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Introduction: CD4 count is a reliable prognostic indicator of immune response to anti retroviral therapy. This study seeks to determine the proportion of HAART naive patients that achieved an early immunologic response at six months of commencing HAART and to predict factors of early immunological response to HAART. Materials and Methods: This was an observational longitudinal study among 287 consecutively recruited HAART naive patients in 11 HIV treatment centres of Akwa Ibom using a semi-structured interviewer administered questionnaire for data collection. Data analysis was done using Stata statistical software at a level of significance of P

CONTEXT Nigeria has the second heaviest burden of Human Immunodeficiency Virus/ Acquired Immune Deficiency Syndrome (HIV/AIDS) in Africa. There is growing debate in favor of starting HIV/AIDS education early in life in order to equip pupils with the knowledge and skills to delay sexual debut and to utilize appropriate preventive measures thereafter. Objectives: To assess the knowledge and attitude of primary school pupils regarding HIV/AIDS and to determine their attitude towards People living with HIV/AIDS (PLWHAs). Materials and Methods A descriptive cross-sectional study carried out among primary schools pupils. A semi-structured self-administered questionnaire was used to collect data from 275 respondents in primary four to six. The study utilized multi-stage sampling method. Results Out of the 275 respondents recruited, 249 questionnaires were analyzable. Out of the 249 respondents, 116 (46.6%) were males while 133 (53.4%) were females. One hundred and eighty-seven (75.1%) respondents indicated that HIV /AIDS can be contracted through sexual intercourse; 50.1% indicated that it was caused by witches and wizards and 48% indicated that it was due to mosquito bite. More respondents in class six (11.7%) than those in class five (5.2%) and class four (0%) were willing to eat from the same plate with someone with HIV/AIDS. The difference was statistically significant (X2=9.547, df=2, P=0.008). Similarly, more respondents in class six (12.5%) than those in class five (6.4%) and class four (0.4%) indicated that they would live in the same room with someone with HIV/AIDS. The difference was statistically significant (X2=6.605, df=2, P=0.037). Conclusion Majority of respondents demonstrated gaps in knowledge of HIV/AIDS. Majority showed evidence of stigmatizing and discriminating attitude towards PLWHAs. Inclusion of HIV/AIDS education in the school curriculum and attitudinal re-orientation is recommended.

Context: According to the UNAIDS, Nigeria has the second heaviest burden of HIV/AIDS in Africa, with 3,459,363 people now living with the condition. Cross River State currently has HIV prevalence of 7.1%, almost double the national prevalence of 4.1%. One of the greatest challenges militating against HIV/AIDS control is stigma and discrimination. When exhibited by health care providers, stigma and discrimination can deter people living with HIV/AIDS from utilising HIV/AIDS care and services. Objective: To assess the attitude of healthcare providers towards people living with HIV/AIDS. Materials and methods: This was a descriptive cross-sectional study among 194 public health workers in Calabar, Cross River State of Nigeria, using a semi-structured questionnaire with a 15- point AIDS Attitude Scale. Data collected from the study were analyzed using SPSS Software. Results: Majority of respondents, 58.8%, agreed that despite all they know concerning how HIV is transmitted, they are still afraid of contacting it while 61.4% indicated that HIV/AIDS has made their jobs a high risk occupation. Nearly 83% of respondents indicated that they don't find it hard to be sympathetic to HIV/AIDS patients and 66% indicated that they would not feel resentful if AIDS patients accounted for a significant part of their caseload. Conclusion: There was evidence of stigmatizing and discriminatory attitude among the respondents that need to be addressed. There is need for further attitudinal orientation and re-orientation and health education of health-workers so as to remove any vestiges of stigmatizing attitude and ensure quality health care for PLWHAs.

Context: Nigeria is presently one of only three countries in the world that are polio endemic. The immunization program in Nigeria has been marred by several factors including myths and misconceptions. Objective: The objective of this study was to identify myths and misconceptions that affect utilization of childhood immunization services in Calabar, Nigeria. Materials and Methods: Focus group discussion sessions were held among caregivers in Calabar, Nigeria. Each group consisted of 12 women of reproductive age. Data obtained from each session were transcribed and analyzed using the content analysis approach. Results: Participants had poor knowledge of vaccine preventable diseases (VPDs). Some mentioned non-VPDs as if they were VPDs. Some believed that “so called” VPDs are caused by mermaid spirits, witches and wizards. The solution to VPDs proffered by participants was sacrificing in the river by midnight. Some caregivers felt that multiple doses of vaccines could harm the children. With regard to polio, one caregiver said that “Polio is due to mammy water (water mermaid). The solution is not immunization. The solution is to sacrifice to the mermaid by 12 midnight in any river close to where the child was born, on the night of the child's birth. Once this is done, the child can never never have polio.” Conclusion: Myths and misconceptions regarding immunization are rife in most Nigerian communities. There is need to debunk them through health education in order to ensure success of the country's immunization program.

IntroductionFractional diffusion equations offer an effective means of describing transport phenomena exhibiting abnormal diffusion pat-terns, often eluding traditional diffusion models.MethodsWe construct four finite difference methods where fractional derivatives are approximated using either conformable or Caputo operators.ResultsStability of the proposed schemes is analyzed using von Neumann stability analysis, and conditions are established to preserve positivity. Consistency analysis is performed for all methods, and numerical results with fractional parameters (α) set to 0.75, 0.90, 0.95, and 1.0 are presented.DiscussionThe rate of convergence in time for the four methods is computed.

Objective: Hazardous use of alcohol is a public health problem which accounts for 4.0% of global disease burden. Although the prevalence of alcohol use among drivers of commercial vehicles in Nigeria has been documented, not much is known about its social determinants. This study was, therefore, aimed at assessing the social determinants of alcohol use among drivers of commercial vehicles in Calabar. Materials and Methods: A cross-sectional descriptive study was conducted among 360 male commercial drivers. A semistructured questionnaire, which included the World Health Organization Alcohol Use Disorders Identification Test, was administered at interview. Binary and multinomial logistic regression analyses were used to identify social determinants of any and hazardous alcohol use. Results: Determinants of any alcohol use (binary logistic) were history of use by parents (adjusted odds ratios (AOR)=2.7; 95% CI=1.1-6.3), friends (AOR=3.2; 95% CI=1.3-7.8) and ready availability (AOR=4.1; 95% CI=1.9-8.8) while determinants of hazardous use (multinomial logistic) were history of use by parents (AOR=5.8; 95% CI=2.0-16.9), siblings (AOR=7.0; 95% CI=2.6-16.9), friends (AOR=6.6; 95% CI=1.8-24.4), hostile upbringing environment (AOR=3.8; 95% CI=1.3-11.1), use of other drugs (AOR=55.6, 95% CI=14.5-200), and respondents who had fathers with a maximum of primary or no formal education (AOR=4.6; 95% CI=1.8-11.8). Conclusion: Alcohol use was associated with family use, friends' use, and use of other drugs. Multiple health education interventions are needed to tackle these challenges. [ABSTRACT FROM AUTHOR]

The diabetic foot is characterised by the triad of neuropathy, infection, and ischaemia, which may ultimately lead to limb amputation. It is important to understand the factors that place diabetic patients at increased risk of amputation in our society, hence the need for this study. The medical records of all patients admitted and treated for diabetic foot complications over a 3-year period (January 2007 to December 2009) were retrieved. Relevant information was obtained from the case notes. Thirty-six (36) patients entered the study, 25 males and 11 females (M:F ratio 2.3:1.0). Mean age was 54 years (range 24-74). Patients presented with foot gangrene (58%), ulceration (31%) and infection (11%) with trauma being the most common precipitating factor (53%). Nineteen patients (53%) had lower limb amputation, the commonest of which was below knee. Of the patients that had amputation, 18 (95%) had type 2 diabetics. Adequate diabetic foot disease preventive strategies need to be designed and implemented to reduce the incidence of lower limb amputations. [ABSTRACT FROM AUTHOR]

The changes occurring in the T cell repertoire during clinical malaria infection in children remain unknown. In this study, we undertook the first detailed comparative study of the T cell repertoire in African children with and without clinical malaria to test the hypothesis that clonotypic expansions that occur during P. falciparum infection will contribute to the generation of a T cell repertoire that is unique to each disease state. We profiled the complementarity-determining region 3 (CDR3) of the TCRβ chain sequences from children with Plasmodium falciparum infections (asymptomatic, uncomplicated and severe malaria) and compared these with sequences from healthy children. Interestingly, we discovered that children with symptomatic malaria have a lower TCR diversity and frequency of shared (or "public") TCR sequences compared to asymptomatic children. Also, TCR diversity was inversely associated with parasitemia. Furthermore, by clustering TCR sequences based on their predicted antigen specificities, we identified a specificity cluster, with a 4-mer amino acid motif, that is overrepresented in the asymptomatic group compared to the diseased groups. Further investigations into this finding may help in delineating important antigenic targets for vaccine and therapeutic development. The results show that the T cell repertoire in children is altered during malaria, suggesting that exposure to P. falciparum antigens disrupts the adaptive immune response, which is an underlying feature of the disease., Competing Interests: Author NN is employed by MIODX Inc, San Jose, California, USA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Frimpong, Ofori, Degoot, Kusi, Gershom, Quartey, Kyei-Baafour, Nguyen and Ndifon.)

COVID-19 transmission rates are often linked to locally circulating strains of SARS-CoV-2. Here we describe 203 SARS-CoV-2 whole genome sequences analyzed from strains circulating in Rwanda from May 2020 to February 2021. In particular, we report a shift in variant distribution towards the emerging sub-lineage A.23.1 that is currently dominating. Furthermore, we report the detection of the first Rwandan cases of the B.1.1.7 and B.1.351 variants of concern among incoming travelers tested at Kigali International Airport. To assess the importance of viral introductions from neighboring countries and local transmission, we exploit available individual travel history metadata to inform spatio-temporal phylogeographic inference, enabling us to take into account infections from unsampled locations. We uncover an important role of neighboring countries in seeding introductions into Rwanda, including those from which no genomic sequences were available. Our results highlight the importance of systematic genomic surveillance and regional collaborations for a durable response towards combating COVID-19., (© 2021. The Author(s).)

The rapid identification and isolation of infected individuals remains a key strategy for controlling the spread of SARS-CoV-2. Frequent testing of populations to detect infection early in asymptomatic or presymptomatic individuals can be a powerful tool for intercepting transmission, especially when the viral prevalence is low. However, RT-PCR testing-the gold standard of SARS-CoV-2 diagnosis-is expensive, making regular testing of every individual unfeasible. Sample pooling is one approach to lowering costs. By combining samples and testing them in groups the number of tests required is reduced, substantially lowering costs. Here we report on the implementation of pooling strategies using 3-d and 4-d hypercubes to test a professional sports team in South Africa. We have shown that infected samples can be reliably detected in groups of 27 and 81, with minimal loss of assay sensitivity for samples with individual Ct values of up to 32. We report on the automation of sample pooling, using a liquid-handling robot and an automated web interface to identify positive samples. We conclude that hypercube pooling allows for the reliable RT-PCR detection of SARS-CoV-2 infection, at significantly lower costs than lateral flow antigen (LFA) tests., (© 2021. The Author(s).)

Long-term effects of the growing population of HIV-treated people in Southern Africa on individuals and the public health sector at large are not yet understood. This study proposes a novel 'ratio' model that relates CD4+ T-cell counts of HIV-infected individuals to the CD4+ count reference values from healthy populations. We use mixed-effects regression to fit the model to data from 1616 children (median age 4.3 years at ART initiation) and 14,542 adults (median age 36 years at ART initiation). We found that the scaled carrying capacity, maximum CD4+ count relative to an HIV-negative individual of similar age, and baseline scaled CD4+ counts were closer to healthy values in children than in adults. Post-ART initiation, CD4+ growth rate was inversely correlated with baseline CD4+ T-cell counts, and consequently higher in adults than children. Our results highlight the impacts of age on dynamics of the immune system of healthy and HIV-infected individuals., Competing Interests: EU, WN, SS, GF, JR, MD, MN No competing interests declared, (© 2021, Ujeneza et al.)

Suppressing infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will probably require the rapid identification and isolation of individuals infected with the virus on an ongoing basis. Reverse-transcription polymerase chain reaction (RT-PCR) tests are accurate but costly, which makes the regular testing of every individual expensive. These costs are a challenge for all countries around the world, but particularly for low-to-middle-income countries. Cost reductions can be achieved by pooling (or combining) subsamples and testing them in groups 1-7 . A balance must be struck between increasing the group size and retaining test sensitivity, as sample dilution increases the likelihood of false-negative test results for individuals with a low viral load in the sampled region at the time of the test 8 . Similarly, minimizing the number of tests to reduce costs must be balanced against minimizing the time that testing takes, to reduce the spread of the infection. Here we propose an algorithm for pooling subsamples based on the geometry of a hypercube that, at low prevalence, accurately identifies individuals infected with SARS-CoV-2 in a small number of tests and few rounds of testing. We discuss the optimal group size and explain why, given the highly infectious nature of the disease, largely parallel searches are preferred. We report proof-of-concept experiments in which a positive subsample was detected even when diluted 100-fold with negative subsamples (compared with 30-48-fold dilutions described in previous studies 9-11 ). We quantify the loss of sensitivity due to dilution and discuss how it may be mitigated by the frequent re-testing of groups, for example. With the use of these methods, the cost of mass testing could be reduced by a large factor. At low prevalence, the costs decrease in rough proportion to the prevalence. Field trials of our approach are under way in Rwanda and South Africa. The use of group testing on a massive scale to monitor infection rates closely and continually in a population, along with the rapid and effective isolation of people with SARS-CoV-2 infections, provides a promising pathway towards the long-term control of coronavirus disease 2019 (COVID-19).

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antigenic variations of influenza A viruses are induced by genomic mutation in their trans-membrane protein HA1, eliciting viral escape from neutralization by antibodies generated in prior infections or vaccinations. Prediction of antigenic relationships among influenza viruses is useful for designing (or updating the existing) influenza vaccines, provides important insights into the evolutionary mechanisms underpinning viral antigenic variations, and helps to understand viral epidemiology. In this study, we present a simple and physically interpretable model that can predict antigenic relationships among influenza A viruses, based on biophysical ideas, using both genomic amino acid sequences and experimental antigenic data. We demonstrate the applicability of the model using a benchmark dataset of four subtypes of influenza A (H1N1, H3N2, H5N1, and H9N2) viruses and report on its performance profiles. Additionally, analysis of the model's parameters confirms several observations that are consistent with the findings of other previous studies, for which we provide plausible explanations.

T cells play significant roles during Plasmodium falciparum infections. Their regulation of the immune response in symptomatic children with malaria has been deemed necessary to prevent immune associated pathology. In this study, we phenotypically characterized the expression of T cell inhibitory(PD-1, CTLA-4) and senescent markers (CD28(-), CD57) from children with symptomatic malaria, asymptomatic malaria and healthy controls using flow cytometry. We observed increased expression of T cell exhaustion and senescence markers in the symptomatic children compared to the asymptomatic and healthy controls. T cell senescence markers were more highly expressed on CD8 T cells than on CD4 T cells. Asymptomatically infected children had comparable levels of these markers with healthy controls except for CD8+ PD-1+ T cells which were significantly elevated in the asymptomatic children. Also, using multivariate regression analysis, CTLA-4 was the only marker that could predict parasitaemia level. The results suggest that the upregulation of immune exhaustion and senescence markers during symptomatic malaria may affect the effector function of T cells leading to inefficient clearance of parasites, hence the inability to develop sterile immunity to malaria.

The quest for a licensed effective vaccine against malaria remains a global priority. Even though classical vaccine design strategies have been successful for some viral and bacterial pathogens, little success has been achieved for Plasmodium falciparum , which causes the deadliest form of malaria due to its diversity and ability to evade host immune responses. Nevertheless, recent advances in vaccinology through high throughput discovery of immune correlates of protection, lymphocyte repertoire sequencing and structural design of immunogens, provide a comprehensive approach to identifying and designing a highly efficacious vaccine for malaria. In this review, we discuss novel vaccine approaches that can be employed in malaria vaccine design.

Haemagglutination inhibition (HI) assays are typically used for comparing and characterizing influenza viruses. Data obtained from the assays (titres) are used quantitatively to determine antigenic differences between influenza strains. However, the use of these titres has been criticized as they sometimes fail to capture accurate antigenic differences between strains. Our previous analytical work revealed how antigenic and non-antigenic variables contribute to the titres. Building on this previous work, we have developed a Bayesian method for decoupling antigenic and non-antigenic contributions to the titres in this paper. We apply this method to a compendium of HI titres of influenza A (H3N2) viruses curated from 1968 to 2016. Remarkably, the results of this fit indicate that the non-antigenic variable, which is inversely correlated with viral avidity for the red blood cells used in HI assays, oscillates during the course of influenza virus evolution, with a period that corresponds roughly to the timescale on which antigenic variants replace each other. Together, the results suggest that the new Bayesian method is applicable to the analysis of long-term dynamics of both antigenic and non-antigenic properties of influenza virus., Competing Interests: The authors have no competing interests.

Background: Asymptomatic Plasmodium infections are characterized by the absence of clinical disease and the ability to restrict parasite replication. Increasing levels of regulatory T cells (Tregs) in Plasmodium falciparum infections have been associated with the risk of developing clinical disease, suggesting that individuals with asymptomatic infections may have reduced Treg frequency. However, the relationship between Tregs, cellular activation and parasite control in asymptomatic malaria remains unclear., Methods: In a cross-sectional study, the levels of Tregs and other T cell activation phenotypes were compared using flow cytometry in symptomatic, asymptomatic and uninfected children before and after stimulation with infected red blood cell lysates (iRBCs). In addition, the association between these T cell phenotypes and parasitaemia were investigated., Results: In children with asymptomatic infections, levels of Tregs and activated T cells were comparable to those in healthy controls but significantly lower than those in symptomatic children. After iRBC stimulation, levels of Tregs remained lower for asymptomatic versus symptomatic children. In contrast, levels of activated T cells were higher for asymptomatic children. Strikingly, the pre-stimulation levels of two T cell activation phenotypes (CD8+CD69+ and CD8+CD25+CD69+) and the post-stimulation levels of two regulatory phenotypes (CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+) were significantly positively correlated with and explained 68% of the individual variation in parasitaemia. A machine-learning model based on levels of these four phenotypes accurately distinguished between asymptomatic and symptomatic children (sensitivity = 86%, specificity = 94%), suggesting that these phenotypes govern the observed variation in disease status., Conclusion: Compared to symptomatic P. falciparum infections, in children asymptomatic infections are characterized by lower levels of Tregs and activated T cells, which are associated with lower parasitaemia. The results indicate that T cell regulatory and activation phenotypes govern both parasitaemia and disease status in paediatric malaria in the studied sub-Saharan African population.

Major histocompatibility complex class two (MHC-II) molecules are trans-membrane proteins and key components of the cellular immune system. Upon recognition of foreign peptides expressed on the MHC-II binding groove, CD4 + T cells mount an immune response against invading pathogens. Therefore, mechanistic identification and knowledge of physicochemical features that govern interactions between peptides and MHC-II molecules is useful for the design of effective epitope-based vaccines, as well as for understanding of immune responses. In this article, we present a comprehensive trans-allelic prediction model, a generalized version of our previous biophysical model, that can predict peptide interactions for all three human MHC-II loci (HLA-DR, HLA-DP, and HLA-DQ), using both peptide sequence data and structural information of MHC-II molecules. The advantage of this approach over other machine learning models is that it offers a simple and plausible physical explanation for peptide-MHC-II interactions. We train the model using a benchmark experimental dataset and measure its predictive performance using novel data. Despite its relative simplicity, we find that the model has comparable performance to the state-of-the-art method, the NetMHCIIpan method. Focusing on the physical basis of peptide-MHC binding, we find support for previous theoretical predictions about the contributions of certain binding pockets to the binding energy. In addition, we find that binding pocket P 5 of HLA-DP, which was not previously considered as a primary anchor, does make strong contribution to the binding energy. Together, the results indicate that our model can serve as a useful complement to alternative approaches to predicting peptide-MHC interactions.

The adaptive immune system (AIS) acquires significant deficiency during chronological ageing, making older individuals more susceptible to infections and less responsive to vaccines compared to younger individuals. At the cellular level, one of the most striking features of this ageing-related immune deficiency is the dramatic loss of T-cell diversity that occurs in elderly humans. After the age of 70 years, there is a sharp decline in the diversity of naïve T cells, including a >10-fold decrease in the CD4+ compartment and a >100-fold decrease in the CD8+ compartment. Such changes are detrimental because the AIS relies on a diverse naïve T-cell pool to respond to novel pathogens. Recent work suggests that this collapse of naïve T-cell diversity results from T cells reaching the Hayflick limit and being eliminated through both antigen-dependent and -independent pathways. The progressive attrition of telomeres is the molecular mechanism that underlies this Hayflick limit. Therefore, we propose that by measuring the telomere lengths of T cells with high resolution, it is possible to develop a unique biomarker of immune deficiency, potentially much better correlated with individual susceptibility to diseases compared to chronological age alone., (© 2017 S. Karger AG, Basel.)

Background and Hypothesis: Recently, the world has experienced a rapidly escalating outbreak of infectious syphilis primarily affecting men who have sex with men (MSM); many are taking highly active antiretroviral therapy (HAART) for HIV-1 infection. The prevailing hypothesis is that HAART availability and effectiveness have led to the perception among both individuals who are HIV-1 infected and those who are uninfected that HIV-1 transmission has become much less likely, and the effects of HIV-1 infection less deadly. This is expected to result in increased sexual risk-taking, especially unprotected anal intercourse, leading to more non-HIV-1 STDs, including gonorrhoea, chlamydia and syphilis. However, syphilis incidence has increased more rapidly than other STDs. We hypothesise that HAART downregulates the innate and acquired immune responses to Treponema pallidum and that this biological explanation plays an important role in the syphilis epidemic., Methods: We performed a literature search and developed a mathematical model of HIV-1 and T. pallidum confection in a population with two risk groups with assortative mixing to explore the consequence on syphilis prevalence of HAART-induced changes in behaviour versus HAART-induced biological effects., Conclusions and Implications: Since rising syphilis incidence appears to have outpaced gonorrhoea and chlamydia, predominantly affecting HIV-1 positive MSM, behavioural factors alone may be insufficient to explain the unique, sharp increase in syphilis incidence. HAART agents have the potential to alter the innate and acquired immune responses in ways that may enhance susceptibility to T. pallidum . This raises the possibility that therapeutic and preventative HAART may inadvertently increase the incidence of syphilis, a situation that would have significant and global public health implications. We propose that additional studies investigating the interplay between HAART and enhanced T. pallidum susceptibility are needed. If our hypothesis is correct, HAART should be combined with enhanced patient management including frequent monitoring for pathogens such as T. pallidum ., Competing Interests: Competing interests: None., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells. In this paper, we propose an even simpler explanation: that it results from the loss of T cells that have attained replicative senescence (i.e., the Hayflick limit). Stochastic numerical simulations of naive T cell population dynamics, based on experimental parameters, show that the rate of homeostatic T cell proliferation increases after the age of ∼60 y because naive T cells collectively approach replicative senescence. This leads to a sharp decline of effective clonal diversity after ∼70 y, in agreement with empirical data. A mathematical analysis predicts that, without an increase in the naive T cell proliferation rate, this decline will occur >50 yr later than empirically observed. These results are consistent with a model in which exhaustion of the proliferative capacity of naive T cells causes a sharp decline of their effective clonal diversity and imply that therapeutic potentiation of thymopoiesis might either prevent or reverse this outcome., (Copyright © 2016 by The American Association of Immunologists, Inc.)

A large number of published studies have shown that adaptive immunity to a particular antigen, including pathogen-derived, can be boosted by another, cross-reacting antigen while inducing suboptimal immunity to the latter. Although this phenomenon, called original antigenic sin (OAS), was first reported approximately 70 years ago (Francis et al. 1947 Am. J. Public Health 37, 1013-1016 (doi:10.2105/AJPH.37.8.1013)), its underlying biological mechanisms are still inadequately understood (Kim et al. Proc. Natl Acad. Sci. USA 109, 13 751-13 756 (doi:10.1073/pnas.0912458109)). Here, focusing on the humoral aspects of adaptive immunity, I propose a simple and testable mechanism: that OAS occurs when T regulatory cells induced by the first antigen decrease the dose of the second antigen that is loaded by dendritic cells and available to activate naive lymphocytes. I use both a parsimonious mathematical model and experimental data to confirm the deductive validity of this proposal. This model also explains the puzzling experimental observation that administering certain dendritic cell-activating adjuvants during antigen exposure alleviates OAS. Specifically, the model predicts that such adjuvants will attenuate T regulatory suppression of naive lymphocyte activation. Together, these results suggest additional strategies for redeeming adaptive immunity from the destructive consequences of antigenic 'sin'., (© 2015 The Author(s).)

Background: Home management of uncomplicated malaria (HMM) is now integrated into the community case management of childhood illness (CCM), an approach that requires parasitological diagnosis before treatment. The success of CCM in resource-constrained settings without access to parasitological testing significantly depends on the caregiver's ability to recognise malaria in children under five years (U5), assess its severity, and initiate early treatment with the use of effective antimalarial drugs in the appropriate regimen at home. Little is known about factors that influence effective presumptive treatment of malaria in U5 by caregivers in resource-constrained malaria endemic areas. This study examined the factors associated with appropriate HMM in U5 by caregivers in rural Kassena-Nankana district, northern Ghana., Methods: A cross-sectional household survey was conducted among 811 caregivers recruited through multistage sampling. A caregiver was reported to have practiced appropriate HMM if an antimalarial drug was administered to a febrile child in the recommended regimen (correct dose and duration for the child's age). Binary logistic regression was used to determine factors associated with appropriate HMM., Results: Of the 811 caregivers, 87% recognised the symptoms of uncomplicated malaria in U5, and 49% (n = 395) used antimalarial drugs for the HMM. Fifty percent (n = 197) of caregivers who administered antimalarial drugs used the appropriate regimen. In the multivariate logistic regression, caregivers with secondary (OR = 1.71, 95% CI: 1.03, 2.83) and tertiary (OR = 3.58, 95% CI: 1.08, 11.87) education had increased odds of practicing appropriate HMM compared with those with no formal education. Those who sought treatment in the hospital for previous febrile illness in U5 had increased odds of practicing appropriate HMM (OR = 2.24, 95% CI: 1.12, 4.60) compared with those who visited the health centres., Conclusions: Half of caregivers who used antimalarial drugs practiced appropriate HMM. Educational status and utilisation of hospitals in previous illness were associated with appropriate HMM. Health education programmes that promote the use of the current first line antimalarial drugs in the appropriate regimen should be targeted at caregivers with no education in order to improve HMM in communities where parasitological diagnosis of malaria may not be feasible.

The T-cell receptor (TCR) repertoire is formed by random recombinations of genomic precursor elements; the resulting combinatorial diversity renders unlikely extensive TCR sharing between individuals. Here, we studied CDR3β amino acid sequence sharing in a repertoire-wide manner, using high-throughput TCR-seq in 28 healthy mice. We uncovered hundreds of public sequences shared by most mice. Public CDR3 sequences, relative to private sequences, are two orders of magnitude more abundant on average, express restricted V/J segments, and feature high convergent nucleic acid recombination. Functionally, public sequences are enriched for MHC-diverse CDR3 sequences that were previously associated with autoimmune, allograft, and tumor-related reactions, but not with anti-pathogen-related reactions. Public CDR3 sequences are shared between mice of different MHC haplotypes, but are associated with different, MHC-dependent, V genes. Thus, despite their random generation process, TCR repertoires express a degree of uniformity in their post-genomic organization. These results, together with numerical simulations of TCR genomic rearrangements, suggest that biases and convergence in TCR recombination combine with ongoing selection to generate a restricted subset of self-associated, public CDR3 TCR sequences, and invite reexamination of the basic mechanisms of T-cell repertoire formation., (© 2014 Madi et al.; Published by Cold Spring Harbor Laboratory Press.)

Reduction in T cell receptor (TCR) diversity in old age is considered as a major cause for immune complications in the elderly population. Here, we explored the consequences of aging on the TCR repertoire in mice using high-throughput sequencing (TCR-seq). We mapped the TCRβ repertoire of CD4+ T cells isolated from bone marrow (BM) and spleen of young and old mice. We found that TCRβ diversity is reduced in spleens of aged mice but not in their BM. Splenic CD4+ T cells were also skewed toward an effector memory phenotype in old mice, while BM cells preserved their memory phenotype with age. Analysis of Vβ and Jβ gene usage across samples, as well as comparison of CDR3 length distributions, showed no significant age dependent changes. However, comparison of the frequencies of amino-acid (AA) TCRβ sequences between samples revealed repertoire changes that occurred at a more refined scale. The BM-derived TCRβ repertoire was found to be similar among individual mice regardless of their age. In contrast, the splenic repertoire of old mice was not similar to those of young mice, but showed an increased similarity with the BM repertoire. Each old-mouse had a private set of expanded TCRβ sequences. Interestingly, a fraction of these sequences was found also in the BM of the same individual, sharing the same nucleotide sequence. Together, these findings show that the composition and phenotype of the CD4+ T cell BM repertoire are relatively stable with age, while diversity of the splenic repertoire is severely reduced. This reduction is caused by idiosyncratic expansions of tens to hundreds of T cell clonotypes, which dominate the repertoire of each individual. We suggest that these private and abundant clonotypes are generated by sporadic clonal expansions, some of which correspond to pre-existing BM clonotypes. These organ- and age-specific changes of the TCRβ repertoire have implications for understanding and manipulating age-associated immune decline.

The adaptive arm of the immune system has been suggested as an important factor in brain function. However, given the fact that interactions of neurons or glial cells with T lymphocytes rarely occur within the healthy CNS parenchyma, the underlying mechanism is still a mystery. Here we found that at the interface between the brain and blood circulation, the epithelial layers of the choroid plexus (CP) are constitutively populated with CD4(+) effector memory cells with a T-cell receptor repertoire specific to CNS antigens. With age, whereas CNS specificity in this compartment was largely maintained, the cytokine balance shifted in favor of the T helper type 2 (Th2) response; the Th2-derived cytokine IL-4 was elevated in the CP of old mice, relative to IFN-γ, which decreased. We found this local cytokine shift to critically affect the CP epithelium, triggering it to produce the chemokine CCL11 shown to be associated with cognitive dysfunction. Partial restoration of cognitive ability in aged mice, by lymphopenia-induced homeostasis-driven proliferation of memory T cells, was correlated with restoration of the IL-4:IFN-γ ratio at the CP and modulated the expression of plasticity-related genes at the hippocampus. Our data indicate that the cytokine milieu at the CP epithelium is affected by peripheral immunosenescence, with detrimental consequences to the aged brain. Amenable to immunomodulation, this interface is a unique target for arresting age-related cognitive decline.

Background: The emergency department (E.D) of any hospital is an important entry point of critically ill patients. The initial management of these patients is often challenging, and for valuable lives to be saved, the in fracture and manpower should be up to date., Objective: To analyze the epidemiology of death in our Emergency Department within 72hours after admission, the death rate, and to establish any contributory factors., Method: Demographic data, time of arrival at the ED, physical finding, the Glasgow coma scale(GCS), the injury severity score(ISS), the diagnosis, investigations done, treatment offered, the time of death and the autopsy report, were entered into a Proforma. These data was analyzed using EPI-Info statistical programme version 3.4.3 of 2007., Results: Four thousand and eleven (4,011) patients were seen in the E.D during the period. A total of three hundred and fifty five (355) mortalities were recorded. Their ages ranged from 4-87years, with an average of 34.5years. The male: female ratio was 2.1:1. The overall mortality in the hospital during the period was 859: the E.D mortality figure representing 41.3%. Fifteen patients were brought in dead. The 355 deaths fell into two categories: trauma and non-trauma. One hundred and forty-seven (41.4%) persons died from trauma; road traffic accidents (RTAs) accounting for 118 (80.3%). Two hundred and eight (58.6%) persons died from nontrauma related causes, with chronic cardiovascular disorders been the most frequent cause of death 52[25.0]. Majority of the mortalities were between 26-50 years age range. 86.2% of the mortalities presented late, greater than 6hours after the incidence. Within the 72 hours period, only 129(36.3%) were able to do the requested tests. Out of the 355 deaths, only 4[1.1%] were autopsied. An in-hospital 72hours death rate of 8.6 was recorded., Conclusion: Road traffic accidents and cardiovascular disorders are the common causes of emergency death in UCTH. A recorded death rate of 8.6% is high, suspected contributory factors include systemic deficiencies such as the lack of a trauma system, prehospital care; late presentation, the role of chemist operators, traditional healers, and delayed referral systems.

T cells play fundamental roles in adaptive immunity, relying on a diverse repertoire of T-cell receptor (TCR) α and β chains. Diversity of the TCR β chain is generated in part by a random yet intrinsically biased combinatorial rearrangement of variable (Vβ), diversity (Dβ), and joining (Jβ) gene segments. The mechanisms that determine biases in gene segment use remain unclear. Here we show, using a high-throughput TCR sequencing approach, that a physical model of chromatin conformation at the DJβ genomic locus explains more than 80% of the biases in Jβ use that we measured in murine T cells. This model also predicts correctly how differences in intersegment genomic distances between humans and mice translate into differences in Jβ bias between TCR repertoires of these two species. As a consequence of these structural and other biases, TCR sequences are produced with different a priori frequencies, thus affecting their probability of becoming public TCRs that are shared among individuals. Surprisingly, we find that many more TCR sequences are shared among all five mice we studied than among only subgroups of three or four mice. We derive a necessary mathematical condition explaining this finding, which indicates that the TCR repertoire contains a core set of receptor sequences that are highly abundant among individuals, if their a priori probability of being produced by the recombination process is higher than a defined threshold. Our results provide evidence for an expanded role of chromatin conformation in VDJ rearrangement, from control of gene accessibility to precise determination of gene segment use.

Background: Two important challenges to the use of serological assays for influenza surveillance include the substantial amount of experimental effort involved and the inherent noisiness of serological data., Results: I show that log-transformed serological data exist in an effectively one-dimensional space. I use this result, together with new mechanistic insights into serological assays, to develop computational methods for accurately and efficiently recovering unmeasured serological data from a sample of measured data, for systematically minimizing noise and other types of non-antigenic variation found in the data, and for quantifying and visualizing antigenic variation. The methods can also be applied to data with effective dimensionality greater than one, under certain conditions., Conclusion: Careful application of the methods developed here would enable the collection of better-quality serological data on a greater number of circulating influenza viruses than is currently possible and improve the ability to identify potential epidemic and pandemic viruses before they become widespread. Although the focus here is on influenza surveillance, the described methods are more widely applicable., (© 2011 Blackwell Publishing Ltd.)

Competing Interests: The authors have declared that no competing interests exist.

Background: Blunt abdominal trauma (BAT) usually results from motor vehicle accidents, assaults, and recreational accidents or falls. This communication is a 3-year report of an ongoing study aimed at providing the current BAT prevalence in our center. It is hoped that this would assist in a better design of prevention and emergency trauma response systems to cope with this epidemic., Methods: All of the patients admitted to the University of Calabar Teaching Hospital (UCTH), Calabar, Nigeria, from February 2005 to January 2008 were prospectively studied based on a questionnaire. Hemodynamic stability and sonography formed the basis for selecting patients for non-operative management (NOM); others were offered laparotomy., Results: In total, 4,391 emergencies were seen during the study period, of which 1,654 (38%) were due to trauma. Seventy-nine patients with abdominal trauma accounted for 4.8% of trauma cases. Forty-two (53%) patients suffered BAT and their ages ranged from 14 and 56 years (mean 28.4 years), with a male:female ratio of 2.5:1. Road traffic accidents accounted for 13 (87%) and 26 (96%) patients in the NOM and laparotomy groups, respectively. The most commonly injured organ was the spleen in both groups: 8 (50%) and 15 (56%) in the NOM and laparotomy groups, respectively. Fifteen (36%) patients were managed successfully in the NOM group., Conclusion: Trauma was mainly due to road traffic injuries. Hemodynamic stability and ultrasonography effectively selected patients for NOM. The establishment of trauma systems, provision of ancillary diagnostic and monitoring facilities, well-designed roads and traffic infrastructure, and health education on road safety would reduce injury, morbidity, and mortality.

The mechanisms by which adaptive phenotypes spread within an evolving population after their emergence are understood fairly well. Much less is known about the factors that influence the evolutionary accessibility of such phenotypes, a pre-requisite for their emergence in a population. Here, we investigate the influence of environmental quality on the accessibility of adaptive phenotypes of Escherichia coli's central metabolic network. We used an established flux-balance model of metabolism as the basis for a genotype-phenotype map (GPM). We quantified the effects of seven qualitatively different environments (corresponding to both carbohydrate and gluconeogenic metabolic substrates) on the structure of this GPM. We found that the GPM has a more rugged structure in qualitatively poorer environments, suggesting that adaptive phenotypes could be intrinsically less accessible in such environments. Nevertheless, on average approximately 74% of the genotype can be altered by neutral drift, in the environment where the GPM is most rugged; this could allow evolving populations to circumvent such ruggedness. Furthermore, we found that the normalized mutual information (NMI) of genotype differences relative to phenotype differences, which measures the GPM's capacity to transmit information about phenotype differences, is positively correlated with (simulation-based) estimates of the accessibility of adaptive phenotypes in different environments. These results are consistent with the predictions of a simple analytic theory that makes explicit the relationship between the NMI and the speed of adaptation. The results suggest an intuitive information-theoretic principle for evolutionary adaptation; adaptation could be faster in environments where the GPM has a greater capacity to transmit information about phenotype differences. More generally, our results provide insight into fundamental environment-specific differences in the accessibility of adaptive phenotypes, and they suggest opportunities for research at the interface between information theory and evolutionary biology.

Metrics for indirectly predicting the folding rates of RNA sequences are of interest. In this letter, we introduce a simple metric of RNA structural complexity, which accounts for differences in the energetic contributions of RNA base contacts toward RNA structure formation. We apply the metric to RNA sequences whose folding rates were previously determined experimentally. We find that the metric has good correlation (correlation coefficient: -0.95, p<<0.01) with the logarithmically transformed folding rates of those RNA sequences. This suggests that the metric can be useful for predicting RNA folding rates. We use the metric to predict the folding rates of bacterial and eukaryotic group II introns. Future applications of the metric (e.g., to predict structural RNAs) could prove fruitful.

It is generally assumed that amino acid mutations in the surface protein, hemagglutinin (HA), of influenza viruses allow these viruses to circumvent neutralization by antibodies induced during infection. However, empirical data on circulating influenza viruses show that certain amino acid changes to HA actually increase the efficiency of neutralization of the mutated virus by antibodies raised against the parent virus. Here, we suggest that this surprising increase in neutralization efficiency after HA mutation could reflect steric interference between antibodies. Specifically, if there is a steric competition for binding to HA by antibodies with different neutralization efficiencies, then a mutation that reduces the binding of antibodies with low neutralization efficiencies could increase overall viral neutralization. We use a mathematical model of virus-antibody interaction to elucidate the conditions under which amino acid mutations to HA could lead to an increase in viral neutralization. Using insights gained from the model, together with genetic and structural data, we predict that amino acid mutations to epitopes C and E of the HA of influenza A/H3N2 viruses could lead on average to an increase in the neutralization of the mutated viruses. We present data supporting this prediction and discuss the implications for the design of more effective vaccines against influenza viruses and other pathogens.