A Gender Hypothesis of sex disparities in adverse drug events.

Pharmacovigilance databases contain larger numbers of adverse drug events (ADEs) that occurred in women compared to men. The cause of this disparity is frequently attributed to sex-linked biological factors. We offer an alternative Gender Hypothesis, positing that gendered social factors are central to the production of aggregate sex disparities in ADE reports. We describe four pathways through which gender may influence observed sex disparities in pharmacovigilance databases: healthcare utilization; bias and discrimination in the clinic; experience of a drug event as adverse; and pre-existing social and structural determinants of health. We then use data from the U.S. FDA Adverse Event Reporting System (FAERS) to explore how the Gender Hypothesis might generate novel predictions and explanations of sex disparities in ADEs in existing widely referenced datasets. Analyzing more than 3 million records of ADEs between 2014 and 2022, we find that patient-reported ADEs show a larger female skew than healthcare provider-reported ADEs and that the sex disparity is markedly smaller for outcomes involving death or hospitalization. We also find that the sex disparity varies greatly across types of ADEs, for example, cosmetically salient ADEs are skewed heavily female and sexual dysfunction ADEs are skewed male. Together, we interpret these findings as providing evidence of the promise of the Gender Hypothesis for identifying intervenable mechanisms and pathways contributing to sex disparities in ADEs. Rigorous application of the Gender Hypothesis to additional datasets and in future research studies could yield new insights into the causes of sex disparities in ADEs.

Identification of immune-related candidate biomarkers in plasma of patients with sporadic vestibular schwannoma.

Vestibular schwannoma (VS) is an intracranial tumor arising from neoplastic Schwann cells and typically presenting with hearing loss. The traditional belief that hearing deficit is caused by physical expansion of the VS, compressing the auditory nerve, does not explain the common clinical finding that patients with small tumors can have profound hearing loss, suggesting that tumor-secreted factors could influence hearing ability in VS patients. We conducted profiling of patients' plasma for 66 immune-related factors in patients with sporadic VS (N > 170) and identified and validated candidate biomarkers associated with tumor size (S100B) and hearing (MCP-3). We further identified a nine-biomarker panel (TNR-R2, MIF, CD30, MCP-3, IL-2R, BLC, TWEAK, eotaxin, and S100B) with outstanding discriminatory ability for VS. These findings revealed possible therapeutic targets for VS, providing a unique diagnostic tool that may predict hearing change and tumor growth in VS patients, and may inform the timing of tumor resection to preserve hearing.

Adverse Drug Events by Sex After Adjusting for Baseline Rates of Drug Use.

This cross-sectional study examines adverse drug events reported by sex in the US Food and Drug Administration (FDA) database after adjusting for drug use by males and females.

Comparing measured dietary variation within and between tropical hunter-gatherer groups to the Paleo Diet.

BACKGROUND: Although human diets varied considerably before the spread of agriculture, public perceptions of preagricultural diets have been strongly influenced by the Paleo Diet, which prescribes percentage calorie ranges of 19-35% protein, 22-40% carbohydrate, and 28-47% fat, and prohibits foods with added sugar, dairy, grains, most starchy tubers, and legumes. However, the empirical basis for Paleolithic nutrition remains unclear, with some of its assumptions challenged by the archaeological record and theoretical first principles. OBJECTIVES: We assessed the variation in diets among tropical hunter-gatherers, including the effect of collection methods on implied macronutrient percentages. METHODS: We analyzed data on animal food, plant food, and honey consumption by weight and kcal from 15 high-quality published ethnographic studies representing 11 recent tropical hunter-gatherer groups. We used Bayesian analyses to perform inference and included data collection methods and environmental variables as predictors in our models. RESULTS: Our analyses reveal high levels of variation in animal versus plant foods consumed and in corresponding percentages of protein, fat, and carbohydrates. In addition, studies that weighed food items consumed in and out of camp and across seasons and years reported higher consumption of animal foods, which varied with annual mean temperature. CONCLUSIONS: The ethnographic evidence from tropical foragers refutes the concept of circumscribed macronutrient ranges modeling preagricultural diets.

Identification of Immune-Related Candidate Biomarkers in Plasma of Patients with Sporadic Vestibular Schwannoma: Candidate Plasma Biomarkers in Vestibular Schwannoma.

Vestibular schwannoma (VS) is intracranial tumor arising from neoplastic Schwann cells, causing hearing loss in about 95% of patients. The traditional belief that hearing deficit is caused by physical expansion of the VS, compressing the auditory nerve, does not explain the common clinical finding that patients with small tumors can have profound hearing loss, suggesting that tumor-secreted factors could influence hearing ability in VS patients. Here, we conducted profiling of patients' plasma for 67 immune-related factors on a large cohort of VS patients (N>120) and identified candidate biomarkers associated with tumor growth (IL-16 and S100B) and hearing (MDC). We identified the 7-biomarker panel composed of MCP-3, BLC, S100B, FGF-2, MMP-14, eotaxin, and TWEAK that showed outstanding discriminatory ability for VS. These findings revealed possible therapeutic targets for VS-induced hearing loss and provided a unique diagnostic tool that may predict hearing change and tumor growth in VS patients and may help inform the ideal timing of tumor resection to preserve hearing.

A year in the social life of a teenager: Within-person fluctuations in stress, phone communication, and anxiety and depression.

Stressful life events (SLEs) are strongly associated with the emergence of adolescent anxiety and depression, but the underlying mechanisms remain poorly understood, especially at the within-person level. We investigated how adolescent social communication (i.e., frequency of calls and texts) following SLEs relates to changes in internalizing symptoms in a multi-timescale intensive year-long study (N=30; n=355 monthly observations; n=~5,000 experience-sampling observations). Within-person increases in SLEs were associated with receiving more calls than usual at both monthly- and momentary-levels, and making more calls at the monthly-level. Increased calls were prospectively associated with worsening internalizing symptoms at the monthly-level only, suggesting that SLEs rapidly influences phone communication patterns, but these communication changes may have a more protracted, cumulative influence on internalizing symptoms. Finally, increased incoming calls prospectively mediated the association between SLEs and anxiety at the monthly-level. We identify adolescent social communication fluctuations as a potential mechanism conferring risk for stress-related internalizing psychopathology.

Urbanization and Knee Cartilage Growth Among Children and Adolescents in Western Kenya.

OBJECTIVE: Previous studies have demonstrated that low physical activity levels during youth are associated with the development of thin knee cartilage, which may increase susceptibility to osteoarthritis later in life. Here, we propose and test the hypothesis that reductions in physical activity impair knee cartilage growth among people in developing countries experiencing urbanization and increased market integration. METHODS: Ultrasonography was used to measure knee cartilage thickness in 168 children and adolescents (aged 8-17 years) from two groups in western Kenya: a rural, physically active group from a small-scale farming community and an urban, less physically active group from the nearby city of Eldoret. We used general linear models to assess the relative effects of age on cartilage thickness in these two groups, controlling for sex and leg length. RESULTS: Both groups exhibited significant reductions in knee cartilage thickness with increasing age (P < 0.0001; 95% confidence interval [CI] 0.15-0.06 mm), yet the rate of reduction was significantly less in the rural than in the urban group (P = 0.012; 95% CI 0.01-0.10 mm). CONCLUSION: The results support our hypothesis by showing that individuals from the more physically active rural group exhibited less knee cartilage loss during youth than the more sedentary urban group. Our findings suggest that reduced physical activity associated with urbanization in developing nations may affect adult knee cartilage thickness and thus could be a factor that increases susceptibility to osteoarthritis.

Built Environment and Self-Rated Health: Comparing Young, Middle-Aged, and Older People in Chengdu, China.

OBJECTIVES: This article explores how the building-scale built environment is associated with self-rated health, examining differences in this association among younger, middle-aged, and older age groups. Features examined included building type, building condition, and sidewalk presence in front of dwellings. BACKGROUND: Understanding how the relationships between built environments and health vary across age groups helps to build a healthy environment for all. However, most studies have concentrated on the neighborhood or indoor environment, rather than whole buildings, and few have compared age groups. METHODS: This study analyzed survey data from 1,019 adults living in 40 neighborhoods in Chengdu, China, recruited through a clustered random sampling approach. It used a Bayesian logistic mixed-effects model with interaction terms between age-group indicators and other variables. RESULTS: Significant differences exist in the relationships of self-rated health with some environmental and other indicators among age groups. For older people, living in multi-floor buildings, having a household smoker, and undertaking fewer hours of weekly exercise were associated with lower odds of reporting good, very good, or excellent health. These relationships were not identified among middle-aged and younger people. More education was associated with higher odds of reporting better health among older and middle-aged groups. CONCLUSIONS: Older people experience more health-related challenges compared to middle-aged and younger people. However, among the examined built environment factors, building type was the only significant factor related to self-rated health among older people. To promote health among older people, this study recommends adding elevators in the multi-floor buildings.

Geometric morphometric investigation of craniofacial morphological change in domesticated silver foxes.

To test the effects of domestication on craniofacial skeletal morphology, we used three-dimensional geometric morphometrics (GM) along with linear and endocranial measurements to compare selected (domesticated) and unselected foxes from the Russian Farm-Fox Experiment to wild foxes from the progenitor population from which the farmed foxes are derived. Contrary to previous findings, we find that domesticated and unselected foxes show minimal differences in craniofacial shape and size compared to the more substantial differences between the wild foxes and both populations of farmed foxes. GM analyses and linear measurements demonstrate that wild foxes differ from farmed foxes largely in terms of less cranial base flexion, relatively expanded cranial vaults, and increased endocranial volumes. These results challenge the assumption that the unselected population of foxes kept as part of the Russian Farm-Fox experiment are an appropriate proxy for 'wild' foxes in terms of craniofacial morphology and highlight the need to include wild populations in further studies of domestication syndrome to disentangle the phenotypic effects of multiple selection pressures. These findings also suggest that marked increases in docility cannot be reliably diagnosed from shape differences in craniofacial skeletal morphology.

How adolescents and adults translate motivational value to action: Age-related shifts in strategic physical effort exertion for monetary rewards.

Adults titrate the degree of physical effort they are willing to expend according to the magnitude of reward they expect to obtain, a process guided by incentive motivation. However, it remains unclear whether adolescents, who are undergoing normative developmental changes in cognitive and reward processing, translate incentive motivation into action in a way that is similarly tuned to reward value and economical in effort utilization. The present study adapted a classic physical effort paradigm to quantify age-related changes in motivation-based and strategic markers of effort exertion for monetary rewards from adolescence to early adulthood. One hundred three participants aged 12-23 years completed a task that involved exerting low or high amounts of physical effort, in the form of a hand grip, to earn low or high amounts of money. Adolescents and young adults exhibited highly similar incentive-modulated effort for reward according to measures of peak grip force and speed, suggesting that motivation for monetary reward is consistent across age. However, young adults expended energy more economically and strategically: Whereas adolescents were prone to exert excess physical effort beyond what was required to earn reward, young adults were more likely to strategically prepare before each grip phase and conserve energy by opting out of low reward trials. This work extends theoretical models of development of incentive-driven behavior by demonstrating that layered on similarity in motivational value for monetary reward, there are important differences in the way behavior is flexibly adjusted in the presence of reward from adolescence to young adulthood. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Professors Prioritize Increasing Female Retention in Academic Physics Over Advisee's Interests.

Decades of initiatives have striven to fix the so-called "leaking pipeline" problem-persistent high attrition of women from the career/educational path toward STEM professorship. Though these initiatives call on academics to increase female retention along this path, it remains unknown whether academics actually prioritize this goal. To investigate this, we tested whether academics would prioritize female retention at the cost of a competing goal when giving career advice to students at risk of leaving the "pipeline." We present results from a national survey in which United States professors (n = 364) responded to vignettes of three hypothetical undergraduates, rating the extent to which they would encourage or discourage each student from pursuing a PhD in physics. Professors were randomly assigned vignettes with either male or female gender pronouns. Two vignettes featured students who cogently explained why remaining in the physics pipeline would not match their individual goals and interests, while another vignette presented a student with goals and interests that clearly matched pursuing physics graduate school. Professors who received female-gendered vignettes were thus forced to choose between prioritizing striving to increase female retention in physics and acting in the best interest of the individual student. We present evidence that professors seem prepared to encourage women more strongly than men to remain in physics, even when remaining is contrary to the stated goals and interests of the student: Our logistic regression results suggest that professors have higher odds of encouraging women over men, net of vignette and other controls. We also find that male professors have higher odds of encouraging undergraduates and find no evidence that, relative to non-STEM professors, STEM professors have higher odds of encouraging women over men.

Machine learning predicts large scale declines in native plant phylogenetic diversity.

Though substantial effort has gone into predicting how global climate change will impact biodiversity patterns, the scarcity of taxon-specific information has hampered the efficacy of these endeavors. Further, most studies analyzing spatiotemporal patterns of biodiversity focus narrowly on species richness. We apply machine learning approaches to a comprehensive vascular plant database for the United States and generate predictive models of regional plant taxonomic and phylogenetic diversity in response to a wide range of environmental variables. We demonstrate differences in predicted patterns and potential drivers of native vs nonnative biodiversity. In particular, native phylogenetic diversity is likely to decrease over the next half century despite increases in species richness. We also identify that patterns of taxonomic diversity can be incongruent with those of phylogenetic diversity. The combination of macro-environmental factors that determine diversity likely varies at continental scales; thus, as climate change alters the combinations of these factors across the landscape, the collective effect on regional diversity will also vary. Our study represents one of the most comprehensive examinations of plant diversity patterns to date and demonstrates that our ability to predict future diversity may benefit tremendously from the application of machine learning.

Selection of endurance capabilities and the trade-off between pressure and volume in the evolution of the human heart.

Chimpanzees and gorillas, when not inactive, engage primarily in short bursts of resistance physical activity (RPA), such as climbing and fighting, that creates pressure stress on the cardiovascular system. In contrast, to initially hunt and gather and later to farm, it is thought that preindustrial human survival was dependent on lifelong moderate-intensity endurance physical activity (EPA), which creates a cardiovascular volume stress. Although derived musculoskeletal and thermoregulatory adaptations for EPA in humans have been documented, it is unknown if selection acted similarly on the heart. To test this hypothesis, we compared left ventricular (LV) structure and function across semiwild sanctuary chimpanzees, gorillas, and a sample of humans exposed to markedly different physical activity patterns. We show the human LV possesses derived features that help augment cardiac output (CO) thereby enabling EPA. However, the human LV also demonstrates phenotypic plasticity and, hence, variability, across a wide range of habitual physical activity. We show that the human LV's propensity to remodel differentially in response to chronic pressure or volume stimuli associated with intense RPA and EPA as well as physical inactivity represents an evolutionary trade-off with potential implications for contemporary cardiovascular health. Specifically, the human LV trades off pressure adaptations for volume capabilities and converges on a chimpanzee-like phenotype in response to physical inactivity or sustained pressure loading. Consequently, the derived LV and lifelong low blood pressure (BP) appear to be partly sustained by regular moderate-intensity EPA whose decline in postindustrial societies likely contributes to the modern epidemic of hypertensive heart disease.

Knee osteoarthritis risk in non-industrial societies undergoing an energy balance transition: evidence from the indigenous Tarahumara of Mexico.

Non-industrial societies with low energy balance levels are expected to be less vulnerable than industrial societies to diseases associated with obesity including knee osteoarthritis. However, as non-industrial societies undergo rapid lifestyle changes that promote positive energy balance, individuals whose metabolisms are adapted to energetic scarcity are encountering greater energy abundance, increasing their propensity to accumulate abdominal adipose tissue and thus potentially their sensitivity to obesity-related diseases. OBJECTIVES: Here, we propose that knee osteoarthritis is one such disease for which susceptibility is amplified by this energy balance transition. METHODS: Support for our hypothesis comes from comparisons of knee radiographs, knee pain and anthropometry among men aged ≥40 years in two populations: Tarahumara subsistence farmers in Mexico undergoing the energy balance transition and urban Americans from Framingham, Massachusetts. RESULTS: We show that despite having markedly lower obesity levels than the Americans, the Tarahumara appear predisposed to accrue greater abdominal adiposity (ie, larger abdomens) for a given body weight, and are more vulnerable to radiographic and symptomatic knee osteoarthritis at lower levels of body mass index. Also, proportionate increases in abdomen size in the two groups are associated with greater increases in radiographic knee osteoarthritis risk among the Tarahumara than the Americans, implying that the abdominal adipose tissue of the Tarahumara is a more potent stimulus for knee degeneration. CONCLUSIONS: Heightened vulnerability to knee osteoarthritis among non-industrial societies experiencing rapid lifestyle changes is a concern that warrants further investigation since such groups represent a large but understudied fraction of the global population.

STEM/Non-STEM Divide Structures Undergraduate Beliefs About Gender and Talent in Academia.

Research and popular debate on female underrepresentation in academia has focused on STEM fields. But recent work has offered a unifying explanation for gender representation across the STEM/non-STEM divide. This proposed explanation, called the field-specific ability beliefs (FAB) hypothesis, postulates that, in combination with pervasive stereotypes that link men but not women with intellectual talent, academics perpetuate female underrepresentation by transmitting to students in earlier stages of education their beliefs about how much intellectual talent is required for success in each academic field. This theory was supported by a nationwide survey of U.S. academics that showed both STEM and non-STEM fields with fewer women are also the fields that academics believe require more brilliance. We test this top-down schema with a nationwide survey of U.S. undergraduates, assessing the extent to which undergraduate beliefs about talent in academia mirror those of academics. We find no evidence that academics transmit their beliefs to undergraduates. We also use a second survey "identical to the first but with each field's gender ratio provided as added information" to explicitly test the relationship between undergraduate beliefs about gender and talent in academia. The results for this second survey suggest that the extent to which undergraduates rate brilliance as essential to success in an academic field is highly sensitive to this added information for non-STEM fields, but not STEM fields. Overall, our study offers evidence that, contrary to FAB hypothesis, the STEM/non-STEM divide principally shapes undergraduate beliefs about both gender and talent in academia.

Taxon sampling effects on the quantification and comparison of community phylogenetic diversity.

Ecologists are increasingly making use of molecular phylogenies, especially in the fields of community ecology and conservation. However, these phylogenies are often used without full appreciation of their underlying assumptions and uncertainties. A frequent practice in ecological studies is inferring a phylogeny with molecular data from taxa only within the community of interest. These "inferred community phylogenies" are inherently biased in their taxon sampling. Despite the importance of comprehensive sampling in constructing phylogenies, the implications of using inferred community phylogenies in ecological studies have not been examined. Here, we evaluate how taxon sampling affects the quantification and comparison of community phylogenetic diversity using both simulated and empirical data sets. We demonstrate that inferred community trees greatly underestimate phylogenetic diversity and that the probability of incorrectly ranking community diversity can reach up to 25%, depending on the dating methods employed. We argue that to reach reliable conclusions, ecological studies must improve their taxon sampling and generate the best phylogeny possible.

Selection of Character Coding Method Is Not Phylogenetically Neutral: A Test Case Using Hominoids.

The early stages of phylogenetic inference from morphological data involve a sequence of choices about which analytical methods to employ. At each stage, the selection of one method over another can dramatically impact tree inference. Phylogenetic hypotheses are sensitive to decisions relating to which taxa and characters to select for analysis, whether and how to delimit character states, which taxa to use as outgroups, and how to account for character dependence. Using extant hominoids as a test case, I quantify the degree to which phylogenetic inferences are sensitive to the choice of method used to transform continuously scaled variables into categorical traits. I demonstrate that the character coding strategy significantly impacts hypotheses of character state identity and phylogenetic branching patterns. To avoid biasing evolutionary hypotheses, I recommend that continuously scaled characters be analyzed without prior discretization.

Prognostic Significance of Surgical Margin Size After Neoadjuvant FOLFOX and/or FOLFIRI for Colorectal Liver Metastases.

PURPOSE: Optimal margin size when resecting colorectal liver metastases (CRLM) remains unclear, particularly in the setting of perioperative chemotherapy. We evaluated the prognostic significance of margin size in patients who received neoadjuvant FOLFOX and/or FOLFIRI prior to resection of CRLM. METHODS: Clinicopathologic factors were collected for patients who underwent curative liver resections for CRLM between 4/2004-1/2016 and received neoadjuvant oxaliplatin and/or irinotecan and 5-FU (FOLFOX, FOLFIRI). Margins were categorized as < 1, ≥ 1-< 5, ≥ 5-< 10, or ≥ 10 mm and evaluated for association with overall survival (OS) and disease-free survival (DFS) by Cox multiple regression analysis. Margin status was classified as positive (< 1 mm) or negative (≥ 1 mm) and similarly evaluated. RESULTS: Of 227 patients, the median age was 58 years and most had synchronous (80%) lesions. The majority had colon cancers (75%). Margin sizes were 13% < 1 mm, 27% ≥ 1-< 5 mm, 23% ≥ 5-< 10 mm, 36% ≥ 10 mm. Most (63%) received chemotherapy post-liver resection. Five-year OS and DFS were 54% (95% CI 46-62%) and 22% (95% CI 16-28%), respectively. Positive margins significantly increased the risk of death without post-liver resection chemotherapy (HR = 3.32, p = 0.0077), but not with post-liver resection chemotherapy (HR = 1.00, p = 0.99). Negative margin sizes of ≥ 1-< 5, ≥ 5-< 10, and ≥ 10 mm were not significant predictors of OS (p > 0.05). CONCLUSION: Patients undergoing liver resection for CRLM should receive post-resection chemotherapy if negative margins (≥ 1 mm) cannot be achieved. For patients receiving FOLFOX and/or FOLFIRI chemotherapy, wider margins did not improve OS.