Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine-platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m(2)) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥10 points (on 100-point scale) and TtD in PS was defined as first worsening to ≥2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. RESULTS: Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from ≥1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to ≥2 (HR = 0.798, P = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS ≥ 3 (HR = 0.656, P = 0.0508), deterioration by ≥1 PS level (HR = 0.802, P = 0.0444), and deterioration by ≥2 PS levels (HR = 0.608, P = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. CONCLUSION: In patients with previously treated advanced gastric/GEJ adenocarcinoma, addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient QoL with delayed symptom worsening and functional status deterioration. CLINICALTRIALSGOV: NCT01170663.

The reliability of (31)P-MRS and NIRS measurements of spinal muscle function.

While phosphorous magnetic resonance spectroscopy ((31)P-MRS) and near-infrared spectroscopy (NIRS) provide methods for measuring spinal muscle function non-invasively, their reliability is not established. The aim of this study was assess the reliability (ICC) and error magnitude (CV%) of measurements of muscle phosphocreatine (PCr), tissue oxygenation index (TOI) and muscle deoxyhaemoglobin (HHb) acquired during fatigue and in recovery after 24 s of exercise in the lumbar muscles. 10 healthy participants (19-25 years, 5 male, 5 female) performed exercise that involved holding the upper body unsupported in slight extension until fatigue and then, after 30 min of rest, for repeated bursts of 24 s. ICCs indicated good to excellent reliability of baseline measures (TOI: 0.75) and of amplitude changes during fatigue (PCr: 0.73, TOI: 0.69, HHb: 0.80) and recovery (HHb: 0.96), and poor to fair reliability for time constants describing rates of change during fatigue (PCr: 0.11) and recovery (PCr: 0.31, HHb: 0.47). CV% indicated varying relative measurement error across baseline measures (TOI: 5%), amplitude changes during fatigue (PCr: 7%, TOI: 38%, HHb: 31%) and recovery (HHb: 31%), and in time constants for fatigue (PCr: 39%) and recovery (PCr: 20%, HHb: 37%). The results suggested that reliability would be sufficient for future studies on spinal muscle function, but that measurement error may be too large to evaluate individuals.

Continuing professional development systems and requirements for graduate dentists in the EU: survey results from the DentCPD project.

INTRODUCTION: By maintaining skills and keeping dentists up-to-date, continuing professional development (CPD) supports safe clinical practice. However, CPD for dentists across Europe is not harmonised. AIM: One aim of the 'DentCPD' project (www.dentcpd.org) was to identify and agree essential CPD requirements for EU dentists. As part of the process, data were collected on existing approaches to CPD for EU dentists. This paper reports those findings. METHODS: Informed by a review of the literature and internet search, the CPD for Graduate Dentists questionnaire gathered data from dental educators on CPD systems, requirements, provision and accreditation in Europe. It sought opinion on mandatory CPD and e-learning. RESULTS: Responses were received from 143 individuals from 30 EU countries. About half the countries had a compulsory CPD system which typically included mandatory core topics. Elsewhere CPD was optional or based on recommended hours. University dental schools and professional dental associations were the most common CPD providers. National regulatory bodies were the most common accrediting body. Only 41% of respondents thought they knew the criteria for successful accreditation of CPD. Eighty-one percent agreed that 'CPD should be obligatory for all dentists'. CONCLUSION: These results present an overview of the status of CPD for EU dentists. Despite a notable trend towards regulated CPD systems, current requirements for dentists to engage in CPD show variation. The harmonisation of requirements would enhance both dentist mobility and safe clinical practice.

Guidelines for the organisation of continuing professional development activities for the European dentist.

AIM: Free movement of dental professionals across the European Union calls for more uniform continuing education in dentistry to ensure up-to-date, high-quality patient care and patient safety. This article provides guidelines for the management and delivery of high-quality continuing professional development (CPD) by European dental schools and other CPD providers. METHOD: The guidelines are based on an extensive literature inventory, a survey of existing practices (both available as separate publications), discussions during meetings of the Association for Dental Education in Europe in 2011 and 2012 and debate amongst the members of the DentCPD project team representing six dental schools. RESULTS: On the basis of the literature review, survey and discussions, we recommend that (i) every dentist should be given the opportunity for CPD, (ii) providers should be quality-approved and impartial, (iii) educators should be approved, impartial, suitably trained, and with educational expertise, (iv) the mode of CPD delivery should suit the educational activity, with clear learning objectives or outcomes, (v) effort should be made to assess the learning, (vi) participant feedback should be collected and analysed to inform future developments and (vii) uniform use of the pan-European system of learning credit points (ECTS) should be implemented. CONCLUSION: Implementation of these guidelines should make dental CPD more transparent to all relevant parties and facilitate the transferability of earned credits across the European Union. It will also enable better quality control within dentistry, resulting in enhanced dental care and ultimately the improvement in patient safety.

Core continuing professional development (CPD) topics for the European dentist.

INTRODUCTION: In the context of free movement, EU-citizens need assurance that dental practitioners providing their care have a degree/license to practice that meets EU-standards and that they maintain their knowledge and skills through ongoing education. AIM: One aim of the 'DentCPD' project (HYPERLINK 'http://www.dentcpd.org' www.dentcpd.org) was to identify and agree essential CPD requirements for EU dentists. This paper reports the consensus process and outcomes. METHODS: Agreement on core components of CPD was achieved through a three stage process: an online survey of dental educators' (n = 143) views on compulsory topics; a paper-based questionnaire to practitioners (n = 411); leading to a proposal discussed at the Association for Dental Education (ADEE) 2011 Lifelong Learning special interest group (SIG). RESULTS: From the online survey and practitioner questionnaire, high levels of agreement were achieved for medical emergencies (89%), infection control (79%) and the medically compromised patient (71%). The SIG (34 attendees from 16 countries) concluded that these three CPD topics plus radiation protection should be core-compulsory and three CPD topics should be core-recommended (health and safety, pain management, and safeguarding children & vulnerable adults). They also agreed that the teaching of all topics should be underpinned by evidence-based dentistry. CONCLUSION: Building four core topics into CPD requirements and making quality-approved education and training available will ensure that all dentists have up-to-date knowledge and skills in topic areas of direct relevance to patient safety. In turn, this will contribute to patients having access to comparably high standards of oral health care across Europe.

The development of an exemplar e-module for the continuing professional development of European dentists.

AIM: To present the development of an exemplar e-module for dental continuing professional development (CPD) provided by dental schools and other dental educational providers. MATERIALS AND METHODS: The exemplar e-module covered the topic of 'Sterilisation and cross-infection control in the dental practice' as this is one of the most recommended topics for dental CPD in Europe. It was developed by a group of topic experts, adult learning and distance learning experts and a technical developer. Major concerns were pedagogy, interoperability, usability and cost reduction. Open-source material was used to reduce the cost of development. RESULTS: The e-module was pre-piloted in dental practitioners for usability and then evaluated by experts in the field and dental academics through an electronic questionnaire and an online presentation and discussion at the ADEE 2012 Special Interest Group on DentCPD-Lifelong learning. This facilitated refinement before final production. A Creative Commons License was implemented to ensure the developers' rights and facilitate wider distribution and access to CPD providers. DISCUSSION AND CONCLUSIONS: The e-module was developed according to well-defined pedagogical and technical guidelines for developing e-learning material for adult learners. It was structured to promote self-study by directing learners through their study, promoting interaction with the material, offering explanation and providing feedback. Content validity was ensured by extensive review by experts. The next step would be to expand the evaluation to practising dentists in various countries after relevant translations, and adaptations to local policies have been made.

Recommendations for the development of e-modules for the continuing professional development of European dentists.

AIMS: To provide evidence-based and peer-reviewed recommendations for the development of dental continuing professional development (CPD) learning e-modules. METHODS: The present recommendations are consensus recommendations of the DentCPD project team and were informed by a literature research, consultations from e-learning and IT expert, discussions amongst the participants attending a special interest group during the 2012 ADEE meeting, and feedback from the evaluation procedures of the exemplar e-module (as described in a companion paper within this Supplement). The main focus of these recommendations is on the courses and modules organised and offered by dental schools. RESULTS AND DISCUSSION: E-modules for dental CPD, as well as for other health professionals' continuing education, have been implemented and evaluated for a number of years. Research shows that the development of e-modules is a team process, undertaken by academics, subject experts, pedagogists, IT and web designers, learning technologists and librarians. The e-module must have clear learning objectives (outcomes), addressing the learners' individual needs, and must be visually attractive, relevant, interactive, promoting critical thinking and providing feedback. The text, graphics and animations must support the objectives and enable the learning process by creating an attractive, easy to navigate and interactive electronic environment. Technology is usually a concern for learners and tutors; therefore, it must be kept simple and interoperable within different systems and software. The pedagogical and technological proficiency of educators is of paramount importance, yet remains a challenge in many instances. CONCLUSIONS: The development of e-courses and modules for dental CPD is an endeavour undertaken by a group of professionals. It must be underpinned by sound pedagogical and e-learning principles and must incorporate elements for effective visual learning and visual design and a simple, consistent technology.

Core continuing professional development (CPD) topics for the European dentist.

INTRODUCTION: In the context of free movement, EU-citizens need assurance that dental practitioners providing their care have a degree/license to practice that meets EU-standards and that they maintain their knowledge and skills through ongoing education. AIM: One aim of the 'DentCPD' project (HYPERLINK 'http://www.dentcpd.org' www.dentcpd.org) was to identify and agree essential CPD requirements for EU dentists. This paper reports the consensus process and outcomes. METHODS: Agreement on core components of CPD was achieved through a three stage process: an online survey of dental educators' (n = 143) views on compulsory topics; a paper-based questionnaire to practitioners (n = 411); leading to a proposal discussed at the Association for Dental Education (ADEE) 2011 Lifelong Learning special interest group (SIG). RESULTS: From the online survey and practitioner questionnaire, high levels of agreement were achieved for medical emergencies (89%), infection control (79%) and the medically compromised patient (71%). The SIG (34 attendees from 16 countries) concluded that these three CPD topics plus radiation protection should be core-compulsory and three CPD topics should be core-recommended (health and safety, pain management, and safeguarding children & vulnerable adults). They also agreed that the teaching of all topics should be underpinned by evidence-based dentistry. CONCLUSION: Building four core topics into CPD requirements and making quality-approved education and training available will ensure that all dentists have up-to-date knowledge and skills in topic areas of direct relevance to patient safety. In turn, this will contribute to patients having access to comparably high standards of oral health care across Europe.

Continuing professional development systems and requirements for graduate dentists in the EU: survey results from the DentCPD project.

INTRODUCTION: By maintaining skills and keeping dentists up-to-date, continuing professional development (CPD) supports safe clinical practice. However, CPD for dentists across Europe is not harmonised. AIM: One aim of the 'DentCPD' project (www.dentcpd.org) was to identify and agree essential CPD requirements for EU dentists. As part of the process, data were collected on existing approaches to CPD for EU dentists. This paper reports those findings. METHODS: Informed by a review of the literature and internet search, the CPD for Graduate Dentists questionnaire gathered data from dental educators on CPD systems, requirements, provision and accreditation in Europe. It sought opinion on mandatory CPD and e-learning. RESULTS: Responses were received from 143 individuals from 30 EU countries. About half the countries had a compulsory CPD system which typically included mandatory core topics. Elsewhere CPD was optional or based on recommended hours. University dental schools and professional dental associations were the most common CPD providers. National regulatory bodies were the most common accrediting body. Only 41% of respondents thought they knew the criteria for successful accreditation of CPD. Eighty-one percent agreed that 'CPD should be obligatory for all dentists'. CONCLUSION: These results present an overview of the status of CPD for EU dentists. Despite a notable trend towards regulated CPD systems, current requirements for dentists to engage in CPD show variation. The harmonisation of requirements would enhance both dentist mobility and safe clinical practice.

Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer.

PURPOSE: This retrospective analysis examined prognostic significance of health-related quality-of-life (HRQoL) parameters combined with baseline clinical factors on outcomes (overall survival, time to progressive disease, and time to treatment failure) in bladder cancer. PATIENTS AND METHODS: Outcome and HRQoL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30) data were collected prospectively in a phase III study assessing gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in locally advanced or metastatic bladder cancer. Prespecified baseline clinical factors (performance status, tumor-node-metastasis staging, visceral metastases [VM], alkaline phosphatase [AP] level, number of metastatic sites, prior radiotherapy, disease measurability, sex, time from diagnosis, and sites of disease) and selected HRQoL parameters (global QoL; all functional scales; symptoms: pain, fatigue, insomnia, dyspnea, anorexia) were evaluated using Cox's proportional hazards model. Factors with individual prognostic value (P <.05) on outcomes in univariate models were assessed for joint prognostic value in a multivariate model. A final model was developed using a backward selection strategy. RESULTS: Patients with baseline HRQoL were included (364 of 405, 90%). The final model predicted longer survival with low/normal AP levels, no VM, high physical functioning, low role functioning, and no anorexia. Positive prognostic factors for time to progressive disease were good performance status, low/normal AP levels, no VM, and minimal fatigue; for time to treatment failure, they were low/normal AP levels, minimal fatigue, and no anorexia. Global QoL was a significant predictor of outcome in univariate analyses but was not retained in the multivariate model. CONCLUSION: HRQoL parameters are independent prognostic factors for outcome in advanced bladder cancer; their prognostic importance needs further evaluation.

Submicrovolt flicker electroretinogram: cycle-by-cycle recording of multiple harmonics with statistical estimation of measurement uncertainty.

PURPOSE: To study cycle-by-cycle recording of small-amplitude flicker-electroretinogram (ERG) responses and analyze results with robust statistical methods to estimate the measurement uncertainty. METHODS: Flicker ERGs at 32 Hz were recorded simultaneously from both eyes of patients with retinal degeneration. The ERG was amplified under wide-band (1-1000 Hz) conditions, digitized at 6144 Hz/eye, and multiplied point for point (192 points/cycle) by sine and cosine functions within each 1/32-second flash cycle to extract coefficients for six harmonic components of a discrete Fourier transform in real time. Amplitude windowing was not used, and all data were saved for subsequent statistical processing to identify and remove large-amplitude artifacts discretely and to search for quiet recording periods that minimized small-amplitude noise. RESULTS: Plots of amplitude and phase indicated far outlying noise points that were excised from the data. The SD of sequential intervals on a time line of the sine component identified quiet periods that minimized small-amplitude noise and improved measurement consistency. The SE of the response mean provided an estimate of measurement uncertainty. CONCLUSIONS: The harmonic components of many individual responses are captured quickly (e.g., 500 responses in 15.6 seconds) for post hoc statistical analysis, using mathematical algorithms that are precisely reproducible to facilitate comparison of results from all laboratories. Graphical time lines of responses allow separation of artifact transients from gaussian noise for elimination of noisy periods without disturbing the stored information. Statistical estimates of measurement uncertainty are determined on-line to allow immediate feedback during the recording session. Amplitude-phase plots of the multiple harmonic components, along with reconstructed analog waveforms, provide results in a readily assimilated manner for comparison of all testing sessions.

Review of the pharmacoeconomic research on gemcitabine in the treatment of advanced non-small cell lung cancer.

BACKGROUND: Gemcitabine is a novel nucleoside analogue with unique activity against a range of solid tumors including non-small cell lung cancer (NSCLC) and pancreatic cancer. STUDY DESIGN AND METHODOLOGY: This report reviews a series of retrospective economic evaluations that have taken place over the past 4 years comparing gemcitabine, both as a single agent and in combination therapy, with other treatment modalities for NSCLC in the following countries: United States, Spain, Germany, Sweden, Belgium, Canada, and Italy. These economic evaluations were in the form of simple cost identification, cost minimization, and cost-effectiveness in order to estimate the economic impact of gemcitabine in NSCLC treatment compared with other treatment modalities. RESULTS AND CONCLUSIONS: The results of these retrospective economic evaluations suggest that gemcitabine as monotherapy or in a combination regimen may be cost saving or perhaps even cost effective. This is largely because the chemotherapy can be administered in an outpatient setting and because the side-effect and toxicity profile is lower. This economic advantage assumes equivalent efficacy of gemcitabine and other treatment modalities for treatment of NSCLC.

NMR and molecular orbital studies of isomerism and tautomerism in oximes of 2-acyl cyclic 1,3-diones.

Molecular orbital calculations and 13C and 15N NMR experiments have been performed on the O-methyl oximes of two types of 2-acyl cyclic 1,3-diones. One (III; X = CH2) was based on cyclohexane, and the other (X = O) on pyran. The data indicate that both the cyclohexane and pyran compounds prefer to exist as the oxime, rather than the enamine isomer. Two equivalent, interconverting, keto-enol tautomers exist in the cyclohexane compound. The pyran compound exists as the lactone-enol tautomer. Our results have implications in the design of herbicidal compounds and drugs containing similar tautomeric systems.