Assessment of the IFN-β response to four feline caliciviruses: Infection in CRFK cells

Feline calicivirus (FCV) is a highly contagious pathogen with a widespread distribution. Although the cat genome has been sequenced, little is known about innate immunity in cats, which limits the understanding of FCV pathogenesis. To investigate the IFN-β response during FCV infection in CRFK cells, we first cloned and identified the feline IFN-β promoter sequence and the positive regulatory domain (PRD) motifs, which shared a high similarity with human and porcine IFN-β promoters. Next, we found that infections with FCV strains F9, Bolin and HRB-SS at the 100 or 1000 TCID₅₀ doses could not activate the IFN-β promoter at 12 and 24 h post-infection. Only strain 2280 infection at a 1000 TCID₅₀ dose could induce the IFN-β promoter mainly through IRF3 and partially through NF-κB, at 24 h post-infection. However, the IFN response occurred much later and was smaller in magnitude compared with that following Sendai virus (SeV) infection. Further, we found that induction of the IFN-β promoter by FCV 2280 infection depended on dsRNA and not on viral proteins. Finally, we examined whether the IFN-β response had an antiviral effect against FCV replication. The over-expression of IFN-β before exposure to the virus reduced viral yields by a range of 2.2–3.2 log₁₀TCID₅₀, but its over-expression at 12 h post-infection did not inhibit FCV replication. Our results indicate that some FCV strains cannot induce IFN-β expression in vitro, which may be a potential factor for FCV survival in cats. Whether this is important in evading the host interferon response in vivo must be investigated.     

Aβ-HBc virus-like particles immunization without additional adjuvant ameliorates the learning and memory and reduces Aβ deposit in PDAPP mice

β-Amyloid peptide (Aβ) immunization is regarded as a promising therapy to Alzheimer's disease. The full length Aβ as antigen might induce meningoencephalitis adverse effect since the middle and C-terminal fragments of Aβ contain T cell epitopes. While N-terminal fragment of Aβ, containing B cell epitope, has weak or no immunogenicity. To improve the immunogenicity, in the previous study, we used HBv core antigen as carrier to make fusion protein containing 2 Aβ_1–15. The fusion protein could form virus-like particles (VLPs) and had strong immunogenicity. The antisera prevented Aβ fiber formation and protected the PC12 cells against toxicity of Aβ. In the present study, we immunized 12-month old AD transgenic mice, PDAPP mice, to observe the therapeutic effect of immunization on behaviour and pathology. During immunization, the titer of anti-Aβ antibody reached to nearly 1:10⁶ after 4th inoculation, and then maintained that level to the end of the experiment. After 6-month immunization, the behavioral changes of mice were tested by Morris Water Maze (MWM). The escape latency of immunized mice was shorter than control, and these mice entered platform quadrant more times. Immunohistochemistry results showed that Aβ-HBc VLPs immunized mice had less amyloid deposit with less microglia in cortex and hippocampus. In conclusion, Aβ-HBc VLPs ameliorated the learning and memory and reduced cerebral Aβ deposit in PDAPP mice.     

Metrics and indicators used to assess health system resilience in response to shocks to health systems in high income countries—A systematic review

Health system resilience has never been more important than with the COVID-19 pandemic. There is need to identify feasible measures of resilience, potential strategies to build resilience and weaknesses of health systems experiencing shocks. The purpose of this systematic review is to examine how the resilience of health systems has been measured across various health system shocks. Following PRISMA guidelines, with double screening at each stage, the review identified 3175 studies of which 68 studies were finally included for analysis. Almost half (46%) were focused on COVID-19, followed by the economic crises, disasters and previous pandemics. Over 80% of studies included quantitative metrics. The most common WHO health system functions studied were resources and service delivery. In relation to the shock cycle, most studies reported metrics related to the management stage (79%) with the fewest addressing recovery and learning (22%). Common metrics related to staff headcount, staff wellbeing, bed number and type, impact on utilisation and quality, public and private health spending, access and coverage, and information systems. Limited progress has been made with developing standardised qualitative metrics particularly around governance. Quantitative metrics need to be analysed in relation to change and the impact of the shock. The review notes problems with measuring preparedness and the fact that few studies have really assessed the legacy or enduring impact of shocks.     

Hepatitis A vaccine response in HIV-infected patients: Are TWINRIX and HAVRIX interchangeable?

Introduction

Hepatitis A virus (HAV) infection remains a health risk for human immunodeficiency virus (HIV)-infected persons. Seroconversion rates among HAV vaccinated HIV-infected patients have been shown to be reduced compared to the general population. Current guidelines regard HAV vaccines as interchangeable, however there no published data comparing their efficacy in HIV patients. Our study evaluated the impact of different factors, including type of vaccination, on the immunologic response to hepatitis A vaccination in HIV-infected patients in the HAART era.

Methods

This was a retrospective review of 226 HIV-infected patients at our clinic in Newark, NJ. Patients were eligible if at least one dose HAVRIX^® (1440 ELISA units) or TWINRIX^® (720 ELISA units) was administered and had anti-HAV antibody data pre- and post-vaccination. Numerous variables were evaluated for their effect on seroconversion.

Results

Seroconversion developed in 53.5% of the population. Responders had higher baseline median CD4 counts (446 versus 362 cells/mm³; P = 0.004) and lower median HIV RNA levels (475 copies/mL versus 5615 copies/mL; P = 0.018) than non-responders. Patients with CD4 counts > 350 cell/mm³ were more likely to respond than those with CD4 counts < 200 cell/mm³, 60% and 35%, respectively (P = 0.0498). Responders were also more likely to be virologically suppressed (48% versus 32%; P = 0.0024). TWINRIX^® recipients had a 7-fold increased probability of seroconversion when virologically suppressed and less likely to respond if the vaccination series was not completed (OR 0.42; 95% CI 0.18–0.96).

Discussion

Seroconversion rates to HAV vaccination are significantly impaired among HIV-infected patients. CD4 cell count and virologic suppression at vaccination impact response. Seroconversion among TWINRIX^® recipients appeared to be more sensitive to these factors and vaccine series completion in comparison to those administered HAVRIX^®. Among HIV-patients requiring hepatitis a and b vaccination, the advantage of TWINRIX^® over HAVRIX^® as a combination product should be reevaluated.     

Early Aβ-HBc virus-like particles immunization had better effects on preventing the deficit of learning and memory abilities and reducing cerebral Aβ load in PDAPP mice

For nearly two decades, immunization against the β-amyloid peptide (Aβ) has been investigated as a potential treatment for Alzheimer’s disease (AD). Despite some disappointing results in clinic trials, greater significance has been attached by some researchers to exploring the immune effects on pathological and cognitive changes in AD or producing new vaccines of AD. In the previous study, we have made a virus-like particles (Aβ-HBc VLPs) as Aβ vaccine candidate. Aβ-HBc VLPs could ameliorate the learning and memory abilities and reduce cerebral Aβ deposit in the old PDAPP mice. In the present study, to observe the preventive effect and the proper time of immunization, 3, 6 and 9-month old PDAPP mice were immunized with Aβ-HBc VLPs for 3 months. All mice generated high titer of anti-Aβ antibody after Aβ-HBc VLPs immunizations. When the mice were 15-month old, Morris Water Maze was used to test their learning and memory abilities. The escape latencies of Aβ-HBc VLPs immunized mice were shorter than that of control mice. These immunized mice entered platform region frequently and spent more time on the platform region and quadrant. 3 m and 6 m Aβ-HBc VLPs immunized groups performed better than the 9 m group. In immunohistochemistry tests, all the Aβ-HBc VLPs immunized mice had less amyloid deposit in cortex and hippocampus. ELISA results showed that soluble Aβ was reduced in the brain homogenates of the Aβ-HBc VLPs immunized mice, and 3- and 6-month groups had less soluble Aβ than the 9-month group. In conclusion, our study showed that Aβ-HBc VLPs immunization could elicit a strong immune response in adult APP mice, and early immunization had better effects on preventing learning and memory deficits, lowering Aβ burden in PDAPP mice.     

Experience or authority? A response to Widdershoven

Medicine, Health Care and Philosophy -     

Blood, sweat and semen: the economy of axé and the response of Afro-Brazilian religions to HIV and AIDS in Recife

This article provides an ethnographic analysis of Afro-Brazilian religious responses to the HIV epidemic in Recife. Drawing on participant observation and in-depth interviews conducted with Afro-Brazilian religious leaders and public health officials, it highlights the importance of the axé--a mystical energy manipulated in religious rituals that is symbolically associated with blood, sweat and semen. In an analysis of the relationship formed between the state AIDS programme and Afro-Brazilian religious centres, we conclude that the recognition of native categories and their meanings is one of the key elements to a fruitful dialogue between public health programmes and religious leaders that in the case studied, resulted in the re-signification of cultural practices to prevent HIV. Although the Afro-Brazilian religious leaders interviewed tended to be more open about sexuality and condom promotion, stigma towards people living with HIV (PLHIV) was still present within the religious temples, yet appeared to be more centred upon the perception of HIV as negatively affecting followers' axé than judgement related to how one may have contracted the virus. We discuss the tensions between taking a more liberal and open stance on prevention, while also fostering attitudes that may stigmatise PLHIV, and make suggestions for improving the current Afro-Brazilian response to the epidemic.     

Are young injection drug users ready and willing to participate in preventive HCV vaccine trials?

Trials to evaluate the efficacy of preventive HCV vaccines will need participation from high risk HCV seronegative injection drug users (IDUs). To guide trial planning, we assessed willingness of young IDU in San Francisco to participate in HCV vaccine efficacy trials and evaluate knowledge of vaccine trial concepts: placebo, randomization and blinding. During 2006 and 2007, a total of 67 participants completed the survey. A substantial proportion (88%) would definitely (44%) or probably (44%) be willing to participate in a randomized trial, but knowledge of vaccine trial concepts was low. Reported willingness to participate in an HCV vaccine trial decreased with increasing trial duration, with 67% of participants surveyed willing to participate in a trial of 1 year duration compared to 43% of participants willing to participate in a trial of 4 years duration. Willingness to enroll in HCV vaccine trials was higher in young IDU than reported by most at-risk populations in HIV vaccine trials. Educational strategies will be needed to ensure understanding of key concepts prior to implementing HCV vaccine trials.     

An opportunity to refine our understanding of “response shift” and to educate researchers on designing quality research studies: response to Ubel,Peeters, and Smith

There is no advantage at this time to abandon the term “response shift” as suggested by Ubel et al. (Qual Life Res, 2010). The term is well known in the research field and has impacted the way we think about measuring quality of life (QOL) longitudinally. However, Ubel et al. (Qual Life Res, 2010) have provided the incentive to start an open dialogue on the subject with opportunities to refine the language of response shift and educate researchers. In this article, we identify opportunities in designing research studies to minimize or account for response shifts by considering the (1) selection of QOL concepts to measure, (2) questionnaires used to assess the QOL concepts, (3) design of the research study, (4) target population, and (5) analyses and reporting of results. Careful consideration of each of these issues will help us identify new methodologies and improved study designs that will move the QOL research field forward.     

Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE® smallpox vaccine

IntroductionPrevious research shows immune response to vaccination differs by sex but this has not been explored for IMVAMUNE^®, a replication-deficient smallpox vaccine developed in response to the potential for bioterrorism using smallpox.MethodsWe conducted a participant-level meta-analysis (N = 275, 136 men, 139 women) of 3 randomized trials of IMVAMUNE conducted at 13 centers in the US through a federally-funded extramural research program. Studies were eligible for inclusion if they tested the standard dose (1 × 10⁸ TCID₅₀/mL on Days 0 and 28) of liquid formulation IMVAMUNE, were completed at the time of our search, and enrolled healthy vaccinia-naïve participants. Models of the peak log₂ ELISA and PRNT titers post-second vaccination were constructed for each study with sex as a covariate. Results from these models were combined into random effects meta-analyses of the sex difference in response to IMVAMUNE. We then compared this approach with fixed effects models using the combined participant level data.ResultsIn each study the mean peak log₂ ELISA titer was higher in men than women but no single study demonstrated a statistically significant difference. Combination of the adjusted study-specific estimates into the random effects model showed a higher mean peak log₂-titer in men compared with women (absolute difference [men–women]: 0.32, 95% CI: 0.02–0.60). Fixed effects models controlling for study showed a similar result (log₂ ELISA titer, men–women: 0.34, 95% CI: 0.04–0.63). This equates to a geometric mean peak titer that is approximately 27% higher in men than women (95% CI: 3–55%). Peak log₂ PRNT titers were also higher (although not significantly) in men (men–women: 0.14, 95% CI: −0.30 to 0.58).ConclusionOur results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.     

Who Adopts Improved Fuels and Cookstoves? A Systematic Review

Background: The global focus on improved cookstoves (ICSs) and clean fuels has increased because of their potential for delivering triple dividends: household health, local environmental quality, and regional climate benefits. However, ICS and clean fuel dissemination programs have met with low rates of adoption.Objectives: We reviewed empirical studies on ICSs and fuel choice to describe the literature, examine determinants of fuel and stove choice, and identify knowledge gaps.Methods: We conducted a systematic review of the literature on the adoption of ICSs or cleaner fuels by households in developing countries. Results are synthesized through a simple vote-counting meta-analysis.Results: We identified 32 research studies that reported 146 separate regression analyses of ICS adoption (11 analyses) or fuel choice (135 analyses) from Asia (60%), Africa (27%), and Latin America (19%). Most studies apply multivariate regression methods to consider 7–13 determinants of choice. Income, education, and urban location were positively associated with adoption in most but not all studies. However, the influence of fuel availability and prices, household size and composition, and sex is unclear. Potentially important drivers such as credit, supply-chain strengthening, and social marketing have been ignored.Conclusions: Adoption studies of ICSs or clean energy are scarce, scattered, and of differential quality, even though global distribution programs are quickly expanding. Future research should examine an expanded set of contextual variables to improve implementation of stove programs that can realize the “win-win-win” of health, local environmental quality, and climate associated with these technologies.     

Randomized clinical trial to assess pain and bruising in medicines administered by means of subcutaneous and intramuscular needle injection: is it necessary to have needles changed?

This clinical trial aimed at comparing the intensity of pain and bruising by subcutaneous and intramuscular injections using and retractable fixed syringes and needles and syringes with no needles combined, at a public hospital in Sao Paulo, for six months. We evaluated the perception of pain in case of intramuscular (n=1000) and subcutaneous injections (n=240). In subcutaneous application, bruise formation was also verified. Pain and bruising scores were higher in the group with no needles combined (p<0.001) and (p<0.029), respectively. The test power in relation to the pain scale of was 0.98. The use of retractable fixed needles is recommended in the application of subcutaneous and intramuscular injections. Clinical trial registration number: NCT01271608.