Two-years Postradiotherapy Biopsies: Lessons from MRC RT01 Trial

Background: The importance of 2-yr postradiotherapy prostate biopsy status remains uncertain. Objective: To assess the value of 2 year post treatment biopsies in a randomised trial of radiotherapy dose escalation. Design, setting, and participants: Between 1998 and 2001, 843 men with localised prostate cancer were randomised to receive either control-64 Gy or escalated-74 Gy conformal radiotherapy (CFRT) in the MRC RT01 trial in combination with 3–6-mo neoadjuvant androgen deprivation therapy. Prostate biopsies were planned at 2 yr from start of CFRT in suitable men. Outcome measurements and statistical analysis: Prostate biopsy results and prostate-specific antigen (PSA) levels performed at 2 yr post-CFRT were evaluated with long-term biochemical progression free survival (bPFS) and overall survival. Outcome measures were timed from the 2-yr biopsy using a landmark approach. Results and limitations: A 2-yr biopsy was performed in 312/843 patients. One hundred and seventy-seven patients were included in the per-protocol group with median follow-up of 7.8 yr from biopsy. Median PSA at biopsy was 0.5 ng/ml. Sixty-four bPFS events were reported: 46/145 (32%) in patients with negative, 6/18 (33%) suspicious, and 12/14 (86%) positive biopsies. A positive biopsy was prognostic of worse bPFS, going forward, compared with negative and suspicious biopsies, hazard ratio (HR) = 4.81 (95% confidence interval [CI]: 2.50–9.26, p < 0.001). The estimate for survival was HR = 1.58 (95% CI: 0.52–4.78, p = 0.42). PSA values at 2 yr between 1.01 ng/ml and 2.09 ng/ml were also associated with subsequent PSA failures (HR = 2.71, 95% CI: 1.98–3.71), bPFS events (HR = 2.45, 95% CI: 1.81–3.32), and prostate cancer-specific survival (HR = 2.87, 95% CI: 1.08–7.64) compared with PSA ≤1.0 ng/ml. Conclusions: Two-year postradiotherapy prostate biopsies have limited value in patients with PSA control but both positive biopsy and higher PSA status are strongly associated with future bPFS events. A policy of selected biopsy may provide an opportunity for early salvage interventions. Patient summary: Routine 2-yr postradiotherapy biopsy is not recommended but can be considered in selected patients with unfavourable post-treatment prostate-specific antigen levels who are suitable for early salvage treatments

Attention deficit hyperactivity symptoms predict problematic mobile phone use

Attention-deficit-hyperactivity disorder (ADHD) is the most commonly diagnosed childhood disorder characterised by inattention, hyperactivity/impulsivity, or both. Some of the key traits of ADHD have previously been linked to addictive and problematic behaviours. The aim of the present study was to examine the relationship between problematic mobile phone use, smartphone addiction risk and ADHD symptoms in an adult population. A sample of 273 healthy adult volunteers completed the Adult ADHD Self-Report Scale (ASRS), the Mobile Phone Problem Usage Scale (MPPUS), and the Smartphone Addiction Scale (SAS). A significant positive correlation was found between the ASRS and both scales. More specifically, inattention symptoms and age predicted smartphone addiction risk and problematic mobile phone use. Our results suggest that there is a positive relationship between ADHD traits and problematic mobile phone use. In particular, younger adults with higher level of inattention symptoms could be at higher risk of developing smartphone addiction. The implication of our findings for theoretical frameworks of problematic mobile phone use and clinical practice are discussed

Risk, Unexpected Uncertainty, and Estimation Uncertainty: Bayesian Learning in Unstable Settings

Recently, evidence has emerged that humans approach learning using Bayesian updating rather than (model-free) reinforcement algorithms in a six-arm restless bandit problem. Here, we investigate what this implies for human appreciation of uncertainty. In our task, a Bayesian learner distinguishes three equally salient levels of uncertainty. First, the Bayesian perceives irreducible uncertainty or risk: even knowing the payoff probabilities of a given arm, the outcome remains uncertain. Second, there is (parameter) estimation uncertainty or ambiguity: payoff probabilities are unknown and need to be estimated. Third, the outcome probabilities of the arms change: the sudden jumps are referred to as unexpected uncertainty. We document how the three levels of uncertainty evolved during the course of our experiment and how it affected the learning rate. We then zoom in on estimation uncertainty, which has been suggested to be a driving force in exploration, in spite of evidence of widespread aversion to ambiguity. Our data corroborate the latter. We discuss neural evidence that foreshadowed the ability of humans to distinguish between the three levels of uncertainty. Finally, we investigate the boundaries of human capacity to implement Bayesian learning. We repeat the experiment with different instructions, reflecting varying levels of structural uncertainty. Under this fourth notion of uncertainty, choices were no better explained by Bayesian updating than by (model-free) reinforcement learning. Exit questionnaires revealed that participants remained unaware of the presence of unexpected uncertainty and failed to acquire the right model with which to implement Bayesian updating

Genomic-Bioinformatic Analysis of Transcripts Enriched in the Third-Stage Larva of the Parasitic Nematode Ascaris suum

Differential transcription in Ascaris suum was investigated using a genomic-bioinformatic approach. A cDNA archive enriched for molecules in the infective third-stage larva (L3) of A. suum was constructed by suppressive-subtractive hybridization (SSH), and a subset of cDNAs from 3075 clones subjected to microarray analysis using cDNA probes derived from RNA from different developmental stages of A. suum. The cDNAs (n = 498) shown by microarray analysis to be enriched in the L3 were sequenced and subjected to bioinformatic analyses using a semi-automated pipeline (ESTExplorer). Using gene ontology (GO), 235 of these molecules were assigned to ‘biological process’ (n = 68), ‘cellular component’ (n = 50), or ‘molecular function’ (n = 117). Of the 91 clusters assembled, 56 molecules (61.5%) had homologues/orthologues in the free-living nematodes Caenorhabditis elegans and C. briggsae and/or other organisms, whereas 35 (38.5%) had no significant similarity to any sequences available in current gene databases. Transcripts encoding protein kinases, protein phosphatases (and their precursors), and enolases were abundantly represented in the L3 of A. suum, as were molecules involved in cellular processes, such as ubiquitination and proteasome function, gene transcription, protein–protein interactions, and function. In silico analyses inferred the C. elegans orthologues/homologues (n = 50) to be involved in apoptosis and insulin signaling (2%), ATP synthesis (2%), carbon metabolism (6%), fatty acid biosynthesis (2%), gap junction (2%), glucose metabolism (6%), or porphyrin metabolism (2%), although 34 (68%) of them could not be mapped to a specific metabolic pathway. Small numbers of these 50 molecules were predicted to be secreted (10%), anchored (2%), and/or transmembrane (12%) proteins. Functionally, 17 (34%) of them were predicted to be associated with (non-wild-type) RNAi phenotypes in C. elegans, the majority being embryonic lethality (Emb) (13 types; 58.8%), larval arrest (Lva) (23.5%) and larval lethality (Lvl) (47%). A genetic interaction network was predicted for these 17 C. elegans orthologues, revealing highly significant interactions for nine molecules associated with embryonic and larval development (66.9%), information storage and processing (5.1%), cellular processing and signaling (15.2%), metabolism (6.1%), and unknown function (6.7%). The potential roles of these molecules in development are discussed in relation to the known roles of their homologues/orthologues in C. elegans and some other nematodes. The results of the present study provide a basis for future functional genomic studies to elucidate molecular aspects governing larval developmental processes in A. suum and/or the transition to parasitism

Towards responsible use of cognitive-enhancing drugs by the healthy

In this article, we propose actions that will help society accept the benefits of enhancement, given appropriate research and evolved regulation. Prescription drugs are regulated as such not for their enhancing properties but primarily for considerations of safety and potential abuse. Still, cognitive enhancement has much to offer individuals and society, and a proper societal response will involve making enhancements available while managing their risks

Critical reflections on evidence, ethics and effectiveness in the management of tuberculosis: public health and global perspectives

BACKGROUND: Tuberculosis is a major cause of morbidity and mortality globally. Recent scholarly attention to public health ethics provides an opportunity to analyze several ethical issues raised by the global tuberculosis pandemic. DISCUSSION: Recently articulated frameworks for public health ethics emphasize the importance of effectiveness in the justification of public health action. This paper critically reviews the relationship between these frameworks and the published evidence of effectiveness of tuberculosis interventions, with a specific focus on the controversies engendered by the endorsement of programs of service delivery that emphasize direct observation of therapy. The role of global economic inequities in perpetuating the tuberculosis pandemic is also discussed. SUMMARY: Tuberculosis is a complex but well understood disease that raises important ethical challenges for emerging frameworks in public health ethics. The exact role of effectiveness as a criterion for judging the ethics of interventions needs greater discussion and analysis. Emerging frameworks are silent about the economic conditions contributing to the global burden of illness associated with tuberculosis and this requires remediation

Differential Regulation of PDE5 Expression in Left and Right Ventricles of Feline Hypertrophy Models

Though long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models.Using a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression.The differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation

Measurements of B --> D_s^{(*)+} D^{*(*)} Branching Fractions

This article describes improved measurements by CLEO of the $B^0 \to D_s^+ D^{*-}$ and $B^0 \to D_s^{*+} D^{*-}$ branching fractions, and first evidence for the decay $B^+ \to D_s^{(*)+} \bar{D}^{**0}$, where $\bar{D}^{**0}$ represents the sum of the $\bar{D}_1(2420)^0$, $\bar{D}_2^*(2460)^0$, and $\bar{D}_1(j=1/2)^0$ L=1 charm meson states. Also reported is the first measurement of the $D_s^{*+}$ polarization in the decay $B^0 \to D_s^{*+} D^{*-}$. A partial reconstruction technique, employing only the fully reconstructed $D_s^+$ and slow pion $\pi_s^-$ from the $D^{*-} \to \bar{D}^0 \pi^-_s$ decay, enhances sensitivity. The observed branching fractions are ${\mathcal B} (B^0 \to D_s^+ D^{*-}) = (1.10 \pm 0.18 \pm 0.10 \pm 0.28)$, ${\mathcal B} (B^0 \to D_s^{*+} D^{*-}) = (1.82 \pm 0.37 \pm 0.24 \pm 0.46)$, and ${\mathcal B} (B^+ \to D_s^{(*)+} \bar{D}^{**0}) = (2.73 \pm 0.78 \pm 0.48 \pm 0.68)$, where the first error is statistical, the second systematic, and the third is due to the uncertainty in the $D_s^+ \to \phi \pi^+$ branching fraction. The measured $D_s^{*+}$ longitudinal polarization, $\Gamma_L/\Gamma = (50.6 \pm 13.9 \pm 3.6)$, is consistent with the factorization prediction of 54%.Comment: 26 pages (LaTeX), 15 figures. To be submitted to PR