Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials

Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naı¨ve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here

Are methodological quality and completeness of reporting associated with citation-based measures of publication impact? A secondary analysis of a systematic review of dementia biomarker studies

Objective: To determine whether methodological and reporting quality are associated with surrogate measures of publication impact in the field of dementia biomarker studies. Methods: We assessed dementia biomarker studies included in a previous systematic review in terms of methodological and reporting quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) and Standards for Reporting of Diagnostic Accuracy (STARD), respectively. We extracted additional study and journal-related data from each publication to account for factors shown to be associated with impact in previous research. We explored associations between potential determinants and measures of publication impact in univariable and stepwise multivariable linear regression analyses. Outcome measures: We aimed to collect data on four measures of publication impact: two traditional measures—average number of citations per year and 5-year impact factor of the publishing journal and two alternative measures—the Altmetric Attention Score and counts of electronic downloads. Results: The systematic review included 142 studies. Due to limited data, Altmetric Attention Scores and electronic downloads were excluded from the analysis, leaving traditional metrics as the only analysed outcome measures. We found no relationship between QUADAS and traditional metrics. Citation rates were independently associated with 5-year journal impact factor (β=0.42; p<0.001), journal subject area (β=0.39; p<0.001), number of years since publication (β=-0.29; p<0.001) and STARD (β=0.13; p<0.05). Independent determinants of 5-year journal impact factor were citation rates (β=0.45; p<0.001), statement on conflict of interest (β=0.22; p<0.01) and baseline sample size (β=0.15; p<0.05). Conclusions: Citation rates and 5-year journal impact factor appear to measure different dimensions of impact. Citation rates were weakly associated with completeness of reporting, while neither traditional metric was related to methodological rigour. Our results suggest that high publication usage and journal outlet is not a guarantee of quality and readers should critically appraise all papers regardless of presumed impact

Meningitis in an Irish community

A series of 26 cases of meningitis occurring in one year in a defined area is presented. The clinical features, and complications are reviewed. Neisseria meningitidis occurred twice as commonly as Haemophilus influenzae, suggesting that the pattern of infection differs from that reported in England and Wales. An incidence of 4·6/100,000 for N. meningitidis is reported exceeding rates of infection in previous UK “epidemics”

AIOps for a Cloud Object Storage Service

With the growing reliance on the ubiquitous availability of IT systems and services, these systems become more global, scaled, and complex to operate. To maintain business viability, IT service providers must put in place reliable and cost efficient operations support. Artificial Intelligence for IT Operations (AIOps) is a promising technology for alleviating operational complexity of IT systems and services. AIOps platforms utilize big data, machine learning and other advanced analytics technologies to enhance IT operations with proactive actionable dynamic insight. In this paper we share our experience applying the AIOps approach to a production cloud object storage service to get actionable insights into system's behavior and health. We describe a real-life production cloud scale service and its operational data, present the AIOps platform we have created, and show how it has helped us resolving operational pain points.Comment: 5 page

Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the diagnosis of dementia within community dwelling populations

<b>Background</b><p></p> Various tools exist for initial assessment of possible dementia with no consensus on the optimal assessment method. Instruments that use collateral sources to assess change in cognitive function over time may have particular utility. The most commonly used informant dementia assessment is the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).<p></p> A synthesis of the available data regarding IQCODE accuracy will help inform cognitive assessment strategies for clinical practice, research and policy.<p></p> <b>Objectives</b><p></p> Our primary objective was to determine the diagnostic accuracy of the informant based questionnaire IQCODE, for detection of all cause (undifferentiated) dementia in community-dwelling adults with no previous cognitive assessment. We sought to describe the accuracy of IQCODE (the index test) against a clinical diagnosis of dementia (the reference standard).<p></p> Our secondary objective was to describe the effect of heterogeneity on the summary estimates. We were particularly interested in the traditional 26-item scale versus the 16-item short form; and language of administration. We explored the effect of varying the threshold IQCODE score used to define 'test positivity'.<p></p> <b>Search methods</b><p></p> We searched the following sources on 28 January 2013: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science with Conference Proceedings (ISI Web of Knowledge), LILACS (BIREME). We also searched sources relevant or specific to diagnostic test accuracy: MEDION (Universities of Maastrict and Leuven); DARE (York University); ARIF (Birmingham University). We used sensitive search terms based on MeSH terms and other controlled vocabulary.<p></p> <b>Selection criteria</b><p></p> We selected those studies performed in community settings that used (not necessarily exclusively) the IQCODE to assess for presence of dementia and, where dementia diagnosis was confirmed, with clinical assessment. Our intention with limiting the search to a 'community' setting was to include those studies closest to population level assessment. Within our predefined community inclusion criteria, there were relevant papers that fulfilled our definition of community dwelling but represented a selected population, for example stroke survivors. We included these studies but performed sensitivity analyses to assess the effects of these less representative populations on the summary results.<p></p> <b>Data collection and analysis</b><p></p> We screened all titles generated by the electronic database searches and abstracts of all potentially relevant studies were reviewed. Full papers were assessed for eligibility and data extracted by two independent assessors. For quality assessment (risk of bias and applicability) we used the QUADAS 2 tool. We included test accuracy data on the IQCODE used at predefined diagnostic thresholds. Where data allowed, we performed meta-analyses to calculate summary values of sensitivity and specificity with corresponding 95% confidence intervals (CIs). We pre-specified analyses to describe the effect of IQCODE format (traditional or short form) and language of administration for the IQCODE.<p></p> <b>Main results</b><p></p> From 16,144 citations, 71 papers described IQCODE test accuracy. We included 10 papers (11 independent datasets) representing data from 2644 individuals (n = 379 (14%) with dementia). Using IQCODE cut-offs commonly employed in clinical practice (3.3, 3.4, 3.5, 3.6) the sensitivity and specificity of IQCODE for diagnosis of dementia across the studies were generally above 75%.<p></p> Taking an IQCODE threshold of 3.3 (or closest available) the sensitivity was 0.80 (95% CI 0.75 to 0.85); specificity was 0.84 (95% CI 0.78 to 0.90); positive likelihood ratio was 5.2 (95% CI 3.7 to 7.5) and the negative likelihood ratio was 0.23 (95% CI 0.19 to 0.29).<p></p> Comparative analysis suggested no significant difference in the test accuracy of the 16 and 26-item IQCODE tests and no significant difference in test accuracy by language of administration. There was little difference in sensitivity across our predefined diagnostic cut-points.<p></p> There was substantial heterogeneity in the included studies. Sensitivity analyses removing potentially unrepresentative populations in these studies made little difference to the pooled data estimates. The majority of included papers had potential for bias, particularly around participant selection and sampling. The quality of reporting was suboptimal particularly regarding timing of assessments and descriptors of reproducibility and inter-observer variability.<p></p> <b>Authors' conclusions</b><p></p> Published data suggest that if using the IQCODE for community dwelling older adults, the 16 item IQCODE may be preferable to the traditional scale due to lesser test burden and no obvious difference in accuracy. Although IQCODE test accuracy is in a range that many would consider 'reasonable', in the context of community or population settings the use of the IQCODE alone would result in substantial misdiagnosis and false reassurance. Across the included studies there were issues with heterogeneity, several potential biases and suboptimal reporting quality

A large National Institute for Health Research (NIHR) Biomedical Research Centre facilitates impactful cross-disciplinary and collaborative translational research publications and research collaboration networks: a bibliometric evaluation study

Background The evaluation of translational health research is important for various reasons such as the research impact assessment, research funding allocation, accountability, and strategic research policy formulation. The purpose of this study was to evaluate the research productivity, strength and diversity of research collaboration networks and impact of research supported by a large biomedical research centre in the United Kingdom (UK). Methods Bibliometric analysis of research publications by translational researchers affiliated with the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) from April 2012 to March 2017. Results Analysis included 2377 translational research publications that were published during the second 5-year funding period of the NIHR Oxford BRC. Author details were available for 99.75% of the publications with DOIs (2359 of 2365 with DOIs), and the number of authors per publication was median 9 (mean  = 18.03, SD  = 3.63, maximum  = 2467 authors). Author lists also contained many consortia, groups, committees, and teams (n  = 165 in total), with 1238 additional contributors, where membership was reported. The BRC co-authorship i.e., research collaboration network for these publications involved 20,229 nodes (authors, of which 1606 nodes had Oxford affiliations), and approximately 4.3 million edges (authorship linkages). Articles with a valid DOIs (2365 of 2377, 99.5%) were collectively cited more than 155,000 times and the average Field Citation Ratio was median 6.75 (geometric mean  = 7.12) while the average Relative Citation Ratio was median 1.50 (geometric mean  = 1.83) for the analysed publications. Conclusions The NIHR Oxford BRC generated substantial translational research publications and facilitated a huge collaborative network of translational researchers working in complex structures and consortia, which shows success across the whole of this BRC funding period. Further research involving continued uptake of unique persistent identifiers and the tracking of other research outputs such as clinical innovations and patents would allow a more detailed understanding of large research enterprises such as NIHR BRCs in the UK

Ketamine treatment for individuals with treatment-resistant depression: a longitudinal qualitative interview study of patient experiences

Background Ketamine has recently received considerable attention regarding its antidepressant and anti-suicidal effects. Trials have generally focused on short-term effects of single intravenous infusions. Research on patient experiences is lacking. Aims To investigate the experiences over time of individuals receiving ketamine treatment in a routine clinic, including impacts on mood and suicidality. Method Twelve fee-paying patients with treatment-resistant depression (6 females, 6 males, age 21-70 years; 11 reporting suicidality and six self-harm) who were assessed as eligible for ketamine treatment participated in up to three semi-structured interviews: before treatment started, a few weeks into treatment and two or more months later. Data were analysed thematically. Results Most participants hoped that ketamine would provide respite from their depression. All experienced improvement in mood following initial treatments, ranging from negligible to dramatic, and eight a reduction in suicidality. Improvements were transitory for most participants, although two experienced sustained consistent benefit and two had sustained but limited improvement. Some participants described hopelessness when treatment stopped working, paralleled by increased suicidal ideation for three. The transient nature and cost of treatment were problematic. Eleven participants experienced side-effects, which in two cases were significant. Suggestions for improving treatment included closer monitoring and adjunctive psychological therapy. Conclusions Ketamine treatment was generally experienced as effective in improving mood and reducing suicidal ideation in the short-term, but the lack of longer-term benefit was challenging for participants, as was treatment cost. Informed consent procedures should refer to the possibilities of relapse and of associated increased hopelessness and suicidality

The humoral immune response to BCG vaccination

Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity

Keeping the proportions of protein complex components in check

How do cells maintain relative proportions of protein complex components? Advances in quantitative, genome-wide measurements have begun to shed light onto the roles of protein synthesis and degradation in establishing the precise proportions in living cells: on the one hand, ribosome profiling studies indicate that proteins are already produced in the correct relative proportions. On the other hand, proteomic studies found that many complexes contain subunits that are made in excess and subsequently degraded. Here, we discuss these seemingly contradictory findings, emerging principles, and remaining open questions. We conclude that establishing precise protein levels involves both coordinated synthesis and post-translational fine-tuning via protein degradation

Effects of ketamine treatment on suicidal ideation: a qualitative study of patients’ accounts following treatment for depression in a UK ketamine clinic

Objective It is recognised that ketamine treatment can reduce suicidal ideation (SI) in people with depression, at least in the short term. However, information is lacking on patients’ perspectives on such effects. Studying these can contribute to greater understanding of the mechanisms underlying impact of ketamine treatment on SI. The aim of this study was to investigate patients’ reports of the impact of treatment on their SI, the duration of effects and possible mechanisms. Design and setting This qualitative study consisted of semi-structured interviews with patients who had received ketamine treatment for depression. Interview data were analysed thematically. Participants Fourteen patients (8 females, 6 males, aged 24–64 years) who had received treatment with ketamine for treatment-resistant depression, and had SI at the initiation of treatment. Two participants also had a diagnosis of bipolar type 1 and two of emotionally unstable personality disorder. Eight had a history of self-harm. Results SI reduced following ketamine treatment in 12 out of 14 participants for periods of a few hours following a single treatment to up to three years with ongoing treatment. Reduction of SI was variable in terms of extent and duration, and re-emergence of suicidal thoughts often occurred when treatment ceased. Participants’ accounts indicated that reduced SI was associated with improved mood and reduced anxiety, as were clarity of thought, focus and concentration, and ability to function. Participants reported experiencing some or all of these effects in various orders of occurrence. Conclusion Generally, ketamine treatment was experienced as effective in reducing SI, although duration of effects varied considerably. Patients’ perspectives indicated similarities in the mechanisms of reduction in SI, but some differences in their manifestation, particularly in relation to chronology. Experiences of this cohort suggest that reduced anxiety and improvement in ability to think and function were important mechanisms alongside, or in some cases independently of, improvement in mood. Further studies of patients’ experiences are required to gain enhanced understanding of the variability of effects of ketamine on SI and functionality