Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy.

BACKGROUND: We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. METHODS AND RESULTS: We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. CONCLUSIONS: ICD therapy is indicated for PP in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.

Multi-centre analysis of incidental findings on low-resolution CT attenuation correction images.

OBJECTIVE: To review new incidental findings detected on low-resolution CT attenuation correction (CTAC) images acquired during single-photon emission CT (SPECT-CT) myocardial perfusion imaging (MPI) and to determine whether the CTAC images had diagnostic value and warrant reporting. METHODS: A multicentre study was performed in four UK nuclear medicine departments. CTAC images acquired as part of MPI performed using SPECT were evaluated to identify incidental findings. New findings considered to be clinically significant were evaluated further. Positive predictive value (PPV) was determined at the time of definitive diagnosis. RESULTS: Of 1819 patients studied, 497 (27.3%) had a positive CTAC finding. 51 (2.8%) patients had findings that were clinically significant at the time of the CTAC report and had not been previously diagnosed. Only four (0.2%) of these were potentially detrimental to patient outcome. CONCLUSION: One centre had a PPV of 0%, and the study suggests that these CTAC images should not be reported. Two centres with more modern equipment had low PPVs of 0% and 6%, respectively, and further research is suggested prior to drawing a conclusion. The centre with best quality CT had a PPV of 67%, and the study suggests that CTAC images from this equipment should be reported. ADVANCES IN KNOWLEDGE: This study is unique compared with previous studies that have reported only the potential to identify incidental findings on low-resolution CT images. This study both identifies and evaluates new clinically significant incidental findings, and it demonstrates that the benefit of reporting the CTAC images depends on the type of equipment used.

Boron environments in Pyrex® glass--a high resolution, Double-Rotation NMR and thermodynamic modelling study.

It is shown, using the important technological glass Pyrex® as an example, that 1D and 2D (11)B Double-Rotation (DOR) NMR experiments, in combination with thermodynamic modelling, are able to provide unique structural information about complex glasses. (11)B DOR NMR has been applied to Pyrex® glass in order to remove both dipolar and quadrupolar broadening of the NMR lines, leading to high resolution spectra that allow unambiguous, accurate peak fitting to be carried out, of particular importance in the case of the 3-coordinated [BO(3)] (B3) trigonal planar environments. The data obtained are of sufficient quality that they can be used to test the distributions of borate and borosilicate superstructural units predicted by the thermodynamics-based Model of Associated Solutions. The model predicts the dominant boron-containing chemical groupings in Pyrex® glass to be those associated with B(2)O(3) and sodium tetraborate (with smaller amounts of sodium triborate, sodium diborate, sodium pentaborate, danburite and reedmergnerite). Excellent agreement is found between model and experiment provided the (11)B peaks with isotropic chemical shifts of -1.4 ppm and 0.5 ppm are assigned to B4 species from borosilicate units ([B(OSi)(4)] and [B(OSi)(3)(OB)]) and borate superstructural units (mainly triborate rings with some pentaborate and diborate) respectively. The peaks with isotropic shifts of 14 ppm and 18.1 ppm are then assigned to B3 in borate superstructural units (mainly triborate and pentaborate along with connecting B3) and boroxol rings respectively. The assignments of the DOR NMR peaks, are supported by the presence of cross-peaks in (11)B spin-diffusion DOR NMR spectra which can be used to develop a structural model in which B(2)O(3)-like regions are linked, via borate and borosilicate superstructural units, to the majority silica network. Pyrex® is thus shown to have a heterogeneous structure, with distinct molecular groupings that are far removed from a random distribution of network polyhedra with only short-range order.

Monte Carlo simulation of mixed lennard-jones nonionic surfactant adsorption at the liquid/vapor interface.

New Monte Carlo simulations are presented for nonionic surfactant adsorption at the liquid/vapor interface of a monatomic solvent specifically investigating the roles of tail attraction and binary mixtures of different tail lengths. Surfactant molecules consist of an amphiphilic chain with a solvophilic head and a solvophobic tail. All molecules in the system, solvent and surfactant, are characterized by the Lennard-Jones (LJ) potential. Adjacent atoms along the surfactant chain are connected by finitely extensible harmonic springs. Solvent molecules move via the Metropolis random-walk algorithm, whereas surfactant molecules move according to the continuum configurational bias Monte Carlo (CBMC) method. We generate thermodynamic adsorption and surface-tension isotherms and compare results quantitatively to single-surfactant adsorption (Langmuir, 2007, 23, 1835). Surfactant tail groups with attractive interaction lead to cooperative adsorption at high surface coverage and higher maximum adsorption at the interface than those without. Moreover, adsorption and surface-tension isotherms with and without tail attraction are identical at low concentrations, deviating only near maximum coverage. Simulated binary mixtures of surfactants with differing lengths give intermediate behavior between that of the corresponding single-surfactant adsorption and surface-tension isotherms both with and without tail attraction. We successfully predict simulated mixture results with the thermodynamically consistent ideal adsorbed solution (IAS) theory for binary mixtures of unequal-sized surfactants using only the simulations from the single surfactants. Ultimately, we establish that a coarse-grained LJ surfactant system is useful for understanding actual surfactant systems when tail attraction is important and for unequal-sized mixtures of amphiphiles.

Determination of NMR interaction parameters from double rotation NMR.

It is shown that the anisotropic NMR parameters for half-integer quadrupolar nuclei can be determined using double rotation (DOR) NMR at a single magnetic field with comparable accuracy to multi-field static and MAS experiments. The (17)O nuclei in isotopically enriched l-alanine and OPPh(3) are used as illustrations. The anisotropic NMR parameters are obtained from spectral simulation of the DOR spinning sideband intensities using a computer program written with the GAMMA spin-simulation libraries. Contributions due to the quadrupolar interaction, chemical shift anisotropy, dipolar coupling and J coupling are included in the simulations. In l-alanine the oxygen chemical shift span is 455 +/- 20 ppm and 350 +/- 20 ppm for the O1 and O2 sites, respectively, and the Euler angles are determined to an accuracy of +/- 5-10 degrees . For cases where effects due to heteronuclear J and dipolar coupling are observed, it is possible to determine the angle between the internuclear vector and the principal axis of the electric field gradient (EFG). Thus, the orientation of the major components of both the EFG and chemical shift tensors (i.e., V(33) and delta(33)) in the molecular frame may be obtained from the relative intensity of the split DOR peaks. For OPPh(3) the principal axis of the (17)O EFG is found to be close to the O-P bond, and the (17)O-(31)P one-bond J coupling ((1)J(OP)=161 +/- 2 Hz) is determined to a much higher accuracy than previously.

Monte Carlo simulations of Lennard-Jones nonionic surfactant adsorption at the liquid/vapor interface.

We present Monte Carlo simulations of nonionic surfactant adsorption at the liquid/vapor interface of a monatomic solvent. All molecules in the system, solvent and surfactant, are characterized by the Lennard-Jones (LJ) potential using differing interaction parameters. Surfactant molecules consist of an amphiphilic chain with a solvophilic head and a solvophobic tail. Adjacent atoms along the surfactant chain are connected by finitely extensible harmonic springs. Solvent molecules move via the Metropolis random-walk algorithm, whereas surfactant molecules move according to the continuum configurational bias Monte Carlo (CBMC) method. We generate quantitative thermodynamic adsorption and surface tension isotherms in addition to surfactant radius of gyration, tilt angles, and potentials of mean force. Surface tension simulations compared to those calculated from the simulated adsorbed amounts and the Gibbs adsorption isotherm agree confirming equilibrium in our simulations. We find that the classical Langmuir isotherm is obeyed for our LJ surfactants over the range of head and tail lengths studied. Although simulated surfactant chains in the bulk solution exhibit random orientations, surfactant chains at the interface orient roughly perpendicular and the tails elongate compared to bulk chains even in the submonolayer adsorption regime. At a critical surfactant concentration, designated as the critical aggregation concentration (CAC), we find aggregates in the solution away from the interface. At higher concentrations, simulated surface tensions remain practically constant. Using the simulated potential of mean force in the submonolayer regime and an estimate of the surfactant footprint at the CAC, we predict a priori the Langmuir adsorption constant, KL, and the maximum monolayer adsorption, Gammam. Adsorption is driven not by proclivity of the surfactant for the interface, but by the dislike of the surfactant tails for the solvent, that is by a "solvophobic" effect. Accordingly, we establish that a coarse-grained LJ surfactant system mimics well the expected equilibrium behavior of aqueous nonionic surfactants adsorbing at the air/water interface.

The effect of oxide additions on medium-range order structures in borosilicate glasses.

Boron-11 nuclear magnetic resonance (MAS NMR) and Raman spectroscopies have been used to study four families of glasses: xCs2O(100-x)ZMW (0

Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours.

This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Furthermore, the pharmacokinetics of each of these agents was evaluated. Patients were treated with tipifarnib b.i.d. on days 1-7 of each 21-day cycle. In addition, gemcitabine was given as a 30-min i.v. infusion on days 1 and 8 and cisplatin as a 3-h i.v. infusion on day 1. An interpatient dose-escalation scheme was used. Pharmacokinetics was determined in plasma and white blood cells. In total, 31 patients were included at five dose levels. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia grade 4, neutropenia grade 4, febrile neutropenia grade 4, electrolyte imbalance grade 3, fatigue grade 3 and decreased hearing grade 2. The MTD was tipifarnib 200 mg b.i.d., gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). Eight patients had a confirmed partial response and 12 patients stable disease. No clinically relevant pharmacokinetic interactions were observed. Tipifarnib can be administered safely at 200 mg b.i.d. in combination with gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting.

33S solid state NMR of sulphur speciation in silicate glasses.

33S solid-state NMR is reported from some model crystalline sulphides, sulphates, sulphites and thiosulphates. This is the first report of (33)S NMR signals of the latter two species from a solid. Good quality spectra, which have distinct, well separated shift ranges can be identified for all these groupings, except for sulphites and hydrogen sulphites whose resonances are very broad. Nonetheless the presence of sulphites and hydrogen sulphites can be confirmed from their characteristic sharp, intense time domain echoes. (33)S MAS NMR is also applied to a range of dry and hydrous silicate glasses with approximately 1wt% 99at% (33)S-enriched sulphur. It is clear that in all these glasses sulphate is present, and in mixed cation systems there is some evidence of preferential association of sulphate with a specific cation. In a dry potassium silicate glass sample two resolved (33)S resonances are observed, a sulphate, and the second from thiosulphate. Hence solid state (33)S NMR is shown to be a feasible probe that can be applied to this problem that can readily distinguish different sulphur species.

Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer.

Antitumor and pharmacodynamic studies were performed in MCF-7 human breast cancer cells and companion xenografts with the farnesyl protein transferase inhibitor, R115777, presently undergoing Phase II clinical trials, including in breast cancer. R115777 inhibited growth of MCF-7 cells in vitro with an IC(50) of 0.31 +/- 0.25 microM. Exposure of MCF-7 cells to increasing concentrations of R115777 for 24 h resulted in the inhibition of protein farnesylation, as indicated by the appearance of prelamin A at concentrations >1 microM. After continuous exposure to 2 microM R115777, prelamin A levels peaked at 2 h post drug exposure and remained high for up to 72 h. R115777 administered p.o. twice daily for 10 consecutive days to mice bearing established s.c. MCF-7 xenografts induced tumor inhibition at a dose of 25 mg/kg [percentage of treated versus control (% T/C) = 63% at day 21]. Greater inhibition was observed at doses of 50 mg/kg (% T/C at day 21 = 38%) or 100 mg/kg (% T/C at day 21 = 43%). The antitumor effect appeared to be mainly cytostatic with little evidence of tumor shrinkage to less than the starting volume. Tumor response correlated with an increase in the appearance of prelamin A, but no changes in the prenylation of lamin B, heat shock protein 40, or N-Ras were detectable. In addition, significant increases in apoptotic index and p21(WAF1/CIP1) expression were observed, concomitant with a decrease in proliferation as measured by Ki-67 staining. An increase in prelamin A was also observed in peripheral blood lymphocytes in a breast cancer patient who responded to R115777. These data show that R115777 possesses preclinical antitumor activity against human breast cancer and that the appearance of prelamin A may provide a sensitive and convenient pharmacodynamic marker of inhibition of prenylation and/or response.

Incidental memory and navigation in panoramic virtual reality for electronic commerce.

Recently much effort has been dedicated to designing and implementing World Wide Web sites for virtual shopping and e-commerce. Despite this effort, relatively little empirical work has been done to determine the effectiveness with which different site designs sell products. We report three experiments in which participants were asked to search for products in various experimental e-commerce sites. Across the experiments participants were asked to search in either QTVR (QuickTime Virtual Reality), hypertext, or pictorially rich hypertext environments; they were then tested for their ability to recall the products seen and to recognize product locations. The experiments demonstrated that when using QTVR (Experiments 1, 2, and 3) or pictorial environments (Experiment 2), participants retained more information about products that were incidental to their goals. In two of the experiments it was shown that participants navigated more efficiently when using a QTVR environment. The costs and benefits of using 3D virtual environments for on-line shops are discussed. Actual or potential applications of this research include support for the development of e-commerce design guidelines.

Increased expression and activity of RhoA are associated with increased DNA synthesis and reduced p27(Kip1) expression in the vasculature of hypertensive rats.

We have previously shown that the function of the small G protein Rho is required for vascular smooth muscle cell proliferation and migration. We hypothesized that changes in Rho or Rho signaling might contribute to enhanced vascular proliferative responses associated with hypertension. Western blot analysis revealed that total RhoA expression was approximately 2-fold higher in aortas, tail arteries, and aortic smooth muscle cells (ASMCs) obtained from adult male spontaneously hypertensive rats (SHR) compared with those from Wistar Kyoto rats (WKY). An increase in active GTP-bound RhoA was detected in aortic homogenates by affinity precipitation with the RhoA effector rhotekin and by examining RhoA-[(35)S]GTPgammaS binding. RhoA protein and activity were also increased in vessels from rats treated with N-nitro-L-arginine methyl ester to increase blood pressure. Thrombin-stimulated RhoA activation was also significantly greater in ASMCs from SHR. As a functional correlate of these changes in Rho signaling, thrombin-stimulated DNA synthesis was enhanced in tail arteries and ASMCs from SHR. Expression of the cyclin-dependent kinase inhibitor p27(Kip1) was decreased by two thirds in SHR, and this decrease was mimicked in ASMCs by expression of a constitutively active (GTPase-deficient) mutant of RhoA. Wortmannin (10 nmol/L) fully inhibited the decrease in p27(Kip1) induced by RhoA, and a membrane-targeted catalytic subunit of phosphatidylinositol-3 kinase (PI3K [p110(CAAX)]) decreased p27(Kip1) expression, suggesting that RhoA signals through PI3K. These data provide evidence that RhoA brings about changes in DNA synthesis through reduced expression of p27(Kip1), mediated in part via PI3K, and suggest that increases in RhoA expression and activity contribute to the enhanced vascular responsiveness observed in hypertension.

The assessment of poorly performing doctors: the development of the assessment programmes for the General Medical Council's Performance Procedures.

BACKGROUND: Modernization of medical regulation has included the introduction of the Professional Performance Procedures by the UK General Medical Council in 1995. The Council now has the power to assess any registered practitioner whose performance may be seriously deficient, thus calling registration (licensure) into question. Problems arising from ill health or conduct are dealt with under separate programmes. METHODS: This paper describes the development of the assessment programmes within the overall policy framework determined by the Council. Peer review of performance in the workplace (Phase 1) is followed by tests of competence (Phase 2) to reflect the relationship between clinical competence and performance. The theoretical and research basis for the approach are presented, and the relationship between the qualitative methods in Phase 1 and the quantitative methods in Phase 2 explored. CONCLUSIONS: The approach is feasible, has been implemented and has stood legal challenge. The assessors judge and report all the evidence they collect and may not select from it. All their judgements are included and the voice of the lay assessor is preserved. Taken together, the output from both phases forms an important basis for remediation and training should it be required.

Training the assessors for the General Medical Council's Performance Procedures.

From July 1997, the General Medical Council (GMC) has had the power to investigate doctors whose performance is considered to be seriously deficient. Assessment procedures have been developed for all medical specialties to include peer review of performance in practice and tests of competence. Peer review is conducted by teams of at least two medical assessors and one lay assessor. A comprehensive training programme for assessors has been developed that simulates the context of a typical practice-based assessment and has been tailored for 12 medical specialties. The training includes the principles of assessment, familiarization with the assessment instruments and supervised practice in assessment methods used during the peer review visit. High fidelity is achieved through the use of actors who simulate third party interviewees and trained doctors who role play the assessee. A subgroup of assessors, selected to lead the assessment teams, undergo training in handling group dynamics, report writing and in defending the assessment report against legal challenge. Debriefing of assessors following real assessments has been strongly positive with regard to their preparedness and confidence in undertaking the assessment.

The General Medical Council's Performance Procedures: peer review of performance in the workplace.

The General Medical Council procedures to assess the performance of doctors who may be seriously deficient include peer review of the doctor's practice at the workplace and tests of competence and skills. Peer reviews are conducted by three trained assessors, two from the same speciality as the doctor being assessed, with one lay assessor. The doctor completes a portfolio to describe his/her training, experience, the circumstances of practice and self rate his/her competence and familiarity in dealing with the common problems of his/her own discipline. The assessment includes a review of the doctor's medical records; discussion of cases selected from these records; observation of consultations for clinicians, or of relevant activities in non-clinicians; a tour of the doctor's workplace; interviews with at least 12 third parties (five nominated by the doctor); and structured interviews with the doctor. The content and structure of the peer review are designed to assess the doctor against the standards defined in Good Medical Practice, as applied to the doctor's speciality. The assessment methods are based on validated instruments and gather 700-1000 judgements on each doctor. Early experience of the peer review visits has confirmed their feasibility and effectiveness.

Determination of titanium NMR parameters of ATiO3 compounds: correlations with structural distortion.

Solid state 47,49Ti NMR spectra have been obtained for a number of perovskite and ilmenite ATiO3 compounds. The 49Ti quadrupole coupling constant varies from 2.75 MHz (CaTiO3) to 15.5 MHz (MgTiO3) and the electric field gradient at the titanium site was found to correlate well with the shear strain, independent of structure. The chemical shift in the perovskite structures varies by approximately 160 ppm and correlates well with the mean Ti-O distance. The 25Mg and 113Cd NMR parameters are also reported for the relevant compounds.

Strategic use of familiarity in display-based problem solving.

The authors report 4 experiments that investigated the role of recognition memory and plausibility in a display-based problem-solving task (computer menu search). It was found that both the familiarity of options and their plausibility played a role in determining choices when the correct options could not be recollected. The use of familiarity was adaptive: Participants relied less on familiarity when it was a less valid guide to correct choices. The implications of these findings for theories of problem solving and learning are discussed.

Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer.

The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established second-line hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with well-established methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophin-releasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was well-tolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical-pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.