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1.  Examining the role of Scotland's telephone advice service (NHS 24) for managing health in the community: analysis of routinely collected NHS 24 data 
BMJ Open  2015;5(8):e007293.
To examine the type, duration and outcome of the symptoms and health problems Scotland's nurse-led telephone advice service (NHS 24) is contacted about and explore whether these vary by time of contact and patient characteristics.
Analysis of routinely collected NHS 24 data.
Scotland, UK.
Users of NHS 24 during 2011.
Main outcome measures
Proportion of the type, duration and outcome of the symptoms and health problems NHS 24 is contacted about.
82.6% of the calls were made out-of-hours and 17.4% in-hours. Abdominal problems accounted for the largest proportion of calls (12.2%) followed by dental (6.8%) and rash/skin problems (6.0%). There were differences in the type of problems presented in-hours and out-of-hours. Most problems (62.9%) had lasted <24 h before people contacted NHS 24. Out-of-hours calls tended to be for problems of shorter duration. Problems reported out-of-hours most commonly resulted in advice to visit an out-of-hours centre and in-hours advice to contact a general practitioner. Most of the service users were female and from more affluent areas. Use of the service declined with age in those over 35 years. The characteristics of users varied according to when NHS 24 was contacted. The number of calls made by an individual in the year ranged from 1 to 866, although most users (69.2%) made only one call. The type of problem presented varied by age and deprivation, but was broadly similar by gender, rural/urban status and geographic area. Call outcomes also varied by user characteristics.
This is the first study to examine how the public uses NHS 24. It has identified the patterns of problems which the service must be equipped to deal with. It has also provided important information about who uses the service and when. This information will help future planning and development of the service.
PMCID: PMC4554912  PMID: 26310396
2.  Exploring preferences for symptom management in primary care: a discrete choice experiment using a questionnaire survey 
The British Journal of General Practice  2015;65(636):e478-e488.
Symptoms are important drivers for the use of primary care services. Strategies aimed at shifting the focus away from the GP have broadened the range of primary healthcare available.
To explore preferences for managing symptoms and investigate trade-offs that the public are willing to make when deciding between different primary care services.
Design and setting
UK-wide postal questionnaire survey of 1370 adults.
A discrete choice experiment examined management preferences for three symptoms of differing seriousness (diarrhoea, dizziness, and chest pain). Willingness-to-pay estimates compared preferences between symptoms, and by sex, age, and income.
Preferences differed significantly between symptoms. ‘Self-care’ was the preferred action for diarrhoea and ‘consulting a GP’ for dizziness and chest pain. ‘Waiting time’ and ‘chance of a satisfactory outcome’ were important factors for all three symptoms, although their relative importance differed. Broadly, people were more prepared to wait longer and less prepared to trade a good chance of a satisfactory outcome for symptoms rated as more serious. Generally, preferences within subgroups followed similar patterns as for the whole sample, although there were differences in the relative strength of preferences.
Despite increased choices in primary care, ‘traditional’ actions of ‘self-care’ for minor symptoms and ‘GP consultation’ for more serious symptoms were preferred. The present findings suggest, however, that people may be willing to trade between different health services, particularly for less serious symptoms. Understanding the relative importance of different factors may help inform interventions aimed at changing management behaviour or improving services.
PMCID: PMC4484949  PMID: 26077269
discrete choice experiment; health services research; primary health care; signs and symptoms; symptom management
3.  Resilience does matter: evidence from a 10-year cohort record linkage study 
BMJ Open  2014;4(1):e003917.
To examine 10-year mortality and hospital use among individuals categorised as resilient and vulnerable to the impact of chronic pain.
A cohort record linkage study.
Grampian, Scotland.
5858 individuals from the Grampian Pain Cohort, established in 1996, were linked, by probability matching, with national routinely collected datasets.
Main outcome measures
HRs for subsequent 10-year mortality and ORs/incidence rate ratios for subsequent 10-year hospital use, each with adjustment for potential confounding variables.
36.5% of those with high pain intensity reported a low pain-related disability (categorised resilient) and 7.1% of those reporting low pain intensity reported a high pain-related disability (categorised vulnerable). Sex, age, housing, employment and long-term limiting illness were independently associated with being vulnerable or resilient. After adjustment for these variables, individuals in the resilient group were 25% less likely to die within 10 years of the survey compared with non-resilient individuals: HR 0.75, 95% CI 0.62 to 0.91 and vulnerable individuals were 45% more likely to die than non-vulnerable individuals: HR 1.45, 95% CI 1.01 to 2.11. Resilient individuals were less likely to have had an outpatient or day-case visit for anaesthetics: OR 0.46, 95% CI 0.27 to 0.79, but no other clinical specialities. Vulnerable individuals were significantly less likely to have had any outpatient or day-case visit (OR 0.43, 0.25 to 0.75); but more likely to have had a psychiatric visit (OR 1.96, 1.06 to 3.61). No significant differences in likelihood of any inpatient visits were found.
Resilient individuals have a better 10-year survival than non-resilient individuals indicating that resilience is a phenomenon worth researching. Further research is needed to explore who is likely to become resilient, why and how, as well as to tease out the internal and external factors that influence resilience.
PMCID: PMC3902361  PMID: 24430878
4.  Treatment with anthelminthics during pregnancy: what gains and what risks for the mother and child? 
Parasitology  2011;138(12):1499-1507.
In 1994 and 2002, respectively, the World Health Organisation proposed that treatment for hookworm and schistosomiasis could be provided during pregnancy. It was hoped that this might have benefits for maternal anaemia, fetal growth and perinatal mortality; a beneficial effect on the infant response to immunisation was also hypothesised. Three trials have now been conducted. Two have examined the effects of benzimidazoles; one (the Entebbe Mother and Baby Study) the effects of albendazole and praziquantel. All three were conducted in settings of high prevalence but low intensity helminth infection. Results suggest that, in such settings and given adequate provision of haematinics, the benefit of routine anthelminthics during pregnancy for maternal anaemia may be small; none of the other expected benefits has yet been demonstrated. The Entebbe Mother and Baby Study found a significant adverse effect of albendazole on the incidence of infantile eczema in the whole study population, and of praziquantel on the incidence of eczema among infants of mothers with Schistosoma mansoni. Further studies are required in settings that differ in helminth species and infection intensities. Further research is required to determine whether increased rates of infantile eczema translate to long-term susceptibility to allergy, and to explore the underlying mechanisms of these effects. The risks and benefits of routine anthelminthic treatment in antenatal clinics may need to be reconsidered.
PMCID: PMC3178871  PMID: 21810307
Anthelminthic; pregnancy; albendazole; praziquantel; hookworm; Schistosoma mansoni; atopic eczema; anaemia
5.  Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: A nested case-control study 
HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases) and among 108 matched HIV/KSHV coinfected controls who did not develop KS. Throughout the 6 years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p < 0.0001), and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting.
PMCID: PMC4529666  PMID: 25395177
HIV-associated Kaposi's sarcoma; sub-Saharan Africa; Kaposi's sarcoma associated-herpesvirus; HIV; AIDS
6.  The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette–Guérin immunization 
Bacille Calmette–Guérin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n = 53) and cellular (n = 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml−1 [3300–11 050] in cord blood) and six weeks (0.00 ng ml−1 [0–288]). Frequencies of PPD-specific IFN-γ-expressing CD4+T cells increased at one week and declined between one and six weeks (p = 0.031). Frequencies of IL-2- and TNF-α-expressing PPD-specific CD4+T cells increased between one and six weeks (p = 0.019, p = 0.009, respectively). At one week, the frequency of PPD-specific CD4+T cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses (p = 0.002) and after adjusting for confounders (mean difference, 95% CI −0.041% (−0.082, −0.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCG immunization. These findings are being explored further in a larger study.
PMCID: PMC4527383  PMID: 25964450
maternal infection; mycobacteria; bacille Calmette–Guérin; purified protein derivative; tuberculosis; immunization
7.  The Lake Victoria island intervention study on worms and allergy-related diseases (LaVIISWA): study protocol for a randomised controlled trial 
Trials  2015;16:187.
The Hygiene Hypothesis proposes that infection exposure protects against inflammatory conditions. Helminths possess allergen-like molecules and may specifically modulate allergy-related immunological pathways to inhibit responses which protect against them. Mass drug administration is recommended for helminth-endemic communities to control helminth-induced pathology, but may also result in increased rates of inflammation-mediated diseases in resource-poor settings. Immunological studies integrated with implementation of helminth control measures may elucidate how helminth elimination contributes to ongoing epidemics of inflammatory diseases. We present the design of the Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA), a cluster-randomised trial evaluating the risks and benefits of intensive versus standard anthelminthic treatment for allergy-related diseases and other health outcomes.
The setting is comprised of island fishing communities in Mukono district, Uganda. Twenty-six communities have been randomised in a 1:1 ratio to receive standard or intensive anthelminthic intervention for a three-year period. Baseline characteristics were collected immediately prior to intervention rollout, commenced in February 2013. Primary outcomes are reported wheeze in the past 12 months and atopy (skin prick test response and allergen-specific immunoglobulin (asIg) E concentration). Secondary outcomes are visible flexural dermatitis, helminth infections, haemoglobin, growth parameters, hepatosplenomegaly, and responses to vaccine antigens. The trial provides a platform for in-depth analysis of clinical and immunological consequences of the contrasting interventions.
The baseline survey has been completed successfully in a challenging environment. Baseline characteristics were balanced between trial arms. Prevalence of Schistosoma mansoni, hookworm, Strongyloides stercoralis and Trichuris trichiura was 52%, 23%, 13%, and 12%, respectively; 31% of Schistosoma mansoni infections were heavy (>400 eggs/gram). The prevalence of reported wheeze and positive skin prick test to any allergen was 5% and 20%, respectively. Respectively, 77% and 87% of participants had Dermatophagoides- and German cockroach-specific IgE above 0.35 kUA/L. These characteristics suggest that the LaVIISWA study will provide an excellent framework for investigating beneficial and detrimental effects of worms and their treatment, and the mechanisms of such effects.
Trial registration
This trial was registered with Current Controlled Trials (identifier: ISRCTN47196031) on 7 September 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0702-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4413531  PMID: 25902705
Helminths; Anthelminthic treatment; Allergy; Atopy; Wheeze; Cluster-randomised trial
8.  Investigating the non-specific effects of BCG vaccination on the innate immune system in Ugandan neonates: study protocol for a randomised controlled trial 
Trials  2015;16:149.
The potential for Bacillus Calmette-Guérin (BCG) vaccination to protect infants against non-mycobacterial disease has been suggested by a randomised controlled trial conducted in low birth-weight infants in West Africa. Trials to confirm these findings in healthy term infants, and in a non-West African setting, have not yet been carried out. In addition, a biological mechanism to explain such heterologous effects of BCG in the neonatal period has not been confirmed. This trial aims to address these issues by evaluating whether BCG non-specifically enhances the innate immune system in term Ugandan neonates, leading to increased protection from a variety of infectious diseases.
This trial will be an investigator-blinded, randomised controlled trial of 560 Ugandan neonates, comparing those receiving BCG at birth with those receiving BCG at 6 weeks of age. This design allows comparison of outcomes between BCG-vaccinated and -naïve infants until 6 weeks of age, and between early and delayed BCG-vaccinated infants from 6 weeks of age onwards. The primary outcomes of the study will be a panel of innate immune parameters. Secondary outcomes will include clinical illness measures.
Investigation of the possible broadly protective effects of neonatal BCG immunisation, and the optimal vaccination timing to produce these effects, could have profound implications for public healthcare policy. Evidence of protection against heterologous pathogens would underscore the importance of prioritising BCG administration in a timely manner for all infants, provide advocacy against the termination of BCG’s use and support novel anti-tuberculous vaccine strategies that would safeguard such beneficial effects.
Trial registration
ISRCTN59683017: registration date: 15 January 2014
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0682-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4413988  PMID: 25872925
Bacillus Calmette-Guérin; Heterologous effects; Innate immunity; Neonate; Invasive infectious disease
9.  Uptake of Mass Drug Administration Programme for Schistosomiasis Control in Koome Islands, Central Uganda 
PLoS ONE  2015;10(4):e0123673.
Schistosomiasis is one of the neglected tropical diseases targeted for elimination in Uganda through the Mass Drug Administration (MDA) programme. Praziquantel has been distributed using community resource persons in fixed sites and house-to-house visits; however the uptake is still below target coverage. In 2011/2012 MDA exercise, uptake stood at 50% yet WHO target coverage is 75% at community level. We assessed the uptake of MDA and the associated factors in Koome Islands, Central Uganda.
In March 2013, we conducted a mixed methods cross sectional study in 15 randomly selected villages. We interviewed a total of 615 respondents aged 18 years and above using semi structured questionnaires and five key informants were also purposively selected. Univariate and multivariate analysis was done. MDA uptake was defined as self reported swallowing of praziquantel during the last (2012) MDA campaign. We conducted key informant interviews with Ministry of Health, district health personnel and community health workers.
Self reported uptake of praziquantel was 44.7% (275/615), 95% confidence interval (CI) 40.8–48.7%. Of the 275 community members who said they had swallowed praziquantel, 142 (51.6%) reported that they had developed side effects. Uptake of MDA was more likely if the respondent was knowledgeable about schistosomiasis transmission and prevention (adjusted odds ratio [AOR] 1.85, 95% CI 1.22–2.81) and reported to have received health education from the health personnel (AOR 5.95, 95% CI 3.67–9.65). Service delivery challenges such as drug shortages and community health worker attrition also influenced MDA in Koome Islands.
Uptake of MDA for schistosomiasis control in Koome was sub optimal. Lack of knowledge about schistosomiasis transmission and prevention, inadequate health education and drug shortages are some of the major factors associated with low uptake. These could be addressed through routine health education and systematic drug supply for the successful elimination of schistosomiasis on the islands.
PMCID: PMC4382187  PMID: 25830917
10.  Pharmacist-led management of chronic pain in primary care: costs and benefits in a pilot randomised controlled trial 
BMJ Open  2015;5(4):e006874.
To explore differences in mean costs (from a UK National Health Service perspective) and effects of pharmacist-led management of chronic pain in primary care evaluated in a pilot randomised controlled trial (RCT), and to estimate optimal sample size for a definitive RCT.
Regression analysis of costs and effects, using intention-to-treat and expected value of sample information analysis (EVSI).
Six general practices: Grampian (3); East Anglia (3).
125 patients with complete resource use and short form-six-dimension questionnaire (SF-6D) data at baseline, 3 months and 6 months.
Patients were randomised to either pharmacist medication review with face-to-face pharmacist prescribing or pharmacist medication review with feedback to general practitioner or treatment as usual (TAU).
Main outcome measures
Differences in mean total costs and effects measured as quality-adjusted life years (QALYs) at 6 months and EVSI for sample size calculation.
Unadjusted total mean costs per patient were £452 for prescribing (SD: £466), £570 for review (SD: £527) and £668 for TAU (SD: £1333). After controlling for baseline costs, the adjusted mean cost differences per patient relative to TAU were £77 for prescribing (95% CI −82 to 237) and £54 for review (95% CI −103 to 212). Unadjusted mean QALYs were 0.3213 for prescribing (SD: 0.0659), 0.3161 for review (SD: 0.0684) and 0.3079 for TAU (SD: 0.0606). Relative to TAU, the adjusted mean differences were 0.0069 for prescribing (95% CI −0.0091 to 0.0229) and 0.0097 for review (95% CI −0.0054 to 0.0248). The EVSI suggested the optimal future trial size was between 460 and 690, and between 540 and 780 patients per arm using a threshold of £30 000 and £20 000 per QALY gained, respectively.
Compared with TAU, pharmacist-led interventions for chronic pain appear more costly and provide similar QALYs. However, these estimates are imprecise due to the small size of the pilot trial. The EVSI indicates that a larger trial is necessary to obtain more precise estimates of differences in mean effects and costs between treatment groups.
Trial registration number
PMCID: PMC4390732  PMID: 25833666
11.  Factors associated with tuberculosis infection, and with anti-mycobacterial immune responses, among five year olds BCG-immunised at birth in Entebbe, Uganda 
Vaccine  2015;33(6):796-804.
•Urban residence and history of TB contact/disease were associated with increased risk of latent TB infection at age five years.•BCG vaccine strain, LTBI, HIV and malaria infections, and anthropometry predict anti-mycobacterial immune responses.•Helminth infections do not influence response to BCG vaccination.•Cytokine responses at one year were not associated with LTBI at age five years.
BCG is used widely as the sole licensed vaccine against tuberculosis, but it has variable efficacy and the reasons for this are still unclear. No reliable biomarkers to predict future protection against, or acquisition of, TB infection following immunisation have been identified. Lessons from BCG could be valuable in the development of effective tuberculosis vaccines.
Within the Entebbe Mother and Baby Study birth cohort in Uganda, infants received BCG at birth. We investigated factors associated with latent tuberculosis infection (LTBI) and with cytokine response to mycobacterial antigen at age five years. We also investigated whether cytokine responses at one year were associated with LTBI at five years of age.
Blood samples from age one and five years were stimulated using crude culture filtrates of Mycobacterium tuberculosis in a six-day whole blood assay. IFN-γ, IL-5, IL-13 and IL-10 production was measured. LTBI at five years was determined using T-SPOT.TB® assay. Associations with LTBI at five years were assessed using multivariable logistic regression. Multiple linear regression with bootstrapping was used to determine factors associated with cytokine responses at age five years.
LTBI prevalence was 9% at age five years. Only urban residence and history of TB contact/disease were positively associated with LTBI. BCG vaccine strain, LTBI, HIV infection, asymptomatic malaria, growth z-scores, childhood anthelminthic treatment and maternal BCG scar were associated with cytokine responses at age five. Cytokine responses at one year were not associated with acquisition of LTBI by five years of age.
Although multiple factors influenced anti-myocbacterial immune responses at age five, factors likely to be associated with exposure to infectious cases (history of household contact, and urban residence) dominated the risk of LTBI.
PMCID: PMC4317190  PMID: 25529292
Tuberculosis; HIV; Helminth; Pregnancy; Bacille Calmette–Guerin; Crude culture filtrate protein
12.  Chronic pain and health status: how do those not using healthcare services fare? 
Relatively little is known about the clinical importance of symptoms not presented to healthcare services. Using data from a community survey we examined the health status among those with chronic pain who reported using or not using healthcare services. Individuals with chronic pain who had used healthcare services in the previous year had poorer health than symptomatic responders who had not used services, irrespective of the severity of chronic pain. The findings suggest that there is little point in trying to detect and treat individuals not currently presenting to healthcare services with their pain.
PMCID: PMC1324844  PMID: 15296563
health services; health services research; health status indicators; pain; signs and symptoms
13.  Blood pressure in primary school children in Uganda: a cross-sectional survey 
BMC Public Health  2014;14:1223.
Non-communicable diseases are an emerging concern in sub-Saharan Africa, and risks for these conditions are often based on exposures in early life, with premonitory signs developing during childhood. The prevalence of hypertension has been reported to be high in African adults, but little is known about blood pressure in African children. We studied prevalence and risk factors for high blood pressure (HBP) among school children in central Uganda.
Two urban and five rural schools were randomly selected from government schools in Wakiso district, Uganda. Questionnaires were administered and anthropometric measures taken. Blood pressure (BP) was measured three times in one sitting (on day 1) and the average compared to internationally-used normograms. Children with BP >95th percentile were re-tested at two additional sittings (day 2 and day 3) within one week, and at two further follow up visits over a period of six months. Those with sustained HBP were referred for further investigation.
Of 552 students included, 539 completed the initial assessments (days 1–3) of whom 92 (17.1%) had HBP at the initial sitting. Age (adjusted odds ratio (aOR) 1.29 (95% confidence interval 1.14, 1.47), p< 0.001), body mass index (1.70 (1.25-2.31) p = 0.001) and soil-transmitted helminths (2.52 (1.04-6.11), 0.04) were associated with increased prevalence of HBP at the initial sitting. After further investigation, sustained HBP was seen in 14 children, yielding an estimated prevalence of 3.8% allowing for losses to follow up. Four children required treatment.
It is feasible to measure blood pressure accurately in the school setting. A high HBP prevalence on initial readings gave cause for concern, but follow up suggested a true HBP prevalence commensurate with international normograms. Extended follow up is important for accurate assessment of blood pressure among African children.
PMCID: PMC4289384  PMID: 25427456
Blood pressure; Hypertension; Children; Uganda; Africa
14.  Impact of Co-Infections and BCG Immunisation on Immune Responses among Household Contacts of Tuberculosis Patients in a Ugandan Cohort 
PLoS ONE  2014;9(11):e111517.
Tuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic.
Adults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11-plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models.
We enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39–2.66; 0.96); hookworm, 2.81 (0.56–14.14; 0.20); malaria, 1.06 (0.48–2.35; 0.87); HIV, 0.74 (0.22–2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBI-positive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNγ 0.20 (0.09–0.42), <0.0001; IL-2 0.34 (0.20–0.59), <0.0001; and TNFα 0.36 (0.16–0.79), 0.01.
We found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.
PMCID: PMC4221037  PMID: 25372043
15.  Circulating B-Lymphocytes as Potential Biomarkers of Tuberculosis Infection Activity 
PLoS ONE  2014;9(9):e106796.
Accurate biomarkers of Mycobacterium tuberculosis infection activity would significantly improve early diagnosis, treatment and management of M. tuberculosis infection. We hypothesised that circulating B-lymphocytes may be useful biomarkers of tuberculosis (TB) infection status in highly TB-endemic settings. Ex-vivo and in-vitro mycobacteria-specific B-cell ELISPOT assays were used to examine the plasmablast (PB) and memory B-cell (MBC) responses in the peripheral blood of adult, healthy, community controls (n = 151) and of active TB patients (n = 48) living in Uganda. Frequencies of mycobacteria-specific PBs were markedly higher in active TB patients compared to healthy controls, and, conversely, MBCs were markedly higher in the healthy controls compared to active TB patients. In addition, the community controls with evidence of latent TB infection had higher peripheral blood PB and MBC responses than those without evidence of TB infection. These data demonstrate that peripheral blood B-cell responses are differentially modulated during latent and active M. tuberculosis infection, and suggest that the PB to MBC ratio may be a useful biomarker of TB infection activity.
PMCID: PMC4156407  PMID: 25192196
16.  Assessing the external validity of a randomized controlled trial of anthelminthics in mothers and their children in Entebbe, Uganda 
Trials  2014;15:310.
The ‘external validity’ of randomized controlled trials is an important measure of quality, but is often not formally assessed. Trials concerning mass drug administration for helminth control are likely to guide public health policy and careful interpretation of their context is needed. We aimed to determine how representative participants in one such trial were of their community. We explore implications for trial interpretation and resulting public health recommendations.
The trial assessed was the Entebbe Mother and Baby Study (EMaBS), a trial of anthelminthic treatment during pregnancy and early childhood. In a novel approach for assessing external validity, we conducted a two-stage cluster sample community survey within the trial catchment area and compared characteristics of potentially-eligible community children with characteristics of children participating in the trial.
A total of 173 children aged three to five-years-old were surveyed from 480 households. Of children surveyed, we estimated that mothers of 60% would have been eligible for recruitment, and of these, 31% had actually been enrolled. Children surveyed were compared to 199 trial children in the same age group reviewed at annual trial visits during the same time period. There were significant differences in ethnicity between the trial participants and the community children, and in socioeconomic status, with those in the trial having, on average, more educated parents and higher maternal employment. Trial children were less likely to have barefoot exposure and more likely to use insecticide-treated bed nets. There were no significant differences in numbers of reported illness events over the last year.
The trial had not enrolled all eligible participants, and those enrolled were of higher socioeconomic status, and had lower risk of exposure to the parasitic infections targeted by the trial interventions. It is possible the trial may have underestimated the absolute effects of anthelminthic treatment during pregnancy and early childhood, although the fact that there were no differences in reported incidence of common infectious diseases (one of the primary outcomes of EMaBS) between the two groups provides reassurance. Concurrent community surveys may be an effective way to test the external validity of trials.
EMaBS Trial registration
ISRCTN32849447, registered 22 July 2005
PMCID: PMC4138365  PMID: 25100338
Helminths; Anthelminthics; External validity; Generalizability; Cluster sample community survey; Uganda
17.  A Description of Congenital Anomalies Among Infants in Entebbe, Uganda 
BACKGROUND: Data on congenital anomalies from developing countries of the sub-Saharan region are scarce. However, it is important to have comprehensive and reliable data on the description and prevalence of congenital anomalies to allow surveillance and the implementation of appropriate public health strategies for prevention and management. In this study, we describe the profile of congenital anomalies seen in a birth cohort in Entebbe, Uganda. METHODS: Congenital anomalies were defined as any structural defect present at birth. Pregnant women were recruited to the cohort between 2003 and 2005. Defects present at birth were recorded by the midwife at delivery and by physicians at the routine six-week postnatal visit and at illness-related visits until 1 year of life. The anomalies were classified by organ system according to the 10th version of the World Health Organization International Classification of Diseases (ICD-10). RESULTS: There were 180 infants with a congenital anomaly among 2365 births. The most commonly affected systems were the musculoskeletal (42.7 per 1000 births) and skin (16.1 per 1000 births). The prevalence of major anomalies was 20.3 per 1000 births; 1.7 per 1000 births for cardiac anomalies and 1.3 per 1000 births for neural system anomalies. Forty (22%) of the congenital anomalies were identified at birth, 131 (73%) at the 6-week postnatal visit, and nine (5%) at illness-related visits. CONCLUSION: Congenital anomalies are common in developing countries. Establishment of comprehensive databases for surveillance would be helpful for surveillance of effects of new exposures, for prevention, management, and health care planning. Birth Defects Research (Part A) 2011. © 2011 Wiley-Liss, Inc.
PMCID: PMC3272344  PMID: 21770020
congenital anomalies; infants; epidemiology; Uganda; Africa
18.  Pregnancy, parturition and preeclampsia in women of African ancestry 
Maternal and associated neonatal mortality rates in sub-Saharan Africa remain unacceptably high. In Mulago Hospital (Kampala, Uganda), 2 major causes of maternal death are preeclampsia and obstructed labor and their complications, conditions occurring at the extremes of the birthweight spectrum, a situation encapsulated as the obstetric dilemma. We have questioned whether the prevalence of these disorders occurs more frequently in indigenous African women and those with African ancestry elsewhere in the world by reviewing available literature. We conclude that these women are at greater risk of preeclampsia than other racial groups. At least part of this susceptibility seems independent of socioeconomic status and likely is due to biological or genetic factors. Evidence for a genetic contribution to preeclampsia is discussed. We go on to propose that the obstetric dilemma in humans is responsible for this situation and discuss how parturition and birthweight are subject to stabilizing selection. Other data we present also suggest that there are particularly strong evolutionary selective pressures operating during pregnancy and delivery in Africans. There is much greater genetic diversity and less linkage disequilibrium in Africa, and the genes responsible for regulating birthweight and placentation may therefore be easier to define than in non-African cohorts. Inclusion of African women into research on preeclampsia is an essential component in tackling this major disparity of maternal health.
PMCID: PMC4046649  PMID: 24184340
evolutionary selective pressure; great obstetric syndromes; length of gestation; obstetric dilemma
19.  Prevalence of Bloodstream Pathogens Is Higher in Neonatal Encephalopathy Cases vs. Controls Using a Novel Panel of Real-Time PCR Assays 
PLoS ONE  2014;9(5):e97259.
In neonatal encephalopathy (NE), infectious co-morbidity is difficult to diagnose accurately, but may increase the vulnerability of the developing brain to hypoxia-ischemia. We developed a novel panel of species-specific real-time PCR assays to identify bloodstream pathogens amongst newborns with and without NE in Uganda.
Multiplex real-time PCR assays for important neonatal bloodstream pathogens (gram positive and gram negative bacteria, cytomegalovirus (CMV), herpes simplex virus(HSV) and P. falciparum) were performed on whole blood taken from 202 encephalopathic and 101 control infants. Automated blood culture (BACTEC) was performed for all cases and unwell controls.
Principal Findings
Prevalence of pathogenic bacterial species amongst infants with NE was 3.6%, 6.9% and 8.9%, with culture, PCR and both tests in combination, respectively. More encephalopathic infants than controls had pathogenic bacterial species detected (8.9%vs2.0%, p = 0.028) using culture and PCR in combination. PCR detected bacteremia in 11 culture negative encephalopathic infants (3 Group B Streptococcus, 1 Group A Streptococcus, 1 Staphylococcus aureus and 6 Enterobacteriacae). Coagulase negative staphylococcus, frequently detected by PCR amongst case and control infants, was considered a contaminant. Prevalence of CMV, HSV and malaria amongst cases was low (1.5%, 0.5% and 0.5%, respectively).
This real-time PCR panel detected more bacteremia than culture alone and provides a novel tool for detection of neonatal bloodstream pathogens that may be applied across a range of clinical situations and settings. Significantly more encephalopathic infants than controls had pathogenic bacterial species detected suggesting that infection may be an important risk factor for NE in this setting.
PMCID: PMC4023955  PMID: 24836781
20.  Treatment Outcomes of New Tuberculosis Patients Hospitalized in Kampala, Uganda: A Prospective Cohort Study 
PLoS ONE  2014;9(3):e90614.
In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda
Methods and findings
Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 – 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 – 4.01, P = 0.045).
Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART.
PMCID: PMC3948371  PMID: 24608875
21.  Hypertension Persisting after Pre-Eclampsia: A Prospective Cohort Study at Mulago Hospital, Uganda  
PLoS ONE  2013;8(12):e85273.
Pre-eclampsia/eclampsia usually resolves after delivery but sometimes hypertension persists and cardiovascular disease develops later. Our objective was to determine the incidence and maternal socio-demographic and obstetric risk factors for persistence of hypertension in women with pre-eclampsia/eclampsia.
This was a prospective cohort study conducted from July 2009 to June 2011 at Mulago Hospital labour ward and postnatal clinics. We followed up 188 women admitted with pre-eclampsia/eclampsia until 3 months after delivery. Data was collected using interviewer-administered questionnaires, examination of participants and review of medical records. Stata (version12) software was used for data analysis. Univariable analysis was used to compute the relative risk of persistent hypertension at the 95% confidence level. This was followed by multivariable logistic regression analysis to determine factors independently associated with persistence of hypertension.
64 (34%) out of the 188 women analysed had persistent hypertension three months after delivery. Maternal age, gestational age at delivery and parity were predictors of persistent hypertension.
The proportion of women with pre-eclampsia/eclampsia at risk of persistent hypertension at three months after delivery was high, with nearly one of three mothers remaining hypertensive. Follow up of mothers who develop pre-eclampsia is important so that early diagnosis and management of chronic hypertension can be made to avoid long term morbidity and mortality.
PMCID: PMC3877387  PMID: 24392003
22.  Radiographic characterization of the hands in Ritscher-Schinzel/3-C syndrome 
SpringerPlus  2013;2:594.
Ritscher-Schinzel Syndrome (RSS) is a clinically variable, autosomal recessive disorder, involving cardiac, cerebellar and craniofacial abnormalities. Numerous reports describe hand changes in RSS patients; however, a detailed characterization of the hands has not previously been performed.
The purpose of this study was to identify whether specific radiographic hand changes were characteristic of RSS and could serve as a diagnostic tool.
Materials and methods
We performed a detailed radiographic hand characterization of 8 RSS patients. The patient population consisted of 5 males and 3 females from ages one month to 26 years, 7 months. The hands were characterized using metacarpophalangeal pattern (MCPP) profiles, carpal height and bone age analyses and assessment of bone morphology.
There was generalized brachydactyly with the second ray being the most severely affected. There was significant shortening of the first metacarpal and the fifth distal phalanx. The MCPP profile generated showed a consistent wavy pattern with average Z-scores ranging from -0.15 (4th proximal phalanx) to -2.13 (1st metacarpal) and 0.53 (4th middle phalanx) to -1.73 (2nd proximal phalanx) for the left and right hands, respectively. Six of eight patients showed a decreased carpal height. Bone age was within normal limits for all patients. Our study population showed consistent radiographic changes including: overtubulation of the bones (especially metacarpals 2-4), prominent tufts of the distal phalanges and a hypoplastic fifth distal phalanx.
The hand findings identified in this study can provide helpful diagnostic tools to clinicians when the diagnosis of RSS is being considered.
PMCID: PMC3830001  PMID: 24255872
Ritscher-Schinzel syndrome; 3-C syndrome; Metacarpophalangeal pattern (MCPP); Profile; Carpal height; Phenotype
23.  Effect of Maternal Schistosoma mansoni Infection and Praziquantel Treatment During Pregnancy on Schistosoma mansoni Infection and Immune Responsiveness among Offspring at Age Five Years 
Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years.
In a trial in Uganda (ISRCTN32849447,, offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years.
Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not.
We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease.
Author Summary
Infections with the blood fluke Schistosoma mansoni that cause schistosomiasis (also called Bilharzia) were not usually treated during pregnancy until 2002, but in 2002 a World Health Organization (WHO) team of experts recommended that praziquantel treatment of S. mansoni during pregnancy should be done. However, there was limited information on the effects of maternal S. mansoni infection and treatment during pregnancy on the outcomes in the offspring. We conducted a study in the Entebbe peninsula within Lake Victoria in Uganda to examine whether maternal S. mansoni infection or its treatment during pregnancy may have effects on the children's susceptibility to the infection. The children were examined at age five years old for the level of S. mansoni infection and for immune responses to schistosomes. At five years old few of the children in our study cohort were infected with S. mansoni. Our findings suggest that maternal infection with, or praziquantel treatment of S. mansoni during pregnancy did not influence the level of S. mansoni infection among the offspring. However our findings suggest an influence on regulation of the body's immune responses to schistosomes, which may have some effect on the progress of disease manifestations. This is an issue that needs further investigation.
PMCID: PMC3798616  PMID: 24147175
24.  Variability of Infectious Aerosols Produced during Coughing by Patients with Pulmonary Tuberculosis 
Rationale: Mycobacterium tuberculosis is transmitted by infectious aerosols, but assessing infectiousness currently relies on sputum microscopy that does not accurately predict the variability in transmission.
Objectives: To evaluate the feasibility of collecting cough aerosols and the risk factors for infectious aerosol production from patients with pulmonary tuberculosis (TB) in a resource-limited setting.
Methods: We enrolled subjects with suspected TB in Kampala, Uganda and collected clinical, radiographic, and microbiological data in addition to cough aerosol cultures. A subset of 38 subjects was studied on 2 or 3 consecutive days to assess reproducibility.
Measurements and Main Results: M. tuberculosis was cultured from cough aerosols of 28 of 101 (27.7%; 95% confidence interval [CI], 19.9–37.1%) subjects with culture-confirmed TB, with a median 16 aerosol cfu (range, 1–701) in 10 minutes of coughing. Nearly all (96.4%) cultivable particles were 0.65 to 4.7 μm in size. Positive aerosol cultures were associated with higher Karnofsky performance scores (P = 0.016), higher sputum acid-fast bacilli smear microscopy grades (P = 0.007), lower days to positive in liquid culture (P = 0.004), stronger cough (P = 0.016), and fewer days on TB treatment (P = 0.047). In multivariable analyses, cough aerosol cultures were associated with a salivary/mucosalivary (compared with purulent/mucopurulent) appearance of sputum (odds ratio, 4.42; 95% CI, 1.23–21.43) and low days to positive (per 1-d decrease; odds ratio, 1.17; 95% CI, 1.07–1.33). The within-test (kappa, 0.81; 95% CI, 0.68–0.94) and interday test (kappa, 0.62; 95% CI, 0.43–0.82) reproducibility were high.
Conclusions: A minority of patients with TB (28%) produced culturable cough aerosols. Collection of cough aerosol cultures is feasible and reproducible in a resource-limited setting.
PMCID: PMC3443801  PMID: 22798319
tuberculosis; cough; air microbiology; infectious disease transmission; infection control
25.  Killer cell immunoglobulin-like receptor (KIR) genes and their HLA-C ligands in a Ugandan population 
Immunogenetics  2013;65(11):765-775.
Killer cell immunoglobulin-like receptor (KIR) genes are expressed by natural killer cells and encoded by a family of genes exhibiting considerable haplotypic and allelic variation. HLA-C molecules, the dominant ligands for KIR, are present in all individuals and are discriminated by two KIR epitopes, C1 and C2. We studied the frequencies of KIR genes and HLA-C1 and C2 groups in a large cohort (n = 492) from Kampala, Uganda, East Africa and compared our findings with published data from other populations in sub-Saharan Africa (SSA) and several European populations. We find considerably more KIR diversity and weaker linkage disequilibrium in SSA compared to the European populations and describe several novel KIR genotypes. C1 and C2 frequencies were similar to other SSA populations with a higher frequency of the C2 epitope (54.9 %) compared to Europe (average 39.7 %). Analysis of this large cohort from Uganda in the context of other African populations reveals variations in KIR and HLA-C1 and C2 that are consistent with migrations within Africa and potential selection pressures on these genes. Our results will help understand how KIR/HLA-C interactions contribute to resistance to pathogens and reproductive success.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-013-0724-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3824577  PMID: 23974321
KIR; HLA-C; Uganda; Africa; Population study; NK cell

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