BAILA: A Randomized Controlled Trial of Latin Dancing to Increase Physical Activity in Spanish-Speaking Older Latinos.

BACKGROUND: Latinos are the fastest growing minority group of the older adult population. Although physical activity (PA) has documented health benefits, older Latinos are less likely to engage in leisure time PA than older non-Latino whites. Dance, popular among Latinos, holds promise as a culturally relevant form of PA. PURPOSE: To describe self-reported and device-assessed changes in PA as a result of a randomized controlled trial of BAILAMOS, a 4-month Latin dance program with a 4-month maintenance program, versus a health education control group. METHODS: Adults, aged 55+, Latino/Hispanic, Spanish speaking, with low PA levels at baseline, and risk for disability were randomized to the dance program (n = 167) or health education condition (n = 166). Data were analyzed using multilevel modeling with full information maximum likelihood. RESULTS: A series of multilevel models revealed significant time × group interaction effects for moderate-to-vigorous physical activity (MVPA), dance PA, leisure PA, and total PA. Exploring the interaction revealed the dance group to significantly increase their MVPA, dance PA, leisure PA, and total PA at months 4 and 8. Household PA and activity counts from accelerometry data did not demonstrate significant interaction effects. CONCLUSIONS: The study supports organized Latin dance programs to be efficacious in promoting self-reported PA among older Latinos. Efforts are needed to make dancing programs available and accessible, and to find ways for older Latinos to add more PA to their daily lives. CLINICAL TRIAL INFORMATION: NCT01988233.

Risk of progression from subjective cognitive decline to mild cognitive impairment: The role of study setting.

INTRODUCTION: We compared risk of progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) in an academic memory clinic versus a population-based study. METHODS: Older adults presenting at a memory clinic were classified as SCD (n = 113) or as noncomplainers (n = 82). Participants from a population study were classified as SCD (n = 592) and noncomplainers (n = 589) based on a memory complaint score. Annual follow-up performed for a mean of 3 years. RESULTS: The adjusted hazard ratio for SCD was 15.97 (95% confidence interval: 6.08-42.02, P < .001) in the memory clinic versus 1.18 (95% confidence interval: 1.00-1.40, P = .047) in the population study, where reported "worry" about memory further increased SCD-associated risk for MCI. DISCUSSION: SCD is more likely to progress to MCI in a memory clinic than the general population; participants' characteristics vary across settings. Study setting should be considered when evaluating SCD as a risk state for MCI and dementia.

Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort.

BACKGROUND: Numerous cross-sectional studies have related exposure to neurotropic infectious agents with cognitive dysfunction in older adults, however, the temporal sequence is uncertain. METHODS: In a representative, well-characterized, population-based aging cohort, we determined whether the temporal trajectories of multiple cognitive domains are associated with exposure to cytomegalovirus (CMV), Herpes Simplex virus, type 1 (HSV-1), Herpes Simplex virus, type 2 (HSV-2), or Toxoplasma gondii (TOX). Complex attention, executive functions, memory, language, and visuospatial function were assessed annually for 5 years among consenting individuals. Study entry IgG antibody titers indexing exposure to each infectious agent were examined in relation to slopes of subsequent temporal cognitive decline using multiple linear regressions adjusted for potential confounders. RESULTS: The IgG levels for HSV-2 were significantly associated with baseline cognitive domain scores (N=1022 participants). Further, the IgG levels for HSV-2, TOX, and CMV, but not HSV-1 were significantly associated with greater temporal cognitive decline that varied by type of infection. CONCLUSIONS: Exposure to CMV, HSV-2, or TOX is associated with cognitive deterioration in older individuals, independent of general age-related variables. An increased understanding of the role of infectious agents in cognitive decline may lead to new methods for its prevention and treatment.

Do Subjective Memory Complaints Lead or Follow Objective Cognitive Change? A Five-Year Population Study of Temporal Influence.

The relationship between subjective memory complaints (SM) and objective memory (OM) performance in aging has been variably characterized in a substantial literature, to date. In particular, cross-sectional studies often observe weak or no associations. We investigated whether subjective memory complaints and objectively measured cognition influence each other over time, and if so, which is the stronger pathway of change-objective to subjective, or subjective to objective-or whether they are both important. Using bivariate latent change score modeling in data from a population study (N=1980) over 5 annual assessment cycles, we tested four corresponding hypotheses: (1) no coupling between SM and OM over time; (2) SM as leading indicator of change in OM; (3) OM as leading indicator of change in SM; (4) dual coupling over time, with both SM and OM leading subsequent change in the other. We also extended objective cognition to two other domains, language and executive functions. The dual-coupling models best fit the data for all three objective cognitive domains. The SM-OM temporal dynamics differ qualitatively compared to other domains, potentially reflecting changes in insight and self-awareness specific to memory impairment. Subjective memory and objective cognition reciprocally influence each other over time. The temporal dynamics between subjective and objective cognition in aging are nuanced, and must be carefully disentangled to shed light on the underlying processes.

Solid-phase synthesis of amidine-substituted phenylbenzimidazoles and incorporation of this DNA binding and recognition motif into amino acid and peptide conjugates.

Amidine-substituted phenylbenzimidazoles are well-established DNA-binding structural motifs that have contributed to the development of diverse classes of DNA-targeted agents; this ring system not only assists in increasing the overall DNA affinity of an agent, but can also influence its site selectivity. Seeking a means to conveniently exploit these attributes, a protocol for the on-resin synthesis of amino acid- and peptide-phenylbenzimidazole-amidine conjugates was developed to facilitate installation of phenylbenzimidazole-amidines into peptide chains during the course of standard solid-phase syntheses. Building from a resin-bound amino acid or peptide on Rink amide resin, 4-formyl benzoic acid was coupled to the resin-bound free amine followed by introduction of 3,4-diamino-N'-hydroxybenzimidamide (in the presence of 1,4-benzoquinone) to construct the benzimidazole heterocycle. Finally, the resin-bound N'-hydroxybenzimidamide functionality was reduced to an amidine via 1 M SnCl2·2H2O in DMF prior to resin cleavage to release final product. This procedure permits the straightforward synthesis of amino acids or peptides that are N-terminally capped by a phenylbenzimidazole-amidine ring system. Employing this protocol, a series of amino acid-phenylbenzimidazole-amidine (Xaa-R) conjugates was synthesized as well as dipeptide conjugates of the general form Xaa-Gly-R (where R is the phenylbenzimidazole-amidine and Xaa is any amino acid).

Pancreatic quantitative sensory testing to predict treatment response of endoscopic therapy or surgery for painful chronic pancreatitis with pancreatic duct obstruction: study protocol for an observational clinical trial.

INTRODUCTION: Treatment for abdominal pain in patients with chronic pancreatitis (CP) remains challenging in the setting of central nervous system sensitisation, a phenomenon of remodelling and neuronal hyperexcitability resulting from persistent pain stimuli. This is suspected to render affected individuals less likely to respond to conventional therapies. Endotherapy or surgical decompression is offered to patients with pancreatic duct obstruction. However, the response to treatment is unpredictable. Pancreatic quantitative sensory testing (P-QST), an investigative technique of standardised stimulations to test the pain system in CP, has been used for phenotyping patients into three mutually exclusive groups: no central sensitisation, segmental sensitisation (pancreatic viscerotome) and widespread hyperalgesia suggestive of supraspinal central sensitisation. We will test the predictive capability of the pretreatment P-QST phenotype to predict the likelihood of pain improvement following invasive treatment for painful CP. METHODS AND ANALYSIS: This observational clinical trial will enrol 150 patients from the University of Pittsburgh, Johns Hopkins and Indiana University. Participants will undergo pretreatment phenotyping with P-QST. Treatment will be pancreatic endotherapy or surgery for clearance of painful pancreatic duct obstruction. PRIMARY OUTCOME: average pain score over the preceding 7 days measured by Numeric Rating Scale at 6 months postintervention. Secondary outcomes will include changes in opioid use during follow-up, and patient-reported outcomes in pain and quality of life at 3, 6 and 12 months after the intervention. Exploratory outcomes will include creation of a model for individualised prediction of response to invasive treatment. ETHICS AND DISSEMINATION: The trial will evaluate the ability of P-QST to predict response to invasive treatment for painful CP and develop a predictive model for individualised prediction of treatment response for widespread use. This trial was approved by the University of Pittsburgh Institutional Review Board. Data and results will be reported and disseminated in conjunction with National Institutes of Health policies. TRIAL REGISTRATION NUMBER: NCT04996628.

Graph Embedding Contrastive Multi-Modal Representation Learning for Clustering.

Multi-modal clustering (MMC) aims to explore complementary information from diverse modalities for clustering performance facilitating. This article studies challenging problems in MMC methods based on deep neural networks. On one hand, most existing methods lack a unified objective to simultaneously learn the inter- and intra-modality consistency, resulting in a limited representation learning capacity. On the other hand, most existing processes are modeled for a finite sample set and cannot handle out-of-sample data. To handle the above two challenges, we propose a novel Graph Embedding Contrastive Multi-modal Clustering network (GECMC), which treats the representation learning and multi-modal clustering as two sides of one coin rather than two separate problems. In brief, we specifically design a contrastive loss by benefiting from pseudo-labels to explore consistency across modalities. Thus, GECMC shows an effective way to maximize the similarities of intra-cluster representations while minimizing the similarities of inter-cluster representations at both inter- and intra-modality levels. So, the clustering and representation learning interact and jointly evolve in a co-training framework. After that, we build a clustering layer parameterized with cluster centroids, showing that GECMC can learn the clustering labels with given samples and handle out-of-sample data. GECMC yields superior results than 14 competitive methods on four challenging datasets. Codes and datasets are available: https://github.com/xdweixia/GECMC.

Assessment of the influence of gluten quality on highland barley dough sheet quality by different instruments.

This study was to compare the results of texture analyzer with those of farinograph and extensograph and determine whether texture analyzer could be used to evaluate the processing quality of highland barley flour (HBF) dough sheet. The farinograph and extensograph tests were used to determine the reconstituted flour properties, a texture analyzer was applied to measure the tensile strength (TS) of HBF dough sheet, and the content of glutenin macropolymer (GMP), free sulfhydryl (-SH) and secondary structure of protein and microstructure in HBF dough sheet were investigated. Furthermore, correlations between these parameters were determined by regression analysis and Pearson correlation coefficient. It was suggested that the reconstituted flours with a higher gluten index showed a higher farinograph quality number (FQN) and greater maximum resistance to extension (Rm ). HBF dough sheets with higher gluten index possessed higher GMP and lower free -SH contents, a more ordered secondary structure of protein, resulting in a more compact gluten network and a stronger TS. The regression and correlation analysis showed that TS was positively correlated with FQN and Rm . In addition, it was significantly correlated with the content of GMP, -SH, secondary structure of protein and gluten network. It was concluded that texture analyzer could be an alternative approach to evaluate the processing quality of HBF dough sheet. Moreover, the gluten index of flours could be used to predict the processing quality of HBF dough sheet.

Latin Dance and Working Memory: The Mediating Effects of Physical Activity Among Middle-Aged and Older Latinos.

Background: Physical activity (PA) is a promising method to improve cognition among middle-aged and older adults. Latinos are at high risk for cognitive decline and engaging in low levels of PA. Culturally relevant PA interventions for middle-aged and older Latinos are critically needed to reduce risk of cognitive decline. We examined changes in cognitive performance among middle-aged and older Latinos participating in the BAILAMOS™ dance program or a health education group and compared the mediating effects of PA between group assignment and change in cognitive domains. Methods: Our 8-month randomized controlled trial tested BAILAMOS™, a 4-month Latin dance program followed by a 4-month maintenance phase. A total of 333 older Latinos aged 55+ were randomized to either BAILAMOS™, or to a health education control group. Neuropsychological tests were administered, scores were converted to z-scores, and specific domains (i.e., executive function, episodic memory, and working memory) were derived. Self-reported PA was assessed, and we reported categories of total PA, total leisure PA, and moderate-to-vigorous PA as minutes/week. A series of ANCOVAs tested changes in cognitive domains at 4 and 8 months. A mediation analysis tested the mediating effects of each PA category between group assignment and a significant change in cognition score. Results: The ANCOVAs found significant improvement in working memory scores among participants in the dance group at month 8 [F (1,328) = 5.79, p = 0.017, d = 0.20], but not in executive functioning [F (2,328) = 0.229, p = 0.80, Cohen's d = 0.07] or episodic memory [F (2,328) = 0.241, p = 0.78, Cohen's d = 0.05]. Follow-up mediation models found that total PA mediated the relationship between group assignment and working memory, in favor of the dance group (ß = 0.027, 95% CI [0.0000, 0.0705]). Similarly, total leisure PA was found to mediate this relationship [ß = 0.035, 95% CI (0.0041, 0.0807)]. Conclusion: A 4-month Latin dance program followed by a 4-month maintenance phase improved working memory among middle-aged and older Latinos. Improvements in working memory were mediated by participation in leisure PA. Our results support the current literature that leisure time PA influences cognition and highlight the importance of culturally relevant PA modalities for Latinos. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT01988233].

PATH 2 Purpose: Design of a comparative effectiveness study of prevention programs for adolescents at-risk for depression in the primary care setting.

The majority of mental, emotional, and behavioral (MEB) disorders have an initial onset before age 24, with 20% annual incidence, and with major depressive disorder (MDD) being the most common MEB. Health systems may be able to reduce costs by transitioning from the current treatment-focused model for MDD to a prevention model. However, evidence is needed for (1) the comparative effectiveness of a "scalable intervention" and (2) an implementation model for such a scalable intervention in the primary care setting. This paper describes a comparative effectiveness trial evaluating the efficacy of two evidence-based cognitive-behavioral prevention (CBP) programs: Teens Achieving Mastery over Stress (TEAMS), the "gold standard," group therapy model, and Competent Adulthood Transition with Cognitive Behavioral, Humanistic and Interpersonal Training (CATCH-IT), a scalable, self-directed, technology-based model. Eligible adolescents, age 13-19, are offered one of these two depression prevention programs across five health systems (30 clinics) in urban and suburban Chicago, IL, rural Western IL, and Louisville, KY. We are comprehensively evaluating patient-centered outcomes and stakeholder-valued moderators of effect versus baseline at two, six, 12, and 18-month assessment points. Using a hybrid clinical trial design that simultaneously examines the implementation process, the study is also assessing adolescents', parents', and providers' experiences (e.g., efficacy, time commitment, cultural acceptability) within each intervention approach.

A Pilot Study of End-Tidal Carbon Dioxide in Prediction of Inhospital Cardiac Arrests.

A validated means to predict inhospital cardiac arrest is lacking. The purpose of this study was to evaluate the changes in end-tidal carbon dioxide, as it correlates with the progression to inhospital cardiac arrest in ICU patients. DESIGN SETTING AND PATIENTS: Single-center, retrospective cohort study of mechanically ventilated ICU patients (age > 18 yr old) having inhospital cardiac arrest with advanced cardiac life support and continuous end-tidal carbon dioxide monitoring at a single academic center from 2014 to 2017. Demographics, clinical variables, and outcomes were collected. End-tidal carbon dioxide was collected from 5 to 2,880 minutes before inhospital cardiac arrest. Data were analyzed using descriptive statistics, and model estimates were generated using a repeated-measures categorical model with restricted maximum likelihood estimation and fully specified (autoregressive) covariance to assess the effect of time on changes in end-tidal carbon dioxide. MEASUREMENTS AND MAIN RESULTS: A total of 788 patients were identified and 104 met inclusion criteria, where 62% were male with an average age of 58.5 years. Seventy-four percent required vasopressors and 72% experienced pulseless electrical activity. Mean end-tidal carbon dioxide 5 minutes prior to inhospital cardiac arrest was significantly lower than all evaluated time points except 180 minutes (p < 0.05). One patient survived to hospital discharge. In multivariate logistic regression modeling for return of spontaneous circulation, a greater change in the prearrest end-tidal carbon dioxide maximum to prearrest end-tidal carbon dioxide minimum was associated with a decreased likelihood of return of spontaneous circulation (odds ratio 0.903; 95% CI, 0.832-0.979; p = 0.014). Additionally, a change from prearrest end-tidal carbon dioxide maximum to prearrest end-tidal carbon dioxide minimum greater than 17 mm Hg was associated with a decreased likelihood of return of spontaneous circulation and odds ratio 0.150; 95% CI, 0.036-0.66; p = 0.012). CONCLUSIONS: Mean end-tidal carbon dioxide is significantly lower immediately before inhospital cardiac arrest. The statistical and clinical significance of end-tidal carbon dioxide may highlight its utility for predicting inhospital cardiac arrest in ICU patients. Comparison analysis and modeling explorations in a larger cohort are needed.

Carrageenan-Free Diet Shows Improved Glucose Tolerance and Insulin Signaling in Prediabetes: A Randomized, Pilot Clinical Trial.

OBJECTIVES: Carrageenan is well known to cause inflammation and is used in laboratory experiments to study mediators and treatments of inflammation. However, carrageenan is added to hundreds of processed foods to improve texture. Previous work indicated that low concentrations of carrageenan in drinking water caused marked glucose intolerance and insulin resistance in a mouse model. This exploratory, clinical study tested the impact of the no-carrageenan diet in prediabetes. Research Design and Methods. Participants with prediabetes (n = 13), defined as HbA1c of 5.7%-6.4%, enrolled in a 12-week, randomized, parallel-arm, feeding trial. One group (n = 8) was provided all meals and snacks with no carrageenan. A second group (n = 5) received a similar diet with equivalent content of protein, fat, and carbohydrate, but with carrageenan. Blood samples were collected at baseline and during oral glucose tolerance tests at 6 and 12 weeks. The primary outcome measure was changed in %HbA1c between baseline and 12 weeks. Statistical analysis included paired and unpaired t-tests, correlations, and 2 × 2 ANOVAs. RESULTS: Subjects on no carrageenan had declines in HbA1c and HOMA-IR (p = 0.006, p = 0.026; paired t-test, two tailed). They had increases in C-peptide (p = 0.029) and Matsuda Index (2.1 ± 0.7 to 4.8 ± 2.3; p = 0.052) and declines in serum IL-8, serum galectin-3, and neutrophil phospho-(Ser307/312)-IRS1 (p = 0.049, p = 0.003, and p = 0.006; paired t-tests, two tailed). Subjects on the diet with carrageenan had no significant changes in these parameters. Significant differences between no-carrageenan and carrageenan-containing diet groups for changes from baseline to 12 weeks occurred in C-peptide, phospho-Ser-IRS1, phospho-AKT1, and mononuclear cell arylsulfatase B (p = 0.007, p = 0.038, p = 0.0012, and p = 0.0008; 2 × 2 ANOVA). Significant correlations were evident between several of the variables. CONCLUSIONS: Findings indicate improvement in HbA1c and HOMA-IR in participants on no-carrageenan diets, but not in participants on carrageenan-containing diets. Significant differences between groups suggest that removing carrageenan may improve insulin signaling and glucose tolerance. Larger studies are needed to further consider the impact of carrageenan on development of diabetes.

Delivery and Impact of a Motivational Intervention for Smoking Cessation: A PROS Study.

OBJECTIVES: We tested a Public Health Service 5As-based clinician-delivered smoking cessation counseling intervention with adolescent smokers in pediatric primary care practice. METHODS: We enrolled clinicians from 120 practices and recruited youth (age ≥14) from the American Academy of Pediatrics Pediatric Research in Office Settings practice-based research network. Practices were randomly assigned to training in smoking cessation (intervention) or social media counseling (attentional control). Youth recruited during clinical visits completed confidential screening forms. All self-reported smokers and a random sample of nonsmokers were offered enrollment and interviewed by phone at 4 to 6 weeks, 6 months, and 12 months after visits. Measures included adolescents' report of clinicians' delivery of screening and counseling, current tobacco use, and cessation behaviors and intentions. Analysis assessed receipt of screening and counseling, predictors of receiving 5As counseling, and effects of interventions on smoking behaviors and cessation at 6 and 12 months. RESULTS: Clinicians trained in the 5As intervention delivered more screening (ß = 1.0605, P < .0001) and counseling (ß = 0.4354, P < .0001). In both arms, clinicians more often screened smokers than nonsmokers. At 6 months, study arm was not significantly associated with successful cessation; however, smokers in the 5As group were more likely to have quit at 12 months. Addicted smokers more often were counseled, regardless of study arm, but were less likely to successfully quit smoking. CONCLUSIONS: Adolescent smokers whose clinicians were trained in 5As were more likely to receive smoking screening and counseling than controls, but the ability of this intervention to help adolescents quit smoking was limited.

Role of gender in perspectives of discrimination, stigma, and attitudes relative to cervical cancer in rural Sénégal.

Cervical cancer is the leading cause of female cancer deaths in Sénégal which is ranked 17th in incidence globally, however, the screening rate there is very low. Nuanced gendered perceptions and health behaviors of both women and men play a significant role in women's health. Our study analyzed gender differences on perceptions of gender roles, discrimination, cancer attitudes, cancer stigma, and influences in healthcare decision making within our study population to inform ongoing cervical cancer prevention work in the rural region of Kédougou, Sénégal. We conducted a cross-sectional survey of 158 participants, 101 women and 57 men (ages 30-59) across nine non-probability-sampled communities from October 2018 through February 2019. Bivariate analysis was conducted to assess gender differences across all variables. We also conducted analyses to determine whether there were significant differences in beliefs and attitudes, by screening behavior and by education. We found significant gender differences regarding the perception of a woman's role (P < 0.001) and a man's role (P = 0.007) as well as in the everyday discrimination questions of "decreased respect by spouse" (P < 0.001). Regarding cancer stigma, among women, 18.00% disagreed and 10.00% strongly disagreed while among men, 3.6% disagreed and 1.8% strongly disagreed that "If I had cancer, I would want my family to know that I have it." When making decisions about one's healthcare, women are more likely than men to trust social contacts such as their spouse (46.5% vs 5.3%, p < 0.001) while men are more likely than women to trust health service personnel such as a nurse (50.9% vs 18.8%, p < 0.001). Furthermore, men and women were both more likely to state that men have the final decision regarding the healthcare decisions of women (p < 0.001). Our data reveal structural disadvantages for women within our study population as well as gender differences in the adapted everyday discrimination scale and cancer stigma scale. Higher rates of both personal and perceived cancer stigma among women has profound implications for how population and community level communication strategies for cancer prevention and control should be designed. Efforts to advance the goal of the elimination of cervical cancer should, in the short-term, seek to gain a more profound understanding of the ways that gender, language, and other social determinants impact negative social influences and other barriers addressable through interventions. Social and behavior change communication may be one approach that can focus both on education while seeking to leverage the social influences that exist in achieving immediate and long-term goals.

Leveraging system sciences methods in clinical trial evaluation: An example concerning African American women diagnosed with breast cancer via the Patient Navigation in Medically Underserved Areas study.

BACKGROUND: Systems science methodologies offer a promising assessment approach for clinical trials by: 1) providing an in-silico laboratory to conduct investigations where purely empirical research may be infeasible or unethical; and, 2) offering a more precise measurement of intervention benefits across individual, network, and population levels. We propose to assess the potential of systems sciences methodologies by quantifying the spillover effects of randomized controlled trial via empirical social network analysis and agent-based models (ABM). DESIGN/METHODS: We will evaluate the effects of the Patient Navigation in Medically Underserved Areas (PNMUA) study on adult African American participants diagnosed with breast cancer and their networks through social network analysis and agent-based modeling. First, we will survey 100 original trial participants (50 navigated, 50 non-navigated) and 150 of members of their social networks (75 from navigated, 75 non-navigated) to assess if navigation results in: 1) greater dissemination of breast health information and breast healthcare utilization throughout the trial participants' networks; and, 2) lower incremental costs, when incorporating navigation effects on trial participants and network members. Second, we will compare cost-effectiveness models, using a provider perspective, incorporating effects on trial participants versus trial participants and network members. Third, we will develop an ABM platform, parameterized using published data sources and PNMUA data, to examine if navigation increases the proportion of early stage breast cancer diagnoses. DISCUSSION: Our study results will provide promising venues for leveraging systems science methodologies in clinical trial evaluation.

Risk assessment of upper tract urothelial carcinoma related to aristolochic acid.

BACKGROUND: Aristolochic acid is a toxin found in plants of the genus Aristolochia, to which humans can be exposed either through certain Chinese herbal medicines or through inadvertent commingling with food crops. Our objective was to estimate cumulative exposures of aristolochic acid associated with increased risk of end-stage renal disease (ESRD), and to conduct a systematic review and meta-analysis on aristolochic acid-induced upper tract urothelial carcinoma (UUC). METHODS: Using epidemiologic studies on aristolochic acid-related disease from multiple different regions of the world, a systematic review was conducted in which relative risks (RR), HRs, and ORs were derived or extracted directly, and a meta-analysis was conducted. One study was used to estimate a benchmark dose lower confidence limit (BMDL) for aristolochic acid-related ESRD. RESULTS: Mean values for risk ratios, ORs, RRs, or HRs, of UUC caused by aristolochic acid ranged from 1 to 49. A meta-analysis of these studies resulted in a pooled OR of 5.97 [95% confidence interval (CI), 2.78-12.84] for this aristolochic acid-related cancer. The obtained BMDL for aristolochic acid-related ESRD was 0.42 g cumulative aristolochic acid exposure. CONCLUSIONS: Aristolochic acid exposure is significantly associated with an increased risk of UUC, and there is a dose-dependent relationship between cumulative aristolochic acid exposure and ESRD risk. IMPACT: Individuals who use certain Chinese herbal medicines may significantly increase their risk of developing UUC and/or ESRD, as would individuals who are inadvertently exposed to aristolochic acid through commingling of Aristolochia plants with harvested food crops.