Surveillance of Depleted Uranium-exposed Gulf War Veterans: More Evidence for Bone Effects.

ABSTRACT: Gulf War I veterans who were victims of depleted uranium (DU) "friendly-fire" incidents have undergone longitudinal health surveillance since 1994. During the spring of 2019, 36 members of the cohort were evaluated with a monitoring protocol including exposure assessment for total and isotopic uranium concentrations in urine and a comprehensive review of health outcomes, including measures of bone metabolism and bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained depleted uranium (DU) shrapnel fragments. In addition, a measure of bone resorption, N-telopeptide, showed a statistically significant increase in those in the high DU subgroup, a finding consistent with a statistically significant decrease in bone mass also observed in this high DU subgroup compared to the low DU subgroup. After more than 25 y since first exposure to DU, an aging cohort of military veterans continues to show few U-related health effects in known target organs of U toxicity. The new finding of impaired BMD in the high DU subgroup has now been detected in two consecutive surveillance visits. While this is a biologically plausible uranium effect, it is not reflected in other measures of bone metabolism in the full cohort, which have largely been within normal limits. However, ongoing accrual of the U burden from fragment absorption over time and the effect of aging further impairing BMD suggest the need for future surveillance assessments of this cohort.

The Utility of Spot vs 24-Hour Urine Samples for Metal Determination in Veterans With Retained Fragments.

OBJECTIVES: The objective of this investigation is to explore the utility of using a spot urine sample in lieu of a 24-hour collection in assessing fragment-related metal exposure in war-injured veterans. METHODS: Twenty-four veterans collected each urine void over a 24-hour period in separate containers. Concentrations of 13 metals were measured in each void and in a pooled 24-hour sample using inductively coupled plasma mass spectrometry. To assess the reliability of spot sample measures over time, intraclass correlations (ICCs) were calculated across all spot samples. Lin's concordance correlation coefficient was used to assess agreement between a randomly selected spot urine sample and each corresponding 24-hour sample. RESULTS: In total, 149 spot urine samples were collected. Ten of the 13 metals measured had ICCs more than 0.4, suggesting "fair to good" reliability. Concordance coefficients were more than 0.4 for all metals, suggesting "moderate" agreement between spot and 24-hour concentrations, and more than 0.6 for seven of the 13 metals, suggesting "good" agreement. CONCLUSIONS: Our fair to good reliability findings, for most metals investigated, and moderate to good agreement findings for all metals, across the range of concentrations observed here, suggest the utility of spot urine samples to obtain valid estimates of exposure in the longitudinal surveillance of metal-exposed populations.

Simultaneous Determination of Uranium and Depleted Uranium Isotopic Ratio Using Inductively Coupled Mass Spectrometry.

We have developed and validated a method for the simultaneous quantitative measurement of total uranium (TU) and uranium 235 U/238 U isotopic ratio (UIR) in urine by inductively coupled plasma mass spectrometry (ICP-MS) using a Thermo Scientific iCAP-Q instrument. The performance characteristics of the assay were determined to be in compliance with clinical laboratory standards. The assay was linear in the concentration range of 1.0 to 500.0 ng/liter TU. The method was precise and accurate with limits of detection of 2.5 ng/liter for TU and 9.8 ng/liter for UIR. The accuracy was >93% and the coefficient of variation (% CV) was <5.0% for both TU and UIR. All results were within established guidelines and agreed-upon criteria, and the results fell within the certified range for the reference controls. The method has thus been shown to be effective as a simple, precise, and sensitive analytical technique for testing urine samples. © 2018 by John Wiley & Sons, Inc.

Type 2 Diabetes Mellitus in Children.

The prevalence of type 2 diabetes mellitus in children and adolescents has increased worldwide over the past three decades. This increase has coincided with the obesity epidemic, and minority groups are disproportionately affected. The American Diabetes Association recommends screening for type 2 diabetes beginning at 10 years of age or the onset of puberty in children who are overweight or obese and have two additional risk factors. Diagnostic criteria include a fasting blood glucose level of 126 mg per dL or greater, a two-hour plasma glucose level of 200 mg per dL or greater during an oral glucose tolerance test, an A1C level of 6.5% or more, or a random plasma glucose level of 200 mg per dL or greater plus symptoms of polyuria, polydipsia, or unintentional weight loss. Management should be focused on a multidisciplinary, family-centered approach. Nutrition and exercise counseling should be started at the time of diagnosis and as a part of ongoing management. Metformin is the first-line therapy in conjunction with lifestyle changes. Insulin therapy should be initiated if there are signs of ketosis or ketoacidosis, or if the patient has significant hyperglycemia (A1C greater than 9% or a random plasma glucose level of 250 mg per dL or greater).

Determination of Thirteen Trace and Toxic Elements in Urine Using Inductively Coupled Mass Spectrometry.

We developed and validated a method for the assessment of thirteen separate trace and toxic elements using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Included elements were as follows: aluminum, chromium, manganese, iron, cobalt, nickel, copper, zinc, arsenic, molybdenum, cadmium, tungsten, and lead. The measurements of all elements in urine samples were conducted using ICAP-Q ICP-MS in a single method. The performance characteristics of the assay were determined according to clinical laboratory standards. The assay was linear in the concentration range of 1.0 to 1000.0 µg/liter for all elements. The method was precise and accurate with limits of quantitation of 1 µg/liter for chromium, manganese, cobalt, nickel, copper, cadmium, tungsten, and lead; 2 µg/liter for iron and arsenic; 5 µg/liter for aluminum; and 50 µg/liter for zinc. This method has successfully been used for the assessment of all thirteen elements included in urine and has been shown to be effective as a simple, precise, and sensitive analytical technique for biological monitoring of urine samples. © 2018 by John Wiley & Sons, Inc.

Fertility after intrauterine device removal: a pilot study.

BACKGROUND: Despite high efficacy, only 7.7% of women in the United States currently using contraception use an IUD. There is little published contemporary data about fertility rates after IUD use, especially in nulliparous women and women using the hormonal IUD. STUDY DESIGN: We recruited sexually active women 18 to 35 years of age enrolled in the Contraceptive CHOICE Project who had discontinued a contraceptive method and desired pregnancy. RESULTS: In this pilot project, we enrolled 69 former IUD users (19 copper and 50 levonorgestrel) and 42 former non-IUD users. Pregnancy rates at 12 months were similar between the two groups; 81% of IUD users became pregnant compared to 70% of non-IUD users (p = 0.18). In the Cox model, there was no difference in the time to pregnancy in IUD users compared to non-IUD users (HRadj 1.19, 95% CI 0.74-1.92). African American race was the only variable associated with reduced fertility (HRadj 0.40, 95% CI 0.24-0.67). CONCLUSIONS: We found no difference in 12-month pregnancy rates or time to pregnancy between former IUD users and users of other contraceptive methods. However, there was a clinically and statistically significant reduction in fertility in African American women.

Medical contraindications in women seeking combined hormonal contraception.

OBJECTIVE: The objective of the study was to evaluate the prevalence of medical contraindications in a large group of women seeking combined hormonal contraception (CHC). STUDY DESIGN: The Contraceptive CHOICE Project is a prospective cohort study designed to promote the use of long-acting reversible contraceptive methods to reduce unintended pregnancies in the St Louis region. During baseline enrollment, participants were asked about their desired methods of contraception and medical history. Potential medical contraindications were defined as self-reported history of hypertension, myocardial infarction, cerebral vascular accidents, migraines with aura, any migraine and age 35 years or older, smoking in women older than 35 years, venous thromboembolism, or liver disease. We reviewed all research charts of women with self-reported medical contraindications to verify all conditions. Binomial 95% confidence intervals (CIs) were calculated around percentages. RESULTS: Between August 2007 and December 2009, 5087 women who enrolled in the CHOICE Project provided information about their medical history and 1010 women (19.9%) desired CHC at baseline. Seventy women (6.93%; 95% CI, 5.44-8.68%) were defined as having a potential medical contraindication to CHC at baseline. After chart review, only 24 of 1010 participants desiring CHC (2.38%; 95% CI, 1.53-3.52%) were found to have true medical contraindications to CHC including 17 with hypertension, 2 with migraines with aura, 2 with a history of venous thromboembolism, and 3 smokers aged 35 years or older. CONCLUSION: The prevalence of medical contraindications to CHC was very low in this large sample of reproductive-aged women. This low prevalence supports provision of CHC without a prescription.

The Gulf War depleted uranium cohort at 20 years: bioassay results and novel approaches to fragment surveillance.

During the 1991 GulfWar, U.S. service members were exposed to depleted uranium (DU) through friendly-fire incidents involving DU munitions and vehicles protected by DU armor. Routes of exposure to DU involved inhalation of soluble and insoluble DU oxide particles, wound contamination, and retained embedded DU metal fragments that continue to oxidize in situ and release DU to the systemic circulation. A biennial health surveillance program established for this group of Veterans by the U.S. Department of Veterans Affairs has shown continuously elevated urine DU concentrations in the subset of veterans with embedded fragments for over 20 years. While the 2011 assessment was comprehensive, few clinically significant U-related health effects were observed. This report is focused on health outcomes associated with two primary target organs of concern for long term effects of this combat-related exposure to DU. Renal biomarkers showed minimal DU-related effects on proximal tubule function and cytotoxicity, but significant biomarker results were observed when urine concentrations of multiple metals also found in fragments were examined together. Pulmonary tests and questionnaire results indicate that pulmonary function after 20 y remains within the clinical normal range. Imaging of DU embedded fragment-associated tissue for signs of inflammatory or proliferative reactions possibly associated with foreign body transformation or with local alpha emissions from DU was also conducted using PET-CT and ultrasound. These imaging tools may be helpful in guiding decisions regarding removal of fragments.

Uranium quantification in semen by inductively coupled plasma mass spectrometry.

In this study we report uranium analysis for human semen samples. Uranium quantification was performed by inductively coupled plasma mass spectrometry. No additives, such as chymotrypsin or bovine serum albumin, were used for semen liquefaction, as they showed significant uranium content. For method validation we spiked 2g aliquots of pooled control semen at three different levels of uranium: low at 5 pg/g, medium at 50 pg/g, and high at 1000 pg/g. The detection limit was determined to be 0.8 pg/g uranium in human semen. The data reproduced within 1.4-7% RSD and spike recoveries were 97-100%. The uranium level of the unspiked, pooled control semen was 2.9 pg/g of semen (n=10). In addition six semen samples from a cohort of Veterans exposed to depleted uranium (DU) in the 1991 Gulf War were analyzed with no knowledge of their exposure history. Uranium levels in the Veterans' semen samples ranged from undetectable (<0.8 pg/g) to 3350 pg/g. This wide concentration range for uranium in semen is consistent with known differences in current DU body burdens in these individuals, some of whom have retained embedded DU fragments.

A randomized trial of home versus clinic-based sexually transmitted disease screening among men.

BACKGROUND: Preventing sexually transmitted diseases (STD) such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) remains a public health challenge. The U.S. Preventive Services Task Force suggests STD screening among men will likely lead to a decrease in infection rates of women. However, innovative approaches are necessary to increase the traditionally low rates of male screening. The purpose of this study is to compare the acceptability and effectiveness of home-based versus clinic-based urine screening for CT and GC in men. METHODS: We conducted a randomized clinical trial of 200 men aged 18 to 45 years who reside in St. Louis, MO. Men were enrolled via telephone and randomly assigned to receive a free urine CT/GC screening kit either in-person at the research clinic or to have it mailed to the participant's preferred address. Participants completed questionnaires at baseline and 10 to 12 weeks postenrollment. The primary outcome was whether STD screening was completed. RESULTS: Sixty percent (120/200) completed STD screening. Men assigned to home-based screening were 60% more likely to complete screening compared with clinic-based screening (72% vs. 48%, RRadj = 1.6, 95% CI = 1.3, 2.00). We identified 4 cases of CT or GC in the home-based group compared with 3 cases of CT in the clinic group. Men who completed screening were significantly more likely to be white, younger, and college educated. CONCLUSIONS: Home-based screening for CT and GC among men is more acceptable than clinic-based screening and resulted in higher rates of screening completion. Incorporating home-based methods as adjuncts to traditional STD screening options shows promise in improving STD screening rates in men.

Contraceptive failure rates of etonogestrel subdermal implants in overweight and obese women.

OBJECTIVE: To estimate the contraceptive failure rates of the etonogestrel subdermal contraceptive implant in overweight and obese women and compare failure rates with women of normal weight and women using intrauterine devices (IUDs). METHODS: The Contraceptive CHOICE Project is a large prospective cohort study designed to promote the use of long-acting reversible contraceptive methods to reduce unintended pregnancies in the St Louis region. Participants are provided reversible contraception of their choice at no cost. We collected baseline height and weight of each participant. During each survey, participants were asked about missed menses and possible pregnancies. Any participant who suspected a pregnancy was asked to come in for urine pregnancy testing. Analysis includes the first 8,445 participants enrolled in CHOICE of which 1,168 chose the implant and 4,200 chose the IUD. Student's t test, χ test, and Kaplan-Meier survival curves were used to perform statistical analyses to estimate failure rates in overweight and obese women using the implant and IUDs. RESULTS: Of the women choosing the implant, 28% were overweight and 35% were obese. Of the women who chose an IUD, 27% were overweight and 35% were obese. The 3-year cumulative failure rates for implant and IUD users were less than one per 100 women-years and did not vary by body mass index. CONCLUSION: We found no decrease in the effectiveness of the implant in overweight or obese women. The implant may be offered as a first-line contraceptive method to any woman seeking a reversible and reliable birth control method.

Surveillance for long-term health effects associated with depleted uranium exposure and retained embedded fragments in US veterans.

OBJECTIVE: To ensure that all veterans with retained embedded fragments are properly monitored for potential health effects of embedded materials. METHODS: Urine biomonitoring and health surveillance programs were developed to gather information about health risks associated with chemicals released from embedded fragments. RESULTS: Elevated systemic exposure to depleted uranium (DU) that continues to occur in veterans with DU fragments remains a concern, although no clinically significant DU-related health effects have been observed to date. Other metals and local tissue reactions to embedded fragments are also of concern. CONCLUSIONS: Knowledge gained from these programs will help to develop guidelines for surgical removal of tissue-embedded fragments.

Are hot flashes associated with sleep disturbance during midlife? Results from the STRIDE cohort study.

OBJECTIVE: Sleep disturbance and hot flashes are common during menopause, but their association is not well understood. We sought to understand the associations among sleep disturbance and the frequency, bothersomeness, and interference of hot flashes in mid-life women. STUDY DESIGN: STRIDE is a study of women ages 40-65 years at varied menopausal stages. We examined the cross-sectional associations of sleep disturbance with the frequency and bothersomeness of hot flashes, and interference of hot flashes with work, social, and leisure activities during the 2nd year of STRIDE. MAIN OUTCOME MEASURE: Self-reported sleep disturbance. RESULTS: Of the 623 women with complete data, 370 (59%) reported having hot flashes. Bivariate analyses showed that reporting hot flashes with bother, but not hot flashes alone, was associated with sleep disturbance (odds ratio [OR] [95% confidence interval (CI)]: 2.8 [2.0-4.0] and 1.3 [0.7-2.5], respectively). In multivariable models, women reporting bothersome hot flashes were more likely to report sleep disturbance (OR [95% CI]: 2.1 [1.4-3.2]) compared to women who reported no hot flashes. When the perceived interference of hot flashes with work, social activities, and leisure activities were included in the model, the relationships between bothersome hot flashes and sleep disturbance disappeared. CONCLUSIONS: Hot flashes are not associated with sleep disturbance, unless they are bothersome. Mid-life patients should routinely be queried about the bothersomeness of their hot flashes.

Biomarkers of mercury exposure in two eastern Ukraine cities.

This study evaluates biomarkers of mercury exposure among residents of Horlivka, a city in eastern Ukraine located in an area with geologic and industrial sources of environmental mercury, and residents of Artemivsk, a nearby comparison city outside the mercury-enriched area. Samples of urine, blood, hair, and nails were collected from study participants, and a questionnaire was administered to obtain data on age, gender, occupational history, smoking, alcohol consumption, fish consumption, tattoos, dental amalgams, home heating system, education, source of drinking water, and family employment in mines. Median biomarker mercury concentrations in Artemivsk were 0.26 µg/g-Cr (urine), 0.92 µg/L (blood), 0.42 µg/g (hair), 0.11 µg/g (toenails), and 0.09 µg/g (fingernails); median concentrations in Horlivka were 0.15 µg/g-Cr (urine), 1.01 µg/L (blood), 0.14 µg/g (hair), 0.31 µg/g (toenails), and 0.31 µg/g (fingernails). Biomarkers of mercury exposure for study participants from Horlivka and Artemivsk are low in comparison with occupationally exposed workers at a mercury recycling facility in Horlivka and in comparison with exposures known to be associated with clinical effects. Blood and urinary mercury did not suggest a higher mercury exposure among Horlivka residents as compared with Artemivsk; however, three individuals living in the immediate vicinity of the mercury mines had elevated blood and urinary mercury, relative to overall results for either city. For a limited number of residents from Horlivka (N = 7) and Artemivsk (N = 4), environmental samples (vacuum cleaner dust, dust wipes, soil) were collected from their residences. Mercury concentrations in vacuum cleaner dust and soil were good predictors of blood and urinary mercury.

Lead and copper in pigeons (Columbia livia) exposed to a small arms-range soil.

Small arms-range (SAR) soils can be contaminated with metals from spent copper (Cu)-jacketed bullets. Avian species are particularly at risk because they are exposed to lead (Pb) through ingestion of grit, soil intake from preening, or ingestion of contaminated food near ranges. Examination of the effects of Pb on birds at ranges have mainly focused on intake and toxicity of Pb shot pellets or fragments; however, Pb in soils may be an important pathway of exposure. To evaluate the uptake and effects of Pb from an actual range, the soil fraction (<250 µm) from a contaminated SAR soil was used to dose pigeons (Columbia livia) for 14 days at low (2700 µg Pb and 215 µg Cu/d) and high (5400 µg Pb and 430 µg Cu/d) doses. At the end of the study, blood Pb and erythrocyte protoporphyrin were determined, and tissues were analyzed for Pb and Cu. Results showed that Pb was absorbed in a dose-response manner in blood, tissues, and feathers, and erythrocyte protoporphyrin, a biomarker of early Pb effect, was increased at blood Pb levels >50 µg/dL. Four tissues showed differential retention of Pb, with kidney having the highest concentration followed by liver, brain, and heart, whereas Cu levels were not changed. To examine possible interactions with other metals, amendments of either Cu or tungstate were made to the soil sample. Although these amendments seemed to decrease the absorption of Pb, the results were ambiguous compared with sodium chloride controls. Overall, this study showed that intake of SAR soils contaminated with Pb and Cu causes an increase in Pb body burdens in birds and that the response can be modulated by amending soils with salts of metals.

Biomarkers of mercury exposure at a mercury recycling facility in Ukraine.

This study evaluates biomarkers of occupational mercury exposure among workers at a mercury recycling operation in Gorlovka, Ukraine. The 29 study participants were divided into three occupational categories for analysis: (1) those who worked in the mercury recycling operation (Group A, n = 8), (2) those who worked at the facility but not in the yard where the recycling was done (Group B, n = 14), and (3) those who did not work at the facility (Group C, n = 7). Urine, blood, hair, and nail samples were collected from the participants, and a questionnaire was administered to obtain data on age, gender, occupational history, smoking, alcohol consumption, fish consumption, tattoos, dental amalgams, home heating system, education, source of drinking water, and family employment in the former mercury mine/smelter located on the site of the recycling facility. Each factor was tested in a univariate regression with total mercury in urine, blood, hair, and nails. Median biomarker concentrations were 4.04 microg/g-Cr (urine), 2.58 microg/L (blood), 3.95 microg/g (hair), and 1.16 microg/g (nails). Occupational category was significantly correlated (p < 0.001) with both blood and urinary mercury concentrations but not with hair or nail mercury. Four individuals had urinary mercury concentrations in a range previously found to be associated with subtle neurological and subjective symptoms (e.g., fatigue, loss of appetite, irritability), and one worker had a urinary mercury concentration in a range associated with a high probability of neurological effects and proteinuria. Comparison of results by occupational category found that workers directly involved with the recycling operation had the highest blood and urinary mercury levels. Those who worked at the facility but were not directly involved with the recycling operation had higher levels than those who did not work at the facility.