Irrefutable evidence for the use of docetaxel in newly diagnosed metastatic prostate cancer: Results from the STAMPEDE and CHAARTED trials

Androgen deprivation therapy (ADT) has been used in the treatment of metastatic prostate cancer since the first description of its hormonal dependence in 1941. In 2004, docetaxel chemotherapy became the mainstay of treatment in metastatic castration-resistant prostate cancer (mCRPC), following robust, albeit modest, survival benefit in two randomized phase 3 trials. The recently published CHAARTED trial was the first to show that combining ADT with docetaxel in men with hormone-naïve (hormone-sensitive) metastatic prostate cancer (mHSPC) yielded a remarkable overall survival benefit of 13.6 months as compared with ADT alone. In the current issue of The Lancet, James et al. report results of the STAMPEDE trial in men with high-risk locally advanced or metastatic prostate cancer initiating long-term hormone therapy. The combination of six cycles of docetaxel with ADT in men commencing long-term ADT demonstrated a similar OS benefit compared with standard of care (SOC) by a median of 10 months. Based on the consistency of the data and the firmness of the benefit provided, docetaxel in addition to ADT should be considered SOC for men with newly diagnosed mHSPC

Administration Launches Next Chapter of Education Reform

Background: Although the recovery of patients suffering from low back pain is highly context dependent, patient preferences about treatment options are seldom incorporated into the therapeutic plan. Shared decision-making (SDM) offers a tool to overcome this deficiency. The reinforcement by the general practitioner (GP) of a 'shared' chosen therapy might increase patients' expectations of favourable outcomes and thus contribute to recovery. Methods: In the Netherlands, a clustered randomised controlled trial was performed to assess the effectiveness of shared decision-making followed by positive reinforcement of the chosen therapy (SDM&PR) on patient-related clinical outcomes. Overall, 68 GPs included 226 patients visiting their GP for a new episode of non-chronic low back pain. GPs in the intervention group were trained in implementing SDM&PR using a structured training programme with a focus on patient preferences in reaching treatment decisions. GPs in the control group provided care as usual. The primary outcome was the change in physical disability measured with the Roland-Morris disability questionnaire (RMD) during the six-month follow-up after the first consultation. Physical disability (RMD), pain, adequate relief, absenteeism and healthcare consumption at 2, 6, 12 and 26 weeks were secondary outcomes. A multivariate analysis with a mixed model was used to estimate the differences in outcomes. Results: Of the patients in the intervention and the control groups, 66 and 62%, respectively, completed the follow-up. Most patients (77%) recovered to no functional restrictions due to back pain within 26 weeks. No significant differences in the mean scores for any outcome were observed between intervention patients and controls during the follow-up, and in multivariate analysis, there was no significant difference in the main outcome during the six-month follow-up. Patients in the intervention group reported more involvement in decision-making. Conclusion: This study did not detect any improvement in clinical outcome or in health care consumption of patients with non-chronic low back pain after the training of GPs in SDM&PR. The implementation of SDM merely introduces task-oriented communication. The training of the GPs may have been more effective if it had focused more on patient-oriented communication techniques and on stressing the expectation of favourable outcomes. Trial registration: The Netherlands National Trial Register (NTR) number: NTR1960. The trial was registered in the NTR on August 20, 2009

Twistors and Black Holes

Motivated by black hole physics in N=2, D=4 supergravity, we study the geometry of quaternionic-Kahler manifolds M obtained by the c-map construction from projective special Kahler manifolds M_s. Improving on earlier treatments, we compute the Kahler potentials on the twistor space Z and Swann space S in the complex coordinates adapted to the Heisenberg symmetries. The results bear a simple relation to the Hesse potential \Sigma of the special Kahler manifold M_s, and hence to the Bekenstein-Hawking entropy for BPS black holes. We explicitly construct the ``covariant c-map'' and the ``twistor map'', which relate real coordinates on M x CP^1 (resp. M x R^4/Z_2) to complex coordinates on Z (resp. S). As applications, we solve for the general BPS geodesic motion on M, and provide explicit integral formulae for the quaternionic Penrose transform relating elements of H^1(Z,O(-k)) to massless fields on M annihilated by first or second order differential operators. Finally, we compute the exact radial wave function (in the supergravity approximation) for BPS black holes with fixed electric and magnetic charges.Comment: 47 pages, v2: typos corrected, reference added, v3: minor change

The effect of shared decision-making on recovery from non-chronic aspecific low back pain in primary care; a post-hoc analysis from the patient, physician and observer perspectives

BACKGROUND: Although shared decision-making (SDM) is increasingly accepted in healthcare and has demonstrated merits for several psychological outcomes, the effect on recovery from somatic conditions is still subject to debate. The objective of this study is to measure the effect of SDM on recovery from non-chronic aspecific low back pain (LBP). METHODS: This study is a post-hoc analysis of data from a cluster-randomised trial that evaluated the effectiveness of SDM on recovery in patients with non-chronic aspecific LBP. In this analysis, we re-evaluate the impact of SDM from three perspectives: that of external observers, participating GPs and participating patients. Recovery was measured with the Visual Analogue Scale (VAS) for pain and with the Roland Morris Disability questionnaire (RMD) and defined as a VAS < 30 and an RMD < 4. Logistic regression was used to analyse the effect of SDM on recovery at 6 and 26 weeks. RESULTS: At 26 weeks, 105 (74%) of all 176 included patients had recovered. No significant effect of SDM on recovery at 6 or 26 weeks after the consultation was found when considering SDM from an observer perspective or a patient perspective. From a GP perspective SDM had a significant effect on recovery, but at 26 weeks only, and with the lowest probability of recovery observed at a medium level of GP-perceived SDM. CONCLUSIONS: We found no evidence that SDM as perceived by the patient or by external observation improves recovery from non-chronic aspecific low back pain. The long-term recovery may be better for patients in whom the GP perceives SDM during their consultations. Further research should highlight the hierarchy and the relation between the perspectives, which is needed to come to an integral effect evaluation of SDM. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR) number: NTR1960

Evident hypopigmentation without other ocular deficits in Dutch patients with oculocutaneous albinism type 4

To describe the phenotype of Dutch patients with oculocutaneous albinism type 4 (OCA4), we collected data on pigmentation (skin, hair, and eyes), visual acuity (VA), nystagmus, foveal hypoplasia, chiasmal misrouting, and molecular analyses of nine Dutch OCA4 patients from the Bartimeus Diagnostic Center for complex visual disorders. All patients had severely reduced pigmentation of skin, hair, and eyes with iris transillumination over 360 degrees. Three unrelated OCA4 patients had normal VA, no nystagmus, no foveal hypoplasia, and no misrouting of the visual pathways. Six patients had poor visual acuity (0.6 to 1.0 logMAR), nystagmus, severe foveal hypoplasia and misrouting. We found two novel variants in the SLC45A2 gene, c.310C > T; (p.Pro104Ser), and c.1368 + 3_1368 + 9del; (p.?). OCA4 patients of this Dutch cohort all had hypopigmentation of skin, hair, and iris translucency. However, patients were either severely affected with regard to visual acuity, foveal hypoplasia, and misrouting, or visually not affected at all. We describe for the first time OCA4 patients with an evident lack of pigmentation, but normal visual acuity, normal foveal development and absence of misrouting. This implies that absence of melanin does not invariably lead to foveal hypoplasia and abnormal routing of the visual pathways.Ophthalmic researc

Prognostic factors in men with metastatic castration-resistant prostate cancer treated with cabazitaxel

Background: Treatment selection for men with metastatic castration-resistant prostate cancer (mCRPC) has become increasingly challenging with the introduction of novel therapies at earlier disease stages. The purpose of this study was to identify prognostic factors for overall survival (OS) and PSA response in patients with mCRPC treated with cabazitaxel. Results: 224 mCRPC patients were included in the current analysis. In multivariable analysis, WHO performance status, baseline hemoglobin, alkaline phosphatase and albumin were all significantly associated with OS. Hemoglobin and alkaline phosphatase were significantly associated with PSA response. Conclusions: This study identified prognostic factors for OS and PSA response of men with mCRPC treated with cabazitaxel. In an increasingly complicated treatment landscape with several treatment options available our findings might serve to estimate the chance of survival of men qualifying for treatment with second-line chemotherapy in daily practice. Furthermore, these data can be used to risk-stratify patients in clinical trials. Methods: We performed a post-hoc analysis of a randomized phase II trial of mCRPC patients treated with cabazitaxel. Cox and logistic regression models were used to investigate the influence of clinical and biochemical variables on OS and PSA response. Nomograms were developed to estimate the chance of PSA response and OS

Multiresolution analysis of active region magnetic structure and its correlation with the Mt. Wilson classification and flaring activity

Two different multi-resolution analyses are used to decompose the structure of active region magnetic flux into concentrations of different size scales. Lines separating these opposite polarity regions of flux at each size scale are found. These lines are used as a mask on a map of the magnetic field gradient to sample the local gradient between opposite polarity regions of given scale sizes. It is shown that the maximum, average and standard deviation of the magnetic flux gradient for alpha, beta, beta-gamma and beta-gamma-delta active regions increase in the order listed, and that the order is maintained over all length-scales. This study demonstrates that, on average, the Mt. Wilson classification encodes the notion of activity over all length-scales in the active region, and not just those length-scales at which the strongest flux gradients are found. Further, it is also shown that the average gradients in the field, and the average length-scale at which they occur, also increase in the same order. Finally, there are significant differences in the gradient distribution, between flaring and non-flaring active regions, which are maintained over all length-scales. It is also shown that the average gradient content of active regions that have large flares (GOES class 'M' and above) is larger than that for active regions containing flares of all flare sizes; this difference is also maintained at all length-scales.Comment: Accepted for publication in Solar Physic

Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection

Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting for thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation

Quantum Attractor Flows

Motivated by the interpretation of the Ooguri-Strominger-Vafa conjecture as a holographic correspondence in the mini-superspace approximation, we study the radial quantization of stationary, spherically symmetric black holes in four dimensions. A key ingredient is the classical equivalence between the radial evolution equation and geodesic motion of a fiducial particle on the moduli space M^*_3 of the three-dimensional theory after reduction along the time direction. In the case of N=2 supergravity, M^*_3 is a para-quaternionic-Kahler manifold; in this case, we show that BPS black holes correspond to a particular class of geodesics which lift holomorphically to the twistor space Z of M^*_3, and identify Z as the BPS phase space. We give a natural quantization of the BPS phase space in terms of the sheaf cohomology of Z, and compute the exact wave function of a BPS black hole with fixed electric and magnetic charges in this framework. We comment on the relation to the topological string amplitude, extensions to N>2 supergravity theories, and applications to automorphic black hole partition functions.Comment: 43 pages, 6 figures; v2: typos and references added; v3: published version, minor change