Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident.

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

Breast cancer risk in Ukrainian women exposed to Chornobyl fallout while pregnant or lactating: standardized incidence ratio analysis, 1998 to 2016.

The radiation-related risk of breast cancer among women following the Chornobyl accident remains uncertain. During pregnancy, there is rapid cell proliferation in the breast while radioactive iodine from fallout exposure can concentrate in lactating breast tissues. We conducted a standardized incidence ratio (SIR) analysis of breast cancer in a cohort of 2,631 women who were lactating and/or pregnant at any time during the 2-month period of radioiodine fallout (April 26, 1986-June 30, 1986). There were 37,151 person-years of follow-up, and 26 incident breast cancers were identified through linkage with the National Cancer Registry of Ukraine. Breast cancer rates among pregnant or lactating women were compared to the general population rates, and SIRs were adjusted for oblast, urban/rural, age, and calendar year. The SIR was not significant for women pregnant at the time of the accident (SIR = 0.75; 95% CI 0.44, 1.18) or for women lactating anytime within 2 months of the accident (SIR = 0.96; 95% CI 0.48, 1.68). However, there was a non-significantly elevated risk for women lactating at the time of accident (SIR = 1.30, 95% CI 0.40, 3.01). The increased SIR for breast cancer among lactating women is consistent with the results of a similar study in Belarus and indicates the need to quantify the radiation risk of breast cancer in a larger study of women lactating during the period of fallout exposure.

Impact of uncertainties in exposure assessment on thyroid cancer risk among cleanup workers in Ukraine exposed due to the Chornobyl accident.

A large excess risk of thyroid cancer was observed among Belarusian/Russian/Baltic Chornobyl cleanup workers. A more recent study of Ukraine cleanup workers found more modest excess risks of thyroid cancer. Dose errors in this data are substantial, associated with model uncertainties and questionnaire response. Regression calibration is often used for dose-error adjustment, but may not adequately account for the full error distribution. We aimed to examine the impact of exposure-assessment uncertainties on thyroid cancer among Ukrainian cleanup workers using Monte Carlo maximum likelihood, and compare with results derived using regression calibration. Analyses assessed the sensitivity of results to various components of internal and external dose. Regression calibration yielded an excess odds ratio per Gy (EOR/Gy) of 0.437 (95% CI - 0.042, 1.577, p = 0.100), compared with the EOR/Gy using Monte Carlo maximum likelihood of 0.517 (95% CI - 0.039, 2.035, p = 0.093). Trend risk estimates for follicular morphology tumors exhibited much more extreme effects of full-likelihood adjustment, the EOR/Gy using regression calibration of 3.224 (95% CI - 0.082, 30.615, p = 0.068) becoming ~ 50% larger, 4.708 (95% CI - 0.075, 85.143, p = 0.066) when using Monte Carlo maximum likelihood. Results were sensitive to omission of external components of dose. In summary, use of Monte Carlo maximum likelihood adjustment for dose error led to increases in trend risks, particularly for follicular morphology thyroid cancers, where risks increased by ~ 50%, and were borderline significant. The unexpected finding for follicular tumors needs to be replicated in other exposed groups.

Risk of thyroid cancer in Ukrainian cleanup workers following the Chornobyl accident.

Although much is known about the radiation-related risk of thyroid cancer in those exposed at young ages, less is known about the risk due to adult exposure, particularly in men. We aimed to examine the association between thyroid radiation dose received during adulthood and thyroid cancer risk in men. We conducted a nested case-control study (149 cases; 458 controls) of male, Ukrainian cleanup workers who first worked in the Chornobyl zone between ages 18 and 59 years, with cases identified through linkage with the National Cancer Registry of Ukraine from 1988 to 2012. Individual thyroid doses due to external and internal exposure during the cleanup mission and during residence in contaminated settlements were estimated (total dose mean 199 mGy; range 0.15 mGy to 9.0 Gy). The excess odds ratio per gray (EOR/Gy) for overall thyroid cancer was 0.40 (95% CI: - 0.05, 1.48; p-value = 0.118). Time since exposure was borderline significant (p-value = 0.061) in modifying this association so that less time since exposure was associated with a stronger EOR/Gy. An elevated, but nonsignificant association was observed for follicular thyroid cancer (EOR/Gy = 1.72; 95% CI: - 0.25, 13.69; p-value = 0.155) based on a small number of cases (n = 24). Our findings for radiation-related overall thyroid cancer risk are consistent with evidence of increased risks observed in most of the other studies of adult exposure, though the magnitude of the effect in this study is lower than in the previous case-control study of Chornobyl cleanup workers.

Breast cancer risk in residents of Belarus exposed to Chernobyl fallout while pregnant or lactating: standardized incidence ratio analysis, 1997 to 2016.

BACKGROUND: Pregnancy and lactation may constitute radiation-sensitive reproductive periods due to rapid cell proliferation and concentration of radioiodine in the lactating breast. However, there are limited epidemiological data among women exposed to radiation during these periods. METHODS: We examined incidence of breast cancer in a cohort of 3214 women who were pregnant and/or lactating within 2 months (26 April to 30 June 1986) of the Chernobyl accident and residing in contaminated regions of Belarus. There were 33 breast cancers identified through linkage with the Belarusian National Cancer Registry. Breast cancer rates among women who were either pregnant and/or lactating were compared with population rates by calculating standardized incidence ratios (SIR) and 95% confidence intervals (CI) adjusting for attained age, oblast, urban/rural residence and calendar year. RESULTS: Among women who were lactating, we found a greater than 2-fold increased risk of breast cancer compared with the general population, SIR = 2.49 (95% CI: 1.55, 3.75). In contrast, women who were pregnant were not at increased risk (SIR = 0.84 95% CI: 0.46, 1.38). The SIR was highest in women who were exposed at a younger age and at the earliest time period since the accident, though stratified analyses had limited sample sizes. CONCLUSIONS: We found a significantly increased risk of breast cancer among women residing in contaminated areas of Belarus who were lactating at the time of the accident and may have had elevated exposure to radioiodine, when compared with the general population. Studies of breast cancer with individual radiation dose estimates among women exposed during lactation are warranted.

Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1 . We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.

Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.

Donors' perspectives on their postdonation information (PDI) event: a qualitative interview study of PDI donors.

BACKGROUND: Postdonation information (PDI) occurs when a donor fails to report a risk that would have resulted in deferral, but at some subsequent point is disclosed. Donors' perspectives on and perceived reasons for their PDIs have not been previously studied. STUDY DESIGN AND METHODS: A qualitative interview study was conducted with PDI, appropriately deferred (and not PDI), and accepted donors from the six REDS-II blood centers. Telephone interviews were conducted with donors using semistructured discussion guides after their most recent donation or donation attempt. Salient themes were identified within and across the three donor categories using interview recordings and notes. RESULTS: Sixty-six donors were interviewed (35 PDIs, 21 appropriately deferred, and 10 accepted). Cases could be grouped into one of three broad clusters according to the apparent primary reason for the PDI event: perceived changes in rules or application of more intensive screening procedures at this visit versus prior visit(s), issues of recall or interpretation of a question, and discrepancies in recollections of timing. CONCLUSIONS: While descriptive and demographic information exists on the numbers and types of PDI events and donors, there has never been a qualitative study exploring donation experiences and possible reasons for their PDIs. This exploratory study based on semistructured interviews of donors identified several potentially actionable areas including the need for screeners to clarify the meaning of and answers to certain questions and helping donors accurately remember the details and dates of deferrable activities.

Donation frequency of blood donors participating in a prospective cohort study of iron status.

BACKGROUND: Blood centers are interested in understanding determinants of frequent blood donation. We hypothesized that participation in uncompensated research could result in higher donation rates. STUDY DESIGN AND METHODS: Donation rates for 2425 subjects from six US blood centers enrolled in the Retrovirus Epidemiology Donor Study-II Donor Iron Status Evaluation Study were compared to those of nonenrolled donors (n = 202,383). Over 15 months, we compared mean donation rates and adjusted rate ratios (RRs) between enrolled and nonenrolled for three subgroups, first-time, reactivated, and frequent donors, and donation rates before and after the study enrollment period for frequent donors only. RESULTS: Enrolled donors had higher 15-month mean donation rates than nonenrolled donors (first-time, 1.21 [RR = 1.91]; reactivated, 1.68 [RR = 1.83]; frequent, 3.40 [RR = 1.12]). However, frequent donors donated at approximately the same rate after enrollment as they did before enrollment in the study (3.62 per 15 months [RR = 1.12]). CONCLUSION: Donors enrolled in the study donated at a higher rate than nonenrolled donors, but frequent donors remained consistent in their donation frequency both before and after enrollment. Although increased donation rates could have been causally related to study enrollment, we cannot rule out an enrollment bias whereby more committed donors were more likely to enroll in the study.

Iron deficiency in blood donors: analysis of enrollment data from the REDS-II Donor Iron Status Evaluation (RISE) study.

BACKGROUND: Regular blood donors are at risk of iron deficiency, but characteristics that predispose to this condition are poorly defined. STUDY DESIGN AND METHODS: A total of 2425 red blood cell donors, either first-time (FT) or reactivated donors (no donations for 2 years) or frequent donors, were recruited for follow-up. At enrollment, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were determined. Donor variables included demographics, smoking, dietary intake, use of iron supplements, and menstrual and/or pregnancy history. Models to predict two measures of iron deficiency were developed: Absent iron stores (AIS) were indicated by a ferritin level of less than 12 ng/mL and iron-deficient erythropoiesis (IDE) by a log(sTfR/ferritin) value of 2.07 or greater. RESULTS: A total of 15.0% of donors had AIS and 41.7% IDE. In frequent donors, 16.4 and 48.7% of males had AIS and IDE, respectively, with corresponding proportions of 27.1 and 66.1% for females. Donation intensity was most closely associated with AIS and/or IDE (odds ratios from 5.3 to 52.2 for different donation intensity compared to FT donors). Being female, younger, and/or menstruating also increased the likelihood of having AIS and/or IDE, as did having a lower weight. Marginally significant variables for AIS and/or IDE were being a nonsmoker, previous pregnancy, and not taking iron supplements. Dietary variables were in general unrelated to AIS and/or IDE, as was race and/or ethnicity. CONCLUSION: A large proportion of both female and male frequent blood donors have iron depletion. Donation intensity, sex and/or menstrual status, weight, and age are important independent predictors of AIS and/or IDE. Reducing the frequency of blood donation is likely to reduce the prevalence of iron deficiency among blood donors, as might implementing routine iron supplementation.

Recalls of spices due to bacterial contamination monitored by the U.S. Food and Drug Administration: the predominance of Salmonellae.

From 1980 to 2000, the annual per capita consumption of spices in the United States increased by 60% (from 1.0 to 1.6 kg per person per year). Although spices are known to harbor various molds, fungi, and bacteria, relatively few reports have documented this group of foods as the cause of human illness. In recent years, however, the U.S. Food and Drug Administration (FDA) has noted an increased number of recalls of dried spices due to bacterial contamination. Accordingly, we reviewed spice recalls that took place in the United States from fiscal years 1970 to 2003. During the study period, the FDA monitored 21 recalls involving 12 spice types contaminated with bacterial pathogens; in all but one instance, the recalled spices contained Salmonella. Paprika was the spice most often involved in the recalls. A wide variety of countries were the source of the recalled spices. Using data from the Centers for Disease Control and Prevention National Salmonella Surveillance System, we were unable to discern any increases in the reported incidence of laboratory-confirmed salmonellosis in states that received spices contaminated with selected rare Salmonella serotypes. A variety of effective methods exist to disinfect spices, procedures that have attained increased importance given the frequent use of spices in ready-to-eat foods and the potential for contaminated spices to cause widespread outbreaks.