Exploring the parity paradox: Differential effects on neuroplasticity and inflammation by APOEe4 genotype at middle age.

Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer's disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOEε4 genotype synergistically modulate inflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscore the importance of considering female-specific factors and genotype in health research.

Menopausal hormone therapy and the female brain: leveraging neuroimaging and prescription registry data from the UK Biobank cohort.

Background and Objectives: Menopausal hormone therapy (MHT) is generally thought to be neuroprotective, yet results have been inconsistent. Here, we present a comprehensive study of MHT use and brain characteristics in middle- to older aged females from the UK Biobank, assessing detailed MHT data, APOE ε4 genotype, and tissue-specific gray (GM) and white matter (WM) brain age gap (BAG), as well as hippocampal and white matter hyperintensity (WMH) volumes. Methods: A total of 19,846 females with magnetic resonance imaging data were included (current-users = 1,153, 60.1 ± 6.8 years; past-users = 6,681, 67.5 ± 6.2 years; never-users = 12,012, mean age 61.6 ± 7.1 years). For a sub-sample (n = 538), MHT prescription data was extracted from primary care records. Brain measures were derived from T1-, T2- and diffusion-weighted images. We fitted regression models to test for associations between the brain measures and MHT variables including user status, age at initiation, dosage and duration, formulation, route of administration, and type (i.e., bioidentical vs synthetic), as well as active ingredient (e.g., estradiol hemihydrate). We further tested for differences in brain measures among MHT users with and without a history of hysterectomy ± bilateral oophorectomy and examined associations by APOE ε4 status. Results: We found significantly higher GM and WM BAG (i.e., older brain age relative to chronological age) as well as smaller left and right hippocampus volumes in current MHT users, not past users, compared to never-users. Effects were modest, with the largest effect size indicating a group difference of 0.77 years (~9 months) for GM BAG. Among MHT users, we found no significant associations between age at MHT initiation and brain measures. Longer duration of use and older age at last use post menopause was associated with higher GM and WM BAG, larger WMH volume, and smaller left and right hippocampal volumes. MHT users with a history of hysterectomy ± bilateral oophorectomy showed lower GM BAG relative to MHT users without such history. Although we found smaller hippocampus volumes in carriers of two APOE ε4 alleles compared to non-carriers, we found no interactions with MHT variables. In the sub-sample with prescription data, we found no significant associations between detailed MHT variables and brain measures after adjusting for multiple comparisons. Discussion: Our results indicate that population-level associations between MHT use, and female brain health might vary depending on duration of use and past surgical history. Future research is crucial to establish causality, dissect interactions between menopause-related neurological changes and MHT use, and determine individual-level implications to advance precision medicine in female health care.

Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition. METHODS: We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French). RESULTS: We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 ± 8.53 years, mean age at menopause = 50.1 ± 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (ß = 0.013, 95% CI 0.001-0.025, p = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; ß = -0.044, 95% CI -0.066 to -0.022, p < 0.001), but not average (ages 49-52 years; ß = -0.007, 95% CI -0.027 to 0.012, p = 0.46) or later menopause (ages 53-65 years; ß = 0.003, 95% CI -0.020 to 0.025, p = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (ß = -0.005, 95% CI -0.032 to 0.021, p = 0.69). DISCUSSION: Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.

Mental Health Outcomes of Endometriosis Patients during the COVID-19 Pandemic: Impact of Pre-pandemic Central Nervous System Sensitization.

To correlate pain-related phenotyping for central nervous system sensitization in endometriosis-associated pain with mental health outcomes during the COVID-19 pandemic, the prospective Endometriosis and Pelvic Pain Interdisciplinary Cohort (ClinicalTrials.gov #NCT02911090) was linked to the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex (RESPPONSE) dataset. The primary outcomes were depression (PHQ-9) and anxiety (GAD-7) scores during the pandemic. The explanatory variables of interest were the Central Sensitization Inventory (CSI) score (0-100) and endometriosis-associated chronic pain comorbidities/psychological variables before the pandemic. The explanatory and response variables were assessed for correlation, followed by multivariable regression analyses adjusting for PHQ-9 and GAD-7 scores pre-pandemic as well as age, body mass index, and parity. A higher CSI score and a greater number of chronic pain comorbidities before the pandemic were both positively correlated with PHQ-9 and GAD-7 scores during the pandemic. These associations remained significant in adjusted analyses. Increasing the CSI score by 10 was associated with an increase in pandemic PHQ-9 by .74 points (P < .0001) and GAD-7 by .73 points (P < .0001) on average. Each additional chronic pain comorbidity/psychological variable was associated with an increase in pandemic PHQ-9 by an average of .63 points (P = .0004) and GAD-7 by .53 points (P = .0002). Endometriosis patients with a history of central sensitization before the pandemic had worse mental health outcomes during the COVID-19 pandemic. As a risk factor for mental health symptoms in the face of major stressors, clinical proxies for central sensitization can be used to identify endometriosis patients who may need additional support. PERSPECTIVE: This article adds to the growing literature of the clinical importance of central sensitization in endometriosis patients, who had more symptoms of depression and anxiety during the COVID-19 pandemic. Clinical features of central sensitization may help clinicians identify endometriosis patients needing additional support when facing major stressors.

Sex steroids and the female brain across the lifespan: insights into risk of depression and Alzheimer's disease.

Despite widespread sex differences in prevalence and presentation of numerous illnesses affecting the human brain, there has been little focus on the effect of endocrine ageing. Most preclinical studies have focused on males only, and clinical studies often analyse data by covarying for sex, ignoring relevant differences between the sexes. This sex- (and gender)-neutral approach is biased and contributes to the absence of targeted treatments and services for all sexes (and genders). Female health has been historically understudied, with grave consequences for their wellbeing and health equity. In this Review, we spotlight female brain health across the lifespan by informing on the role of sex steroids, particularly oestradiol, on the female brain and on risk for diseases more prevalent in females, such as depression and Alzheimer's disease.

Higher perceived stress during the COVID-19 pandemic increased menstrual dysregulation and menopause symptoms.

BACKGROUND: The increased stress the world experienced with the coronavirus disease (COVID-19) pandemic affected mental health, disproportionately affecting females. However, how perceived stress in the first year affected menstrual and menopausal symptoms has not yet been investigated. OBJECTIVES: This study evaluates the effect that the first year of the COVID-19 pandemic had on female reproductive and mental health. METHODS: Residents in British Columbia, Canada, were surveyed online as part of the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex. A subgroup of participants (n = 4171), who were assigned female sex at birth (age 25-69 years) and were surveyed within the first 6-12 months of the pandemic (August 2020-February 2021), prior to the widespread rollout of vaccines, was retrospectively asked if they noticed changes in their menstrual or menopausal symptoms, and completing validated measures of stress, depression and anxiety. DESIGN: This is a population-based online retrospective survey. RESULTS: We found that 27.8% reported menstrual cycle disturbances and 6.7% reported increased menopause symptoms. Those who scored higher on perceived stress, depression and anxiety scales were more likely to report reproductive cycle disturbances. Free-text responses revealed that reasons for disturbances were perceived to be related to the pandemic. CONCLUSION: The COVID-19 pandemic has highlighted the need to research female-specific health issues, such as menstruation. Our data indicate that in the first year of the pandemic, almost one-third of the menstruating population reported disturbances in their cycle, which was related to percieved stress, depression and anxiety scores.

High estradiol reduces adult neurogenesis but strengthens functional connectivity within the hippocampus during spatial pattern separation in adult female rats.

Adult neurogenesis in the dentate gyrus plays an important role for pattern separation, the process of separating similar inputs and forming distinct neural representations. Estradiol modulates neurogenesis and hippocampus function, but to date no examination of estradiol's effects on pattern separation have been conducted. Here, we examined estrogenic regulation of adult neurogenesis and functional connectivity in the hippocampus after the spatial pattern separation task in female rats. Ovariectomized Sprague-Dawley rats received daily injections of vehicle, 0.32 µg (Low) or 5 µg (High) of estradiol benzoate until the end of experiment. A single bromodeoxyuridine (BrdU) was injected one day after initiation of hormone or vehicle treatment and rats were tested in the delayed nonmatching to position spatial pattern separation task in the 8-arm radial maze for 12 days beginning two weeks after BrdU injection. Rats were perfused 90 min after the final trial and brain sections were immunohistochemically stained for BrdU/neuronal nuclei (NeuN) (new neurons), Ki67 (cell proliferation), and the immediate early gene, zif268 (activation). Results showed that high, but not low, estradiol reduced the density of BrdU/NeuN-ir cells and had significant inter-regional correlations of zif268-ir cell density in the hippocampus following pattern separation. Estradiol treatment did not influence pattern separation performance or strategy use. These results show that higher doses of estradiol can reduce neurogenesis but at the same time increases correlations of activity of neurons within the hippocampus during spatial pattern separation.

Are we moving the dial? Canadian health research funding trends for women's health, 2S/LGBTQ + health, sex, or gender considerations.

BACKGROUND: Sex and gender impacts health outcomes and disease risk throughout life. The health of women and members of the Two-Spirit, Lesbian, Gay, Bisexual, Transgender, Queer or Questioning (2S/LGBTQ +) community is often compromised as they experience delays in diagnosis. Distinct knowledge gaps in the health of these populations have prompted funding agencies to mandate incorporation of sex and gender into research. Sex- and gender-informed research perspectives and methodology increases rigor, promotes discovery, and expands the relevance of health research. Thus, the Canadian Institutes of Health Research (CIHR) implemented a sex and gender-based analysis (SGBA) framework recommending the inclusion of SGBA in project proposals in 2010 and then mandating the incorporation of SGBA into grant proposals in 2019. To examine whether this mandate resulted in increased mention of sex or gender in funded research abstracts, we searched the publicly available database of grant abstracts funded by CIHR to analyze the percentage of abstracts that mentioned sex or gender of the population to be studied in the funded research. To better understand broader health equity issues we also examined whether the funded grant abstracts mentioned either female-specific health research or research within the 2S/LGBTQ + community. RESULTS: We categorized a total of 8,964 Project and Operating grant abstracts awarded from 2009 to 2020 based on their study of female-specific or a 2S/LGBTQ + populations or their mention of sex or gender. Overall, under 3% of grant abstracts funded by CIHR explicitly mentioned sex and/or gender, as 1.94% of grant abstracts mentioned sex, and 0.66% mentioned gender. As one of the goals of SGBA is to inform on health equity and understudied populations with respect to SGBA, we also found that 5.92% of grant abstracts mentioned female-specific outcomes, and 0.35% of grant abstracts focused on the 2S/LGBTQ + community. CONCLUSIONS: Although there was an increased number of funded grants with abstracts that mentioned sex and 2S/LGBTQ + health across time, these increases were less than 2% between 2009 and 2020. The percentage of funded grants with abstracts mentioning female-specific health or gender differences did not change significantly over time. The percentage of funding dollars allocated to grants in which the abstracts mentioned sex or gender also did not change substantially from 2009 to 2020, with grant abstracts mentioning sex or female-specific research increasing by 1.26% and 3.47%, respectively, funding allocated to research mentioning gender decreasing by 0.49% and no change for 2S/LGBTQ +-specific health. Our findings suggest more work needs to be done to ensure the public can evaluate what populations will be examined with the funded research with respect to sex and gender to advance awareness and health equity in research.

This paper examined the publicly available database of grant abstracts funded by the Canadian Institute of Health Research (CIHR) from 2009 to 2020 to determine the percentage of abstracts that mentioned sex or gender of the population to be studied. To better understand broader health equity issues we also examined whether the funded grant abstracts mentioned either female-specific health research or research within the 2S/LGBTQ + community. Although there was an increased number of funded grants with abstracts that mentioned sex and 2S/LGBTQ + health across time, these increases were less than 2% between 2009 and 2020. The percentage of funded grants with abstracts mentioning female-specific health or gender differences did not change significantly over time. The percentage of CIHR funding dollars allocated to grants in which the abstracts mentioned sex or female-specific research increased by 1.26% and 3.47%, respectively. However, funding allocated to research mentioning gender decreased by 0.49% and there was no significant change in funding amounts for 2S/LGBTQ +-specific health across time. We outline several recommendations for funding agencies to improve access to information especially on sex, gender and broader health equity populations to ensure the public can evaluate what populations will be examined within the funded research. Our findings suggest that to advance greater health equity in research, different strategies need to be employed to improve researcher utilization of sex and gender-based analysis as well as to advance health equity with respect to 2S/LGBTQ and women's health questions in research.

Beyond sex differences: short- and long-term effects of pregnancy on the brain.

Growing attention has been directed to the inclusion of females in neuroscience studies, and to the importance of studying sex as a biological variable. However, how female-specific factors such as menopause and pregnancy, affect the brain remains understudied. In this review, we use pregnancy as a case in point of a female-unique experience that can alter neuroplasticity, neuroinflammation, and cognition. We examine studies in both humans and rodents indicating that pregnancy can modify neural function in the short term, as well as alter the trajectory of brain aging. Furthermore, we discuss the influence of maternal age, fetal sex, number of pregnancies, and presence of pregnancy complications on brain health outcomes. We conclude by encouraging the scientific community to prioritize researching female health by recognizing and including factors such as pregnancy history in research.

Sex and BDNF Val66Met polymorphism matter for exercise-induced increase in neurogenesis and cognition in middle-aged mice.

Females show greater benefits of exercise on cognition in both humans and rodents, which may be related to brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP), the Val66Met polymorphism, within the human BDNF gene, causes impaired activity-dependent secretion of neuronal BDNF and impairments to some forms of memory. We evaluated whether sex and BDNF genotype (Val66Met polymorphism (Met/Met) versus wild-type (Val/Val)) influenced the ability of voluntary running to enhance cognition and hippocampal neurogenesis in mice. Middle-aged C57BL/6J (13 months) mice were randomly assigned to either a control or an aerobic training (AT) group (running disk access). Mice were trained on the visual discrimination and reversal paradigm in a touchscreen-based technology to evaluate cognitive flexibility. BDNF Met/Met mice had fewer correct responses compared to BDNF Val/Val mice on both cognitive tasks. Female BDNF Val/Val mice showed greater cognitive flexibility compared to male mice regardless of AT. Despite running less than BDNF Val/Val mice, AT improved performance in both cognitive tasks in BDNF Met/Met mice. AT increased neurogenesis in the ventral hippocampus of BDNF Val/Val mice of both sexes and increased the proportion of mature type 3 doublecortin-expressing cells in the dorsal hippocampus of female mice only. Our results indicate AT improved cognitive performance in BDNF Met/Met mice and increased hippocampal neurogenesis in BDNF Val/Val mice in middle age. Furthermore, middle-aged female mice may benefit more from AT than males in terms of neuroplasticity, an effect that was influenced by the BDNF Val66Met polymorphism.

Sex Differences in Cognition Across Aging.

Sex and gender differences are seen in cognitive disturbances in a variety of neurological and psychiatry diseases. Men are more likely to have cognitive symptoms in schizophrenia whereas women are more likely to have more severe cognitive symptoms with major depressive disorder and Alzheimer's disease. Thus, it is important to understand sex and gender differences in underlying cognitive abilities with and without disease. Sex differences are noted in performance across various cognitive domains - with males typically outperforming females in spatial tasks and females typically outperforming males in verbal tasks. Furthermore, there are striking sex differences in brain networks that are activated during cognitive tasks and in learning strategies. Although rarely studied, there are also sex differences in the trajectory of cognitive aging. It is important to pay attention to these sex differences as they inform researchers of potential differences in resilience to age-related cognitive decline and underlying mechanisms for both healthy and pathological cognitive aging, depending on sex. We review literature on the progressive neurodegenerative disorder, Alzheimer's disease, as an example of pathological cognitive aging in which human females show greater lifetime risk, neuropathology, and cognitive impairment, compared to human males. Not surprisingly, the relationships between sex and cognition, cognitive aging, and Alzheimer's disease are nuanced and multifaceted. As such, this chapter will end with a discussion of lifestyle factors, like education and diet, as modifiable factors that can alter cognitive aging by sex. Understanding how cognition changes across age and contributing factors, like sex differences, will be essential to improving care for older adults.

Sex differences in inflammation in the hippocampus and amygdala across the lifespan in rats: associations with cognitive bias.

BACKGROUND: Cognitive symptoms of major depressive disorder, such as negative cognitive bias, are more prevalent in women than in men. Cognitive bias involves pattern separation which requires hippocampal neurogenesis and is modulated by inflammation in the brain. Previously, we found sex differences in the activation of the amygdala and the hippocampus in response to negative cognitive bias in rats that varied with age. Given the association of cognitive bias to neurogenesis and inflammation, we examined associations between cognitive bias, neurogenesis in the hippocampus, and cytokine and chemokine levels in the ventral hippocampus (HPC) and basolateral amygdala (BLA) of male and female rats across the lifespan. RESULTS: After cognitive bias testing, males had more IFN-γ, IL-1ß, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1ß, IL-6, and IL-10 in the BLA than males. Middle-aged rats had more IL-13, TNF-α, and CXCL1 in both regions than younger groups. Adolescent male rats had higher hippocampal neurogenesis than adolescent females after cognitive bias testing and young rats that underwent cognitive bias testing had higher levels of hippocampal neurogenesis than controls. Neurogenesis in the dorsal hippocampus was negatively associated with negative cognitive bias in young adult males. CONCLUSIONS: Overall, the association between negative cognitive bias, hippocampal neurogenesis, and inflammation in the brain differs by age and sex. Hippocampal neurogenesis and inflammation may play greater role in the cognitive bias of young males compared to a greater role of BLA inflammation in adult females. These findings lay the groundwork for the discovery of sex-specific novel therapeutics that target region-specific inflammation in the brain and hippocampal neurogenesis.

Automated classification of estrous stage in rodents using deep learning.

The rodent estrous cycle modulates a range of biological functions, from gene expression to behavior. The cycle is typically divided into four stages, each characterized by distinct hormone concentration profiles. Given the difficulty of repeatedly sampling plasma steroid hormones from rodents, the primary method for classifying estrous stage is by identifying vaginal epithelial cell types. However, manual classification of epithelial cell samples is time-intensive and variable, even amongst expert investigators. Here, we use a deep learning approach to achieve classification accuracy at expert level. Due to the heterogeneity and breadth of our input dataset, our deep learning approach ("EstrousNet") is highly generalizable across rodent species, stains, and subjects. The EstrousNet algorithm exploits the temporal dimension of the hormonal cycle by fitting classifications to an archetypal cycle, highlighting possible misclassifications and flagging anestrus phases (e.g., pseudopregnancy). EstrousNet allows for rapid estrous cycle staging, improving the ability of investigators to consider endocrine state in their rodent studies.

Coping during the COVID-19 pandemic: A mixed methods approach to understand how social factors influence coping ability.

The COVID-19 pandemic and public health protection measures aimed at mitigating the transmission of the virus have both resulted in tremendous physical and mental health impacts. The study at hand used a gender-based analysis and social determinants of health approach to investigate which communities had trouble coping during times of strict protection measures and symptoms and strategies employed during the COVID-19 pandemic. Participants were recruited from previously established cohorts as a part of the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex (RESPPONSE) study. Being a young adult, female, woman, gender diverse, low-income earner or LGBTQ/2S+ was significantly associated with not being able to cope during the first wave of the pandemic. The effects for females, women, and gender diverse were attenuated yet still significant when controlling for various covariates. Those who reported not coping were more likely to present maladaptive coping symptoms and strategies. Our findings demonstrate the need to support marginalized communities in coping with the current ongoing COVID-19 pandemic and build proactive support for future pandemics.

Reshaping the path of mild cognitive impairment by refining exercise prescription: a study protocol of a randomized controlled trial to understand the "what," "for whom," and "how" of exercise to promote cognitive function.

BACKGROUND: Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. METHODS: Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). DISCUSSION: Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as "medicine" to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.

Characterizing intentions to receive the COVID-19 vaccine among the general population in British Columbia based on their future intentions towards the seasonal influenza vaccine.

Introduction: This study assessed the relationship between intention to receive a COVID-19 vaccine and intention to receive a seasonal influenza vaccine, as well as how intention to receive a COVID-19 vaccine has changed during the pandemic. Methods: Residents of British Columbia aged 25-69 years were invited to complete an online cross-sectional survey from August 2020 - March 2021. Mixed-effects logistic regression models assessed the relationship between intention to receive a COVID-19 vaccine and intention to receive the seasonal influenza vaccine. A generalized additive mixed model was used to investigate changes in COVID-19 vaccine intention during the pandemic (August 2020-March 2021). The relationship between intention to receive a COVID-19 vaccine and retrospective overall perceived value of vaccines prior to and during the pandemic was also considered. Results: Of 6,333 participants, 80.2 % of participants were 'somewhat or very likely' to receive a COVID-19 vaccine and 69 % of participants reported intending to receive a seasonal influenza vaccine. In multivariable modeling, intention to receive a COVID-19 vaccine was strongly associated with intention to receive a seasonal influenza vaccine (aOR = 4.25, 95 %CI 3.33-5.43). Intention to receive a COVID-19 vaccine increased over the study period (p < 0.0001), with the largest increase coinciding with the announcement of forthcoming approvals of COVID-19 vaccines in November 2020 (aOR = 1.45, 95 %CI 1.11-1.91). Conclusion: Intention to receive the COVID-19 vaccine was associated seasonal influenza vaccine intention, which is an important relationship to measure for implementation and future planning of COVID-19 booster doses. We found an increase in the intention to receive a COVID-19 vaccine after public announcements of forthcoming vaccine approval, which highlights the importance of ongoing monitoring and reporting of vaccine uptake, and the potential impact of emerging vaccine safety and efficacy information may have on vaccine acceptance.

Seropositivity of SARS-CoV-2 in an unvaccinated cohort in British Columbia, Canada: a cross-sectional survey with dried blood spot samples.

OBJECTIVES: Gathering population-based data on prevalence of SARS-CoV-2 infection is vital to the public health response and planning. Current seroprevalence data in BC are limited with respect to considerations of how socioeconomic and demographic factors, such as age, sex, gender, income, identifying as a visibility minority and occupation, are related to SARS-CoV-2 antibody detection due to infection-acquired immunity. We aimed to estimate the SARS-CoV-2 seropositivity in a cohort of British Columbians, using at-home self-collected dried blood spot (DBS) samples. DESIGN: This cross-sectional study included online surveys that collected sociodemographic and COVID-19 vaccine receipt information, and an at-home DBS collection kit. SETTING: British Columbia (BC), Canada. PARTICIPANTS: Eligible participants were aged 25-69 years and residents of BC. PRIMARY OUTCOME MEASURE: SARS-CoV-2 anti-spike IgG antibody detection in unvaccinated individuals. Adjusted incidence rate ratios (aIRR) explored factors associated with seropositivity. RESULTS: SARS-CoV-2 serology was performed on a total of 4048 unvaccinated participants 25-69 years of age who submitted DBS samples taken from November 2020 to June 2021. A total of 118 seropositive cases were identified, for an estimated overall seropositivity of 2.92% (95% CI 2.42% to 3.48%). Participants identifying as a visible minority had a higher seropositivity, 5.1% vs 2.6% (p=0.003), compared with non-visible minority participants. After adjustment by age and sex, identifying as a visible minority (aIRR=1.85, 95% CI 1.20 to 2.84) remained the only significant factor associated with SARS-CoV-2 antibody detection in this cohort of unvaccinated individuals. CONCLUSIONS: SARS-CoV-2 seropositivity in the BC population due to infection-acquired immunity was low. Seropositivity indicated that among those unvaccinated, visible minority communities have been most impacted. Continued monitoring of SARS-CoV-2 serology due to both infection-acquired and vaccine-acquired immunity will be vital in public health planning and pandemic response.

Sex differences in contextual pattern separation, neurogenesis, and functional connectivity within the limbic system.

BACKGROUND: Females are more likely to present with anxiety disorders such as post-traumatic stress disorder (PTSD) compared to males, which are associated with disrupted hippocampal integrity. Sex differences in the structure and function of hippocampus exist. Here, we examined sex differences in contextual pattern separation, functional connectivity, and activation of new neurons during fear memory. METHODS: Two-month-old male and female Sprague-Dawley rats were injected with the DNA synthesis markers, iododeoxyuridine (IdU) and chlorodeoxyuridine (CldU) 3 weeks and 4 weeks before perfusion, respectively. One week after CldU injection, the rats underwent a context discrimination task in which rats were placed in context A (shock) and context A' (no shock) every day for 12 days. On the test day, rats were placed in the shock context (context A) to measure fear memory and expression of zif268, an immediate early gene across 16 different limbic and reward regions. Repeated-measures or factorial analysis of variance was conducted on our variables of interest. Pearson product-moment calculations and principal component analyses on zif268 expression across regions were also performed. RESULTS: We found that females, but not males, showed contextual discrimination during the last days of training. On the test day, both sexes displayed similar levels of freezing, indicating equivalent fear memory for context A. Despite similar fear memory, males showed more positive correlations of zif268 activation between the limbic regions and the striatum, whereas females showed more negative correlations among these regions. Females showed greater activation of the frontal cortex, dorsal CA1, and 3-week-old adult-born dentate granular cells compared to males. CONCLUSIONS: These results highlight the importance of studying sex differences in fear memory and the contribution of adult neurogenesis to the neuronal network and may contribute to differences in susceptibility to fear-related disorders such as post-traumatic stress disorder. Highlights Female rats, but not male rats, show faster discrimination during a contextual pattern separation task. Three-week-old adult-born neurons are more active in response to fear memory in females compared to males. Females had greater neural activation compared to males in the frontal cortex and dorsal CA1 region of the hippocampus in response to fear memory. Males and females show distinct patterns in functional connectivity for fear memory across limbic regions. Males have many positive correlations between activated new neurons of different ages between the dorsal and ventral hippocampus, while females show more correlations between activated new neurons and other limbic regions.