Mortality and cancer incidence in UK military veterans involved in human experiments at Porton Down: 48-year follow-up.

BACKGROUND: We investigated whether military personnel involved in chemical warfare agent research at Porton Down had increased rates of mortality or cancer incidence. METHODS: This was a historical cohort study comprising male UK veterans who participated in the 'Service Volunteer Programme', 1941-89, identified from Porton Down experiment books, and a comparison group of similar 'non-Porton Down' veterans identified from military personnel files. Of 19 233 records retrieved for each group, 18 133 (94%) Porton Down and 17 591 (92%) non-Porton Down were included in our analytical sample. Mortality and cancer incidence data were obtained from national registries up to December 2019. RESULTS: Over a median follow-up of 48.1 years, 10 935 Porton Down veterans (60.3%) and 10 658 non-Porton Down veterans (60.6%) had died. After adjustment for age, year of birth and military service characteristics, overall, Porton Down veterans had a 6% higher rate of all-cause mortality compared with non-Porton Down veterans [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 1.03-1.09]. For cause-specific mortality, Porton Down veterans had higher rates of death from genitourinary diseases (HR = 1.34, 95% CI 1.05-1.70) and deaths attributable to alcohol (HR = 1.44, 95% CI 1.07-1.94), with weaker associations observed for deaths from infectious and parasitic diseases (HR = 1.32, 95% CI 0.99-1.78), lung cancer (HR = 1.10, 95% CI 1.01-1.20) and external causes (HR = 1.15, 95% CI 1.00-1.32). Associations with all-cause mortality were stronger for veterans who attended Porton Down between 1960 and 1964 (HR = 1.34, 95% CI 1.19-1.50); likelihood-ratio test, P = 0.006. There was no association between attendance at Porton Down and overall cancer incidence (HR = 1.00, 95% CI 0.95-1.03). CONCLUSIONS: Overall, mortality rates were slightly higher in Porton Down veterans, but there was no difference in cancer incidence. Associations for mortality were stronger in Porton Down veterans who attended in the early 1960s.

Sarin Exposures in A Cohort of British Military Participants in Human Experimental Research at Porton Down 1945-1987.

Background: The effects of exposure to chemical warfare agents in humans are topical. Porton Down is the UK's centre for research on chemical warfare where, since WWI, a programme of experiments involving ~30000 participants drawn from the UK armed services has been undertaken. Objectives: Our aim is to report on exposures to nerve agents, particularly sarin, using detailed exposure data not explored in a previous analysis. Methods: In this paper, we have used existing data on exposures to servicemen who attended the human volunteer programme at Porton Down to examine exposures to nerve agents in general and to sarin in particular. Results: Six principal nerve agents were tested on humans between 1945 and 1987. Of all 4299 nerve agent tests recorded, 3511 (82%) were with sarin, most commonly in an exposure chamber, with inhalation being the commonest exposure route (85%). Biological response to sarin exposure was expressed as percentage change in cholinesterase activity and, less commonly, change in pupil size. For red blood cell cholinesterase, median inhibition for inhalation tests was 41% (interquartile range 28-51%), with a maximum of 87%. For dermal exposures the maximum inhibition recorded was 99%. There was a clear association between increasing exposure to sarin and depression of cholinesterase activity but the strength and direction of the association varied by exposure route and the presence of chemical or physical protection. Pupil size decreased with increased exposure but this relationship was less clear when modifiers, such as atropine drops, were present. Conclusions: These results, drawn from high quality experimental data, offer a unique insight into the effects of these chemical agents on humans.

Seroprevalence of HTLV-1 and HTLV-2 amongst mothers and children in Malawi within the context of a systematic review and meta-analysis of HTLV seroprevalence in Africa.

OBJECTIVES: Human T-lymphotropic virus (HTLV)-1 causes T-cell leukaemia and myelopathy. Together with HTLV-2, it is endemic in some African nations. Seroprevalence data from Malawi are scarce, with no reports on associated disease incidence. HTLV seroprevalence and type were tested in 418 healthy mothers from Malawi. In addition, we tested the sera of 534 children to investigate mother-to-child transmission. To provide context, we conducted a systematic review and meta-analysis of HTLV seroprevalence in African women and children. METHODS: Stored samples from a previous childhood cancer and BBV study were analysed. ELISA was used for HTLV screening followed by immunoblot for confirmation and typing. Standard methods were used for the systematic review. RESULTS: HTLV seroprevalence was 2.6% (11/418) in mothers and 2.2% (12/534) in children. Three mothers carried HTLV-1 alone, seven had HTLV-2 and one was dually infected. Three children carried HTLV-1 alone, seven had HTLV-2 and two were dually infected. Only two corresponding mothers of the 12 HTLV-positive children were HTLV positive. The systematic review included 66 studies of women and 13 of children conducted in 25 African countries. Seroprevalence of HTLV-1 varied from 0 to 17% and of HTLV-2 from 0 to 4%. CONCLUSIONS: In contrast to findings from other studies in Africa, the seroprevalence of HTLV-2 was higher than that of HTLV-1 in Malawi and one of the highest for the African region. The lack of mother-child concordance suggests alternative sources of infection among children. Our data and analyses contribute to HTLV prevalence mapping in Africa.

Prevalence of hepatitis C virus in mothers and their children in Malawi.

OBJECTIVES: Hepatitis C virus (HCV) prevalence is poorly mapped in the East African region; with the advent of novel HCV therapies, better epidemiological data are required to target the infection. We sought to estimate HCV prevalence in healthy Malawian mothers and assess mother-to-child transmission (MTCT); context is provided by reviewing previously published HCV prevalence data from the region. METHODS: Using ELISA screening and confirmatory blot, serological testing of 418 healthy Malawian mothers for HCV was performed. To examine MTCT, the children of any positive women were also tested for HCV; all children had malignant disease unrelated to hepatocellular carcinoma. We compared our results to published literature on HCV prevalence in Malawi and its neighbouring countries. RESULTS: Three of 418 women were HCV reactive by ELISA; two were confirmed positive by immunoblot (0.5%). One child of an HCV-infected mother was HCV seropositive. The literature review revealed HCV prevalence ranging from 0 to 7.2% in the region, being highest in Tanzania and specifically for cohorts of inpatients and HIV-co-infected people. The overall estimated prevalence of HCV in Malawi was 1.0% (95%CI 0.7-1.4) when all studies were included (including this one), but lower in healthy cohorts alone at 0.3% (95%CI 0.1-1.2). CONCLUSIONS: This is the first study using confirmatory tests to examine HCV prevalence in healthy Malawian mothers; the prevalence was low. Future studies need to address the source of infection in healthy women.

Relationship between Plasmodium falciparum malaria prevalence, genetic diversity and endemic Burkitt lymphoma in Malawi.

Endemic Burkitt lymphoma (eBL) has been linked to Plasmodium falciparum (Pf) malaria infection, but the contribution of infection with multiple Pf genotypes is uncertain. We studied 303 eBL (cases) and 274 non eBL-related cancers (controls) in Malawi using a sensitive and specific molecular-barcode array of 24 independently segregating Pf single nucleotide polymorphisms. Cases had a higher Pf malaria prevalence than controls (64.7% versus 45.3%; odds ratio [OR] 2.1, 95% confidence interval (CI): 1.5 to 3.1). Cases and controls were similar in terms of Pf density (4.9 versus 4.5 log copies, p = 0.28) and having ≥3 non-clonal calls (OR 2.7, 95% CI: 0.7-9.9, P = 0.14). However, cases were more likely to have a higher Pf genetic diversity score (153.9 versus 133.1, p = 0.036), which measures a combination of clonal and non-clonal calls, than controls. Further work is needed to evaluate the possible role of Pf genetic diversity in the pathogenesis of endemic BL.

The impact of HIV on maternal morbidity in the Pre-HAART era in Uganda.

OBJECTIVE: To compare maternal morbidity in HIV-infected and uninfected pregnant women. METHODS: Major maternal morbidity (severe febrile illness, illnesses requiring hospital admissions, surgical revisions, or illnesses resulting in death) was measured prospectively in a cohort of HIV-infected and uninfected women followed from 36 weeks of pregnancy to 6 weeks after delivery. Odds ratios of major morbidity and associated factors were examined using logistic regression. RESULTS: Major morbidity was observed in 46/129 (36%) and 104/390 (27%) of the HIV-infected and HIV-uninfected women, respectively, who remained in followup. In the multivariable analysis, major morbidity was independently associated with HIV infection, adjusted odds ratio (AOR) 1.7 (1.1 to 2.7), nulliparity (AOR 2.0 (1.3 to 3.0)), and lack of, or minimal, formal education (AOR 2.1 (1.1 to 3.8)). CONCLUSIONS: HIV was associated with a 70% increase in the odds of major maternal morbidity in these Ugandan mothers.

Immune reconstitution and risk of Kaposi sarcoma and non-Hodgkin lymphoma in HIV-infected adults.

OBJECTIVE: Given the well documented occurrence of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients who recently started combination antiretroviral therapy (cART), we examined whether cART initiation increased the risk of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) using data from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) collaboration. DESIGN: A nested matched case-control study design was used to assess the effects of individual CD4 cell trajectories and exposure to cART close to the time of cancer diagnosis. METHODS: Cases were patients diagnosed with either cancer during follow-up with a minimum of two consecutive CD4 cell readings within the year preceding diagnosis. For each case, up to 10 controls, matched by sex and cohort, were selected by random sampling. Changes in CD4 cell count, calculated by simple and piecewise linear regression, and recent exposure to cART were compared within matched case-control sets using conditional logistic regression. RESULTS: Using data on 689 cases and 4588 controls, we found that an initially low and decreasing CD4 cell count during the year prior to cancer diagnosis is predictive of both Kaposi sarcoma and NHL. Most of this cancer risk is explained by the immunodeficiency characteristic of the period before cART initiation; however, an increased cancer risk was seen in patients who initiated cART in the previous 3 months (odds ratio 2.31; 95% confidence interval 1.33, 4.00). CONCLUSION: Although IRIS may transiently increase the risk of Kaposi sarcoma or NHL in HIV-infected patients, the timely initiation of cART remains the best strategy to avoid the development of these malignancies.

Impact of infection with human immunodeficiency virus-1 (HIV) on the risk of cancer among children in Malawi - preliminary findings.

BACKGROUND: The impact of infection with HIV on the risk of cancer in children is uncertain, particularly for those living in sub-Saharan Africa. In an ongoing study in a paediatric oncology centre in Malawi, children (aged /= 5 years) and sex) using children with other cancers and non-malignant conditions as a comparison group (excluding the known HIV-associated cancers, Kaposi sarcoma and lymphomas, as well as children with other haematological malignancies or with confirmed non-cancer diagnoses). RESULTS: Of the 586 children recruited, 541 (92%) met the inclusion criteria and 525 (97%) were tested for HIV. Overall HIV seroprevalence was 10%. Infection with HIV was associated with Kaposi sarcoma (29 cases; OR = 93.5, 95% CI 26.9 to 324.4) and with non-Burkitt, non-Hodgkin lymphoma (33 cases; OR = 4.4, 95% CI 1.1 to 17.9) but not with Burkitt lymphoma (269 cases; OR = 2.2, 95% CI 0.8 to 6.4). CONCLUSIONS: In this study, only Kaposi sarcoma and non-Burkitt, non-Hodgkin lymphoma were associated with HIV infection. The endemic form of Burkitt lymphoma, which is relatively frequent in Malawi, was not significantly associated with HIV. While the relatively small numbers of children with other cancers, together with possible limitations of diagnostic testing may limit our conclusions, the findings may suggest differences in the pathogenesis of HIV-related malignancies in different parts of the world.

Associations between Burkitt lymphoma among children in Malawi and infection with HIV, EBV and malaria: results from a case-control study.

BACKGROUND: Burkitt lymphoma, a childhood cancer common in parts of sub-Saharan Africa, has been associated with Epstein Barr Virus (EBV) and malaria, but its association with human immunodeficiency virus (HIV) is not clear. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a case-control study of Burkitt lymphoma among children (aged < or = 15 years) admitted to the pediatric oncology unit in Blantyre, Malawi between July 2005 and July 2006. Cases were 148 children diagnosed with Burkitt lymphoma and controls were 104 children admitted with non-malignant conditions or cancers other than hematological malignancies and Kaposi sarcoma. Interviews were conducted and serological samples tested for antibodies against HIV, EBV and malaria. Odds ratios for Burkitt lymphoma were estimated using unconditional logistic regression adjusting for sex, age, and residential district. Cases had a mean age of 7.1 years and 60% were male. Cases were more likely than controls to be HIV positive (Odds ratio (OR)) = 12.4, 95% Confidence Interval (CI) 1.3 to 116.2, p = 0.03). ORs for Burkitt lymphoma increased with increasing antibody titers against EBV (p = 0.001) and malaria (p = 0.01). Among HIV negative participants, cases were thirteen times more likely than controls to have raised levels of both EBV and malaria antibodies (OR = 13.2; 95% CI 3.8 to 46.6; p = 0.001). Reported use of mosquito nets was associated with a lower risk of Burkitt lymphoma (OR = 0.2, 95% CI, 0.03 to 0.9, p = 0.04). CONCLUSIONS: Our findings support prior evidence that EBV and malaria act jointly in the pathogenesis of Burkitt lymphoma, suggesting that malaria prevention may decrease the risk of Burkitt lymphoma. HIV may also play a role in the etiology of this childhood tumor.

Antibodies against malaria and Epstein-Barr virus in childhood Burkitt lymphoma: a case-control study in Uganda.

Burkitt lymphoma, a childhood tumor common in parts of sub-Saharan Africa, has been directly associated with Epstein-Barr virus (EBV) and indirectly with prevalence of malaria. We studied antibodies to both EBV and malaria in children diagnosed with this cancer in Uganda. We performed a case-control study of HIV-seronegative children (

Cancer mortality by occupation among New Zealand women: 1988-1997.

AIM: To examine cancer mortality by occupation among New Zealand women, 1988-1997. METHOD: Proportional mortality ratios (PMRs) were calculated for the six most common general occupations among women: clerical workers, health professionals, teachers, farmers, cleaners and textile workers. Age groups examined were those aged 20-59 and those > or =20 years. Data on occupation was obtained from death certificates. RESULTS: From 1988-1997, annually 12-54% of women had a codeable occupation on their death certificate, leaving 3079 deaths among women 20-59 years, and 7236 in those > or =20 years for analysis. Leukaemia was significantly increased in health professionals aged > or =20 years (PMR=1.52; 95% CI: 1.08-2.09, n=38). In nurses alone, the PMR for leukaemia was 1.42; 95% CI: 0.96-2.01, n=31). CONCLUSION: This study represents the first systematic examination of cancer mortality by occupation among women in New Zealand. These data should be examined routinely as part of regular surveillance of occupational cancer among women. Avenues for further research identified particularly include an analytical study of leukaemia and other cancers among female health professionals.

Symptoms, ill-health and quality of life in a support group of Porton Down veterans.

BACKGROUND: There has been a Human Volunteer Programme at the British chemical weapons research facility at Porton Down since the First World War, in which some of the participants were exposed to chemical warfare agents. AIM: To identify any striking specific morbidity patterns in members of the Porton Down Veterans Support Group (PDVSG). METHODS: A self-completed postal questionnaire was prepared including health immediately after the visits to Porton Down, subsequent diagnoses and hospital admissions, symptoms in, and after, the first 5 years after the visits, fatigue symptoms and current quality of life, measured using the SF-36. RESULTS: Responses were received from 289 of 436 (66%). Results reported here relate to 269 male respondents of mean age 66.8 years. Sixty-six per cent reported their first visit to Porton Down in the 1950s. The most common diagnoses or hospital admissions reported were diseases of the circulatory system. In the first 5 years after their visits the most common symptoms were headache, irritability or outbursts of anger and feeling un-refreshed after sleep. In the later period, most common symptoms were fatigue, feeling un-refreshed after sleep and sleeping difficulties. Sixty-five per cent met the definition for a case of 'fatigue'. Current quality of life dimensions were consistently lower than age-specific estimates from general population samples. CONCLUSIONS: Members of the PDVSG responding to this survey reported poorer quality of life than the general population. Despite there being no clear pattern of specific morbidities, we cannot rule out ill-health being potentially associated with past experience at Porton Down.

The impact of attending a behavioural intervention on HIV incidence in Masaka, Uganda.

OBJECTIVE: Changing behaviour is an important method for preventing HIV infection. We examined why a community randomized trial of a behavioural intervention found no significant effect of this on HIV incidence in rural Uganda. DESIGN: An individual-level analysis of a community randomized trial. METHODS: All sexually active, initially HIV-seronegative individuals with data on sexual behaviour were included (1558 men and 1836 women). Uptake of the intervention was measured using self-reported attendance at meetings, videos, dramas, and interactions with community educators in the past year. Sexual behaviour was assessed using self-reported condom use and the number of sexual partners in the past year. RESULTS: Overall, 81% of individuals in the intervention communities and 9% in the comparison communities reported attending at least one of the intervention activities in the past year. Attendance was lower in women, in those aged 55 years or older, and in the widowed. There was a lower HIV incidence in those who reported attending at least one intervention activity compared with those who attended none, and in women this effect was statistically significant (in women, adjusted rate ratio 0.41, 95% CI 0.19-0.89, P = 0.024; in men, adjusted rate ratio 0.66, 95% CI 0.25-1.79, P = 0.42). Reported behaviour change did not differ markedly between those who did and did not report attending any intervention activities. CONCLUSION: Although the intervention had no significant benefit in the communities as a whole, it resulted in a reduced risk of HIV acquisition in women who attended it. The methodological implications for future trials are discussed.

Mortality from cerebrovascular disease in a cohort of 23 000 patients with insulin-treated diabetes.

BACKGROUND AND PURPOSE: Disease of the cardiovascular system is the main cause of long-term complications and mortality in patients with type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. Cerebrovascular mortality rates have been shown to be raised in patients with type II diabetes but have not previously been reported by age and sex in patients with type I diabetes. METHODS: A cohort of 23 751 patients with insulin-treated diabetes, diagnosed under the age of 30 years from throughout the United Kingdom, was identified during 1972 to 1993 and followed up for mortality until the end of December 2000. Age- and sex-specific mortality rates and standardized mortality ratios (SMRs) were calculated. RESULTS: There were 1437 deaths during the follow-up, 80 due to cerebrovascular disease. Overall, the cerebrovascular mortality rates in the cohort were higher than the corresponding rates in the general population, and the SMRs were 3.1 (95% CI, 2.2 to 4.3) for men and 4.4 (95% CI, 3.1 to 6.0) for women. When stratified by age, the SMRs were highest in the 20- to 39-year age group. After subdivision of cause of death into hemorrhagic and nonhemorrhagic origins, there remained a significant increase in mortality from stroke of nonhemorrhagic origin. CONCLUSIONS: Analyses of mortality from this cohort, essentially one of patients with type I diabetes, has shown for the first time that cerebrovascular mortality is raised at all ages in these patients. Type I diabetes is at least as great a risk factor for cerebrovascular mortality as type II diabetes.

A community randomized controlled trial to investigate impact of improved STD management and behavioural interventions on HIV incidence in rural Masaka, Uganda: trial design, methods and baseline findings.

OBJECTIVE: To describe study design, methods and baseline findings of a behavioural intervention alone and in combination with improved management of sexually transmitted diseases (STDs) aimed at reducing HIV incidence and other STDs. DESIGN: A three-arm community randomized controlled trial (RCT) of 18 rural communities (approximately 96 000 adults) in SW Uganda. A standardized behavioural intervention was implemented in 12 communities (arms A and B) through community-based education, meetings and information leaflets. Six of these communities in addition received improved STD management through government and private health units (arm B). Arm C communities received routine government health services. Impact assessment was through three questionnaire and serological surveys of 750-1000 adults in each community at 18-24-month intervals. The primary outcome measure was HIV incidence and secondary measures were syphilis and herpes simplex virus type 2 incidence, prevalence of Neisseria gonorrhoea and Chlamydia trachomatis and sexual behaviour changes. RESULTS: Approximately 15 000 adults (72% of eligible population) were enrolled at baseline. HIV baseline prevalence rates were 9-10% in all arms and demographic and behavioural characteristics and STD prevalence were also similar. In intervention communities, there were 391 995 attendance at 81 502 activities (6.1 per target adult), 164 063 leaflets distributed (2.6 per person) and 1 586 270 condoms (16.5 condoms per adult). In the STD communities a total of 12 239 STD cases (65% women) were seen over a 5-year period (7.7 per 100 adults/year). CONCLUSION: This is the first community RCT of its type with a behavioural component. There is fair baseline comparability between study arms and process data suggest that interventions were adequately implemented.

Independent effects of reported sexually transmitted infections and sexual behavior on HIV-1 prevalence among adult women, men, and teenagers in rural Uganda.

OBJECTIVE: To assess whether sexually transmitted infections (STIs) and sexual behavior are independently associated with HIV-1 among adult women, men, and teenagers in rural Uganda. DESIGN: Cross-sectional survey. METHODS: All adults (13 years and older) residing in 18 communities were invited to participate. HIV status was determined from serum samples and data collected during confidential interview. Independent effects of risk factors for HIV were estimated using adjusted odds ratios (ORs) with 95% confidence intervals (CIs) from logistic regression. RESULTS: Women reporting genital ulcers in the last 12 months were over twice as likely to be HIV positive after adjustment for sociodemographic factors and number of lifetime sexual partners (OR, 2.5; 95% CI, 1.9-3.4). Equivalent associations were stronger for men (OR, 3.2; 95% CI, 2.2-4.7) but weaker for teenagers (OR, 2.0, 95% CI, 0.5-8.7). Number of lifetime sexual partners was associated ( p <.05) with HIV status for women, men, and teenagers independently of reported genital ulcers. Teenagers reporting casual partners were over four times ( p <.001), and men reporting condom use almost twice ( p <.001), as likely to be HIV positive. Neither history of genital discharge nor other measures of sexual behavior were independently related to HIV status. CONCLUSION: Reported STIs and sexual behavior are independently associated with HIV in rural Uganda. Community-based interventions to reduce HIV should target both and should include teenagers.