Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 166 Records) |
Query Trace: Ruiz A[original query] |
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In silico approaches in organ toxicity hazard assessment: Current status and future needs for predicting heart, kidney and lung toxicities
Bassan A , Alves VM , Amberg A , Anger LT , Beilke L , Bender A , Bernal A , Cronin MTD , Hsieh JH , Johnson C , Kemper R , Mumtaz M , Neilson L , Pavan M , Pointon A , Pletz J , Ruiz P , Russo DP , Sabnis Y , Sandhu R , Schaefer M , Stavitskaya L , Szabo DT , Valentin JP , Woolley D , Zwickl C , Myatt GJ . Comput Toxicol 12/28/2021 20 The kidneys, heart and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict these adverse effects based on in vitro and in silico approaches. This paper reviews the current state of the art in predicting these organ toxicities. It outlines the biological basis, processes and endpoints for kidney toxicity, pulmonary toxicity, respiratory irritation and sensitization as well as functional and structural cardiac toxicities. The review also covers current experimental approaches, including off-target panels from secondary pharmacology batteries. Current in silico approaches for prediction of these effects and mechanisms are described as well as obstacles to the use of in silico methods. Ultimately, a commonly accepted protocol for performing such assessment would be a valuable resource to expand the use of such approaches across different regulatory and industrial applications. However, a number of factors impede their widespread deployment including a lack of a comprehensive mechanistic understanding, limited in vitro testing approaches and limited in vivo databases suitable for modeling, a limited understanding of how to incorporate absorption, distribution, metabolism, and excretion (ADME) considerations into the overall process, a lack of in silico models designed to predict a safe dose and an accepted framework for organizing the key characteristics of these organ toxicants. |
Outbreak of fusarium solani meningitis in immunocompetent persons associated with neuraxial blockade in Durango, Mexico, 2022-2023
García-Rodríguez G , Duque-Molina C , Kondo-Padilla I , Zaragoza-Jiménez CA , González-Cortés VB , Flores-Antonio R , Villa-Reyes T , Vargas-Rubalcava A , Ruano-Calderon LÁ , Tinoco-Favila JC , Sánchez-Salazar HC , Rivas-Ruiz R , Castro-Escamilla O , Martínez-Gamboa RA , González-Lara F , López-Martínez I , Chiller TM , Pelayo R , Bonifaz LC , Robledo-Aburto Z , Alcocer-Varela J . Open Forum Infect Dis 2024 11 (2) ofad690 BACKGROUND: Fungal meningitis can be associated with epidural anesthesia procedures. Fusariosis is a rare infection typically affecting immunocompromised patients and rarely causes meningitis. During 2022-2023, public health officials responded to a large outbreak of Fusarium solani meningitis associated with epidural anesthesia in Durango, Mexico. METHODS: The public health response and epidemiological and clinical features of patients affected by this outbreak were described. Coordinated actions were addressed to identify the etiological agent, determine its drug susceptibility, develop diagnostic tests, and implement clinical and epidemiological protocols. Retrospective analyses of clinical variables and outcomes were performed to determine association with better patient survival. RESULTS: A total of 1801 persons exposed to epidural anesthesia were identified, of whom 80 developed meningitis. Fusarium solani was found in 3 brain biopsies and showed susceptibility to voriconazole and amphotericin B. After F solani polymerase chain reaction (PCR) implementation, 57 patients with meningitis were PCR-screened, and 31 (38.8%) had a positive result. Most patients were female (95%), and cesarean section was the most common surgical procedure (76.3%). The case fatality rate was 51.3% (41 patients) and the median hospitalization duration was 39.5 days (interquartile range, 18-86 days). Seventy-one patients (88.8%) received voriconazole/amphotericin B and 64 subjects (80%) additionally received steroids. Cox regression analysis showed an increased lethality risk in patients who received antifungal treatment after 5 days (hazard ratio, 2.1 [95% confidence interval, 1.01-4.48], P < .05). CONCLUSIONS: The F solani meningitis outbreak in Durango was an unprecedented medical challenge. Timely treatment and effective healthcare management were associated with better survival outcomes. |
COVID-19 disease burden, vaccine uptake, and workplace disease prevention efforts in temporary agricultural workers in the US. (Movilidad, migracion y salud en el contexto de la pandemia por Covid-19.)
Boggess B , Thomas H , Ruiz J , Mandujano-Acevedo N , Rodriguez-Lainz A . Salud Publica Mex 2024 66 (2) 119-129 Objective. To compare Covid-19 risk factors, self-reported Covid-19 testing and infection, and Covid-19 vaccination among H-2A workers and agricultural workers without H-2A visas. Materials and methods. Farmworkers completed surveys at randomly selected sites in five U.S. states from March - August 2022. Descriptive statistics and bivariate analyses were conducted for key characteristics and outcomes. Results. A total of 532 H-2A workers and 748 non-H-2A workers participated in the surveys. H-2A workers had significantly higher Covid-19 primary vaccine series uptake than non-H-2A workers (94.7 vs. 65.9%). More than one in four H-2A workers (29.6%) continued working while ill or positive with Covid-19. Fewer H-2A than non-H-2A workers reported receiving a Covid-19 test (51.5 vs. 59.2%, respectively) and a positive test result for Covid-19 (24.5 vs. 44.9% among those tested). Conclusions. Although H-2A workers had a lower self-reported prevalence of Covid-19 and higher Covid-19 primary vaccine series uptake than non-H-2A workers, findings such as reporting to work while ill or positive for Covid-19 indicate areas for improvement by binational public health leaders. |
The contribution of declines in blood lead levels to reductions in blood pressure levels: Longitudinal evidence in the Strong Heart Family Study
Lieberman-Cribbin W , Li Z , Lewin M , Ruiz P , Jarrett JM , Cole SA , Kupsco A , O'Leary M , Pichler G , Shimbo D , Devereux RB , Umans JG , Navas-Acien A , Nigra AE . J Am Heart Assoc 2024 13 (2) e031256 BACKGROUND: Chronic lead exposure is associated with both subclinical and clinical cardiovascular disease. We evaluated whether declines in blood lead were associated with changes in systolic and diastolic blood pressure in adult American Indian participants from the SHFS (Strong Heart Family Study). METHODS AND RESULTS: Lead in whole blood was measured in 285 SHFS participants in 1997 to 1999 and 2006 to 2009. Blood pressure and measures of cardiac geometry and function were obtained in 2001 to 2003 and 2006 to 2009. We used generalized estimating equations to evaluate the association of declines in blood lead with changes in blood pressure; cardiac function and geometry measures were considered secondary. Mean blood lead was 2.04 μg/dL at baseline. After ≈10 years, mean decline in blood lead was 0.67 μg/dL. In fully adjusted models, the mean difference in systolic blood pressure comparing the highest to lowest tertile of decline (>0.91 versus <0.27 μg/dL) in blood lead was -7.08 mm Hg (95% CI, -13.16 to -1.00). A significant nonlinear association between declines in blood lead and declines in systolic blood pressure was detected, with significant linear associations where blood lead decline was 0.1 μg/dL or higher. Declines in blood lead were nonsignificantly associated with declines in diastolic blood pressure and significantly associated with declines in interventricular septum thickness. CONCLUSIONS: Declines in blood lead levels in American Indian adults, even when small (0.1-1.0 μg/dL), were associated with reductions in systolic blood pressure. These findings suggest the need to further study the cardiovascular impacts of reducing lead exposures and the importance of lead exposure prevention. |
An antibody-free evaluation of an mRNA COVID-19 vaccine
Branham PJ , Cooper HC , Williamson YM , Najjar FN , Sutton WJH , Pierce-Ruiz CL , Barr JR , Williams TL . Biologicals 2023 85 101738 This manuscript describes the use of an analytical assay that combines transfection of mammalian cells and isotope dilution mass spectrometry (IDMS) for accurate quantification of antigen expression. Expired mRNA COVID-19 vaccine material was stored at 4 °C, room temperature (∼25 °C), and 56 °C over a period of 5 weeks. The same vaccine was also exposed to 5 freeze-thaw cycles. Every week, the spike protein antigenic expression in mammalian (BHK-21) cells was evaluated. Housekeeping proteins, β-actin and GAPDH, were simultaneously quantified to account for the variation in cell counts that occurs during maintenance and growth of cell cultures. Data show that vaccine stored at elevated temperatures results in reduced spike protein expression. Also, maintaining the vaccine in ultracold conditions or exposing the vaccine to freeze-thaw cycles had less effect on the vaccine's ability to produce the antigen in mammalian cells. We describe the use of IDMS as an antibody-free means to accurately quantify expressed protein from mammalian cells transfected with mRNA vaccine. |
The inflammatory response to birth requires MyD88 and is driven by both mother and offspring
Gray JM , Castillo-Ruiz A , Major KM , Shipley M , Gangappa S , Forger NG . Brain Behav Immun 2023 115 617-630 Birth is an inflammatory event for the newborn, characterized by elevations in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α peripherally and/or centrally, as well as changes in brain microglia. However, the mechanism(s) underlying these responses is unknown. Toll-like receptors (TLRs) play crucial roles in innate immunity and initiate inflammatory cascades upon recognition of endogenous or exogenous antigens. Most TLR signaling depends on the adaptor molecule myeloid differentiation primary response 88 (MyD88). We independently varied MyD88 gene status in mouse dams and their offspring to determine whether the inflammatory response to birth depends on MyD88 signaling and, if so, whether that signaling occurs in the offspring, the mother, or both. We find that the perinatal surges in plasma IL-6 and brain expression of TNF-α depend solely on MyD88 gene status of the offspring, whereas postnatal increases in plasma IL-10 and TNF-α depend on MyD88 in both the pup and dam. Interestingly, MyD88 genotype of the dam primarily drives differences in offspring brain microglial density and has robust effects on developmental neuronal cell death. Milk cytokines were evaluated as a possible source of postnatal maternal influence; although we found high levels of CXCL1/GROα and several other cytokines in ingested post-partum milk, their presence did not require MyD88. Thus, the inflammatory response previously described in the late-term fetus and newborn depends on MyD88 (and, by extension, TLRs), with signaling in both the dam and offspring contributing. Unexpectedly, naturally-occuring neuronal cell death in the newborn is modulated primarily by maternal MyD88 gene status. |
Cleaning tasks and products and asthma among healthcare professionals
Patel J , Gimeno Ruiz de Porras D , Mitchell LE , Carson A , Whitehead LW , Han I , Pompeii L , Conway S , Zock JP , Henneberger PK , Patel R , De Los Reyes J , Delclos GL . J Occup Environ Med 2023 66 (1) 28-34 OBJECTIVE: Healthcare workers (HCWs) are at risk for work-related asthma, which may be affected by changes in cleaning practices. We examined associations of cleaning tasks and products with work-related asthma in HCWs in 2016, comparing them to prior results from 2003. METHODS: We estimated asthma prevalence by professional group, and explored associations of self-reported asthma with job-exposure matrix-based cleaning tasks/products in a representative Texas sample of 9914 physicians, nurses, respiratory/occupational therapists, and nurse aides. RESULTS: Response rate was 34.8%(n = 2,421). The weighted prevalences of physician-diagnosed(15.3%), work-exacerbated (4.1%), and new-onset asthma(NOA) (6.7%), and bronchial hyperresponsiveness symptoms(31.1%) were similar to 2003. NOA was associated with building surface cleaning(OR = 1.91; 95%CI:1.10-3.33), use of orthophthalaldehyde(OR = 1.77; 95%CI:1.15-2.72), bleach/quaternary compounds(OR = 1.91; 95%CI:1.10-3.33), and sprays(OR = 1.97; 95%CI:1.12-3.47). CONCLUSION: Prevalence of asthma/BHR appears unchanged, whereas associations of NOA with exposures to surface cleaning remained, and decreased for instrument cleaning. |
Individual, community, and health facility predictors of postnatal care utilization in rural Tanzania: A multilevel analysis
Serbanescu F , Abeysekara P , Ruiz A , Schmitz M , Dominico S , Hsia J , Stupp P . Glob Health Sci Pract 2023 11 (4) INTRODUCTION: Postnatal care (PNC) is an underused service in the continuum of care for mothers and infants in sub-Saharan Africa. There is little evidence on health facility characteristics that influence PNC utilization. Understanding PNC use in the context of individual, community, and health facility characteristics may help in the development of programs for increased use. METHODS: We analyzed data from 4,353 women with recent births in Kigoma Region, Tanzania, and their use of PNC (defined as at least 1 checkup in a health facility in the region within 42 days of delivery). We used a mixed-effects multilevel logistic regression analysis to explain PNC use while accounting for household, individual, and community characteristics from a regionwide population-based reproductive health survey and for distance to and adequacy of proximal health facilities from a health facility assessment. RESULTS: PNC utilization rate was low (15.9%). Women had significantly greater odds of PNC if they had a high level of decision-making autonomy (adjusted odds ratio [aOR]: 1.56; 95% confidence interval [CI]=1.11, 2.17); had a companion at birth (aOR: 1.57; 95% CI=1.19, 2.07); had cesarean delivery (aOR: 2.27; 95% CI=1.47, 3.48); resided in Kasulu district (aOR: 3.28; 95% CI=1.94, 5.52); or resided in a community that had at least 1 adequate health facility within 5 km (aOR: 2.15; 95% CI=1.06, 3.88). CONCLUSION: Women's decision-making autonomy and presence of companionship at birth, as well as proximity to a health facility with adequate infrastructure, equipment, and workforce, were associated with increased PNC use. More efforts toward advocating for the health benefits of PNC using multiple channels and increasing quality of care in health facilities, including companionship at birth, can increase utilization rates. |
The Field Epidemiology Training Program's contribution to essential public health functions in seven National Public Health Institutes
Cui A , Hamdani S , Woldetsadik MA , Clerville JW , Hu A , Abedi AA , Bratton S , Turcios-Ruiz RM . Int J Public Health 2023 68 1606191 Objective: This study explores how Field Epidemiology Training Programs (FETP) whose National Public Health Institutes (NPHI) are supported by U.S. Centers for Disease Control and Prevention (CDC) have contributed to strengthening essential public health functions. Methods: We conducted 96 semi-structured interviews with public health experts including NPHI staff, non-NPHI government staff, and staff from non-governmental and international organizations in Cambodia, Colombia, Liberia, Mozambique, Nigeria, Rwanda, and Zambia. We managed data using MAXQDA and employed direct content analysis to derive themes. Results: Three overarching themes emerged in relation to FETPs' role within the NPHIs' public health functions. These themes included contribution to improving country surveillance systems, role in providing leadership in outbreak responses, and strengthening countries' and the NPHIs' surveillance workforce capacity. Participants also shared challenges around FETPs' implementation and suggestions for improvement. Conclusion: The results demonstrate the value of FETPs in strengthening public health systems through building workforce capacity and improving surveillance systems. By identifying the successes of FETPs in contributing to essential public health functions, our findings might inform current and future FETP implementation and its integration into NPHIs. |
Genome-wide patterns of gene expression in a wild primate indicate species-specific mechanisms associated with tolerance to natural simian immunodeficiency virus infection (preprint)
Simons ND , Eick GN , Ruiz-Lopez MJ , Hyeroba D , Omeja PA , Weny G , Chapman CA , Goldberg TL , Zheng H , Shankar A , Switzer WM , Frost SDW , Jones JH , Sterner KN , Ting N . bioRxiv 2018 395152 Over 40 species of nonhuman primates host simian immunodeficiency viruses (SIVs). In natural hosts, infection is generally assumed to be nonpathogenic due to a long coevolutionary history between host and virus, although pathogenicity is difficult to study in wild nonhuman primates. We used whole-blood RNA-seq and SIV prevalence from 29 wild Ugandan red colobus (Piliocolobus tephrosceles) to assess the effects of SIV infection on host gene expression in wild, naturally SIV-infected primates. We found no evidence for chronic immune activation in infected individuals, suggesting that SIV is not immunocompromising in this species, in contrast to HIV in humans. Notably, an immunosuppressive gene, CD101, was upregulated in infected individuals. This gene has not been previously described in the context of nonpathogenic SIV infection. This expands the known variation associated with SIV infection in natural hosts, and may suggest a novel mechanism for tolerance of SIV infection in the Ugandan red colobus. |
Heterogeneous susceptibility to rotavirus infection and gastroenteritis in two birth cohort studies: parameter estimation and epidemiological implications (preprint)
Lewnard JA , Lopman BA , Parashar UD , Bennett A , Bar-Zeev N , Cunliffe NA , Samuel P , Guerrero ML , Ruiz-Palacios G , Kang G , Pitzer VE . bioRxiv 2018 242172 Variation in susceptibility is a known contributor to bias in studies estimating immune protection acquired from vaccination or natural infection. However, difficulty measuring this heterogeneity hinders assessment of its influence on estimates. Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis in low- and middle-income countries (LMICs). We sought to understand differences in susceptibility among children enrolled in two birth-cohort studies of rotavirus in LMICs, and to explore the implications for estimation of immune protection. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 unvaccinated children experienced 1418 rotavirus infections and 371 episodes of rotavirus gastroenteritis (RVGE) over 17,636 child-months. We developed a model characterizing susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings, and tested whether modelgenerated susceptibility measurements were associated with demographic and anthropometric factors. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of diarrhea due to other causes. Simulations suggest that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in transmission intensity and susceptibility of children. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that bias owing to differences in rotavirus transmission intensity and population susceptibility may hinder comparison of estimated immune protection against RVGE.Author summary Differences in susceptibility can help explain why some individuals, and not others, acquire infection and exhibit symptoms when exposed to infectious disease agents. However, it is difficult to distinguish between differences in susceptibility versus exposure in epidemiological studies. We developed a modeling approach to distinguish transmission intensity and susceptibility in data from cohort studies of rotavirus infection among children in Mexico City, Mexico, and Vellore, India, and evaluated how these factors may have contributed to differences in estimates of naturally-acquired immune protection between the studies. We found that more children were at “high risk” of acquiring rotavirus infection, and of experiencing gastroenteritis when infected, in Vellore versus Mexico City. The probability of belonging to this high-risk stratum was associated with recognized risk factors such as lower socioeconomic status, lower birth weight, and risk of diarrhea due to other causes. We also found the risk for rotavirus infections to cause symptoms declined with age, and was independent of acquired immunity. Together, these findings can account for estimates of lower protective efficacy of acquired immunity against rotavirus gastroenteritis in high-incidence settings, which mirrors estimates of reduced effectiveness of live oral rotavirus vaccines in low- and middle-income countries. |
Quantification of SARS-CoV-2 spike protein expression from mRNA vaccines using isotope dilution mass spectrometry
Sutton WJH , Branham PJ , Williamson YM , Cooper HC , Najjar FN , Pierce-Ruiz CL , Barr JR , Williams TL . Vaccine 2023 The advent of mRNA vaccine technology has been vital in rapidly creating and manufacturing COVID-19 vaccines at an industrial scale. To continue to accelerate this leading vaccine technology, an accurate method is needed to quantify antigens produced by the transfection of cells with a mRNA vaccine product. This will allow monitoring of protein expression during mRNA vaccine development and provide information on how changes to vaccine components affects the expression of the desired antigen. Developing novel approaches that allow for high-throughput screening of vaccines to detect changes in antigen production in cell culture prior to in vivo studies could aid vaccine development. We have developed and optimized an isotope dilution mass spectrometry method to detect and quantify the spike protein expressed after transfection of baby hamster kidney cells with expired COVID-19 mRNA vaccines. Five peptides of the spike protein are simultaneously quantified and provide assurance that protein digestion in the region of the target peptides is complete since results between the five peptides had a relative standard deviation of less than 15 %. In addition, two housekeeping proteins, actin and GAPDH, are quantified in the same analytical run to account for any variation in cell growth within the experiment. IDMS allows a precise and accurate means to quantify protein expression by mammalian cells transfected with an mRNA vaccine. |
Remdesivir for the Treatment of Covid-19 - Final Report
Beigel JH , Tomashek KM , Dodd LE , Mehta AK , Zingman BS , Kalil AC , Hohmann E , Chu HY , Luetkemeyer A , Kline S , Lopez de Castilla D , Finberg RW , Dierberg K , Tapson V , Hsieh L , Patterson TF , Paredes R , Sweeney DA , Short WR , Touloumi G , Lye DC , Ohmagari N , Oh MD , Ruiz-Palacios GM , Benfield T , Fätkenheuer G , Kortepeter MG , Atmar RL , Creech CB , Lundgren J , Babiker AG , Pett S , Neaton JD , Burgess TH , Bonnett T , Green M , Makowski M , Osinusi A , Nayak S , Lane HC , ACTT-1 Study Group Members , Uyeki Timothy . N Engl J Med 2020 383 (19) 1813-1826 BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.). |
In silico toxicology protocols.
Myatt GJ , Ahlberg E , Akahori Y , Allen D , Amberg A , Anger LT , Aptula A , Auerbach S , Beilke L , Bellion P , Benigni R , Bercu J , Booth ED , Bower D , Brigo A , Burden N , Cammerer Z , Cronin MTD , Cross KP , Custer L , Dettwiler M , Dobo K , Ford KA , Fortin MC , Gad-McDonald SE , Gellatly N , Gervais V , Glover KP , Glowienke S , Van Gompel J , Gutsell S , Hardy B , Harvey JS , Hillegass J , Honma M , Hsieh JH , Hsu CW , Hughes K , Johnson C , Jolly R , Jones D , Kemper R , Kenyon MO , Kim MT , Kruhlak NL , Kulkarni SA , Kümmerer K , Leavitt P , Majer B , Masten S , Miller S , Moser J , Mumtaz M , Muster W , Neilson L , Oprea TI , Patlewicz G , Paulino A , Lo Piparo E , Powley M , Quigley DP , Reddy MV , Richarz AN , Ruiz P , Schilter B , Serafimova R , Simpson W , Stavitskaya L , Stidl R , Suarez-Rodriguez D , Szabo DT , Teasdale A , Trejo-Martin A , Valentin JP , Vuorinen A , Wall BA , Watts P , White AT , Wichard J , Witt KL , Woolley A , Woolley D , Zwickl C , Hasselgren C . Regul Toxicol Pharmacol 2018 96 1-17 The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information. |
Evaluation of Ethiopia's field epidemiology training program - frontline: perspectives of implementing partners
Kebebew T , Woldetsadik MA , Barker J , Cui A , Abedi AA , Sugerman DE , Williams DE , Turcios-Ruiz RM , Takele T , Zeynu N . BMC Health Serv Res 2023 23 (1) 406 BACKGROUND: Field Epidemiology Training Program (FETP) has been adopted as an epidemiology and response capacity building strategy worldwide. FETP-Frontline was introduced in Ethiopia in 2017 as a three-month in-service training. In this study, we evaluated implementing partners' perspectives with the aim of understanding program effectiveness and identifying challenges and recommendations for improvement. METHODS: A qualitative cross-sectional design was utilized to evaluate Ethiopia's FETP-Frontline. Using a descriptive phenomenological approach, qualitative data were collected from FETP-Frontline implementing partners, including regional, zonal, and district health offices across Ethiopia. We collected data through in-person key informant interviews, using semi-structured questionnaires. Thematic analysis was conducted, assisted with MAXQDA, while ensuring interrater reliability by using the consistent application of theme categorization. The major themes that emerged were program effectiveness, knowledge and skills differences between trained and untrained officers, program challenges, and recommended actions for improvement. Ethical approval was obtained from the Ethiopian Public Health Institute. Informed written consent was obtained from all participants, and confidentiality of the data was maintained throughout. RESULTS: A total of 41 interviews were conducted with key informants from FETP-Frontline implementing partners. The regional and zonal level experts and mentors had a Master of Public Health (MPH), whereas district health managers were Bachelor of Science (BSc) holders. Majority of the respondents reflected a positive perception towards FETP-Frontline. Regional and zonal officers as well as mentors mentioned that there were observable performance differences between trained and untrained district surveillance officers. They also identified various challenges including lack of resources for transportation, budget constraints for field projects, inadequate mentorship, high staff turnover, limited number of staff at the district level, lack of continued support from stakeholders, and the need for refresher training for FETP-Frontline graduates. CONCLUSIONS: Implementing partners reflected a positive perception towards FETP-Frontline in Ethiopia. In addition to scaling-up the program to reach all districts to achieve the International Health Regulation 2005 goals, the program also needs to consider addressing immediate challenges, primarily lack of resources and poor mentorship. Continued monitoring of the program, refresher training, and career path development could improve retention of the trained workforce. |
Whole-Genome Sequencing of Candida haemulonii species complex from Brazil and the United States: genetic diversity and antifungal susceptibility.
de Barros Rodrigues DK , Lockhart SR , Berkow EL , Gade L , Bonfietti LX , Gimenes VMF , Ruiz LS , Macioni MB , de Souza Carvalho Melhem M . Med Mycol 2023 61 (4) Candida haemulonii complex species can be multidrug-resistant (MDR) and cause infections such as candidemia. This study determined the genetic relationship between isolates from Brazil and the United States through whole-genome sequencing and performed antifungal susceptibility testing to investigate drug resistance. Contrary to what is widely described, most isolates were susceptible to azoles. However, an atypical susceptibility profile was found in 50% of C. pseudohaemulonii strains including resistance to the three echinocandins. Isolates from both countries formed distinct clusters with wide genetic diversity. Isolates from three hospitals in Brazil were clonal and involved in candidemia cases, pointing to the importance of improving hospital infection control measures and molecular identification. | Candida haemulonii complex species is worldwide distributed and this study aimed to evaluate the resistance to antifungal drugs in cases from Brazil and the United States, and also compare their genetic relationship. Fifty strains were studied, most of them from Brazil were from cases of bloodstream infections while the strains from the United States came from cases of wounds and may be associated with diabetic patients. The vast majority of strains were resistant to amphotericin B, one of the most effective drugs, and susceptible to fluconazole. In addition, 50% of C. pseudohaemulonii strains were resistant to echinocandins. The strains from Brazil and the United States had no genetic relationship and formed two distinct groups. In 3 Brazilian hospitals, strains were clonal indicating an intrahospital transmission. Our findings contribute to guiding therapy in bloodstream fungal infections caused by Candida haemulonii species and alert for nosocomial transmission of this yeast complex species. | eng |
Continuing contributions of field epidemiology training programs to global COVID-19 response
Bell E , Mittendorf C , Meyer E , Barnum O , Reddy C , Williams S , Baggett H , Turcios-Ruiz R . Emerg Infect Dis 2022 28 (13) S129-s137 We documented the contributions of Field Epidemiology Training Program (FETP) trainees and graduates to global COVID-19 preparedness and response efforts. During February-July 2021, we conducted surveys designed in accordance with the World Health Organization's COVID-19 Strategic Preparedness and Response Plan. We quantified trainee and graduate engagement in responses and identified themes through qualitative analysis of activity descriptions. Thirty-two programs with 2,300 trainees and 7,372 graduates reported near-universal engagement across response activities, particularly those aligned with the FETP curriculum. Graduates were more frequently engaged than were trainees in pandemic response activities. Common themes in the activity descriptions were epidemiology and surveillance, leading risk communication, monitoring and assessment, managing logistics and operations, training and capacity building, and developing guidelines and protocols. We describe continued FETP contributions to the response. Findings indicate the wide-ranging utility of FETPs to strengthen countries' emergency response capacity, furthering global health security. |
Notes from the field: Clinical and epidemiologic characteristics of mpox cases from the initial phase of the outbreak - New York city, May 19-July 15, 2022
Kyaw NTT , Kipperman N , Alroy KA , Baumgartner J , Crawley A , Peterson E , Ross A , Fowler RC , Ruiz VE , Leelawong M , Hughes S , Juste-Tranquille M , Lovingood K , Joe CD , Chase M , Shinall A , Ackelsberg J , Bergeron-Parent C , Badenhop B , Slavinski S , Reddy V , Lee EH . MMWR Morb Mortal Wkly Rep 2022 71 (5152) 1631-1633 Monkeypox virus (MPXV), an Orthopoxvirus that can cause monkeypox (mpox) disease in humans, was rarely seen outside Africa before 2022. Since May 2022, mpox has been reported in multiple countries and regions without endemic transmission, including the United States (1). New York City (NYC) quickly became one of the major foci of the 2022 outbreak after the first case in a NYC resident was diagnosed on May 19.* Epidemiologic profiles and clinical characteristics of mpox cases in the United States during this outbreak have been described (2,3), but previous summaries were limited by incomplete data or inclusion of only a subset of cases (2,3). Most case investigation data from mpox cases reported to the NYC Department of Health and Mental Hygiene (DOHMH) surveillance system have a high degree of completeness for gender, race or ethnicity, sexual orientation, and clinical signs and symptoms. To describe the characteristics of mpox in NYC, case investigation data for NYC residents with mpox diagnosed during May 19–July 15, 2022, were analyzed. Using a standardized form, DOHMH staff members attempted to interview all NYC residents with probable (a positive non-variola Orthopoxvirus polymerase chain reaction [PCR] test result)† or confirmed (a positive MPXV–specific PCR test result) mpox reported to DOHMH through mandated laboratory reporting. For patients who declined an interview or were unreachable, information obtained from medical care providers during DOHMH consultation calls was used. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy.§ |
High Level of Pretreatment and Acquired Human Immunodeficiency Virus Drug Resistance in El Salvador: A Nationally Representative Survey, 2018-2019.
Girón-Callejas A , García-Morales C , Mendizabal-Burastero R , Quezada A , Ruiz L , Arguera N , Sorto S , Nieto AI , Tapia-Trejo D , López-Sánchez DM , Pérez-García M , Cruz L , Andino R , Sajquim E , Juárez SI , Farach N , Ravasi G , Northbrook S , Reyes-Terán G , Ávila-Ríos S . Open Forum Infect Dis 2022 9 (11) ofac580 BACKGROUND: Human immunodeficiency virus drug resistance (HIVDR) can negatively impact the effectiveness of antiretroviral therapy (ART). We aimed to estimate the prevalence of pretreatment HIVDR (PDR) among ART initiators and the prevalence of viral load (VL) suppression and acquired HIVDR among individuals receiving ART for 12 ± 3 months (ADR12) and ≥48 months (ADR48) in El Salvador. METHODS: Nationally representative cross-sectional PDR, ADR12 and ADR48 surveys were conducted among adults with HIV from October 2018 to August 2019, following World Health Organization-recommended methods. Demographic and clinic data and blood specimens were collected. RESULTS: Two hundred sixty participants were enrolled in the PDR survey, 230 in ADR12 and 425 in ADR48. Twenty-seven percent (95% confidence interval [CI], 17.1%-39.9%) of ART initiators had PDR to efavirenz or nevirapine. The prevalence of VL suppression was 88.8% (95% CI, 83.1%-92.8%) in ADR12 and 80.5% (95% CI, 76.6%-84.0%) in ADR48 surveys. Among people with HIV receiving a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens and with unsuppressed VL, the prevalence of ADR to efavirenz or nevirapine was 72.0% (95% CI, 32.3%-93.3%) and 95.0% (68.5%-99.4%) in the ADR12 and ADR28 surveys, respectively. ADR12 to boosted protease inhibitors (PI/r) or integrase strand transfer inhibitors (INSTIs) was not observed. ADR48 was 1.3% (95% CI, 0.2%-9.6%) and 2.1% (0.3%-13.7%), respectively. CONCLUSIONS: Programmatic improvements in ART delivery are urgently needed in El Salvador to address the high levels of resistance to efavirenz or nevirapine among ART initiators and the low VL suppression prevalence among individuals on treatment. |
Editorial: Application of computational tools to health and environmental sciences, Volume II
Ruiz P , Loizou G . Front Pharmacol 2022 13 1102431 The scarcity of human data, the limitation of time and resources for experimental testing, and societal pressure to develop animal-free testing strategies are driving the field of toxicology toward new methods to generate and interpret data for chemical risk assessment (Luechtefeld and Hartung, 2017). Computational toxicology is an emerging multi-disciplinary research field that incorporates diverse disciplines such as computational sciences, bioinformatics, machine learning, chemo-informatics, systems biology, toxicogenomics, and toxicokinetics (Baskin, 2018; Ciallella and Zhu, 2019). |
Mortality trends in type 1 diabetes: a multicountry analysis of six population-based cohorts
Ruiz PLD , Chen L , Morton JI , Salim A , Carstensen B , Gregg EW , Pavkov ME , Mata-Cases M , Mauricio D , Nichols GA , Pildava S , Read SH , Wild SH , Shaw JE , Magliano DJ . Diabetologia 2022 65 (6) 964-972 AIMS/HYPOTHESIS: Mortality has declined in people with type 1 diabetes in recent decades. We examined how the pattern of decline differs by country, age and sex, and how mortality trends in type 1 diabetes relate to trends in general population mortality. METHODS: We assembled aggregate data on all-cause mortality during the period 2000-2016 in people with type 1 diabetes aged 0-79 years from Australia, Denmark, Latvia, Scotland, Spain (Catalonia) and the USA (Kaiser Permanente Northwest). Data were obtained from administrative sources, health insurance records and registries. All-cause mortality rates in people with type 1 diabetes, and standardised mortality ratios (SMRs) comparing type 1 diabetes with the non-diabetic population, were modelled using Poisson regression, with age and calendar time as quantitative variables, describing the effects using restricted cubic splines with six knots for age and calendar time. Mortality rates were standardised to the age distribution of the aggregate population with type 1 diabetes. RESULTS: All six data sources showed a decline in age- and sex-standardised all-cause mortality rates in people with type 1 diabetes from 2000 to 2016 (or a subset thereof), with annual changes in mortality rates ranging from -2.1% (95% CI -2.8%, -1.3%) to -5.8% (95% CI -6.5%, -5.1%). All-cause mortality was higher for male individuals and for older individuals, but the rate of decline in mortality was generally unaffected by sex or age. SMR was higher in female individuals than male individuals, and appeared to peak at ages 40-70 years. SMR declined over time in Denmark, Scotland and Spain, while remaining stable in the other three data sources. CONCLUSIONS/INTERPRETATION: All-cause mortality in people with type 1 diabetes has declined in recent years in most included populations, but improvements in mortality relative to the non-diabetic population are less consistent. |
Leveraging informatics to improve environmental health practice and innovation
Coleman EW , Jagne AF , Ruiz AJ . J Environ Health 2022 85 (4) 44-46 Environmental health professionals are embracing informatics as a tool to improve the health of populations across the nation. It is essential to ensure the public has access to environmental health-related data, such as restaurant and recreational water inspections, to help make informed decisions about health and safety. While many environmental health programs across the country share their data using online platforms, this practice is not universal and the timeliness, ease of access, and extent of data sharing vary across programs. | | The Centers for Disease Control and Prevention partnered with the Public Health Informatics Institute to better understand how environmental health programs collect and share data. This month's column highlights the information gathered from key informants to provide insight into data standardization. |
Lifetime risk, life expectancy, and years of life lost to type 2 diabetes in 23 high-income jurisdictions: a multinational, population-based study
Tomic D , Morton JI , Chen L , Salim A , Gregg EW , Pavkov ME , Arffman M , Balicer R , Baviera M , Boersma-van Dam E , Brinks R , Carstensen B , Chan JCN , Cheng YJ , Fosse-Edorh S , Fuentes S , Gardiner H , Gulseth HL , Gurevicius R , Ha KH , Hoyer A , Jermendy G , Kautzky-Willer A , Keskimäki I , Kim DJ , Kiss Z , Klimek P , Leventer-Roberts M , Lin CY , Lopez-Doriga Ruiz P , Luk AOY , Ma S , Mata-Cases M , Mauricio D , McGurnaghan S , Imamura T , Paul SK , Peeters A , Pildava S , Porath A , Robitaille C , Roncaglioni MC , Sugiyama T , Wang KL , Wild SH , Yekutiel N , Shaw JE , Magliano DJ . Lancet Diabetes Endocrinol 2022 10 (11) 795-803 BACKGROUND: Diabetes is a major public health issue. Because lifetime risk, life expectancy, and years of life lost are meaningful metrics for clinical decision making, we aimed to estimate these measures for type 2 diabetes in the high-income setting. METHODS: For this multinational, population-based study, we sourced data from 24 databases for 23 jurisdictions (either whole countries or regions of a country): Australia; Austria; Canada; Denmark; Finland; France; Germany; Hong Kong; Hungary; Israel; Italy; Japan; Latvia; Lithuania; the Netherlands; Norway; Scotland; Singapore; South Korea; Spain; Taiwan; the UK; and the USA. Our main outcomes were lifetime risk of type 2 diabetes, life expectancy in people with and without type 2 diabetes, and years of life lost to type 2 diabetes. We modelled the incidence and mortality of type 2 diabetes in people with and without type 2 diabetes in sex-stratified, age-adjusted, and calendar year-adjusted Poisson models for each jurisdiction. Using incidence and mortality, we constructed life tables for people of both sexes aged 20-100 years for each jurisdiction and at two timepoints 5 years apart in the period 2005-19 where possible. Life expectancy from a given age was computed as the area under the survival curves and lifetime lost was calculated as the difference between the expected lifetime of people with versus without type 2 diabetes at a given age. Lifetime risk was calculated as the proportion of each cohort who developed type 2 diabetes between the ages of 20 years and 100 years. We estimated 95% CIs using parametric bootstrapping. FINDINGS: Across all study cohorts from the 23 jurisdictions (total person-years 1 577 234 194), there were 5 119 585 incident cases of type 2 diabetes, 4 007 064 deaths in those with type 2 diabetes, and 11 854 043 deaths in those without type 2 diabetes. The lifetime risk of type 2 diabetes ranged from 16·3% (95% CI 15·6-17·0) for Scottish women to 59·6% (58·5-60·8) for Singaporean men. Lifetime risk declined with time in 11 of the 15 jurisdictions for which two timepoints were studied. Among people with type 2 diabetes, the highest life expectancies were found for both sexes in Japan in 2017-18, where life expectancy at age 20 years was 59·2 years (95% CI 59·2-59·3) for men and 64·1 years (64·0-64·2) for women. The lowest life expectancy at age 20 years with type 2 diabetes was observed in 2013-14 in Lithuania (43·7 years [42·7-44·6]) for men and in 2010-11 in Latvia (54·2 years [53·4-54·9]) for women. Life expectancy in people with type 2 diabetes increased with time for both sexes in all jurisdictions, except for Spain and Scotland. The life expectancy gap between those with and without type 2 diabetes declined substantially in Latvia from 2010-11 to 2015-16 and in the USA from 2009-10 to 2014-15. Years of life lost to type 2 diabetes ranged from 2·5 years (Latvia; 2015-16) to 12·9 years (Israel Clalit Health Services; 2015-16) for 20-year-old men and from 3·1 years (Finland; 2011-12) to 11·2 years (Israel Clalit Health Services; 2010-11 and 2015-16) for 20-year-old women. With time, the expected number of years of life lost to type 2 diabetes decreased in some jurisdictions and increased in others. The greatest decrease in years of life lost to type 2 diabetes occurred in the USA between 2009-10 and 2014-15 for 20-year-old men (a decrease of 2·7 years). INTERPRETATION: Despite declining lifetime risk and improvements in life expectancy for those with type 2 diabetes in many high-income jurisdictions, the burden of type 2 diabetes remains substantial. Public health strategies might benefit from tailored approaches to continue to improve health outcomes for people with diabetes. FUNDING: US Centers for Disease Control and Prevention and Diabetes Australia. |
Association between breastfeeding, host genetic factors, and calicivirus gastroenteritis in a Nicaraguan birth cohort.
Vielot NA , Franois R , Huseynova E , Gonzlez F , Reyes Y , Gutierrez L , Nordgren J , Toval-Ruiz C , Vilchez S , Vinj J , Becker-Dreps S , Bucardo F . PLoS One 2022 17 (10) e0267689 BACKGROUND: Norovirus and sapovirus are important causes of childhood acute gastroenteritis (AGE). Breastfeeding prevents AGE generally; however, it is unknown if breastfeeding prevents AGE caused specifically by norovirus and sapovirus. METHODS: We investigated the association between breastfeeding and norovirus or sapovirus AGE episodes in a birth cohort. Weekly data on breastfeeding and AGE episodes were captured during the first year of life. Stools were collected from children with AGE and tested by RT-qPCR for norovirus and sapovirus. Time-dependent Cox models estimated associations between weekly breastfeeding and time to first norovirus or sapovirus AGE. FINDINGS: From June 2017 to July 2018, 444 newborns were enrolled in the study. In the first year of life, 69 and 34 children experienced a norovirus and a sapovirus episode, respectively. Exclusive breastfeeding lasted a median of 2 weeks, and any breastfeeding lasted a median of 43 weeks. Breastfeeding in the last week did not prevent norovirus (HR: 1.09, 95% CI: 0.62, 1.92) or sapovirus (HR: 1.00, 95% CI: 0.82, 1.21) AGE in a given week, adjusting for household sanitation, consumption of high-risk foods, and mother's and child's histo-blood group phenotypes. Maternal secretor-positive phenotype was protective against norovirus AGE, whereas child's secretor-positive phenotype was a risk factor for norovirus AGE. INTERPRETATION: Exclusive breastfeeding in this population was short-lived, and no conclusions could be drawn about its potential to prevent norovirus or sapovirus AGE. Non-exclusive breastfeeding did not prevent norovirus or sapovirus AGE in the first year of life. However, maternal secretor-positive phenotype was associated with a reduced hazard of norovirus AGE. |
Implementation and uptake of the Massachusetts Drug Supply Data Stream: A statewide public health-public safety partnership drug checking program
Green TC , Olson R , Jarczyk C , Erowid E , Erowid F , Thyssen S , Wightman R , Del Pozo B , Michelson L , Consigli A , Reilly B , Ruiz S . J Public Health Manag Pract 2022 28 S347-s354 CONTEXT: The illicit drug supply is rapidly evolving. Equally important to gathering drug supply data for monitoring is timely sharing of information with people who use drugs, the providers who care for them, law enforcement partners, and public health stakeholders so that efforts to avoid harmful substances, take preventive actions, and better target interventions can occur. PROGRAM: The Massachusetts Drug Supply Data Stream (MADDS) is the country's first statewide community drug checking program. Founded on public health-public safety partnerships, MADDS collects remnant drug packaging and paraphernalia with residue from people who use drugs and noncriminal samples from partnering police departments. MADDS tests samples using simultaneous immunoassay fentanyl test strips, Fourier-transform infrared spectrometry (FTIR), and off-site laboratory testing by gas chromatography-mass spectrometry (GC/MS). Results are accessible to community programs and municipalities, while trend analyses inform public health for cross-site alerts and informational bulletins. IMPLEMENTATION: MADDS was launched statewide in 2020 and rapidly expanded to a multisite program. Program staff approached communities and met with municipal police and community partners to secure written agreements to host drug checking. Community partners designed sample collection consistent with their pandemic era workflows. Consultations with stakeholders gathered feedback on design and deliverables. EVALUATION: The program tests sample donations on-site from community agencies and police departments, incorporates review by a medical toxicologist for health and safety concerns, crafts stakeholder-specific communications, and disseminates English, Spanish, and Portuguese language materials. For 2020, a total of 427 samples were tested, of which 47.1% were positive for fentanyl. By early 2021, MADDS detected shifts in cocaine purity, alerted communities of a new toxic fentanyl analogue and a synthetic cannabinoid contaminant, and confirmed the increase of xylazine (a veterinary sedative) in Massachusetts. DISCUSSION: Community drug checking programs can be collaboratively designed with public health and public safety to generate critical health and safety information for people who use drugs and the communities where they live. |
The use of readily available laboratory tests for the identification of the emerging yeast Candida auris in Mexico
González-Durán E , Contreras-Pérez CU , Caceres DH , Ríos-Rosas C , Piñón-Ortega JJ , Téllez-Saucedo MD , Marín-Suro ES , Wong-Arámbula CE , Moreno-Escobar EA , Ramírez-González JE , Ramírez-Barrios JG , Montes-Colima NA , Lockhart SR , Martínez-Montiel N , Martínez-Contreras RD , García-Ruíz P , Salazar-Sánchez MI , Hernández-Rivas L , López-Martínez I . Arch Microbiol 2022 204 (9) 592 Identification of the emerging multidrug-resistant yeast Candida auris is challenging. Here, we describe the role of the Mexico national reference laboratory Instituto de Diagnóstico y Referencia Epidemiológicos Dr. Manuel Martínez Báez (InDRE) and the Mexican national laboratory network in the identification of C. auris. Reference identification of six suspected isolates was done based on phenotypic and molecular laboratory methods, including growth in special media, evaluation of isolate micromorphology, and species-specific PCR and pan-fungal PCR and sequencing. The four C. auris isolates identified were able to grow on modified Sabouraud agar with 10% NaCl incubated at 42 °C. With one exception, isolates of C. auris were spherical to ovoid yeast-like cells and blastoconidia, with no hyphae or pseudohyphae on cornmeal agar. C. auris isolates were resistant to fluconazole. Species-specific and pan-fungal PCR confirmed isolates as C. auris. Sequence analysis revealed the presence of two different C. auris clades in Mexico, clade I (South Asia) and clade IV (South America). |
Metabolism of 3-chlorobiphenyl (PCB 2) in a human-relevant cell line: Evidence of dechlorinated metabolites
Zhang CY , Li X , Flor S , Ruiz P , Kruve A , Ludewig G , Lehmler HJ . Environ Sci Technol 2022 56 (17) 12460-12472 Lower chlorinated polychlorinated biphenyls (LC-PCBs) and their metabolites make up a class of environmental pollutants implicated in a range of adverse outcomes in humans; however, the metabolism of LC-PCBs in human models has received little attention. Here we characterize the metabolism of PCB 2 (3-chlorobiphenyl), an environmentally relevant LC-PCB congener, in HepG2 cells with in silico prediction and nontarget high-resolution mass spectrometry. Twenty PCB 2 metabolites belonging to 13 metabolite classes, including five dechlorinated metabolite classes, were identified in the cell culture media from HepG2 cells exposed for 24 h to 10 μM or 3.6 nM PCB 2. The PCB 2 metabolite profiles differed from the monochlorinated metabolite profiles identified in samples from an earlier study with PCB 11 (3,3'-dichlorobiphenyl) under identical experimental conditions. A dechlorinated dihydroxylated metabolite was also detected in human liver microsomal incubations with monohydroxylated PCB 2 metabolites but not PCB 2. These findings demonstrate that the metabolism of LC-PCBs in human-relevant models involves the formation of dechlorination products. In addition, untargeted metabolomic analyses revealed an altered bile acid biosynthesis in HepG2 cells. Our results indicate the need to study the disposition and toxicity of complex PCB 2 metabolites, including novel dechlorinated metabolites, in human-relevant models. |
Blood cadmium, lead, manganese, mercury, and selenium levels in American Indian populations: The Strong Heart Study
Li Z , Lewin M , Ruiz P , Nigra AE , Henderson N , Jarrett JM , Ward C , Zhu J , Umans JG , O'Leary M , Zhang Y , Ragin-Wilson A , Navas-Acien A . Environ Res 2022 215 114101 BACKGROUND: Many American Indian (AI) communities are in areas affected by environmental contamination, such as toxic metals. However, studies assessing exposures in AI communities are limited. We measured blood metals in AI communities to assess historical exposure and identify participant characteristics associated with these levels in the Strong Heart Study (SHS) cohort. METHOD: Archived blood specimens collected from 2014 participants (all participants were 50 years of age and older) in Arizona, Oklahoma, and North and South Dakota during SHS Phase-III (1998-1999) were analyzed for cadmium, lead, manganese, mercury, and selenium using inductively coupled plasma triple quadrupole mass spectrometry. We conducted descriptive analyses for the entire cohort and stratified by selected subgroups, including selected demographics, health behaviors, income, waist circumference, and body mass index. Bivariate associations were conducted to examine associations between blood metal levels and selected socio-demographic and behavioral covariates. Finally, multivariate regression models were used to assess the best model fit that predicted blood metal levels. FINDINGS: All elements were detected in 100% of study participants, with the exception of mercury (detected in 73% of participants). The SHS population had higher levels of blood cadmium and manganese than the general U.S. population 50 years and older. The blood mercury median of the SHS population was at about 30% of the U.S. reference population, potentially due to low fish consumption. Participants in North and South Dakota had the highest blood cadmium, lead, manganese, and selenium, and the lowest total mercury levels, even after adjusting for covariates. In addition, each of the blood metals was associated with selected demographic, behavioral, income, and/or weight-related factors in multivariate models. These findings will help guide the tribes to develop education, outreach, and strategies to reduce harmful exposures and increase beneficial nutrient intake in these AI communities. |
First Episodes of Norovirus and Sapovirus Gastroenteritis Protect Against Subsequent Episodes in a Nicaraguan Birth Cohort.
Vielot NA , Reyes Y , Blette B , González F , Toval-Ruiz C , Gutiérrez L , Vilchez S , Diez-Valcarce M , Vinjé J , Becker-Dreps S , Bucardo F . Epidemiology 2022 33 (5) 650-653 BACKGROUND: Norovirus and sapovirus cause a large burden of acute gastroenteritis (AGE) in young children. We assessed protection conferred by norovirus and sapovirus AGE episodes against future episodes. METHODS: Between June 2017 and July 2018, we recruited 444 newborns in León, Nicaragua. Weekly household surveys identified AGE episodes over 36 months, and AGE stools were tested by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) for norovirus genogroup (G)I/GII and sapovirus. We used recurrent-event Cox models and negative control methods to estimate protection conferred by first episodes, controlling for observed and unobserved risk factors, respectively. RESULTS: Sapovirus episodes conferred a 69% reduced hazard of subsequent episodes using the negative control method. Norovirus GI (hazard ratio [HR] = 0.67; 95% confidence interval [CI] = 0.31, 1.3) and GII (HR = 0.20; 95% CI = 0.04, 0.44) episodes also appeared highly protective. Protection against norovirus GII was enhanced following two episodes. CONCLUSIONS: Evidence of natural immunity in early childhood provides optimism for the future success of pediatric norovirus and sapovirus vaccines. |
Principles and procedures for assessment of acute toxicity incorporating in silico methods
Zwickl CM , Graham JC , Jolly RA , Bassan A , Ahlberg E , Amberg A , Anger LT , Beilke L , Bellion P , Brigo A , Burleigh-Flayer H , Cronin MTD , Devlin AA , Fish T , Glowienke S , Gromek K , Karmaus AL , Kemper R , Kulkarni S , Lo Piparo E , Madia F , Martin M , Masuda-Herrera M , McAtee BL , Mestres J , Milchak L , Moudgal C , Mumtaz M , Muster W , Neilson L , Patlewicz G , Paulino A , Roncaglioni A , Ruiz P , Szabo DT , Valentin JP , Vardakou I , Woolley D , Myatt GJ . Comput Toxicol 2022 24 Acute toxicity in silico models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing how to perform and document an in silico analysis. To address this issue, a framework for an acute toxicity hazard assessment is proposed. This framework combines results from different sources including in silico methods and in vitro or in vivo experiments. In silico methods that can assist the prediction of in vivo outcomes (i.e., LD50) are analyzed concluding that predictions obtained using in silico approaches are now well-suited for reliably supporting assessment of LD50-based acute toxicity for the purpose of the Globally Harmonized System (GHS) classification. A general overview is provided of the endpoints from in vitro studies commonly evaluated for predicting acute toxicity (e.g., cytotoxicity/cytolethality as well as assays targeting specific mechanisms). The increased understanding of pathways and key triggering mechanisms underlying toxicity and the increased availability of in vitro data allow for a shift away from assessments solely based on endpoints such as LD50, to mechanism-based endpoints that can be accurately assessed in vitro or by using in silico prediction models. This paper also highlights the importance of an expert review of all available information using weight-of-evidence considerations and illustrates, using a series of diverse practical use cases, how in silico approaches support the assessment of acute toxicity. © 2022 Elsevier B.V. |
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