Advancing Global Health Surveillance of Mycotoxin Exposures using Minimally Invasive Sampling Techniques: A State-of-the-Science Review.

Mycotoxins are a heterogeneous group of toxins produced by fungi that can grow in staple crops (e.g., maize, cereals), resulting in health risks due to widespread exposure from human consumption and inhalation. Dried blood spot (DBS), dried serum spot (DSS), and volumetric tip microsampling (VTS) assays were developed and validated for several important mycotoxins. This review summarizes studies that have developed these assays to monitor mycotoxin exposures in human biological samples and highlights future directions to facilitate minimally invasive sampling techniques as global public health tools. A systematic search of PubMed (MEDLINE), Embase (Elsevier), and CINAHL (EBSCO) was conducted. Key assay performance metrics were extracted to provide a critical review of the available methods. This search identified 11 published reports related to measuring mycotoxins (ochratoxins, aflatoxins, and fumonisins) using DBS/DSS and VTS assays. Multimycotoxin assays adapted for DBS/DSS and VTS have undergone sufficient laboratory validation for applications in large-scale population health and human biomonitoring studies. Future work should expand the number of mycotoxins that can be measured in multimycotoxin assays, continue to improve multimycotoxin assay sensitivities of several biomarkers with low detection rates, and validate multimycotoxin assays across diverse populations with varying exposure levels. Validated low-cost and ultrasensitive minimally invasive sampling methods should be deployed in human biomonitoring and public health surveillance studies to guide policy interventions to reduce inequities in global mycotoxin exposures.

A state-of-the-science review and guide for measuring environmental exposure biomarkers in dried blood spots.

BACKGROUND: Dried blood spot (DBS) sampling is a simple, cost-effective, and minimally invasive alternative to venipuncture for measuring exposure biomarkers in public health and epidemiological research. DBS sampling provides advantages in field-based studies conducted in low-resource settings and in studies involving infants and children. In addition, DBS samples are routinely collected from newborns after birth (i.e., newborn dried blood spots, NDBS), with many states in the United States permitting access to archived NDBS samples for research purposes. OBJECTIVES: We review the state of the science for analyzing exposure biomarkers in DBS samples, both archived and newly collected, and provide guidance on sample collection, storage, and blood volume requirements associated with individual DBS assays. We discuss recent progress regarding analytical methods, analytical sensitivity, and specificity, sample volume requirements, contamination considerations, estimating extracted blood volumes, assessing stability and analyte recovery, and hematocrit effects. METHODS: A systematic search of PubMed (MEDLINE), Embase (Elsevier), and CINAHL (EBSCO) was conducted in March 2022. DBS method development and application studies were divided into three main chemical classes: environmental tobacco smoke, trace elements (including lead, mercury, cadmium, and arsenic), and industrial chemicals (including endocrine-disrupting chemicals and persistent organic pollutants). DBS method development and validation studies were scored on key quality-control and performance parameters by two members of the review team. RESULTS: Our search identified 47 published reports related to measuring environmental exposure biomarkers in human DBS samples. A total of 28 reports (37 total studies) were on methods development and validation and 19 reports were primarily the application of previously developed DBS assays. High-performing DBS methods have been developed, validated, and applied for detecting environmental exposures to tobacco smoke, trace elements, and several important endocrine-disrupting chemicals and persistent organic pollutants. Additional work is needed for measuring cadmium, arsenic, inorganic mercury, and bisphenol A in DBS and NDBS samples. SIGNIFICANCE: We present an inventory and critical review of available assays for measuring environmental exposure biomarkers in DBS and NDBS samples to help facilitate this sampling medium as an emerging tool for public health (e.g., screening programs, temporal biomonitoring) and environmental epidemiology (e.g., field-based studies).

Does a Cancer Diagnosis in Mid-to-Later Life Modify Racial Disparities in Memory Aging?

BACKGROUND: It is unknown whether an incident cancer diagnosis differentially impacts acute and long-term memory aging between older White and Black Americans. METHODS: Incident cancer diagnoses and memory (immediate and delayed recall, combined with proxy-reported memory) were assessed at biennial study interviews in the US Health and Retirement Study (N=14,235, 1998-2016). We used multivariable segmented linear mixed-effects models to evaluate the rate of change in standardized memory score (SD/decade) in the years before, acutely at the time of, and in the years following an incident cancer diagnosis, compared to cancer-free adults, by race. RESULTS: Black participants experienced faster memory decline than White participants (cancer-free group: -1.211 vs. -1.077; P<0.0001). An incident cancer diagnosis was associated with an acute memory drop in White, but not Black participants (-0.065 vs. 0.024; P<0.0001). However, White cancer survivors experienced slower memory decline than cancer-free White adults before and after diagnosis, but this memory advantage was not observed among Black cancer survivors. CONCLUSIONS: Racial disparities in memory aging are not modified by an incident cancer diagnosis. The acute cancer-related memory decline and long-term memory advantage experienced by White, but not Black, cancer survivors relative to cancer-free older adults, requires further investigation.

Validation of Self-reported Cancer Diagnoses Using Medicare Diagnostic Claims in the US Health and Retirement Study, 2000-2016.

BACKGROUND: The US Health Retirement Study (HRS) is an ongoing population-representative cohort of US adults ages >50 with rich data on health during aging. Self-reported cancer diagnoses have been collected since 1998, but they have not been validated. We compared self-reported cancer diagnoses in HRS interviews against diagnostic claims from linked Medicare records. METHODS: Using HRS-Medicare linked data, we examined the validity of first incident cancer diagnoses self-reported in biennial interviews from 2000 to 2016 against ICD-9 and ICD-10 diagnostic claim records as the gold standard. Data were from 8,242 HRS participants ages ≥65 with 90% continuous enrollment in fee-for-service Medicare. We calculated the sensitivity, specificity, and κ for first incident invasive cancer diagnoses (all cancers combined, and each of bladder, breast, colorectal/anal, uterine, kidney, lung, and prostate cancers) cumulatively over the follow-up and at each biennial study interview. RESULTS: Overall, self-reports of first incident cancer diagnoses from 2000 to 2016 had 73.2% sensitivity and 96.2% specificity against Medicare claims (κ = 0.73). For specific cancer types, sensitivities ranged from 44.7% (kidney) to 75.0% (breast), and specificities ranged from 99.2% (prostate) and 99.9% (bladder, uterine, and kidney). Results were similar in sensitivity analyses restricted to individuals with 100% continuous fee-for-service Medicare enrollment and when restricted to individuals with at least 24 months of Medicare enrollment. CONCLUSIONS: Self-reported cancer diagnoses in the HRS have reasonable validity for use in population-based research that is maximized with linkage to Medicare. IMPACT: These findings inform the use of the HRS for population-based cancer and aging research.

Coping During the COVID-19 Pandemic: A Qualitative Study of Older Adults Across the United States.

Objective: Older adults may struggle with stresses and daily life challenges associated with the Coronavirus Disease 2019 (COVID-19) pandemic. Yet they may also utilize emotional and behavioral coping strategies. This qualitative paper aims to identify ways of coping with worries and stress during the pandemic from the perspectives of older adults in the United States. Methods: The COVID-19 Coping Study recruited 6,938 adults aged ≥55 through online multi-frame sampling from April 2-May 31, 2020 across all 50 US states, the District of Columbia, and Puerto Rico. The online questionnaire focused on the effects of COVID-19 on daily life, mental health, and well-being. This included an open-ended question regarding participants' coping strategies. We used qualitative content analysis to identify and code diverse coping strategies. Our general inductive approach enabled findings to emerge from the most frequent and dominant themes in the raw data. Results: A total of 5,180 adults [74% of the total sample; mean age 67.3 (SD 7.9); 63.8% female] responded to the question about using strategies to cope with living through the COVID-19 pandemic. Frequently-reported strategies included exercising and going outdoors, modifying routines, following public health guidelines, adjusting attitudes, and staying socially connected. Some coping strategies were health-limiting (e.g., overeating), while most strategies encouraged self-improvement, positive adjustment, and wellness. Conclusions: This study provides novel qualitative evidence on coping strategies of older adults early in the COVID-19 pandemic. Findings can inform community and clinical interventions to support older adults that harness positive coping strategies such as exercise, modified routines, and social strategies to improve physical and mental health, foster social support, and encourage meaningful daily activities during times of stress and trauma.

Cohort profile: the COVID-19 Coping Study, a longitudinal mixed-methods study of middle-aged and older adults' mental health and well-being during the COVID-19 pandemic in the USA.

PURPOSE: The COVID-19 pandemic, beginning in early 2020, has resulted in massive social, economic, political and public health upheaval around the world. We established a national longitudinal cohort study, the COVID-19 Coping Study, to investigate the effects of pandemic-related stressors and changes in life circumstances on mental health and well-being among middle-aged and older adults in the USA. PARTICIPANTS: From 2 April to 31 May 2020, 6938 adults aged ≥55 years were recruited from all 50 US states, the District of Columbia and Puerto Rico using online, multi-frame non-probability-based sampling. FINDINGS TO DATE: Mean age of the baseline sample was 67.3 years (SD: 7.9 years) and 64% were women. Two in three adults reported leaving home only for essential purposes in the past week (population-weighted proportion: 69%; 95% CI: 68% to 71%). Nearly one in five workers aged 55-64 years was placed on a leave of absence or furloughed since the start of the pandemic (17%; 95% CI: 14% to 20%), compared with one in three workers aged ≥75 years (31%; 95% CI: 21% to 44%). Nearly one-third of adults screened positive for each of depression (32%; 95% CI: 30% to 34%), anxiety (29%; 28% to 31%) and loneliness (29%; 95% CI: 27% to 31%), with decreasing prevalence of each with increasing age. FUTURE PLANS: Monthly and annual follow-ups of the COVID-19 Coping Study cohort will assess longitudinal changes to mental health, cognitive health and well-being in relation to social, behavioural, economic and other COVID-19-related changes to life circumstances. Quantitative and in-depth qualitative interview data will be collected through online questionnaires and telephone interviews. Cohort data will be archived for public use.

Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites.

In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825-34. ©2018 AACR.

Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma.

BACKGROUND AND PURPOSE: We recently reported a time-sensitive, cooperative, anti-tumor effect elicited by radiation (RT) and intra-tumoral-immunocytokine injection in vivo. We hypothesized that RT triggers transcriptional-mediated changes in tumor expression of immune susceptibility markers at delayed time points, which may explain these previously observed time-dependent effects. MATERIALS AND METHODS: We examined the time course of changes in expression of immune susceptibility markers following in vitro or in vivo RT in B78 murine melanoma and A375 human melanoma using flow cytometry, immunoblotting, and qPCR. RESULTS: Flow cytometry and immunoblot revealed time-dependent increases in expression of death receptors and T cell co-stimulatory/co-inhibitory ligands following RT in murine and human melanoma. Using high-throughput qPCR, we observed comparable time courses of RT-induced transcriptional upregulation for multiple immune susceptibility markers. We confirmed analogous changes in B78 tumors irradiated in vivo. We observed upregulated expression of DNA damage response markers days prior to changes in immune markers, whereas phosphorylation of the STAT1 transcription factor occurred concurrently with changes following RT. CONCLUSION: This study highlights time-dependent, transcription-mediated changes in tumor immune susceptibility marker expression following RT. These findings may help in the design of strategies to optimize sequencing of RT and immunotherapy in translational and clinical studies.