A comparative phase I study of combination, homologous subtype-C DNA, MVA, and Env gp140 protein/adjuvant HIV vaccines in two immunization regimes

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders,  = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen

Essentials in Accident and Emergency Medicine Radiation Injury: Response and Treatment

The discovery of radiation has enabled great healthcare advances as well as catastrophic injury. This paper reviews major historical incidents of public radiation exposure and the evolution of standards affecting today’s public and health care workers. Current patient care and response assessment to radiation exposure are reviewed. The strengths of modern radiation therapy and the need for continuous process improvements to ensure optimal patient care and secure safe environments are identified. The discovery of radiation has brought significant scientific achievements as well as catastrophic injury

Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study

Background PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design. Methods Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants. Results Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported ‘being deferred’ as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design. Conclusion The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study

Behavioral correlations across activity, mating, exploration, aggression, and antipredator contexts in the European house cricket, Acheta domesticus

Recently, there has been increasing interest in behavioral syndrome research across a range of taxa. Behavioral syndromes are suites of correlated behaviors that are expressed either within a given behavioral context (e. g., mating) or between different contexts (e. g., foraging and mating). Syndrome research holds profound implications for animal behavior as it promotes a holistic view in which seemingly autonomous behaviors may not evolve independently, but as a "suite" or "package." We tested whether laboratory-reared male and female European house crickets, Acheta domesticus, exhibited behavioral syndromes by quantifying individual differences in activity, exploration, mate attraction, aggressiveness, and antipredator behavior. To our knowledge, our study is the first to consider such a breadth of behavioral traits in one organism using the syndrome framework. We found positive correlations across mating, exploratory, and antipredatory contexts, but not aggression and general activity. These behavioral differences were not correlated with body size or condition, although age explained some of the variation in motivation to mate. We suggest that these across-context correlations represent a boldness syndrome as individual risk-taking and exploration was central to across-context mating and antipredation correlations in both sexes. © Springer-Verlag 2009

The development of a new fusion inhibitor for the treatment of HIV

Since the introduction of combination antiretroviral therapy (ART), there has been a dramatic improvement in the prognosis of people living with HIV. Indeed, data from numerous cohorts now show that for people commenced on ART at high CD4 counts and who are retained in care, life expectancy is similar to matched HIV-negative people. Consequently, the number of years an individual diagnosed with HIV can expect to be treated with ART is set to increase markedly. With the emergence of an older population, polypharmacy and drug-drug interactions are now more prominent clinical problems in the management of HIV. Furthermore, as the number of years an individual spends on ART increases, treatment fatigue leading to suboptimal adherence and antiretroviral resistance are frequently observed. As such, the development of long-acting parenteral antiretroviral drugs with low propensity for drug-drug interactions, low toxicity and high genetic barriers to resistance is highly desirable. Fusion inhibitors are a class of antiretroviral drugs which display limited systemic toxicities and few drug-drug interactions. They are rarely used, however, owing to injection site reactions associated with their delivery. C34-PEG4-Chol is a novel fusion inhibitor derived from the lead molecule, C34, but modified with the addition of polyethylene glycol (PEG) and cholesterol (Chol). With addition of cholesterol, potency of the drug is enhanced by concentrating it in cell membrane domains where viral fusion occurs. Moreover, the addition of cholesterol has been shown to markedly enhance its circulatory half-life in rodents such that it may potentially act as a long-acting antiretroviral drug in humans with infrequent subcutaneous injections. In this thesis, I assess the antiretroviral resistance pattern of C34-PEG4-Chol in vitro. An adaptive clinical trial design was simulated to examine options of optimising the output of useful pharmacokinetic data after administration of single doses of C34-PEG4-Chol to HIV-positive men. Finally, I undertook a ‘first-in-man’ study to examine the pharmacokinetic profile of C34-PEG4-Chol and potential of this agent as a long-acting antiretroviral drug. My work demonstrates the emergence of mutations to C34-PEG4-Chol via novel pathways within the heptad repeat (HR)-1 domains of gp41. Compensatory mutations were also observed within the HR-2 domain. The phenotypic effect of a HR-1 mutation was demonstrated following generation of mutant viral clones and assessing viral entry into cells in the presence of drug. An adaptive clinical trial design has shown, through simulations, to lead to more efficient allocation of trial participants across potentially therapeutic doses of the drug. Following a ‘first-in-man’ study, a promising pharmacokinetic profile was characterised which showed an extended drug half-life several fold above the 90% inhibitory concentration of the drug for over 4-days. This is the first time a cholesterol-endowed antiviral peptide has been entered into clinical trials in humans and has demonstrated the potential value of cholesterol-endowed peptides drugs in the field of various infectious diseases such as HIV, influenza and paraomyxoviruses.Open Acces

Digital assessment of falls risk, frailty, and mobility impairment using wearable sensors

Falls are among the most frequent and costly population health issues, costing $50bn each year in the US. In current clinical practice, falls (and associated fall risk) are often self-reported after the “first fall”, delaying primary prevention of falls and development of targeted fall prevention interventions. Current methods for assessing falls risk can be subjective, inaccurate, have low inter-rater reliability, and do not address factors contributing to falls (poor balance, gait speed, transfers, turning). 8521 participants (72.7 ± 12.0 years, 5392 female) from six countries were assessed using a digital falls risk assessment protocol. Data consisted of wearable sensor data captured during the Timed Up and Go (TUG) test along with self-reported questionnaire data on falls risk factors, applied to previously trained and validated classifier models. We found that 25.8% of patients reported a fall in the previous 12 months, of the 74.6% of participants that had not reported a fall, 21.5% were found to have a high predicted risk of falls. Overall 26.2% of patients were predicted to be at high risk of falls. 29.8% of participants were found to have slow walking speed, while 19.8% had high gait variability and 17.5% had problems with transfers. We report an observational study of results obtained from a novel digital fall risk assessment protocol. This protocol is intended to support the early identification of older adults at risk of falls and inform the creation of appropriate personalized interventions to prevent falls. A population-based approach to management of falls using objective measures of falls risk and mobility impairment, may help reduce unnecessary outpatient and emergency department utilization by improving risk prediction and stratification, driving more patients towards clinical and community-based falls prevention activities.Science Foundation IrelandInsight Research Centr

Digital assessment of falls risk, frailty, and mobility impairment using wearable sensors

Falls are among the most frequent and costly population health issues, costing $50bn each year in the US. In current clinical practice, falls (and associated fall risk) are often self-reported after the “first fall”, delaying primary prevention of falls and development of targeted fall prevention interventions. Current methods for assessing falls risk can be subjective, inaccurate, have low inter-rater reliability, and do not address factors contributing to falls (poor balance, gait speed, transfers, turning). 8521 participants (72.7 ± 12.0 years, 5392 female) from six countries were assessed using a digital falls risk assessment protocol. Data consisted of wearable sensor data captured during the Timed Up and Go (TUG) test along with self-reported questionnaire data on falls risk factors, applied to previously trained and validated classifier models. We found that 25.8% of patients reported a fall in the previous 12 months, of the 74.6% of participants that had not reported a fall, 21.5% were found to have a high predicted risk of falls. Overall 26.2% of patients were predicted to be at high risk of falls. 29.8% of participants were found to have slow walking speed, while 19.8% had high gait variability and 17.5% had problems with transfers. We report an observational study of results obtained from a novel digital fall risk assessment protocol. This protocol is intended to support the early identification of older adults at risk of falls and inform the creation of appropriate personalized interventions to prevent falls. A population-based approach to management of falls using objective measures of falls risk and mobility impairment, may help reduce unnecessary outpatient and emergency department utilization by improving risk prediction and stratification, driving more patients towards clinical and community-based falls prevention activities.Science Foundation IrelandInsight Research Centr

Sensor-based Assessment of Falls Risk of the Timed Up and Go in Real-World Settings

Falls are the leading cause of older adult injury and cost $50bn annually. New digital technologies can quantitatively measure falls risk. Objective is to report on a validated wearable sensor-based Timed Up and Go (QTUG) assessment detailing 11 measures of falls risk, frailty and mobility impairment in older adults in six countries in 38 clinical and community settings.Science Foundation IrelandInsight Research Centr

Use of β-D-glucan in diagnosis of suspected Pneumocystis jirovecii pneumonia in adults with HIV infection

OBJECTIVES: An elevated serum (1-3)-β-D-glucan (BDG) concentration has high sensitivity for a diagnosis of Pneumocystis pneumonia (PCP) in people with HIV (PWH). At the current manufacturer-recommended positive threshold of 80 pg/mL (Fungitell), specificity for PCP is variable and other diagnostic tests are required. We evaluated the utility of serum BDG for diagnosis of suspected PCP in PWH at three inner-London hospitals to determine BDG concentrations for diagnosis and exclusion of PCP. METHODS: From clinical case records, we abstracted demographic and clinical information and categorised patients as having confirmed or probable PCP, or an alternative diagnosis. We calculated sensitivity, specificity and positive predictive value (PPV) of serum BDG concentrations >400 pg/mL and negative predictive value (NPV) of BDG 400 pg/mL had a sensitivity of 83%, specificity of 97% and PPV 97% for diagnosis of PCP; BDG 400 pg/mL effectively confirm the diagnosis. Values 80-400 pg/mL should prompt additional diagnostic tests