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1.  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
2.  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.
doi:10.1016/j.ajog.2013.10.879
PMCID: PMC4046649  PMID: 24184340
evolutionary selective pressure; great obstetric syndromes; length of gestation; obstetric dilemma
3.  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.
Background
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.
Methodology
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).
Conclusion/Significance
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.
doi:10.1371/journal.pone.0097259
PMCID: PMC4023955  PMID: 24836781
4.  Hypertension Persisting after Pre-Eclampsia: A Prospective Cohort Study at Mulago Hospital, Uganda  
PLoS ONE  2013;8(12):e85273.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0085273
PMCID: PMC3877387  PMID: 24392003
5.  Radiographic characterization of the hands in Ritscher-Schinzel/3-C syndrome 
SpringerPlus  2013;2:594.
Abstract
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.
Objective
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.
Results
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.
Conclusion
The hand findings identified in this study can provide helpful diagnostic tools to clinicians when the diagnosis of RSS is being considered.
doi:10.1186/2193-1801-2-594
PMCID: PMC3830001  PMID: 24255872
Ritscher-Schinzel syndrome; 3-C syndrome; Metacarpophalangeal pattern (MCPP); Profile; Carpal height; Phenotype
6.  Effect of Maternal Schistosoma mansoni Infection and Praziquantel Treatment During Pregnancy on Schistosoma mansoni Infection and Immune Responsiveness among Offspring at Age Five Years 
Introduction
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.
Methods
In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), 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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pntd.0002501
PMCID: PMC3798616  PMID: 24147175
7.  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.
doi:10.1164/rccm.201203-0444OC
PMCID: PMC3443801  PMID: 22798319
tuberculosis; cough; air microbiology; infectious disease transmission; infection control
8.  Killer cell immunoglobulin-like receptor (KIR) genes and their HLA-C ligands in a Ugandan population 
Immunogenetics  2013;65:765-775.
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.
doi:10.1007/s00251-013-0724-7
PMCID: PMC3824577  PMID: 23974321
KIR; HLA-C; Uganda; Africa; Population study; NK cell
9.  Risk Factors for Seropositivity to Kaposi Sarcoma–Associated Herpesvirus Among Children in Uganda 
Background:
Determinants of Kaposi sarcoma–associated herpesvirus (KSHV) seropositivity among children living in sub-Saharan African populations where infection is endemic are not well understood. Local environmental factors, including other infectious agents, may be key.
Methods:
Within the context of a well-characterized birth cohort, we examined associations between various factors and antibodies against KSHV, measured in stored plasma samples from 1823 mother–child pairs in Entebbe, Uganda.
Results:
Seroprevalence increased with increasing age of the child (P = 0.0003) and was higher among those with KSHV seropositive mothers than in those without (12% vs 9%; odds ratio: 1.4, 95% confidence interval: 1.1 to 2.0). It was also higher among children with HIV infection (29% vs 10%; odds ratio: 3.1, 95% confidence interval: 1.2 to 8.3) or malaria parasitemia (30% vs 10%; odds ratio: 4.1, 95% confidence interval: 2.4 to 7.0) than in children without. These associations were not explained by socioeconomic status.
Conclusions:
The finding that KSHV serostatus is associated with malaria parasitemia in children is novel. In a country endemic for KSHV, malaria may be a cofactor for KSHV infection or reactivation among children.
doi:10.1097/QAI.0b013e31828a7056
PMCID: PMC3707567  PMID: 23403859
Kaposi sarcoma-associated herpesvirus; Sub-Saharan Africa; children; HIV; Kaposi sarcoma
10.  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
11.  The effect of anthelminthic treatment during pregnancy on HIV plasma viral load; results from a randomised, double blinded, placebo-controlled trial in Uganda 
Background
To investigate the effect of helminth infections and their treatment during pregnancy on HIV load, we conducted a 2×2 factorial randomised controlled trial of albendazole versus placebo and praziquantel versus placebo in pregnant women in Entebbe, Uganda
Methods
Two hundred and sixty-four HIV-infected women from the Entebbe Mother and Baby Study (ISRCTN32849447) were included in this analysis. Women were tested for helminth infections at enrolment and mean HIV load was compared between infected and uninfected groups. The effect of anthelminthic treatment on HIV load was evaluated at six weeks post-treatment and at delivery using linear regression and adjusting for enrolment viral load.
Results
Hookworm and Trichuris infections were associated with higher mean viral load at enrolment (adjusted mean difference 0.24log10 copies/ml, 95% confidence interval (CI): 0.01 to 0.47, p=0.03 and 0.37log10 copies/ml, 95%CI: 0.00 to 0.74, p=0.05, respectively). There were no associations between viral load and other helminth species. There was some evidence that albendazole reduced viral load at six weeks post-treatment (adjusted mean difference −0.17, 95% CI: −0.36 to 0.01, p=0.07), however this effect did not differ according to mother’s hookworm infection status and had diminished at delivery (adjusted mean difference −0.11, 95% CI: −0.28 to 0.07, p=0.23). There was no effect of praziquantel treatment on HIV load at any time point.
Conclusions
Infection with some soil-transmitted helminth species is associated with increased HIV load in pregnancy. Treatment with albendazole causes a small decrease in HIV load, however this may not represent a direct effect of worm removal.
doi:10.1097/QAI.0b013e3182511e42
PMCID: PMC3383620  PMID: 22728750
HIV; viral load; helminths; anthelminthic treatment; clinical trial
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.  Incongruous consultation behaviour: results from a UK-wide population survey 
BMC Family Practice  2012;13:21.
Background
Symptom characteristics are strong drivers of care seeking. Despite this, incongruous consultation behaviour occurs and has implications for both individuals and health-care services. The aim of this study was to determine how frequently incongruous consultation behaviour occurs, to examine whether it is more common for certain types of symptoms and to identify the factors associated with being an incongruous consulter.
Methods
An age and sex stratified random sample of 8,000 adults was drawn from twenty UK general practices. A postal questionnaire was used to collect detailed information on the presence and characteristics of 25 physical and psychological symptoms, actions taken to manage the symptoms, general health, attitudes to symptom management and demographic/socio-economic details. Two types of incongruous consultation behaviour were examined: i) consultation with a GP for symptoms self-rated as low impact and ii) no consultation with a GP for symptoms self-rated as high impact.
Results
A fifth of all symptoms experienced resulted in consultation behaviour which was incongruous based on respondents' own rating of the symptoms' impact. Low impact consultations were not common, although symptoms indicative of a potentially serious condition resulted in a higher proportion of low impact consultations. High impact non-consultations were more common, although there was no clear pattern in the type of associated symptoms. Just under half of those experiencing symptoms in the previous two weeks were categorised as an incongruous consulter (low impact consulter: 8.3%, high impact non-consulter: 37.1%). Employment status, having a chronic condition, poor health, and feeling that reassurance or advice from a health professional is important were associated with being a low impact consulter. Younger age, employment status, being an ex-smoker, poor health and feeling that not wasting the GPs time is important were associated with being a high impact non-consulter.
Conclusions
This is one of the first studies to examine incongruous consultation behaviour for a range of symptoms. High impact non-consultations were common and may have important health implications, particularly for symptoms indicative of serious disease. More research is now needed to examine incongruous consultation behaviour and its impact on both the public's health and health service use.
doi:10.1186/1471-2296-13-21
PMCID: PMC3338366  PMID: 22433072
Signs & symptoms; Community-based; Health care services; Primary care
14.  The influence of BCG vaccine strain on mycobacteria-specific and non-specific immune responses in a prospective cohort of infants in Uganda 
Vaccine  2012;30(12):2083-2089.
Highlights
► Largest study comparing BCG strains and first to assess strain effects on non-specific responses. ► Cytokine responses to both mycobacterial and non-mycobacterial stimuli are strain-dependent. ► BCG-Denmark causes higher cytokine levels and more scars and adverse events than two other strains. ► Sex may interact with the effect of strain; non-specific responses are not associated with scars. ► BCG strain choice may be important and should be evaluated in novel vaccine strategies using BCG.
Background
Globally, BCG vaccination varies in efficacy and has some non-specific protective effects. Previous studies comparing BCG strains have been small-scale, with few or no immunological outcomes and have compared TB-specific responses only. We aimed to evaluate both specific and non-specific immune responses to different strains of BCG within a large infant cohort and to evaluate further the relationship between BCG strain, scarring and cytokine responses.
Methods
Infants from the Entebbe Mother and Baby Study (ISRCTN32849447) who received BCG-Russia, BCG-Bulgaria or BCG-Denmark at birth, were analysed by BCG strain group. At one year, interferon-gamma (IFN-γ), interleukin (IL)-5, IL-13 and IL-10 responses to mycobacteria-specific antigens (crude culture filtrate proteins and antigen 85) and non-mycobacterial stimuli (tetanus toxoid and phytohaemagglutinin) were measured using ELISA. Cytokine responses, scar frequency, BCG associated adverse event frequency and mortality rates were compared across groups, with adjustments for potential confounders.
Results
Both specific and non-specific IFN-γ, IL-13 and IL-10 responses in 1341 infants differed between BCG strain groups including in response to stimulation with tetanus toxoid. BCG-Denmark immunised infants showed the highest cytokine responses. The proportion of infants who scarred differed significantly, with BCG scars occurring in 52.2%, 64.1% and 92.6% of infants immunised with BCG Russia, BCG-Bulgaria and BCG-Denmark, respectively (p < 0.001). Scarred infants had higher IFN-γ and IL-13 responses to mycobacterial antigens only than infants without a scar. The BCG-Denmark group had the highest frequency of adverse events (p = 0.025). Mortality differences were not significant.
Conclusions
Both specific and non-specific immune responses to the BCG vaccine differ by strain. Scarring after BCG vaccination is also strain-dependent and is associated with higher IFN-γ and IL-13 responses to mycobacterial antigens. The choice of BCG strain may be an important factor and should be evaluated when testing novel vaccine strategies that employ BCG in prime–boost sequences, or as a vector for other vaccine antigens.
doi:10.1016/j.vaccine.2012.01.053
PMCID: PMC3314967  PMID: 22300718
BCG; Strain; Immune response; Non-specific effects; BCG scar
15.  Ascertaining the size of the symptom iceberg in a UK-wide community-based survey 
Background
The symptom iceberg describes the phenomenon that most symptoms are managed in the community without people seeking professional health care. The size of the iceberg for many symptoms is unknown, as is their association with personal characteristics, including history of a chronic disease.
Aim
To ascertain the size of the symptom iceberg in the UK.
Design of study
A UK-wide community-based postal survey.
Setting
Urban and rural communities across the UK.
Method
A postal survey was sent to an age- and sex-stratified random sample of 2474 adults, aged 18–60 years, drawn from 20 practices around the UK. Questions were aimed at investigating adults' experiences of 25 different symptoms in the previous 2 weeks.
Results
The number of symptoms experienced by one individual in the previous 2 weeks ranged from 0 to 22 (mean 3.66). Of the symptoms examined, the three most common were: feeling tired/run down; headaches; and joint pain. Univariate analysis found symptom prevalence to be significantly associated with a wide range of participant characteristics. However, after adjustment, many of these associations no longer remained significant for a number of the symptoms. Presence of a chronic condition, age, and employment status were the three factors most commonly associated with the 2-week prevalence of symptoms. Reported symptom characteristics (severity, duration, interference, and time off work) varied little by sex or age.
Conclusion
Symptoms in the UK community are common. Symptom prevalence was associated with a number of participant characteristics, although the extent of this association was less than has been reported in previous research. This study provides an important current baseline prevalence of 25 symptoms in the community for those who do, and do not, have a chronic condition.
doi:10.3399/bjgp11X548910
PMCID: PMC3020067  PMID: 21401979
community-based; epidemiology; prevalence; signs and symptoms; symptom iceberg
16.  Impact of lifestyle in middle-aged women on mortality: evidence from the Royal College of General Practitioners' Oral Contraception Study 
Background
Although many individuals have multiple lifestyle risk factors, few studies have investigated the impact of lifestyle risk factor combinations among women.
Aim
To investigate the relationship between individual and combinations of lifestyle risk factors in middle-aged women with subsequent mortality, and to estimate the associated population attributable risks.
Design of study
Prospective cohort study.
Setting
Royal College of General Practitioners' (RCGP) Oral Contraception Study, UK.
Method
In 1994–1995, women remaining under follow-up in the RCGP Oral Contraception Study were sent a lifestyle survey, from which modifiable risk factors were identified: pack-years smoked, physical inactivity, never drinking versus consuming at least 7 units of alcohol weekly, and being underweight, overweight, or obese. The cohort was followed to December 2006 or death. Population attributable risks were calculated.
Results
Of 10 059 women studied, 896 died. Pack-years smoked (11–20 years: adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.46 to 2.27; >20 years: adjusted HR = 2.34, 95% CI = 2.00 to 2.74); never drinking alcohol (adjusted HR = 1.66, 95% CI = 1.34 to 2.05); being underweight (adjusted = HR 1.66, 95% CI = 1.03 to 2.68); and physical inactivity (<15 hours/week: adjusted HR = 1.73, 95% CI = 1.46 to 2.04) were significantly associated with mortality compared with their respective reference group. Women with multiple lifestyle risk factors had higher mortality risks than those reporting one factor. The population attributable risk of the combination of smoking, physical inactivity, body mass index outside normal range, and alcohol (never drinking or excess intake) was 59% (95% CI = 31% to 78%).
Conclusion
Assuming a causal relationship between lifestyle and mortality, avoidance of four lifestyle risk factors would have prevented 60% of the deaths. The importance of avoiding smoking and undertaking physical inactivity during midlife should continue to be emphasised.
doi:10.3399/bjgp10X515052
PMCID: PMC2913736  PMID: 20822689
epidemiology; follow-up studies; lifestyle; mortality; women
17.  Revisiting the symptom iceberg in today's primary care: results from a UK population survey 
BMC Family Practice  2011;12:16.
Background
Recent changes in UK primary care have increased the range of services and healthcare professionals available for advice. Furthermore, the UK government has promoted greater use of both self-care and the wider primary care team for managing symptoms indicative of self-limiting illness. We do not know how the public has been responding to these strategies. The aim of this study was to describe the current use of different management strategies in the UK for a range of symptoms and identify the demographic, socio-economic and symptom characteristics associated with these different approaches.
Methods
An age and sex stratified random sample of 8,000 adults (aged 18-60), drawn from twenty general practices across the UK, were sent a postal questionnaire. The questionnaire collected detailed information on 25 physical and psychological symptoms ranging from those usually indicative of minor illness to those which could be indicative of serious conditions. Information on symptom characteristics, actions taken to manage the symptoms and demographic/socio-economic details were also collected.
Results
Just under half of all symptoms reported resulted in respondents doing nothing at all. Lay-care was used for 35% of symptoms and primary care health professionals were consulted for 12% of symptoms. OTC medicine use was the most common lay-care strategy (used for 25% of all symptom episodes). The GP was the most common health professional consulted (consulted for 8% of all symptom episodes) while use of other primary care health professionals was very small (each consulted for less than 2% of symptom episodes). The actions taken for individual symptoms varied substantially although some broad patterns emerged. Symptom characteristics (in particular severity, duration and interference with daily life) were more commonly associated with actions taken than demographic or socio-economic characteristics.
Conclusion
While the use of lay-care was widespread, use of the primary care team other than the GP was low. Further research is needed to examine the public's knowledge and opinions of different primary care services to investigate why certain services are not being used to inform the future development of primary care services in the UK.
doi:10.1186/1471-2296-12-16
PMCID: PMC3083353  PMID: 21473756
Signs and symptoms; Symptom iceberg; Community-based; Health care services; Primary care
18.  Authors’ reply 
BMJ : British Medical Journal  2008;336(7635):60.
doi:10.1136/bmj.39450.650289.3A
PMCID: PMC2190231
19.  Effects of maternal and infant co-infections, and of maternal immunisation, on the infant response to BCG and tetanus immunisation 
Vaccine  2010;29(2-2):247-255.
Some vaccines show poor efficacy in tropical countries. Within a birth cohort in Uganda, we investigated factors that might influence responses to BCG and tetanus immunisation. Whole blood assay responses to crude culture filtrate proteins of Mycobacterium tuberculosis (cCFP)) and tetanus toxoid (TT) were examined among 1506 and 1433 one-year-olds, respectively. Maternal Mansonella perstans infection was associated with higher interleukin (IL)-10 responses to both immunogens but no reduction in gamma interferon (IFN-γ), IL-5 and IL-13 responses; other maternal helminth infections showed little effect. Tetanus immunisation during pregnancy was associated with higher infant responses to TT; maternal BCG scar (from past immunisation) with lower infant IL-5 and IL-13 responses to cCFP. IFN-γ, IL-5 and IL-13 to TT were reduced in HIV-exposed-uninfected infants; infant malaria and HIV were associated with lower IFN-γ, IL-5 and IL-13 responses to both immunogens. We conclude that maternal helminth infections are unlikely to explain poor vaccine efficacy in the tropics. Effects of maternal immunisation on infant responses to vaccines should be explored. Prevention of infant malaria and HIV could contribute to effectiveness of immunisation programmes.
doi:10.1016/j.vaccine.2010.10.047
PMCID: PMC3021124  PMID: 21040693
BCG; Tetanus; Immunisation
20.  Effect of praziquantel treatment during pregnancy on cytokine responses to schistosome antigens: results of a randomised, placebo-controlled trial 
The Journal of infectious diseases  2008;198(12):1870-1879.
Background:
Praziquantel treatment of schistosomiasis boosts anti-schistosome responses, with ‘type 2 helper T-cell’ bias that may contribute to immunologically mediated killing and to protection against re-infection. Praziquantel treatment during pregnancy was recommended in 2002 but immunological effects of the treatment had not been investigated.
Methods:
A cohort of 387 S. mansoni infected women was recruited within a larger trial of de-worming during pregnancy (ISRCTN32849447; http://www.controlled-trials.com/ISRCTN32849447/elliott). Women were randomised to receive either praziquantel or placebo during pregnancy. Six weeks after delivery all women received praziquantel. Whole blood culture cytokine responses to S. mansoni worm and egg antigens were measured before and six weeks after each treatment.
Results:
Schistosome specific cytokine responses were suppressed during pregnancy. Praziquantel treatment during pregnancy caused significant boosts in gamma interferon (IFNγ), interleukin (IL)-2, IL-4, IL-5 IL-13 and IL-10 responses to schistosome worm antigen and IFNγ, IL-5 and IL-13 to schistosome egg antigen; but these boosts were not as substantial as those seen for treatment after delivery.
Conclusion:
Pregnancy suppresses potentially beneficial boost in cytokine responses associated with praziquantel treatment. Further studies are needed on the long term effect of treating schistosomiasis during pregnancy on morbidity and resistance to reinfection among treated women and their offspring.
doi:10.1086/593215
PMCID: PMC2892302  PMID: 18983246
Schistosomiasis; Schistosoma mansoni; human; praziquantel; treatment; pregnancy; cytokines; immunology; immune responses
21.  Plasmodium falciparum and helminth co-infection in a semi-urban population of pregnant women in Uganda 
The Journal of infectious diseases  2008;198(6):920-927.
Introduction
Helminth infections and malaria are widespread in the tropics. Recent studies suggest helminth infections may increase susceptibility to malaria. If confirmed, this could be particularly important during pregnancy-induced immunosuppression.
Aim
To evaluate the geographical distribution of Plasmodium falciparum-helminth co-infection, and associations between parasite species in pregnant women in Entebbe, Uganda.
Methods
A cross-sectional study was conducted at baseline in a trial of anti-helminthics during pregnancy. Helminth and P.falciparum infections were quantified in 2507 asymptomatic women; socio-demographic and geographical details were recorded.
Results
Hookworm and Mansonella perstans were associated with P.falciparum but the effect of hookworm was seen only in the absence of M.perstans (OR for P.falciparum, adjusted for age, tribe, socioeconomic status, HIV and location: hookworm without M.perstans 1.53 (95% CI 1.09-2.14); M.perstans without hookworm 2.33 (1.47-3.69), both hookworm and M.perstans, 1.85 (1.24-2.76)). No association was observed between Schistosoma mansoni, Trichuris or Strongyloides and P.falciparum.
Conclusions
Hookworm-P.falciparum and M.perstans-P.falciparum co-infection amongst pregnant women in Entebbe is more common than expected by chance. Further studies are needed to elucidate the mechanism of this association. Helminth-induced increased susceptibility to P.falciparum could have important consequences for pregnancy outcome and responses to malaria in infancy.
doi:10.1086/591183
PMCID: PMC2886962  PMID: 18721060
Malaria; Helminth; Hookworm; Mansonella perstans; Plasmodium falciparum; Co-Infection; Spatial; Geographic Factors; Pregnancy; Uganda
22.  Rate and Amplification of Drug Resistance among Previously-Treated Patients with Tuberculosis in Kampala, Uganda 
Background
Drug-resistant Mycobacterium tuberculosis has emerged as a global threat. In resource-constrained settings, patients with a history of tuberculosis (TB) treatment may have drug-resistant disease and may experience poor outcomes. There is a need to measure the extent of and risk factors for drug resistance in such patients.
Methods
From July 2003 through November 2006, we enrolled 410 previously treated patients with TB in Kampala, Uganda. We measured the prevalence of resistance to first- and second-line drugs and analyzed risk factors associated with baseline and acquired drug resistance.
Results
The prevalence of multidrug-resistant TB was 12.7% (95% confidence interval [95% CI], 9.6%–16.3%). Resistance to second-line drugs was low. Factors associated with multidrug-resistant TB at enrollment included a history of treatment failure (odds ratio, 23.6; 95% CI, 7.7–72.4), multiple previous TB episodes (odds ratio, 15.6; 95% CI, 5.0–49.1), and cavities present on chest radiograph (odds ratio, 5.9; 95% CI, 1.2–29.5). Among a cohort of 250 patients, 5.2% (95% CI, 2.8%–8.7%) were infected with M. tuberculosis that developed additional drug resistance. Amplification of drug resistance was associated with existing drug resistance at baseline (P<.01) and delayed sputum culture conversion (P<.01).
Conclusions
The burden of drug resistance in previously treated patients with TB in Uganda is sizeable, and the risk of generating additional drug resistance is significant. There is an urgent need to improve the treatment for such patients in low-income countries.
doi:10.1086/592252
PMCID: PMC2883442  PMID: 18808360
23.  Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study 
Objective To see if the mortality risk among women who have used oral contraceptives differs from that of never users.
Design Prospective cohort study started in 1968 with mortality data supplied by participating general practitioners, National Health Service central registries, or both.
Setting 1400 general practices throughout the United Kingdom.
Participants 46 112 women observed for up to 39 years, resulting in 378 006 woman years of observation among never users of oral contraception and 819 175 among ever users.
Main outcome measures Directly standardised adjusted relative risks between never and ever users for all cause and cause specific mortality.
Results 1747 deaths occurred in never users of oral contraception and 2864 in ever users. Compared with never users, ever users of oral contraception had a significantly lower rate of death from any cause (adjusted relative risk 0.88, 95% confidence interval 0.82 to 0.93). They also had significantly lower rates of death from all cancers; large bowel/rectum, uterine body, and ovarian cancer; main gynaecological cancers combined; all circulatory disease; ischaemic heart disease; and all other diseases. They had higher rates of violent deaths. No association between overall mortality and duration of oral contraceptive use was observed, although some disease specific relations were apparent. An increased relative risk of death from any cause between ever users and never users was observed in women aged under 45 years who had stopped using oral contraceptives 5-9 years previously but not in those with more distant use. The estimated absolute reduction in all cause mortality among ever users of oral contraception was 52 per 100 000 woman years.
Conclusion Oral contraception was not associated with an increased long term risk of death in this large UK cohort; indeed, a net benefit was apparent. The balance of risks and benefits, however, may vary globally, depending on patterns of oral contraception usage and background risk of disease.
doi:10.1136/bmj.c927
PMCID: PMC2837145  PMID: 20223876
24.  The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447] 
Background
Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects "spill-over", altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life.
Purpose
To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood.
Methods
The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 X 2(x2) factorial design.
Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed.
Conclusion
This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy. Clinical Trials 2007; 4: 42–57. http://ctj.sagepub.com
doi:10.1177/1740774506075248
PMCID: PMC2643383  PMID: 17327245
25.  Uptake of HIV and syphilis testing of pregnant women and their male partners in a programme for prevention of mother-to-child HIV transmission in Uganda 
Objective
To describe uptake of HIV and syphilis testing in a prevention of mother-to-child HIV transmission programme in Uganda.
Methods
Analysis of data from routine HIV and syphilis testing at Entebbe Hospital antenatal services.
Results
A total of 20 738 women attended antenatal services. Exactly 62.8% of women, but only 1.8% of their male partners, accepted testing for HIV; 82.2% of women, but only 1.1% of their male partners accepted syphilis testing. Partners of women with positive HIV results were more likely to come for subsequent testing. Of 200 couples whose partners accepted HIV-testing within 30 days of one another, 19 (9.5%) were HIV-discordant, representing 65.5% of couples with at least one partner HIV-positive. HIV prevalence was 12.6% for women and 10.8% for men; syphilis prevalence was 4.0% for women and 6.2% for men.
Conclusion
Uptake of HIV and syphilis testing was fairly good among pregnant women attending antenatal clinics at Entebbe Hospital, but very low among their male partners. The level of HIV-discordant couples was high. These clinics should be made more couples-friendly to identify both HIV-positive men for treatment and discordant couples for HIV prevention.
doi:10.1111/j.1365-3156.2008.02052.x
PMCID: PMC2592475  PMID: 18331533
HIV; PMTCT; Uganda; pregnant; couple; syphilis

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