Using epitope predictions to evaluate efficacy and population coverage of the Mtb72f vaccine for tuberculosis

<p>Abstract</p> <p>Background</p> <p>The Mtb72f subunit vaccine for tuberculosis, currently in clinical trials, is hoped to provide improved protection compared to the current BCG vaccine. It is not clear, however, whether Mtb72f would be equally protective in the different human populations suffering from a high burden of tuberculosis. Previous work by Hebert and colleagues demonstrated that the PPE18 protein of Mtb72f had significant variability in a sample of clinical <it>M. tuberculosis </it>isolates. However, whether this variation might impact the efficacy of Mtb72f in the context of the microbial and host immune system interactions remained to be determined. The present study assesses Mtb72f's predicted efficacy in people with different DRB1 genotypes to predict whether the vaccine will protect against diverse clinical strains of <it>M. tuberculosis </it>in a diverse host population.</p> <p>Results</p> <p>We evaluated the binding of epitopes in the vaccine to different alleles of the human DRB1 Class II MHC protein using freely available epitope prediction programs and compared protein sequences from clinical isolates to the sequences included in the Mtb72f vaccine. This analysis predicted that the Mtb72f vaccine would be less effective for several DRB1 genotypes, due either to limited vaccine epitope binding to the DRB1 proteins or to binding primarily by unconserved PPE18 epitopes. Furthermore, we found that these less-protective DRB1 alleles are found at a very high frequency in several populations with a high burden of tuberculosis.</p> <p>Conclusion</p> <p>Although the Mtb72f vaccine candidate has shown promise in animal and clinical trials thus far, it may not be optimally effective in some genotypic backgrounds. Due to variation in both <it>M. tuberculosis </it>protein sequences and epitope-binding capabilities of different HLA alleles, certain human populations with a high burden of tuberculosis may not be optimally protected by the Mtb72f vaccine. The efficacy of the Mtb72f vaccine should be further examined in these particular populations to determine whether additional protective measures might be necessary for these regions.</p

HIV-1 Infection of Hematopoietic Progenitor Cells.

Latent HIV infection allows virus to persist in HIV-infected individuals in spite of antiretroviral therapy. In addition to the well-studied reservoir of latent virus in resting memory CD4+ T cells, we have recently proposed that hematopoietic progenitor cells (HPCs) in the bone marrow serve as a reservoir for latent HIV. Here, I first investigate whether HIV envelope tropism impacts the ability of the virus to infect different types of HPCs. I find that HIV envelopes that are able to use CXCR4 as a co-receptor permit infection of immature, multipotent HPCs defined by expression of the cell surface marker CD133, whereas CCR5-tropic HIV has a greatly reduced capacity to infect these cells. Furthermore, I find that a CXCR4-tropic HIV envelope can infect hematopoietic stem cells that support long-term, multilineage engraftment in mice. As hematopoietic stem cells can live for the entire lifespan of a person, latent HIV infection of these cells could create a very long-lived reservoir of virus. I next examine the cellular factors that promote latency in HPCs and find that HIV can establish a latent infection in multiple HPC subsets, including immature HPCs. Latent infection in these cells can be reversed by activation of the transcription factor NF-kappaB as well as by inhibition of histone deacetylases. Finally, I investigate whether the CD133+ subset of HPCs harbors HIV genomes in HAART-treated patients with undetectable viral loads. I detect HIV genomes in CD133-sorted cell populations in 6 of 11 donors, including two donors who have had undetectable viral loads for more than 8 years. Furthermore, for at least 5 of these 6 donors I demonstrate that CD3+ T cells are present at extremely low levels in the CD133-sorted populations and are therefore unlikely to contribute to the HIV DNA detected in these samples. Together, these findings illuminate the potential of long-lived, CD133+ HPCs to serve as a reservoir for latent virus in HIV-infected individuals. Further study of how latent infection in HPCs and T cells can be reversed to eliminate these viral reservoirs may lead us closer to a cure for HIV.PhDMicrobiology & ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96161/1/mcnamarl_1.pd

Real-Time Probe Data Dashboard for Monitoring Detour Route during I-65 N Road Closure

On August 7, 2015, a 37 mile stretch of I-65 N from MM 141 to 178 was closed due to a structural evaluation of a bridge. Traffic was detoured onto US-52, SR-26, and US-231 before returning to the highway. In order to monitor delay and congestion on the detour route, a real-time dashboard was implemented in the style of the interstate Traffic Ticker. Throughout the detour, this website was used to monitor congestion in real time and measure the impact of mitigation actions. The improvement in travel can be seen from the addition of temporary signals, retiming of the US-231 corridor, and conversion of US-231 and SR-18 to a two-way stop

Evaluation of Mobile Advanced Road Weather Information Sensor (MARWIS) by Lufft for Indiana Winter Road Operations

The students of the Field Infrastructure Assessment course evaluated the Mobile Advanced Road Weather Information Sensor by Lufft on behalf of the Indiana Department of Transportation. The device is mounted on a vehicle, takes roadway condition measurements 100 times per second, and aggregates the measurements into one-second intervals. The data is transmitted real-time to the cloud. The class specifically evaluated the following measurements: road condition, surface temperature, and friction. It was found that the MARWIS temperature reading was systematically 4˚F lower than the probe readings. Skid test empirical results were consistent with the MARWIS friction readings. It was also found, using two devices on the back of the test vehicle, that the friction in the wheel track was greater than the friction in the center of the lane, as expected. Lastly, the “chemically wet” road condition was not consistently observed by MARWIS where expected

Hematopoietic stem and progenitor cells are a distinct HIV reservoir that contributes to persistent viremia in suppressed patients

Long-lived reservoirs of persistent HIV are a major barrier to a cure. CD4+ hematopoietic stem and progenitor cells (HSPCs) have the capacity for lifelong survival, self-renewal, and the generation of daughter cells. Recent evidence shows that they are also susceptible to HIV infection in vitro and in vivo. Whether HSPCs harbor infectious virus or contribute to plasma virus (PV) is unknown. Here, we provide strong evidence that clusters of identical proviruses from HSPCs and their likely progeny often match residual PV. A higher proportion of these sequences match residual PV than proviral genomes from bone marrow and peripheral blood mononuclear cells that are observed only once. Furthermore, an analysis of near-full-length genomes isolated from HSPCs provides evidence that HSPCs harbor functional HIV proviral genomes that often match residual PV. These results support the conclusion that HIV-infected HSPCs form a distinct and functionally significant reservoir of persistent HIV in infected people

Infrared Observations of Nova Muscae 1991: Black Hole Mass Determination from Ellipsoidal Variations

We have obtained infrared photometry for the soft x-ray transient GU Mus. We present J and K_s band light curves modeled with WD98, the newest version of the Wilson-Devinney light curve modeling code. Using detailed models for the expected ellipsoidal variations due to the non-spherical secondary star, we show that the most likely value for the orbital inclination is 54 +/-1.5 deg. This inclination angle is consistent with those previously published, but has a much smaller error. This inclination implies a primary black hole mass of 6.95 +/-0.6 M_sun. While we do not see any evidence for contamination of our infrared light curves from other sources in the system, a conservative model with a contamination level of 15% increases the uncertainty in the inclination angle to 54 +4/-1.5 deg.Comment: 20 pages, 4 figures, Accepted to A

Children’s views on research without prior consent in emergency situations:a UK qualitative study

Objectives We explored children’s views on research without prior consent (RWPC) and sought to identify ways of involving children in research discussions. Design Qualitative interview study. Setting Participants were recruited through a UK children’s hospital and online advertising. Participants 16 children aged 7–15 years with a diagnosis of asthma (n=14) or anaphylaxis (n=2) with recent (<12 months) experience of emergency care. Results Children were keen to be included in medical research and viewed RWPC as acceptable in emergency situations if trial interventions were judged safe. Children trusted that doctors would know about their trial participation and act in their best interests. All felt that children should be informed about the research following their recovery and involved in discussions with a clinician or their parent(s) about the use of data already collected as well as continued participation in the trial (if applicable). Participants suggested methods to inform children about their trial participation including an animation. Conclusions Children supported, and were keen to be involved in, clinical trials in emergency situations. We present guidance and an animation that practitioners and parents might use to involve children in trial discussions following their recovery

The acceptability of a guided internet-based trauma-focused self-help programme (Spring) for post-traumatic stress disorder (PTSD)

Background Guided internet-based, cognitive behavioural therapy with a trauma-focus (i-CBT-TF) is recommended in guidelines for post-traumatic stress disorder (PTSD). There is limited evidence regarding its acceptability, with significant dropout from individual face-to-face CBT-TF, suggesting non-acceptability at least in some cases. Objective To determine the acceptability of a guided internet-based CBT-TF intervention, ‘Spring’, in comparison with face-to-face CBT-TF for mild to moderate PTSD. Method Treatment adherence, satisfaction, and therapeutic alliance were measured quantitatively for participants receiving ‘Spring’ or face-to-face CBT-TF as part of a Randomised Controlled Trial. Qualitative interviews were conducted with a purposive sample of therapists and participants. Results ‘Spring’ guided internet-based CBT-TF was found to be acceptable, with over 89% participants fully or partially completing the programme. Therapy adherence and alliance for ‘Spring’ and face-to-face CBT-TF did not differ significantly, apart from post-treatment participant-reported alliance, which was in favour of face-to-face CBT-TF. Treatment satisfaction was high for both treatments, in favour of face-to-face CBT-TF. Interviews with participants receiving, and therapists delivering ‘Spring’ corroborated its acceptability. Conclusions Guided internet-based CBT-TF is acceptable for many people with mild to moderate PTSD. Findings provide insights into future implementation, highlighting the importance of personalising guided self-help, depending on an individual’s presentation, and preferences. Keywords: post-traumatic stress disorder, internet-based cbt, guided self-help, acceptability, dropout

Surveillance and control of meningococcal disease in the COVID-19 era: A Global Meningococcal Initiative review

RevisiónThis review article incorporates information from the 4th Global Meningococcal Initiative summit meeting. Since the introduction of stringent COVID-19 infection control and lockdown measures globally in 2020, there has been an impact on IMD prevalence, surveillance, and vaccination compliance. Incidence rates and associated mortality fell across various regions during 2020. A reduction in vaccine uptake during 2020 remains a concern globally. In addition, several Neisseria meningitidis clonal complexes, particularly CC4821 and CC11, continue to exhibit resistance to antibiotics, with resistance to ciprofloxacin or beta-lactams mainly linked to modifications of gyrA or penA alleles, respectively. Beta-lactamase acquisition was also reported through horizontal gene transfer (blaROB-1) involving other bacterial species. Despite the challenges over the past year, progress has also been made on meningococcal vaccine development, with several pentavalent (serogroups ABCWY and ACWYX) vaccines currently being studied in late-stage clinical trial programmes.Medical writing support was funded by Sanofi Pasteur.S

Understanding the support experiences of families of children with autism and sensory processing difficulties: A qualitative study.

Background: Support, such as information, advice and therapies, can play a vital role in the lives of families of autistic children. However, little is known about the support experiences of UK parents and carers. Aim: To explore experiences of and access to support for families of children with autism and sensory processing difficulties, from the perspective of parents and carers. Methods: Semi‐structured, timeline‐assisted interviews were conducted with parents/carers of 30 children aged 5–11, exploring experiences of support. Framework analysis was used to identify themes in the interview data. Results: Support varied widely and was not accessed equitably. Specialist autism support, together with support from other parents and voluntary organizations, was perceived as more useful than statutory and nonspecialist provision. Unmet support needs included an ongoing point of contact for information and advice for parents, and access to direct therapy and specialist mental health provision for children