Last data update: May 06, 2024. (Total: 46732 publications since 2009)
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Identifying risk factors for Attention-Deficit/Hyperactivity Disorder (ADHD): A public health concern and opportunity
Rattay K , Robinson LR . Prev Sci 2024 Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant individual and societal negative impacts of the disorder continuing into adulthood (Danielson et al. in Journal of Clinical Child and Adolescent Psychology, in press; Landes and London in Journal of Attention Disorders 25:3-13, 2021). Genetic and environmental risk (e.g., modifiable exposures such as prenatal tobacco exposure and child maltreatment) for ADHD is likely multifactorial (Faraone et al. in Neuroscience & Biobehavioral Reviews 128:789-818, 2021). However, the evidence for potentially modifiable contextual risks is spread across studies with different methodologies and ADHD criteria limiting understanding of the relationship between early risk factors and later childhood ADHD. Using common methodology across six meta-analyses (Bitsko et al. in Prevention Science, 2022; Claussen et al. in Prevention Science 1-23, 2022; Dimitrov et al. in Prevention Science, 2023; Maher et al. in Prevention Science, 2023; Robinson, Bitsko et al. in Prevention Science, 2022; So et al. in Prevention Science, 2022) examining 59 risk factors for childhood ADHD, the papers in this special issue use a public health approach to address prior gaps in the literature. This introductory paper provides examples of comprehensive public health approaches focusing on policy, systems, and environmental changes across socio-ecological contexts to improve health and wellbeing through prevention, early intervention, and support across development using findings from these meta-analyses. Together, the findings from these studies and a commentary by an author independent from the risk studies have the potential to minimize risk conditions, prioritize prevention efforts, and improve the long-term health and wellbeing of children and adults with ADHD. |
Estimating the contribution of HIV-infected adults to household pneumococcal transmission in South Africa, 2016-2018: A hidden Markov modelling study (preprint)
Thindwa D , Wolter N , Pinsent A , Carrim M , Ojal J , Tempia S , Moyes J , McMorrow M , Kleynhans J , Gottberg AV , French N , Cohen C , Flasche S . medRxiv 2021 2021.05.21.21257622 Human immunodeficiency virus (HIV) infected adults are at a higher risk of pneumococcal colonisation and disease, even while receiving antiretroviral therapy (ART). To help evaluate potential indirect effects of vaccination of HIV-infected adults, we assessed whether HIV-infected adults disproportionately contribute to household transmission of pneumococci. We constructed a hidden Markov model to capture the dynamics of pneumococcal carriage acquisition and clearance observed during a longitudinal household-based nasopharyngeal swabbing study, while accounting for sample misclassifications. Households were followed-up twice weekly for 10 months for nasopharyngeal carriage detection via real-time PCR. We estimated the effect of participant’s age, HIV status, presence of a HIV-infected adult within the household and other covariates on pneumococcal acquisition and clearance probabilities. Of 1,684 individuals enrolled, 279 (16.6%) were younger children (<5 years-old) of whom 4 (1.5%) were HIV-infected and 726 (43.1%) were adults (≥18 years-old) of whom 214 (30.4%) were HIV-infected, most (173, 81.2%) with high CD4+ count. The observed range of pneumococcal carriage prevalence across visits was substantially higher in younger children (56.9-80.5%) than older children (5-17 years-old) (31.7-50.0%) or adults (11.5-23.5%). We estimate that 14.4% (95% Confidence Interval [CI]: 13.7-15.0) of pneumococcal-negative swabs were false negatives. Daily carriage acquisition probabilities among HIV-uninfected younger children were similar in households with and without HIV-infected adults (hazard ratio: 0.95, 95%CI: 0.91-1.01). Longer average carriage duration (11.4 days, 95%CI: 10.2-12.8 vs 6.0 days, 95%CI: 5.6 - 6.3) and higher median carriage density (622 genome equivalents per millilitre, 95%CI: 507-714 vs 389, 95%CI: 311.1-435.5) were estimated in HIV-infected vs HIV-uninfected adults. The use of ART and antibiotics substantially reduced carriage duration in all age groups, and acquisition rates increased with household size. Although South African HIV-infected adults on ART have longer carriage duration and density than their HIV-uninfected counterparts, they show similar patterns of pneumococcal acquisition and onward transmission.Author summary We assessed the contribution of HIV-infected adults to household pneumococcal transmission by applying a hidden Markov model to pneumococcal cohort data comprising 115,595 nasopharyngeal samples from 1,684 individuals in rural and urban settings in South Africa. We estimated 14.4% of sample misclassifications (false negatives), representing 85.6% sensitivity of a test that was used to detect pneumococcus. Pneumococcal carriage prevalence and acquisition rates, and average duration were usually higher in younger or older children than adults. The use of ART and antibiotics reduced the average carriage duration across all age and HIV groups, and carriage acquisition risks increased in larger household sizes. Despite the longer average carriage duration and higher median carriage density in HIV-infected than HIV-uninfected adults, we found similar carriage acquisition and onward transmission risks in the dual groups. These findings suggest that vaccinating HIV-infected adults on ART with PCV would reduce their risk for pneumococcal disease but may add little to the indirect protection against carriage of the rest of the population.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT02519803Clinical Protocols https://www.medrxiv.org/content/10.1101/2021.01.06.21249313v1.full.pdf Funding StatementThis research was commissioned by the National Institute for Health Research (NIHR) Global Health Research Unit on Mucosal Pathogens under the UK Government. PHIRST study was funded by a cooperative agreement with the United States Centers for Disease Control and Prevention (grant number 1U01IP001048) (https://www.cdc.gov) and the Bill and Melinda Gates Foundation (Grant number: OPP1164778) (https://www.gatesfoundation.org). DT, OJ are supported by th National Institute for Health Research (NIHR) Global Health Research Unit on Mucosal Pathogens (MPRU) using UK aid from the UK Government (16/136/46) (https://www.mpru.org). AP is supported by the Bill and Melinda Gates Foundation (https://www.gatesfoundation.org). SF is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number 208812/Z/17/Z) (https://wellcome.org). CC and AvG receive grant support through their institution from Sanofi Pasteur (https://www.sanofi.com/en). The funders had no involvement in the study design; collection, analysis and interpretation of data; writing of the report; or decision to submit the article for publication.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The longitudinal pneumococcal carriage data described in this study were obtained from consenting South African children and adults as part of the PHIRST study. The use of data was granted by the University of Witwatersrand, Human Research Ethics Committee (HREC) and the Protocol Review Committee (PRC) under approval 150808, the US CDC Institutional Review Board relied on the local review (6840), and the London School of Hygiene and Tropical Medicine Observational Research Ethics Committee under approval 17902.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData cannot be shared publicly because of confidentiality. Data are available from the National Institute of Communicable Disease (NICD) if authorised by Institutional Data Access / Ethics Committee (contact via Professor Cherly Cohen, cherylc@nicd.ac.za) for researchers who meet the criteria for access to confidential data. The code underlying the results presented in the study are available from GitHub through the following link (https://github.com/deusthindwa/hmm.pneumococcus.hiv.south-africa) or contact Deus Thindwa through email: deus.thindwa@gmail.com |
Multimodeling approach to evaluating the efficacy of layering pharmaceutical and nonpharmaceutical interventions for influenza pandemics
Prasad PV , Steele MK , Reed C , Meyers LA , Du Z , Pasco R , Alfaro-Murillo JA , Lewis B , Venkatramanan S , Schlitt J , Chen J , Orr M , Wilson ML , Eubank S , Wang L , Chinazzi M , Pastore YPiontti A , Davis JT , Halloran ME , Longini I , Vespignani A , Pei S , Galanti M , Kandula S , Shaman J , Haw DJ , Arinaminpathy N , Biggerstaff M . Proc Natl Acad Sci U S A 2023 120 (28) e2300590120 When an influenza pandemic emerges, temporary school closures and antiviral treatment may slow virus spread, reduce the overall disease burden, and provide time for vaccine development, distribution, and administration while keeping a larger portion of the general population infection free. The impact of such measures will depend on the transmissibility and severity of the virus and the timing and extent of their implementation. To provide robust assessments of layered pandemic intervention strategies, the Centers for Disease Control and Prevention (CDC) funded a network of academic groups to build a framework for the development and comparison of multiple pandemic influenza models. Research teams from Columbia University, Imperial College London/Princeton University, Northeastern University, the University of Texas at Austin/Yale University, and the University of Virginia independently modeled three prescribed sets of pandemic influenza scenarios developed collaboratively by the CDC and network members. Results provided by the groups were aggregated into a mean-based ensemble. The ensemble and most component models agreed on the ranking of the most and least effective intervention strategies by impact but not on the magnitude of those impacts. In the scenarios evaluated, vaccination alone, due to the time needed for development, approval, and deployment, would not be expected to substantially reduce the numbers of illnesses, hospitalizations, and deaths that would occur. Only strategies that included early implementation of school closure were found to substantially mitigate early spread and allow time for vaccines to be developed and administered, especially under a highly transmissible pandemic scenario. |
CC16 polymorphisms in asthma, asthma subtypes, and asthma control in adults from the Agricultural Lung Health Study.
Gribben KC , Wyss AB , Poole JA , Farazi PA , Wichman C , Richards-Barber M , BeaneFreeman LE , Henneberger PK , Umbach DM , London SJ , LeVan TD , Gribben KC . Respir Res 2022 23 (1) 305 BACKGROUND: The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects and is a potential early biomarker of lung damage. The CC16 single nucleotide polymorphism (SNP) rs3741240 risk allele (A) has been inconsistently linked to asthma; other tagging SNPs in the gene have not been explored. The aim was to determine whether CC16 tagging polymorphisms are associated with adult asthma, asthma subtypes or asthma control in the Agricultural Lung Health Study (ALHS). METHODS: The ALHS is an asthma case-control study nested in the Agricultural Health Study cohort. Asthma cases were individuals with current doctor diagnosed asthma, likely undiagnosed asthma, or asthma-COPD overlap defined by questionnaire. We also examined asthma subtypes and asthma control. Five CC16 tagging SNPs were imputed to 1000 Genomes Integrated phase 1 reference panel. Logistic regression was used to estimate associations between CC16 SNPs and asthma outcomes adjusted for covariates. RESULTS: The sample included 1120 asthma cases and 1926 controls of European ancestry, with a mean age of 63 years. The frequency of the risk genotype (AA) for rs3741240 was 12.5% (n=382). CC16 rs3741240 was not associated with adult asthma outcomes. A tagging SNP in the CC16 gene, rs12270961 was associated with uncontrolled asthma (n=208, OR(adj)= 1.4, 95% CI 1.0, 1.9; p=0.03). CONCLUSION: This study, the largest study to investigate associations between CC16 tagging SNPs and asthma phenotypes in adults, did not confirm an association of rs3741240 with adult asthma. A tagging SNP in CC16 suggests a potential relationship with asthma control. |
Allergic and non-allergic wheeze among farm women in the Agricultural Health Study (2005-2010)
Islam JY , Mohamed A , Umbach DM , London SJ , Henneberger PK , BeaneFreeman LE , Sandler DP , Hoppin JA . Occup Environ Med 2022 BACKGROUND: Farms represent complex environments for respiratory exposures including hays, grains and pesticides. Little is known about the impact of these exposures on women's respiratory health. We evaluated the association of farm exposures with allergic and non-allergic wheeze among women in the Agricultural Health Study, a study of farmers and their spouses based in Iowa and North Carolina. METHODS: We used self-reported data (2005-2010) on current use (12 months) of 15 pesticides (selected based on frequency of use) and occupational farm activities from 20164women. We defined allergic wheeze as reporting wheeze and doctor-diagnosed hay fever (7%) and non-allergic wheeze as wheeze but not hay fever (8%) in the past 12 months. Using polytomous logistic regression, we evaluated associations of wheeze subtypes with pesticides and other farm exposures (eg, raising farm animals) using no wheeze/hay fever as the referent, adjusting for age, body mass index, state, current asthma, glyphosate use and smoking. RESULTS: Current use of any pesticide, reported by 7% of women, was associated with both allergic (OR: 1.36, 95% CI: 1.10 to 1.67) and non-allergic (OR: 1.25, 95%CI: 1.04 to 1.51) wheeze. Four pesticides were associated with at least one wheeze subtype: glyphosate, with both wheeze subtypes; diazinon and fly spray with only allergic wheeze; carbaryl with only non-allergic wheeze. Working weekly with mouldy hay was associated with allergic (OR: 1.88, 95%CI: 1.26 to 2.80) and non-allergic wheeze (OR: 1.69, 95%CI: 1.18 to 2.42). CONCLUSION: Use of specific pesticides and certain farm activities may contribute to wheeze among farm women. |
Association between viral suppression during the third trimester of pregnancy and unintended pregnancy among women on antiretroviral therapy: Results from the 2019 antenatal HIV Sentinel Survey, South Africa
Woldesenbet S , Kufa T , Manda S , Ayalew K , Lombard C , Cheyip M , Puren A . PLoS One 2022 17 (3) e0265124 OBJECTIVES: About half of the pregnancies among women living with HIV (WLWH) receiving antiretroviral therapy (ART) in sub-Saharan African countries are reported to be unintended. Unintended pregnancy is associated with late initiation of antenatal care (ANC), and may delay provision of viral load monitoring services, antenatal adherence counselling and support, and other services that promote sustained viral suppression throughout pregnancy. This study examines the association between unsuppressed viral load during the third trimester of pregnancy and unintended pregnancy among women who initiated ART before pregnancy. METHODS: This was an analysis of data from a national antenatal survey conducted at 1 589 public health facilities in South Africa between 1 October and 15 November 2019. Consenting pregnant women aged 15-49 years attending ANC during the survey period were enrolled. Demographic and clinical data were collected through interview and medical record review. Pregnancy intention was assessed using two questions from the London Measure of Unplanned Pregnancy, and responses were categorized as "unintended," "undecided," and "intended." Blood specimens were collected from all women and tested for HIV; and if positive, a viral load test was performed. A survey domain-based poisson regression model examined the association between unsuppressed viral load during the third trimester of pregnancy and unintended pregnancy among women who initiated ART before pregnancy. Viral suppression was defined as viral load <50 copies/mL. RESULTS: Of 10 901 WLWH with viral load data available, 63.3% (95% confidence interval (CI): 62.4%-64.1%) were virally suppressed. Among the 2 681 women (representing 24.1% of all WLWH with viral load data) who initiated ART before pregnancy and were in their third trimester at the time of enrolment, 74.4% (95% CI: 73.0%-75.8%) were virally suppressed. In the same population, the proportion virally suppressed was lower among women whose current pregnancies were unintended (72.1%, 95% CI: 70.1%-74.1%) compared to women whose pregnancies were intended (78.3%, 95% CI: 75.9%-80.5%). In multivariable analyses adjusted for age, gravity, marital status, education, location of facility and syphilis status, unintended pregnancy was associated with unsuppressed viral load during the third trimester (adjusted relative risk: 1.3, 95% CI: 1.1-1.4) among women who initiated ART before pregnancy. CONCLUSION: The identified association between unsuppressed viral load and unintended pregnancy among pregnant women who initiated ART before pregnancy highlights the need to strengthen routine assessment of fertility preferences and provision of contraceptive services to reproductive age WLWH receiving ART. |
Global, regional, and national minimum estimates of children affected by COVID-19-associated orphanhood and caregiver death, by age and family circumstance up to Oct 31, 2021: an updated modelling study.
Unwin HJT , Hillis S , Cluver L , Flaxman S , Goldman PS , Butchart A , Bachman G , Rawlings L , Donnelly CA , Ratmann O , Green P , Nelson CA , Blenkinsop A , Bhatt S , Desmond C , Villaveces A , Sherr L . Lancet Child Adolesc Health 2022 6 (4) 249-259 BACKGROUND: In the 6 months following our estimates from March 1, 2020, to April 30, 2021, the proliferation of new coronavirus variants, updated mortality data, and disparities in vaccine access increased the amount of children experiencing COVID-19-associated orphanhood. To inform responses, we aimed to model the increases in numbers of children affected by COVID-19-associated orphanhood and caregiver death, as well as the cumulative orphanhood age-group distribution and circumstance (maternal or paternal orphanhood). METHODS: We used updated excess mortality and fertility data to model increases in minimum estimates of COVID-19-associated orphanhood and caregiver deaths from our original study period of March 1, 2020-April 30, 2021, to include the new period of May 1-Oct 31, 2021, for 21 countries. Orphanhood was defined as the death of one or both parents; primary caregiver loss included parental death or the death of one or both custodial grandparents; and secondary caregiver loss included co-residing grandparents or kin. We used logistic regression and further incorporated a fixed effect for western European countries into our previous model to avoid over-predicting caregiver loss in that region. For the entire 20-month period, we grouped children by age (0-4 years, 5-9 years, and 10-17 years) and maternal or paternal orphanhood, using fertility contributions, and we modelled global and regional extrapolations of numbers of orphans. 95% credible intervals (CrIs) are given for all estimates. FINDINGS: The number of children affected by COVID-19-associated orphanhood and caregiver death is estimated to have increased by 90·0% (95% CrI 89·7-90·4) from April 30 to Oct 31, 2021, from 2 737 300 (95% CrI 1 976 100-2 987 000) to 5 200 300 (3 619 400-5 731 400). Between March 1, 2020, and Oct 31, 2021, 491 300 (95% CrI 485 100-497 900) children aged 0-4 years, 736 800 (726 900-746 500) children aged 5-9 years, and 2 146 700 (2 120 900-2 174 200) children aged 10-17 years are estimated to have experienced COVID-19-associated orphanhood. Globally, 76·5% (95% CrI 76·3-76·7) of children were paternal orphans, whereas 23·5% (23·3-23·7) were maternal orphans. In each age group and region, the prevalence of paternal orphanhood exceeded that of maternal orphanhood. INTERPRETATION: Our findings show that numbers of children affected by COVID-19-associated orphanhood and caregiver death almost doubled in 6 months compared with the amount after the first 14 months of the pandemic. Over the entire 20-month period, 5·0 million COVID-19 deaths meant that 5·2 million children lost a parent or caregiver. Our data on children's ages and circumstances should support pandemic response planning for children globally. FUNDING: UK Research and Innovation (Global Challenges Research Fund, Engineering and Physical Sciences Research Council, and Medical Research Council), Oak Foundation, UK National Institute for Health Research, US National Institutes of Health, and Imperial College London. |
The prevalence of unintended pregnancy and its association with HIV status among pregnant women in South Africa, a national antenatal survey, 2019
Woldesenbet S , Kufa T , Lombard C , Manda S , Morof D , Cheyip M , Ayalew K , Puren A . Sci Rep 2021 11 (1) 23740 To describe the prevalence of unintended pregnancy and its association with HIV status among pregnant women in South Africa. A cross-sectional survey was conducted between October and mid-November 2019 among pregnant women aged 15-49 years in 1589 selected public antenatal care facilities. Pregnancy intention was assessed using two questions from the London Measure of Unplanned Pregnancy. Survey logistic regression examined factors associated with unintended pregnancy. Among 34,946 participants, 51.6% had an unintended pregnancy. On multivariable analysis, the odds of unintended pregnancy was higher among women who knew their HIV-positive status before pregnancy but initiated treatment after the first antenatal visit (adjusted odds ratio [aOR], 1.5 [95% confidence interval (CI):1.2-1.8]), women who initiated treatment before pregnancy (aOR, 1.3 [95% CI:1.2-1.3]), and women with a new HIV diagnosis during pregnancy (aOR, 1.2 [95% CI:1.1-1.3]) compared to HIV-negative women. Women who were single, in a non-cohabiting or a cohabiting relationship, and young women (15-24 years) had significantly higher risk of unintended pregnancy compared to married women and women aged 30-49 years, respectively. A comprehensive approach, including regular assessment of HIV clients' pregnancy intention, and adolescent and youth-friendly reproductive health services could help prevent unintended pregnancy. |
Global minimum estimates of children affected by COVID-19-associated orphanhood and deaths of caregivers: a modelling study.
Hillis SD , Unwin HJT , Chen Y , Cluver L , Sherr L , Goldman PS , Ratmann O , Donnelly CA , Bhatt S , Villaveces A , Butchart A , Bachman G , Rawlings L , Green P , Nelson CA3rd , Flaxman S . Lancet 2021 398 (10298) 391-402 BACKGROUND: The COVID-19 pandemic priorities have focused on prevention, detection, and response. Beyond morbidity and mortality, pandemics carry secondary impacts, such as children orphaned or bereft of their caregivers. Such children often face adverse consequences, including poverty, abuse, and institutionalisation. We provide estimates for the magnitude of this problem resulting from COVID-19 and describe the need for resource allocation. METHODS: We used mortality and fertility data to model minimum estimates and rates of COVID-19-associated deaths of primary or secondary caregivers for children younger than 18 years in 21 countries. We considered parents and custodial grandparents as primary caregivers, and co-residing grandparents or older kin (aged 60-84 years) as secondary caregivers. To avoid overcounting, we adjusted for possible clustering of deaths using an estimated secondary attack rate and age-specific infection-fatality ratios for SARS-CoV-2. We used these estimates to model global extrapolations for the number of children who have experienced COVID-19-associated deaths of primary and secondary caregivers. FINDINGS: Globally, from March 1, 2020, to April 30, 2021, we estimate 1 134 000 children (95% credible interval 884 000-1 185 000) experienced the death of primary caregivers, including at least one parent or custodial grandparent. 1 562 000 children (1 299 000-1 683 000) experienced the death of at least one primary or secondary caregiver. Countries in our study set with primary caregiver death rates of at least one per 1000 children included Peru (10·2 per 1000 children), South Africa (5·1), Mexico (3·5), Brazil (2·4), Colombia (2·3), Iran (1·7), the USA (1·5), Argentina (1·1), and Russia (1·0). Numbers of children orphaned exceeded numbers of deaths among those aged 15-50 years. Between two and five times more children had deceased fathers than deceased mothers. INTERPRETATION: Orphanhood and caregiver deaths are a hidden pandemic resulting from COVID-19-associated deaths. Accelerating equitable vaccine delivery is key to prevention. Psychosocial and economic support can help families to nurture children bereft of caregivers and help to ensure that institutionalisation is avoided. These data show the need for an additional pillar of our response: prevent, detect, respond, and care for children. FUNDING: UK Research and Innovation (Global Challenges Research Fund, Engineering and Physical Sciences Research Council, Medical Research Council), UK National Institute for Health Research, US National Institutes of Health, and Imperial College London. |
Applying a machine learning modelling framework to predict delayed linkage to care in patients newly diagnosed with HIV in Mecklenburg County, North Carolina, USA.
Chen S , Owolabi Y , Dulin M , Robinson P , Witt B , Samoff E . AIDS 2021 35 S29-s38 BACKGROUND: Machine learning has the potential to help researchers better understand and close the gap in HIV care delivery in large metropolitan regions such as Mecklenburg County, North Carolina, USA. OBJECTIVES: We aim to identify important risk factors associated with delayed linkage to care for HIV patients with novel machine learning models and identify high-risk regions of the delay. METHODS: Deidentified 2013-2017 Mecklenburg County surveillance data in eHARS format were requested. Both univariate analyses and machine learning random forest model (developed in R 3.5.0) were applied to quantify associations between delayed linkage to care (>30 days after diagnosis) and various risk factors for individual HIV patients. We also aggregated linkage to care by zip codes to identify high-risk communities within the county. RESULTS: Types of HIV-diagnosing facility significantly influenced time to linkage; first diagnosis in hospital was associated with the shortest time to linkage. HIV patients with lower CD4+ cell counts (<200/ml) were twice as likely to link to care within 30 days than those with higher CD4+ cell count. Random forest model achieved high accuracy (>80% without CD4+ cell count data and >95% with CD4+ cell count data) to predict risk of delay in linkage to care. In addition, we also identified top high-risk zip codes of delayed linkage. CONCLUSION: The findings helped public health teams identify high-risk communities of delayed HIV care continuum across Mecklenburg County. The methodology framework can be applied to other regions with HIV epidemic and challenge of delayed linkage to care. |
Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in children and infants: two clinical trials.
Sáez-Llorens X , Bandyopadhyay AS , Gast C , Leon T , DeAntonio R , Jimeno J , Caballero MI , Aguirre G , Oberste MS , Weldon WC , Konopka-Anstadt JL , Modlin J , Bachtiar NS , Fix A , Konz J , Clemens R , Costa Clemens SA , Rüttimann R . Lancet 2020 397 (10268) 27-38 BACKGROUND: Continued emergence and spread of circulating vaccine-derived type 2 polioviruses and vaccine-associated paralytic poliomyelitis from Sabin oral poliovirus vaccines (OPVs) has stimulated development of two novel type 2 OPV candidates (OPV2-c1 and OPV2-c2) designed to have similar immunogenicity, improved genetic stability, and less potential to reacquire neurovirulence. We aimed to assess safety and immunogenicity of the two novel OPV candidates compared with a monovalent Sabin OPV in children and infants. METHODS: We did two single-centre, multi-site, partly-masked, randomised trials in healthy cohorts of children (aged 1-4 years) and infants (aged 18-22 weeks) in Panama: a control phase 4 study with monovalent Sabin OPV2 before global cessation of monovalent OPV2 use, and a phase 2 study with low and high doses of two novel OPV2 candidates. All participants received one OPV2 vaccination and subsets received two doses 28 days apart. Parents reported solicited and unsolicited adverse events. Type 2 poliovirus neutralising antibodies were measured at days 0, 7, 28, and 56, and stool viral shedding was assessed up to 28 days post-vaccination. Primary objectives were to assess safety in all participants and non-inferiority of novel OPV2 day 28 seroprotection versus monovalent OPV2 in infants (non-inferiority margin 10%). These studies were registered with ClinicalTrials.gov, NCT02521974 and NCT03554798. FINDINGS: The control study took place between Oct 23, 2015, and April 29, 2016, and the subsequent phase 2 study between Sept 19, 2018, and Sept 30, 2019. 150 children (50 in the control study and 100 of 129 assessed for eligibility in the novel OPV2 study) and 684 infants (110 of 114 assessed for eligibility in the control study and 574 of 684 assessed for eligibility in the novel OPV2 study) were enrolled and received at least one study vaccination. Vaccinations were safe and well tolerated with no causally associated serious adverse events or important medical events in any group. Solicited and unsolicited adverse events were overwhelmingly mild or moderate irrespective of vaccine or dose. Nearly all children were seroprotected at baseline, indicating high baseline immunity. In children, the seroprotection rate 28 days after one dose was 100% for monovalent OPV2 and both novel OPV2 candidates. In infants at day 28, 91 (94% [95% CI 87-98]) of 97 were seroprotected after receiving monovalent OPV2, 134 (94% [88-97]) of 143 after high-dose novel OPV2-c1, 122 (93% [87-97]) of 131 after low-dose novel OPV2-c1, 138 (95% [90-98]) of 146 after high-dose novel OPV2-c2, and 115 (91% [84-95]) of 127 after low-dose novel OPV2-c2. Non-inferiority was shown for low-dose and high-dose novel OPV2-c1 and high-dose novel OPV2-c2 despite monovalent OPV2 recipients having higher baseline immunity. INTERPRETATION: Both novel OPV2 candidates were safe, well tolerated, and immunogenic in children and infants. Novel OPV2 could be an important addition to our resources against poliovirus given the current epidemiological situation. FUNDING: Fighting Infectious Diseases in Emerging Countries and Bill & Melinda Gates Foundation. |
Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in healthy adults: two clinical trials.
De Coster I , Leroux-Roels I , Bandyopadhyay AS , Gast C , Withanage K , Steenackers K , De Smedt P , Aerssens A , Leroux-Roels G , Oberste MS , Konopka-Anstadt JL , Weldon WC , Fix A , Konz J , Wahid R , Modlin J , Clemens R , Costa Clemens SA , Bachtiar NS , Van Damme P . Lancet 2020 397 (10268) 39-50 BACKGROUND: Two novel type 2 oral poliovirus vaccine (OPV2) candidates, novel OPV2-c1 and novel OPV2-c2, designed to be more genetically stable than the licensed Sabin monovalent OPV2, have been developed to respond to ongoing polio outbreaks due to circulating vaccine-derived type 2 polioviruses. METHODS: We did two randomised studies at two centres in Belgium. The first was a phase 4 historical control study of monovalent OPV2 in Antwerp, done before global withdrawal of OPV2, and the second was a phase 2 study in Antwerp and Ghent with novel OPV2-c1 and novel OPV2-c2. Eligible participants were healthy adults aged 18-50 years with documented history of at least three polio vaccinations, including OPV in the phase 4 study and either OPV or inactivated poliovirus vaccine (IPV) in the novel OPV2 phase 2 study, with no dose within 12 months of study start. In the historical control trial, participants were randomly assigned to either one dose or two doses of monovalent OPV2. In the novel OPV2 trial, participants with previous OPV vaccinations were randomly assigned to either one or two doses of novel OPV2-c1 or to one or two doses of novel OPV2-c2. IPV-vaccinated participants were randomly assigned to receive two doses of either novel OPV2-c1, novel OPV2-c2, or placebo. Vaccine administrators were unmasked to treatment; medical staff performing safety and reactogenicity assessments or blood draws for immunogenicity assessments were masked. Participants received the first vaccine dose on day 0, and a second dose on day 28 if assigned to receive a second dose. Primary objectives were assessments and comparisons of safety up to 28 days after each dose, including solicited adverse events and serious adverse events, and immunogenicity (seroprotection rates on day 28 after the first vaccine dose) between monovalent OPV2 and the two novel OPV2 candidates. Primary immunogenicity analyses were done in the per-protocol population. Safety was assessed in the total vaccinated population-ie, all participants who received at least one dose of their assigned vaccine. The phase 4 control study is registered with EudraCT (2015-003325-33) and the phase 2 novel OPV2 study is registered with EudraCT (2018-001684-22) and ClinicalTrials.gov (NCT04544787). FINDINGS: In the historical control study, between Jan 25 and March 18, 2016, 100 volunteers were enrolled and randomly assigned to receive one or two doses of monovalent OPV2 (n=50 in each group). In the novel OPV2 study, between Oct 15, 2018, and Feb 27, 2019, 200 previously OPV-vaccinated volunteers were assigned to the four groups to receive one or two doses of novel OPV2-c1 or novel OPV2-c2 (n=50 per group); a further 50 participants, previously vaccinated with IPV, were assigned to novel OPV2-c1 (n=17), novel OPV2-c2 (n=16), or placebo (n=17). All participants received the first dose of assigned vaccine or placebo and were included in the total vaccinated population. All vaccines appeared safe; no definitely vaccine-related withdrawals or serious adverse events were reported. After first doses in previously OPV-vaccinated participants, 62 (62%) of 100 monovalent OPV2 recipients, 71 (71%) of 100 recipients of novel OPV2-c1, and 74 (74%) of 100 recipients of novel OPV2-c2 reported solicited systemic adverse events, four (monovalent OPV2), three (novel OPV2-c1), and two (novel OPV2-c2) of which were considered severe. In IPV-vaccinated participants, solicited adverse events occurred in 16 (94%) of 17 who received novel OPV2-c1 (including one severe) and 13 (81%) of 16 who received novel OPV2-c2 (including one severe), compared with 15 (88%) of 17 placebo recipients (including two severe). In previously OPV-vaccinated participants, 286 (97%) of 296 were seropositive at baseline; after one dose, 100% of novel OPV2 vaccinees and 97 (97%) of monovalent OPV2 vaccinees were seropositive. INTERPRETATION: Novel OPV2 candidates were as safe, well tolerated, and immunogenic as monovalent OPV2 in previously OPV-vaccinated and IPV-vaccinated adults. These data supported the further assessment of the vaccine candidates in children and infants. FUNDING: University of Antwerp and Bill & Melinda Gates Foundation. |
Human monkeypox - After 40 years, an unintended consequence of smallpox eradication.
Simpson K , Heymann D , Brown CS , Edmunds WJ , Elsgaard J , Fine P , Hochrein H , Hoff NA , Green A , Ihekweazu C , Jones TC , Lule S , Maclennan J , McCollum A , Muhlemann B , Nightingale E , Ogoina D , Ogunleye A , Petersen B , Powell J , Quantick O , Rimoin AW , Ulaeato D , Wapling A . Vaccine 2020 38 (33) 5077-5081 Smallpox eradication, coordinated by the WHO and certified 40 years ago, led to the cessation of routine smallpox vaccination in most countries. It is estimated that over 70% of the world's population is no longer protected against smallpox, and through cross-immunity, to closely related orthopox viruses such as monkeypox. Monkeypox is now a re-emerging disease. Monkeypox is endemic in as yet unconfirmed animal reservoirs in sub-Saharan Africa, while its human epidemiology appears to be changing. Monkeypox in small animals imported from Ghana as exotic pets was at the origin of an outbreak of human monkeypox in the USA in 2003. Travellers infected in Nigeria were at the origin of monkeypox cases in the UK in 2018 and 2019, Israel in 2018 and Singapore in2019. Together with sporadic reports of human infections with other orthopox viruses, these facts invite speculation that emergent or re-emergent human monkeypox might fill the epidemiological niche vacated by smallpox. An ad-hoc and unofficial group of interested experts met to consider these issues at Chatham House, London in June 2019, in order to review available data and identify monkeypox-related research gaps. Gaps identified by the experts included:The experts further agreed on the need for a better understanding of the genomic evolution and changing epidemiology of orthopox viruses, the usefulness of in-field genomic diagnostics, and the best disease control strategies, including the possibility of vaccination with new generation non-replicating smallpox vaccines and treatment with recently developed antivirals. |
Incident infection in high-priority HIV molecular transmission clusters in the united states.
Wertheim JO , Panneer N , France AM , Saduvala N , Oster AM . AIDS 2020 34 (8) 1187-1193 OBJECTIVE: To identify correlates of incident HIV infection in rapidly growing HIV molecular clusters. DESIGN: Phylogenetic analysis of HIV public health surveillance data. METHODS: High-priority HIV genetic transmission clusters with evidence of rapid growth in 2012 (i.e., clusters with a pairwise genetic distance </=0.005 substitutions/site and at least 3 cases diagnosed in 2012) were identified using HIV-TRACE. Then, we investigated cluster growth, defined as HIV cases diagnosed in the following 5 years that were genetically linked to these clusters. For clusters that grew during the follow-up period, Bayesian molecular clock phylogenetic inference was performed to identify clusters with evidence of incident HIV infection (as opposed to diagnosis of previously infected cases) during this follow-up period. RESULTS: Of the 116 rapidly growing clusters identified, 73 (63%) had phylogenetic evidence for an incident HIV case during the 5-year follow-up period. Correlates of an incident HIV case arising in clusters included a greater number of diagnosed but virally unsuppressed cases in 2012, a greater number of inferred undiagnosed cases in the cluster in 2012, and a younger time of most recent common ancestor for the cluster. CONCLUSIONS: These findings suggest that incident infections in rapidly growing clusters originate equally from diagnosed but unsuppressed cases and undiagnosed infections. These results highlight the importance of promoting retention in care and viral suppression as well as partner notification and other case-finding activities when investigating and intervening on high-priority molecular transmission clusters. |
The science of vaccine safety: Summary of meeting at Wellcome Trust
Plotkin SA , Offit PA , DeStefano F , Larson HJ , Arora NK , Zuber PLF , Fombonne E , Sejvar J , Lambert PH , Hviid A , Halsey N , Garcon N , Peden K , Pollard AJ , Markowitz LE , Glanz J . Vaccine 2020 38 (8) 1869-1880 Vaccines are everywhere hugely successful but are also under attack. The reason for the latter is the perception by some people that vaccines are unsafe. However that may be, vaccine safety, life any other scientific subject, must be constantly studied. It was from this point of view that a meeting was organized at the Wellcome Trust in London in May 2019 to assess some aspects of vaccine safety as subjects for scientific study. The objective of the meeting was to assess what is known beyond reasonable doubt and conversely what areas need additional studies. Although the meeting could not cover all aspects of vaccine safety science, many of the most important issues were addressed by a group of about 30 experts to determine what is already known and what additional studies are merited to assess the safety of the vaccines currently in use. The meeting began with reviews of the current situation in different parts of the world, followed by reviews of specific controversial areas, including the incidence of certain conditions after vaccination and the safety of certain vaccine components. Lastly, information about the human papillomavirus vaccine was considered because its safety has been particularly challenged by vaccine opponents. The following is a summary of the meeting findings. In addition to this summary, the meeting organizers will explore opportunities to perform studies that would enlarge knowledge of vaccine safety. |
HIV-1 genetic diversity to estimate time of infection and infer adherence to pre-exposure prophylaxis.
Council OD , Ruone S , Mock PA , Khalil G , Martin A , Curlin ME , McNicholl JM , Heneine W , Leelawiwat W , Choopanya K , Vanichseni S , Cherdtrakulkiat T , Anekvorapong R , Martin M , Garcia-Lerma JG . AIDS 2019 33 (15) 2299-2307 OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for pre-exposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10 to 25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median=47 [IQR=35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and non-adherence in three. CONCLUSIONS: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%. |
HIV-1 genetic diversity to estimate time of infection and infer adherence to preexposure prophylaxis.
Council OD , Ruone S , Mock PA , Khalil G , Martin A , Curlin ME , McNicholl JM , Heneine W , Leelawiwat W , Choopanya K , Vanichseni S , Cherdtrakulkiat T , Anekvorapong R , Martin M , Garcia-Lerma JG . AIDS 2019 33 (15) 2299-2307 OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for pre-exposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10 to 25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median=47 [IQR=35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and non-adherence in three. CONCLUSIONS: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%. |
State variability in diagnosed conditions for IDEA Part C Eligibility
Barger B , Squires J , Greer M , Noyes-Grosser D , Eile JM , Rice C , Shaw E , Surprenant KS , Twombly E , London S , Zubler J , Wolf RB . Infants Young Child 2019 32 (4) 231-244 An infant or toddler can begin the process of receiving Part C early intervention services by having a diagnosed condition with a high probability of developmental delay (Individuals with Disabilities Education Improvement Act, 2004). How states define those diagnosed conditions that begin the initiation process varies widely. Lists of diagnosed conditions were collected from state Part C websites and Part C coordinators for a descriptive analysis. Across 49 states, the District of Columbia, and 4 territories, a final list of 620 unique conditions was compiled. No single condition was listed by all jurisdictions. Hearing impairment was the condition listed by the most states (n = 38), followed by fetal alcohol syndrome (n = 34). Of the 620 conditions, 168 (27%) were listed by only 1 state, 554 (89%) were listed by fewer than 10 states, and 66 (11%) were listed by 10 or more states. Of these 66 conditions, 47 (71%) were listed by fewer than 20 states. Most of these 66 conditions (n = 48; 72.7%) had a prevalence of "very rare or rare," 8 (12%) were "common," 6 (9%) were "very common," and 4 (6.1%) were "unknown." The wide heterogeneity in the number and type of diagnostic conditions listed across states should be further investigated as it may represent imbalances in children with diagnosed conditions gaining access to Part C evaluations and individualized family service plans and potentially the services themselves across states. In addition, providing ready access to lists of diagnosed conditions is a simple step that could help states and Part C programs facilitate access to services. |
Update: Interim guidance for health care providers evaluating and caring for patients with suspected e-cigarette, or vaping, product use associated lung injury - United States, October 2019
Siegel DA , Jatlaoui TC , Koumans EH , Kiernan EA , Layer M , Cates JE , Kimball A , Weissman DN , Petersen EE , Reagan-Steiner S , Godfred-Cato S , Moulia D , Moritz E , Lehnert JD , Mitchko J , London J , Zaki SR , King BA , Jones CM , Patel A , Meaney Delman D , Koppaka R . MMWR Morb Mortal Wkly Rep 2019 68 (41) 919-927 Forty-nine states, the District of Columbia, and one U.S. territory have reported 1,299 cases of lung injury associated with the use of electronic cigarette (e-cigarette), or vaping, products. Twenty-six deaths have been reported from 21 states. Based on the most current data, CDC's updated interim guidance provides a framework for health care providers in their initial assessment, evaluation, management, and follow-up of persons with symptoms of e-cigarette, or vaping, product use associated lung injury (EVALI). Rapid recognition by health care providers of patients with EVALI and an increased understanding of treatment considerations could reduce morbidity and mortality associated with this injury. |
From epidemiology to action: The case for addressing social determinants of health to end HIV in the southern United States
Jeffries WL4th , Henny KD . AIDS Behav 2019 23 340-346 In response to cholera outbreaks in London during 1853–1854, John Snow conducted an historic investigation that launched the field of modern epidemiology [1]. Snow hypothesized that unsanitary conditions caused by sewage dumped into city cesspools contaminated local drinking water, resulting in the rapid spread of Cholera. To test his hypothesis, he collected data from Londoners who acquired and did not acquire cholera, paying close attention to where individuals who contracted cholera lived and acquired their water. Almost all individuals who acquired cholera drank from wells that were near cesspools in or near the Soho district of London. One well in particular, “the Broad Street pump,” was a primary water source for hundreds of cholera victims in Soho. To intervene, Snow persuaded London city officials to remove the handle from the Broad Street pump to prevent townspeople from consuming the contaminated water. After doing so, the cholera epidemic ceased. |
Meeting report: Convening on the influenza human viral challenge model for universal influenza vaccines, Part 1: Value; challenge virus selection; regulatory, industry and ethical considerations; increasing standardization, access and capacity
Innis BL , Berlanda Scorza F , Blum JS , Jain VK , Older Aguilar A , Post DJ , Roberts PC , Wairagkar N , White J , Bresee J . Vaccine 2019 37 (35) 4823-4829 In response to global interest in the development of a universal influenza vaccine, the Bill & Melinda Gates Foundation, PATH, and the Global Funders Consortium for Universal Influenza Vaccine Development convened a meeting of experts (London, UK, May 2018) to assess the role of a standardized controlled human influenza virus infection model (CHIVIM) towards the development of novel influenza vaccine candidates. This report (in two parts) summarizes those discussions and offers consensus recommendations. This article (Part 1) covers challenge virus selection, regulatory and ethical considerations, and issues concerning standardization, access, and capacity. Part 2 covers specific methodologic considerations. Current methods for influenza vaccine development and licensure require large costly field trials. The CHIVIM requires fewer subjects and the controlled setting allows for better understanding of influenza transmission and host immunogenicity. The CHIVIM can be used to identify immune predictors of disease for at-risk populations and to measure efficacy of potential vaccines for further development. Limitations to the CHIVIM include lack of standardization, limited access to challenge viruses and assays, lack of consensus regarding role of the CHIVIM in vaccine development pathway, and concerns regarding risk to study participants and community. To address these issues, the panel of experts recommended that WHO and other key stakeholders provide guidance on standardization, challenge virus selection, and risk management. A common repository of well-characterized challenge viruses, harmonized protocols, and standardized assays should be made available to researchers. A network of research institutions performing CHIVIM trials should be created, and more study sites are needed to increase capacity. Experts agreed that a research network of institutions working with a standardized CHIVIM could contribute important data to support more rapid development and licensure of novel vaccines capable of providing long-lasting protection against seasonal and pandemic influenza strains. |
Convening on the influenza human viral challenge model for universal influenza vaccines, Part 2: Methodologic considerations
Innis BL , Scorza FB , Blum JS , Jain VK , Aguilar AO , Post DJ , Roberts PC , Wairagkar N , White J , Bresee J . Vaccine 2019 37 (35) 4830-4834 In response to global interest in the development of a universal influenza vaccine, the Bill & Melinda Gates Foundation, PATH, and the Global Funders Consortium for Universal Influenza Vaccine Development convened a meeting of experts (London, UK, May 2018) to assess the role of a standardized controlled human influenza virus infection model (CHIVIM) towards the development of novel influenza vaccine candidates. This report (in two parts) summarizes those discussions and offers consensus recommendations. Part 1 covers challenge virus selection, regulatory and ethical considerations, and issues concerning standardization, access, and capacity. This article (Part 2) summarizes the discussion and recommendations concerning CHIVIM methods. The panelists identified an overall need for increased standardization of CHIVIM trials, in order to produce comparable results that can support universal vaccine licensure. Areas of discussion included study participant selection and screening, route of exposure and dose, devices for administering challenge, rescue therapy, protection of participants and institutions, clinical outcome measures, and other considerations. The panelists agreed upon specific recommendations to improve the standardization and usefulness of the model for vaccine development. Experts agreed that a research network of institutions working with a standardized CHIVIM could contribute important data to support more rapid development and licensure of novel vaccines capable of providing long-lasting protection against seasonal and pandemic influenza strains. |
A pharmacokinetic and pharmacogenetic evaluation of contraceptive implants and antiretroviral therapy among women in Kenya and Uganda.
Patel RC , Stalter RM , Thomas KK , Tamraz B , Blue SW , Erikson DW , Kim CJ , Kelley EJ , Nanda K , Kourtis AP , Lingappa JR , Mugo N , Baeten JM , Scarsi KK . AIDS 2019 33 (13) 1995-2004 OBJECTIVES: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz- or nevirapine-containing antiretroviral therapy (ART). DESIGN: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study. METHODS: Plasma samples collected every six months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared to pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on efavirenz and nevirapine to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on efavirenz, nevirapine, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations. RESULTS: Our analysis included 11 women who initiated efavirenz, 13 who initiated nevirapine, and 36 who remained ART-naive. In the efavirenz group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 (90% confidence intervals (0.31, 0.49); p < 0.001) and the etonogestrel aGMR was 0.51 (0.34, 0.76); p = 0.006) compared to the control group. No difference was observed in the nevirapine group compared to controls (levonorgestrel 0.93 (0.74, 1.18); p = 0.64; etonogestrel 1.07 (0.77, 1.50); p = 0.73). Possession of four allele variants were found to result in further reductions in progestin concentrations among those receiving efavirenz. CONCLUSIONS: Concomitant use of efavirenz significantly reduces levonorgestrel or etonogestrel concentrations by 61% and 49%, respectively, compared to no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and efavirenz. |
Animal production, insecticide use and self-reported symptoms and diagnoses of COPD, including chronic bronchitis, in the Agricultural Health Study
Rinsky JL , Richardson DB , Kreiss K , Nylander-French L , Beane Freeman LE , London SJ , Henneberger PK , Hoppin JA . Environ Int 2019 127 764-772 BACKGROUND: Occupational exposure to animal production is associated with chronic bronchitis symptoms; however, few studies consider associations with chronic obstructive pulmonary disease (COPD). We estimated associations between animal production activities and prevalence of self-reported COPD among farmers in the Agricultural Health Study. METHODS: During a 2005-2010 interview, farmers self-reported information about: their operations (i.e., size, type, number of animals, insecticide use), respiratory symptoms, and COPD diagnoses (i.e., COPD, chronic bronchitis, emphysema). Operations were classified as small or medium/large based on regulatory definitions. Farmers were classified as having a COPD diagnosis, chronic bronchitis symptoms (cough and phlegm for >/=3months during 2 consecutive years), or both. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Of 22,491 participating farmers (median age: 59years), 922 (4%) reported a COPD diagnosis only, 254 (1%) reported a diagnosis and symptoms, and 962 (4%) reported symptoms only. Compared to raising no commercial animals, raising animals on a medium/large operation was positively associated with chronic bronchitis symptoms with (OR: 1.59; 95% CI: 1.16, 2.18) and without a diagnosis (OR: 1.69; 95% CI: 1.42, 2.01). Ever use of multiple organophosphates, carbaryl, lindane, and permethrin were positively associated with chronic bronchitis symptoms. CONCLUSION: Animal production work, including insecticide use, was positively associated with chronic bronchitis symptoms; but not consistently with COPD diagnosis alone. Our results support the need for further investigation into the role of animal production-related exposures in the etiology of COPD and better respiratory protection for agricultural workers. |
Taking aim at cholera
Mintz E . Lancet 2018 391 (10133) 1868-1870 In 1854, John Snow's work on cholera in London immortalised the power of mapping as a tool for disease prevention and control.1 Over 160 years later, a more ambitious effort to map cholera has been reported in The Lancet.2 Forgoing so-called shoe leather epidemiology in favour of big data, Justin Lessler and colleagues2 used 279 cholera datasets covering 2283 locations in 37 countries, and cluster-level maps of access to improved water and sanitation in 41 countries, to map cholera incidence across sub-Saharan Africa at a 20 km × 20 km grid scale. They merged this incidence grid with census data and subnational administrative borders to identify and rank districts by their mean annual cholera incidence. Based on these analyses, they estimate that 151 of 3751 districts (4·0%, 95% credible interval [CrI] 1·7 to 16·8) in sub-Saharan Africa, home to 87·2 million people (95% CrI 60·3 million to 118·9 million), can be classified as high incidence (>1 case per 1000 people), and that targeting just 35·3 million people (95% CrI 26·3 million to 62·0 million) in the highest incidence districts with proven interventions—safe water, sanitation, and cholera vaccination—could reduce mean annual cholera incidence in the entire region by 50%. Alternatively, targeting 50·8 million people (95% CrI 39·7 million to 62·8 million) in just five countries (Somalia, Nigeria, Democratic Republic of the Congo, Sierra Leone, and Ghana) could prevent over 38% of all regional cholera cases. |
Time to first positive HIV-1 DNA PCR may differ with antiretroviral regimen in infants infected with non-B subtype HIV-1.
Balasubramanian R , Fowler MG , Dominguez K , Lockman S , Tookey PA , Huong NNG , Nesheim S , Hughes MD , Lallemant M , Tosswill J , Shaffer N , Sherman G , Palumbo P , Shapiro DE . AIDS 2017 31 (18) 2465-2474 OBJECTIVE: To evaluate the association of type and timing of prophylactic maternal and infant antiretroviral regimen with time to first positive HIV-1 DNA PCR test, in nonbreastfed HIV-infected infants, from populations infected predominantly with HIV-1 non-B subtype virus. DESIGN: Analysis of combined data on nonbreastfed HIV-infected infants from prospective cohorts in Botswana, Thailand, and the United Kingdom (N = 405). METHODS: Parametric models appropriate for interval-censored outcomes estimated the time to first positive PCR according to maternal or infant antiretroviral regimen category and timing of maternal antiretroviral initiation, with adjustment for covariates. RESULTS: Maternal antiretroviral regimens included: no antiretrovirals (n = 138), single-nucleoside analog reverse transcriptase inhibitor (n = 165), single-dose nevirapine with zidovudine (n = 66), and combination prophylaxis with 3 or more antiretrovirals [combination antiretroviral therapy (cART), n = 36]. Type of maternal/infant antiretroviral regimen and timing of maternal antiretroviral initiation were each significantly associated with time to first positive PCR (multivariate P < 0.0001). The probability of a positive test with no antiretrovirals compared with the other regimen/timing groups was significantly lower at 1 day after birth, but did not differ significantly after age 14 days. In a subgroup of 143 infants testing negative at birth, infant cART was significantly associated with longer time to first positive test (multivariate P = 0.04). CONCLUSION: Time to first positive HIV-1 DNA PCR in HIV-1-infected nonbreastfed infants (non-B HIV subtype) may differ according to maternal/infant antiretroviral regimen and may be longer with infant cART, which may have implications for scheduling infant HIV PCR-diagnostic testing and confirming final infant HIV status. |
Sleep apnea and pesticide exposure in a study of US farmers
Baumert BO , Carnes MU , Hoppin JA , Jackson CL , Sandler DP , Freeman LB , Henneberger PK , Umbach DM , Shrestha S , Long S , London SJ . Sleep Health 2017 4 (1) 20-26 Introduction: Carbamate and organophosphate pesticides inhibit acetylcholinesterase, and poisoning leads to respiratory depression. Thus, involvement in sleep apnea is plausible, but no data exist at lower levels of exposure. Other pesticides could impact sleep apnea by different mechanisms but have not been studied. Our study examines the associations between pesticide exposure and sleep apnea among pesticide applicators from a US farming population. Participants and methods: We analyzed data from 1569 male pesticide applicators, mostly farmers, from an asthma case-control study nested within the prospective Agricultural Health Study. On questionnaires, participants reported use of specific pesticides and physician diagnosis plus prescribed treatments for sleep apnea. We used multivariable logistic regression to estimate associations between ever use of 63 pesticides and sleep apnea (234 cases, 1335 noncases). Results: The most notable association was for carbofuran, a carbamate (100 exposed cases, odds ratio 1.83, 95% confidence interval 1.34-2.51, P = .0002). Carbofuran use began before reported onset of sleep apnea in all cases. Discussion: This study adds to the known adverse health outcomes of exposure to carbofuran, a pesticide canceled in the United States in 2009 for most agricultural purposes but persists in the environment and remains in use in some other countries. Conclusions: We conducted the first epidemiological study investigating the association of pesticide exposure and sleep apnea. Our results in a male agricultural population suggests that exposure to carbofuran is positively associated with sleep apnea. |
Raw milk consumption and other early-life farm exposures and adult pulmonary function in the Agricultural Lung Health Study
Wyss AB , House JS , Hoppin JA , Richards M , Hankinson JL , Long S , Henneberger PK , Beane Freeman LE , Sandler DP , O'Connell EL , Cummings CB , Umbach DM , London SJ . Thorax 2017 73 (3) 279-282 Literature suggests that early exposure to the farming environment protects against atopy and asthma; few studies have examined pulmonary function. We evaluated associations between early-life farming exposures and pulmonary function in 3061 adults (mean age=63) from a US farming population using linear regression. Childhood raw milk consumption was associated with higher FEV1 (beta=49.5 mL, 95% CI 2.8 to 96.1 mL, p=0.04) and FVC (beta=66.2 mL, 95% CI 13.2 to 119.1 mL, p=0.01). We did not find appreciable associations with other early-life farming exposures. We report a novel association between raw milk consumption and higher pulmonary function that lasts into older adulthood. |
Performance of the SAMBA I and II HIV-1 Semi-Q Tests for viral load monitoring at the point-of-care
Goel N , Ritchie AV , Mtapuri-Zinyowera S , Zeh C , Stepchenkova T , Lehga J , De Ruiter A , Farleigh LE , Edemaga D , So R , Sembongi H , Wisniewski C , Nadala L , Schito M , Lee H . J Virol Methods 2017 244 39-45 Although access to antiretroviral therapy for HIV infection is increasing in resource-poor countries, viral load testing for monitoring of treatment efficacy remains limited, expensive, and confined to centralized laboratories. The SAMBA HIV-1 Semi-Q Test is a nucleic acid-based amplification assay developed for viral load monitoring performed on either the semi-automated SAMBA I system for laboratory use or the fully automated SAMBA II system for point-of care use. We have assessed the performance characteristics of the SAMBA HIV-1 Semi-Q Test on SAMBA I and SAMBA II systems according to the Common Technical Specifications of the European Community's 98/79 In Vitro Diagnostic Medical Devices Directive. The sensitivity, specificity, reproducibility, and viral subtype coverage of the test were similar on the SAMBA I and SAMBA II platforms. The clinical performance on the SAMBA I system was compared with the Roche CAP/CTM assay and evaluated in-house with 130 patient specimens from London as well as in the field with 390 specimens in Kenya and Zimbabwe. The overall concordance between the SAMBA and CAP/CTM assays was 98.1%. The clinical performance of the test on the SAMBA II platform in comparison with the Abbott HIV-1 RealTime Assay was evaluated in-house with 150 specimens from Ukraine, yielding a concordance of 98.0%. The results thus show that the SAMBA HIV-1 Semi-Q Test performs equivalently on SAMBA I and SAMBA II, and they suggest that the test is suitable for implementation at the point-of-care in resource-poor regions where viral load testing is desperately needed but often unavailable. |
House dust endotoxin levels are associated with adult asthma in a U.S. farming population
Carnes MU , Hoppin JA , Metwali N , Wyss AB , Hankinson JL , O'Connell EL , Richards M , Long S , Beane Freeman LE , Sandler DP , Henneberger PK , Barker-Cummings C , Umbach DM , Thorne PS , London SJ . Ann Am Thorac Soc 2016 14 (3) 324-331 RATIONALE: Endotoxin initiates a pro-inflammatory response from the innate immune system. Studies in children suggest endotoxin exposure from house dust may be an important risk factor for asthma, but few studies have been conducted in adult populations. OBJECTIVES: To investigate the association of house dust endotoxin levels with asthma and related phenotypes (wheeze, atopy, and pulmonary function) in a large U.S. farming population. METHODS: Dust was collected from the bedrooms (n=2,485) of participants enrolled in a case-control study of current asthma (927 cases) nested within the Agricultural Health Study. Dust endotoxin was measured by Limulus amebocyte lysate assay. Outcomes were measured by questionnaire, spirometry, and blood draw. We evaluated associations using linear and logistic regression. MEASUREMENTS AND MAIN RESULTS: Endotoxin was significantly associated with current asthma (Odds Ratio (OR)=1.30, 95% confidence interval (CI)=1.14-1.47), and this relationship was modified by early life farm exposure (born on a farm: OR=1.18, 95% CI=1.02-1.37; not born on a farm: OR=1.67, 95% CI=1.26-2.20, Interaction p-value=0.05). Significant positive associations were seen with both atopic and nonatopic asthma. Endotoxin was not related to either atopy or wheeze. Higher endotoxin was related to lower FEV1/FVC in asthma cases only (Interaction p=0.01). For asthma, there was suggestive evidence of a gene by environment interaction for the CD14 variant, rs2569190 (Interaction p=0.16), but not for the TLR4 variants, rs4986790 or rs4986791. CONCLUSIONS: House dust endotoxin was associated with current atopic and nonatopic asthma in a U.S. farming population. The degree of the association with asthma depended on early life farm exposures. Furthermore, endotoxin was associated with lower pulmonary function in asthmatics. |
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