A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB-3644 in patients with solid tumours.

BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal DLT by day 84, defining the MTD as 5 mg bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended

Look Who’s Talking:Using creative, playful arts-based methods in research with young children

Young children are often ignored or marginalised in the drive to address children’s participation and their wider set of rights. This is the case generally in social research, as well as within the field of Arts-Based Education Research. This article contributes to the growing literature on young children’s involvement in arts-based research, by providing a reflective account of our learning and playful engagement with children using creative methods. This small pilot project forms part of a larger international project titled Look Who’s Talking: Eliciting the Voices of Children from Birth to Seven, led by Professor Kate Wall at the University of Strathclyde. Visiting one nursery in Scotland, we worked with approximately 30 children from 3 to 5 years old. Seeking to connect with their play-based nursery experiences, we invited children to participate in a range of arts-based activities including drawing, craft-making, sculpting, a themed ‘play basket’ with various props, puppetry and videography. In this article, we develop reflective, analytical stories of our successes and dilemmas in the project. We were keen to establish ways of working with children that centred their own creativity and play, shaped by the materials we provided but not directed by us. However, we struggled to balance our own agenda with the more open-ended methods we had used. We argue that an intergenerational approach to eliciting voice with young children – in which adults are not afraid to shape the agenda, but do so in responsive, gradual and sensitive ways – creates the potential for a more inclusive experience for children that also meets researcher needs

Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy

<p>Abstract</p> <p>Background</p> <p>Causes of neuropathic pain following nerve injury remain unclear, limiting the development of mechanism-based therapeutic approaches. Animal models have provided some directions, but little is known about the specific sensory neurons that undergo changes in such a way as to induce and maintain activation of sensory pain pathways. Our previous studies implicated changes in the Aβ, normally non-nociceptive neurons in activating spinal nociceptive neurons in a cuff-induced animal model of neuropathic pain and the present study was directed specifically at determining any change in excitability of these neurons. Thus, the present study aimed at recording intracellularly from Aβ-fiber dorsal root ganglion (DRG) neurons and determining excitability of the peripheral receptive field, of the cell body and of the dorsal roots.</p> <p>Methods</p> <p>A peripheral neuropathy was induced in Sprague Dawley rats by inserting two thin polyethylene cuffs around the right sciatic nerve. All animals were confirmed to exhibit tactile hypersensitivity to von Frey filaments three weeks later, before the acute electrophysiological experiments. Under stable intracellular recording conditions neurons were classified functionally on the basis of their response to natural activation of their peripheral receptive field. In addition, conduction velocity of the dorsal roots, configuration of the action potential and rate of adaptation to stimulation were also criteria for classification. Excitability was measured as the threshold to activation of the peripheral receptive field, the response to intracellular injection of depolarizing current into the soma and the response to electrical stimulation of the dorsal roots.</p> <p>Results</p> <p>In control animals mechanical thresholds of all neurons were within normal ranges. Aβ DRG neurons in neuropathic rats demonstrated a mean mechanical threshold to receptive field stimulation that were significantly lower than in control rats, a prolonged discharge following this stimulation, a decreased activation threshold and a greater response to depolarizing current injection into the soma, as well as a longer refractory interval and delayed response to paired pulse electrical stimulation of the dorsal roots.</p> <p>Conclusions</p> <p>The present study has demonstrated changes in functionally classified Aβ low threshold and high threshold DRG neurons in a nerve intact animal model of peripheral neuropathy that demonstrates nociceptive responses to normally innocuous cutaneous stimuli, much the same as is observed in humans with neuropathic pain. We demonstrate further that the peripheral receptive fields of these neurons are more excitable, as are the somata. However, the dorsal roots exhibit a decrease in excitability. Thus, if these neurons participate in neuropathic pain this differential change in excitability may have implications in the peripheral drive that induces central sensitization, at least in animal models of peripheral neuropathic pain, and Aβ sensory neurons may thus contribute to allodynia and spontaneous pain following peripheral nerve injury in humans.</p

“<i>I do it because they do it</i>”:social-neutralisation in information security practices of Saudi medical interns

Successful implementation of information security policies (ISP) and IT controls play an important role in safeguarding patient privacy in healthcare organizations. Our study investigates the factors that lead to healthcare practitioners' neutralisation of ISPs, leading to non-compliance. The study adopted a qualitative approach and conducted a series of semi-structured interviews with medical interns and hospital IT department managers and staff in an academic hospital in Saudi Arabia. The study's findings revealed that the MIs imitate their peers' actions and employ similar justifications when violating ISP dictates. Moreover, MI team superiors' (seniors) ISP non-compliance influence MIs tendency to invoke neutralisation techniques. We found that the trust between the medical team members is an essential social facilitator that motivates MIs to invoke neutralisation techniques to justify violating ISP policies and controls. These findings add new insights that help us to understand the relationship between the social context and neutralisation theory in triggering ISP non-compliance

A population-based cross-sectional study of age-specific risk factors for high risk human papillomavirus prevalence in rural Nigeria

<p>Abstract</p> <p>Background</p> <p>Cervical cancer, caused by persistent infection with carcinogenic human papillomavirus (HR-HPV), is particularly prevalent in Sub-Saharan Africa and is associated with a high mortality rate. Some studies in West Africa, including our own, have found unusually high HR-HPV across all ages with a slight peak in older women. This increased prevalence at older ages may complicate screen-and-treat programs, which are implemented in regions where HPV prevalence declines with age and typically target women between 30-49 years. A better understanding of the determinants of high HR-HPV prevalence at older ages is needed. The goal of this study is to explore risk factors for HR-HPV prevalence by age among women in our population-based study in Irun, a rural town in southwestern Nigeria.</p> <p>Methods</p> <p>1,420 women were administered a clinic-based questionnaire regarding sexual and reproductive behavior, marital status (including co-wives), and malaria exposure. Logistic regression compared questionnaire responses and PCR positivity for a set of 13 carcinogenic HR-HPV types. Results were stratified by age (15-29, 30-45, 46-55, and 56+ years).</p> <p>Results</p> <p>Birth control use and age at first pregnancy were associated with HR-HPV (<it>p-value </it>= 0.03 and 0.05, respectively). Early age at sexual debut and multiple sex partners were risks for HR-HPV, but did not reach significance (<it>p-value </it>= 0.1 and 0.07, respectively). Neither self-reported malaria nor presence of co-wives in the household was associated with HR-HPV (<it>p-value </it>= 0.85 and 0.24, respectively). In age sub-categories, early age at sexual debut was a significant risk factor for HR-HPV among women 35-45 years (<it>p-value = 0.02</it>). Early age at first pregnancy remained a significant risk factor for women aged 56+ years (<it>p-value </it>= 0.04). Greater than 2 sex partners and use of birth control were associated (though not significantly) with HR-HPV in women aged 30-45 (<it>p-value </it>= 0.08, respectively).</p> <p>Conclusions</p> <p>In this high-risk region with elevated HR-HPV prevalence at older ages, we confirmed previously described, behavioral determinants of HR-HPV. There was no association with self-reported malaria or co-wives, which we had hypothesized might correlate with HR-HPV at older ages.</p

Additional psychometric data for the Spanish Modified Dental Anxiety Scale, and psychometric data for a Spanish version of the Revised Dental Beliefs Survey

<p>Abstract</p> <p>Background</p> <p>Hispanics comprise the largest ethnic minority group in the United States. Previous work with the Spanish Modified Dental Anxiety Scale (MDAS) yielded good validity, but lower test-retest reliability. We report the performance of the Spanish MDAS in a new sample, as well as the performance of the Spanish Revised Dental Beliefs Survey (R-DBS).</p> <p>Methods</p> <p>One hundred sixty two Spanish-speaking adults attending Spanish-language church services or an Hispanic cultural festival completed questionnaires containing the Spanish MDAS, Spanish R-DBS, and dental attendance questions, and underwent a brief oral examination. Church attendees completed the questionnaire a second time, for test-retest purposes.</p> <p>Results</p> <p>The Spanish MDAS and R-DBS were completed by 156 and 136 adults, respectively. The test-retest reliability of the Spanish MDAS was 0.83 (95% CI = 0.60-0.92). The internal reliability of the Spanish R-DBS was 0.96 (95% CI = 0.94-0.97), and the test-retest reliability was 0.86 (95% CI = 0.64-0.94). The two measures were significantly correlated (Spearman's rho = 0.38, p < 0.001). Participants who do not currently go to a dentist had significantly higher MDAS scores (t = 3.40, df = 106, p = 0.003) as well as significantly higher R-DBS scores (t = 2.21, df = 131, p = 0.029). Participants whose most recent dental visit was for pain or a problem, rather than for a check-up, scored significantly higher on both the MDAS (t = 3.00, df = 106, p = 0.003) and the R-DBS (t = 2.85, df = 92, p = 0.005). Those with high dental fear (MDAS score 19 or greater) were significantly more likely to have severe caries (Chi square = 6.644, df = 2, p = 0.036). Higher scores on the R-DBS were significantly related to having more missing teeth (Spearman's rho = 0.23, p = 0.009).</p> <p>Conclusion</p> <p>In this sample, the test-retest reliability of the Spanish MDAS was higher. The significant relationships between dental attendance and questionnaire scores, as well as the difference in caries severity seen in those with high fear, add to the evidence of this scale's construct validity in Hispanic samples. Our results also provide evidence for the internal and test-retest reliabilities, as well as the construct validity, of the Spanish R-DBS.</p

Methods to Recruit Hard-to-Reach Groups: Comparing Two Chain Referral Sampling Methods of Recruiting Injecting Drug Users Across Nine Studies in Russia and Estonia

Evidence suggests rapid diffusion of injecting drug use and associated outbreaks of HIV among injecting drug users (IDUs) in the Russian Federation and Eastern Europe. There remains a need for research among non-treatment and community-recruited samples of IDUs to better estimate the dynamics of HIV transmission and to improve treatment and health services access. We compare two sampling methodologies “respondent-driven sampling” (RDS) and chain referral sampling using “indigenous field workers” (IFS) to investigate the relative effectiveness of RDS to reach more marginal and hard-to-reach groups and perhaps to include those with the riskiest behaviour around HIV transmission. We evaluate the relative efficiency of RDS to recruit a lower cost sample in comparison to IFS. We also provide a theoretical comparison of the two approaches. We draw upon nine community-recruited surveys of IDUs undertaken in the Russian Federation and Estonia between 2001 and 2005 that used either IFS or RDS. Sampling effects on the demographic composition and injecting risk behaviours of the samples generated are compared using multivariate analysis. Our findings suggest that RDS does not appear to recruit more marginalised sections of the IDU community nor those engaging in riskier injecting behaviours in comparison with IFS. RDS appears to have practical advantages over IFS in the implementation of fieldwork in terms of greater recruitment efficiency and safety of field workers, but at a greater cost. Further research is needed to assess how the practicalities of implementing RDS in the field compromises the requirements mandated by the theoretical guidelines of RDS for adjusting the sample estimates to obtain estimates of the wider IDU population

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal