Analysis of multicenter clinical trials with very low event rates

INTRODUCTION: In a five-arm randomized clinical trial (RCT) with stratified randomization across 54 sites, we encountered low primary outcome event proportions, resulting in multiple sites with zero events either overall or in one or more study arms. In this paper, we systematically evaluated different statistical methods of accounting for center in settings with low outcome event proportions. METHODS: We conducted a simulation study and a reanalysis of a completed RCT to compare five popular methods of estimating an odds ratio for multicenter trials with stratified randomization by center: (i) no center adjustment, (ii) random intercept model, (iii) Mantel-Haenszel model, (iv) generalized estimating equation (GEE) with an exchangeable correlation structure, and (v) GEE with small sample correction (GEE-small sample correction). We varied the number of total participants (200, 500, 1000, 5000), number of centers (5, 50, 100), control group outcome percentage (2%, 5%, 10%), true odds ratio (1, > 1), intra-class correlation coefficient (ICC) (0.025, 0.075), and distribution of participants across the centers (balanced, skewed). RESULTS: Mantel-Haenszel methods generally performed poorly in terms of power and bias and led to the exclusion of participants from the analysis because some centers had no events. Failure to account for center in the analysis generally led to lower power and type I error rates than other methods, particularly with ICC = 0.075. GEE had an inflated type I error rate except in some settings with a large number of centers. GEE-small sample correction maintained the type I error rate at the nominal level but suffered from reduced power and convergence issues in some settings when the number of centers was small. Random intercept models generally performed well in most scenarios, except with a low event rate (i.e., 2% scenario) and small total sample size (n ≤ 500), when all methods had issues. DISCUSSION: Random intercept models generally performed best across most scenarios. GEE-small sample correction performed well when the number of centers was large. We do not recommend the use of Mantel-Haenszel, GEE, or models that do not account for center. When the expected event rate is low, we suggest that the statistical analysis plan specify an alternative method in the case of non-convergence of the primary method

Activated Magnetospheres of Magnetars

Like the solar corona, the external magnetic field of magnetars is twisted by surface motions of the star. The twist energy is dissipated over time. We discuss the theory of this activity and its observational status. (1) Theory predicts that the magnetosphere tends to untwist in a peculiar way: a bundle of electric currents (the "j-bundle") is formed with a sharp boundary, which shrinks toward the magnetic dipole axis. Recent observations of shrinking hot spots on magnetars are consistent with this behavior. (2) Continual discharge fills the j-bundle with electron-positron plasma, maintaining a nonthermal corona around the neutron star. The corona outside a few stellar radii strongly interacts with the stellar radiation and forms a "radiatively locked" outflow with a high e+- multiplicity. The locked plasma annihilates near the apexes of the closed magnetic field lines. (3) New radiative-transfer simulations suggest a simple mechanism that shapes the observed X-ray spectrum from 0.1 keV to 1 MeV: part of the thermal X-rays emitted by the neutron star are reflected from the outer corona and then upscattered by the inner relativistic outflow in the j-bundle, producing a beam of hard X-rays.Comment: 23 pages, 7 figures; review chapter in the proceedings of ICREA Workshop on the High-Energy Emission from Pulsars and Their Systems, Sant Cugat, Spain, April 201

A preliminary report of an educational intervention in practice management

BACKGROUND: Practice management education continues to evolve, and little information exists regarding its curriculum design and effectiveness for resident education. We report the results of an exploratory study of a practice management curriculum for primary care residents. METHODS: After performing a needs assessment with a group of primary care residents at Wright State University, we designed a monthly seminar series covering twelve practice management topics. The curriculum consisted of interactive lectures and practice-based application, whenever possible. We descriptively evaluated two cognitive components (practice management knowledge and skills) and the residents' evaluation of the curriculum. RESULTS: The mean correct on the knowledge test for this group of residents was 74% (n = 12) and 91% (n = 12) before and after the curriculum, respectively. The mean scores for the practice management skill assessments were 2.62 before (n = 12), and 3.65 after (n = 12) the curriculum (modified Likert, 1 = strongly disagree, 5 = strongly agree). The residents rated the curriculum consistently high. CONCLUSIONS: This exploratory study suggests that this curriculum may be useful in developing knowledge and skills in practice management for primary care residents. This study suggests further research into evaluation of this curriculum may be informative for practice-based education

Life History of Female Preferences for Male Faces: A Comparison of Pubescent Girls, Nonpregnant and Pregnant Young Women, and Middle-aged Women

Although scientific interest in facial attractiveness has developed substantially in recent years, few studies have contributed to our understanding of the ontogeny of facial preferences. In this study, attractiveness of 30 male faces was evaluated by four female groups: girls at puberty, nonpregnant and pregnant young women, and middle-aged women. The main findings are as follows: (1) Preference for sexy-looking faces was strongest in young, nonpregnant women. (2) Biologically more mature girls displayed more adultlike preferences. (3) The intragroup consistency for postmenopausal women was relatively low. (4) In terms of the preference pattern, pregnant women were more similar to perimenopausal women than they were to their nonpregnant peers. (5) Preference for youthful appearance decreased with the age of the women. I argue that the life history of female preferences for male faces is, to a large extent, hormone-driven and underpinned by a set of evolutionary adaptations

Does offering an incentive payment improve recruitment to clinical trials and increase the proportion of socially deprived and elderly participants?

BACKGROUND: Patient recruitment into clinical trials is a major challenge, and the elderly, socially deprived and those with multiple comorbidities are often underrepresented. The idea of paying patients an incentive to participate in research is controversial, and evidence is needed to evaluate this as a recruitment strategy. METHOD: In this study, we sought to assess the impact on clinical trial recruitment of a £100 incentive payment and whether the offer of this payment attracted more elderly and socially deprived patients. A total of 1,015 potential patients for five clinical trials (SCOT, FAST and PATHWAY 1, 2 and 3) were randomised to receive either a standard trial invitation letter or a trial invitation letter containing an incentive offer of £100. To receive payment, patients had to attend a screening visit and consent to be screened (that is, sign a consent form). To maintain equality, eventually all patients who signed a consent form were paid £100. RESULTS: The £100 incentive offer increased positive response to the first invitation letter from 24.7% to 31.6%, an increase of 6.9% (P < 0.05). The incentive offer increased the number of patients signing a consent form by 5.1% (P < 0.05). The mean age of patients who responded positively to the invitation letter was 66.5 ± 8.7 years, whereas those who responded negatively were significantly older, with a mean age of 68.9 ± 9.0 years. The incentive offer did not influence the age of patients responding. The incentive offer did not improve response in the most socially deprived areas, and the response from patients in these areas was significantly lower overall. CONCLUSION: A £100 incentive payment offer led to small but significant improvements in both patient response to a clinical trial invitation letter and in the number of patients who consented to be screened. The incentive payment did not attract elderly or more socially deprived patients. TRIAL REGISTRATIONS: Standard care versus Celecoxib Outcome Trial (SCOT) (ClinicalTrials.gov identifier: NCT00447759). Febuxostat versus Allopurinol Streamlined Trial (FAST) (EudraCT number: 2011-001883-23). Prevention and Treatment of Hypertension with Algorithm Guided Therapy (British Heart Foundation funded trials) (PATHWAY) 1: Monotherapy versus dual therapy for initiating treatment (EudraCT number: 2008-007749-29). PATHWAY 2: Optimal treatment of drug-resistant hypertension (EudraCT number: 2008-007149-30). PATHWAY 3: Comparison of single and combination diuretics in low-renin hypertension (EudraCT number: 2009-010068-41). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-015-0582-8) contains supplementary material, which is available to authorized users

An unbiased survey of 500 nearby stars for debris disks: A JCMT legacy program

We present the scientific motivation and observing plan for an upcoming detection survey for debris disks using the James Clerk Maxwell Telescope. The SCUBA‐2 Unbiased Nearby Stars (SUNS) survey will observe 500 nearby main‐sequence and subgiant stars (100 of each of the A, F, G, K, and M spectral classes) to the 850 μm extragalactic confusion limit to search for evidence of submillimeter excess, an indication of circumstellar material. The survey distance boundaries are 8.6, 16.5, 22, 25, and 45 pc for M, K, G, F, and A stars, respectively, and all targets lie between the declinations of −40° to 80°. In this survey, no star will be rejected based on its inherent properties: binarity, presence of planetary companions, spectral type, or age. The survey will commence in late 2007 and will be executed over 390 hr, reaching 90% completion within 2 years. This will be the first unbiased survey for debris disks since the Infrared Astronomical Satellite. We expect to detect ~125 debris disks, including ~50 cold disks not detectable in current shorter wavelength surveys. To fully exploit the order of magnitude increase in debris disks detected in the submillimeter, a substantial amount of complementary data will be required, especially at shorter wavelengths, to constrain the temperatures and masses of discovered disks. High‐resolution studies will likely be required to resolve many of the disks. Therefore, these systems will be the focus of future observational studies using a variety of observatories, including Herschel, ALMA, and JWST, to characterize their physical properties. For nondetected systems, this survey will set constraints (upper limits) on the amount of circumstellar dust, of typically 200 times the Kuiper Belt mass, but as low as 10 times the Kuiper Belt mass for the nearest stars in the sample (≈2 pc)

So Different, yet So Similar: Meta-Analysis and Policy Modeling of Willingness to Participate in Clinical Trials among Brazilians and Indians

BACKGROUND: With the global expansion of clinical trials and the expectations of the rise of the emerging economies known as BRICs (Brazil, Russia, India and China), the understanding of factors that affect the willingness to participate in clinical trials of patients from those countries assumes a central role in the future of health research. METHODS: We conducted a systematic review and meta-analysis (SRMA) of willingness to participate in clinical trials among Brazilian patients and then we compared it with Indian patients (with results of another SRMA previously conducted by our group) through a system dynamics model. RESULTS: Five studies were included in the SRMA of Brazilian patients. Our main findings are 1) the major motivation for Brazilian patients to participate in clinical trials is altruism, 2) monetary reimbursement is the least important factor motivating Brazilian patients, 3) the major barrier for Brazilian patients to not participate in clinical trials is the fear of side effects, and 4) Brazilian patients are more likely willing to participate in clinical trials than Indians. CONCLUSION: Our study provides important insights for investigators and sponsors for planning trials in Brazil (and India) in the future. Ignoring these results may lead to unnecessary fund/time spending. More studies are needed to validate our results and for better understanding of this poorly studied theme

Psychological and behavioural factors associated with sexual risk behaviour among Slovak students

Background: Knowledge about the prevalence of sexual risk behaviour (SRB) in adolescence is needed to prevent unwanted health consequences. Studies on SRB among adolescents in Central Europe are rare and mostly rely on a single indicator for SRB. This study aims to assess the association of behavioural and psychological factors with three types of SRB in adolescents in Central Europe. Methods: We obtained data on behavioural factors (having been drunk during previous month, smoking during previous week, early sexual initiation), psychological factors (self-esteem, wellbeing, extroversion, neuroticism, religiousness), and SRB (intercourse under risky conditions, multiple sexual partners, and inconsistent condom use) in 832 Slovak university students (response 94.3%). Results: Among those with sexual experience (62%), inconsistent condom use was the most prevalent risk behaviour (81% in females, 72% in males). With the exception of having been drunk in males, no factor was associated with inconsistent condom use. Regarding the other types of SRB, early sexual initiation was most strongly associated. In addition, other, mostly behavioural, factors were associated, in particular having been drunk. Conclusion: Results suggest that behavioural factors are more closely related to SRB than psychological factors. Associations differ by type of SRB and gender but offer few clues to target risk groups for inconsistent condom use. Results show a high need for health-promotion programmes in early adolescence that target SRB in conjunction with other health risk behaviours such as alcohol abuse

Forward Masking Estimated by Signal Detection Theory Analysis of Neuronal Responses in Primary Auditory Cortex

Psychophysical forward masking is an increase in threshold of detection of a sound (probe) when it is preceded by another sound (masker). This is reminiscent of the reduction in neuronal responses to a sound following prior stimulation. Studies in the auditory nerve and cochlear nucleus using signal detection theory techniques to derive neuronal thresholds showed that in centrally projecting neurons, increases in masked thresholds were significantly smaller than the changes measured psychophysically. Larger threshold shifts have been reported in the inferior colliculus of awake marmoset. The present study investigated the magnitude of forward masking in primary auditory cortical neurons of anaesthetised guinea-pigs. Responses of cortical neurons to unmasked and forward masked tones were measured and probe detection thresholds estimated using signal detection theory methods. Threshold shifts were larger than in the auditory nerve, cochlear nucleus and inferior colliculus. The larger threshold shifts suggest that central, and probably cortical, processes contribute to forward masking. However, although methodological differences make comparisons difficult, the threshold shifts in cortical neurons were, in contrast to subcortical nuclei, actually larger than those observed psychophysically. Masking was largely attributable to a reduction in the responses to the probe, rather than either a persistence of the masker responses or an increase in the variability of probe responses