Using Deep Learning Artificial Intelligence Algorithms to Verify N-Nitroso-N-Methylurea and Urethane Positive Control Proliferative Changes in Tg-RasH2 Mouse Carcinogenicity Studies.

In Tg-rasH2 carcinogenicity mouse models, a positive control group is treated with a carcinogen such as urethane or N-nitroso-N-methylurea to test study validity based on the presence of the expected proliferative lesions in the transgenic mice. We hypothesized that artificial intelligence-based deep learning (DL) could provide decision support for the toxicologic pathologist by screening for the proliferative changes, verifying the expected pattern for the positive control groups. Whole slide images (WSIs) of the lungs, thymus, and stomach from positive control groups were used for supervised training of a convolutional neural network (CNN). A single pathologist annotated WSIs of normal and abnormal tissue regions for training the CNN-based supervised classifier using INHAND criteria. The algorithm was evaluated using a subset of tissue regions that were not used for training and then additional tissues were evaluated blindly by 2 independent pathologists. A binary output (proliferative classes present or not) from the pathologists was compared to that of the CNN classifier. The CNN model grouped proliferative lesion positive and negative animals at high concordance with the pathologists. This process simulated a workflow for review of these studies, whereby a DL algorithm could provide decision support for the pathologists in a nonclinical study.

Sleep quality and duration in relation to memory in the elderly: Initial results from the Hellenic Longitudinal Investigation of Aging and Diet.

BACKGROUND: Sleep is crucial for cognition, particularly for memory, given its complex association with neurodegenerative processes. The aim of the present study was to examine the association between sleep quality as well as sleep duration and memory performance in a Greek elderly population. SETTING: Cross-sectional design in the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD), a population representative study of Greek elderly (65years or older). METHODS: Data from 1589 participants free of sleep medication were included. Sleep quality was estimated by using the Sleep Scale from the Medical Outcomes Study. An extensive neuropsychological assessment examining memory was administered to each participant. Linear regression analyses were used to examine whether sleep quality (higher score, poor quality) and/or sleep duration were associated with memory expressed in the form of a z-score. Age, sex, education, and body mass index were included as covariates. The main analyses were conducted first on the total sample, then with the exclusion of demented participants, and finally with the exclusion of both demented and participants with Mild Cognitive Impairment (MCI). We then conducted further analyses on the non-demented, non-MCI group, initially stratified by Apolipoprotein E-ε4 gene. We further examined the role of co-morbidities, as well as the association between sleep duration groups and memory. We also explored any interaction effect between sex and sleep quality/duration on memory. We then examined the associations between components of sleep measures and memory scores. Lastly, we examined the associations between sleep quality/duration and verbal/non-verbal memory separately. RESULTS: In the total sample, we noted significant associations between sleep duration and memory (B=-0.001, p≤0.0001), but not for sleep quality and memory (B=-0.038, p=0.121). After excluding the demented participants, the associations were significant for: sleep quality and memory (B=-0.054, p=0.023), and sleep duration and memory (B=-0.001, p≤0.0001). After excluding both the MCI and the demented subjects, the associations between sleep quality and memory (B=-0.065, p=0.006), and sleep duration and memory (B=-0.001, p=0.003) were still significant. The association between the sleep duration groups and memory function was also significant, such that poor memory performance was associated with the longer sleep duration group. The results remained significant even after controlling for the co-morbidities, as well as after adding in the model anxiety and depression as covariates. Associations between sleep quality and memory, and sleep duration and memory were present in the ApoE-ε4 non-carriers. The individual sleep questions that were probably shown to be driving the associations between sleep and memory were: time to fall asleep, sleep not quiet, getting enough sleep to feel rested upon waking in the morning, and getting the amount of sleep needed. Sleep duration was associated with both verbal and non-verbal memory, while sleep quality was only associated with verbal memory. CONCLUSION: Poor sleep quality and longer sleep duration were linked to low memory performance, independent of demographic and clinical factors, in a large sample of cognitively healthy older Greek adults. Other parameters than sleep and memory measurements could play an important role on the association. Levels of melatonin, or circadian rhythms dysregulation might play a crucial role in the above associations.

Aging perceptions and self-efficacy mediate the association between personality traits and depressive symptoms in older adults.

OBJECTIVE: Personality traits have been shown to be predictors of depressive symptoms in late life. Thus, we examined whether other more modifiable sources of individual differences such as self-efficacy and self-perceptions of aging would mediate the association between personality traits and depressive symptoms in older adults. METHOD: Data were obtained from 3,507 older adult participants who took part in the 2012 Health and Retirement Study. The "Big Five" personality traits, self-efficacy, aging perceptions, and depressive symptoms were assessed. Mediation analyses tested the hypothesis that self-efficacy and aging perceptions would mediate the relationship between personality traits and depressive symptoms. RESULTS: All five personality traits were significant predictors of depressive symptoms. Neuroticism was positively associated with depressive symptoms and had the greatest effect compared with the other personality traits. There was a significant indirect effect of neuroticism, extraversion, and conscientiousness on depressive symptoms (including both mediators). The mediating effect of aging perceptions on the relationship between neuroticism and depressive symptoms was the strongest compared with self-efficacy, accounting for approximately 80% of the total indirect effect. CONCLUSION: Our results provide support for interventions aimed at improving self-perceptions related to efficacy and aging in order to reduce depressive symptoms in older adults. Copyright © 2016 John Wiley & Sons, Ltd.

Complexity of Host Micro-RNA Response to Cytomegalovirus Reactivation After Organ Transplantation.

Human (Homo sapiens) micro-RNAs (hsa-miRNAs) regulate virus and host-gene translation, but the biological impact in patients with human cytomegalovirus (hCMV) infection is not well defined in a clinically relevant model. First, we compared hsa-miRNA expression profiles in peripheral blood mononuclear cells from 35 transplant recipients with and without CMV viremia by using a microarray chip covering 847 hsa-miRNAs. This approach demonstrated a set of 142 differentially expressed hsa-miRNAs. Next, we examined the effect of each of these miRNAs on viral growth by using human fibroblasts (human foreskin fibroblast-1) infected with the hCMV Towne strain, identifying a subset of proviral and antiviral hsa-miRNAs. miRNA-target prediction software indicated potential binding sites within the hCMV genome (e.g., hCMV-UL52 and -UL100 [UL = unique long]) and host-genes (e.g., interleukin-1 receptor, IRF1). Luciferase-expressing plasmid constructs and immunoblotting confirmed several predicted miRNA targets. Finally, we determined the expression of selected proviral and antiviral hsa-miRNAs in 242 transplant recipients with hCMV-viremia. We measured hsa-miRNAs before and after antiviral therapy and correlated hsa-miRNA expression levels to hCMV-replication dynamics. One of six antiviral hsa-miRNAs showed a significant increase during treatment, concurrent with viral decline. In contrast, six of eight proviral hsa-miRNAs showed a decrease during viral decline. Our results indicate that a complex and multitargeted hsa-miRNA response occurs during CMV replication in immunosuppressed patients. This study provides mechanistic insight and potential novel biomarkers for CMV replication.

A qualitative investigation of patients' understanding of carbohydrate in the clinical management of type 2 diabetes.

BACKGROUND: A healthy diet is the cornerstone of type 2 diabetes (T2DM) self-management. Carbohydrate is of particular interest as the nutrient with the greatest direct effect on blood glucose (BG) levels. The present study aimed to explore T2DM patients' understanding of carbohydrate and beliefs around the role of carbohydrate in T2DM management. METHODS: Fifteen semi-structured interviews were conducted with T2DM patients. Interviews were audio-recorded and transcribed, and a deductive thematic approach to analysis was employed using the Framework method. RESULTS: Four significant themes emerged: (i) a naïve conceptual understanding of carbohydrate and sugar-centric specificity to dietary behaviours; (ii) a narrow focus on BG management to the neglect of overall dietary balance; (iii) positive reception of moderate dietary advice focused on portion control from healthcare professionals (HCPs); and (iv) the impact of external moderators of dietary choices, including the influence of significant others, emotional and opportunistic eating and budgetary constraints. CONCLUSIONS: Participants' beliefs and understanding of carbohydrate led to an overemphasis on sugar restriction for blood glucose control to the neglect of their overall dietary balance. Diabetes educators need to place greater emphasis on the role of various types of carbohydrate foods for glycaemic control, as well as on concepts of wider metabolic health, during T2DM dietary education. Participants placed a high level of trust and value on practical, moderate portion control advice from HCPs regarding carbohydrate foods. However, HCPs need to be cognisant of external moderators of behaviour, such as the influence of family and friends, budgetary constraints and environmental eating triggers.

CCL8 and the Immune Control of Cytomegalovirus in Organ Transplant Recipients.

Monitoring of cytomegalovirus cell-mediated immunity is a promising tool for the refinement of preventative and therapeutic strategies posttransplantation. Typically, the interferon-γ response to T cell stimulation is measured. We evaluated a broad range of cytokine and chemokines to better characterize the ex vivo host-response to CMV peptide stimulation. In a cohort of CMV viremic organ transplant recipients, chemokine expression-specifically CCL8 (AUC 0.849 95% CI 0.721-0.978; p = 0.003) and CXCL10 (AUC 0.841, 95% CI 0.707-0.974; p = 0.004)-was associated with control of viral replication. In a second cohort of transplant recipients at high-risk for CMV, the presence of a polymorphism in the CCL8 promoter conferred an increased risk of viral replication after discontinuation of antiviral prophylaxis (logrank hazard ratio 3.6; 95% CI 2.077-51.88). Using cell-sorting experiments, we determined that the primary cell type producing CCL8 in response to CMV peptide stimulation was the monocyte fraction. Finally, in vitro experiments using standard immunosuppressive agents demonstrated a dose-dependent reduction in CCL8 production. Chemokines appear to be important elements of the cell-mediated response to CMV infection posttransplant, as here suggested for CCL8, and translation of this knowledge may allow for the tailoring and improvement of preventative strategies.

Hcmv-miR-UL22A-5p: A Biomarker in Transplantation With Broad Impact on Host Gene Expression and Potential Immunological Implications.

Cytomegalovirus (CMV) encodes multiple microRNAs. While these have been partially characterized in vitro, their relevance to clinical CMV infection has not been evaluated. We analyzed samples from a cohort of solid organ transplant patients with CMV disease (n = 245) for viral microRNA expression. Several CMV microRNAs were readily detectable in patients with CMV disease in variable relative abundance. Expression level generally correlated with DNA viral load and the absence of viral microRNA was associated with faster viral clearance. Detection of hcmv-miR-UL22A-5p at baseline independently predicted the recurrence of CMV viremia upon discontinuation of antiviral therapy (OR 3.024, 95% CI: 1.35-6.8; p = 0.007). A combination of direct mRNA targeting by the microRNA and indirect modulation of gene expression involving isoforms of the transcriptional regulator C-MYC may be responsible for the broad effects seen in the association of gene transcripts with the RNA-induced silencing complex and in global protein expression upon hcmv-miR-UL22A-5p transfection. This novel study of in vivo viral microRNA expression profiles provides unique insight into the complexity of clinical CMV infection following transplantation. We provide evidence that viral microRNAs may have complex effects on gene expression and be associated with specific virologic and clinical outcomes, and thus could be further evaluated as biomarkers.

The prevalence of cardiovascular risk factors in obese children.

Childhood Obesity poses a public health problem in Ireland. Complications associated include metabolic disease and cardiovascular disease risk. Our aim was to determine the prevalence of cardiovascular risk factors in a cohort of obese Irish children. Assessments were performed on obese children attending weight management clinic. Pedometers and self report physical activity questionnaires were administered to each participant to determine physical activity levels. Fifty-nine children (21 prepubertal and 38 pubertal/post-pubertal) were metabolically profiled. Mean ± SD of z scores for BMI, Waist Circumference and Body Fat % were +3.29 ± 0.48, +3.98 ± 0.73 and +2.75 ± 0.50 respectively. 43% (n = 9) prepubertal and 68% (n = 26) pubertal/postpubertal children had at least one other cardiovascular risk factor in addition to obesity. Increased moderate-vigorous physical activity levels correlated with reduced incidence of cardiovascular risk factors. There is a significant prevalence of cardiovascular risk factors among obese pre-pubertal children and pubertal/post-pubertal adolescents attending an Irish obesity clinic.

Experimental classification of dynamical regimes in optically injected lasers.

We present a reliable and fast technique to experimentally categorise the dynamical state of optically injected two mode and single mode lasers. Based on the experimentally obtained time-traces locked, unlocked and chaotic states are distinguished for varying injection strength and detuning. For the two mode laser, the resulting experimental stability diagram provides a map of the various single mode and two mode regimes and the transitions between them. This stability diagram is in strong agreement with the theoretical predictions from low-dimensional dynamical models for two mode lasers. We also apply our method to the single mode laser and retain the close agreement between theory and experiment.

Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection.

Dendritic cells (DCs) are key immune sentinels linking the innate and adaptive immune systems. DCs recognise danger signals and initiate T-cell tolerance, memory and polarisation. They are critical cells in responding to a viral illness. Obese individuals have been shown to have an impaired response to vaccinations against virally mediated conditions and to have an increased susceptibility to multi-organ failure in response to viral illness. We investigated if DCs are altered in an obese cohort (mean body mass index 51.7±7.3 kg m(-2)), ultimately resulting in differential T-cell responses. Circulating DCs were found to be significantly decreased in the obese compared with the lean cohort (0.82% vs 2.53%). Following Toll-like receptor stimulation, compared with lean controls, DCs generated from the obese cohort upregulated significantly less CD83 (40% vs 17% mean fluorescence intensity), a molecule implicated in the elicitation of T-cell responses, particularly viral responses. Obese DCs produced twofold more of the immunosuppressive cytokine interleukin (IL)-10 than lean controls, and in turn stimulated fourfold more IL-4-production from allogenic naive T cells. We conclude that obesity negatively impacts the ability of DCs to mature and elicit appropriate T-cell responses to a general stimulus. This may contribute to the increased susceptibility to viral infection observed in severe obesity.

Community-acquired Klebsiella pneumoniae liver abscess: an emerging infection in Ireland and Europe.

INTRODUCTION: Klebsiella pneumoniae has emerged as a predominant cause of community-acquired mono-microbial pyogenic liver abscess. This was first described in Taiwan and has been widely reported in Asia. This infectious entity has been described in Europe, with single case reports predominating. METHODS: We present three cases in one year from our institution in Ireland and review the European literature to date. RESULTS/CONCLUSION: Klebsiella pneumoniae invasive liver abscess syndrome is now emerging in Europe and notably is not restricted to individuals of Asian descent.

Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study.

BACKGROUND: Diabetes and obesity are more prevalent amongst psoriasis patients as is disturbance of the innate immune system. GLP-1 analogue therapy considerably improves weight and glycaemic control in people with type 2 diabetes and its receptor is present on innate immune cells. OBJECTIVE: We aimed to determine the effect of liraglutide, a GLP-1 analogue, on psoriasis severity. METHODS: Before and after 10 weeks of liraglutide therapy (1.2 mg subcutaneously daily) we determined the psoriasis area and severity index (PASI) and the dermatology life quality index (DLQI) in seven people with both psoriasis and diabetes (median age 48 years, median body mass index 48.2 kg/m(2) ). We also evaluated the immunomodulatory properties of liraglutide by measuring circulating lymphocyte subset numbers and monocyte cytokine production. RESULTS: Liraglutide therapy decreased the median PASI from 4.8 to 3.0 (P = 0.03) and the median DLQI from 6.0 to 2.0 (P = 0.03). Weight and glycaemic control improved significantly. Circulating invariant natural killer T (iNKT) cells increased from 0.13% of T lymphocytes to 0.40% (P = 0.03). Liraglutide therapy also effected a non-significant 54% decrease in the proportion of circulating monocytes that produced tumour necrosis factor alpha (P = 0.07). CONCLUSION: GLP-1 analogue therapy improves psoriasis severity, increases circulating iNKT cell number and modulates monocyte cytokine secretion. These effects may result from improvements in weight and glycaemic control as well as from direct immune effects of GLP-1 receptor activation. Prospective controlled trials of GLP-1 therapies are warranted, across all weight groups, in psoriasis patients with and without type 2 diabetes.

A profile of elderly fallers referred for physiotherapy in the emergency department of a Dublin teaching hospital.

Ireland has an ageing population and the elderly are over-represented in Emergency Departments (ED)--a quarter of these presentations resulting from falls. A prospective study design was employed using a convenience sample to profile elderly fallers referred for physiotherapy in ED. Forty-subjects were assessed over 14 weeks. Mean age was 84.88 years (s.d. 7.3) and 31 (77.5%) were female. All demonstrated slow walking speed and 26 (65%) demonstrated poor grip strength. A quarter of subjects reported fear of falling and 30 (75%) were classified as frail. Elderly fallers in ED are a frail group of socially vulnerable patients who demonstrate a risk of further falls. Osteoporosis had been diagnosed in 9 (22.5%) subjects--a low prevalence compared with international research, but 25 (62.5%) subjects had never had a DEXA scan. The prevalence of frailty in the sample of elderly fallers in this study was very high (75%).

Weight management services for adults--highlighting the role of primary care.

Ireland has the fourth highest prevalence of overweight and obese men in the European Union and the seventh highest prevalence among women. This study focuses on 777 referrals on the waiting list for Ireland's only fully funded hospital-based adult weight management service with special emphasis on the role of primary care in the referral process. Since our last review two years ago, we found that patients are now being referred at a younger age (mean 43 years). The mean BMI at referral has increased from 44 to 46. Five hundred and forty eight (70%) referrals were from primary care with males accounting for 163 (30%) of these, despite male obesity being more prevalent. Interestingly, as the distance from Dublin increased, the number of referrals decreased. Overall this is a concerning trend showing the increasing burden of obesity on a younger population and a health system inadequately equipped to deal with the problem. It also highlights the central role of the primary care physician in the timely and appropriate referral to optimise use of our available resources.

Geriatric medicine in the emergency department.

Studies suggest older adults attending emergency departments(ED) benefit from specialist geriatric medicine evaluation. Findings from a pilot ED Geriatric Medicine(GM) liaison service in our 480-bed university hospital are presented. This is not a randomized controlled trial. Service comprised consultant geriatrician and senior trainee-led sessions during daytime working hours. Senior ED personnel selected appropriate patients. GM service also took over ED medical admissions aged 80, 1 in 9 days from General Internal Medicine(GIM). 49% of 284 patients (83.5 +/- 6.8 years) referred, were discharged from ED with appropriate follow-up. Inpatient analysis comprised 51% admitted to GIM, GM and specialist services as per on-call rota and 268 patients taken over from GIM. Patients under GM had shorter length of stay (p < 0.001). The findings suggest specialty specific geriatric medicine management of the older adult presenting to ED can improve service and patient outcomes.

Hopes and fears regarding care robots: Content analysis of newspapers in East Asia and Western Europe, 2001-2020.

Background: As a type of welfare technology, care robotics is now widely seen as a potential aide to rehabilitation, increasing independence and enhancing the wellbeing of people with disabilities and older adults. Research into and development of care robots have both been vigorously promoted in North America, Europe and Asia, and the competition for technological advancement in robotics is becoming fierce. AI ethics and policy guidelines are being established. However, there are still differences in attitudes and perceptions, as well as national policies regarding this type of welfare technology. Moreover, despite the anticipated usefulness, it is believed that progress has been slow in the diffusion of care robots. Purpose: In order to explore how public discourses support technological innovation, such as care robots, while preparing society for potential risks and impact, we sought to ascertain whether public discourse on care robots varies from region to region. For example, what are the hopes and promises associated with care robots and what are the concerns? Methods: To address these questions, this article explored how care robots have been portrayed in five major broadsheet newspapers in five jurisdictions in Asia and Europe (France, Great Britain, Hong Kong SAR, Ireland and Japan). We obtained 545 articles for the period between January 2001 and September 2020, more than half of which originated in Japan. A thematic analysis was conducted of these articles written in four languages (Chinese, English, French and Japanese). Results: Positive and negative narratives were teased out, alongside other key prominent themes identified, such as Japan as the land of robots, the pandemic, and the impact of robots on the economy. As the number of robot-related articles grew from the year 2012 onwards, narratives became more nuanced in European newspapers, but not in Asian ones. Furthermore, recent articles began to address the social and relational impact of care robots, while providing concrete examples of improvements in the quality of life for users. Further careful examination will be necessary in the future in order to establish the impact of robotics use in rehabilitation for people with disabilities, older adults, their carers and society at large.