Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma.

We analysed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (+/-R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (+/-R) followed by ASCT in CR1/PR1 and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P = 0.006). Patients in the CHOP (+/-R) group had a higher risk of failure for PFS compared with patients in the HyperCVAD (+/-R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P = 0.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (+/-R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1

HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa

Background: Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART. Methods and Findings: Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results. Conclusions: Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact

Sexual Behaviors and HIV Status: A Population-Based Study Among Older Adults in Rural South Africa

Objective: To identify the unmet needs for HIV prevention among older adults in rural South Africa. Methods: We analyzed data from a population-based sample of 5059 men and women aged 40 years and older from the study Health and Aging in Africa: Longitudinal Studies of INDEPTH Communities (HAALSI), which was carried out in the Agincourt health and sociodemographic surveillance system in the Mpumalanga province of South Africa. We estimated the prevalence of HIV (laboratory-confirmed and self-reported) and key sexual behaviors by age and sex. We compared sexual behavior profiles across HIV status categories with and without age–sex standardization. Results: HIV prevalence was very high among HAALSI participants (23%, 95% confidence interval [CI]: 21 to 24), with no sex differences. Recent sexual activity was common (56%, 95% CI: 55 to 58) across all HIV status categories. Condom use was low among HIV-negative adults (15%, 95% CI: 14 to 17), higher among HIV-positive adults who were unaware of their HIV status (27%, 95% CI: 22 to 33), and dramatically higher among HIV-positive adults who were aware of their status (75%, 95% CI: 70 to 80). Casual sex and multiple partnerships were reported at moderate levels, with slightly higher estimates among HIV-positive compared to HIV-negative adults. Differences by HIV status remained after age–sex standardization. Conclusions: Older HIV-positive adults in an HIV hyperendemic community of rural South Africa report sexual behaviors consistent with high HIV transmission risk. Older HIV-negative adults report sexual behaviors consistent with high HIV acquisition risk. Prevention initiatives tailored to the particular prevention needs of older adults are urgently needed to reduce HIV risk in this and similar communities in sub-Saharan Africa.The HAALSI study was funded by the NIA of the NIH (P01 AG041710). HAALSI is nested within the Agincourt Health and Socio-Demographic Surveillance System, with funding from Wellcome Trust (058893/Z/99/A; 069683/Z/02/Z; 085477/Z/08/Z; 085477/B/08/Z), University of the Witwatersrand, and Medical Research Council, South Africa. T.W.B. received funding from the Wellcome Trust and NICHD of NIH (R01-HD084233) and NIAID of NIH (R01-AI124389 and R01-AI112339)

Performance of self-reported HIV status in determining true HIV status among older adults in rural South Africa: a validation study

Introduction: In South Africa, older adults make up a growing proportion of people living with HIV. HIV programmes are likely to reach older South Africans in home-based interventions where testing is not always feasible. We evaluate the accuracy of self-reported HIV status, which may provide useful information for targeting interventions or offer an alternative to biomarker testing. Methods: Data were taken from the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI) baseline survey, which was conducted in rural Mpumalanga province, South Africa. A total of 5059 participants aged ≥40 years were interviewed from 2014 to 2015. Self-reported HIV status and dried bloodspots for HIV biomarker testing were obtained during at-home interviews. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for self-reported status compared to “gold standard” biomarker results. Log-binomial regression explored associations between demographic characteristics, antiretroviral therapy (ART) status and sensitivity of self-report. Results: Most participants (93%) consented to biomarker testing. Of those with biomarker results, 50.9% reported knowing their HIV status and accurately reported it. PPV of self-report was 94.1% (95% confidence interval (CI): 92.0–96.0), NPV was 87.2% (95% CI: 86.2–88.2), sensitivity was 51.2% (95% CI: 48.2–54.3) and specificity was 99.0% (95% CI: 98.7–99.4). Participants on ART were more likely to report their HIV-positive status, and participants reporting false-negatives were more likely to have older HIV tests. Conclusions: The majority of participants were willing to share their HIV status. False-negative reports were largely explained by lack of testing, suggesting HIV stigma is retreating in this setting, and that expansion of HIV testing and retesting is still needed in this population. In HIV interventions where testing is not possible, self-reported status should be considered as a routine first step to establish HIV status.This study was funded by the National Institute on Aging (NIA) of the National Institutes of Health (NIH) [P01-AG041710] and is nested within the MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt) and funded by Wellcome Trust [058893/Z/99/A; 069683/Z/02/Z; 085477/Z/08/Z; 085477/B/08/Z] with important contributions from the University of the Witwatersrand and the South African Medical Research Council. Till Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. He is also supported by the Wellcome Trust, the European Commission, the Clinton Health Access Initiative and NICHD of NIH [R01-HD084233], NIAID of NIH [R01-AI124389 and R01-AI112339] and FIC of NIH [D43-TW009775]

Sexual Behaviors and HIV Status: A Population-Based Study Among Older Adults in Rural South Africa

Objective: To identify the unmet needs for HIV prevention among older adults in rural South Africa. Methods: We analyzed data from a population-based sample of 5059 men and women aged 40 years and older from the study Health and Aging in Africa: Longitudinal Studies of INDEPTH Communities (HAALSI), which was carried out in the Agincourt health and sociodemographic surveillance system in the Mpumalanga province of South Africa. We estimated the prevalence of HIV (laboratory-confirmed and self-reported) and key sexual behaviors by age and sex. We compared sexual behavior profiles across HIV status categories with and without age–sex standardization. Results: HIV prevalence was very high among HAALSI participants (23%, 95% confidence interval [CI]: 21 to 24), with no sex differences. Recent sexual activity was common (56%, 95% CI: 55 to 58) across all HIV status categories. Condom use was low among HIV-negative adults (15%, 95% CI: 14 to 17), higher among HIV-positive adults who were unaware of their HIV status (27%, 95% CI: 22 to 33), and dramatically higher among HIV-positive adults who were aware of their status (75%, 95% CI: 70 to 80). Casual sex and multiple partnerships were reported at moderate levels, with slightly higher estimates among HIV-positive compared to HIV-negative adults. Differences by HIV status remained after age–sex standardization. Conclusions: Older HIV-positive adults in an HIV hyperendemic community of rural South Africa report sexual behaviors consistent with high HIV transmission risk. Older HIV-negative adults report sexual behaviors consistent with high HIV acquisition risk. Prevention initiatives tailored to the particular prevention needs of older adults are urgently needed to reduce HIV risk in this and similar communities in sub-Saharan Africa

Characterization of Irradiated Metal Waste from the Pyrometallurgical Treatment of Used EBR-II Fuel

As part of the pyrometallurgical treatment of used Experimental Breeder Reactor-II fuel, a metal waste stream is generated consisting primarily of cladding hulls laden with fission products noble to the electrorefining process. Consolidation by melting at high temperature [1873 K (1600 degrees C)] has been developed to sequester the noble metal fission products (Zr, Mo, Tc, Ru, Rh, Te, and Pd) which remain in the iron-based cladding hulls. Zirconium from the uranium fuel alloy (U-10Zr) is also deposited on the hulls and forms Fe-Zr intermetallics which incorporate the noble metals as well as residual actinides during processing. Hence, Zr has been chosen as the primary indicator for consistency of the metal waste. Recently, the first production-scale metal waste ingot was generated and sampled to monitor Zr content for Fe-Zr intermetallic phase formation and validation of processing conditions. Chemical assay of the metal waste ingot revealed a homogeneous distribution of the noble metal fission products as well as the primary fuel constituents U and Zr. Microstructural characterization of the ingot confirmed the immobilization of the noble metals in the Fe-Zr intermetallic phase

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe

Estimating global injuries morbidity and mortality : methods and data used in the Global Burden of Disease 2017 study

Background: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods: In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results: GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions: GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future

Subnational mapping of HIV incidence and mortality among individuals aged 15–49 years in sub-Saharan Africa, 2000–18 : a modelling study

Background: High-resolution estimates of HIV burden across space and time provide an important tool for tracking and monitoring the progress of prevention and control efforts and assist with improving the precision and efficiency of targeting efforts. We aimed to assess HIV incidence and HIV mortality for all second-level administrative units across sub-Saharan Africa. Methods: In this modelling study, we developed a framework that used the geographically specific HIV prevalence data collected in seroprevalence surveys and antenatal care clinics to train a model that estimates HIV incidence and mortality among individuals aged 15–49 years. We used a model-based geostatistical framework to estimate HIV prevalence at the second administrative level in 44 countries in sub-Saharan Africa for 2000–18 and sought data on the number of individuals on antiretroviral therapy (ART) by second-level administrative unit. We then modified the Estimation and Projection Package (EPP) to use these HIV prevalence and treatment estimates to estimate HIV incidence and mortality by second-level administrative unit. Findings: The estimates suggest substantial variation in HIV incidence and mortality rates both between and within countries in sub-Saharan Africa, with 15 countries having a ten-times or greater difference in estimated HIV incidence between the second-level administrative units with the lowest and highest estimated incidence levels. Across all 44 countries in 2018, HIV incidence ranged from 2 ·8 (95% uncertainty interval 2·1–3·8) in Mauritania to 1585·9 (1369·4–1824·8) cases per 100 000 people in Lesotho and HIV mortality ranged from 0·8 (0·7–0·9) in Mauritania to 676· 5 (513· 6–888·0) deaths per 100 000 people in Lesotho. Variation in both incidence and mortality was substantially greater at the subnational level than at the national level and the highest estimated rates were accordingly higher. Among second-level administrative units, Guijá District, Gaza Province, Mozambique, had the highest estimated HIV incidence (4661·7 [2544·8–8120·3]) cases per 100000 people in 2018 and Inhassunge District, Zambezia Province, Mozambique, had the highest estimated HIV mortality rate (1163·0 [679·0–1866·8]) deaths per 100 000 people. Further, the rate of reduction in HIV incidence and mortality from 2000 to 2018, as well as the ratio of new infections to the number of people living with HIV was highly variable. Although most second-level administrative units had declines in the number of new cases (3316 [81· 1%] of 4087 units) and number of deaths (3325 [81·4%]), nearly all appeared well short of the targeted 75% reduction in new cases and deaths between 2010 and 2020. Interpretation: Our estimates suggest that most second-level administrative units in sub-Saharan Africa are falling short of the targeted 75% reduction in new cases and deaths by 2020, which is further compounded by substantial within-country variability. These estimates will help decision makers and programme implementers expand access to ART and better target health resources to higher burden subnational areas