Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective

The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four healthy older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n = 13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulation. Moreover, Met carriers, but not Val/Val homozygotes, exhibited larger responses to TMS (p = 0.046) after 20 min atDCS, than following 10 min atDCS. On an individual level, two-step cluster analysis revealed a considerable degree of inter-individual variability, with under half of the total sample (42%) showing the expected potentiation of CSE in response to atDCS across both sessions. Intra-individual variability in response to different durations of atDCS was also apparent, with one-third of the total sample (34%) exhibiting LTP-like effects in one session but LTD-like effects in the other session. Both the inter-individual (p = 0.027) and intra-individual (p = 0.04) variability was associated with BDNF genotype. In older adults, the BDNF Val66Met polymorphism along with stimulation duration appears to play a role in modulating tDCS-induced motor cortex plasticity. The results may have implications for the design of NBS protocols for healthy and diseased aged populations.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND: Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

METHODS: We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

FINDINGS: We received data on 18 766 women (18 206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02).

INTERPRETATION: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

FUNDING: Cancer Research UK, Medical Research Council.

Individual Participant Data (IPD) Meta-analyses of Randomised Controlled Trials: Guidance on Their Use

Jayne Tierney and colleagues offer guidance on how to spot a well-designed and well-conducted individual participant data meta-analysis.

Summary Points 

• Systematic reviews are most commonly based on aggregate data extracted from publications or obtained from trial investigators. 

• Systematic reviews involving the central collection and analysis of individual participant data (IPD) usually are larger-scale, international, collaborative projects that can bring about substantial improvements to the quantity and quality of data, give greater scope in the analyses, and provide more detailed and robust results. 

• The process of collecting, checking, and analysing IPD is more complex than for aggregate data, and not all IPD meta-analyses are done to the same standard, making it difficult for researchers, clinicians, patients, policy makers, funders, and publishers to judge their quality. 

• Following our step-by-step guide will help reviewers and users of IPD meta-analyses to understand them better and recognise those that are well designed and conducted and so help ensure that policy, practice, and research are informed by robust evidence about the effects of interventions.

How individual participant data meta-analyses have influenced trial design, conduct, and analysis

OBJECTIVES: To demonstrate how individual participant data (IPD) meta-analyses have impacted directly on the design and conduct of trials and highlight other advantages IPD might offer.

STUDY DESIGN AND SETTING: Potential examples of the impact of IPD meta-analyses on trials were identified at an international workshop, attended by individuals with experience in the conduct of IPD meta-analyses and knowledge of trials in their respective clinical areas. Experts in the field who did not attend were asked to provide any further examples. We then examined relevant trial protocols, publications, and Web sites to verify the impacts of the IPD meta-analyses. A subgroup of workshop attendees sought further examples and identified other aspects of trial design and conduct that may inform IPD meta-analyses.

RESULTS: We identified 52 examples of IPD meta-analyses thought to have had a direct impact on the design or conduct of trials. After screening relevant trial protocols and publications, we identified 28 instances where IPD meta-analyses had clearly impacted on trials. They have influenced the selection of comparators and participants, sample size calculations, analysis and interpretation of subsequent trials, and the conduct and analysis of ongoing trials, sometimes in ways that would not possible with systematic reviews of aggregate data. We identified additional potential ways that IPD meta-analyses could be used to influence trials.

CONCLUSIONS: IPD meta-analysis could be better used to inform the design, conduct, analysis, and interpretation of trials.

UK publicly funded Clinical Trials Units supported a controlled access approach to share individual participant data but highlighted concerns

OBJECTIVES: Evaluate current data sharing activities of UK publicly funded Clinical Trial Units (CTUs) and identify good practices and barriers.

STUDY DESIGN AND SETTING: Web-based survey of Directors of 45 UK Clinical Research Collaboration (UKCRC)-registered CTUs.

RESULTS: Twenty-three (51%) CTUs responded: Five (22%) of these had an established data sharing policy and eight (35%) specifically requested consent to use patient data beyond the scope of the original trial. Fifteen (65%) CTUs had received requests for data, and seven (30%) had made external requests for data in the previous 12 months. CTUs supported the need for increased data sharing activities although concerns were raised about patient identification, misuse of data, and financial burden. Custodianship of clinical trial data and requirements for a CTU to align its policy to their parent institutes were also raised. No CTUs supported the use of an open access model for data sharing.

CONCLUSION: There is support within the publicly funded UKCRC-registered CTUs for data sharing, but many perceived barriers remain. CTUs are currently using a variety of approaches and procedures for sharing data. This survey has informed further work, including development of guidance for publicly funded CTUs, to promote good practice and facilitate data sharing.

Type Ia supernovae from exploding oxygen-neon white dwarfs

Context. The progenitor problem of Type Ia supernovae (SNe Ia) is still unsolved. Most of these events are thought to be explosions of carbon-oxygen (CO) white dwarfs (WDs), but for many of the explosion scenarios, particularly those involving the externally triggered detonation of a sub-Chandrasekhar mass WD (sub-M-Ch, WD), there is also a possibility of having an oxygen-neon (ONe) WD as progenitor.

Aims. We simulate detonations of ONe WDs and calculate synthetic observables from these models. The results are compared with detonations in CO WDs of similar mass and observational data of SNe Ia.

Methods. We perform hydrodynamic explosion simulations of detonations in initially hydrostatic ONe WDs for a range of masses below the Chandrasekhar mass (M-Ch), followed by detailed nucleosynthetic postprocessing with a 384-isotope nuclear reaction network. The results are used to calculate synthetic spectra and light curves, which are then compared with observations of SNe Ia. We also perform binary evolution calculations to determine the number of SNe Ia involving ONe WDs relative to the number of other promising progenitor channels.

Results. The ejecta structures of our simulated detonations in sub-M-Ch, ONe WDs are similar to those from CO WDs. There are, however, small systematic deviations in the mass fractions and the ejecta velocities. These lead to spectral features that are systematically less blueshifted. Nevertheless, the synthetic observables of our ONe WD explosions are similar to those obtained from CO models.

Conclusions. Our binary evolution calculations show that a significant fraction (3-10%) of potential progenitor systems should contain an ONe WD. The comparison of our ONe models with our CO models of comparable mass (similar to 1.2 M-circle dot) shows that the less blueshifted spectral features fit the observations better, although they are too bright for normal SNe Ia.

Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control.

METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights.

FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease.

INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems.

The ejected mass distribution of Type Ia supernovae: a significant rate of non-Chandrasekhar-mass progenitors

The ejected mass distribution of Type Ia supernovae (SNe Ia) directly probes progenitor evolutionary history and explosion mechanisms, with implications for their use as cosmological probes. Although the Chandrasekhar mass is a natural mass scale for the explosion of white dwarfs as SNe Ia, models allowing SNe Ia to explode at other masses have attracted much recent attention. Using an empirical relation between the ejected mass and the light-curve width, we derive ejected masses Mej and 56Ni masses MNi for a sample of 337 SNe Ia with redshifts z <0.7 used in recent cosmological analyses. We use hierarchical Bayesian inference to reconstruct the joint Mej-MNi distribution, accounting for measurement errors. The inferred marginal distribution of Mej has a long tail towards sub-Chandrasekhar masses, but cuts off sharply above 1.4 M⊙. Our results imply that 25-50 per cent of normal SNe Ia are inconsistent with Chandrasekhar-mass explosions, with almost all of these being sub-Chandrasekhar mass; super-Chandrasekhar-mass explosions make up no more than 1 per cent of all spectroscopically normal SNe Ia. We interpret the SN Ia width-luminosity relation as an underlying relation between Mej and MNi, and show that the inferred relation is not naturally explained by the predictions of any single known explosion mechanism.

The white dwarf's carbon fraction as a secondary parameter of Type Ia supernovae

Context. Binary stellar evolution calculations predict thatChandrasekhar-mass carbon/oxygen white dwarfs (WDs) show a radiallyvarying profile for the composition with a carbon depleted core. Manyrecent multi-dimensional simulations of Type Ia supernovae (SNe Ia),however, assume the progenitor WD has a homogeneous chemicalcomposition.
Aims: In this work, we explore the impact ofdifferent initial carbon profiles of the progenitor WD on the explosionphase and on synthetic observables in the Chandrasekhar-mass delayeddetonation model. Spectra and light curves are compared to observationsto judge the validity of the model.
Methods: The explosion phaseis simulated using the finite volume supernova code Leafs, which isextended to treat different compositions of the progenitor WD. Thesynthetic observables are computed with the Monte Carlo radiativetransfer code Artis. Results: Differences in binding energies ofcarbon and oxygen lead to a lower nuclear energy release for carbondepleted material; thus, the burning fronts that develop are weaker andthe total nuclear energy release is smaller. For otherwise identicalconditions, carbon depleted models produce less 56Ni.Comparing different models with similar 56Ni yields showslower kinetic energies in the ejecta for carbon depleted models, butonly small differences in velocity distributions and line velocities inspectra. The light curve width-luminosity relation (WLR) obtained formodels with differing carbon depletion is roughly perpendicular to theobserved WLR, hence the carbon mass fraction is probably only asecondary parameter in the family of SNe Ia.
Tables 3 and 4 are available in electronic form at http://www.aanda.org