Doubleâ blind, randomized phase 3 trial of lowâ dose 13â cis retinoic acid in the prevention of second primaries in head and neck cancer: Longâ term followâ up of a trial of the Eastern Cooperative Oncology Groupâ ACRIN Cancer Research Group (C0590)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139904/1/cncr30920.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139904/2/cncr30920_am.pd

The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

BACKGROUND: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. OBJECTIVES: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. STUDY DESIGN: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. PARTICIPANTS: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. INTERVENTIONS: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. MAIN OUTCOME MEASURES: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. METHODS: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. RESULTS: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. CONCLUSIONS: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. LIMITATIONS: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. FUTURE WORK: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr

Ferroelectricity in Si-Doped hafnia: probing challenges in absence of screening charges

The ability to develop ferroelectric materials using binary oxides is critical to enable novel low-power, high-density non-volatile memory and fast switching logic. The discovery of ferroelectricity in hafnia-based thin films, has focused the hopes of the community on this class of materials to overcome the existing problems of perovskite-based integrated ferroelectrics. However, both the control of ferroelectricity in doped-HfO2 and the direct characterization at the nanoscale of ferroelectric phenomena, are increasingly difficult to achieve. The main limitations are imposed by the inherent intertwining of ferroelectric and dielectric properties, the role of strain, interfaces and electric field-mediated phase, and polarization changes. In this work, using Si-doped HfO2 as a material system, we performed a correlative study with four scanning probe techniques for the local sensing of intrinsic ferroelectricity on the oxide surface. Putting each technique in perspective, we demonstrated that different origins of spatially resolved contrast can be obtained, thus highlighting possible crosstalk not originated by a genuine ferroelectric response. By leveraging the strength of each method, we showed how intrinsic processes in ultrathin dielectrics, i.e., electronic leakage, existence and generation of energy states, charge trapping (de-trapping) phenomena, and electrochemical effects, can influence the sensed response. We then proceeded to initiate hysteresis loops by means of tip-induced spectroscopic cycling (i.e., “wake-up”), thus observing the onset of oxide degradation processes associated with this step. Finally, direct piezoelectric effects were studied using the high pressure resulting from the probe’s confinement, noticing the absence of a net time-invariant piezo-generated charge. Our results are critical in providing a general framework of interpretation for multiple nanoscale processes impacting ferroelectricity in doped-hafnia and strategies for sensing it.This project received funding from the EU-H2020 research and innovation programme under grant agreement No ID606 having benefitted from the access provided by ICMAB-CSIC in Barcelona within the framework of the NFFA-Europe. The analysis involving BE-PFM and cKPFM was conducted at the Center for Nanophase Materials Sciences, which is a DOE Office of Science User Facility. (L.C., S.J.) BE-PFM measurements were partially supported by the U.S. Department of Energy, Office of Science, Basic Energy Sciences, Materials Science and Engineering Division. (S.N.)Peer reviewe

Safe Handling of Hazardous Drugs: ASCO Standards.

PURPOSE: To provide 2019 ASCO standards on the safe handling of hazardous drugs. METHODS: An Expert Panel was formed, and a systematic review of the literature on closed system transfer devices was performed to May 2017 using PubMed. The Cochrane Database of Systematic Reviews, PubMed, and Google Scholar were used to search for studies of medical surveillance and external ventilation/health effects of exposure to vapors to November 2017. Available standards were considered for endorsement. Public comments were solicited and considered in preparation of the final manuscript. RESULTS: The search for primary research found no studies that addressed health outcomes as they relate to the identified interventions of interest. The ASCO Expert Panel endorses the best practices for safe handling of hazardous drugs as issued by the Occupational Safety and Health Administration, US Pharmacopeia Chapter 800, and Oncology Nursing Society with clarifications in four key areas: medical surveillance, closed system transfer devices, external ventilation of containment secondary engineering controls or containment segregated compounding areas, and alternative duties. CONCLUSION: The ASCO standards address the need for clear standards concerning safe handling of hazardous oncology drugs. More research is needed in several key areas to quantify the level of risk associated with handling hazardous drugs in current workplace settings where the hierarchy of controls is consistently applied. Additional information is available at www.asco.org/safe-handling-standards

Direct Probing of the Dielectric Scavenging-Layer Interface in Oxide Filamentary-Based Valence Change Memory

A great improvement in valence change memory performance has been recently achieved by adding another metallic layer to the simple metal–insulator–metal (MIM) structure. This metal layer is often referred to as oxygen exchange layer (OEL) and is introduced between one of the electrodes and the oxide. The OEL is believed to induce a distributed reservoir of defects at the metal–insulator interface thus providing an unlimited availability of building blocks for the conductive filament (CF). However, its role remains elusive and controversial owing to the difficulties to probe the interface between the OEL and the CF. Here, using Scalpel SPM we probe multiple functions of the OEL which have not yet been directly measured, for two popular VCMs material systems: Hf/HfO₂ and Ta/Ta₂O₅. We locate and characterize in three-dimensions the volume containing the oxygen exchange layer and the CF with nanometer lateral resolution. We demonstrate that the OEL induces a thermodynamic barrier for the CF and estimate the minimum thickness of the OEL/oxide interface to guarantee the proper switching operations is ca. 3 nm. Our experimental observations are combined to first-principles thermodynamics and defect kinetics to elucidate the role of the OEL for device optimization