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1.  Early cranial ultrasound findings among infants with neonatal encephalopathy in Uganda: an observational study 
Pediatric Research  2016;80(2):190-196.
Background:
In sub-Saharan Africa, the timing and nature of brain injury and their relation to mortality in neonatal encephalopathy (NE) are unknown. We evaluated cranial ultrasound (cUS) scans from term Ugandan infants with and without NE for evidence of brain injury.
Methods:
Infants were recruited from a national referral hospital in Kampala. Cases (184) had NE and controls (100) were systematically selected unaffected term infants. All had cUS scans <36 h reported blind to NE status.
Results:
Scans were performed at median age 11.5 (interquartile range (IQR): 5.2–20.2) and 8.4 (IQR: 3.6–13.5) hours, in cases and controls respectively. None had established antepartum injury. Major evolving injury was reported in 21.2% of the cases vs. 1.0% controls (P < 0.001). White matter injury was not significantly associated with bacteremia in encephalopathic infants (odds ratios (OR): 3.06 (95% confidence interval (CI): 0.98–9.60). Major cUS abnormality significantly increased the risk of neonatal death (case fatality 53.9% with brain injury vs. 25.9% without; OR: 3.34 (95% CI: 1.61–6.95)).
Conclusion:
In this low-resource setting, there was no evidence of established antepartum insult, but a high proportion of encephalopathic infants had evidence of major recent and evolving brain injury on early cUS imaging, suggesting prolonged or severe acute exposure to hypoxia–ischemia (HI). Early abnormalities were a significant predictor of death.
doi:10.1038/pr.2016.77
PMCID: PMC4992358  PMID: 27064242
2.  Early cranial ultrasound findings amongst infants with neonatal encephalopathy in Uganda: an observational study 
Pediatric research  2016;80(2):190-196.
Background
In sub-Saharan Africa, the timing and nature of brain injury and their relation to mortality in neonatal encephalopathy (NE) is unknown. We evaluated cranial ultrasound (cUS) scans from term Ugandan infants with and without NE for evidence of brain injury.
Methods
Infants were recruited from a national referral hospital in Kampala. Cases (184) had NE and controls (100) were systematically selected unaffected term infants. All had cUS scans <36h reported blind to NE status.
Results
Scans were performed at median age 11.5 (IQR 5.2-20.2) and 8.4 (IQR 3.6-13.5) hours, in cases and controls respectively. None had established antepartum injury. Major evolving injury was reported in 21.2% of cases vs 1.0% controls (p<0.001). White matter injury was not significantly associated with bacteraemia in encephalopathic infants (OR 3.06 (95%CI 0.98-9.60). Major cUS abnormality significantly increased the risk of neonatal death (case fatality 53.9% with brain injury vs 25.9% without; OR 3.34(95%CI, 1.61-6.95)).
Conclusions
In this low-resource setting, there was no evidence of established antepartum insult, but a high proportion of encephalopathic infants had evidence of major recent and evolving brain injury on early cUS imaging, suggesting prolonged or severe acute exposure to hypoxia-ischaemia. Early abnormalities were a significant predictor of death.
doi:10.1038/pr.2016.77
PMCID: PMC4992358  PMID: 27064242
3.  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.
Objectives
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.
Design
Analysis of routinely collected NHS 24 data.
Setting
Scotland, UK.
Participants
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.
Results
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.
Conclusions
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.
doi:10.1136/bmjopen-2014-007293
PMCID: PMC4554912  PMID: 26310396
PRIMARY CARE; PUBLIC HEALTH
4.  Effect of Schistosoma mansoni Infection on Innate and HIV-1-Specific T-Cell Immune Responses in HIV-1-Infected Ugandan Fisher Folk 
Abstract
In Uganda, fisher folk have HIV prevalence rates, about four times higher than the national average, and are often coinfected with Schistosoma mansoni. We hypothesized that innate immune responses and HIV-specific Th1 immune responses might be downmodulated in HIV/S. mansoni-coinfected individuals compared with HIV+/S. mansoni-negative individuals. We stimulated whole blood with innate receptor agonists and analyzed supernatant cytokines by Luminex. We evaluated HIV-specific responses by intracellular cytokine staining for IFN-γ, IL-2, and TNF-α. We found that the plasma viral load and CD4 count were similar between the HIV+SM+ and HIV+SM− individuals. In addition, the TNF-α response to the imidazoquinoline compound CL097 and β-1, 3-glucan (curdlan), was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. The frequency of HIV-specific IFN-γ+IL-2–TNF-α− CD8 T cells and IFN-γ+IL-2–TNF-α+ CD4 T cells was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. These findings do not support the hypothesis that S. mansoni downmodulates innate or HIV-specific Th1 responses in HIV/S. mansoni-coinfected individuals.
doi:10.1089/aid.2015.0274
PMCID: PMC4931742  PMID: 26864743
5.  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.
Background
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.
Aim
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.
Method
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.
Results
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.
Conclusion
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.
doi:10.3399/bjgp15X685705
PMCID: PMC4484949  PMID: 26077269
discrete choice experiment; health services research; primary health care; signs and symptoms; symptom management
6.  Schistosoma mansoni and HIV infection in a Ugandan population with high HIV and helminth prevalence 
Abstract
Objectives
Recent reports suggest that Schistosoma infection may increase the risk of acquiring human immunodeficiency virus (HIV). We used data from a large cross‐sectional study to investigate whether Schistosoma mansoni infection is associated with increased HIV prevalence.
Methods
We conducted a household survey of residents in island fishing communities in Mukono district, Uganda, between October 2012 and July 2013. HIV status was assessed using rapid test kits. Kato‐Katz (KK) stool tests and urine‐circulating cathodic antigen (CCA) were used to test for Schistosoma infection. Multivariable logistic regression, allowing for the survey design, was used to investigate the association between S. mansoni infection and HIV infection.
Results
Data from 1412 participants aged 13 years and older were analysed (mean age 30.3 years, 45% female). The prevalence of HIV was 17.3%. Using the stool Kato‐Katz technique on a single sample, S. mansoni infection was detected in 57.2% (719/1257) of participants; urine CCA was positive in 73.8% (478/650) of those tested. S. mansoni infection was not associated with HIV infection. [KK (aOR = 1.04; 95% CI: 0.74–1.47, P = 0.81), CCA (aOR = 1.53; 95% CI: 0.78–3.00, P = 0.19)]. The median S. mansoni egg count per gram was lower in the HIV‐positive participants (P = 0.005).
Conclusions
These results add to the evidence that S. mansoni has little effect on HIV transmission, but may influence egg excretion.
doi:10.1111/tmi.12545
PMCID: PMC4568314  PMID: 25976017
Schistosoma mansoni; schistosomiasis; Bilharzia; HIV; Schistosoma mansoni; schistosomiase; bilharziose; VIH
7.  CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL 
Nature Communications  2016;7:10961.
The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
Low density lipoprotein receptor (LDLR) is crucial for cholesterol homeostasis. Here, the authors show that components of the CCC-protein complex, CCDC22 and COMMD1, facilitate the endosomal sorting of LDLR and that mutations in these genes cause hypercholesterolemia in dogs and mice, providing new insights into regulation of cholesterol homeostasis.
doi:10.1038/ncomms10961
PMCID: PMC4792963  PMID: 26965651
8.  Schistosoma mansoni and HIV acquisition in fishing communities of Lake Victoria, Uganda: a nested case–control study 
Abstract
Objective
It has been suggested that Schistosoma mansoni, which is endemic in African fishing communities, might increase susceptibility to human immunodeficiency virus (HIV) acquisition. If confirmed, this would be of great public health importance in these high HIV‐risk communities. This study was undertaken to determine whether S. mansoni infection is a risk factor for HIV infection among the fishing communities of Lake Victoria, Uganda. We conducted a matched case–control study, nested within a prospective HIV incidence cohort, including 50 HIV seroconverters (cases) and 150 controls during 2009‐2011.
Methods
S. mansoni infection prior to HIV seroconversion was determined by measuring serum circulating anodic antigen (CAA) in stored serum. HIV testing was carried out using the Determine rapid test and infection confirmed by enzyme‐linked immunosorbent assays.
Results
About 49% of cases and 52% of controls had S. mansoni infection prior to HIV seroconversion (or at the time of a similar study visit, for controls): odds ratio, adjusting for ethnicity, religion, marital status, education, occupation, frequency of alcohol consumption in previous 3 months, number of sexual partners while drunk, duration of stay in the community, and history of schistosomiasis treatment in the past 2 years was 1.23 (95% CI 0.3–5.7) P = 0.79. S. mansoni infections were chronic (with little change in status between enrolment and HIV seroconversion), and there was no difference in median CAA concentration between cases and controls.
Conclusions
These results do not support the hypothesis that S. mansoni infection promotes HIV acquisition.
doi:10.1111/tmi.12531
PMCID: PMC4529482  PMID: 25940951
Schistosoma mansoni; circulating anodic antigen; HIV; susceptibility; fishing communities; Uganda; Schistosoma mansoni; antigène anodique circulant; VIH; sensibilité; communautés de pêcheurs; Ouganda
9.  Immunology in Africa 
Abstract
Africa is a continent with a large burden of both infectious and non‐communicable diseases. If we are to move forward as a continent, we need to equip our growing cadre of exceptional young scientists with the skills needed to tackle the diseases endemic to this continent. For this, immunology is among the key disciplines. Africans should be empowered to study and understand the diseases that affect them, and to perform their cutting‐edge research in their country of origin. This requires a multifaceted approach, with buy‐in from funders, overseas partners and perhaps, most important of all, African governments themselves.
doi:10.1111/tmi.12599
PMCID: PMC4737115  PMID: 26391634
immunology; Africa
10.  The Use of Interferon Gamma Inducible Protein 10 as a Potential Biomarker in the Diagnosis of Latent Tuberculosis Infection in Uganda 
PLoS ONE  2016;11(1):e0146098.
Background
In the absence of a gold standard for the diagnosis of latent tuberculosis (TB) infection (LTBI), the current tests available for the diagnosis of LTBI are limited by their inability to differentiate between LTBI and active TB disease. We investigated IP-10 as a potential biomarker for LTBI among household contacts exposed to sputum positive active TB cases.
Methods
Active TB cases and contacts were recruited into a cohort with six months’ follow-up. Contacts were tested for LTBI using QuantiFERON®-TB Gold In-Tube (QFN) assay and the tuberculin skin test (TST). Baseline supernatants from the QFN assay of 237 contacts and 102 active TB cases were analysed for Mycobacterium tuberculosis (MTB) specific and mitogen specific IP-10 responses.
Results
Contacts with LTBI (QFN+TST+) had the highest MTB specific IP-10 responses at baseline, compared to uninfected contacts (QFN-TST-) p<0.0001; and active cases, p = 0.01. Using a cut-off of 8,239 pg/ml, MTB specific IP-10 was able to diagnose LTBI with a sensitivity of 87.1% (95% CI, 76.2–94.3) and specificity of 90.9% (95% CI, 81.3–96.6). MTB specific to mitogen specific IP-10 ratio was higher in HIV negative active TB cases, compared to HIV negative latently infected contacts, p = 0.0004. Concentrations of MTB specific IP-10 were higher in contacts with TST conversion (negative at baseline, positive at 6-months) than in those that were persistently TST negative, p = 0.001.
Conclusion
IP-10 performed well in differentiating contacts with either latent or active TB from those who were uninfected but was not able to differentiate LTBI from active disease except when MTB specific to mitogen specific ratios were used in HIV negative adults. In addition, IP-10 had the potential to diagnose ‘recent TB infection’ in persons classified as having LTBI using the TST. Such individuals with strong IP-10 responses would likely benefit from chemoprophylaxis.
doi:10.1371/journal.pone.0146098
PMCID: PMC4714877  PMID: 26771653
11.  Resilience does matter: evidence from a 10-year cohort record linkage study 
BMJ Open  2014;4(1):e003917.
Objectives
To examine 10-year mortality and hospital use among individuals categorised as resilient and vulnerable to the impact of chronic pain.
Design
A cohort record linkage study.
Setting
Grampian, Scotland.
Participants
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.
Results
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.
Conclusions
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.
doi:10.1136/bmjopen-2013-003917
PMCID: PMC3902361  PMID: 24430878
EPIDEMIOLOGY; PAIN MANAGEMENT; PRIMARY CARE
12.  Treatment with anthelminthics during pregnancy: what gains and what risks for the mother and child? 
Parasitology  2011;138(12):1499-1507.
SUMMARY
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.
doi:10.1017/S0031182011001053
PMCID: PMC3178871  PMID: 21810307
Anthelminthic; pregnancy; albendazole; praziquantel; hookworm; Schistosoma mansoni; atopic eczema; anaemia
13.  Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study 
BMC Infectious Diseases  2015;15:438.
Background
With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis.
Methods
Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months’ follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months.
Results
Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95 % confidence interval (CI), p-value) -1488.6 pg/ml ((−2682.5, −294.8), p = 0.01), and IL- 2 (−213.1 pg/ml (−419.2, −7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95 % CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6.
Conclusions
IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries.
Trial registration
ISRCTN registry, ISRCTN15705625. Registered on 30th September 2015.
doi:10.1186/s12879-015-1201-8
PMCID: PMC4619204  PMID: 26493989
Latent tuberculosis infection; Household contacts; Randomised design; Cytokines; Antibodies; Isoniazid preventive therapy
14.  Schistosoma mansoni and HIV infection in a Ugandan population with high HIV and helminth prevalence 
OBJECTIVES
Recent reports suggest that Schistosoma infection may increase the risk of acquiring human immunodeficiency virus (HIV). We used data from a large cross-sectional study to investigate whether Schistosoma mansoni infection is associated with increased HIV prevalence.
METHODS
We conducted a household survey of residents in island fishing communities in Mukono district, Uganda, between October 2012 and July 2013. HIV status was assessed using rapid test kits. Kato-Katz (KK) stool tests and urine-circulating cathodic antigen (CCA) were used to test for Schistosoma infection. Multivariable logistic regression, allowing for the survey design, was used to investigate the association between S. mansoni infection and HIV infection.
RESULTS
Data from 1412 participants aged 13 years and older were analysed (mean age 30.3 years, 45% female). The prevalence of HIV was 17.3%. Using the stool Kato-Katz technique on a single sample, S. mansoni infection was detected in 57.2% (719/1257) of participants; urine CCA was positive in 73.8% (478/650) of those tested. S. mansoni infection was not associated with HIV infection. [KK (aOR = 1.04; 95% CI: 0.74–1.47, P = 0.81), CCA (aOR = 1.53; 95% CI: 0.78–3.00, P = 0.19)]. The median S. mansoni egg count per gram was lower in the HIV-positive participants (P = 0.005).
CONCLUSIONS
These results add to the evidence that S. mansoni has little effect on HIV transmission, but may influence egg excretion.
doi:10.1111/tmi.12545
PMCID: PMC4568314  PMID: 25976017
Schistosoma mansoni; schistosomiasis; Bilharzia; HIV
15.  Schistosoma mansoni and HIV acquisition in fishing communities of Lake Victoria, Uganda: a nested case–control study 
OBJECTIVE
It has been suggested that Schistosoma mansoni, which is endemic in African fishing communities, might increase susceptibility to human immunodeficiency virus (HIV) acquisition. If confirmed, this would be of great public health importance in these high HIV-risk communities. This study was undertaken to determine whether S. mansoni infection is a risk factor for HIV infection among the fishing communities of Lake Victoria, Uganda. We conducted a matched case–control study, nested within a prospective HIV incidence cohort, including 50 HIV seroconverters (cases) and 150 controls during 2009-2011.
METHODS
S. mansoni infection prior to HIV seroconversion was determined by measuring serum circulating anodic antigen (CAA) in stored serum. HIV testing was carried out using the Determine rapid test and infection confirmed by enzyme-linked immunosorbent assays.
RESULTS
About 49% of cases and 52% of controls had S. mansoni infection prior to HIV seroconversion (or at the time of a similar study visit, for controls): odds ratio, adjusting for ethnicity, religion, marital status, education, occupation, frequency of alcohol consumption in previous 3 months, number of sexual partners while drunk, duration of stay in the community, and history of schistosomiasis treatment in the past 2 years was 1.23 (95% CI 0.3–5.7) P = 0.79. S. mansoni infections were chronic (with little change in status between enrolment and HIV seroconversion), and there was no difference in median CAA concentration between cases and controls.
CONCLUSIONS
These results do not support the hypothesis that S. mansoni infection promotes HIV acquisition.
doi:10.1111/tmi.12531
PMCID: PMC4529482  PMID: 25940951
Schistosoma mansoni; circulating anodic antigen; HIV; susceptibility; fishing communities; Uganda
16.  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.
doi:10.1002/ijc.29329
PMCID: PMC4529666  PMID: 25395177
HIV-associated Kaposi's sarcoma; sub-Saharan Africa; Kaposi's sarcoma associated-herpesvirus; HIV; AIDS
17.  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.
doi:10.1098/rstb.2014.0137
PMCID: PMC4527383  PMID: 25964450
maternal infection; mycobacteria; bacille Calmette–Guérin; purified protein derivative; tuberculosis; immunization
18.  The Lake Victoria island intervention study on worms and allergy-related diseases (LaVIISWA): study protocol for a randomised controlled trial 
Trials  2015;16:187.
Background
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.
Methods/Design
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.
Discussion
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.
doi:10.1186/s13063-015-0702-5
PMCID: PMC4413531  PMID: 25902705
Helminths; Anthelminthic treatment; Allergy; Atopy; Wheeze; Cluster-randomised trial
19.  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.
Background
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.
Methods
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.
Discussion
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.
doi:10.1186/s13063-015-0682-5
PMCID: PMC4413988  PMID: 25872925
Bacillus Calmette-Guérin; Heterologous effects; Innate immunity; Neonate; Invasive infectious disease
20.  Uptake of Mass Drug Administration Programme for Schistosomiasis Control in Koome Islands, Central Uganda 
PLoS ONE  2015;10(4):e0123673.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0123673
PMCID: PMC4382187  PMID: 25830917
21.  Pharmacist-led management of chronic pain in primary care: costs and benefits in a pilot randomised controlled trial 
BMJ Open  2015;5(4):e006874.
Objectives
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.
Design
Regression analysis of costs and effects, using intention-to-treat and expected value of sample information analysis (EVSI).
Setting
Six general practices: Grampian (3); East Anglia (3).
Participants
125 patients with complete resource use and short form-six-dimension questionnaire (SF-6D) data at baseline, 3 months and 6 months.
Interventions
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.
Results
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.
Conclusions
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
ISRCTN06131530.
doi:10.1136/bmjopen-2014-006874
PMCID: PMC4390732  PMID: 25833666
HEALTH ECONOMICS; PAIN MANAGEMENT; PRIMARY CARE
22.  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.
Highlights
•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.
Background
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.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.vaccine.2014.12.015
PMCID: PMC4317190  PMID: 25529292
Tuberculosis; HIV; Helminth; Pregnancy; Bacille Calmette–Guerin; Crude culture filtrate protein
23.  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
24.  Blood pressure in primary school children in Uganda: a cross-sectional survey 
BMC Public Health  2014;14:1223.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2458-14-1223
PMCID: PMC4289384  PMID: 25427456
Blood pressure; Hypertension; Children; Uganda; Africa
25.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0111517
PMCID: PMC4221037  PMID: 25372043

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