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Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Funder: National Health Service, Funder: European Research Council (Advanced Researcher Award) Cancer Research UK Cambridge Cancer Centre Medical Research Council (Infrastructure Award) National Health Service, Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare. Here, we report a mother-son diad who developed wtGIST at age 66 and 34 years, respectively. Comprehensive genetic testing revealed germline truncating variants in both SDHA (c.1534C>T (p.Arg512*)) and PALB2 (c.3113G>A (p.Trp1038*)) in both affected individuals. The mother also developed breast ductal carcinoma in-situ at age 70 years. Immunohistochemistry and molecular analysis of the wtGISTs revealed loss of SDHB expression and loss of the wild-type SDHA allele in tumour material. No allele loss was detected at PALB2 suggesting that wtGIST tumourigenesis was principally driven by succinate dehydrogenase deficiency. However, we speculate that the presence of multilocus inherited neoplasia alleles syndrome (MINAS) in this family might have contributed to the highly unusual occurrence of familial wtGIST. Systematic reporting of tumour risks and phenotypes in individuals with MINAS will facilitate the clinical interpretation of the significance of this diagnosis, which is becoming more frequent as strategies for genetic testing for hereditary cancer becomes more comprehensive.

Zika virus (ZIKV) has caused large, brief outbreaks in isolated populations, however ZIKV can also persist at low levels over multiple years. The reasons for these diverse transmission dynamics remain poorly understood. In Fiji, which has experienced multiple large single-season dengue epidemics, there was evidence of multi-year transmission of ZIKV between 2013 and 2017. To identify factors that could explain these differences in dynamics between closely related mosquito-borne flaviviruses, we jointly fit a transmission dynamic model to surveillance, serological and molecular data. We estimate that the observed dynamics of ZIKV were the result of two key factors: strong seasonal effects, which created an ecologically optimal time of year for outbreaks; and introduction of ZIKV after this optimal time, which allowed ZIKV transmission to persist over multiple seasons. The ability to jointly fit to multiple data sources could help identify a similar range of possible outbreak dynamics in other settings., Dengue and Zika virus are closely related flaviviruses but can have contrasting transmission dynamics in the same populations. Here, the authors use a model combining serological, surveillance and viral sequence data to explain differences in transmission dynamics in Fiji.

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Constitutional translocations, typically involving chromosome 3, have been recognized as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterized the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC. In one individual with constitutional t(10;17)(q11.21;p11.2), the translocation breakpoint disrupted two genes: the known renal tumor suppressor gene (TSG) FLCN (and clinical features of Birt‐Hogg‐Dubé syndrome were detected) and RASGEF1A. In four cases, the rearrangement breakpoints did not disrupt known inherited RCC genes. In the second case without chromosome 3 involvement, the translocation breakpoint in an individual with a constitutional t(2;17)(q21.1;q11.2) mapped 12 Kb upstream of NLK. Interestingly, NLK has been reported to interact indirectly with FBXW7 and a previously reported RCC‐associated translocation breakpoint disrupted FBXW7. In two cases of constitutional chromosome 3 translocations, no candidate TSGs were identified in the vicinity of the breakpoints. However, in an individual with a constitutional chromosome 3 inversion, the 3p breakpoint disrupted the FHIT TSG (which has been reported previously to be disrupted in two apparently unrelated families with an RCC‐associated t(3;8)(p14.2;q24.1). These findings (a) expand the range of constitutional chromosome rearrangements that may be associated with predisposition to RCC, (b) confirm that chromosome rearrangements not involving chromosome 3 can predispose to RCC, (c) suggest that a variety of molecular mechanisms are involved the pathogenesis of translocation‐associated RCC, and (d) demonstrate the utility of GS for investigating such cases.

We describe a case of prolonged COVID-19 caused by the SARS-CoV-2 Gamma variant in a fully vaccinated healthcare worker, 387 days after an infection caused by lineage B.1.1.33. Infections were confirmed by whole-genome sequencing and corroborated by the detection of neutralizing antibodies in convalescent serum samples. Considering the permanent exposure of this healthcare worker to SARS-CoV-2, the waning immunity after the first infection, the low efficacy of the inactivated vaccine at preventing COVID-19, the immune escape of the Gamma variant (VOC), and the burden of post-COVID syndrome, this individual would have benefited from an additional dose of a heterologous vaccine.

Background Visceral leishmaniasis (VL) is a zoonotic protozoal vector-borne disease that is a major public health challenge. In Argentina, canine (CVL) and human visceral leishmaniasis (HVL) have recently emerged. There is a lack of standardised diagnostic tests for CVL, which hinders control of CVL and HVL. Methodology/Principal findings Sampling was carried out in Puerto Iguazú, Argentina, comprising 190 asymptomatic, oligosymptomatic and polysymptomatic dogs. The following diagnostics were applied: microscopy of lymph node aspirate (LNA); three immunochromatographic rapid diagnostic tests (RDTs), prototype rK28-ICT, rK39-ICT (both Coris BioConcept), commercial rK39 (InBios); ELISA for IgG, IgG1 and IgG2, against rK28, rK39 or crude lysate antigen. DNA detection and analysis, with 30 dogs, was of the ITS1 region using skin samples, and loop-mediated isothermal amplification (LAMP; Eiken Loopamp) of buffy coat, skin scrape or LNA. 15.4% of dogs were positive by LNA microscopy. The rK28 RDT had higher seropositivity rate (61%) than either a prototype rK39 RDT (31.4%) or commercial rK39 RDT (18.8%), without cross-reactivity with six other pathogens. IgG anti-rK39 ELISA antibody titres, but not IgG2, were positively correlated with number of clinical signs. LAMP with LNA had a higher positivity rate than PCR; buffy coat sampling was more sensitive than skin scrape. ITS1 confirmed Leishmania (Leishmania) infantum as the agent of CVL. Leishmania (Viannia) spp. was detected in skin samples from two dogs, compatible with Leishmania (Viannia) braziliensis. Conclusions/Significance Seroprevalence confirmed rapid increase in CVL in Puerto Iguazú. The rK28 RDT test potentially has great value for improved point-of-care diagnosis. Given cost reduction and accessibility, commercial LAMP may be applicable to buffy coat. RDT biomarkers of CVL clinical status are required to combat spread of CVL and HVL. The presence of Viannia, perhaps as an agent of human mucocutaneous leishmaniasis (MCL), highlights the need for vigilance and surveillance., Author summary Visceral leishmaniasis (VL) is a widespread parasitic disease caused by sand fly-borne parasites of the Leishmania donovani complex (L. donovani and L. infantum). Without early diagnosis and successful chemotherapy symptomatic human VL is fatal. Dogs are reservoir hosts of L. infantum, and canine visceral leishmaniasis (CVL) often precedes outbreaks in local human populations. With dogs sampled within a region of emergent CVL in northern Argentina, we compared a range of diagnostic techniques, including microscopy, serology by enzyme linked immunosorbent assays (ELISAs) and rapid diagnostic tests (RDTs), and detection and identification of Leishmania DNA. Novel serological assays based on the rK28 antigen were more sensitive than those based on rK39, and without evidence of cross reaction with six other canine pathogens. A commercial DNA detection kit (LAMP; Eiken Loopamp), used for the first time with CVL, was more sensitive than PCR on lymph node samples. Unexpectedly, we also found canine infection with the Viannia sub-genus of Leishmania. Our results reinforce the need for improved diagnosis, vigilance, surveillance and control of CVL.

OBJECTIVES To investigate the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a vulnerable population of children and their household contacts. METHODS SARS-CoV-2 reverse transcription polymerase chain reaction assays and coronavirus disease 2019 (COVID-19) immunoglobulin G serology tests were performed in children and their household contacts after enrollment during primary health care clinic visits. Participants were followed prospectively with subsequent specimens collected through household visits in Manguinhos, an impoverished urban slum (a favela) in Rio de Janeiro at 1, 2, and 4 weeks and quarterly post study enrollment. RESULTS Six hundred sixty-seven participants from 259 households were enrolled from May to September 2020. This included 323 children (0–13 years), 54 adolescents (14–19 years), and 290 adults. Forty-five (13.9%) children had positive test results for SARS-CoV-2 polymerase chain reaction. SARS-CoV-2 infection was most frequent in children aged CONCLUSIONS In our setting, children do not seem to be the source of SARS-CoV-2 infection and most frequently acquire the virus from adults. Our findings suggest that, in settings such as ours, schools and child care potentially may be reopened safely if adequate COVID-19 mitigation measures are in place and staff are appropriately immunized.

INTRODUCTION: A year into the pandemic, the knowledge of SARS-CoV-2 infection risks among healthcare workers remains limited. In this cross-sectional study, we examined whether healthcare workers with high exposure to Covid-19 patients had a higher risk of SARS-CoV-2 infection than other healthcare workers in a Norwegian University Hospital. We also investigated the prevalence of asymptomatic healthcare workers in a ward with a SARS-CoV-2 outbreak. METHODS: Healthcare workers from five wards at Akershus University Hospital were included between May 11 and June 11, 2020. Blood samples were analyzed for SARS-CoV-2 antibodies and seroprevalences compared between participants with high and low exposure to Covid-19 patients. Demographic data and SARS-CoV-2 infection risk factors were recorded in a questionnaire. Naso-/oropharyngeal swabs from participants from the outbreak ward were analyzed by reverse transcriptase-polymerase chain reaction. RESULTS: 360/436 (82.6%) healthcare workers participated. 9/262 (3.4%) participants from wards with high exposure to Covid-19 patients were SARS-CoV-2 seropositive versus 3/98 (3.1%) from wards with low exposure (OR 1.13; 95%CI 0.3-4.26, p = .861). SARS-CoV-2 antibodies were found in 11/263 (4.2%) participants who had worked one or more shifts caring for Covid-19 patients versus in 1/85 (1.2%) without any known occupational Covid-19 exposure (OR 3.67; 95%CI 0.46-29.06, p = .187). SARS-CoV-2 was detected in naso-/oropharyngeal swabs from 2/78 (2.6%) participants. CONCLUSION: We found no significantly increased risk of SARS-CoV-2 infection in healthcare workers with high exposure to COVID-19 patients. Five healthcare workers had either serologic or molecular evidence of past or present unrecognized SARS-CoV-2 infection.

It has been commonly assumed that Zika virus (ZIKV) infection confers long-term protection against reinfection, preventing ZIKV from re-emerging in previously affected areas for several years. However, the long-term immune response to ZIKV following an outbreak remains poorly documented. We compared results from eight serological surveys before and after known ZIKV outbreaks in French Polynesia and Fiji, including cross-sectional and longitudinal studies. We found evidence of a decline in seroprevalence in both countries over a two-year period following first reported ZIKV transmission. This decline was concentrated in adults, while high seroprevalence persisted in children. In the Fiji cohort, there was also a significant decline in neutralizing antibody titres against ZIKV, but not against dengue viruses that circulated during the same period., eLife digest Since the Zika virus first emerged in the Pacific Islands in 2007, it has caused many outbreaks in the Pacific and Latin America. Some scientists thought that after exposure to the virus people would develop long-term immunity to it, reducing the number of outbreaks in the future. Several studies supported this idea. These studies showed that many people recently infected with Zika developed antibodies in their blood that might protect them from becoming ill during future outbreaks. But it was not clear how long this protection would last. To better understand how immunity to the Zika virus changes over time, Henderson, Aubry et al. combined data from eight surveys that collected blood samples at different time points during Zika outbreaks in French Polynesia and Fiji. The analysis showed that the proportion of people with detectable antibodies against the Zika virus increased in both countries after the outbreaks. In children these immune responses persisted for years, but antibody levels declined over time in adults. By contrast, antibodies to the closely related dengue virus did not wane over time in individuals tested for both viruses in Fiji in 2013, 2015 and 2017. The data suggest that immunity against the Zika virus may not last as long as previously thought, which could affect the chances of future outbreaks. The findings may also have implications for researchers studying the virus, because the number of people with antibodies against the virus is not a good estimate of how many people were initially infected. More studies are needed to understand immunity to Zika virus over time and how it may affect future outbreaks.

Background Chikungunya is an arbovirus, transmitted by Aedes mosquitoes, which emerged in the Americas in 2013 and spread rapidly to almost every country on this continent. In Brazil, where the first cases were detected in 2014, it currently has reached all regions of this country and more than 900,000 cases were reported. The clinical spectrum of chikungunya ranges from an acute self-limiting form to disabling chronic forms. The purpose of this study was to estimate the seroprevalence of chikungunya infection in a large Brazilian city and investigate the association between viral circulation and living condition. Methodology/principal findings We conducted a population-based ecological study in selected Sentinel Areas (SA) through household interviews and a serologic survey in 2016/2017. The sample was of 1,981 individuals randomly selected. The CHIKV seroprevalence was 22.1% (17.1 IgG, 2.3 IgM, and 1.4 IgG and IgM) and varied between SA from 2.0% to 70.5%. The seroprevalence was significantly lower in SA with high living conditions compared to SA with low living condition. There was a positive association between CHIKV seroprevalence and population density (r = 0.2389; p = 0.02033). Conclusions/significance The seroprevalence in this city was 2.6 times lower than the 57% observed in a study conducted in the epicentre of the CHIKV epidemic of this same urban centre. So, the herd immunity in this general population, after four years of circulation of this agent is relatively low. It indicates that CHIKV transmission may persist in that city, either in endemic form or in the form of a new epidemic, because the vector infestation is persistent. Besides, the significantly lower seroprevalences in SA of higher Living Condition suggest that beyond the surveillance of the disease, vector control and specific actions of basic sanitation, the reduction of the incidence of this infection also depends on the improvement of the general living conditions of the population., Author summary Chikungunya is a disease caused by viruses transmitted by Aedes mosquitoes. It stands out because it can produce chronic cases and disabling forms. This survey was conducted in a large city in Brazil, involving 1,981 people living in different living conditions/LC, distributed in 30 urban areas. Interviews and blood collection were performed to know the seroprevalence of chikungunya virus (CHIKV). The global seroprevalence was 22.1%, ranged from 2.0 to 70.5%. The areas where the highest and lowest seroprevalence were of low LC, but population density was different among them, which was related to seroprevalence. The mosquito index was not associated with the seroprevalence. Our results showed that lower seroprevalence than another survey conducted in the epicentre of the epidemic of this same city. So, a considerable proportion of the population of Feira de Santana is susceptible to the CHIKV. Possibly the virus will continue to circulate and manifest itself as endemic or epidemic, as long as LC remain favourable to the reproduction of the transmitting vector of CHIKV.

Funding: Hong Kong Jockey Club Charity Trust within the collaborative project “Training and Research Development for Emergency Medical Teams with reference to the WHO Global EMTs initiative, classification, and standards” between the Humanitarian and Conflict Response Institute (HCRI; Manchester, United Kingdom) and the Hong Kong Jockey Club Disaster Preparedness and Response Institute (HKJCDPRI; Aberdeen, Hong Kong). Medical and epidemiological documentation in disasters is pivotal: the former for recording patient care and the latter for providing real-time information to the host country. Furthermore, documentation informs post-hoc analysis to improve the effectiveness of future deployments. Although documentation is considered important and indeed integral to health care response, there are many barriers and challenges. Some of these challenges include: working without well-established standards for medical documentation; and working with international guidelines which provide minimal guidance as to how health data should be managed practically to ensure accuracy and completion. Furthermore, there is a shift in mindset in disaster contexts wherein most health care focus shifts to direct clinical care and diverts almost all attention from quality documentation. This report distinguishes between the tasks of the epidemiologist and the data manager (DM) in an emergency medical team (EMT) and discusses the importance of data collection in the specific case of an EMT deployment. While combining these roles is sometimes possible if resources are limited, it is better to separate them, as the two are quite distinct. Although there is overlap, to achieve the goals of either role, preferentially they should be carried out by two people working closely together with complementary skill sets. The main objective of this report is to provide guidance and task descriptions to EMTs and field hospitals when training, recruiting, and preparing DMs and epidemiologists to work within their teams. Clear delineation of tasks will lead to better quality data, as it commits DMs to being concerned with the provision of real-time documentation from patient arrival through to compiling daily reports. It also commits epidemiologists to providing enhanced disease surveillance; outbreak investigation; and a source of reliable and actionable information for decision makers and stakeholders in the disaster management cycle. Postprint

During the Ebola outbreak in 2014-2015 in Sierra Leone, residual clinical specimens and accompanying data were collected from routine diagnostic testing in Public Health England (PHE) led laboratories. Most of the samples with all the accompanying data were transferred to PHE laboratories in the UK for curation by PHE. The remainder have been kept securely in Sierra Leone. The biobank holds approximately 9955 samples of which 1108 tested positive for Ebola virus. Researchers from the UK and overseas, from academia, government other research organisations and commercial companies can submit proposals to the biobank to access and use the samples. The Ministry of Health and Sanitation in Sierra Leone (MOHS) retains ownership of the data and materials and is working with PHE and other researchers to develop and conduct a series of research projects that will inform future healthcare and public health strategies relating to Ebola. The Ebola Biobank Governance Group (EBGG) was established to guarantee equality of access to the biobank for the most scientifically valuable research including by researchers from low and middle-income countries. Ensuring benefit to the people of Sierra Leone is an over-arching principle for decisions of the EBGG. Four ongoing research collaborations are based on the first wave of biobank proposals approved by EBGG. Whilst the biobank is a valuable resource its completeness and sample quality are consistent with the outbreak conditions under which they were collected.

SUMMARYBackgroundSerosurveys published following major outbreaks of Zika virus (ZIKV) have so far shown a high level of seroprevalence from samples collected within 12 months of the first confirmed case. A common assumption is that ZIKV infection confers long-term protection against reinfection, preventing ZIKV from re-emerging in previously affected areas for many years. However, the long-term immune response to ZIKV following an outbreak remains poorly documented.MethodsWe compared results from eight serological surveys, with sample sizes ranging from 49 to 700, before and after known ZIKV outbreaks in the Pacific region: five from cross-sectional studies of schoolchildren and the general population in French Polynesia over a seven-year period; and three from a longitudinal cohort in Fiji over a four-year period.FindingsWe found strong evidence of a decline in seroprevalence in both countries over a two-year period following first reported ZIKV transmission. In the cohort in Fiji, there was also a significant decline in antibody titres against ZIKV. However, the decline in seroprevalence was concentrated in adults, while high seroprevalence persisted in children.InterpretationThe observed patterns of long-term anti-ZIKV antibody levels following outbreaks in the Pacific could be an early indication of the dynamics of population immunity in Latin America. Given that ZIKV antibody levels can wane substantially over time, follow-up seroprevalence studies and prospective clinical trial designs in Latin America may need to be revised, and assumptions about the potential for ZIKV to re-emerge may need to be revisited.FundingPacific Funds, ANR, MRC, Wellcome, Royal Society.

The frequency of reported outbreaks of infectious diseases has increased over the past 3 decades, with predictions that this rise will continue. Outbreak response continues to follow nine basic principles: establish the presence of an outbreak, verify the diagnosis, make a case definition, find cases and contacts, conduct basic epidemiology, test hypotheses, institute control measures, communicate the situation and establish ongoing surveillance. Within each of these areas, significant advances have been made over the past 5 years using progress in digital, laboratory, epidemiology and anthropological equipment or techniques. Irrespective of these, future outbreaks of high-consequence are inevitable, and vigilance and preparation must continue in order to prevent significant mortality, morbidity and socio-economic crisis.

The 2013–16 epidemic of Ebola virus disease underscored the shortcomings of the international community to both respond to outbreaks and conduct critical research in complex humanitarian crises. To address these concerns, the UK Government has formed the UK Public Health Rapid Support Team (UK- PHRST). The UK-PHRST is a collaboration between Public Health England and the London School of Hygiene and Tropical Medicine with the University of Oxford and Kings College London as academic partners. The UK-PHRST has a novel triple mandate to work in low- and middle-income countries (LMICs) to: Respond to outbreaks Conduct innovative operational research during and between outbreaks to generate evidence on best practices Build LMIC and regional capacity for outbreak response

Acromegaly is associated with increased growth hormone (GH) and insulin-like growth factor-I (IGF-I) secretion which may support tumour development and growth. A 68-year-old woman was diagnosed with acromegaly due to typical clinical and hormonal characteristics. While contrast-enhanced MRI at diagnosis did not reveal a pituitary adenoma, a 5-mm lesion was identified on repeat scanning 13 months later. Abdominal and chest CT showed tumours of the stomach, right adrenal gland, and right lung. The CT also showed a hypodense lesion in the liver and heterogeneous echostructure of the thyroid gland with left lobe solid-cystic tumour. Somatostatin receptor scintigraphy revealed increased tracer accumulation in the right thyroid lobe. No tracer accumulation was noted at the location of the other tumours. The resected stomach, adrenal, chest, and thyroid lesions did not show GH secretion. The patient refused pituitary surgery, and her acromegaly is currently well-controlled with somatostatin analogue therapy. A CT scan 19 months later revealed a contrast-enhancing left kidney tumour that was a G1-grade clear cell carcinoma. Four years after the acromegaly diagnosis multiple myeloma were diagnosed with secondary renal amyloidosis. Genetic screening for a paraganglioma gene panel, AIP, MEN1, and CDKN1B mutations were negative. A next-generation cancer panel containing 94 cancer genes did not identify any possible unifying gene abnormality in her germline DNA. Coexistence of acromegaly and numerous other tumours suggests a common aetiology of these disorders. However, no genetic abnormality could be identified with the tests that have been performed.

Background Undifferentiated febrile illness (UFI) is one of the most common reasons for people seeking healthcare in low-income countries. While illness and death due to specific infections such as malaria are often well-quantified, others are frequently uncounted and their impact underappreciated. A number of high consequence infectious diseases, including Ebola virus, are endemic or epidemic in the Federal Republic of Sudan which has experienced at least 12 UFI outbreaks, frequently associated with haemorrhage and high case fatality rates (CFR), since 2012. One of these occurred in Darfur in 2015/2016 with 594 cases and 108 deaths (CFR 18.2%). The aetiology of these outbreaks remains unknown. Methodology/Principal findings We report a retrospective cohort study of the 2015/2016 Darfur outbreak, using a subset of 65 of 263 outbreak samples received by the National Public Health Laboratory which met selection criteria of sufficient sample volume and epidemiological data. Clinical features included fever (95.8%), bleeding (95.7%), headache (51.6%) and arthralgia (42.2%). No epidemiological patterns indicative of person-to-person transmission or health-worker cases were reported. Samples were tested at the Public Health England Rare and Imported Pathogens Laboratory using a bespoke panel of likely pathogens including haemorrhagic fever viruses, arboviruses and Rickettsia, Leptospira and Borrelia spp. Seven (11%) were positive for Crimean-Congo haemorrhagic fever virus (CCHFV) by real-time reverse transcription PCR. The remaining samples tested negative on all assays. Conclusions/Significance CCHFV is an important cause of fever and haemorrhage in Darfur, but not the sole major source of UFI outbreaks in Sudan. Prospective studies are needed to explore other aetiologies, including novel pathogens. The presence of CCHFV has critical infection, prevention and control as well as clinical implications for future response. Our study reinforces the need to boost surveillance, lab and investigative capacity to underpin effective response, and for local and international health security., Author summary The Federal Republic of Sudan has had at least 12 outbreaks of febrile illness of unknown cause associated with symptoms of haemorrhage and high case fatality rates since 2012. Outbreaks without clear diagnosis are concerning, particularly in countries such as Sudan where a range of high consequence diseases, including viral haemorrhagic fevers, are endemic or epidemic, and local laboratory capacity is limited. We transferred historical samples stored in the National Public Health Authority from one of these outbreaks that occurred in Darfur 2015–2016 to the Public Health England Laboratory at Porton, UK, and tested them against a wide range of infectious diseases to try to identify the cause, and to help the Sudanese Federal Ministry of Health to develop and target their limited laboratory capacity. We found that Crimean-Congo Haemorrhagic Fever was an important cause but not the only source of cases in this outbreak. This has implications for prevention and control as well as for treating cases. Our study also highlighted the need for future studies to explore other possible causes, including new pathogens, and reinforced the need to boost surveillance, lab and investigative capacity for more timely and complete outbreak response.

OBJECTIVE: To determine to what extent the higher impact of treatment for sexually transmitted diseases (STD) on HIV incidence in Mwanza, Tanzania than in Rakai and Masaka, Uganda might be explained by baseline differences between the trial populations. DESIGN: A re-analysis of baseline data from the three trial populations comparing demography, sexual risk behaviour and HIV/STD epidemiology. METHODS: Data were compared after age-standardization and adjustments for sample selection where necessary. STD rates were also adjusted for the sensitivities and specificities of the diagnostic techniques used. RESULTS: Demographic patterns were similar across populations, apart from effects of AIDS on fertility and mortality (including widowhood) in Uganda. Higher sexual risk behaviours, including younger age of sexual debut, higher numbers of recent partners and lower frequency of condom use, were apparent in Mwanza compared to Masaka and Rakai. High-titre serological syphilis, gonorrhoea, chlamydia infection and trichomoniasis were all more prevalent in Mwanza, except for chlamydia infection in males. There was little difference between sites in the seroprevalence of Herpes simplex virus type-2. Age patterns in the prevalence of short-duration STD and current risk behaviours were similar across sites but all-titre serological syphilis was more prevalent among older participants in Rakai and Masaka than Mwanza. CONCLUSIONS: Differences between trial populations included higher reported risk behaviour and higher rates of curable STD in Mwanza compared to Rakai and Masaka. These differences probably relate to previous reductions in risk behaviour in Uganda and may explain, at least in part, the contrasting results of these trials.

Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence

Identifying correlates of immunity or susceptibility to disease promotes understanding of pathogenesis and development of diagnostic tools, treatments, and vaccines. There is evidence that type 1 cytokine responses are associated with protection against tuberculosis, and suppression of type 1, or switching to type 2 responses, with susceptibility, but this has not been studied prospectively. We studied a cohort of 631 HIV-1-infected Ugandan adults. At enrollment we performed whole blood cultures for type 1 (interferon [IFN]-gamma, interleukin [IL]-2) and type 2/immunosuppressive (IL-5, IL-10) responses to mycobacterial antigens (purified protein derivative [PPD] and culture filtrate proteins [CFP]). The incidence of tuberculosis was not associated with IFN-gamma responses, but was higher among participants with IL-2 responses (adjusted rate ratios [RR]: PPD 3.48; CFP 3.99; P < 0.001). For tuberculin skin test-positive participants, high incidence was also associated with an IL-10 response to PPD (adjusted RR 6.24, P = 0.03); for those with a BCG scar, high incidence was associated with positive IL-5 responses (adjusted RRs: PPD 3.64, P = 0.006; CFP 3.44, P = 0.04). The association with IL-2 production may reflect a response to tuberculous infection or to activating disease; the associations with IL-10 and IL-5 are in keeping with the expected role of immunosuppressive or type 2 cytokines.

BACKGROUND: An association between HIV-1 and malaria is expected in theory, but has not been convincingly shown in practice. We studied the effects of HIV-1 infection and advancing immunosuppression on falciparum parasitaemia and clinical malaria. METHODS: HIV-1-positive and HIV-1-negative adults selected from a population-based cohort in rural Uganda were invited to attend a clinic every 3 months (routine visits) and whenever they were sick (interim visits). At each visit, information was collected on recent fever, body temperature, and malaria parasites. Participants were assigned a clinical stage at each routine visit and had regular CD4-cell measurements. FINDINGS: 484 participants made 7220 routine clinic visits between 1990 and 1998. Parasitaemia was more common at visits by HIV-1-positive individuals (328 of 2788 [11.8%] vs 231 of 3688 [6.3%], p

The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Abnormal CD45 splicing has been recognized in humans, caused by a C77G transversion in the gene encoding CD45 (PTPRC). Recently the C77G polymorphism has been associated with multiple sclerosis and increased susceptibility to HIV-1 infection. These studies suggest that the regulation of CD45 splicing may be critical for the proper function of the immune system. Because of these data we examined the frequency of the C77G allele in African and Asian populations from countries with high or low prevalence of HIV infection. Here we report that the variant CD45 C77G allele is absent in African populations. We further show that populations living in the Pamir mountains of Central Asia have a very high prevalence of the C77G variant.

Summary Background Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections. Methods In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447. Findings Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30–0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34–0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3–43·7), of diarrhoea was 134·1 (129·2–139·2), and of pneumonia was 22·3 (20·4–24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79–1.14], diarrhoea [1·06, 0·96–1·16], pneumonia [1·11, 0·90–1·38]) or praziquantel treatment (malaria [1·00, 0·84–1·20], diarrhoea [1·07, 0·98–1·18], pneumonia [1·00, 0·80–1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35–1·42) or praziquantel (0·60, 0·29–1·23) treatment. Interpretation These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed. Funding Wellcome Trust.

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.

Identification of drug resistance before it becomes a public health concern requires a clear distinction between what constitutes a normal and a suboptimal treatment response. A novel method of analyzing drug efficacy studies in human helminthiases is proposed and used to investigate recent claims of atypical responses to ivermectin in the treatment of River Blindness. The variability in the rate at which Onchocerca volvulus microfilariae repopulate host's skin following ivermectin treatment is quantified using an individual-based onchocerciasis mathematical model. The model estimates a single skin repopulation rate for every host sampled, allowing reports of suboptimal responses to be statistically compared with responses from populations with no prior exposure to ivermectin. Statistically faster rates of skin repopulation were observed in 3 Ghanaian villages (treated 12–17 times), despite the wide variability in repopulation rates observed in ivermectin-naïve populations. Another village previously thought to have high rates of skin repopulation was shown to be indistinguishable from the normal treatment response. The model is used to generate testable hypotheses to identify whether atypical rates of skin repopulation by microfilariae could result from low treatment coverage alone or provide evidence of decreased ivermectin efficacy. Further work linking phenotypic poor responses to treatment with parasite molecular genetics markers will be required to confirm drug resistance. Limitations of the skin-snipping method for estimating parasite load indicates that changes in the distribution of microfilarial repopulation rates, rather than their absolute values, maybe a more sensitive indicator of emerging ivermectin resistance.

Objective: To describe sexual behaviour trends in a rural Ugandan cohort in the context of an evolving HIV epidemic, 1993–2006. Methods: Sexual behaviour data were collected annually from a population cohort in which HIV serological surveys were also conducted. Behaviour trends were determined using survival analysis and logistic regression. Trends are reported based on the years in which the respective indicators were collected. Results: Between 1993 and 2006, median age at first sex increased from 16.7 years to 18.2 years among 17–20-year-old girls and from 18.5 years to 19.9 years among boys. Both sexes reported a dip in age at sexual debut between 1998 and 2001. One or more casual partners in the past 12 months among men rose from 11.6% in 1997 to 12.7% in 2004 and then declined to 10.2% in 2006. Among women it increased from 1.4% in 1997 to 3.7% in 2004 and then reduced to 1.4% in 2006. The rise in casual partners between 1997 and 2004 was driven mainly by older age groups. Trends in condom use with casual partners varied by age, increasing among those aged 35+ years, declining in the middle age groups and presenting a dip and then a rise in the youngest aged group (13–19 years). Conclusion: Among youth, risky behaviour declined but increased in the late 1990s/early 2000s. Among those aged 35+ years, condom use rose but casual partners also rose. Several indicators portrayed a temporary increase in risk taking behaviour from 1998 to 2002.

Two significant challenges face researchers tracking HIV-related socio-economic and demographic change over time in large cohort studies. Firstly, data collected in cohort studies established to describe the dynamics of HIV infection may contain no systematic data on household consumption expenditures which is an established measure of current and long-run household welfare. The second challenge is the choice of the unit of analysis in order to recognise and record impact; this is because most cohorts use the household as that unit. This means that the influence of factors outside that unit cannot easily be tracked. In this paper we show how a detailed understanding of the impact of HIV and AIDS on wider families and social networks, obtained through in-depth longitudinal research with a small number of households, can shed light on the findings from quantitative analysis from a larger cohort in the same population in rural Uganda. The findings of large-scale survey data from more than 2000 households over a 12-year period showed a lack of a strong association between poverty, HIV status and/or death of the household head. In-depth ethnographic research with 26 households in 1991/2 and a restudy of the same households in 2006/7 provide insights into the reasons for this finding: the choice of socio-economic indicators and support from other family and community members play a part in affecting survey findings on the impact of HIV at household level. One other factor is important in explaining the findings. HIV-infected family members from outside the household may drain resources from the household, so looking at the impact of HIV and AIDS on people's wider families provides pointers to why those who have not had an AIDS-related death in their own household may have failed to prosper. Our qualitative findings show that AIDS may well throw households into disarray and poverty, but more often reduces development and hinders families from getting out of poverty. Used strategically, small longitudinal studies can provide important information with which to explain patterns observed in large-scale quantitative datasets.

Throughout the 1990s, HIV-1 prevalence and incidence were falling in Uganda. Recently, some researchers have noticed that HIV-1 prevalence is levelling off. We examine prevalence, incidence, and sexual behaviour trends in a rural population cohort in Uganda over 16 years.We report prevalence by survey round and incidence by calendar year from a prospective general population cohort study. Using logistic regression Wald tests, we examined casual partners, condom use, and pregnancies. We examined age at sexual debut by means of life tables.HIV-1 prevalence declined from 8.5% in 1990/1991 to 6.2% in 1999/2000, and thereafter rose to 7.7% in 2004/2005. Incidence (per 1000 person-years at risk) fell from 7.5 in 1990 to 4.1 in 1998, and thereafter increased to 5.0 by 2004. The 2005 incidence estimate reached an all-time low of 2.5, but the preliminary 2006 estimate shows a rise again. Incidence trends varied by age and sex. Some sexual behaviour indicators showed more risky behaviour in recent years compared with the 1990s, whereas others indicated that the reduction in risky behaviour that began in the 1990s continues.HIV-1 prevalence is rising in this cohort. Incidence is stabilizing, and shows signs of increasing among some subgroups. The extent to which changing sexual behaviour has played a role in these epidemiological trends is unclear, but it is likely to have contributed. To solidify the success that Uganda had throughout the 1990s in controlling the HIV epidemic, the efforts in HIV prevention need to be re-strengthened, using all strategies known.

The Southeast Asia Influenza Clinical Research Network (SEA ICRN) (www.seaclinicalresearch.org) is a recently developed multilateral, collaborative partnership that aims to advance scientific knowledge and management of human influenza through integrated clinical investigation. The partnership of hospitals and institutions in Indonesia, Thailand, United Kingdom, United States, and Viet Nam was established in late 2005 after agreement on the general principles and mission of the initiative and after securing initial financial support. The establishment of the SEA ICRN was both a response to the re-emergence of the highly pathogenic avian influenza A(H5N1) virus in Southeast Asia in late 2003 and an acknowledgment that clinical trials on emerging infectious diseases require prepared and coordinated research capacity. The objectives of the Network also include building sustainable research capacity in the region, compliance with international standards, and prompt dissemination of information and sharing of samples. The scope of research includes diagnosis, pathogenesis, treatment and prevention of human influenza due to seasonal or novel viruses. The Network has overcome numerous logistical and scientific challenges but has now successfully initiated several clinical trials. The establishment of a clinical research network is a vital part of preparedness and an important element during an initial response phase to a pandemic.

OBJECTIVES To determine the prevalence and incidence of anaemia in HIV-positive and negative individuals; to identify risk factors for anaemia, prior to the introduction of HAART; and to determine the validity of the clinical diagnosis of anaemia. METHODS Between 1990 and 2003, we followed a rural population based cohort of HIV-infected and uninfected participants. Prevalence and incidence of anaemia were determined clinically and by laboratory measurements. The sensitivity, specificity and predictive values of clinical diagnosis were calculated. RESULTS The prevalence of anaemia at enrolment was 18.9% among HIV-positive and 12.9% among HIV-negative participants (P = 0.065). Incidence of anaemia increased with HIV disease progression, from 103 per 1000 person-years of observation among those with CD4 counts >500 to 289 per 1000 person-years of observation among those with CD4 counts

Journal article published in THE LANCET. Health research has a key role in the development of low-income and middle-income countries. There are several current initiatives that have greatly contributed to capacity strengthening of health research in sub-Saharan Africa, including those supported by WHO and Tropical Disease Research (TDR), the Swedish International Development Agency (SIDA) and Department for Research Cooperation (SAREC), the European Union, the Bill & Melinda Gates Foundation, the International Clinical Epidemiology Network (INCLEN), the Fogarty International Centre, the National Institutes of Health (NIH), and the Wellcome Trust. However, enormous challenges remain for sub-Saharan Africa to establish a common framework for sustainable research capacity strengthening. The Global Ministerial Forum on Research for Health in Bamako will give emphasis to the challenges of research for development and health, the need for more health-system research, and a greater intersectoral approach to science, technology, and health. That health research is indispensable for improving health, equity, and development is now widely accepted,1 yet how sub-Saharan African countries can develop their fragile health systems and their own capacity to do health research is rarely discussed.2 A recent African-led initiative—the Initiative to Strengthen Health Research Capacity in Africa (ISHReCA)—has identified nine key requirements to strengthening health-research capacity in Africa (panel 1). We focus on these requirements and suggest practical strategies for sustainable capacity strengthening in African institutions. Health research has a key role in the development of low-income and middle-income countries. There are several current initiatives that have greatly contributed to capacity strengthening of health research in sub-Saharan Africa, including those supported by WHO and Tropical Disease Research (TDR), the Swedish International Development Agency (SIDA) and Department for Research Cooperation (SAREC), the European Union, the Bill & Melinda Gates Foundation, the International Clinical Epidemiology Network (INCLEN), the Fogarty International Centre, the National Institutes of Health (NIH), and the Wellcome Trust. However, enormous challenges remain for sub-Saharan Africa to establish a common framework for sustainable research capacity strengthening. The Global Ministerial Forum on Research for Health in Bamako will give emphasis to the challenges of research for development and health, the need for more health-system research, and a greater intersectoral approach to science, technology, and health. That health research is indispensable for improving health, equity, and development is now widely accepted,1 yet how sub-Saharan African countries can develop their fragile health systems and their own capacity to do health research is rarely discussed.2 A recent African-led initiative—the Initiative to Strengthen Health Research Capacity in Africa (ISHReCA)—has identified nine key requirements to strengthening health-research capacity in Africa (panel 1). We focus on these requirements and suggest practical strategies for sustainable capacity strengthening in African institutions.

Limited research has been conducted outside Western settings on how HIV-positive parents decide to test and disclose their own HIV status to children. We conducted a qualitative study in 2001 and 2005 to assess parent attitudes and current counselling policy and practice regarding child testing and parental disclosure in Uganda prior to the roll-out of antiretroviral therapy. Parent perspectives were obtained through extended in-depth interviews with 10 HIV-positive parents recruited from The AIDS Support Organization (TASO) Entebbe branch. Counselling policy and practice were explored through key informant interviews with directors and two counsellors from each of five Ugandan counselling institutions with national or regional coverage. Respondents had 51 children ranging from 4 to 36 years with a median age of 13. Five of 10 parents had disclosed their status to their children usually to all and four of these had tested one child for HIV. All those who tested any child had also disclosed their status to some or all of their children. Parents regularly worried that their children may be infected but all preferred to wait for emergence of symptoms before considering HIV tests citing fear of childrens emotional reaction and lack of perceived benefits from knowing status. Counselling policy directors confirmed the absence of policy and training guidelines on the subject of parent-child disclosure. Counsellors reported improvising and giving inconsistent advice on this common concern of clients. Concerns over disclosure to children of parents HIV status and testing children for HIV represent a major psychological burden for HIV-positive parents. Further research is needed but current counselling practice could be improved now by adapting lessons learned from existing research. (authors)

OBJECTIVE: To provide estimates of survival and progression to different HIV disease endpoints after HIV infection among adults in a rural Ugandan setting. DESIGN: A prospective population-based cohort study. METHODS: Eligible individuals at least 15 years of age with documented HIV seroconversion were recruited from a general population cohort in rural Uganda, along with a randomly selected proportion of HIV-prevalent and HIV-negative individuals. All participants were followed up every 3 months, and CD4 cell counts taken every 6 months in HIV-positive participants. Life tables and Kaplan-Meier functions were used to estimate survival patterns for all endpoints [death, time to World Health Organization (WHO) stage 2, 3, AIDS and CD4 cell count < 200 cells/mul]. Analysis of follow-up time was truncated when antiretroviral therapy (ART) became available in the area in January 2004. RESULTS: We recruited 240 HIV incident cases, 108 prevalent cases and 257 HIV-negative controls. Crude mortality rates were 70.0 per 1000 person-years in HIV-positive, and 12.1 per 1000 person-years in HIV-negative individuals. The median time from seroconversion to death was 9.0 years (N = 240) and 6.2 years to a CD4 cell count less than 200 cells/mul or WHO stage 4 (N = 229). The median time from ART eligibility (CD4 cell count < 200 cells/mul, < 350 cells/mul and WHO stage 3, or WHO stage 4) to death was 34.7 months. Older age at seroconversion was a risk factor for faster progression to death and ART eligibility. CONCLUSION: HIV progression in this African cohort is similar to that reported in industrialized countries before the widespread introduction of ART.

Onchocerca volvulus nodules were removed from 77 fully compliant patients in a longitudinal study of ivermectin treatment in Sierra Leone. The patients had participated in a randomized controlled trial and received either 4 annual doses of ivermectin or 10 6-monthly doses over 6 years. Worms were examined 9 months after the last treatment for evidence of changes in morphology, viability and reproductivity. The findings were compared with results for the 2 groups obtained at earlier surveys of the same study population. Repeated treatment at 6 and 12-month intervals has resulted in a marked ageing of the male worm population profile and a significant reduction in the proportion of live female worms found in the nodules. In addition, there has been a reduction in reproductivity of 90% or more. However, most of the worms found were still alive and potentially fertile, underlining the need for the continuation of regular ivermectin treatment to maintain the benefits achieved.

The objective was to investigate the effect of pregnancy on HIV disease progression and survival among HIV-infected women in rural Uganda prior to the introduction of anti-retroviral therapy (ART). From a clinical cohort established in 1990 we selected records from HIV-infected women of reproductive age. We conducted two analyses: (1) all HIV-infected cases contributing to analysis of CD4 decline using a linear regression model with random intercepts and slopes; (b) incident cases with known date of seroconversion contributed to analyses of median time to CD4 less than 200 cells/microl AIDS and death. A total of 139 women were included in the analysis of CD4 decline. Women who subsequently became pregnant had higher CD4 counts at enrolment and had a slower CD4 decline than those who did not become pregnant. In women who became pregnant CD4 decline was faster after pregnancy than before (P less than 0.0001). The survival analyses showed no significant differences between women who became pregnant and those who did not with respect to median time to CD4 count less than 200 AIDS or death. The initial comparative immunological advantage possessed by fertile women before they become pregnant is subsequently lost as a result of their pregnancy. Women should be informed about the potential negative effect of pregnancy on their immunological status and should be offered contraception. In resource-limited settings women determined to become pregnant should be given priority for ART if eligible. (authors)

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 × 2(×2) 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.

Assessments of the importance of different routes of HIV-1 (HIV) transmission are vital for prioritization of control efforts. Lack of consistent direct data and large uncertainty in the risk of HIV transmission from HIV-contaminated injections has made quantifying the proportion of transmission caused by contaminated injections in sub-Saharan Africa difficult and unavoidably subjective. Depending on the risk assumed, estimates have ranged from 2.5% to 30% or more. We present a method based on an age-structured transmission model that allows the relative contribution of HIV-contaminated injections, and other routes of HIV transmission, to be robustly estimated, both fully quantifying and substantially reducing the associated uncertainty. To do this, we adopt a Bayesian perspective, and show how prior beliefs regarding the safety of injections and the proportion of HIV incidence due to contaminated injections should, in many cases, be substantially modified in light of age-stratified incidence and injection data, resulting in improved (posterior) estimates. Applying the method to data from rural southwest Uganda, we show that the highest estimates of the proportion of incidence due to injections are reduced from 15.5% (95% credible interval) (0.7%, 44.9%) to 5.2% (0.5%, 17.0%) if random mixing is assumed, and from 14.6% (0.7%, 42.5%) to 11.8% (1.2%, 32.5%) under assortative mixing. Lower, and more widely accepted, estimates remain largely unchanged, between 1% and 3% (0.1–6.3%). Although important uncertainty remains, our analysis shows that in rural Uganda, contaminated injections are unlikely to account for a large proportion of HIV incidence. This result is likely to be generalizable to many other populations in sub-Saharan Africa.

Studies report substantial sexual behaviour change in Africa in response to HIV/AIDS. Generally there seems to be an increase in condom use and a reduction in partners, with men reporting more change than women. However, it is not only important to know whether people are changing their sexual behaviour but also their reasons for changing and the consistency and extent of change. Between 1996 and 2000 a study involving 196 respondents was carried out in rural southwest Uganda to investigate the exact nature of behaviour change and the reasons for change or lack of change since people became aware of HIV/AIDS. Data were collected from three rounds of questionnaire surveys, four rounds of open in-depth interviews, six rounds of semi-structured interviews and from informal conversations and participant observation. In order to obtain a comprehensive assessment of behaviour change the data for each participant from all sources were compared and discrepancies were then followed up by re-interviewing participants. After triangulation between all sources of data, 48% of respondents had ever used a condom. Condom use in 76% of all cases was at least partly AIDS related, while 19% was exclusively for protection against HIV. Condom use tended to be sporadic: only 13% of condom users currently used a condom regularly and most of this use was for family planning. After triangulation, 45% had reduced the number of sexual partners. Of all partner reductions, 93% was at least partly AIDS related; 29% was exclusively to avoid HIV. Half of those who had reduced the number of partners either stuck to one partner or abstained. Men reported more change than women. Of those who reported no partner reduction, 89% could not reduce the number of partners because they already had only few or a single partner or abstained; most of these were women. Most of those who could change their sexual behaviour had already changed, though the degree of change (particularly condom use) was often minimal. Not only behaviour change, but also the maintenance of safe behaviour is important. Also, understanding reasons for change and extent and consistency of change are important when planning and evaluating interventions.

Background: Cotrimoxazole is recommended for prevention of opportunistic infections in symptomatic HIV patients in sub-Saharan Africa. Methods: We examined the feasibility and effectiveness of daily cotrimoxazole prophylaxis in a well-established cohort of HIV-infected adults attending clinics in Entebbe, Uganda. We compared mortality and morbidity rates for 12 months before and after the introduction of cotrimoxazole. Results: Between August 2000 and February 2002, 94% of cohort members were enrolled onto cotrimoxazole prophylaxis. Revisits were scheduled every 4 weeks to replenish pills; patients attended 61% of revisits. The main reasons for nonenrollment and defaulting were lack of transport, being away from home, and sickness. Drug-related adverse events, mainly itching and rash, were seen in 4% of participants. Although bacterial resistance rate to cotrimoxazole was high, the adjusted mortality incidence rate ratio was significantly reduced after the introduction of cotrimoxazole (0.76; 95% confidence interval, 0.60-0.96; P = 0.020). Overall febrile events and morbidity rates were unchanged after the introduction of cotrimoxazole, but the incidence of malaria was reduced (incidence rate ratio, 0.31; 95% confidence interval, 0.13-0.72). Conclusions: Cotrimoxazole prophylaxis can be introduced into routine HIV clinic activities and is associated with a reduction in overall mortality and malaria morbidity, even in all area with high bacterial resistance. These results reinforce the need for large-scale provision of cotrimoxazole prophylaxis for all HIV-positive patients in developing countries.

BACKGROUND Previous studies have found that in Africa, a greater risk of HIV infection is often found in groups with higher educational attainment. However, some serial cross-sectional studies have found greater reductions in HIV prevalence among more educated groups, especially in cohorts of young adults. More recent studies have found some instances where higher schooling levels are associated with lower HIV prevalence. METHODS We describe changes in the association between schooling levels, HIV prevalence and condom use in a rural population-based cohort between 1989/1990 and 1999/2000, in Masaka District, Uganda. RESULTS In 1989-1990, higher educational attainment was associated with higher risk of HIV-1 infection, especially among males, but once odds ratios are adjusted for age, no significant relation between schooling and HIV infection remains. In 1999-2000, there is, for females aged 18-29 years, a significant relationship between higher educational attainment and lower HIV prevalence, even after adjustment for age, gender, marital status and wealth (P for trend 0.01). Tests for interaction, significant for males and both genders combined, show that more schooling has been shifting towards an association with less HIV infection between 1989-1990 and 1999-2000, especially for young individuals. Condom use increased during the study period and this increase has been concentrated among more educated individuals. CONCLUSIONS These findings suggest that over a decade more educated young adults, especially females, have become more likely to respond to HIV/AIDS information and prevention campaigns by effectively reducing their sexual risk behaviour.

Summary Objectives To investigate the effects of malaria parasitaemia and clinical malaria on mortality in HIV seropositive and seronegative adults. Methods A cohort of adults in rural Uganda were followed from 1990 to 1998. Participants attended routine clinic visits every 3 months and also when sick (interim visits). Information was collected on HIV serostatus, history of fever, current fever and malaria parasite levels. Malaria was categorized as any parasitaemia, significant parasitaemia (≥1.25 × 106 parasites/ml at routine or ≥50 parasites per 200 white blood cells at interim visits) or clinical malaria. The effect of malaria on all-cause mortality was assessed using Cox models. Results The 222 HIV seropositive participants made 2762 routine visits and 1522 interim visits. During follow-up, of the 211 participants with full records, 69% had at least one episode of parasitaemia, 51% experienced significant parasitaemia and 28% had clinical malaria. There were 90 deaths in 922 person-years of observation. There were no significant associations between numbers of visits with any parasitaemia, significant parasitaemia or clinical malaria on mortality rates. The highest mortality rates were observed in those making four or more routine visits with significant parasitaemia [adjusted mortality rate ratio (RR) 3.27 compared with those making 0 such visits; P = 0.078] and those making two or more visits with clinical malaria (adjusted RR 2.23; P = 0.093). There was no significant interaction between any malaria category and HIV serostatus. Conclusion We found no evidence of a strong detrimental effect of malaria on all-cause mortality in HIV seropositive adults in this setting.

BACKGROUND: Studies showing that helminths stimulate type 2 cytokine responses and influence responses to unrelated antigens suggest that helminths may accelerate human immunodeficiency virus type 1 (HIV-1) disease progression in coinfected individuals and that antihelminthic therapy may be beneficial. By the same logic, however, the increase in type 2 cytokines occurring immediately after antischistosomal treatment might increase viral replication and be detrimental. METHODS: To assess the effect of antischistosomal therapy on immune responses and HIV-1 replication, a cohort of 163 Ugandans coinfected with Schistosoma mansoni and HIV-1 was treated with praziquantel. CD4(+) T lymphocyte counts, eosinophil counts, and plasma HIV-1 RNA concentrations were measured before treatment and 1 month and 5 months after treatment. Schistosoma mansoni- and Mycobacterium tuberculosis-specific cytokine responses and serum interleukin (IL)-10 concentrations were analyzed. RESULTS: Transient increases in viral load and sustained decreases in CD4(+) T lymphocyte count were observed, especially in subjects with higher-intensity infections. Despite enhanced posttreatment S. mansoni-specific type 2 responses, no increase in eosinophils or in M. tuberculosis-specific type 2 responses nor any decline in M. tuberculosis-specific interferon (IFN)-gamma responses were seen. A significant decline in circulating IL-10 concentrations was observed. CONCLUSION: Although the mechanisms underlying the increase in viral load after treatment with praziquantel are unclear, these results do not support the hypothesis that treating schistosomiasis is beneficial in the management of HIV-1 disease in Africa.

To monitor the collective national impact of initiatives to expand the availability of HIV therapy including antiretroviral treatment (ART) countries need to monitor the proportion of HIV-infected individuals who are receiving HIV therapy, whether morbidity is decreasing, and HIV-infected individuals are experiencing increased survival, and if there is an overall decrease in the number of individuals dying of HIV. However, in many resource-constrained countries these data are limited or unavailable. Morbidity surveillance relies primarily on AIDS case reporting, but severe under-reporting limits the usefulness of these data. A variety of AIDS case definitions are in use and case definitions do not concur with clinical staging definitions. Harmonizing AIDS case definitions with clinical staging, providing resources and training to improve reporting, and using other surveillance systems, such as tuberculosis programme data to monitor morbidity are urgently needed. A cohort analysis of individuals in ART programmes to follow the progress and outcomes of these patients longitudinally is important to monitor quality of care and impact. Because the rapid scale-up of ART programmes may result in HIV drug resistance, surveillance for drug resistant viruses is also required. Very few resource-constrained countries have well-functioning vital registration systems to assess mortality trends and cause-specific mortality. Alternative approaches to measuring mortality trends, such as sample vital registration with verbal autopsy should be considered. Strong commitments from governments, international organizations and other partners are needed to establish and strengthen the HIV morbidity and mortality monitoring surveillance systems.

Objective: The objective of this study was to investigate the management of sexually transmitted diseases (STDs) in the Ugandan private sector clinics and drug shops. Study: Men with urethral discharge who had consulted clinics (264) or drug shops (141) for treatment in 5 districts were interviewed using a precoded questionnaire 1 to 3 weeks after initiation of treatment. Results: Seventy-seven percent of patients sought treatment within 1 week of onset of symptoms but only 7% were properly managed (treated according to National Guidelines, told to use a condom or abstain, and to refer their partner). The reported cure rate was 47% and only 9% were treated according to National Guidelines. Eighteen percent of patients used condoms during treatment, 36% persuaded their partner to go for treatment, and 87% completed the recommended treatment course. Of patients not reporting cure, 56% would still recommend the treatment to a friend. Conclusion: Quality of STD management by private providers is poor. Improvement should occur concurrently at public and private facilities. Possible strategies include training and social marketing of prepackaged treatment for STDs.

Background. Active tuberculosis may accelerate progression of human immunodeficiency virus (HIV) infection by promoting viral replication in activated lymphocytes. Glucocorticoids are used in pleural tuberculosis to reduce inflammation-induced pathology, and their use also might reduce progression of HIV by suppressing immune activation. We examined the effect that prednisolone has on survival in HIV-1-associated pleural tuberculosis. Methods. We conducted a randomized, double-blind, placebo-controlled trial of prednisolone as an adjunct to tuberculosis treatment, in adults with HIV-1-associated pleural tuberculosis. The primary outcome was death. Analysis was by intention to treat. Results. Of 197 participants, 99 were assigned to the prednisolone group and 98 to the placebo group. The mortality rate was 21 deaths/100 person-years (pyr) in the prednisolone group and 25 deaths/100 pyr in the placebo group (age-, sex-, and initial CD4 + T cell count-adjusted mortality rate ratio, 0.99 [95% confidence interval, 0.62-1.56] [P = .95]). Resolution of tuberculosis was faster in the prednisolone group, but recurrence rates were slightly (though not significantly) higher, and use of prednisolone was associated with a significantly higher incidence of Kaposi sarcoma (4.2 cases/100 pyr, compared with 0 cases/100 pyr [P = .02]). Conclusions. In view of the lack of survival benefit and the increased risk of Kaposi sarcoma, the use of prednisolone in HIV-associated tuberculous pleurisy is not recommended.