Ethics of Artificial Intelligence Demarcations

In this paper we present a set of key demarcations, particularly important when discussing ethical and societal issues of current AI research and applications. Properly distinguishing issues and concerns related to Artificial General Intelligence and weak AI, between symbolic and connectionist AI, AI methods, data and applications are prerequisites for an informed debate. Such demarcations would not only facilitate much-needed discussions on ethics on current AI technologies and research. In addition sufficiently establishing such demarcations would also enhance knowledge-sharing and support rigor in interdisciplinary research between technical and social sciences.Comment: Proceedings of the Norwegian AI Symposium 2019 (NAIS 2019), Trondheim, Norwa

Comorbid chronic tic disorder and tourette syndrome in children requiring inpatient mental health treatment

Objective: Children needing admission to an inpatient mental health unit often present with severe neuropsychiatric disorders characterised by complex psychopathology. We aimed to examine all admitted children with comorbid chronic tic disorder (CTD) and Tourette syndrome (TS) over a 10-year period and determine the clinical significance of these diagnoses. Method: A retrospective, naturalistic study was conducted, comparing children with and without CTD/TS in terms of co-morbid diagnoses, medication use, access to education, aggression contributing to the admission, duration of admission, functional outcomes and satisfaction with treatment. Data were analysed using Chi-square/Fisher’s exact test and t-test for categorical and continuous variables, respectively, and subsequently with unadjusted and adjusted linear and logistic regression analyses. Results: A relatively high proportion of children had co-morbid CTD/TS (19.7%). There was a significant association with co-morbid obsessive-compulsive disorder, intellectual disability and autism spectrum disorder but not attention deficit hyperactivity disorder. CTD/TS were associated with longer admissions even after adjustments for confounding but did not seem to be independently associated with other examined clinical characteristics. Conclusions: The prevalence of CTD/TS in children needing inpatient treatment is significant. In our sample, comorbid CTD/TS seem to represent a marker of overall symptom severity as evidenced by longer admissions

Mr. Meteo: Providing climate information for the unconnected

A majority of the world remain unconnected to the World Wide Web due to issues like low literacy and relevant information. This study presents Mr. Meteo, a system that provides weather information via voice calls in local languages to rural farmers in Ghana. The study used an interdisciplinary approach to identify relevant informational needs and socio-economic implications, and early end-user and stakeholder involvement. Mr. Meteo was deployed in Bolgatanga, Ghana and represents a novel design in terms of actual web data access to rural areas. The positive feedback from farmers, and stakeholder’s interest in continuity, shows this approach to be an appropriate method of development and implementation of information systems for rural areas; successful due to end-user and stakeholder involvement, focus on existing technologies, the use of voice technologies to mitigate the problem of illiteracy, and information relevance to end-users. This paper presents the methodology and results of this novel, practical, local-context ICT4D project,that has produced a viable information system for rural communities

Therapeutic drug monitoring of immunotherapies with novel Affimer–NanoBiT sensor construct

Concentration–therapeutic efficacy relationships have been observed for several therapeutic monoclonal antibodies (TmAb), where low circulating levels can result in ineffective treatment and high concentrations can cause adverse reactions. Rapid therapeutic drug monitoring (TDM) of TmAb drugs would provide the opportunity to adjust an individual patient's dosing regimen to improve treatment results. However, TDM for immunotherapies is currently limited to centralised testing methods with long sample-collection to result timeframes. Here, we show four point-of-care (PoC) TmAb biosensors by combining anti-idiotypic Affimer proteins and NanoBiT split luciferase technology at a molecular level to provide a platform for rapid quantification (<10 minutes) for four clinically relevant TmAb (rituximab, adalimumab, ipilimumab and trastuzumab). The rituximab sensor performed best with 4 pM limit of detection (LoD) and a quantifiable range between 8 pM–2 nM with neglectable matrix effects in serum up to 1%. After dilution of serum samples, the resulting quantifiable range for all four sensors falls within the clinically relevant range and compares favourably with the sensitivity and/or time-to-result of current ELISA standards. Further development of these sensors into a PoC test may improve treatment outcome and quality of life for patients receiving immunotherapy

Developing a comprehensive information security framework for mHealth: a detailed analysis

It has been clearly shown that mHealth solutions, which is the use of mobile devices and other wireless technology to provide healthcare services, deliver more patient-focused healthcare, and improve the overall efficiency of healthcare systems. In addition, these solutions can potentially reduce the cost of providing healthcare in the context of the increasing demands of the aging populations in advanced economies. These solutions can also play an important part in intelligent environments, facilitating real-time data collection and input to enable various functionalities. However, there are several challenges regarding the development of mHealth solutions: the most important of these being privacy and data security. Furthermore, the use of cloud computing is becoming an option for the healthcare sector to store healthcare data; but storing data in the cloud raises serious concerns. This paper investigates how data are managed both on mHealth devices as well as in the cloud. Firstly, a detailed analysis of the entire mHealth domain is undertaken to determine domain-specific features and a taxonomy for mHealth, from which a set of security requirements are identified in order to develop a new information security framework. It then examines individual information security frameworks for mHealth devices and the cloud, noting similarities and differences. Furthermore, key mechanisms to implement the new framework are discussed and the new framework is then presented. Finally, the paper presents how the new framework could be implemented in order to develop an Advanced Digital Medical Platform

HES5 silencing is an early and recurrent change in prostate tumourigenesis.

Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.The authors are grateful to study volunteers for their participation and staff at the Welcome Trust Clinical Research Facility, Addenbrooke’s Clinical Research Centre, Cambridge. They also thank the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository, The University of Cambridge, Hutchison Whampoa Limited and Cancer Research UK for funding. They are grateful to the CRUK Cambridge Institute Genomics and Bioinformatics Core Facilities. Cross-validation of HES5 methylation includes the use of data generated by the TCGA Research Network.This is the final version of the article. It was originally published in the Endocrine-Related Cancer, April 1, 2015 22 131-144 doi: 10.1530/ERC-14-0454

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).We thank CRUK, The NIHR, The Academy of Medical Sciences(RG:63397) and the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (ProMPT) collaborative (G0500966/75466), Hutchison Whampoa Limited, the Human Research Tissue Bank (Addenbrooke’s Hospital, supported by the NIHR Cambridge BRC), and Cancer Research UK

Comparing counselling alone versus counselling supplemented with guided use of a well-being app for university students experiencing anxiety or depression (CASELOAD): protocol for a feasibility trial.

BACKGROUND: University counselling services face a unique challenge to offer short-term therapeutic support to students presenting with complex mental health needs and in a setting which suits the academic timetable. The recent availability of mobile phone applications (apps) offers an opportunity to supplement face-to-face therapy and has the potential to reach a wider audience, maintain engagement between therapy sessions, and enhance therapeutic outcomes. The present study, entitled Counselling plus Apps for Students Experiencing Levels of Anxiety or Depression (CASELOAD), aims to explore the feasibility of supplementing counselling with guided use of a well-being app. METHODS/DESIGN: Forty help-seeking university students (aged 18 years and over) with symptoms of moderate anxiety or depression will be recruited from a University Counselling Service (UCS) in the United Kingdom (UK). Participants will be recruited via counsellors who provide the initial clinical assessment and who determine treatment allocation to one of two treatments on the basis of client-treatment fit. The two conditions comprise (1) counselling alone (treatment as usual/TAU) or (2) counselling supplemented with guided use of a well-being app (enhanced intervention). Trained counsellors will deliver up to six counselling sessions in each treatment arm across a 6-month period, and the session frequency will be decided by client-counsellor discussion. Assessments will occur at baseline, every counselling session, post-intervention (3 months after consent) and follow-up (6 months after consent). Assessments will include clinical measures of anxiety, depression, psychological functioning, specific mental health concerns (e.g. academic distress and substance misuse), resilience and therapeutic alliance. The usage, acceptability, feasibility and potential implications of combining counselling with guided use of the well-being app will be assessed through audio recordings of counselling sessions, telephone interviews with participants, focus groups with counsellors and counsellor notes. DISCUSSION: This study will inform the design of a randomised pilot trial and a definitive trial which aim to improve therapy engagement, reduce dropout and enhance clinical outcomes of student counselling. TRIAL REGISTRATION: ISRCTN55102899

The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

Background: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results: Single nucleotide variants (P = 7.0 × 10–03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10–06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10–05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10–09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches

Kaposi's Sarcoma-Associated Herpesvirus ORF45 Interacts with Kinesin-2 Transporting Viral Capsid-Tegument Complexes along Microtubules

Open reading frame (ORF) 45 of Kaposi's sarcoma-associated herpesvirus (KSHV) is a tegument protein. A genetic analysis with a null mutant suggested a possible role for this protein in the events leading to viral egress. In this study, ORF45 was found to interact with KIF3A, a kinesin-2 motor protein that transports cargoes along microtubules to cell periphery in a yeast two-hybrid screen. The association was confirmed by both co-immunoprecipitation and immunoflorescence approaches in primary effusion lymphoma cells following virus reactivation. ORF45 principally mediated the docking of entire viral capsid-tegument complexes onto the cargo-binding domain of KIF3A. Microtubules served as the major highways for transportation of these complexes as evidenced by drastically reduced viral titers upon treatment of cells with a microtubule depolymerizer, nocodazole. Confocal microscopic images further revealed close association of viral particles with microtubules. Inhibition of KIF3A–ORF45 interaction either by the use of a headless dominant negative (DN) mutant of KIF3A or through shRNA-mediated silencing of endogenous KIF3A expression noticeably decreased KSHV egress reflecting as appreciable reductions in the release of extracellular virions. Both these approaches, however, failed to impact HSV-1 egress, demonstrating the specificity of KIF3A in KSHV transportation. This study thus reports on transportation of KSHV viral complexes on microtubules by KIF3A, a kinesin motor thus far not implicated in virus transportation. All these findings shed light on the understudied but significant events in the KSHV life cycle, delineating a crucial role of a KSHV tegument protein in cellular transport of viral particles