The development of imaging biomarkers for the diagnosis of human prion disease

Future therapeutic trials in human prion disease will require the use of biomarkers of disease activity such as MRI in order to assess efficacy of treatment. Whilst the development of biomarkers is of importance it is also necessary to be able to understand and interpret what imaging findings characterise at post-mortem and furthermore how they correlate with clinical symptoms. In this thesis I investigate whether both conventional and quantitative imaging parameters can act as biomarkers to predict disease progression in symptomatic patients. I also assess what conventional MRI findings represent on a microstructural level and how imaging findings correlate with clinical symptoms of prion disease such as sleep disturbance. This work is detailed in four projects, the first of which I investigate if abnormalities found on conventional MRI brain scans, PRNP genotype and prion strain can act as predictors of disease progression in patients with the sporadic form of prion disease. I was unable to show that conventional MR brain imaging helps to predict disease progression in this patient group, but I was able to show that codon 129 remains the main predictor of disease progression and strain subtype has an additional effect. In the second project I test the hypothesis that MTR, a quantitative imaging parameter can predict disease progression in symptomatic patients. I found that both on cross-sectional and longitudinal analysis there were significant differences in symptomatic patients and that there was a strong correlation with the MRC Scale score, clinical outcome measure, and MTR value in patients with symptomatic disease which could be used as a clinical biomarker in combination to predict response to therapeutics in future clinical trials. In the third project I focus on investigating the prevalence of sleep disturbance and its association with other features of disease and imaging findings. I found that sleep disturbance was highly prevalent in all forms of prion disease. I also found that there was a significant association found between thalamic signal change seen on MRI scan and sleep symptomatology. In order to capture more data on the diversity of sleep symptoms in this population I constructed the Prion Disease Sleep Questionnaire a bedside screening tool that can be used to both record and monitor the incidence and severity of sleep disturbance. In the final project I assess if specific histopathological findings on post-mortem correlate with cortical imaging abnormalities seen on DWI in patients diagnosed with sporadic CJD. I found that there were significant difference between patients with and without cortical ribboning present on their MRI brain scans those with DWI signal change had more frontal cortex spongiosis than those that didn’t. There was also a modest correlation identified between the 3 histopathological parameters: PrPSc, deposition, gliosis and spongiosis

Population-Level Benefits from Providing Effective HIV Prevention Means to Pregnant Women in High Prevalence Settings

Background:HIV prevalence among pregnant women in Southern Africa is extremely high. Epidemiological studies suggest that pregnancy increases the risk of HIV sexual acquisition and that HIV infections acquired during pregnancy carry higher risk of mother-to-child transmission (MTCT). We analyze the potential benefits from extending the availability of effective microbicide to pregnant women (in addition to non-pregnant women) in a wide-scale intervention.Methods and Findings:A transmission dynamic model was designed to assess the impact of microbicide use in high HIV prevalence settings and to estimate proportions of new HIV infections, infections acquired during pregnancy, and MTCT prevented over 10 years. Our analysis suggests that consistent use of microbicide with 70% efficacy by 60% of non-pregnant women may prevent approximately 40% and 15% of new infections in women and men respectively over 10 years, assuming no additional increase in HIV risk to either partner during pregnancy (RRHIV/preg = 1). It may also prevent 8-15% MTCT depending on the increase in MTCT risk when HIV is acquired during pregnancy compared to before pregnancy (RRMTCT/preg). Extending the microbicides use during pregnancy may improve the effectiveness of the intervention by 10% (RRHIV/preg = 1) to 25% (RRHIV/preg = 2) and reduce the number of HIV infections acquired during pregnancy by 40% to 70% in different scenarios. It may add between 6% (RRHIV/preg = 1, RRMTCT/preg = 1) and 25% (RRHIV/preg = 2, RRMTCT/preg = 4) to the reduction in the residual MTCT.Conclusion:Providing safe and effective microbicide to pregnant women in the context of wide-scale interventions would be desirable as it would increase the effectiveness of the intervention and significantly reduce the number of HIV infections acquired during pregnancy. The projected benefits from covering pregnant women by the HIV prevention programs is more substantial in communities in which the sexual risk during pregnancy is elevated. © 2013 Dimitrov et al

Yes, we should! EU priorities for 2019-2024. EPC Challenge Europe Issue 24, April 2019

The European Union (EU) is not alone in its struggle to grapple with the major headaches of our times. The Western world as a whole is affected. Inside the Union, the crises in and of its national societies and democracies have radiated to the EU level. Half of the member states have minority governments. If they are politically weak in their own countries, how can the Union be strong? The EU is, after all, also the sum of its member states

The political, research, programmatic, and social responses to adolescent sexual and reproductive health and rights in the 25 years since the International Conference on Population and Development

Among the ground-breaking achievements of the International Conference on Population and Development (ICPD) was its call to place adolescent sexual and reproductive health (ASRH) on global health and development agendas. This article reviews progressmade in low- and middle-income countries in the 25 years since the ICPD in six areas central to ASRH-adolescent pregnancy, HIV, child marriage, violence against women and girls, female genital mutilation, and menstrual hygiene and health. It also examines the ICPD's contribution to the progress made. The article presents epidemiologic levels and trends; political, research, programmatic and social responses; and factors that helped or hindered progress. To do so, it draws on research evidence and programmatic experience and the expertise and experiences of a wide number of individuals, including youth leaders, in numerous countries and organizations. Overall, looking across the six health topics over a 25-year trajectory, there has been great progress at the global and regional levels in putting adolescent health, and especially adolescent sexual and reproductive health and rights, higher on the agenda, raising investment in this area, building the epidemiologic and evidence-base, and setting norms to guide investment and action. At the national level, too, there has been progress in formulating laws and policies, developing strategies and programs and executing them, and engaging communities and societies in moving the agenda forward. Still, progress has been uneven across issues and geography. Furthermore, it has raced ahead sometimes and has stalled at others. The ICPD's Plan of Action contributed to the progress made in ASRH not just because of its bold call in 1994 but also because it provided a springboard for advocacy, investment, action, and research that remains important to this day. (C) 2019 Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine

A Phylogenetic Analysis of Human Immunodeficiency Virus Type 1 Sequences in Kiev: Findings Among Key Populations

Background: The human immunodeficiency virus (HIV) epidemic in Ukraine has been driven by a rapid rise among people who inject drugs, but recent studies have shown an increase through sexual transmission. Methods: Protease and reverse transcriptase sequences from 876 new HIV diagnoses (April 2013–March 2015) in Kiev were linked to demographic data. We constructed phylogenetic trees for 794 subtype A1 and 64 subtype B sequences and identified factors associated with transmission clustering. Clusters were defined as ≥2 sequences, ≥80% local branch support, and maximum genetic distance of all sequence pairs in the cluster ≤2.5%. Recent infection was determined through the limiting antigen avidity enzyme immunoassay. Sequences were analyzed for transmitted drug resistance mutations. Results Thirty percent of subtype A1 and 66% of subtype B sequences clustered. Large clusters (maximum 11 sequences) contained mixed risk groups. In univariate analysis, clustering was significantly associated with subtype B compared to A1 (odds ratio [OR], 4.38 [95% confidence interval {CI}, 2.56–7.50]); risk group (OR, 5.65 [95% CI, 3.27–9.75]) for men who have sex with men compared to heterosexual males; recent, compared to long-standing, infection (OR, 2.72 [95% CI, 1.64–4.52]); reported sex work contact (OR, 1.93 [95% CI, 1.07–3.47]); and younger age groups compared with age ≥36 years (OR, 1.83 [95% CI, 1.10–3.05] for age ≤25 years). Females were associated with lower odds of clustering than heterosexual males (OR, 0.49 [95% CI, .31–.77]). In multivariate analysis, risk group, subtype, and age group were independently associated with clustering (P < .001, P = .007, and P = .033, respectively). Eighteen sequences (2.1%) indicated evidence of transmitted drug resistance. Conclusions Our findings suggest high levels of transmission and bridging between risk groups

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p &lt; 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed

Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 \ub5M gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10 3690] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box