209 research outputs found
Practical considerations for a TB controlled human infection model (TB-CHIM); the case for TB-CHIM in Africa, a systematic review of the literature and report of 2 workshop discussions in UK and Malawi [version 1; peer review: 2 approved, 1 approved with reservations]
No full textBackground: Tuberculosis (TB) remains a major challenge in many domains including diagnosis, pathogenesis, prevention, treatment, drug resistance and long-term protection of the public health by vaccination. A controlled human infection model (CHIM) could potentially facilitate breakthroughs in each of these domains but has so far been considered impossible owing to technical and safety concerns. Methods: A systematic review of mycobacterial human challenge studies was carried out to evaluate progress to date, best possible ways forward and challenges to be overcome. We searched MEDLINE (1946 to current) and CINAHL (1984 to current) databases; and Google Scholar to search citations in selected manuscripts. The final search was conducted 3rd February 2022. Inclusion criteria: adults ≥18 years old; administration of live mycobacteria; and interventional trials or cohort studies with immune and/or microbiological endpoints. Exclusion criteria: animal studies; studies with no primary data; no administration of live mycobacteria; retrospective cohort studies; case-series; and case-reports. Relevant tools (Cochrane Collaboration for RCTs and Newcastle-Ottawa Scale for non-randomised studies) were used to assess risk of bias and present a narrative synthesis of our findings. Results: The search identified 1,388 titles for review; of these 90 were reviewed for inclusion; and 27 were included. Of these, 15 were randomised controlled trials and 12 were prospective cohort studies. We focussed on administration route, challenge agent and dose administered for data extraction. Overall, BCG studies including fluorescent BCG show the most immediate utility, and genetically modified Mycobacteria tuberculosis is the most tantalising prospect of discovery breakthrough. Conclusions: The TB-CHIM development group met in 2019 and 2022 to consider the results of the systematic review, to hear presentations from many of the senior authors whose work had been reviewed and to consider best ways forward. This paper reports both the systematic review and the deliberations. Registration: PROSPERO (CRD42022302785; 21 January 2022)
Characterization of CD8 T cell responses in Mycobacterium Tuberculosis infection
No full textThe aim of this project was to compare the breadth and magnitude of CFP10 and ESAT6-specific CD8 T cell responses in individuals with latent Mycobacterium tuberculosis (MTB) infection (LTBI) and active TB disease, and further define MTB-specific CD8 T cell phenotypes associated with latent infection and active disease. Ex vivo IFN? Elispots and proliferation assays were used to identify immunodominant ESAT6 and CFP10 15mer peptides targeted by CD8 T cells in LTBI and TB donors. A multiparameter flow cytometry panel was designed and optimized to assess turnover, susceptibility to apoptosis and terminal differentiation/senescence in CD8 T cells from TB and LTBI donors. Bcl-2, Ki67,CD95, CD57, CD127 and IFNγ were thus measured in each group
Generation of a neonatal sepsis model in humanized mice
No full textStreptococcus agalactiae (group B streptococcus (GBS)) is a gram-positive bacterium and a harmless commensal in the gastrointestinal and vaginal flora of healthy adults. In neonates however, GBS is a leading cause for pneumonia, respiratory failure, bacteremia, sepsis and meningitis. In this study, a new animal model for GBS-induced sepsis is introduced, a mouse featuring a human immune system (humanized mouse). The immune system of humanized mice and human neonates exhibit similar deficiencies, making the animals a well suited infection model for human newborn infants. This novel animal model was used to analyze the effect of two drugs routinely used in the clinic: Betamethasone, for fetal lung maturation and Indomethacin to prevent labor. Although both drugs are frequently utilized in the perinatal care, little is known about their effect on the neonatal immune system and on disease progression in GBS-induced sepsis. Initially (1 day post infection) Betamethasone treatment did not induce marked changes in cytokine levels and leukocyte populations, but resulted in a systemic reduction of live bacteria in infected animals. After 3 days, both Betamethasone and Indomethacin led to a reduction of T and B cells in the spleen, an increase in B cells in the bone marrow (BM) and a decrease in myeloid cells in the BM. These changes in leukocyte populations were accompanied by a systemic increase of live bacteria. While the systemic increase in live GBS and the changes in leukocyte populations in the BM after Indomethacin treatment were not pronounced, the drug led to increased interleukin-8 levels in the serum of infected animals. Both drugs did not induce prominent changes in the analyzed leukocyte populations and in bacterial clearance after prolonged infection (7 days). This study shows that both drugs exerted influences on human immune cells in vivo during an ongoing bacterial infection. Since treatment also increases the bacterial load, which can induce or increase organ damage, both drugs should be given in combination with antibiotics to reduce the bacterial burden
Evaluation of tuberculosis diagnostics: establishing an evidence base around the public health impact.
No full textThe limitations of existing tuberculosis diagnostic tools are significantly hampering tuberculosis control efforts, most noticeably in areas with high prevalence of human immunodeficiency virus (HIV) infection and antituberculosis drug resistance. However, renewed global interest in tuberculosis research has begun to bear fruit, with several new diagnostic technologies progressing through the development pipeline. There are significant challenges in building a sound evidence base to inform public health policies because most diagnostic research focuses on the accuracy of individual tests, with often significant limitations in the design, conduct, and reporting of diagnostic accuracy studies. Diagnostic accuracy studies may not be appropriate to guide public health policies, and clinical trials may increasingly be required to determine the incremental value and cost-effectiveness of new tools. The urgent need for new diagnostics should not distract from pursuing rigorous scientific evaluation focused on public health impact
Investigations of mycobacteria-specific memoryy/effector T cell responses in HIV infected children receiving antiretroviral therapy
No full textIncludes abstract.Includes bibliographical references (leaves 170-210).Human immunodeficiency virus (HIV) infected children are at greater risk of developing tuberculosis disease, and might benefit from vaccination with novel TB vaccines. However, little is known about the effect of HIV-infection on function and phenotype of T cell responses to mycobacterial antigens in children. This study compares both CD4 and CD8 T cell cytokine expression and memory phenotype in children, following in vitro stimulation with mycobacterial antigens, also contained in novel anti-TB vaccines that are currently undergoing clinical trials
Taenia solium cysticercosis.
No full textThe larval stage of the pork tapeworm (Taenia solium) infects the human nervous system, causing neurocysticercosis. This disease is one of the main causes of epileptic seizures in many less developed countries and is also increasingly seen in more developed countries because of immigration from endemic areas. Little information is available on the natural evolution of taeniasis or cysticercosis. Available therapeutic measures include steroids, treatments for symptoms, surgery, and, more controversially, antiparasitic drugs to kill brain parasites. Efforts to control and eliminate this disease are underway through antiparasitic treatment of endemic populations, development of pig vaccines, and other measures
The potential impact of male circumcision on HIV in Sub-Saharan Africa.
No full text\ud
A randomized controlled trial (RCT) has shown that male circumcision (MC) reduces sexual transmission of HIV from women to men by 60% (32%-76%; 95% CI) offering an intervention of proven efficacy for reducing the sexual spread of HIV. We explore the implications of this finding for the promotion of MC as a public health intervention to control HIV in sub-Saharan Africa. Using dynamical simulation models we consider the impact of MC on the relative prevalence of HIV in men and women and in circumcised and uncircumcised men. Using country level data on HIV prevalence and MC, we estimate the impact of increasing MC coverage on HIV incidence, HIV prevalence, and HIV-related deaths over the next ten, twenty, and thirty years in sub-Saharan Africa. Assuming that full coverage of MC is achieved over the next ten years, we consider three scenarios in which the reduction in transmission is given by the best estimate and the upper and lower 95% confidence limits of the reduction in transmission observed in the RCT. MC could avert 2.0 (1.1-3.8) million new HIV infections and 0.3 (0.1-0.5) million deaths over the next ten years in sub-Saharan Africa. In the ten years after that, it could avert a further 3.7 (1.9-7.5) million new HIV infections and 2.7 (1.5-5.3) million deaths, with about one quarter of all the incident cases prevented and the deaths averted occurring in South Africa. We show that a) MC will increase the proportion of infected people who are women from about 52% to 58%; b) where there is homogenous mixing but not all men are circumcised, the prevalence of infection in circumcised men is likely to be about 80% of that in uncircumcised men; c) MC is equivalent to an intervention, such as a vaccine or increased condom use, that reduces transmission in both directions by 37%. This analysis is based on the result of just one RCT, but if the results of that trial are confirmed we suggest that MC could substantially reduce the burden of HIV in Africa, especially in southern Africa where the prevalence of MC is low and the prevalence of HIV is high. While the protective benefit to HIV-negative men will be immediate, the full impact of MC on HIV-related illness and death will only be apparent in ten to twenty years.\u
Burden of HIV infection and HIV-associated morbidity in Zimbabwean adolescents
No full textThis thesis concerns the clinical epidemiology of HIV infection in Zimbabwean adolescents. Without treatment, there is a very high risk of death in the early years of life in HIV-infected infants. However, in recent years increasing numbers of adolescents have been presenting to health care services with symptomatic HIV infection and with features suggesting longstanding disease. Population-based surveys in Southern Africa have shown HIV prevalence rates among older children and adolescents to be much higher than would be anticipated if HIV-infants were not surviving early childhood. The burden and spectrum of HIV-associated morbidity among adolescents was investigated with two studies at secondary and primary care level, respectively. The main finding was of an extremely high prevalence of HIV infection at both levels of the health system, with HIV infection being the single most common cause of hospital admission and death among adolescents. Mother-to-child transmission was the most likely source of HIV infection in the majority, suggesting a substantial epidemic of older survivors of vertical HIV infection. Other countries with severe HIV epidemics may be experiencing a similar trend as their HIV epidemics mature. The lack of awareness of the possibility of survival to older childhood and adolescence with maternally-acquired, untreated HIV infection results in many missed opportunities for diagnosis, with HIV infection frequently not diagnosed until presentation with a severe HIV-related illness. The median CD4 count in 3 HIV-infected adolescents in primary care was 350cells/µl compared to a median CD4 count of 151cells/µl among hospitalised adolescents, suggesting that HIV testing in primary care identifies HIV-infected adolescents at an earlier stage of infection. Provider-initiated HIV testing and counselling in primary care was highly acceptable to adolescents and guardians. Provision of care has been adversely affected by under-appreciation of the numbers of surviving adolescents living with HIV, and the special needs of this age-group have not been distinguished from those of younger children. Young people who have acquired HIV perinatally are stigmatised by society who assume they must have acquired it through "bad" behaviour themselves, since it is not widely appreciated that long-term survival following vertical infection is possible. Immediate priorities are earlier diagnosis of HIV infection and improved management of HIV-infected adolescents. Possible areas of intervention are discussed in the final chapter. Similar studies are needed in neighbouring countries to investigate the generalisability of these findings
Limited impact of tuberculosis control in Hong Kong: attributable to high risks of reactivation disease.
No full textOver 50% of the global burden of tuberculosis occurs in South East Asia and the Western Pacific. Since 1950, notification rates in high-income countries in these settings have declined slowly and have remained over ten-fold greater than those in Western populations. The reasons for the slow decline are poorly understood. Using an age-structured model describing the incidence of Mycobacterium tuberculosis infection and disease applied to notification data from Hong Kong, we illustrate that in Hong Kong, a high prevalence of M. tuberculosis infection among older individuals and a high risk of disease through reactivation (e.g. up to 17-fold greater than that estimated for infected males in the United Kingdom) may explain this slow decline. If this feature of the epidemiology of tuberculosis is widespread, the WHO directly observed treatment short-course (DOTS) strategy may have a smaller impact in Asia in the short term than has been implied by recent predictions, all of which have been based on disease risk estimates derived from Western Europe. As a result, it may be difficult to meet the targets for tuberculosis control, which have been prescribed by the UN Millennium Development Goals
Long-chain omega-3 polyunsaturated fatty acids in relation to gut integrity, growth and cognitive development of rural African children
No full textBackground
and
rationale:
Weaning
foods
fed
to
infants
in
rural
Gambia
are
often
contaminated,
resulting
in
infections
which
contribute
to
initiating
a
persistent
inflammation
of
the
gut.
This
enteropathy,
which
causes
intestinal
damage
and
malabsorption,
is
strongly
associated
with
the
high
degree
of
growth
faltering
seen
in
Gambian
infants.
There
is
evidence
that
supplementary
omega-3
long-chain
polyunsaturated
fatty
acids
(n-3
LCPs)
might
ameliorate
this
damage
by
reducing
gastro-intestinal
inflammation.
Additionally,
n-3
LCPs
have
been
shown
to
benefit
mental
development
and
problem-solving
ability
in
infants,
but
this
has
not
yet
been
tested
in
an
African
population.
Methods:
A
randomised,
double-blind,
controlled
trial
(500mg
combined
n-3
LCPs
per
day
for
six
months)
was
conducted
in
a
population
of
rural
African
infants
aged
3
months
-
9
months.
The
primary
outcomes
were
infant
anthropometric
indicators
and
gut
integrity
(measured
by
urinary
lactulose-mannitol
ratios).
Plasma
fatty
acid
status
(plasma
fatty
acid
profiles),
cognitive
development
(Willatts
Test
and
an
attention
assessment
at
12
months
of
age),
intestinal
mucosal
inflammation
(faecal
calprotectin),
and
daily
morbidities
were
the
secondary
outcome
measures.
Results:
One-hundred
and
seventy-two
Gambian
infants
completed
the
trial.
Except
for
an
increase
in
mid-upper-arm
circumference
z-scores
in
the
intervention
group
(95%
Cl:
0.06,0.56;
p=0.017),
no
significant
differences
between
treatment
groups
were
detected
for
growth
and
lactulose-mannitol
ratios
at
9
months.
At
12
months
mid-upper-arm
circumference
remained
greater
in
the
intervention
group,
and
significant
increases
in
skinfold
thicknesses
were
detected
(pSO.022
for
ali).
Supplementation
resulted
in
a
significant
increase
in
plasma
n-3
LCP
levels
(p<O.001)
and
decrease
in
n-6
LCP:n-3
LCP
ratios
(p<O.OOl).
Plasma
n-6
fatty
acid
levels
were
not
affected.
No
difference
was
detected
for
the
other
secondary
outcomes.
Conclusion:
Fish
oil
supplementation
proved
safe
and
successfully
increased
plasma
n-3
fatty
acid
status,
but
the
results
of
this
trial
do
not
support
the
use
of
supplementary
n-3
LCPs
in
young,
breast-fed,
rural
Gambian
infants
for
improving
overall
growth
performance,
intestinal
integrity,
and
cognitive
development,
or
reducing
intestinal
and
systemic
inflammatio
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