Occupational exposure to benzene and mortality risk of lymphohaematopoietic cancers in the Swiss National Cohort.

OBJECTIVES: Previous studies established a causal relationship between occupational benzene exposure and acute myeloid leukemia (AML). However, mixed results have been reported for associations between benzene exposure and other myeloid and lymphoid malignancies. Our work examined whether occupational benzene exposure is associated with increased mortality from overall lymphohaematopoietic (LH) cancer and major subtypes. METHODS: Mortality records were linked to a Swiss census-based cohort from two national censuses in 1990 and 2000. Cases were defined as having any LH cancers registered in death certificates. We assessed occupational exposure by applying a quantitative benzene job-exposure matrix (BEN-JEM) to census-reported occupations. Exposure was calculated as the products of exposure proportions and levels (P × L). Cox proportional hazards models were used to calculate LH cancer death hazard ratios (HR) and 95% confidence intervals (CI) associated with benzene exposure, continuously and in ordinal categories. RESULTS: Our study included approximately 2.97 million persons and 13 415 LH cancer cases, including 3055 cases with benzene exposure. We observed increased mortality risks per unit (P × L) increase in continuous benzene exposure for AML (HR 1.03, 95% CI 1.00-1.06) and diffuse large B-cell lymphoma (HR 1.09, 95% CI 1.04-1.14). When exposure was assessed categorically, increasing trends in risks were observed with increasing benzene exposure for AML (P=0.04), diffuse large B-cell lymphoma (P=0.02), and follicular lymphoma (P=0.05). CONCLUSION: In a national cohort from Switzerland, we found that occupational exposure to benzene is associated with elevated mortality risks for AML, diffuse large B-cell lymphoma, and possibly follicular lymphoma.

Cohort profile: the South African HIV Cancer Match (SAM) Study, a national population-based cohort.

PURPOSE: The South African HIV Cancer Match (SAM) Study is a national cohort of people living with HIV (PLWH). It was created using probabilistic record linkages of routine laboratory records of PLWH retrieved by National Health Laboratory Services (NHLS) and cancer data from the National Cancer Registry. The SAM Study aims to assess the spectrum and risk of cancer in PLWH in the context of the evolving South African HIV epidemic. The SAM Study's overarching goal is to inform cancer prevention and control programmes in PLWH in the era of antiretroviral treatment in South Africa. PARTICIPANTS: PLWH (both adults and children) who accessed HIV care in public sector facilities and had HIV diagnostic or monitoring laboratory tests from NHLS. FINDINGS TO DATE: The SAM cohort currently includes 5 248 648 PLWH for the period 2004 to 2014; 69% of these are women. The median age at cohort entry was 33.0 years (IQR: 26.2-40.9). The overall cancer incidence in males and females was 235.9 (95% CI: 231.5 to 240.5) and 183.7 (181.2-186.2) per 100 000 person-years, respectively.Using data from the SAM Study, we examined national cancer incidence in PLWH and the association of different cancers with immunodeficiency. Cancers with the highest incidence rates were Kaposi sarcoma, cervix, breast, non-Hodgkin's lymphoma and eye cancer. FUTURE PLANS: The SAM Study is a unique, evolving resource for research and surveillance of malignancies in PLWH. The SAM Study will be regularly updated. We plan to enrich the SAM Study through record linkages with other laboratory data within the NHLS (eg, tuberculosis, diabetes and lipid profile data), mortality data and socioeconomic data to facilitate comprehensive epidemiological research of comorbidities among PLWH.

Cohort-based association study of germline genetic variants with acute and chronic health complications of childhood cancer and its treatment: Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study protocol.

INTRODUCTION: Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer. METHODS AND ANALYSIS: The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. DISCUSSION: GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects. ETHICS AND DISSEMINATION: The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online. TRIAL REGISTRATION NUMBER: NCT04702321.

Cancer incidence among people living with HIV in Zimbabwe: A record linkage study.

BACKGROUND: People living with HIV (PLWH) are at increased risk of developing cancer. Cancer diagnoses are often incompletely captured at antiretroviral therapy (ART) clinics. AIM: To estimate the incidence and explore risk factors of cancer in a cohort of PLWH in Harare using probabilistic record linkage (PRL). METHODS: We conducted a retrospective cohort study that included PLWH aged ≥16 years starting ART between 2004 and 2017. We used PRL to match records from the Zimbabwe National Cancer Registry (ZNCR) with electronic medical records from an ART clinic in Harare to investigate the incidence of cancer among PLWH initiating ART. We matched records based on demographic data followed by manual clerical review. We followed PLWH up until first cancer diagnosis, death, loss to follow-up, or 31 December 2017, whichever came first. RESULTS: We included 3442 PLWH (64.9% female) with 19 346 person-years (PY) of follow-up. Median CD4 count at ART initiation was 169 cells/mm3 (interquartile range [IQR]: 82-275), median age was 36.6 years (IQR: 30.6-43.4). There were 66 incident cancer cases for an overall incidence rate of 341/100 000 PY (95% confidence interval [CI]: 268-434). Twenty-two of these cases were recorded in the ZNCR only. The most common cancers were cervical cancer (n = 16; 123/100 000 PY; 95% CI: 75-201), Kaposi sarcoma, and lymphoma (both n = 12; 62/100 000 PY; 95% CI: 35-109). Cancer incidence increased with age and decreased with higher CD4 cell counts at ART initiation. CONCLUSION: PRL was key to correct for cancer under-ascertainment in this cohort. The most common cancers were infection-related types, reinforcing the role of early HIV treatment, human papillomavirus vaccination, and cervical cancer screening for cancer prevention in this setting.

Predictors for participation in DNA self-sampling of childhood cancer survivors in Switzerland.

BACKGROUND: Research on germline genetic variants relies on enough eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits, participants can contribute genetic samples conveniently from their home. Demographic and clinical factors were identified previously that influenced participation in mailed self-collection. People with pre-existing heritable diagnoses might participate differently in germline DNA collection which might render sampling biased in this group. In this nationwide cross-sectional study, we analysed predictive factors of participation in DNA self-collection including heritable diagnoses. METHODS: We identified childhood cancer survivors from the Swiss Childhood Cancer Registry for invitation to germline DNA self-sampling in September 2019. Participants received saliva sampling kits by postal mail at their home, were asked to fill them, sign an informed consent, and send them back by mail. Two reminders were sent to non-participants by mail. We compared demographic, clinical, and treatment information of participants with non-participants using univariable and multivariable logistic regression models. RESULTS: We invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 19-37), of which 463 (50%) participated. After the initial send out of the sampling kit, 291 (63%) had participated, while reminder letters led to 172 additional participants (37%). Foreign nationality (odds ratio [OR] 0.5; 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5; CI 0.4-0.8), and survivors with a known cancer predisposition syndrome (OR 0.5; CI 0.3-1.0) were less likely to participate in germline DNA collection. Survivors with a second primary neoplasm (OR 1.9; CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3; CI 1.0-1.8) tended to participate more. CONCLUSIONS: We showed that half of childhood cancer survivors participated in germline DNA self-sampling relying completely on mailing of sample kits. Written reminders increased the response by about one third. More targeted recruitment strategies may be advocated for people of foreign nationality, aged 30-39 years, and those with cancer predisposition syndromes. Perceptions of genetic research and potential barriers to participation of survivors need to be better understood. TRIAL REGISTRATION: Biobank: https://directory.bbmri-eric.eu/#/collection/bbmri-eric:ID:CH_HopitauxUniversitairesGeneve:collection:CH_BaHOP Research project : Clinicaltrials.gov: NCT04702321 .

Cancer in HIV-positive and HIV-negative adolescents and young adults in South Africa: a cross-sectional study.

OBJECTIVE: To determine the spectrum of cancers in adolescents and young adults (AYAs) living with and without HIV in South Africa. DESIGN: Cross-sectional study with cancer records provided by the National Cancer Registry (NCR) and HIV records from the National Health Laboratory Service (NHLS). SETTING AND PARTICIPANTS: The NHLS is the largest provider of pathology services in the South African public sector. The NCR is a division of the NHLS. We included AYAs (aged 10-24 years) diagnosed with cancer by public health sector laboratories between 2004 and 2014 (n=8479). HIV status was obtained through record linkages and text mining. PRIMARY AND SECONDARY OUTCOMES: We determined the spectrum of cancers by HIV status in AYAs. We used multivariable logistic regression to describe the association of cancer in AYAs with HIV, adjusting for age, sex, ethnicity and calendar period. We imputed (post hoc) the HIV status for AYA with unknown HIV status. RESULTS: 8479 AYAs were diagnosed with cancer, HIV status was known for 45% (n=3812). Of those whose status was known, about half were HIV positive (n=1853). AYAs living with HIV were more likely to have Kaposi's sarcoma (adjusted OR (aOR) 218, 95% CI 89.9 to 530), cervical cancer (aOR 2.18, 95% CI 1.23 to 3.89), non-Hodgkin's lymphoma (aOR 2.12, 95% CI 1.69 to 2.66) and anogenital cancers other than cervix (aOR 2.73, 95% CI 1.27 to 5.86) than AYAs without HIV. About 44% (n=1062) of AYAs with HIV-related cancers had not been tested for HIV. CONCLUSIONS: Targeted HIV testing for AYAs diagnosed with cancer, followed by immediate start of antiretroviral therapy, screening for cervical precancer and vaccination against human papilloma virus is needed to decrease cancer burden in AYAs living with HIV in South Africa.

Data linkage to evaluate the long-term risk of HIV infection in individuals seeking post-exposure prophylaxis.

Evidence on the long-term risk of HIV infection in individuals taking HIV post-exposure prophylaxis remains limited. In this retrospective data linkage study, we evaluate the occurrence of HIV infection in 975 individuals who sought post-exposure prophylaxis in a tertiary hospital between 2007 and 2013. Using privacy preserving probabilistic linkage, we link these 975 records with two observational databases providing data on HIV events (Zurich Primary HIV Infection study and the Swiss HIV Cohort Study). This enables us to identify 22 HIV infections and to obtain long-term follow-up data, which reveal a median of 4.1 years between consultation for post-exposure prophylaxis and HIV diagnosis. Even though men who have sex with men constitute only 35.8% of those seeking post-exposure prophylaxis, all 22 events occur in this subgroup. These findings should strongly encourage early consideration of pre-exposure prophylaxis in men who have sex with men after a first episode of post-exposure prophylaxis.

The burden of cancers associated with HIV in the South African public health sector, 2004-2014: a record linkage study.

INTRODUCTION: The impact of South Africa's high human immunodeficiency virus (HIV) burden on cancer risk is not fully understood, particularly in the context of antiretroviral treatment (ART) availability. We examined national cancer trends and excess cancer risk in people living with HIV (PLHIV) compared to those who are HIV-negative. METHODS: We used probabilistic record linkage to match cancer records provided by the National Cancer Registry to HIV data provided by the National Health Laboratory Service (NHLS). We also used text search of specific HIV terms from the clinical section of pathology reports to determine HIV status of cancer patients. We used logistic and Joinpoint regression models to evaluate the risk and trends in cancers in PLHIV compared to HIV-negative patients from 2004 to 2014. In sensitivity analysis, we used inverse probability weighting (IPW) to correct for possible selection bias. RESULTS: A total of 329,208 cancer cases from public sector laboratories were reported to the NCR from 2004 to 2014 with the HIV status known for 95,279 (28.9%) cancer cases. About 50% of all the female cancer cases (n = 30,486) with a known status were HIV-positive. PLHIV were at higher risk of AIDS-defining cancers (Kaposi sarcoma [adjusted OR:134, 95% CI:111-162], non-Hodgkin lymphoma [adjusted OR:2.73, 95% CI:2.56-2.91] and, cervix [adjusted OR:1.70, 95% CI:1.63-1.77], conjunctival cancer [adjusted OR:21.5, 95% CI:16.3-28.4] and human papilloma virus (HPV) related cancers (including; penis [adjusted OR:2.35, 95% CI:1.85-2.99], and vulva [adjusted OR:1.94, 95% CI:1.67-2.25]) compared to HIV-negative patients. Analysis using the IPW population yielded comparable results. CONCLUSION: There is need for improved awareness and screening of conjunctival cancer and HPV-associated cancers at HIV care centres. Further research and discussion is warranted on inclusive HPV vaccination in PLHIV.

Data management of clinical trials during an outbreak of Ebola virus disease.

INTRODUCTION: Clinical trial data management (DM) conducted during outbreaks like that of Ebola virus disease (EVD) in West Africa, 2014-2016, has to adapt to specific, unique circumstances. CTU Bern was asked to set up a safe data capture/management system that could be launched within a few weeks and cover two different vaccine trials. This article describes some of the challenges we faced and our solutions during the two different trials. METHODS: Setting up a DM system was split into four phases/tasks: (1) quick set-up of the (electronic) data capture system (EDC) and mobile infrastructure in Bern, (2) moving the EDC and infrastructure to Conakry, Guinea and implementation of a local data management centre (DMC), (3) running the DMC, and (4) data cleaning. The DMC had to meet the following criteria: (1) quick implementation, (2) efficient maintenance and handling of data, and (3) procedures to guarantee data quality. The EDC (REDCap) was setup as a local area network. In order to ensure high data quality, double data entry, and then review of inconsistencies and offline plausibility checks were implemented. RESULTS: From the start of CTU Bern's involvement to the productive EDC took 11 weeks. It was necessary to adapt processes for dealing with data continuously throughout the trial conduct phase. The data management team processed 171,794 case report form pages from a total of 14,203 participants in the period between March and December 2015. CONCLUSION: Data management is a key task supporting trial conduct. For trials in emergency situations, many of our approaches are suitable, but we also provide a list of aspects that might be done differently.

High Cancer Burden Among Antiretroviral Therapy Users in Malawi: A Record Linkage Study of Observational Human Immunodeficiency Virus Cohorts and Cancer Registry Data.

BACKGROUND: With antiretroviral therapy (ART), AIDS-defining cancer incidence has declined and non-AIDS-defining cancers (NADCs) are now more frequent among human immunodeficiency virus (HIV)-infected populations in high-income countries. In sub-Saharan Africa, limited epidemiological data describe cancer burden among ART users. METHODS: We used probabilistic algorithms to link cases from the population-based cancer registry with electronic medical records supporting ART delivery in Malawi's 2 largest HIV cohorts from 2000-2010. Age-adjusted cancer incidence rates (IRs) and 95% confidence intervals were estimated by cancer site, early vs late incidence periods (4-24 and >24 months after ART start), and World Health Organization (WHO) stage among naive ART initiators enrolled for at least 90 days. RESULTS: We identified 4346 cancers among 28 576 persons. Most people initiated ART at advanced WHO stages 3 or 4 (60%); 12% of patients had prevalent malignancies at ART initiation, which were predominantly AIDS-defining eligibility criteria for initiating ART. Kaposi sarcoma (KS) had the highest IR (634.7 per 100 000 person-years) followed by cervical cancer (36.6). KS incidence was highest during the early period 4-24 months after ART initiation. NADCs accounted for 6% of new cancers. CONCLUSIONS: Under historical ART guidelines, NADCs were observed at low rates and were eclipsed by high KS and cervical cancer burden. Cancer burden among Malawian ART users does not yet mirror that in high-income countries. Integrated cancer screening and management in HIV clinics, especially for KS and cervical cancer, remain important priorities in the current Malawi context.

Weight gain of HIV-exposed, uninfected children born before and after introduction of the 'Option B+' programme in Malawi.

OBJECTIVE: To compare birth weight and weight gain in HIV-exposed, uninfected (HEU) infants up to 24 months old, who enrolled in the Malawian national HIV care clinic (HCC) programme either before or after Option B+ (OB+) was implemented. DESIGN, SETTING AND PARTICIPANTS: HIV-exposed infants enrol in the HCC programme as soon as possible after birth and are followed up to at least 24 months old. This analysis includes HEU infants with recorded birth weight, date of birth, gender and at least one follow-up weight measurement from 21 health facilities in central and southern Malawi (January 2010-December 2014). Weight-for-age z scores (WAZ) were derived and compared by birth period using linear regression at birth and mixed effects models for postnatal weight gain up to 24 months old. RESULTS: Of 6845 HEU infants included in this study, 88.5% were born after OB+. The proportion of infants exposed in utero to combination antiretroviral therapy (ART) significantly increased after OB+ was implemented, and infants were exposed to ART for a longer time. There was no significant difference in WAZ at birth (P = 0.654) among HEU infants by birth period, but postnatal weight gain was faster among HEU infants born in the Option B+ period than infants born pre-Option B+. CONCLUSION: Birth weight was not affected by longer exposure to ART during pregnancy after OB+ was introduced, when weight gain in HEU infants was faster, possibly because their mothers were in better health.

Occupational extremely low frequency magnetic fields (ELF-MF) exposure and hematolymphopoietic cancers - Swiss National Cohort analysis and updated meta-analysis.

PURPOSE: Previous studies have examined risks of leukaemia and selected lymphoid malignancies in workers exposed to extremely low frequency magnetic fields (ELF-MF). Most studies evaluated hematolymphopoietic malignancies as a combined category, but some analyses suggested that effects may be contained to some specific leukaemia or lymphoma subtypes, with inconsistent results. METHODS: We examined exposure to ELF-MF and mortality 1990-2008 from different types of hematolymphopoietic cancers in the Swiss National Cohort, using a job exposure matrix for occupations recorded at censuses 1990 and 2000. We analysed 3.1 million workers exposed at different levels to ELF-MF: ever-high, only-medium, only-low exposure using Cox proportional hazard models. We evaluated risk of death from acute myeloid leukaemia (AML), chronic myeloid leukaemia, lymphoid leukaemia, diffuse large B-cell lymphomas, follicular lymphoma, Waldenström's macroglobulinemia, multiple myeloma and Hodgkin lymphoma. RESULTS: Mortality from hematolymphopoietic cancers was not associated with exposure to ELF-MF with the exception of an increase in ever-high exposed men of myeloid leukaemias (HR 1.31, 95% CI 1.02-1.67), and AML (HR 1.26, 95%CI 0.93-1.70). If workers had been high exposed during their vocational training and at both censuses, these HR increased to 2.24 (95%CI 0.91-5.53) and 2.75 (95%CI 1.11-6.83), respectively. CONCLUSIONS: Our analysis provided no convincing evidence for an increased risk of death from a range of hematolymphopoietic cancers in workers exposed to high or medium levels of ELF magnetic fields. However, we observed an increased risk of acute myeloid leukaemia in workers exposed to high levels for a longer duration. Observed risks are in line with meta-analysed previous reports on ELF-MF exposure and AML risk, with a summary relative risk of 1.21 (95%CI 1.08-1.37).

HIV-1 Drug Resistance and Third-Line Therapy Outcomes in Patients Failing Second-Line Therapy in Zimbabwe.

OBJECTIVES: To analyze the patterns and risk factors of HIV drug resistance mutations among patients failing second-line treatment and to describe early treatment responses to recommended third-line antiretroviral therapy (ART) in a national referral HIV clinic in Zimbabwe. METHODS: Patients on boosted protease inhibitor (PI) regimens for more than 6 months with treatment failure confirmed by 2 viral load (VL) tests >1000 copies/mL were genotyped, and susceptibility to available antiretroviral drugs was estimated by the Stanford HIVdb program. Risk factors for major PI resistance were assessed by logistic regression. Third-line treatment was provided as Darunavir/r, Raltegravir, or Dolutegravir and Zidovudine, Abacavir Lamivudine, or Tenofovir. RESULTS: Genotypes were performed on 86 patients who had good adherence to treatment. The median duration of first- and second-line ART was 3.8 years (interquartile range [IQR], 2.3-5.1) and 2.6 years (IQR, 1.6-4.9), respectively. The median HIV viral load and CD4 cell count were 65 210 copies/mL (IQR, 8728-208 920 copies/mL) and 201 cells/mm3 (IQR, 49-333 cells/mm3). Major PI resistance-associated mutations (RAMs) were demonstrated in 44 (51%) non-nucleoside reverse transcriptase inhibitor RAMs in 72 patients (83%) and nucleoside reverse transcriptase inhibitors RAMs in 62 patients (72%). PI resistance was associated with age >24 years (P = .003) and CD4 cell count <200 cells/mm3 (P = .007). In multivariable analysis, only age >24 years was significantly associated (adjusted odds ratio, 4.75; 95% confidence interval, 1.69-13.38; P = .003) with major PI mutations. Third-line DRV/r- and InSTI-based therapy achieved virologic suppression in 29/36 patients (81%) after 6 months. CONCLUSIONS: The prevelance of PI mutations was high. Adolescents and young adults had a lower risk of acquiring major PI resistance mutations, possibly due to poor adherence to ART. Third-line treatment with a regimen of Darunavir/r, Raltegravir/Dolutegravir, and optimized nucleoside reverse transcriptase inhibitors was effective.

HIV transmission and retention in care among HIV-exposed children enrolled in Malawi's prevention of mother-to-child transmission programme.

INTRODUCTION: In Malawi, HIV-infected pregnant and breastfeeding women are offered lifelong antiretroviral therapy (ART) regardless of CD4 count or clinical stage (Option B+). Their HIV-exposed children are enrolled in the national prevention of mother-to-child transmission (PMTCT) programme, but many are lost to follow-up. We estimated the cumulative incidence of vertical HIV transmission, taking loss to follow-up into account. METHODS: We abstracted data from HIV-exposed children enrolled into care between September 2011 and June 2014 from patient records at 21 health facilities in central and southern Malawi. We used competing risk models to estimate the probability of loss to follow-up, death, ART initiation and discharge, and used pooled logistic regression and inverse probability of censoring weighting to estimate the vertical HIV transmission risk. RESULTS: A total of 11,285 children were included; 9285 (82%) were born to women who initiated ART during pregnancy. At age 30 months, an estimated 57.9% (95% CI 56.6-59.2) of children were lost to follow-up, 0.8% (0.6-1.0) had died, 2.6% (2.3-3.0) initiated ART, 36.5% (35.2-37.9) were discharged HIV-negative and 2.2% (1.5-2.8) continued follow-up. We estimated that 5.3% (95% CI 4.7-5.9) of the children who enrolled were HIV-infected by the age of 30 months, but only about half of these children (2.6%; 95% CI 2.3-2.9) were diagnosed. CONCLUSIONS: Confirmed mother-to-child transmission rates were low, but due to poor retention only about half of HIV-infected children were diagnosed. Tracing of children lost to follow-up and HIV testing in outpatient clinics should be scaled up to ensure that all HIV-positive children have access to early ART.

Parental occupational exposure to benzene and the risk of childhood cancer: A census-based cohort study.

BACKGROUND: Previous studies on occupational exposures in parents and cancer risks in their children support a link between solvents and paints with childhood leukaemia. Few studies have focused specifically on benzene. OBJECTIVES: To examine whether parental occupational exposure to benzene is associated with an increased cancer risk in a census-based cohort of children. METHODS: From a census-based cohort study in Switzerland, we included children aged <16years at national censuses (1990, 2000). We retrieved parental occupations reported at census and assessed exposure to benzene using a job exposure matrix. We identified incident cancer cases through record linkage with the Swiss Childhood Cancer Registry. We fitted Cox proportional-hazards models to assess associations between exposures and the following outcomes: any cancer, leukaemia, acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), lymphoma, non-Hodgkin lymphoma, central nervous system (CNS) tumours, and glioma. We adjusted models for a range of socio-economic, perinatal and environmental factors. RESULTS: Analyses of maternal (paternal) exposure were based on 9.0 (13.2)millionperson years at risk and included 1004 (1520) cases of cancer, of which 285 (438) had leukaemia, 186 (281) lymphoma, 227 (339) a CNS tumour. Maternal exposure was associated with an increased risk of childhood leukaemia (hazard ratio 1.73, 95% CI 1.12-2.67) and ALL (1.88, 1.16-3.04). We found little evidence of an association for other outcomes or for paternal exposure. Adjusting for potential confounders did not materially affect the results. CONCLUSIONS: This nationwide cohort study suggests an increased risk of leukaemia among children whose mothers were exposed to benzene at work.

On the plausibility of socioeconomic mortality estimates derived from linked data: a demographic approach.

BACKGROUND: Reliable estimates of mortality according to socioeconomic status play a crucial role in informing the policy debate about social inequality, social cohesion, and exclusion as well as about the reform of pension systems. Linked mortality data have become a gold standard for monitoring socioeconomic differentials in survival. Several approaches have been proposed to assess the quality of the linkage, in order to avoid the misclassification of deaths according to socioeconomic status. However, the plausibility of mortality estimates has never been scrutinized from a demographic perspective, and the potential problems with the quality of the data on the at-risk populations have been overlooked. METHODS: Using indirect demographic estimation (i.e., the synthetic extinct generation method), we analyze the plausibility of old-age mortality estimates according to educational attainment in four European data contexts with different quality issues: deterministic and probabilistic linkage of deaths, as well as differences in the methodology of the collection of educational data. We evaluate whether the at-risk population according to educational attainment is misclassified and/or misestimated, correct these biases, and estimate the education-specific linkage rates of deaths. RESULTS: The results confirm a good linkage of death records within different educational strata, even when probabilistic matching is used. The main biases in mortality estimates concern the classification and estimation of the person-years of exposure according to educational attainment. Changes in the census questions about educational attainment led to inconsistent information over time, which misclassified the at-risk population. Sample censuses also misestimated the at-risk populations according to educational attainment. CONCLUSION: The synthetic extinct generation method can be recommended for quality assessments of linked data because it is capable not only of quantifying linkage precision, but also of tracking problems in the population data. Rather than focusing only on the quality of the linkage, more attention should be directed towards the quality of the self-reported socioeconomic status at censuses, as well as towards the accurate estimation of the at-risk populations.

Bioimpedance-Derived Phase Angle and Mortality Among Older People.

BACKGROUND: Phase angle measured by bioelectrical impedance analysis (BIA) may be a marker of health state. OBJECTIVE: This historical cohort study of prospectively collected BIA measurements aims to investigate the link between phase angle and mortality in older people and evaluate whether a phase angle cutoff can be defined. DESIGN: We included all adults aged ≥65 years who underwent a BIA measurement by the Nutriguard® device at the Geneva University Hospitals. We retrieved retrospectively the phase angle and comorbidities at the last BIA measurement and mortality until December 2012. We calculated phase angle standardized for sex, age, and body mass index (BMI), using reference values determined with the same brand of BIA device. Sex-specific and standardized phase angle were categorized into quartiles. The association of mortality with sex-specific or standardized phase angle was evaluated through univariate and multivariate Cox regression models, Kaplan-Meier curves, and receiver operating characteristic (ROC) curves. RESULTS: We included 1307 (38% women) participants, among whom 628 (44% women) died. In a multivariate Cox regression model adjusted for comorbidities and setting of measurement (ambulatory vs. hospitalized), the protective effect against mortality increased progressively as the standardized phase angle quartile increased (HR 0.71 [95% CI 0.58, 0.86], 0.53 [95% CI 0.42, 0.67], and 0.32 [95% CI 0.23, 0.43]). The discriminative value of continuous standardized phase angle, assessed as the area under the ROC curve, was 0.72 (95%CI 0.70, 0.75). We could not define an acceptable phase angle cutoff for individual prediction of mortality (LK), based on sensibility and specificity values. CONCLUSIONS: This study shows the association of phase angle and mortality in older patients, independent of age, sex, comorbidities, BMI categories, and setting of measurement.

Adherence to Antiretroviral Therapy During and After Pregnancy: Cohort Study on Women Receiving Care in Malawi's Option B+ Program.

BACKGROUND: Adherence to antiretroviral therapy (ART) is crucial to preventing mother-to-child transmission of human immunodeficiency virus (HIV) and ensuring the long-term effectiveness of ART, yet data are sparse from African routine care programs on maternal adherence to triple ART. METHODS: We analyzed data from women who started ART at 13 large health facilities in Malawi between September 2011 and October 2013. We defined adherence as the percentage of days "covered" by pharmacy claims. Adherence of ≥90% was deemed adequate. We calculated inverse probability of censoring weights to adjust adherence estimates for informative censoring. We used descriptive statistics, survival analysis, and pooled logistic regression to compare adherence between pregnant and breastfeeding women eligible for ART under Option B+, and nonpregnant and nonbreastfeeding women who started ART with low CD4 cell counts or World Health Organization clinical stage 3/4 disease. RESULTS: Adherence was adequate for 73% of the women during pregnancy, for 66% in the first 3 months post partum, and for about 75% during months 4-21 post partum. About 70% of women who started ART during pregnancy and breastfeeding adhered adequately during the first 2 years of ART, but only about 30% of them had maintained adequate adherence at every visit. Risk factors for inadequate adherence included starting ART with an Option B+ indication, at a younger age, or at a district hospital or health center. CONCLUSIONS: One-third of women retained in the Option B+ program adhered inadequately during pregnancy and breastfeeding, especially soon after delivery. Effective interventions to improve adherence among women in this program should be implemented.

Retention in care during the first 3 years of antiretroviral therapy for women in Malawi's option B+ programme: an observational cohort study.

BACKGROUND: Studies of Malawi's option B+ programme for HIV-positive pregnant and breastfeeding women have reported high loss to follow-up during pregnancy and at the start of antiretroviral therapy (ART), but few data exist about retention during breastfeeding and after weaning. We examined loss to follow-up and retention in care in patients in the option B+ programme during their first 3 years on ART. METHODS: We analysed two data sources: aggregated facility-level data about patients in option B+ who started ART between Oct 1, 2011, and June 30, 2012, at 546 health facilities; and patient-level data from 20 large facilities with electronic medical record system for HIV-positive women who started ART between Sept 1, 2011, and Dec 31, 2013, under option B+ or because they had WHO clinical stages 3 or 4 disease or had CD4 counts of less than 350 cells per µL. We used facility-level data to calculate representative estimates of retention and loss to follow-up. We used patient-level data to study temporal trends in retention, timing of loss to follow-up, and predictors of no follow-up and loss to follow-up. We defined patients who were more than 60 days late for their first follow-up visit as having no follow-up and patients who were more than 60 days late for a subsequent visit as being lost to follow-up. We calculated proportions and cumulative probabilities of patients who had died, stopped ART, had no follow-up, were lost to follow-up, or were retained alive on ART for 36 months. We calculated odds ratios and hazard ratios to examine predictors of no follow-up and loss to follow-up. FINDINGS: Analysis of facility-level data about patients in option B+ who had not transferred to a different facility showed retention in care to be 76·8% (20 475 of 26,658 patients) after 12 months, 70·8% (18,306 of 25,849 patients) after 24 months, and 69·7% (17,787 of 25,535 patients) after 36 months. Patient-level data included 29,145 patients. 14,630 (50·2%) began treatment under option B+. Patients in option B+ had a higher risk of having no follow-up and, for the first 2 years of ART, higher risk of loss to follow-up than did patients who started ART because they had CD4 counts less than 350 cells per µL or WHO clinical stage 3 or 4 disease. Risk of loss to follow-up during the third year was low and similar for patients retained for 2 years. Retention rates did not change as the option B+ programme matured. INTERPRETATION: Our data suggest that pregnant and breastfeeding women who start ART immediately after they are diagnosed with HIV can be retained on ART through the option B+ programme, even after many have stopped breastfeeding. Interventions might be needed to improve retention in the first year on ART in option B+. FUNDING: Bill & Melinda Gates Foundation, Partnerships for Enhanced Engagement in Research Health, and National Institute of Allergy and Infectious Diseases.