & measurements We performed a post hoc analysis of simultaneous blood gene expression profile and donor-derived cfDNA assays in 428 samples paired with surveillance biopsies from 208 subjects enrolled in an observational clinical trial (Clinical Trials in Organ Transplantation-08). Assay results were analyzed as binary variables, and then, their continuous scores were combined using logistic regression. The performance of each assay alone and in combination was compared. Results For diagnosing subclinical rejection, the gene expression profile demonstrated a negative predictive value of 82%, a positive predictive value of 47%, a balanced accuracy of 64%, and an area under the receiver operating curve of 0.75. The donor-derived cfDNA assay showed similar negative predictive value (84%), positive predictive value (56%), balanced accuracy (68%), and area under the receiver operating curve (0.72). When both assays were negative, negative predictive value increased to 88%. When both assays were positive, positive predictive value increased to 81%. Combining assays using multivariable logistic regression, area under the receiver operating curve was 0.81, significantly higher than the gene expression profile (P Conclusions A combination of blood-based biomarkers can improve detection and provide less invasive monitoring for subclinical rejection. In this study, the gene expression profile detected more cellular rejection, whereas donor-derived cfDNA detected more antibody-mediated rejection.

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti‐CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUC inf, C max, and AUC last. The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUC inf and AUC last demonstrated a more than dose‐proportional increase in the range of 50‐500 mg, and C max increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment‐emergent anti‐bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose‐dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538)., In this randomized, phase 1b study in kidney transplant recipients, bleselumab, a nondepleting, fully human, anti‐CD40 monoclonal antibody, demonstrates tolerability, nonlinear pharmacokinetics, and prolonged, dose‐dependent B‐cell CD40 receptor occupancy. See the article by Harland et al on http://onlinelibrary.wiley.com/doi/10.1111/ajt.15591/abstract.

Two randomized, double-blind, placebo-controlled studies are reported that had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus kinase (JAK) inhibitor, in healthy subjects. The single-dose study included 7 male groups (3-300 mg) and 2 female groups (30 or 200 mg), n = 8/group (6 on ASP015K and 2 on placebo in each group). The multiple-dose study included 1 female and 3 male groups, n = 12/group (9 on ASP015K and 3 on placebo in each group), who received ASP015K (30 mg) or placebo every 12 hours (twice a day) for 14 days. In the single-dose study, plasma ASP015K concentration increased dose-proportionally. Food increased ASP015K exposure (AUCinf ) by 27%. Mean peak JAK inhibition increased with dose, from 6% at 4 hours (median) following ASP015K 3 mg to 93% (range, 89%-98%) at 2 hours (median) after ASP015K 300 mg. In the multiple-dose study, ASP015K plasma exposure reached steady state by day 3. On day 14, mean ASP015K peak concentration was 38%-65% higher than after the first dose; peak JAK inhibition following 100 or 200 mg twice daily was >85%. The most common adverse events (AEs) were neutropenia, headache, and abdominal pain; no serious AEs occurred. The safety findings at pharmacologically effective doses of ASP015K support further clinical development.

This study assessed the efficacy and safety of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate-release tacrolimus [IR-TAC]; target minimum blood concentration [Ctrough ] 4-11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR-TAC (0.1 mg/kg per day; target Ctrough 4-11 ng/mL days 0-30, then 2-5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3-5 posttransplant) and corticosteroids. One hundred thirty-eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR-TAC [n = 44]). For the primary endpoint (incidence of biopsy-proven acute rejection [BPAR] at 6 months), bleselumab + IR-TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] -8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%-46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR-TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit-risk ratio. Most treatment-emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).

Much of financial engineering is based on so-called “complete markets” and on the use of the Black-Scholes formula. The formula relies on the assumption that asset prices follow a log-normal distribution, or in other words, the daily fluctuations in prices viewed as percentage changes follow a Gaussian distribution. On the contrary, studies of actual asset prices show that they do not follow a log-normal distribution. In this paper, we investigate several widely-used heavy-tailed distributions. Our results indicate that the Skewed t distribution has the best empirical performance in fitting the Canadian stock market returns. We claim the results are valuable for market participants and the financial industry.

Professional development of science teachers has been a strong focus of efforts in the UK since 2006, in order to improve the quality of science learning by primary and secondary school students. Lessons have been learned from this effort, which are here applied to the particular goal of science education in the context of sustainable development and climate change. Beyond transmitting knowledge, the challenge for teachers is to introduce their students to the very nature of science and scientific thinking processes, as well as to ethical questions.

"… Our job is to make absolutely sure that the needs of science are made very clear to government, and are emphasised again and again and again. Because I really believe that strong science benefits everyone. It's not just scientists who benefit: we all benefit from scientific discoveries, and a country with a strong base in science will have a strong knowledge economy …" Read more in the Editorial by Sir John Holman and Edwin Silvester.

This report characterizes acute rejection and rejection outcomes in subjects randomized to continuous corticosteroid therapy (CCS) or early corticosteroid withdrawal (CSWD; 7 days after transplantation) in the Astellas Blinded CSWD Trial.The Astellas Blinded CSWD Trial was a 5-year, prospective, multicenter, randomized, double-blind trial of early CCS withdrawal in 386 kidney transplant recipients (195 CCS and 191 CSWD). Tacrolimus and mycophenolate mofetil were required as well as either rabbit antithymocyte globulin or interleukin-2 receptor antibody induction. Biopsy-confirmed acute rejection (BCAR) was grade 1A or higher by Banff criteria. This report also provides borderline changes (BL) that did not meet Banff grade 1A included with BCAR (BCAR+BL).BCAR+BL was 25 (12.8%) in CCS group and 42 (22.0%) in CSWD group (P=0.022). Early BCAR+BL (first 90 days after transplantation) was less frequent in CCS (n=5 [2.6%]) than in CSWD (n=22 [11.5%]; P0.001). Among non-African-American subjects, early BCAR+BL occurred more often in CSWD (n=20 [12.7%]) versus CCS (n=2 [1.3%]; P0.001). Late acute rejection (2 years) occurred more often in African-American subjects in CCS (n=5 [13.9%]) than in CSWD (n=0; P=0.056). Risk factors were CSWD (hazard ratio [HR], 4.72; P0.002) and human leukocyte antigen mismatch (HR, 1.48; P0.005) for early BCAR+BL and CSWD (HR, 1.9; P0.02), human leukocyte antigen mismatch (HR, 1.2; P0.01), and age (HR, 0.97; P0.002) for 5-year rejection. The HR for graft loss associated with BCAR+BL was 8.8.BCAR+BL may occur more frequently during the early period after transplantation under an early CSWD regimen with tacrolimus plus induction compared with CCS, particularly among non-African-Americans.

Psychotherapists from all professions and perspectives periodically struggle to effectively manage a patient's resistance to change. This article provides definitions and examples of patient-treatment matching applied to patient resistance or reactance. We report the results from an original meta-analysis of 12 select studies (N = 1,102) on matching therapist directiveness to patient reactance. Our findings support the hypothesis that patients exhibiting low levels of trait-like resistance respond better to directive types of treatment, while patients with high levels of resistance respond best to nondirective treatments (d = .82). Limitations of the research reviewed are noted, and practice recommendations are advanced.

Background BK polyomavirus infection has been reported in 10% to 60% of renal transplant recipients with progression to BK nephropathy (BKN) occurring in 1% to 5% of patients. Graft loss occurs in up to 60% of renal transplant recipients with BKN. Because BK polyomavirus infection is believed, in part, to be a manifestation of overimmunosuppression, the current standard of care involves the reduction of immunosuppressants. This strategy has been associated with clearance of viral load, preservation of renal function, and improvement in graft survival; however, this may come at a risk of rejection. A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation. Methods In a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in renal transplant patients, FK778 (an investigational immunosuppressant from the malononitrilamides class) was compared with the current standard of care (reduction of immunosuppression) for treatment of newly diagnosed or untreated BKN, which was confirmed by renal biopsy. Results Demographic characteristics were similar between the two groups, except there were numerically more females in the FK778 group than in the standard care group. Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression. Conclusions Data from this study are consistent with the findings of previous studies that found no benefit of drug therapy in the treatment of BKN in kidney transplant recipients.

1507Background: Recent studies have identified single-nucleotide polymorphisms (SNPs) that individually confer modest risk but together explain genetic BC predisposition in many women testing negat...

Many of financial engineering theories are based on so-called “complete markets” and on the use of the Black-Scholes formula. The formula relies on the assumption that asset prices follow a log-normal distribution, or in other words, the daily fluctuations in prices viewed as percentage changes follow a Gaussian distribution. On the contrary, studies of actual asset prices show that they do not follow a log-normal distribution. In this paper, we investigate several widely-used heavy-tailed distributions. Our results indicate that the Skewed t distribution has the best empirical performance in fitting the Canadian stock market returns. We claim the results are valuable for market participants and the financial industry.

Two randomized, double-blind, placebo-controlled studies are reported that had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus kinase (JAK) inhibitor, in healthy subjects. The single-dose study included 7 male groups (3-300 mg) and 2 female groups (30 or 200 mg), n = 8/group (6 on ASP015K and 2 on placebo in each group). The multiple-dose study included 1 female and 3 male groups, n = 12/group (9 on ASP015K and 3 on placebo in each group), who received ASP015K (30 mg) or placebo every 12 hours (twice a day) for 14 days. In the single-dose study, plasma ASP015K concentration increased dose-proportionally. Food increased ASP015K exposure (AUC

Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel.BackgroundNeointimal hyperplasia occurs commonly at the anastomoses of arteriovenous grafts for chronic hemodialysis, causing stenosis and occlusion. Antiproliferative drugs may be effective in inhibiting hyperplasia, but local drug delivery would be required to minimize systemic side effects. We examined the feasibility of local drug delivery to inhibit neointimal hyperplasia at dialysis grafts in a canine model.MethodsBilateral polytetrafluoroethylene loop grafts (10-cm length and 6-mm internal diameter) were placed between the femoral artery and ipsilateral femoral vein of five mongrel dogs. At the time of surgery or 1 to 5 weeks later, 2 mL of a thermosensitive biodegradable copolymer (ReGel®) mixed with 0.26 mg or 0.65 mg paclitaxel were applied to the external surface of one graft around the anastomoses to provide a depot for sustained release of the drug. ReGel alone without paclitaxel was applied to the contralateral graft as a control. The grafts and the connecting vessels were explanted at eight or nine weeks, and the cross-sections were examined histologically. The degree of hyperplasia at the anastomoses was graded by five blinded independent reviewers, with scores ranging from 0 to 5.ResultsThe median (25th–75th percentile) hyperplasia score of both arterial and venous anastomoses was 1.80 (0.90–3.05) in the grafts treated with ReGel alone, and 0.95 (0.70–1.50) in the grafts treated with ReGel/paclitaxel (N = 8; P < 0.05 by Wilcoxon signed rank test). There were no noticeable localized or systemic complications attributed to the treatments in these animals. Paclitaxel levels in the plasma obtained from forelimb veins were undetectable (

Background Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract. Objective To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon. Methods The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters C max , T max after the capsule activation, AUC 0–24 , and mean residence time were determined from the concentration–time profiles. Results Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC 0–24 values revealed some site-specific absorption tendencies, the mean AUC 0–24 values obtained were similar regardless of the location of tacrolimus release from the capsule. Conclusions Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC 0–24 , possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.

This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 μg/mL and 6.5 to 55409.6 h·μg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested.

Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade ≥ 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm.

BACKGROUND There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P

Background. The determination of optimal tacrolimus (TAC) trough levels is needed to prevent adverse effects of calcineurin inhibitors. Methods. Stable transplant recipients currently receiving cyclosporine (CsA) were assigned randomly (1:1:1) to continue CsA (target trough level of 50-250 ng/mL); or convert to "reduced" TAC (target trough level 3.0-5.9 ng/mL) or "standard" TAC (target trough level 6.0-8.9 ng/mL). Results. At 12 months, there was a significant improvement in renal function in the reduced TAC versus CsA group with lower serum creatinine (P=0.004) and cystatin C (P

Background This study compared the long-term effects of switching from cyclosporine to tacrolimus on the incidence, progression, and severity of chronic renal allograft failure in patients with elevated serum creatinine levels. Methods Patients were assigned randomly (2:1) to switch to tacrolimus or remain on cyclosporine. Tacrolimus was initiated at 1/50th of the cyclosporine dose or 0.15 mg/kg/day, whichever dose was lower, to maintain trough concentrations between 5 and 15 ng/mL. Cyclosporine doses were adjusted to achieve trough concentrations between 100 and 300 ng/mL. Results At 60 months, the median change from baseline in serum creatinine was -0.2 mg/dL in the tacrolimus group and 0.3 mg/dL in the cyclosporine group (P=0.003). Median change in estimated creatinine clearance was 1.2 mL/min in the tacrolimus group and -4.1 mL/min in the cyclosporine group (P=0.019). The incidence of new-onset diabetes, hyperglycemia, hypertension, lymphoma, and malignancies was generally low and comparable between groups. Fewer patients in the tacrolimus group than in the cyclosporine group developed new cardiac conditions (11% vs. 28%, P=0.004), had low-density lipoprotein (LDL) cholesterol values more than 130 mg/dL (29% vs. 57%, P=0.002), or developed hyperlipidemia (24% vs. 67%, P=0.046) during the 60-month follow-up period. Despite these changes, patient and graft survival were similar for both groups. Conclusion Switching from cyclosporine to tacrolimus resulted in improved renal function and a reduction in the occurrence of new-onset cardiac conditions and hyperlipidemia, with no increase in the incidence of new-onset diabetes or new-onset hyperglycemia. However, after 5 years there was no impact on patient or graft survival.

Compliance with complex immunosuppressant drug therapies in transplant recipients might be improved with regimens that require less frequent dosing. A once-daily extended release (XL) formulation of tacrolimus has been developed that allows a 1:1 conversion from the twice-a-day tacrolimus (TAC) formulation and has a good exposure to trough concentration correlation. In an open-label, multicenter study, stable liver transplant recipients (n=69) were converted from twice-a-day TAC to XL once-daily in the morning, and were maintained for at least 2 years postconversion using the same therapeutic monitoring and patient care techniques employed with TAC. Two years after conversion, the incidence of biopsy-confirmed acute rejection was 5.8% (4 of 69); patient and graft survival was 98.6% (68 of 69). The safety profile of XL was consistent with that previously reported for TAC. Liver transplant recipients can be converted from twice-a-day TAC to once-daily XL and maintained for at least 2 years postconversion with neither unique efficacy nor safety concerns.

Once-daily tacrolimus extended-release formulation (Prograf XL, formerly referred to as MR or MR4) was compared with the twice-a-day tacrolimus formulation (TAC) and cyclosporine microemulsion (CsA), all administered in combination with mycophenolate mofetil (MMF), corticosteroids and basiliximab induction, in a phase 3, randomized (1:1:1), open-label trial in 638 de novo kidney transplant recipients. In combination with MMF and corticosteroids, XL had an efficacy profile comparable to TAC and CsA. XL/MMF and TAC/MMF were statistically noninferior at 1-year posttransplantation to CsA/MMF for the primary efficacy endpoint, efficacy failure (death, graft loss, biopsy-confirmed acute rejection (BCAR) or lost to follow-up). One-year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety profile of XL in comparison with CsA was similar to that observed with TAC in this study and consistent with previously published reports of TAC in comparison with CsA. The results support the safety and efficacy of tacrolimus in combination with MMF, corticosteroids and basiliximab induction, as well as XL as a safe and effective once-daily dosing alternative.

The UK-wide network of science learning centres is helping to re-entuse science teachers, who can in turn pass on their inspiration to their classes. John Holman explains

Background ASP015K is an oral Janus kinase (JAK) inhibitor with moderate selectivity for JAK3, a key enzyme for interleukin-2 (IL-2) signaling. With IL-2 stimulation, JAK1/3 augments STAT5 phosphorylation (STAT5-P), which is an integral step in the T cell activation pathway. Objectives In two phase1 dose-escalation trials, we evaluated the pharmacodynamics (PD) of ASP015K after single and multiple doses in healthy subjects measuring STAT5-P as a biomarker of JAK1/3 activity. Methods Study A: single doses of ASP015K (3, 10, 30, 60, 120, 200, 300 mg) or placebo (PBO) were given in 9 sequential groups (n=6 active and 2 PBO per group). Study B: 3 groups of men received ASP015K (30, 100, 200 mg twice daily [BID]) or PBO, and 1 group of women received ASP015K (100 mg BID) or PBO (n=9 active and 3 PBO per group) for 13.5 days. PD variables included serial measures of percentage reduction of IL-2–stimulated STAT5-P in T cells; total lymphocyte count and peripheral lymphocyte subtypes pre- and postdose. Results The median peak STAT5-P inhibition occurred at 1–2 hours after a single dose, consistent with the median t max in plasma ASP015K concentrations. ASP015K inhibited STAT5-P in a dose dependent manner, with mean peak percentage inhibitions of 84%, 85%, 92%, and 93% after 60, 120, 200, and 300 mg doses, respectively. The relationship between plasma ASP015K concentration and percentage STAT5-P inhibition was described by an E max model with 50% of maximum effect (EC 50 ) achieved at 48 ng/mL, estimated E max close to 100%, and a shape factor (γ) of ~1.2. With multiple doses on days 1, 7, and 14, median percentage of STAT5-P inhibition peaked at ~2 hours postdose, median peak inhibition ranged from 89%–98% with ASP015K at 100 and 200 mg on all days. The percentage STAT5-P inhibition was similar in men and women after single-dose 30 mg as well as with multiple doses (100 mg BID). After multiple doses, a small decrease in lymphocyte count from baseline was seen with 100 and 200 mg BID doses in men on day 17, with no dose dependency. Dose-dependent decreases in NK cells, a lymphocyte subset, were seen with ASP015K on day 17. Conclusions ASP015K showed dose- and concentration-dependent inhibition of STAT5-P. Total lymphocyte count showed no dose-dependent changes. A dose-dependent reduction in NK cells was seen with multiple doses. These results are consistent with the pharmacologic effect of JAK1/3 inhibition by ASP015K. In a phase 2a study, ASP015K decreased disease severity in psoriasis patients; studies to test safety and efficacy of ASP015K in rheumatoid arthritis patients are underway. Disclosure of Interest T. Zhu Employee of: Astellas Pharma Global Development, U. Valluri Employee of: Astellas Pharma Global Development, M. Lewand Employee of: Astellas Pharma Global Development, Y. Cao Employee of: Astellas Pharma Global Development, K. Cho Employee of: Astellas Pharma Global Development, J. Holman Employee of: Astellas Pharma Global Development, T. Sawamoto Employee of: Astellas Pharma, Inc., J. Keirns Employee of: Astellas Pharma Global Development

Background ASP015K is an oral Janus kinase (JAK) inhibitor of JAK1/3 in development for treatment of autoimmune diseases (eg, psoriasis, rheumatoid arthritis). Objectives Pharmacokinetics (PK), safety, and tolerability of ASP015K were assessed in 2 double-blind, placebo-controlled, dose-escalation trials in healthy subjects. Methods Study A: single doses of ASP015K 3–300 mg or placebo (PBO) were given in 9 sequential groups (n=6 active: 2 PBO/group). Study B: 3 groups of men received ASP015K 30, 100, or 200 mg twice daily (BID) or PBO, and 1 group of women received 100 mg BID or PBO (n=9 active:3 PBO/group) for 13.5 days. Plasma PK parameters were calculated with noncompartmental methods. Adverse events (AEs), clinical labs, vital signs, and electrocardiograms (ECGs) were evaluated. Results After single doses under fasted conditions, ASP015K was rapidly absorbed with median time to maximum observed concentration (tmax) ≤1.75 hours. Mean maximum observed concentration (Cmax) and area under the curve from time 0 extrapolated to infinity (AUCinf) increased dose proportionally. Elimination was multiphasic with terminal mean half-life (t1/2) of 7.0–13 hours at clinically relevant doses (≥60 mg). Food increased Cmax by 5% and AUCinf by 27% and delayed tmax by ∼2.5 hours. After BID dosing in a fed state, exposure reached steady state on day 3, with Cmax and AUC12h increasing relatively dose proportionally. Mean accumulation factor (day 14 vs day 1) was 1.12–1.65 for Cmax, 1.38–1.65 for AUC12h, and 2.02–2.71 for Ctrough. There was no statistically significant sex difference in PK with single or multiple doses. There was no evidence of dose-limiting toxicities or significant safety findings with single doses. With multiple doses, 75% (27/36) of ASP015K subjects and 42% (5/12) of PBO subjects had AEs, mostly mild or moderate; no serious AEs occurred. The most common AEs were neutropenia, headache, and abdominal pain, with apparent dose dependency. Three subjects discontinued due to AEs (1 man with moderate vomiting [100 mg]; 1 man with mild-to-moderate neutropenia [200 mg BID]; 1 woman with severe neutropenia [100 mg BID]). There were no clinically significant changes in labs, vital signs, or ECG (no positive correlation between ASP015K concentration and QTcF). Conclusions ASP015K was generally well tolerated and showed rapid absorption with small food effect, elimination t1/2 >7 hours at clinically relevant doses, and modest accumulation after BID dosing. Plasma exposure was relatively dose proportional, with no significant sex differences in PK. Disclosure of Interest T. Zhu Employee of: Astellas Pharma Global Development, T. Sawamoto Employee of: Astellas Pharma, Inc., U. Valluri Employee of: Astellas Pharma Global Development, M. Lewand Employee of: Astellas Pharma Global Development, Y. Cao Employee of: Astellas Pharma Global Development, S. Swan: None Declared, K. Lasseter: None Declared, M. Matson: None Declared, J. Holman Employee of: Astellas Pharma Global Development, J. Keirns Employee of: Astellas Pharma Global Development

Thermodynamics is often considered to be a dry and theoretical area of undergraduate chemistry. To make it more accessible, a contextualized approach to first-year university thermodynamics has been developed, building on the experiences at the high school level of ChemCom in the United States and Salters Advanced Chemistry in the United Kingdom. A constructivist approach takes into account students' prior understanding of enthalpy and energy transfer from high school chemistry. Contextualized lectures, tutorials, workshops, and examination questions are supported by a bank of Web-based questions designed to practice the basic mathematical manipulations. Contexts used include fuels, explosives, food, and bioenergetics. The course, which is aimed at chemistry majors, has been used at the University of Leeds and the University of York in the United Kingdom. Initial evaluation suggests that the approach increases the appeal of thermodynamics and improves learning of fundamental principles. The article seeks ...

A project is described which, although not explicitly related to Materials Science, does perhaps offer a model for the way in which schools in different European countries can collaborate. It has the advantage of being a functioning project that is actually in operation in over 200 schools in Europe.

Ken Dobson's article "The education time tunnel" (Forum, May p15) and the ensuing correspondence show that there is some enthusiasm for bringing more up-to-date physics and applications into A-level courses. The continuing decline in numbers of physics students also indicates that syllabuses may be in need of an overhaul.

The SATIS team set out to produce a set of resource units which attempt to remedy the shortcomings of traditional science material. The material would aim to illustrate the social, economic and technological implications of the science curriculum and try to avoid the cultural and gender bias that inadvertently pervades many of the present resources. It was hoped to provide not only original and interactive resources but also an opportunity to experiment with a wider range of teaching techniques. The method of publication was to be unconventional. The priority was to make the resource units available to every science department, however stringent its budget, and to produce them in the most versatile and economical form. They were to be short, simple and easy to use. The material is now available from the Association for Science Education as loosely bound books of copyright-waived masters from which teachers can select the units they require.

It is neither appropriate nor desirable to teach the detailed formalities of chemical engineering in secondary schools. The aim should be to raise awareness and arouse interest, in order to encourage students to take up the study of chemical engineering at a higher level. This aim can be achieved by infusing the school science curriculum with simple case studies and applications drawn from the chemical industry. Some examples of appropriate resource materials are described in this paper.

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