Last data update: Sep 16, 2024. (Total: 47680 publications since 2009)
Records 1-30 (of 47 Records) |
Query Trace: Shepherd A [original query] |
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Time-specific impact of mono-benzyl phthalate (MBzP) and perfluorooctanoic acid (PFOA) on breast density of a Chilean adolescent cohort
Kim CE , Binder AM , Corvalan C , Pereira A , Shepherd J , Calafat AM , Botelho JC , Hampton JM , Trentham-Dietz A , Michels KB . Environ Int 2023 181 108241 INTRODUCTION: High mammographic density is among the strongest and most established predictors for breast cancer risk. Puberty, the period during which breasts undergo exponential mammary growth, is considered one of the critical stages of breast development for environmental exposures. Benzylbutyl phthalate (BBP) and perfluorooctanoic acid (PFOA) are pervasive endocrine disrupting chemicals that may increase hormone-sensitive cancers. Evaluating the potential impact of BBP and PFOA exposure on pubertal breast density is important to our understanding of early-life environmental influences on breast cancer etiology. OBJECTIVE: To prospectively assess the effect of biomarker concentrations of monobenzyl phthalate (MBzP) and PFOA at specific pubertal window of susceptibility (WOS) on adolescent breast density. METHOD: This study included 376 Chilean girls from the Growth and Obesity Cohort Study with data collection at four timepoints: Tanner breast stages 1 (B1) and 4 (B4), 1- year post- menarche (1YPM) and 2-years post-menarche (2YPM). Dual-energy X-ray absorptiometry was used to assess the absolute fibroglandular volume (FGV) and percent breast density (%FGV) at 2YPM. We used concentrations of PFOA in serum and MBzP in urine as an index of exposure to PFOA and BBP, respectively. Parametric G-formula was used to estimate the time-specific effects of MBzP and PFOA on breast density. The models included body fat percentage as a time-varying confounder and age, birthweight, age at menarche, and maternal education as fixed covariates. RESULTS: A doubling of serum PFOA concentration at B4 resulted in a non-significant increase in absolute FGV (β:11.25, 95% confidence interval (CI): -0.28, 23.49)), while a doubling of PFOA concentration at 1YPM resulted in a decrease in % FGV (β:-4.61, 95% CI: -7.45, -1.78). We observed no associations between urine MBzP and breast density measures. CONCLUSION: In this cohort of Latina girls, PFOA serum concentrations corresponded to a decrease in % FGV. No effect was observed between MBzP and breast density measures across pubertal WOS. |
Correction: Building capacity for injury prevention: a process evaluation of a replication of the Cardiff Violence Prevention Programme in the Southeastern USA
Mercer Kollar LM , Sumner SA , Bartholow B , Wu DT , More JC , Mays EW , Atkins EV , Fraser DA , Flood CE , Shepherd JP . Inj Prev 2021 27 (1) 101 The article is previously published with incorrect and missing information. The updates are as follows: | | The last sentence in the third paragraph of ‘Building hospital capacity for data collection’ in ‘Results’ section has been updated as ‘A one-way ANOVA revealed a significant difference between April 2015 and April 2016 triage times, F(1,2734)=5.33, p=0.02. Triage times were on average 16.2 s longer in April 2016 compared with April 2015. No post-hoc analyses were done to control for other, non-CMST-related changes that occurred during the triage process (eg, additional triage screen) from April 2015 to April 2016.’ | Below statement has been added in the sixth paragraph of the ‘Discussion’ section after ‘Nurse participation in the satisfaction … a different US hospital.’ | The statistically significant increase in triage time of 16.2 s, which is unlikely to be clinically significant, may reflect other non-CMST-related triage process changes - such as addition of another triage screen - that were not accounted for in the analyses. |
Variability in urinary phthalates, phenols, and parabens across childhood and relation to adolescent breast composition in Chilean girls
Yoon LS , Binder AM , Pereira A , Calafat AM , Shepherd J , Corvalán C , Michels KB . Environ Int 2022 170 107586 BACKGROUND: Epidemiologic evidence suggests that environmental factors acting as endocrine disrupting chemicals (EDCs) are associated with mammographic breast density and the risk of breast cancer. Exposure to EDCs during puberty, a period of rapid breast development, may affect susceptibility to breast carcinogenesis. METHODS: In a cohort of 366 Chilean adolescents from the Growth and Obesity Cohort Study, we evaluated the relation between urinary concentrations of 15 suspected EDC biomarkers across three pubertal time points (Tanner breast stage 1 (B1), 4 (B4), and 1-year post-menarche) and breast fibroglandular volume (FGV; percent FGV [%FGV] and absolute FGV [aFGV]) and total breast volume (tBV) at 2-years post-menarche. We used linear mixed models to test differences in creatinine-corrected EDC biomarker concentrations at B4 and 1-year post-menarche compared to B1 and calculated intraclass correlation coefficients (ICC) of EDC concentrations across time points to appraise the consistency of measurements. We fit multivariable generalized estimating equations (GEEs) to evaluate windows of susceptibility for the association between log(10)-transformed EDCs and log(10)-transformed breast outcomes. GEEs were adjusted for age, body fat percentage, total caloric intake, and maternal education. RESULTS: Urinary EDC biomarker concentrations highly varied across pubertal time points (ICC range 0.01-0.30). For 12 EDCs, biomarker concentrations decreased over time. Triclosan measured at 1-year post-menarche was inversely associated with %FGV at 2-years post-menarche (β = -0.025, 95 % confidence interval = -0.041, -0.008). Mono(2-ethyl-5-carboxypentyl) phthalate and the sum of di(2-ethylhexyl) phthalate metabolite concentrations at B4 were positively associated with aFGV and tBV at 2-years post-menarche. No measured phenols were associated with aFGV and tBV, while no measured parabens were associated with %FGV and aFGV. CONCLUSIONS: Our study suggests relatively high variability in EDC biomarker concentrations across the peripubertal time period. We also found evidence to suggest that there may be pubertal windows of susceptibility to select EDCs for the association with adolescent breast density. |
Impact of tenofovir disoproxil fumarate use during pregnancy on maternal bone mineral density
Wang L , Kourtis AP , Wiener J , Chen L , Liu W , Fan B , Shepherd J , Bulterys M . Pediatr Infect Dis J 2022 41 (12) 976-978 Chronic hepatitis B virus (HBV) infection and HIV infection are diseases of great public health importance. Tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor, is effective for the treatment of both HIV and HBV.1,2 However, information on the bone safety of TDF during pregnancy, a time with increased demands on bone metabolism, has not been systematically assessed. | We conducted a phase II randomized controlled trial (RCT) in Guangxi Zhuang Autonomous Region of the People’s Republic of China, to evaluate the bone mineral density (BMD) effects of TDF on women and their infants. Effects of TDF on bone health of infants have been reported elsewhere3; this report presents our findings on the effects of TDF on maternal BMD. |
Derivation and external validation of a risk score for predicting HIV-associated tuberculosis to support case finding and preventive therapy scale-up: A cohort study.
Auld AF , Kerkhoff AD , Hanifa Y , Wood R , Charalambous S , Liu Y , Agizew T , Mathoma A , Boyd R , Date A , Shiraishi RW , Bicego G , Mathebula-Modongo U , Alexander H , Serumola C , Rankgoane-Pono G , Pono P , Finlay A , Shepherd JC , Ellerbrock TV , Grant AD , Fielding K . PLoS Med 2021 18 (9) e1003739 BACKGROUND: Among people living with HIV (PLHIV), more flexible and sensitive tuberculosis (TB) screening tools capable of detecting both symptomatic and subclinical active TB are needed to (1) reduce morbidity and mortality from undiagnosed TB; (2) facilitate scale-up of tuberculosis preventive therapy (TPT) while reducing inappropriate prescription of TPT to PLHIV with subclinical active TB; and (3) allow for differentiated HIV-TB care. METHODS AND FINDINGS: We used Botswana XPRES trial data for adult HIV clinic enrollees collected during 2012 to 2015 to develop a parsimonious multivariable prognostic model for active prevalent TB using both logistic regression and random forest machine learning approaches. A clinical score was derived by rescaling final model coefficients. The clinical score was developed using southern Botswana XPRES data and its accuracy validated internally, using northern Botswana data, and externally using 3 diverse cohorts of antiretroviral therapy (ART)-naive and ART-experienced PLHIV enrolled in XPHACTOR, TB Fast Track (TBFT), and Gugulethu studies from South Africa (SA). Predictive accuracy of the clinical score was compared with the World Health Organization (WHO) 4-symptom TB screen. Among 5,418 XPRES enrollees, 2,771 were included in the derivation dataset; 67% were female, median age was 34 years, median CD4 was 240 cells/μL, 189 (7%) had undiagnosed prevalent TB, and characteristics were similar between internal derivation and validation datasets. Among XPHACTOR, TBFT, and Gugulethu cohorts, median CD4 was 400, 73, and 167 cells/μL, and prevalence of TB was 5%, 10%, and 18%, respectively. Factors predictive of TB in the derivation dataset and selected for the clinical score included male sex (1 point), ≥1 WHO TB symptom (7 points), smoking history (1 point), temperature >37.5°C (6 points), body mass index (BMI) <18.5kg/m2 (2 points), and severe anemia (hemoglobin <8g/dL) (3 points). Sensitivity using WHO 4-symptom TB screen was 73%, 80%, 94%, and 94% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, but increased to 88%, 87%, 97%, and 97%, when a clinical score of ≥2 was used. Negative predictive value (NPV) also increased 1%, 0.3%, 1.6%, and 1.7% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, when the clinical score of ≥2 replaced WHO 4-symptom TB screen. Categorizing risk scores into low (<2), moderate (2 to 10), and high-risk categories (>10) yielded TB prevalence of 1%, 1%, 2%, and 6% in the lowest risk group and 33%, 22%, 26%, and 32% in the highest risk group for XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively. At clinical score ≥2, the number needed to screen (NNS) ranged from 5.0 in Gugulethu to 11.0 in XPHACTOR. Limitations include that the risk score has not been validated in resource-rich settings and needs further evaluation and validation in contemporary cohorts in Africa and other resource-constrained settings. CONCLUSIONS: The simple and feasible clinical score allowed for prioritization of sensitivity and NPV, which could facilitate reductions in mortality from undiagnosed TB and safer administration of TPT during proposed global scale-up efforts. Differentiation of risk by clinical score cutoff allows flexibility in designing differentiated HIV-TB care to maximize impact of available resources. |
Association Between COVID-19 Lockdown Measures and Emergency Department Visits for Violence-Related Injuries in Cardiff, Wales.
Shepherd JP , Moore SC , Long A , Mercer Kollar LM , Sumner SA . JAMA 2021 325 (9) 885-887 This study investigates emergency department visits for violence-related injuries occurring at home and outside the home in Cardiff, Wales, before and after COVID-19 lockdown measures were instituted in March 2020. |
Risk scores for predicting early antiretroviral therapy mortality in sub-Saharan Africa to inform who needs intensification of care: a derivation and external validation cohort study
Auld AF , Fielding K , Agizew T , Maida A , Mathoma A , Boyd R , Date A , Pals SL , Bicego G , Liu Y , Shiraishi RW , Ehrenkranz P , Serumola C , Mathebula U , Alexander H , Charalambous S , Emerson C , Rankgoane-Pono G , Pono P , Finlay A , Shepherd JC , Holmes C , Ellerbrock TV , Grant AD . BMC Med 2020 18 (1) 311 BACKGROUND: Clinical scores to determine early (6-month) antiretroviral therapy (ART) mortality risk have not been developed for sub-Saharan Africa (SSA), home to 70% of people living with HIV. In the absence of validated scores, WHO eligibility criteria (EC) for ART care intensification are CD4 < 200/μL or WHO stage III/IV. METHODS: We used Botswana XPRES trial data for adult ART enrollees to develop CD4-independent and CD4-dependent multivariable prognostic models for 6-month mortality. Scores were derived by rescaling coefficients. Scores were developed using the first 50% of XPRES ART enrollees, and their accuracy validated internally and externally using South African TB Fast Track (TBFT) trial data. Predictive accuracy was compared between scores and WHO EC. RESULTS: Among 5553 XPRES enrollees, 2838 were included in the derivation dataset; 68% were female and 83 (3%) died by 6 months. Among 1077 TBFT ART enrollees, 55% were female and 6% died by 6 months. Factors predictive of 6-month mortality in the derivation dataset at p < 0.01 and selected for the CD4-independent score included male gender (2 points), ≥ 1 WHO tuberculosis symptom (2 points), WHO stage III/IV (2 points), severe anemia (hemoglobin < 8 g/dL) (3 points), and temperature > 37.5 °C (2 points). The same variables plus CD4 < 200/μL (1 point) were included in the CD4-dependent score. Among XPRES enrollees, a CD4-independent score of ≥ 4 would provide 86% sensitivity and 66% specificity, whereas WHO EC would provide 83% sensitivity and 58% specificity. If WHO stage alone was used, sensitivity was 48% and specificity 89%. Among TBFT enrollees, the CD4-independent score of ≥ 4 would provide 95% sensitivity and 27% specificity, whereas WHO EC would provide 100% sensitivity but 0% specificity. Accuracy was similar between CD4-independent and CD4-dependent scores. Categorizing CD4-independent scores into low (< 4), moderate (4-6), and high risk (≥ 7) gave 6-month mortality of 1%, 4%, and 17% for XPRES and 1%, 5%, and 30% for TBFT enrollees. CONCLUSIONS: Sensitivity of the CD4-independent score was nearly twice that of WHO stage in predicting 6-month mortality and could be used in settings lacking CD4 testing to inform ART care intensification. The CD4-dependent score improved specificity versus WHO EC. Both scores should be considered for scale-up in SSA. |
Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States.
Kujawski SA , Wong KK , Collins JP , Epstein L , Killerby ME , Midgley CM , Abedi GR , Ahmed NS , Almendares O , Alvarez FN , Anderson KN , Balter S , Barry V , Bartlett K , Beer K , Ben-Aderet MA , Benowitz I , Biggs HM , Binder AM , Black SR , Bonin B , Bozio CH , Brown CM , Bruce H , Bryant-Genevier J , Budd A , Buell D , Bystritsky R , Cates J , Charles EM , Chatham-Stephens K , Chea N , Chiou H , Christiansen D , Chu V , Cody S , Cohen M , Conners EE , Curns AT , Dasari V , Dawson P , DeSalvo T , Diaz G , Donahue M , Donovan S , Duca LM , Erickson K , Esona MD , Evans S , Falk J , Feldstein LR , Fenstersheib M , Fischer M , Fisher R , Foo C , Fricchione MJ , Friedman O , Fry A , Galang RR , Garcia MM , Gerber SI , Gerrard G , Ghinai I , Gounder P , Grein J , Grigg C , Gunzenhauser JD , Gutkin GI , Haddix M , Hall AJ , Han GS , Harcourt J , Harriman K , Haupt T , Haynes AK , Holshue M , Hoover C , Hunter JC , Jacobs MW , Jarashow C , Joshi K , Kamali T , Kamili S , Kim L , Kim M , King J , Kirking HL , Kita-Yarbro A , Klos R , Kobayashi M , Kocharian A , Komatsu KK , Koppaka R , Layden JE , Li Y , Lindquist S , Lindstrom S , Link-Gelles R , Lively J , Livingston M , Lo K , Lo J , Lu X , Lynch B , Madoff L , Malapati L , Marks G , Marlow M , Mathisen GE , McClung N , McGovern O , McPherson TD , Mehta M , Meier A , Mello L , Moon SS , Morgan M , Moro RN , Murray J , Murthy R , Novosad S , Oliver SE , O’Shea J , Pacilli M , Paden CR , Pallansch MA , Patel M , Patel S , Pedraza I , Pillai SK , Pindyck T , Pray I , Queen K , Quick N , Reese H , Reporter R , Rha B , Rhodes H , Robinson S , Robinson P , Rolfes MA , Routh JA , Rubin R , Rudman SL , Sakthivel SK , Scott S , Shepherd C , Shetty V , Smith EA , Smith S , Stierman B , Stoecker W , Sunenshine R , Sy-Santos R , Tamin A , Tao Y , Terashita D , Thornburg NJ , Tong S , Traub E , Tural A , Uehara A , Uyeki TM , Vahey G , Verani JR , Villarino E , Wallace M , Wang L , Watson JT , Westercamp M , Whitaker B , Wilkerson S , Woodruff RC , Wortham JM , Wu T , Xie A , Yousaf A , Zahn M , Zhang J . Nat Med 2020 26 (6) 861-868 Data on the detailed clinical progression of COVID-19 in conjunction with epidemiological and virological characteristics are limited. In this case series, we describe the first 12 US patients confirmed to have COVID-19 from 20 January to 5 February 2020, including 4 patients described previously(1-3). Respiratory, stool, serum and urine specimens were submitted for SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing, viral culture and whole genome sequencing. Median age was 53 years (range: 21-68); 8 patients were male. Common symptoms at illness onset were cough (n = 8) and fever (n = 7). Patients had mild to moderately severe illness; seven were hospitalized and demonstrated clinical or laboratory signs of worsening during the second week of illness. No patients required mechanical ventilation and all recovered. All had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2-3 weeks after illness onset. Lowest real-time PCR with reverse transcription cycle threshold values in the upper respiratory tract were often detected in the first week and SARS-CoV-2 was cultured from early respiratory specimens. These data provide insight into the natural history of SARS-CoV-2. Although infectiousness is unclear, highest viral RNA levels were identified in the first week of illness. Clinicians should anticipate that some patients may worsen in the second week of illness. |
Effect of tuberculosis screening and retention interventions on early antiretroviral therapy mortality in Botswana: a stepped-wedge cluster randomized trial
Auld AF , Agizew T , Mathoma A , Boyd R , Date A , Pals SL , Serumola C , Mathebula U , Alexander H , Ellerbrock TV , Rankgoane-Pono G , Pono P , Shepherd JC , Fielding K , Grant AD , Finlay A . BMC Med 2020 18 (1) 19 BACKGROUND: Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. METHODS: At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. RESULTS: We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/muL in SOC, 246/muL in EC, and 241/muL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees. CONCLUSIONS: Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed. TRIAL REGISTRATION: Retrospectively registered: ClinicalTrials.gov (NCT02538952). |
Maternal and infant bone mineral density 1 year after delivery in a randomized, controlled trial of maternal tenofovir disoproxil fumarate to prevent mother-to-child transmission of hepatitis B virus
Salvadori N , Fan B , Teeyasoontranon W , Ngo-Giang-Huong N , Phanomcheong S , Luvira A , Puangsombat A , Suwannarat A , Srirompotong U , Putiyanun C , Cressey TR , Decker L , Khamduang W , Harrison L , Tierney C , Shepherd JA , Kourtis AP , Bulterys M , Siberry GK , Jourdain G . Clin Infect Dis 2019 69 (1) 144-146 In a randomized, double-blind, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) use from 28 weeks gestational age to 2 months postpartum to prevent mother-to-child transmission of hepatitis B virus, there was no significant effect of maternal TDF use on maternal or infant bone mineral density 1 year after delivery/birth. Clinical Trials Registration. NCT01745822. |
miRNA-378a as a key regulator of cardiovascular health following engineered nanomaterial inhalation exposure.
Hathaway QA , Durr AJ , Shepherd DL , Pinti MV , Brandebura AN , Nichols CE , Kunovac A , Goldsmith WT , Friend SA , Abukabda AB , Fink GK , Nurkiewicz TR , Hollander JM . Nanotoxicology 2019 13 (5) 1-20 Nano-titanium dioxide (nano-TiO2), though one of the most utilized and produced engineered nanomaterials (ENMs), diminishes cardiovascular function through dysregulation of metabolism and mitochondrial bioenergetics following inhalation exposure. The molecular mechanisms governing this cardiac dysfunction remain largely unknown. The purpose of this study was to elucidate molecular mediators that connect nano-TiO2 exposure with impaired cardiac function. Specifically, we were interested in the role of microRNA (miRNA) expression in the resulting dysfunction. Not only are miRNA global regulators of gene expression, but also miRNA-based therapeutics provide a realistic treatment modality. Wild type and MiRNA-378a knockout mice were exposed to nano-TiO2 with an aerodynamic diameter of 182 +/- 1.70 nm and a mass concentration of 11.09 mg/m(3) for 4 h. Cardiac function, utilizing the Vevo 2100 Imaging System, electron transport chain complex activities, and mitochondrial respiration assessed cardiac and mitochondrial function. Immunoblotting and qPCR examined molecular targets of miRNA-378a. MiRNA-378a-3p expression was increased 48 h post inhalation exposure to nano-TiO2. Knockout of miRNA-378a preserved cardiac function following exposure as revealed by preserved E/A ratio and E/SR ratio. In knockout animals, complex I, III, and IV activities ( approximately 2- to 6-fold) and fatty acid respiration ( approximately 5-fold) were significantly increased. MiRNA-378a regulated proteins involved in mitochondrial fusion, transcription, and fatty acid metabolism. MiRNA-378a-3p acts as a negative regulator of mitochondrial metabolic and biogenesis pathways. MiRNA-378a knockout animals provide a protective effect against nano-TiO2 inhalation exposure by altering mitochondrial structure and function. This is the first study to manipulate a miRNA to attenuate the effects of ENM exposure. |
Building capacity for injury prevention: a process evaluation of a replication of the Cardiff Violence Prevention Programme in the Southeastern USA
Mercer Kollar LM , Sumner SA , Bartholow B , Wu DT , Moore JC , Mays EW , Atkins EV , Fraser DA , Flood CE , Shepherd JP . Inj Prev 2019 26 (3) 221-228 OBJECTIVES: Violence is a major public health problem in the USA. In 2016, more than 1.6 million assault-related injuries were treated in US emergency departments (EDs). Unfortunately, information about the magnitude and patterns of violent incidents is often incomplete and underreported to law enforcement (LE). In an effort to identify more complete information on violence for the development of prevention programme, a cross-sectoral Cardiff Violence Prevention Programme (Cardiff Model) partnership was established at a large, urban ED with a level I trauma designation and local metropolitan LE agency in the Atlanta, Georgia metropolitan area. The Cardiff Model is a promising violence prevention approach that promotes combining injury data from hospitals and LE. The objective was to describe the Cardiff Model implementation and collaboration between hospital and LE partners. METHODS: The Cardiff Model was replicated in the USA. A process evaluation was conducted by reviewing project materials, nurse surveys and interviews and ED-LE records. RESULTS: Cardiff Model replication centred around four activities: (1) collaboration between the hospital and LE to form a community safety partnership locally called the US Injury Prevention Partnership; (2) building hospital capacity for data collection; (3) data aggregation and analysis and (4) developing and implementing violence prevention interventions based on the data. CONCLUSIONS: The Cardiff Model can be implemented in the USA for sustainable violent injury data surveillance and sharing. Key components include building a strong ED-LE partnership, communicating with each other and hospital staff, engaging in capacity building and sustainability planning. |
Pre-pubertal and pubertal endocrine disrupting chemicals exposure and breast density among Chilean adolescents
Binder AM , Corvalan C , Pereira A , Calafat AM , Ye X , Shepherd J , Michels KB . Cancer Epidemiol Biomarkers Prev 2018 27 (12) 1491-1499 BACKGROUND: During puberty, mammary tissue undergoes rapid development, which provides a window of heightened susceptibility of breast composition to the influence of endogenous and exogenous hormones. Exposure to endocrine disrupting chemicals (EDCs) may affect breast development and composition and the risk of developing breast cancer in adulthood. METHODS: We evaluated the associations between breast density and urinary concentrations of phenols and phthalates collected at Tanner 1 (B1) and Tanner 4 (B4) in 200 Chilean girls. Total breast volume (BV), fibroglandular volume (FGV), and percent dense breast (%FGV) were evaluated at B4 using dual x-ray absorptiometry. Generalized estimating equations were used to analyze the association between concentrations of EDC biomarkers across puberty and breast density. RESULTS: The geometric mean %FGV was 7% higher among girls in the highest relative to the lowest tertile of monocarboxyisooctyl phthalate (1.07; 95% CI: 1.01-1.14). Monoethyl phthalate concentrations at B4 were positively associated with FGV (highest vs lowest tertile: 1.22; 95% CI: 1.06-1.40). Bisphenol A displayed a u-shaped association with FGV; girls in the middle tertile had at least 10% lower FGV than girls in the lowest or highest tertiles. Monocarboxyisononyl phthalate showed a non-linear association with BV. No other statistically significant associations were observed. CONCLUSIONS: Our results suggest that the developing breast tissue is susceptible to select EDCs during childhood and adolescence. IMPACT: This study may spur further investigations into environmental influences on breast development during puberty, and how shifts in pubertal breast density track through the life course to modify breast cancer risk. |
Tenofovir disoproxil fumarate use during pregnancy and infant bone health: The tenofovir in pregnancy pilot study
Kourtis AP , Wiener J , Wang L , Fan B , Shepherd JA , Chen L , Liu W , Shepard C , Wang L , Wang A , Bulterys M . Pediatr Infect Dis J 2018 37 (11) e264-e268 The effects of maternal tenofovir use on infant bone mineral content (BMC) and bone mineral density (BMD) were evaluated in a pilot study of HIV/Hepatitis B-coinfected pregnant women in China. BMD and BMC were assessed at age 6 months of life in 14 tenofovir-exposed and 13 unexposed infants. Trends toward lower BMC and BMD were observed in infants exposed to maternal tenofovir but were not statistically significant. |
Food safety practices linked with proper refrigerator temperatures in retail delis
Brown LG , Hoover ER , Faw BV , Hedeen NK , Nicholas D , Wong MR , Shepherd C , Gallagher DL , Kause JR . Foodborne Pathog Dis 2018 15 (5) 300-307 Listeria monocytogenes (L. monocytogenes) causes the third highest number of foodborne illness deaths annually. L. monocytogenes contamination of sliced deli meats at the retail level is a significant contributing factor to L. monocytogenes illness. The Centers for Disease Control and Prevention's Environmental Health Specialists Network (EHS-Net) conducted a study to learn more about retail delis' practices concerning L. monocytogenes growth and cross-contamination prevention. This article presents data from this study on the frequency with which retail deli refrigerator temperatures exceed 41 degrees F, the Food and Drug Administration (FDA)-recommended maximum temperature for ready-to-eat food requiring time and temperature control for safety (TCS) (such as retail deli meat). This provision was designed to control bacterial growth in TCS foods. This article also presents data on deli and staff characteristics related to the frequency with which retail delis refrigerator temperatures exceed 41 degrees F. Data from observations of 445 refrigerators in 245 delis showed that in 17.1% of delis, at least one refrigerator was >41 degrees F. We also found that refrigeration temperatures reported in this study were lower than those reported in a related 2007 study. Delis with more than one refrigerator, that lacked refrigerator temperature recording, and had a manager who had never been food safety certified had greater odds of having a refrigerator temperature >41 degrees F. The data from this study suggest that retail temperature control is improving over time. They also identify a food safety gap: some delis have refrigerator temperatures that exceed 41 degrees F. We also found that two food safety interventions were related to better refrigerated storage practices: kitchen manager certification and recording refrigerated storage temperatures. Regulatory food safety programs and the retail industry may wish to consider encouraging or requiring kitchen manager certification and recording refrigerated storage temperatures. |
Evidence-based guidelines for supportive care of patients with Ebola virus disease
Lamontagne F , Fowler RA , Adhikari NK , Murthy S , Brett-Major DM , Jacobs M , Uyeki TM , Vallenas C , Norris SL , Fischer WANd , Fletcher TE , Levine AC , Reed P , Bausch DG , Gove S , Hall A , Shepherd S , Siemieniuk RA , Lamah MC , Kamara R , Nakyeyune P , Soka MJ , Edwin A , Hazzan AA , Jacob ST , Elkarsany MM , Adachi T , Benhadj L , Clement C , Crozier I , Garcia A , Hoffman SJ , Guyatt GH . Lancet 2017 391 (10121) 700-708 The 2013-16 Ebola virus disease outbreak in west Africa was associated with unprecedented challenges in the provision of care to patients with Ebola virus disease, including absence of pre-existing isolation and treatment facilities, patients' reluctance to present for medical care, and limitations in the provision of supportive medical care. Case fatality rates in west Africa were initially greater than 70%, but decreased with improvements in supportive care. To inform optimal care in a future outbreak of Ebola virus disease, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to develop evidence-based guidelines for the delivery of supportive care to patients admitted to Ebola treatment units. Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief. |
Water quality survey of splash pads after a waterborne salmonellosis outbreak - Tennessee, 2014
Clayton JL , Manners J , Miller S , Shepherd C , Dunn JR , Schaffner W , Jones TF . J Environ Health 2017 79 (10) 8-13 Waterborne outbreaks of salmonellosis are uncommon. The Tennessee Department of Health investigated a salmonellosis outbreak of 10 cases with the only common risk factor being exposure to a single splash pad. Risks included water splashed in the face at the splash pad and no free residual chlorine in the water system. We surveyed water quality and patron behaviors at splash pads statewide. Of the 29 splash pads participating in the water quality survey, 24 (83%) used a recirculating water system. Of the 24, 5 (21%) water samples were tested by polymerase chain reaction and found to be positive for E. coli, Giardia, norovirus, or Salmonella. Among 95 patrons observed, we identified common high-risk behaviors of sitting on the fountain or spray head and putting mouth to water. Water venue regulations and improved education of patrons are important to aid prevention efforts. |
Policing and public health-strategies for collaboration
Shepherd JP , Sumner SA . JAMA 2017 317 (15) 1525-1526 Policing and public health have largely been perceived by clinicians, researchers, and policy makers as 2 entirely separate approaches to reducing violence. This long-standing tradition, reinforced by the different languages of criminal justice systems (eg, deterrence, culpability, victimhood, and offending) and public health systems (eg, injury, risk factors, and epidemiology), has perhaps contributed to limited collaboration between local law enforcement agencies and public health to prevent violence. It has also probably limited collaboration between criminologists and population health researchers relative to other cross-discipline areas such as road traffic safety, prisoner health, and prevention of substance abuse. | Yet the safety of populations and individuals is a chief concern of both policing and public health. Furthermore, both citizens and law enforcement officials experience morbidity and mortality from violence, and policing actions can directly affect the provision of public health services.1 In light of the need for improved multisector efforts to prevent violence, there have been calls for greater collaboration between the various disciplines that are tasked to prevent and respond to violence. However, most health professionals have limited knowledge about the rationale for partnership between the health sector and police, and how this might be done. This Viewpoint discusses strategies for such work. |
Trends in osteoporosis and low bone mass in older US adults, 2005-2006 through 2013-2014
Looker AC , Sarafrazi Isfahani N , Fan B , Shepherd JA . Osteoporos Int 2017 28 (6) 1979-1988 This study examined trends in osteoporosis and low bone mass in older US adults between 2005 and 2014 using bone mineral density (BMD) data from the National Health and Nutrition Examination Survey (NHANES). Osteoporosis and low bone mass appear to have increased at the femur neck but not at the lumbar spine during this period. INTRODUCTION: Recent preliminary data from Medicare suggest that the decline in hip fracture incidence among older US adults may have plateaued in 2013-2014, but comparable data on BMD trends for this time period are currently lacking. This study examined trends in the prevalence of osteoporosis and low bone mass since 2005 using BMD data from NHANES. The present study also updated prevalence estimates to 2013-2014 and included estimates for non-Hispanic Asians. METHODS: Femur neck and lumbar spine BMD by DXA were available for 7954 adults aged 50 years and older from four NHANES survey cycles between 2005-2006 and 2013-2014. RESULTS: Significant trends (quadratic or linear) were observed for the femur neck (mean T-score and osteoporosis in both sexes; low bone mass in women) but not for the lumbar spine. The trend in femur neck status was somewhat U-shaped, with prevalences being most consistently significantly higher (by 1.1-6.6 percentage points) in 2013-2014 than 2007-2008. Adjusting for changes in body mass index, smoking, milk intake, and physician's diagnosis of osteoporosis between surveys did not change femur neck trends. In 2013-2014, the percent of older adults with osteoporosis was 6% at the femur neck, 8% at the lumbar spine, and 11% at either site. CONCLUSIONS: There was some evidence of a decline in femur neck BMD between 2005-2006 and 2013-2014, but not in lumbar spine BMD. Changes in the risk factors that could be examined did not explain the femur neck BMD trends. |
Spine fracture prevalence in a nationally representative sample of US women and men aged ≥40 years: results from the National Health and Nutrition Examination Survey (NHANES) 2013-2014
Cosman F , Krege JH , Looker AC , Schousboe JT , Fan B , Sarafrazi Isfahani N , Shepherd JA , Krohn KD , Steiger P , Wilson KE , Genant HK . Osteoporos Int 2017 28 (6) 1857-1866 Spine fracture prevalence is similar in men and women, increasing from <5 % in those <60 to 11 % in those 70-79 and 18 % in those ≥80 years. Prevalence was higher with age, lower bone mineral density (BMD), and in those meeting criteria for spine imaging. Most subjects with spine fractures were unaware of them. INTRODUCTION: Spine fractures have substantial medical significance but are seldom recognized. This study collected contemporary nationally representative spine fracture prevalence data. METHODS: Cross-sectional analysis of 3330 US adults aged ≥40 years participating in NHANES 2013-2014 with evaluable Vertebral Fracture Assessment (VFA). VFA was graded by semiquantitative measurement. BMD and an osteoporosis questionnaire were collected. RESULTS: Overall spine fracture prevalence was 5.4 % and similar in men and women. Prevalence increased with age from <5 % in those <60 to 11 % in those 70-79 and 18 % in those ≥80 years. Fractures were more common in non-Hispanic whites and in people with lower body mass index and BMD. Among subjects with spine fracture, 26 % met BMD criteria for osteoporosis. Prevalence was higher in subjects who met National Osteoporosis Foundation (NOF) criteria for spine imaging (14 vs 4.7 %, P < 0.001). Only 8 % of people with a spine fracture diagnosed by VFA had a self-reported fracture, and among those who self-reported a spine fracture, only 21 % were diagnosed with fracture by VFA. CONCLUSION: Spine fracture prevalence is similar in women and men and increases with age and lower BMD, although most subjects with spine fracture do not meet BMD criteria for osteoporosis. Since most (>90 %) individuals were unaware of their spine fractures, lateral spine imaging is needed to identify these women and men. Spine fracture prevalence was threefold higher in individuals meeting NOF criteria for spine imaging ( approximately 1 in 7 undergoing VFA). Identifying spine fractures as part of comprehensive risk assessment may improve clinical decision making. |
Locally acquired eastern equine encephalitis virus disease, Arkansas, USA
Garlick J , Lee TJ , Shepherd P , Linam WM , Pastula DM , Weinstein S , Schexnayder SM . Emerg Infect Dis 2016 22 (12) 2216-2217 Eastern equine encephalitis virus (EEEV) is an arbovirus (family Togaviridae, genus Alphavirus) transmitted to humans primarily from Aedes, Coquillettidia, and Culex mosquitoes. EEEV is maintained in a transmission cycle between Culiseta melanura mosquitoes and birds in freshwater hardwood swamps (1). Affected humans and horses are considered to be dead-end hosts; that is, they usually do not develop sufficient levels of viremia to infect mosquitoes. Although human EEEV disease is rare, it has a case-fatality rate of >30% and >50% of survivors may have permanent neurologic sequelae (2–5). Cases occur sporadically each year, primarily along the eastern and Gulf coasts of North America, but no cases have been previously reported in Arkansas (1). We report a locally acquired case of human EEEV disease in Arkansas. | In October 2013, a male teenager from southwestern Arkansas sought care at a local hospital after 3 days of headache and 3 new-onset focal seizures. He had a history of recent multiple mosquito bites and no history of recent travel. Initial laboratory studies on postsymptom onset day (PSOD) 3 showed normal peripheral leukocyte count, electrolytes, and liver function tests. Cerebrospinal fluid (CSF) exam showed 5 leukocytes/mm3 (reference 0–5), 7 erythrocytes/mm3 (reference 0), 55 mg/dL glucose (reference 45–80), and 36 mg/dL protein (reference 15–40). Noncontrast computed tomography (CT) of the head was normal. He was transferred to a regional academic pediatric hospital on PSOD 3. |
Implementation of a pragmatic, stepped-wedge cluster randomized trial to evaluate impact of Botswana's Xpert MTB/RIF diagnostic algorithm on TB diagnostic sensitivity and early antiretroviral therapy mortality
Auld AF , Agizew T , Pals S , Finlay A , Ndwapi N , Boyd R , Alexander H , Mathoma A , Basotli J , Gwebe-Nyirenda S , Shepherd J , Ellerbrock TV , Date A . BMC Infect Dis 2016 16 (1) 606 BACKGROUND: In 2012, as a pilot for Botswana's national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the "Xpert package". METHODS: The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the "Xpert package" on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster-randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is ≤52.5 % and post-Xpert sensitivity ≥82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is ≥13/100 person-years. DISCUSSION: Only one small previous trial (N = 424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov: NCT02538952 . |
Protocol for a population-based molecular epidemiology study of tuberculosis transmission in a high HIV-burden setting: the Botswana Kopanyo study.
Zetola NM , Modongo C , Moonan PK , Click E , Oeltmann JE , Shepherd J , Finlay A . BMJ Open 2016 6 (5) e010046 INTRODUCTION: Mycobacterium tuberculosis (Mtb) is transmitted from person to person via airborne droplet nuclei. At the community level, Mtb transmission depends on the exposure venue, infectiousness of the tuberculosis (TB) index case and the susceptibility of the index case's social network. People living with HIV infection are at high risk of TB, yet the factors associated with TB transmission within communities with high rates of TB and HIV are largely undocumented. The primary aim of the Kopanyo study is to better understand the demographic, clinical, social and geospatial factors associated with TB and multidrug-resistant TB transmission in 2 communities in Botswana, a country where 60% of all patients with TB are also infected with HIV. This manuscript describes the methods used in the Kopanyo study. METHODS AND ANALYSIS: The study will be conducted in greater Gaborone, which has high rates of HIV and a mobile population; and in Ghanzi, a rural community with lower prevalence of HIV infection and home to the native San population. Kopanyo aims to enrol all persons diagnosed with TB during a 4-year study period. From each participant, sputum will be cultured, and for all Mtb isolates, molecular genotyping (24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats) will be performed. Patients with matching genotype results will be considered members of a genotype cluster, a proxy for recent transmission. Demographic, behavioural, clinical and social information will be collected by interview. Participant residence, work place, healthcare facilities visited and social gathering venues will be geocoded. We will assess relationships between these factors and cluster involvement to better plan interventions for reducing TB transmission. ETHICS: Ethical approval from the Independent Review Boards at the University of Pennsylvania, US Centers for Disease Control and Prevention, Botswana Ministry of Health and University of Botswana has been obtained. |
Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables
Looker AC , Sarafrazi Isfahani N , Fan B , Shepherd JA . Osteoporos Int 2016 27 (8) 2467-75 This study examines demographic patterns and body size relationships in trabecular bone score and lumbar spine BMD of US adults from NHANES 2005-2008. INTRODUCTION: Limited data exist on demographic and body size relationships for trabecular bone score (TBS), a new variable derived from bone texture analysis of lumbar spine dual-energy X-ray absorptiometry (DXA) scans. This study compares demographic patterns and correlations with body size (body mass index (BMI), weight, waist circumference, total body fat, trunk fat, trunk lean) between TBS and lumbar spine bone mineral density (LSBMD) for adults age ≥20 years from the National Health and Nutrition Examination Survey (NHANES) 2005-2008 with BMI in the optimal range for TBS (15-37 kg/m2). METHODS: LSBMD, TBS, body fat, and lean were obtained by DXA. Weight, height, and waist circumference were measured. BMI was calculated from height and weight. RESULTS: Sex differences in TBS varied by age and race/ethnicity (p sex X age interaction and p sex X race/ethnicity interaction < 0.001). In most of the nine demographic subgroups examined, TBS did not differ by sex (four subgroups) or was significantly higher in women (three subgroups). TBS differences by race/ethnicity were inconsistent in men; in women, non-Hispanic whites (NHWs) had higher TBS than non-Hispanic blacks (NHBs) or Mexican Americans (MAs) in all age groups. In contrast, LSBMD was either significantly higher in men (five subgroups) or did not differ by sex (four subgroups). Race/ethnic differences in LSBMD were consistent across age and sex (NHB > NHW > MA). All body size variables were negatively related to TBS but positively related to LSBMD. CONCLUSIONS: Demographic patterns and body size relationships differed between TBS and LSBMD. |
Cardiac and mitochondrial dysfunction following acute pulmonary exposure to mountaintop removal mining particulate matter
Nichols CE , Shepherd DL , Knuckles TL , Thapa D , Stricker JC , Stapleton PA , Minarchick VC , Erdely A , Zeidler-Erdely PC , Alway SE , Nurkiewicz TR , Hollander JM . Am J Physiol Heart Circ Physiol 2015 309 (12) ajpheart 00353 2015 Throughout the United States, air pollution correlates with adverse health outcomes and cardiovascular disease incidence is commonly increased following environmental exposure. In areas surrounding active mountaintop removal mines (MTM) a further increase in cardiovascular morbidity is observed and may be attributed in part to particulate matter (PM) released from the mine. The mitochondrion has been shown to be central in the etiology of many cardiovascular diseases, yet its role in PM related cardiovascular effects are not realized. In this study we sought to elucidate the cardiac processes that are disrupted following exposure to mountaintop removal mining particulate matter (PMMTM). To address this question we exposed male Sprague-Dawley rats to PMMTM, collected within one mile of an active MTM site, using intratracheal instillation. Twenty-four hours following exposure we evaluated cardiac function, apoptotic indices and mitochondrial function. PMMTM exposure, elicited a significant decrease in ejection fraction and fractional shortening compared to controls. Investigation into the cellular impacts of PMMTM exposure identified a significant increase in mitochondrial-induced apoptosis as reflected by an increase in TUNEL positive nuclei and increased caspase-3 and -9 activities. Finally, a significant increase in mitochondrial transition pore opening leading to decreased mitochondrial function was identified following exposure. In conclusion, our data suggest that pulmonary exposure to PMMTM increases cardiac mitochondrial-associated apoptosis and decreases mitochondrial function concomitant with decreased cardiac function. These results suggest that increased cardiovascular disease incidence in populations surrounding MTM mines may be associated with increased cardiac cell apoptosis and decreased mitochondrial function. |
Rising obesity prevalence and weight gain among adults starting antiretroviral therapy in the United States and Canada
Koethe JR , Jenkins CA , Lau B , Shepherd BE , Justice AC , Tate JP , Buchacz K , Napravnik S , Mayor AM , Horberg MA , Blashill AJ , Willig A , Wester CW , Silverberg MJ , Gill J , Thorne JE , Klein M , Eron JJ , Kitahata MM , Sterling TR , Moore RD . AIDS Res Hum Retroviruses 2015 32 (1) 50-8 The proportion of overweight and obese adults in the United States and Canada has increased over the past decade, but temporal trends in body mass index (BMI) and weight gain on antiretroviral therapy (ART) among HIV-infected adults have not been well characterized. We conducted a cohort study comparing HIV-infected adults in the North America AIDS Cohort Collaboration on Research and Design (NA-ACCORD) to United States National Health and Nutrition Examination Survey (NHANES) controls matched by sex, race, and age over the period 1998 to 2010. Multivariable linear regression assessed the relationship between BMI and year of ART initiation, adjusting for sex, race, age, and baseline CD4+ count. Temporal trends in weight on ART were assessed using a generalized least-squares model further adjusted for HIV-1 RNA and first ART regimen class. A total of 14,084 patients from 17 cohorts contributed data; 83% were male, 57% were nonwhite, and the median age was 40 years. Median BMI at ART initiation increased from 23.8 to 24.8 kg/m2 between 1998 and 2010 in NA-ACCORD, but the percentage of those obese (BMI ≥30 kg/m2) at ART initiation increased from 9% to 18%. After 3 years of ART, 22% of individuals with a normal BMI (18.5-24.9 kg/m2) at baseline had become overweight (BMI 25.0-29.9 kg/m2), and 18% of those overweight at baseline had become obese. HIV-infected white women had a higher BMI after 3 years of ART as compared to age-matched white women in NHANES (p = 0.02), while no difference in BMI after 3 years of ART was observed for HIV-infected men or non-white women compared to controls. The high prevalence of obesity we observed among ART-exposed HIV-infected adults in North America may contribute to health complications in the future. |
A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants
Tameris M , Hokey DA , Nduba V , Sacarlal J , Laher F , Kiringa G , Gondo K , Lazarus EM , Gray GE , Nachman S , Mahomed H , Downing K , Abel B , Scriba TJ , McClain JB , Pau MG , Hendriks J , Dheenadhayalan V , Ishmukhamedov S , Luabeya AK , Geldenhuys H , Shepherd B , Blatner G , Cardenas V , Walker R , Hanekom WA , Sadoff J , Douoguih M , Barker L , Hatherill M . Vaccine 2015 33 (25) 2944-54 BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine. |
Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study
Sterling TR , Moro RN , Borisov AS , Phillips E , Shepherd G , Adkinson NF , Weis S , Ho C , Villarino ME . Clin Infect Dis 2015 61 (4) 527-35 BACKGROUND: Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid (9H) for 9 months for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome. METHODS: We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT TB study. RESULTS: Among 7,552 persons who received >1 dose of study drug, 153 had a SDR: 138/3,893(3.5%) with 3HP vs. 15/3,659(0.4%) with 9H(P<0.001). In the 3HP arm, 87(63%) had flu-like syndrome and 23(17%) had cutaneous reactions; 13/3,893(0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (aOR 9.4;95%CI:5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3;95%CI:2.3, 4.7), female sex (aOR 2.0;95% CI:1.4, 2.9), age >35 years (aOR 2.0;95% CI:1.4, 2.9), and lower body mass index (BMI; P=0.009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4;95% CI:1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9;95% CI:1.3, 27.1). CONCLUSIONS: SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear. |
Tuberculosis incidence after 36 months' isoniazid prophylaxis in HIV-infected adults in Botswana: a posttrial observational analysis
Samandari T , Agizew TB , Nyirenda S , Tedla Z , Sibanda T , Mosimaneotsile B , Motsamai OI , Shang N , Rose CE , Shepherd J . AIDS 2015 29 (3) 351-9 OBJECTIVE: Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit. DESIGN: A 36-month double-blind placebo controlled trial (1 : 1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011. METHODS: One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test ≥5 mm (TST-positive). A minimum CD4 lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4 cell count at baseline and updated at 36 months. RESULTS: In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17-0.75) but not TB (0.92, 95% CI 0.55-1.53) in the posttrial period. CONCLUSION: The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings. |
Stop gambling with your hearing
Murphy WJ , Grantham MA . Int J Audiol 2014 54 Suppl 1 1-2 In 2014, the National Hearing Conservation Association took its chances and held its 39th annual conference, titled Stop Gambling with your Hearing, in Las Vegas. The authors who contributed to this issue of the International Journal of Audiology demonstrated that they could be relied upon to deliver a royal flush when it comes to advancing research and knowledge for worker hearing loss prevention. The papers that we were privileged to shepherd through the review process share common themes: epidemiologic and workplace assessments of hearing and new methods to better assess hearing and the effects of wearing hearing protection upon the speech intelligibility and localization. | Hearing loss prevention starts with education and testing. The study by Flamme et al. has expanded the work from last year’s supplement, considering how audiometric testing may be changed. Will pure-tone audiometry become passé? The potential to integrate hearing testing with hearing protector fit-testing seems natural, and combining testing with training in the use of personal protection technology makes sense. Without question, occupational hearing conservation programs must begin with engineering noise controls to reduce exposures for at risk workers. Cantley et al. explored the relationship between hearing loss and tinnitus and workplace injury. They found an increased risk of acute injury among workers with tinnitus and high-frequency hearing loss. Although their research does not draw strong correlations between tinnitus and increased incidence of workplace injury, the communication needs of hearing impaired workers cannot be overlooked. Helleman et al. considered the effects of interrupted exposures to loud music at night clubs - often cited as a potential cause of hearing loss. Their research suggests that quiet zones within clubs little effect on the hearing of the subjects they evaluated. However, providing club patrons a place to get out of the noise was still thought to be important because high noise levels present a risk in and of themselves. Hong et al. investigated the relationships between occupational exposures and hearing among elderly Latino Americans. They concluded that a reduction of occupational exposure to noise and chemicals will have a positive impact on better hearing later in life. |
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