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Item Age Effects and Sex Differences in Human Brain White Matter of Young to Middle-Aged Adults: A DTI, NODDI, and q-Space Study(Elsevier, 2016-03) Kodiweera, Chandana; Alexander, Andrew L.; Andrew L., Jaroslaw; McAllister, Thomas W.; Wu, Yu-Chien; Department of Biostatistics, Richard M. Fairbanks School of Public HealthMicrostructural changes in human brain white matter of young to middle-aged adults were studied using advanced diffusion Magnetic Resonance Imaging (dMRI). Multiple shell diffusion-weighted data were acquired using the Hybrid Diffusion Imaging (HYDI). The HYDI method is extremely versatile and data were analyzed using Diffusion Tensor Imaging (DTI), Neurite Orientation Dispersion and Density Imaging (NODDI), and q-space imaging approaches. Twenty-four females and 23 males between 18 and 55years of age were included in this study. The impact of age and sex on diffusion metrics were tested using least squares linear regressions in 48 white matter regions of interest (ROIs) across the whole brain and adjusted for multiple comparisons across ROIs. In this study, white matter projections to either the hippocampus or the cerebral cortices were the brain regions most sensitive to aging. Specifically, in this young to middle-aged cohort, aging effects were associated with more dispersion of white matter fibers while the tissue restriction and intra-axonal volume fraction remained relatively stable. The fiber dispersion index of NODDI exhibited the most pronounced sensitivity to aging. In addition, changes of the DTI indices in this aging cohort were correlated mostly with the fiber dispersion index rather than the intracellular volume fraction of NODDI or the q-space measurements. While men and women did not differ in the aging rate, men tend to have higher intra-axonal volume fraction than women. This study demonstrates that advanced dMRI using a HYDI acquisition and compartmental modeling of NODDI can elucidate microstructural alterations that are sensitive to age and sex. Finally, this study provides insight into the relationships between DTI diffusion metrics and advanced diffusion metrics of NODDI model and q-space imaging.Item "Churches in the Vanguard:" Margaret Sanger and the Morality of Birth Control in the 1920s(2015-03-30) Maurer, Anna C.; Robertson, Nancy Marie; Cramer, Kevin; Lantzer, Jason S.Many religious leaders in the early 1900s were afraid of the immoral associations and repercussions of birth control. The Catholic Church and some Protestants never accepted contraception, or accepted it much later, but many mainline Protestants leaders did change their tune dramatically between the years of 1920 and 1931. This investigation seeks to understand how Margaret Sanger was able to use her rhetoric to move her reform from the leftist outskirts and decadent, sexual connotations into the mainstream of family-friendly, morally virtuous, and even conservative religious approval. Securing the approval of religious leaders subsequently provided the impetus for legal and medical acceptance by the late-1930s. Margaret Sanger used conferences, speeches, articles, her magazine (Birth Control Review), and several books to reinforce her message as she pragmatically shifted from the radical left closer to the center and conservatives. She knew the power of the churches to influence their members, and since the United States population had undeniably a Judeo-Christian base, this power could be harnessed in order to achieve success for the birth control movement, among the conservative medical and political communities and the public at large. Despite the clear consensus against birth control by all mainline Christian churches in 1920, including Roman Catholics and Protestants alike, the decade that followed would bring about a great divide that would continue to widen in successive decades. Sanger put forward many arguments in her works, but the ones which ultimately brought along the relatively conservative religious leaders were those that presented birth control not as a gender equity issue, but rather as a morally constructive reform that had the power to save and strengthen marriages; lessen prostitution and promiscuity; protect the health of women; reduce abortions, infanticide, and infant mortality; and improve the quality of life for children and families. Initially, many conservatives and religious leaders associated the birth control movement with radicals, feminists, prostitutes, and promiscuous youth, and feared contraception would lead to immorality and the deterioration of the family. Without the threat of pregnancy, conservatives feared that youth and even married adults would seize the opportunity to have sex outside of marriage. Others worried the decreasing size of families was a sign of growing selfishness and materialism. In response, Sanger promoted the movement as a way for conservatives to stop the rising divorce rates by strengthening and increasing marriages, and to improve the lives of families by humanely increasing the health and standard of living, for women and children especially. In short, she argued that birth control would not lead to deleterious consequences, but would actually improve family moral values and become an effective humanitarian reform. She recognized that both liberals and conservatives were united in hoping to strengthen the family, and so she emphasized those virtues and actively courted those same conservative religious leaders that had previously shunned birth control and the movement. Throughout the 1920s, she emphasized the ways in which birth control could strengthen marriages and improve the quality of life of women and children, and she effectively won over the relatively conservative religious leaders that she needed to bring about the movement’s public, medical, and political progress.Item Clinical Reaction-Time Performance Factors in Healthy Collegiate Athletes(Allen Press, 2020-06-23) Caccese, Jaclyn B.; Eckner, James T.; Franco-MacKendrick, Lea; Hazzard, Joseph B.; Ni, Meng; Broglio, Steven P.; McAllister, Thomas W.; McCrea, Michael; Buckley, Thomas A.; Psychiatry, School of MedicineContext: In the absence of baseline testing, normative data may be used to interpret postconcussion scores on the clinical reaction-time test (RTclin). However, to provide normative data, we must understand the performance factors associated with baseline testing. Objective: To explore performance factors associated with baseline RTclin from among candidate variables representing demographics, medical and concussion history, self-reported symptoms, sleep, and sport-related features. Design: Cross-sectional study. Setting: Clinical setting (eg, athletic training room). Patients or other participants: A total of 2584 National Collegiate Athletic Association student-athletes (n = 1206 females [47%], 1377 males [53%], and 1 unreported (<0.1%); mass = 76.7 ± 18.7 kg; height = 176.7 ± 11.3 cm; age = 19.0 ± 1.3 years) from 3 institutions participated in this study as part of the Concussion Assessment, Research and Education Consortium. Main outcome measure(s): Potential performance factors were sex; race; ethnicity; dominant hand; sport type; number of prior concussions; presence of anxiety, learning disability, attention-deficit disorder or attention-deficit/hyperactivity disorder, depression, or migraine headache; self-reported sleep the night before the test; mass; height; age; total number of symptoms; and total symptom burden at baseline. The primary study outcome measure was mean baseline RTclin. Results: The overall RTclin was 202.0 ± 25.0 milliseconds. Female sex (parameter estimate [B] = 8.6 milliseconds, P < .001, Cohen d = 0.54 relative to male sex), black or African American race (B = 5.3 milliseconds, P = .001, Cohen d = 0.08 relative to white race), and limited-contact (B = 4.2 milliseconds, P < .001, Cohen d = 0.30 relative to contact) or noncontact (B = 5.9 milliseconds, P < .001, Cohen d = 0.38 relative to contact) sport participation were associated with slower RTclin. Being taller was associated with a faster RTclin, although this association was weak (B = -0.7 milliseconds, P < .001). No other predictors were significant. When adjustments are made for sex and sport type, the following normative data may be considered (mean ± standard deviation): female, noncontact (211.5 ± 25.8 milliseconds), limited contact (212.1 ± 24.3 milliseconds), contact (203.7 ± 21.5 milliseconds); male, noncontact (199.4 ± 26.7 milliseconds), limited contact (196.3 ± 23.9 milliseconds), contact (195.0 ± 23.8 milliseconds). Conclusions: Potentially clinically relevant differences existed in RTclin for sex and sport type. These results provide normative data adjusting for these performance factors.Item Comparison of Risk Factors for Pediatric Kidney Stone Formation: The Effects of Sex(Frontiers, 2019-02-12) Schwaderer, Andrew L.; Raina, Rupesh; Khare, Anshika; Safadi, Fayez; Moe, Sharon M.; Kusumi, Kirsten; Pediatrics, School of MedicineBackground: Urinary stones are affecting more children, and pediatric stone formers have unique pathophysiology compared to adults. While adult stone formers are most frequently male, children have an age dependent sex prevalence. Under 10 years, a majority of stone formers are boys; adolescent stone formers are mostly female. Previous adult studies have shown that stone composition is influenced by the sex and age of the stone former. Thus, we hypothesize that female and male stone forming children will also have sex and age specific stone phenotypes. Methods: Retrospective chart review of a large pediatric center's stone forming children 6/1/2009 to 6/1/2016. Patients were identified by ICD 9 codes: N20, N20.1, and N20.9. Charts were reviewed for radiographic evidence of stones or documented visualized stone passage. Results: One hundred and thirty six subjects: 54 males and 82 females. Females were older, median age 14 years [interquartile range (IQR): 11, 15] vs. males' median age 12 years (IQR: 11, 14) (p < 0.01). Females had lower height z-scores, median 0.2 (IQR: -0.8, 0.8) vs. males' median 0.8 (IQR: -0.2, 1.8) (p < 0.01). Presenting symptoms were similar except flank pain affecting 39% of females vs. 22% of males (p = 0.04). Leukocyte esterase was positive in more females than males (33 vs. 4%) (p < 0.001). Males had a higher BUN/Cr ratio, mean ± standard deviation of 19.8 ± 6.3 vs. 16.6 ± 6.5 in females (p = 0.01). Glomerular hyperfiltration was present in 9% of patients while 35% of patients had estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m2. Treatment strategies and clinical course were similar except females were told to increase dietary citrate more frequently than males (21 vs. 4%) (p < 0.01). Conclusion: We have provided a novel analysis and demonstrated that low height z-score and pyuria are more common in female stone formers. We have also shown that 9% of pediatric stone formers have labs consistent with hyperfiltration. Whether high protein intake and/or chronic dehydration are associated with hyperfiltration and long-term renal function in children with kidney stones will be an area for future research.Item A conserved female-specific larval requirement for MtnB function facilitates sex separation in multiple species of disease vector mosquitoes(BMC, 2021-06-26) Mysore, Keshava; Sun, Longhua; Roethele, Joseph B.; Li, Ping; Igiede, Jessica; Misenti, Joi K.; Duman‑Scheel, Molly; Medical and Molecular Genetics, School of MedicineBackground: Clusters of sex-specific loci are predicted to shape the boundaries of the M/m sex-determination locus of the dengue vector mosquito Aedes aegypti, but the identities of these genes are not known. Identification and characterization of these loci could promote a better understanding of mosquito sex chromosome evolution and lead to the elucidation of new strategies for male mosquito sex separation, a requirement for several emerging mosquito population control strategies that are dependent on the mass rearing and release of male mosquitoes. This investigation revealed that the methylthioribulose-1-phosphate dehydratase (MtnB) gene, which resides adjacent to the M/m locus and encodes an evolutionarily conserved component of the methionine salvage pathway, is required for survival of female larvae. Results: Larval consumption of Saccharomyces cerevisiae (yeast) strains engineered to express interfering RNA corresponding to MtnB resulted in target gene silencing and significant female death, yet had no impact on A. aegypti male survival or fitness. Integration of the yeast larvicides into mass culturing protocols permitted scaled production of fit adult male mosquitoes. Moreover, silencing MtnB orthologs in Aedes albopictus, Anopheles gambiae, and Culex quinquefasciatus revealed a conserved female-specific larval requirement for MtnB among different species of mosquitoes. Conclusions: The results of this investigation, which may have important implications for the study of mosquito sex chromosome evolution, indicate that silencing MtnB can facilitate sex separation in multiple species of disease vector insects.Item Differences in the Presentation and Progression of Parkinson's Disease by Sex(Wiley, 2021) Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton L.; Makarious, Mary B.; Kim, Jonggeol J.; Liu, Ganqiang; Maple-Grødem, Jodie; Corvol, Jean-Christophe; Pihlstrøm, Lasse; van Nimwegen, Marlies; Smolensky, Luba; Amondikar, Ninad; Hutten, Samantha J.; Frasier, Mark; Nguyen, Khanh-Dung H.; Rick, Jacqueline; Eberly, Shirley; Faghri, Faraz; Auinger, Peggy; Scott, Kirsten M.; Wijeyekoon, Ruwani; Van Deerlin, Vivianna M.; Hernandez, Dena G.; Gibbs, Raphael J.; Day-Williams, Aaron G.; Brice, Alexis; Alves, Guido; Noyce, Alastair J.; Tysnes, Ole-Bjørn; Evans, Jonathan R.; Breen, David P.; Estrada, Karol; Wegel, Claire E.; Danjou, Fabrice; Simon, David K.; Andreassen, Ole A.; Ravina, Bernard; Toft, Mathias; Heutink, Peter; Bloem, Bastiaan R.; Weintraub, Daniel; Barker, Roger A.; Williams-Gray, Caroline H.; van de Warrenburg, Bart P.; Van Hilten, Jacobus J.; Scherzer, Clemens R.; Singleton, Andrew B.; Nalls, Mike A.; Medical and Molecular Genetics, School of MedicineBackground: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. Methods: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. Results: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. Conclusions: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management.Item Distinctive Temporal Trajectories of Alzheimer's Disease Biomarkers According to Sex and APOE Genotype: Importance of Striatal Amyloid(Frontiers Media, 2022-02-07) Kim, Jun Pyo; Chun, Min Young; Kim, Soo-Jon; Jang, Hyemin; Kim, Hee Jin; Jeong, Jee Hyang; Na, Duk L.; Seo, Sang Won; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicinePurpose: Previously, sex and apolipoprotein E (APOE) genotype had distinct effects on the cognitive trajectory across the Alzheimer's disease (AD) continuum. We therefore aimed to investigate whether these trajectory curves including β-amyloid (Aβ) accumulation in the cortex and striatum, and tau accumulation would differ according to sex and APOE genotype. Methods: We obtained 534 subjects for 18F-florbetapir (AV45) PET analysis and 163 subjects for 18F-flortaucipir (AV1451) PET analysis from the Alzheimer's Disease Neuroimaging Initiative database. For cortical Aβ, striatal Aβ, and tau SUVR, we fitted penalized splines to model the slopes of SUVR value as a non-linear function of baseline SUVR value. By integrating the fitted splines, we obtained the predicted SUVR curves as a function of time. Results: The time from initial SUVR to the cutoff values were 14.9 years for cortical Aβ, 18.2 years for striatal Aβ, and 22.7 years for tau. Although there was no difference in cortical Aβ accumulation rate between women and men, striatal Aβ accumulation was found to be faster in women than in men, and this temporal difference according to sex was more pronounced in tau accumulation. However, APOE ε4 carriers showed faster progression than non-carriers regardless of kinds of AD biomarkers' trajectories. Conclusion: Our temporal trajectory models illustrate that there is a distinct progression pattern of AD biomarkers depending on sex and APOE genotype. In this regard, our models will be able to contribute to designing personalized treatment and prevention strategies for AD in clinical practice.Item Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network(Wiley, 2024) Wagemann, Olivia; Li, Yan; Hassenstab, Jason; Aschenbrenner, Andrew J.; McKay, Nicole S.; Gordon, Brian A.; Benzinger, Tammie L. S.; Xiong, Chengjie; Cruchaga, Carlos; Renton, Alan E.; Perrin, Richard J.; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lopera, Francisco; Mori, Hiroshi; Noble, James M.; Sánchez-Valle, Raquel; Schofield, Peter R.; Morris, John C.; Daniels, Alisha; Levin, Johannes; Bateman, Randall J.; McDade, Eric; Llibre-Guerra, Jorge J.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineIntroduction: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD). Methods: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11 C-PiB PET) and structural magnetic resonance imaging (MRI). Results: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences. Discussion: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.Item Prenatal Alcohol Exposure Reduces Posterior Dorsomedial Striatum Excitability and Motivation in a Sex- and Age-Dependent Fashion(Elsevier, 2020-12) Roselli, Victoria; Guo, Changyong; Huang, Donald; Wen, Di; Zona, Daniel; Liang, Tiebing; Ma, Yao-Ying; Pharmacology and Toxicology, School of MedicinePrenatal alcohol exposure (PAE)-induced clinical symptoms have been widely reported but effective treatments are not yet available due to our limited knowledge of the neuronal mechanisms underlying behavioral outputs. Operant behaviors, including both goal-directed and habitual actions, are essential for everyday life. The dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) have been identified as mediating each type of instrumental behavior, respectively. The current studies were designed to evaluate the effects of PAE (i.e., 3 g/kg, twice a day on gestational days 17-20) on goal-directed vs. habitual behaviors in both females and males during their adolescent and adult stages. We found that PAE-treated adult, but not adolescent, males display similar habitual oral sucrose self-administration but reduced goal-directed sucrose self-administration, compared to those treated by prenatal control (water) exposure (PCE). There were no differences in either habitual or goal-directed sucrose taking between PCE- vs. PAE-treated adolescent and adult females. These results indicate sex- and age-specific effects of PAE on operant behaviors. Further, whole-cell patch clamp recordings showed that the excitability of medium-sized spiny neurons (MSNs) in the posterior DMS (pDMS), but not the anterior DMS (aDMS), was significantly decreased in PAE-treated adult male rats. Notably, chemogenetic enhancement of MSN excitability in the pDMS by the DREADD agonist, compound 21, rescued the motivation of PAE-treated male adult rats. These data suggest that the pDMS may be a key neuronal substrate mediating the PAE-induced low motivation in male adults.Item A prospective examination of sex differences in posttraumatic autonomic functioning(Elsevier, 2021-08-21) Seligowski, Antonia V.; Steuber, Elizabeth R.; Hinrichs, Rebecca; Reda, Mariam H.; Wiltshire, Charis N.; Wanna, Cassandra P.; Winters, Sterling J.; Phillips, Karlye A.; House, Stacey L.; Beaudoin, Francesca L.; An, Xinming; Stevens, Jennifer S.; Zeng, Donglin; Neylan, Thomas C.; Clifford, Gari D.; Linnstaedt, Sarah D.; Germine, Laura T.; Bollen, Kenneth A.; Guffanti, Guia; Rauch, Scott L.; Haran, John P.; Storrow, Alan B.; Lewandowski, Christopher; Musey, Paul I., Jr.; Hendry, Phyllis L.; Sheikh, Sophia; Jones, Christopher W.; Punches, Brittany E.; Kurz, Michael C.; Murty, Vishnu P.; McGrath, Meghan E.; Hudak, Lauren A.; Pascual, Jose L.; Seamon, Mark J.; Datner, Elizabeth M.; Chang, Anna M.; Pearson, Claire; Peak, David A.; Merchant, Roland C.; Domeier, Robert M.; Rathlev, Niels K.; O'Neil, Brian J.; Sanchez, Leon D.; Bruce, Steven E.; Miller, Mark W.; Pietrzak, Robert H.; Joormann, Jutta; Barch, Deanna M.; Pizzagalli, Diego A.; Sheridan, John F.; Luna, Beatriz; Harte, Steven E.; Elliott, James M.; Koenen, Karestan C.; Kessler, Ronald C.; McLean, Samuel A.; Ressler, Kerry J.; Jovanovic, Tanja; Emergency Medicine, School of MedicineBackground: Cross-sectional studies have found that individuals with posttraumatic stress disorder (PTSD) exhibit deficits in autonomic functioning. While PTSD rates are twice as high in women compared to men, sex differences in autonomic functioning are relatively unknown among trauma-exposed populations. The current study used a prospective design to examine sex differences in posttraumatic autonomic functioning. Methods: 192 participants were recruited from emergency departments following trauma exposure (Mean age = 35.88, 68.2% female). Skin conductance was measured in the emergency department; fear conditioning was completed two weeks later and included measures of blood pressure (BP), heart rate (HR), and high frequency heart rate variability (HF-HRV). PTSD symptoms were assessed 8 weeks after trauma. Results: 2-week systolic BP was significantly higher in men, while 2-week HR was significantly higher in women, and a sex by PTSD interaction suggested that women who developed PTSD demonstrated the highest HR levels. Two-week HF-HRV was significantly lower in women, and a sex by PTSD interaction suggested that women with PTSD demonstrated the lowest HF-HRV levels. Skin conductance response in the emergency department was associated with 2-week HR and HF-HRV only among women who developed PTSD. Conclusions: Our results indicate that there are notable sex differences in autonomic functioning among trauma-exposed individuals. Differences in sympathetic biomarkers (BP and HR) may have implications for cardiovascular disease risk given that sympathetic arousal is a mechanism implicated in this risk among PTSD populations. Future research examining differential pathways between PTSD and cardiovascular risk among men versus women is warranted.