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At least 217 records · Page 12

All sources NASA NTRS DOE OSTI

NASA NTRS2010

Gender Differences in Isokinetic Strength after 60 and 90 d Bed Rest

Recent reports suggest that changes in muscle strength following disuse may differ between males and females. PURPOSE: To examine potential gender differences in strength changes following 60 and 90 d of experimental bed rest. METHODS: Isokinetic extensor and flexor strength of the knee (60deg and 180deg/s, concentric only), ankle (30deg/s, concentric and eccentric), and trunk (60deg/s, concentric only) were measured following 60 d (males: n=4, 34.5+/-9.6 y; females: n=4, 35.5+/-8.2 y) and 90 d (males: n=10, 31.4+/-4.8 y; females: n=5, 37.6+/-9.9 y) of 6-degree head-down-tilt bed rest (BR; N=23). Subjects were fed a controlled diet (55%/15%/ 30%, CHO/PRO/FAT) that maintained body weight within 3% of the weight recorded on Day 3 of bed rest. After a familiarization session, testing was conducted 6 d before BR and 2 d after BR completion. Peak torque and total work were calculated for the tests performed. To allow us to combine data from both 60- and 90-d subjects, we used a mixed-model statistical analysis in which time and gender were fixed effects and bed rest duration was a random effect. Log-transformations of strength measures were utilized when necessary in order to meet statistical assumptions. RESULTS: Main effects were seen for both time and gender (p<0.05), showing decreased strength in response to bed rest for both males and females, and males stronger than females for most strength measures. Only one interaction effect was observed: females exhibited a greater loss of trunk extensor peak torque at 60 d versus pre-BR, relative to males (p=0.004). CONCLUSION: Sixty and 90 d of BR induced significant losses in isokinetic muscle strength of the locomotor and postural muscles of the knee, ankle, and trunk. Although males were stronger than females for most of the strength measures that we examined, only changes in trunk extensor peak torque were greater for females than males at day 60 of bed rest

English, K. L.↗

DOE OSTI2022

Sex comparisons in physiological and cognitive performance during hypoxic challenge

Within the tactical aviation community, human performance research lags in considering potential psychophysiological differences between male and female aviators due to little inclusion of females during the design and development of aircraft systems. A poor understanding of how male and female aviators differ with respect to human performance results in unknown potential sex differences on aeromedically relevant environmental stressors, perchance leading to suboptimal performance, safety, and health guidelines. For example, previous hypoxia studies have excluded female participants or lacked a sizeable sample to examine sex comparisons. As such, progress toward sensor development and improving hypoxia familiarization training are stunted due to limited knowledge of how individual differences, including sex, may or may not underlie hypoxia symptoms and performance impairment. Investigating sex differences bridges the gap between aerospace medicine and operational health, and addressing hypoxia is one of many facets yet to be studied. In the current study, we retrospectively examined N = 6 hypoxia studies with male-female participant samples (total, N = 189; male, n = 118; female, n = 71). We explored sex as a predictor of physiological response, sensory deficits, the severity of cognitive performance declines, and symptom manifestation via linear and binary logistic regression models. We found that the female sex predicted lower peripheral oxygen saturation and the likelihood of headache reporting in response to hypoxic challenge, yet explained little variance when combined with age and body mass index. The sensory and cognitive performance models did not converge, suggesting high intra-individual variability. Together, sex, age, and body mass index were not the most robust predictors in responses to hypoxic challenge; we cannot infer this for sensory deficits and cognitive performance within an experimentally induced hypoxic environment. The findings have implications for improving hypoxia familiarization training, monitoring sensor development, and emergency response and recovery protocols in case of a hypoxia occurrence suitable for all aircrew. We recommend continuing to elucidate the impact of sex and intrapersonal differences in hypoxia and other aeromedically relevant stressors in tactical aviation.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2002

Sexually dimorphic effects of NMDA receptor antagonism on brain-pituitary-gonad axis development in the platyfish

The N-methyl-D-aspartate glutamate receptor (NMDAR) is found in hypothalamic nuclei involved in the regulation of reproduction in several species of mammals and fishes. NMDAR is believed to affect reproductive development and function by regulating gonadotropin releasing hormone (GnRH)-producing cells. These pathways are likely to be sexually dimorphic, as are several other neurotransmitter systems involved in reproductive function. In this report, male and female platyfish received intraperitoneal injections of 0, 5, 10, 20, 40 or 60 microg/g body wt. of the non-competitive NMDAR antagonist MK-801. Injections began at 6 weeks of age and continued thrice weekly until control animals reached puberty, as evidenced by anal fin maturation. The percent of pubescent animals was significantly affected by sex and treatment, with fewer MK-801-injected females in puberty than control females at each dose (P<0.001), and fewer pubescent females than males at 10, 20 and 40 microg/g (P<0.05). There were no MK-801-related effects in males. Histological analyses revealed typical immature gonads and pituitary glands in treated females, and typical mature morphology in control females and all males. Immunocytochemical distribution of the R1 subunit of the NMDAR within the brain-pituitary-gonad (BPG) axis was limited to GnRH-containing brain cells in all animals; however, NMDAR1 distribution was in an immature pattern in treated females and a mature pattern in all others. Neural concentrations of GnRH were unaffected by MK-801 treatment in both sexes. These data suggest that in the platyfish, NMDAR influence on reproductive development is sexually dimorphic and occurs at, or above, the level of GnRH-containing cells of the BPG axis.

Non-NASA Center↗

DOE OSTI2018

Cyclosporine A exhibits gender-specific nephrotoxicity in rats: Effect on renal tissue inflammation

Cyclosporine A (CSA) is a widely used immunosuppressant drug known to commonly cause cardio and nephrotoxicity. A study looking at the sex specificity of the cardiotoxicity of CSA revealed that sexual dimorphism existed when looking at the electrocardiographs and left ventricles of CSA-treated rats. We hypothesized that cyclosporine A exhibited gender-specific nephrotoxicity by testing various parameters of kidney function in male and female rats treated for 21 days with 15 mg/kg CSA versus control male and female rats that received a vehicle consisting of 18% kolliphore and 2% ethanol in sterile saline. It was found that male rats treated with CSA had significantly higher levels of serum creatinine and lower creatinine clearance than control males. However, serum creatinine and creatinine clearance were not affected by CSA treatment in females. Histopathological examination of kidney cross-sections revealed a heavy aggregation of inflammatory cells and significant vascular congestion in males treated with CSA, which was less prominent in female rats receiving CSA. In addition CSA treated male rats had higher levels of serum cholesterol compared with control while, CSA did not affect serum cholesterol in female rats. Kidney tumor necrosis factor alpha (TNF-α) levels were found to drop in female rats following CSA treatment, whereas no change was observed in male rats before and after treatment. These results suggest that CSA exhibits gender-related nephrotoxicity in rats that might be mediated by differences in the inflammatory response between males and females.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common biological implications. • Both sexes exhibit deregulation of cardiovascular and endocrine pathways.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

Differences Among Incidence Rates of Invasive Listeriosis in the U.S. FoodNet Population by Age, Sex, Race/Ethnicity, and Pregnancy Status, 2008-2016

Listeria monocytogenes is a foodborne pathogen that disproportionally affects pregnant females, older adults, and immunocompromised individuals. Using U.S. Foodborne Diseases Active Surveillance Network (FoodNet) surveillance data, we examined listeriosis incidence rates and rate ratios (RRs) by age, sex, race/ethnicity, and pregnancy status across three periods from 2008 to 2016, as recent incidence trends in U.S. subgroups had not been evaluated. The invasive listeriosis annual incidence rate per 100,000 for 2008–2016 was 0.28 cases among the general population (excluding pregnant females), and 3.73 cases among pregnant females. For adults ≥ 70 years, the annual incidence rate per 100,000 was 1.33 cases. No significant change in estimated listeriosis incidence was found over the 2008–2016 period, except for a small, but significantly lower pregnancy-associated rate in 2011–2013 when compared with 2008– 2010. Among the nonpregnancy-associated cases, RRs increased with age from 0.43 (95% confidence interval: 0.25– 0.73) for 0- to 14-year olds to 44.9 (33.5–60.0) for ≥ 85-year olds, compared with 15- to 44-year olds. Males had an incidence of 1.28 (1.12–1.45) times that of females. Compared with non-Hispanic whites, the incidence was 1.57 (1.18–1.20) times higher among non-Hispanic Asians, 1.49 (1.22–1.83) among non-Hispanic blacks, and 1.73 (1.15– 2.62) among Hispanics. Among females of childbearing age, non-Hispanic Asian females had 2.72 (1.51–4.89) and Hispanic females 3.13 (2.12–4.89) times higher incidence than non-Hispanic whites. We observed a higher percentage of deaths among older patient groups compared with 15- to 44-year olds. This study is the first characterizing higher RRs for listeriosis in the United States among non-Hispanic blacks and Asians compared with non-Hispanic whites. This information for public health risk managers may spur further research to understand if differences in listeriosis rates relate to differences in consumption patterns of foods with higher contamination levels, food handling practices, comorbidities, immunodeficiencies, health care access, or other factors.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Clonality, local population structure, and gametophyte sex ratios in cryptic species of the Sphagnum magellanicum complex

Sphagnum (peatmoss) comprises a moss (Bryophyta) clade with approximately 300-500 species. The genus has unparalleled ecological importance because Sphagnum-dominated peatlands store almost a third of the terrestrial carbon pool and peatmosses engineer the formation and microtopography of peatlands. Genomic resources for Sphagnum are being actively expanded, but many aspects of their biology are still poorly known. Among these are the degree to which Sphagnum species reproduce asexually, and the relative frequencies of male and female gametophytes in these haploid-dominant plants. Here, we assess clonality and gametophyte sex ratios and test hypotheses about the local-scale distribution of clones and sexes in four North American species of the S. magellanicum complex. These four species are difficult to distinguish morphologically and are very closely related. We also assess microbial communities associated with Sphagnum host plant clones and sexes at two sites. 405 samples of the four species, representing 57 populations, were subjected to RADseq. Analyses of population structure and clonality based on the molecular data utilized both phylogenetic and phenetic approaches. Multi-locus genotypes (genets) were identified using the RADseq data. Sexes of sampled ramets were determined using a molecular approach that utilized coverage of loci on the sex chromosomes after the method was validated using a sample of plants that expressed sex phenotypically. Sex ratios were estimated for each species, and populations within species. Differences in fitness between genets was estimated as the numbers of ramets each genet comprised. Degree of clonality (numbers of genets/numbers of ramets [samples]) within species, among sites, and between gametophyte sexes were estimated. Sex ratios were estimated for each species, and populations within species. Sphagnum-associated microbial communities were assessed at two sites in relation to Sphagnum clonality and sex. All four species appear to engage in a mixture of sexual and asexual (clonal) reproduction. A single ramet represents most genets but 2-8 ramets were detected for some genets. Only one genet is represented by ramets in multiple populations; all other genets are restricted to a single population. Within populations ramets of individual genets are spatially clustered, suggesting limited dispersal even within peatlands. Sex ratios are male-biased in S. diabolicum but female-biased in the other three species, although significantly so only in S. divinum. Neither species nor males/females differ in levels of clonal propagation. At St. Regis Lake (NY) and Franklin Bog (VT), microbial community composition is strongly differentiated between the sites, but differences between species, genets, and sexes were not detected. Within S. divinum, however, female gametophytes harbored 2-3 times the number oi of microbial taxa as males. These four Sphagnum species all exhibit a similar reproductive patterns that result from a mixture of sexual and asexual reproduction. The spatial patterns of clonally replicated ramets of genets suggest that these species fall between the so-called phalanx patterns where genets abut one another but do not extensively mix, because of limited ramet fragmentation, and the guerrilla patterns where extensive genet fragmentation and dispersal results in greater mixing of different genets. Although sex ratios in bryophytes are most often female-biased, both male and female biases occur in this complex of closely related species. The association of far greater microbial diversity for female gametophytes in S. divinum, which has a female-biased sex ratio, suggests additional research to determine if levels of microbial diversity are consistently correlated with differing patterns of sex ratio biases.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2001

NASA Rodent Foodbar: Long Term Effects in Swiss Webster Mice

Swiss Webster male and female mice (150 of each) were fed NASA Rodent Foodbar for more than 110 days to test the diet's nutritional adequacy for use in future long-term studies aboard the International Space Station. Mice were grouped three to a cage (one cage = one sample) and cages were assigned to either Foodbar or Purina Chow #5001 (control) diet groups. Body weights, food intake, and water intake were obtained throughout the study. There were no significant differences in body weights between male Foodbar fed and Chow fed males (p=0.58), and at 15 weeks into the female mouse study there appear to be no significant body weight differences. Both male and female Foodbar fed groups consumed more food and less water than their Chow controls, both factors thought to be attributable to the high moisture content of the Foodbars (26% versus 10% for Chow). All differences in gross food and water consumption had p-values of less than 0.01. When food and water intake were adjusted for the moisture content in the food, both male and female Foodbar fed animals consumed less food, but still had a lower water intake rate than their controls. (p is less than 0.01). Preliminary analysis on blood samples from male and female halfway point dissections suggests differences in glucose and fat metabolism. In both male and female Foodbar fed animals, blood glucose values were significantly lower (p is less than 0.01) but there were no significant differences in cholesterol levels (p=0.51). In Foodbar fed females, triglycerides were significantly higher (p is less than 0.01). These data suggest that Foodbars allow for normal growth in Swiss Webster mice, but affect some blood chemistry parameters.

Santiago, D. L.↗

NASA NTRS2010

60 Days of Head-down Bedrest Differentially Alters Venous Function in Lower and Upper Body Between Healthy Men and Women

The incidence of orthostatic intolerance after space flight is disproportionally higher in female compared to male crewmembers (83% vs. 20%). Experimental and human data suggest that the loss of orthostatic tolerance is due, at least in part, to microgravity-induced changes in venous compliance and that these changes are specific to the lower body. It is unknown however, whether the changes in venous compliance are different between males and females after space flight, and whether this is related to the disparity in orthostatic intolerance between the sexes. Using 6deg head-down bed rest (BR) as a model of space flight, we tested the following hypotheses; 1) females, compared to males, would experience a greater increase in venous compliance in dorsal foot veins as an effect of BR and 2) no differences in venous compliance would be found in dorsal hand veins between sexes and across BR days. Using 2-D ultrasound, dorsal hand (DHV) and foot vein (DFV) responses (diameter; expressed as sq mm) to 40 mmHg of congestion pressure (compliance) and to intravenous infusion of phenylephrine (PE; 3160ng/min) were determined in 10 females and 16 males before and after 60 days of BR. The relation between changes in vein diameter (in response to pressure and PE), sex, limb, and BR days were determined using a mixed-effect linear regression. It was found that after 60 days of BR, DFV dilator response to pressure was significantly greater in females and significantly less in males compared to pre-BR. As expected, there were no differences in DHV dilator response between sexes nor was there a significant difference between pre and post measures within groups. Notably, the venoconstrictor response to infusions of PE in the DHV and DFV where similar between sexes and across BR days. In conclusion, this study demonstrates that after 60 days of BR, dorsal foot veins are more compliant in women and less compliant in men. Moreover, the changes in lower body vein compliance in females do not appear to be due to changes in vasoconstrictor tone as their response to PE was preserved and similar to that in males. Taken together these data suggest that the higher incidence of orthostatic intolerance in females after space flight is due to increased venous compliance in the lower body which could translate to lower venous filling pressures and a reduced stroke volume.

Westby, Christian M.↗

DOE OSTI2017

Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells

Despite the well-established sex-specific differences in the incidence of bronchopulmonary dysplasia (BPD), the molecular mechanism(s) behind these are not completely understood. Pulmonary angiogenesis is critical for alveolarization and arrest in vascular development adversely affects lung development. Human neonatal umbilical vein endothelial cells (HUVECs) provide a robust in vitro model for the study of endothelial cell physiology and function. Male and Female HUVECs were exposed to room air (21% O{sub 2}, 5% CO{sub 2}) or hyperoxia (95% O{sub 2}, 5% CO{sub 2}) for up to 72 h. Cell viability, proliferation, H{sub 2}O{sub 2} production and angiogenesis were analyzed. Sex-specific differences in the expression of VEGFR2 and modulation of NF-kappa B pathway were measured. Male HUVECs have decreased survival, greater oxidative stress and impairment in angiogenesis compared to similarly exposed female cells. There is differential expression of VEGFR2 between male and female HUVECs and greater activation of the NF-kappa B pathway in female HUVECs under hyperoxic conditions. The results indicate that sex differences exist between male and female HUVECs in vitro after hyperoxia exposure. Since endothelial dysfunction has a major role in the pathogenesis of BPD, these differences could explain in part the mechanisms behind sex-specific differences in the incidence of this disease. - Highlights: • Cellular sex effects viability and oxidative stress in HUVECs exposed to hyperoxia. • Male HUVECs show greater impairment in angiogenesis compared to female cells. • Sex-specific modulation of VEGFR2 and the NF-kappaB pathway was noted.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice

In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50 μg/kg/day) or diethylstilbestrol (DES; 0.05 μg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9 months were conducted to evaluate reproductive capacity over time. Further, studies were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50 μg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05 μg/kg/day) and BPA (50 μg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5 μg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature. - Highlights: • In utero BPA delayed vaginal opening in the F3 generation compared to control. • In utero BPA delayed estrus in the F3 generation compared to control. • In utero BPA reduced the ability of F1 and F2 female mice to maintain pregnancies. • In utero BPA compromised the ability of F3 female mice to become pregnant. • Some effects of in utero BPA may be transgenerational in nature.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Sex-specific effects of developmental lead exposure on the immune-neuroendocrine network

The environmental toxicant lead (Pb) has long been known to induce neurological deficits. The 1st century Greek physician Pedanius Dioscorides noted that “lead makes the mind give way”. Current studies are suggesting the effects of Pb on behaviors may involve the immune system and conversely some immunomodulatory changes may be due to Pb effects in the central nervous system. Although Pb-induced disorders do not appear to discriminate among females and males, this report discusses the differences observed in human and animal studies regarding differential gender effects on gene expression after Pb exposure. The overall ill health outcomes are apparent with variant levels of Pb exposure and exposures at different times in development. However, the consensus is that doses leading to blood lead levels > 5 μg/dl and prenatal exposures are most pathogenic. Although the general detriments induced by Pb may be similar in females and males, there are sex specific outcomes on health and behavior. It is suggested that Pb induces more oxidative stress in females and more upregulation of genes responding to oxidative stress, while males have more proteolytic destruction; but in both cases, there is generation of altered/denatured self-constituents causing inflammation and loss of homeostasis of neuronal and immune functions. The higher estrogen levels of females are indicated as the reason for more Pb-induced reactive oxygen species in females. This review describes some of the different genes involved in female and male responses to Pb exposure and involved pathways.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-F-T-119: Development of Heart Prediction Model to Increase Accuracy of Dose Reconstruction for Radiotherapy Patients

Purpose: To assess individual variation in heart volume and location in order to develop a prediction model of the heart. This heart prediction model will be used to calculate individualized heart doses for radiotherapy patients in epidemiological studies. Methods: Chest CT images for 30 adult male and 30 adult female patients were obtained from NIH Clinical Center. Image-analysis computer programs were used to segment the whole heart and 8 sub-regions and to measure the volume of each sub- region and the dimension of the whole heart. An analytical dosimetry method was used for the 30 adult female patients to estimate mean heart dose during conventional left breast radiotherapy. Results: The average volumes of the whole heart were 803.37 cm{sup 3} (COV 18.8%) and 570.19 cm{sup 3} (COV 18.8%) for adult male and female patients, respectively, which are comparable with the international reference volumes of 807.69 cm{sup 3} for males and 596.15 cm{sup 3} for females. Some patient characteristics were strongly correlated (R{sup 2}>0.5) with heart volume and heart dimensions (e.g., Body Mass Index vs. heart depth in males: R{sup 2}=0.54; weight vs. heart width in the adult females: R{sup 2}=0.63). We found that the mean heart dose 3.805 Gy (assuming prescribed dose of 50 Gy) in the breast radiotherapy simulations of the 30 adult females could be an underestimate (up to 1.6-fold) or overestimate (up to 1.8-fold) of the patient-specific heart dose. Conclusion: The study showed the significant variation in patient heart volumes and dimensions, resulting in substantial dose errors when a single average heart model is used for retrospective dose reconstruction. We are completing a multivariate analysis to develop a prediction model of the heart. This model will increase accuracy in dose reconstruction for radiotherapy patients and allow us to individualize heart dose calculations for patients whose CT images are not available.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Optimal Stopping Ages for Colorectal Cancer Screening

Importance Prior studies have shown that the benefits, harms, and costs of colorectal cancer (CRC) screening at older ages are associated with a patient’s sex, health, and screening history. However, these studies were hypothetical exercises and not directly informed by data on CRC risk. Objective To identify the optimal stopping ages for CRC screening by sex, comorbidity, and screening history from a cost-effectiveness perspective. Design, Setting, and Participants This economic evaluation first validated the MISCAN-Colon (Microsimulation Screening Analysis–Colon) model against community-based CRC incidence and mortality rates for 2 subcohorts of the PRECISE (Optimizing Colorectal Cancer Screening Precision and Outcomes in Community-Based Populations) cohort. Subsequently, different CRC screening scenarios were simulated in older individuals. Cohorts of US adults aged 76 to 90 years varied by sex and comorbidity status (none, low, moderate, or severe). Statistical and sensitivity analyses were performed from March 2023 to May 2024. Exposures CRC screening histories including fecal immunochemical test (FIT) or colonoscopy, such as a negative colonoscopy result from 10, 15, 20, 25, or 30 years before the index age; 1 to 5 negative FIT results within 5 years of the index age, with different patterns of recency; or a combination of negative colonoscopy and negative FIT results. Main Outcomes and Measures The main outcomes included estimated lifetime clinical outcomes, incremental costs, and quality-adjusted life-years gained (QALYG) associated with 1 additional FIT or colonoscopy. Optimal stopping age for screening, defined as the oldest age for which the incremental cost-effectiveness ratio was still below the willingness-to-pay threshold of $\$$100 000 per QALYG, was evaluated. Results The first of the 2 PRECISE subcohorts used in validating the simulation model included 25 974 adults (15 060 females [58.0%]; 54.7% aged 76 to 80 years) with a negative colonoscopy result 10 years before the index date. The second subcohort consisted of 118 269 adults (67 058 females [56.7%]; 90.5% aged 76 to 80 years) with a negative FIT result 1 year before the index date. Older age, male sex, higher comorbidity levels, and recent CRC screenings were associated with reduced incremental benefit and cost-effectiveness of additional screening. For the reference cohort of 76-year-old females without comorbidities and a negative colonoscopy result 10 years before the index age, 1 additional colonoscopy cost $\$$38 226 per QALYG. For cohorts with otherwise equivalent characteristics, associated costs increased to $\$$1 689 945 per QALYG for females at age 90 years without comorbidities and a negative colonoscopy results 10 years before the index age, $\$$51 604 per QALYG for males at age 76 years without comorbidities and a negative colonoscopy result 10 years before the index age, and $\$$108 480 per QALYG for females at age 76 years with severe comorbidities and a negative colonoscopy result 10 years before the index age and decreased to $\$$16 870 per QALYG for females without comorbidities and a negative colonoscopy result 30 years before the index age. The optimal stopping ages across different cohorts ranged from younger than 76 to 86 years for colonoscopy and younger than 76 to 88 years for FIT. Conclusions and Relevance In this economic evaluation, age, sex, screening history, comorbidity, and future screening modality were associated with the clinical outcomes, cost-effectiveness, and optimal stopping age for CRC screening. These results can inform guideline development and patient-directed informed decision-making.

Harlass, Matthias [Erasmus Erasmus University Medi↗

DOE OSTI2020

Cell fusing agent virus (Flavivirus) infection in Aedes aegypti in Texas: seasonality, comparison by trap type, and individual viral loads

Abstract South Texas has experienced local transmission of Zika virus and of other mosquito-borne viruses such as chikungunya virus and dengue virus in the last decades. Using a mosquito surveillance program in the Lower Rio Grande Valley (LRGV) and San Antonio, TX, from 2016 to 2018, we detected the presence of an insect-specific virus, cell fusing agent virus (CFAV), in the Aedes aegypti mosquito population. We tested 6,326 females and 1,249 males from the LRGV and 659 females from San Antonio for CFAV by RT-PCR using specific primers. Infection rates varied from 0 to 261 per 1,000 mosquitoes in the LRGV and 115 to 208 per 1,000 in San Antonio depending on the month of collection. Infection rates per 1,000 individuals appeared higher in females collected from BG Sentinel 2 traps compared to Autocidal Gravid Ovitraps, but the ratio of the percentage of infected pools did not differ by trap type. The natural viral load in individual males ranged from 1.25 x 10 2 to 5.50 x 10 6 RNA copies and in unfed females from 5.42 x 10 3 to 8.70 x 10 6 RNA copies. Gravid females were found to harbor fewer viral particles than males and unfed females.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

MABAL: a Novel Deep-Learning Architecture for Machine-Assisted Bone Age Labeling

Bone age assessment (BAA) is a commonly performed diagnostic study in pediatric radiology to assess skeletal maturity. The most commonly utilized method for assessment of BAA is the Greulich and Pyle method (Pediatr Radiol 46.9:1269–1274, 2016; Arch Dis Child 81.2:172–173, 1999) atlas. The evaluation of BAA can be a tedious and time-consuming process for the radiologist. As such, several computer-assisted detection/diagnosis (CAD) methods have been proposed for automation of BAA. Classical CAD tools have traditionally relied on hard-coded algorithmic features for BAA which suffer from a variety of drawbacks. Recently, the advent and proliferation of convolutional neural networks (CNNs) has shown promise in a variety of medical imaging applications. There have been at least two published applications of using deep learning for evaluation of bone age (Med Image Anal 36:41–51, 2017; JDI 1–5, 2017). However, current implementations are limited by a combination of both architecture design and relatively small datasets. The purpose of this study is to demonstrate the benefits of a customized neural network algorithm carefully calibrated to the evaluation of bone age utilizing a relatively large institutional dataset. In doing so, this study will aim to show that advanced architectures can be successfully trained from scratch in the medical imaging domain and can generate results that outperform any existing proposed algorithm. The training data consisted of 10,289 images of different skeletal age examinations, 8909 from the hospital Picture Archiving and Communication System at our institution and 1383 from the public Digital Hand Atlas Database. The data was separated into four cohorts, one each for male and female children above the age of 8, and one each for male and female children below the age of 10. The testing set consisted of 20 radiographs of each 1-year-age cohort from 0 to 1 years to 14–15+ years, half male and half female. The testing set included left-hand radiographs done for bone age assessment, trauma evaluation without significant findings, and skeletal surveys. A 14 hidden layer-customized neural network was designed for this study. The network included several state of the art techniques including residual-style connections, inception layers, and spatial transformer layers. Data augmentation was applied to the network inputs to prevent overfitting. A linear regression output was utilized. Mean square error was used as the network loss function and mean absolute error (MAE) was utilized as the primary performance metric. MAE accuracies on the validation and test sets for young females were 0.654 and 0.561 respectively. For older females, validation and test accuracies were 0.662 and 0.497 respectively. For young males, validation and test accuracies were 0.649 and 0.585 respectively. Finally, for older males, validation and test set accuracies were 0.581 and 0.501 respectively. The female cohorts were trained for 900 epochs each and the male cohorts were trained for 600 epochs. An eightfold cross-validation set was employed for hyperparameter tuning. Test error was obtained after training on a full data set with the selected hyperparameters. Using our proposed customized neural network architecture on our large available data, we achieved an aggregate validation and test set mean absolute errors of 0.637 and 0.536 respectively. To date, this is the best published performance on utilizing deep learning for bone age assessment. Our results support our initial hypothesis that customized, purpose-built neural networks provide improved performance over networks derived from pre-trained imaging data sets. We build on that initial work by showing that the addition of state-of-the-art techniques such as residual connections and inception architecture further improves prediction accuracy. This is important because the current assumption for use of residual and/or inception architectures is that a large pre-trained network is required for successful implementation given the relatively small datasets in medical imaging. Instead we show that a small, customized architecture incorporating advanced CNN strategies can indeed be trained from scratch, yielding significant improvements in algorithm accuracy. It should be noted that for all four cohorts, testing error outperformed validation error. One reason for this is that our ground truth for our test set was obtained by averaging two pediatric radiologist reads compared to our training data for which only a single read was used. This suggests that despite relatively noisy training data, the algorithm could successfully model the variation between observers and generate estimates that are close to the expected ground truth.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Maternal body burden of cadmium and offspring size at birth

Increasing evidence suggests an inverse association between cadmium (Cd) and size at birth, potentially greatest among female neonates. We evaluated whether greater maternal body burden of Cd is associated with reduced neonatal anthropometry (birthweight, birth length, head circumference, and ponderal index) and assessed whether these associations differ by infant sex. The analytic sample for the present study (n=396) was derived from a subcohort of 750 women randomly drawn from among all participants (N=4344) in the Omega Study, a prospective pregnancy cohort. Creatinine-corrected Cd in maternal clean-catch spot urine samples (U-Cd) was quantified by inductively coupled plasma mass spectrometry. Continuous log{sub 2}-transformed Cd (log{sub 2}-Cd) and U-Cd tertiles (low<0.29 μg/g creatinine, middle 0.29–0.42 μg/g creatinine, high≥0.43 μg/g creatinine) were used in multivariable linear regression models. Females had reduced birth length with greater U-Cd tertile, whereas males birth length marginally increased [β(95% CI) females: low=reference, middle=−0.59 cm (−1.37, 0.19), high=−0.83 cm (−1.69, 0.02), p-trend=0.08; males: low=reference, middle=0.18 cm (−0.59, 0.95), high=0.78 cm (–0.04, 1.60), p-trend=0.07; p for interaction=0.03]. The log{sub 2}-Cd by infant sex interaction was statistically significant for ponderal index [p=0.003; β(95% CI): female=0.25 kg/m{sup 3} (−0.20, 0.70); male=−0.63 kg/m{sup 3} (−1.01, −0.24)] and birth length [p<0.001; β(95% CI): female=−0.47 cm (−0.74, −0.20), male=0.32 cm (0.00, 0.65)]. Our findings suggest potential sex-specific reversal of Cd’s associations on birth length and contribute to the evidence suggesting Cd impairs fetal growth. - Highlights: • Cadmium levels in the general population potentially adversely affect size at birth. • Maternal urinary cadmium was inversely related to birth length among female infants. • For male infants, maternal cadmium was positively associated with birth length. • Maternal cadmium was also inversely related to ponderal index among male infants.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2018

Diphenyl diselenide regulates Nrf2/Keap-1 signaling pathway and counteracts hepatic oxidative stress induced by bisphenol A in male mice

Highlights: • BPA exposure induced hepatic oxidative stress in a sex-dependent manner in mice. • BPA exposure deregulates Nrf2/keap1 pathway in the mouse liver. • (PhSe){sub 2} reversed hepatic oxidative stress caused by BPA in male mice. • (PhSe){sub 2} modulates NrF2/keap1 pathway in male mice exposed to BPA. Bisphenol A (BPA) is a chemical toxicant that has deleterious effects on human. BPA causes oxidative stress in tissues, including the liver. Diphenyl diselenide (PhSe){sub 2} improves the antioxidant response via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein (keap 1) pathway in macrophage cells. In the present study, we investigated whether (PhSe){sub 2} counteracts hepatic oxidative stress induced by BPA in male and female Swiss mice. Three-week-old mice received by the intragastric (i.g.) route BPA (5 mg/kg) from 21st to 60th postnatal day (PND). At PND 61, the mice were treated with (PhSe){sub 2} (1 mg/kg, i.g.) for seven days. Parameters of hepatic damage and oxidative stress were determined in male and female mice. The results show that BPA increased the activity of aspartate aminotransferase in female mice, and in male mice the activity of alanine aminotranseferase was increased. Male and female mice had an increase in fat mass accumulation. Male mice showed an increase in hepatic oxidative damage of proteins and a decrease in non-enzymatic (ascorbic acid and non-protein thiol) and enzymatic (superoxide dismutase) defenses, which are consistent with oxidative stress status. Male mice were more susceptible than female mice to hepatic oxidative stress induced by BPA. BPA decreased Nrf2/Keap1 protein content in male mice. (PhSe){sub 2} reduced hepatic oxidative stress induced by BPA in male mice. Our results demonstrate that male mice were more susceptible to hepatic oxidative stress induced by BPA than female mice. (PhSe){sub 2} regulated Nrf2/Keap-1 signaling pathway and countered hepatic oxidative stress induced by BPA in male mice.

60 APPLIED LIFE SCIENCES↗