Gender and Racial Diversity Among Obstetrics and Gynecology Departments and Gynecologic Oncology Divisions in Canada: Are We There Yet?

OBJECTIVES: Gender and racial diversity in academic Canadian departments of obstetrics and gynecology (OBGYN) have not been previously described. We examined gender representation in leadership in academic OBGYN departments and gynecologic oncology (GO) divisions, and determined factors predictive of leadership and promotion including racialized status. METHODS: This cross-sectional study of Canadian residency-affiliated academic OBGYN departments queried institutional websites in January 2021 to compile a list of academic faculty. Subjective gender was assessed using photographs and pronouns, and racialized status was determined using photographs. Logistic regression analyses determined predictive factors for leadership roles. Fassiotto et al. rank equity indices (REI) and Hofler et al. representation ratios were calculated. RESULTS: Within 16 Canadian institutions there were 354 (33.6%) men and 699 (66.4%) women, with 18.3% racialized faculty. Men were more likely to reach full professorship (P < 0.00001) and leadership positions of department chair, vice-chair or division head (P = 0.01). Representation ratios for women in OBGYN were <1 for all administrative leadership positions, and pairwise comparisons of the probability of promotion for women OBGYNs using REI reveal significant disparities between senior and junior administrative leadership and professorial ranks. Racialized physicians were less likely to have attained full professorship (P = 0.002). Ninety-seven academic GOs were identified: 68 (70.1%) were women, 17 (17.5%) racialized. Seven GO divisions (44%) had no racialized members. On multivariate analysis, only year of completion of fellowship was predictive of leadership. CONCLUSION: In academic Canadian OBGYN departments women are underrepresented in leadership and full professor positions. Racialized faculty are underrepresented in full professorship.

Exploring the use of experimental small area estimates to examine the relationship between individual-level and area-level community belonging and self-rated health.

Background: Small area estimation refers to statistical modelling procedures that leverage information or "borrow strength" from other sources or variables. This is done to enhance the reliability of estimates of characteristics or outcomes for areas that do not contain sufficient sample sizes to provide disaggregated estimates of adequate precision and reliability. There is growing interest in secondary research applications for small area estimates (SAEs). However, it is crucial to assess the analytic value of these estimates when used as proxies for individual-level characteristics or as distinct measures that offer insights at the area level. This study assessed novel area-level community belonging measures derived using small area estimation and examined associations with individual-level measures of community belonging and self-rated health. Data and methods: SAEs of community belonging within census tracts produced from the 2016-2019 cycles of the Canadian Community Health Survey (CCHS) were merged with respondent data from the 2020 CCHS. Multinomial logistic regression models were run between area-level SAEs, individual-level sense of community belonging, and self-rated health on the study sample of people aged 18 years and older. Results: Area-level community belonging was associated with individual-level community belonging, even after adjusting for individual-level sociodemographic characteristics, despite limited agreement between individual- and area-level measures. Living in a neighbourhood with low community belonging was associated with higher odds of reporting being in fair or poor health, versus being in very good or excellent health (odds ratio: 1.53; 95% confidence interval: 1.22, 1.91), even after adjusting for other factors such as individual-level sense of community belonging, which was also associated with self-rated health. Interpretation: Area-level and individual-level sense of community belonging were independently associated with self-rated health. The novel SAEs of community belonging can be used as distinct measures of neighbourhood-level community belonging and should be understood as complementary to, rather than proxies for, individual-level measures of community belonging.

Palliative care utilization across health sectors for patients with gynecologic malignancies in Ontario, Canada from 2006 to 2018.

OBJECTIVE: Early palliative care (PC) is associated with improved patient quality of life, less aggressive end-of-life care, and prolonged survival. We evaluated patterns of PC delivery in gynecologic oncology. METHODS: We conducted a population-based, retrospective cohort study of gynecologic cancer decedents in Ontario from 2006 to 2018 using linked administrative health care data. RESULTS: The cohort included 16,237 decedents; 51.1% died of ovarian cancer, 30.3% uterine cancer, 12.1% cervical cancer, and 6.5% vulvar/vaginal cancers. Palliative care was most often delivered in the hospital inpatient setting in 81%, and 53% received specialist PC. PC was first received during hospital admission in 53%, and by outpatient physician care in only 23%. Palliative care was initiated a median 193 days prior to death, with the lowest two quintiles initiating care ≤70 days before death. The average user of PC resources (third quintile) received 68 days of PC. While cumulative use of community PC gradually increased over the final year of life, institutional palliative care use exponentially rose from 12 weeks until death. On multivariable analyses, predictors of initiating palliative care during a hospital admission included age ≥70 years at death, ≤3 month cancer survival, having cervical or uterine cancer, not having a primary care provider, or being in the lowest 3 income quintiles. CONCLUSION: Most palliative care is initiated and delivered during hospital admission, and is initiated late in a significant proportion. Strategies to increase access to anticipatory and integrated palliative care may improve the quality of the disease course and the end of life.

A double-blinded, randomized trial comparing surgeon-administered transversus abdominis plane block with placebo after midline laparotomy in gynecologic oncology surgery.

BACKGROUND: Surgeon-administered transversus abdominis plane block is a contemporary approach to providing postoperative analgesia, and this approach is performed by transperitoneally administering local anesthetic in the plane between the internal oblique and transversus abdominis muscles to target the sensory nerves of the anterolateral abdominal wall. Although this technique is used in many centers, it has not been studied prospectively in patients undergoing a midline laparotomy. OBJECTIVE: This study aimed to evaluate whether surgeon-administered transversus abdominis plane block reduces postoperative opioid requirements and improves clinical outcomes. STUDY DESIGN: In this double-blind, randomized, placebo-controlled trial, patients with a suspected or proven gynecologic malignancy undergoing surgery through a midline laparotomy at 1 Canadian tertiary academic center were randomized to either the bupivacaine group (surgeon-administered transversus abdominis plane blocks with 40 mL of 0.25% bupivacaine) or the placebo group (surgeon-administered transversus abdominis plane blocks with 40 mL of normal saline solution) before fascial closure. The primary outcome was the total dose of opioids (in morphine milligram equivalents) received in the first 24 hours after surgery. The secondary outcomes included opioid doses between 24 and 48 hours, pain scores, postoperative nausea and vomiting, incidence of clinical ileus, time to flatus, and hospital length of stay. The exclusion criteria included contraindications to study medication, history of chronic opioid use, significant adhesions on the anterior abdominal wall preventing access to the injection site, concurrent nonabdominal surgical procedure, and the planned use of neuraxial anesthesia or analgesia. To detect a 20% decrease in opioid requirements with a 2-sided type 1 error of 5% and power of 80%, a sample size of 36 patients per group was calculated. RESULTS: From October 2020 to November 2021, 38 patients were randomized to the bupivacaine arm, and 41 patients were randomized to the placebo arm. The mean age was 60 years, and the mean body mass index was 29.3. A supraumbilical incision was used in 30 of 79 cases (38.0%), and bowel resection was performed in 10 of 79 cases (12.7%). Patient and surgical characteristics were evenly distributed. The patients in the bupivacaine group required 98.0±59.2 morphine milligram equivalents in the first 24 hours after surgery, whereas the patients in the placebo group required 100.8±44.0 morphine milligram equivalents (P=.85). The mean pain score at 4 hours after surgery was 3.1±2.4 (0-10 scale) in the intervention group vs 3.1±2.0 in the placebo group (P=.93). Clinically significant nausea or vomiting was reported in 1 of 38 patients (2.6%) in the intervention group vs 1 of 41 patients (2.4%) in the placebo group (P=.95). Time to first flatus, rates of clinical ileus, and length of stay were similar between groups. Subgroup analysis of patients with a body mass index of <25 and patients who received an infraumbilical incision showed similarly comparable outcomes. CONCLUSION: Surgeon-administered transversus abdominis plane block with bupivacaine was not found to be superior to the placebo intervention in reducing postoperative opioid requirements or improving other postoperative outcomes for patients undergoing a midline laparotomy. These results differed from previous reports evaluating the ultrasound-guided transversus abdominis plane block approach. Surgeon-administered transversus abdominis plane block should not be considered standard of care in postoperative multimodal analgesia.

The five-factor modified frailty index predicts adverse postoperative and chemotherapy outcomes in gynecologic oncology.

INTRODUCTION: Frailty is increasingly recognized as a predictor of postoperative morbidity and oncologic outcomes. Evidence of the predictive value of frailty assessment in gynecologic oncology remains sparse. OBJECTIVES: To evaluate the National Surgical Quality Improvement Program (NSQIP) comorbidity-based modified Frailty Index-5 (mFI-5) as predictor of severe postoperative complications, non-completion of chemotherapy and other patient-centered outcomes in gynecologic oncology patients >70 years-old undergoing surgery. METHODS: Prospectively-collected NSQIP data and retrospective chart review of patients undergoing elective laparotomies for gynecologic malignances at a tertiary academic center in Ontario, Canada, between 01/2016-09/2020 were reviewed. Primary outcome was rate of 30-day Clavien-Dindo (Clavien) grade III-V complications. Secondary outcomes included Clavien II-V complications, postoperative length of stay (LOS), non-home discharge and non-completion of chemotherapy. Logistic regression analyses and receiver-operator curves were performed. RESULTS: Two-hundred and fifty-nine patients were included; 103 were planned to receive adjuvant chemotherapy. Fifty-three patients (20.5%) had an mFI ≥ 2 and were categorized as frail. On multivariable analyses, frailty independently predicted grade III-V complications (OR 24.49, 95%CI 9.72-70.67, p < 0.0001), grade II-V complications (OR 4.64, 95%CI 2.31-9.94, p < 0.0001), non-home discharge (OR 7.37, 95%CI 2.81-20.46, p < 0.0001), LOS ≥ 7d (OR 3.6, 95% CI 1.54-8.6, p = 0.003) and non-completion of chemotherapy (OR 8.42, 95%CI 2.46-32.79, p = 0.001). Adjusted C-statistics demonstrated strong predictive value of the mFI-5 for grade III-V (0.92, 95%CI 0.86-0.97) and grade II-V (0.74, 95%CI 0.68-0.8) complications as well as non-home discharge (0.86, 95%CI 0.78-0.95) and chemotherapy non-completion (0.87, 95%CI 0.8-0.95). CONCLUSION: Frailty as assessed with the mFI-5 predicted adverse postoperative and chemotherapy outcomes in gynecologic oncology patients aged ≥70 undergoing a laparotomy. The mFI-5 is a concise tool that can be used for routine frailty screening and risk stratification.

Trends in quality indicators of end-of-life care for women with gynecologic malignancies in Ontario, Canada.

OBJECTIVE: A large body of research has validated several quality indicators of end-of-life (EOL) cancer care, but few have examined these in gynecologic cancer at a population-level. We examined patterns of EOL care quality in patients with gynecologic cancers across 13 years in Ontario, Canada. METHODS: We conducted a population-based, retrospective cohort study of gynecologic cancer decedents in Ontario from 2006 to 2018 using linked administrative health care databases. Proportions of quality indices were calculated, including: emergency department (ED) use, hospital or intensive care unit (ICU) admission, chemotherapy ≤14 days of death, cancer-related surgery, tube or intravenous feeds, palliative home visits, and hospital death. We used multivariable logistic regression to examine factors associated with receipt of aggressive and supportive care. RESULTS: There were 16,237 included decedents over the study period; hospital death rates decreased from 47% to 37%, supportive care use rose from 65% to 74%, and aggressive care remained stable (16%). Within 30 days of death, 50% were hospitalized, 5% admitted to ICU, and 67% accessed palliative homecare. Within 14 days of death, 31% visited the ED and 4% received chemotherapy. Patients with vulvovaginal cancers received the lowest rates of aggressive and supportive care. Using multivariable analyses, factors associated with increased aggressive EOL care use included younger age, shorter disease duration, lower income quintiles, and rural residence. CONCLUSIONS: Over time, less women dying with gynecologic cancers in Ontario experienced death in hospital, and more accessed supportive care. However, the majority were still hospitalized and a significant proportion received aggressive care in the final 30 days of life.

Gender imbalance in gynecologic oncology authorship and impact of COVID-19 pandemic.

OBJECTIVE: Despite increased participation of women in academic medicine in recent decades, gender disparities persist. The gender gap in authorship and editorial boards in gynecologic oncology, and impact of the COVID-19 pandemic, have not been recently evaluated. We examined gender representation and the impact of COVID-19 on authorship and editorial boards of two major peer-reviewed gynecologic oncology journals. METHODS: We conducted a bibliometric analysis of original articles published in Gynecologic Oncology and the International Journal of Gynecological Cancer, comparing the most contemporary 5-year period (2016-2020) to single years in the two prior decades (1996, 2006). To assess the early impact of COVID-19, we compared publications from May 2020-April 2021 to 2019. Editorial boards were analyzed for gender composition. First names, pronouns, and institutional photographs were used to determine gender. RESULTS: There were 3022 original articles published between 2016 and 2020, 763 in 2006, and 203 in 1996. Gender was identified for 91.3% of first authors (3641 articles) and 95.6% of senior authors (3813 articles). Men comprised the majority of the editorial boards in 2021 at 57% and 61% for Gynecologic Oncology and the International Journal of Gynecological Cancer, respectively. Men were overrepresented as senior authors across all study periods: 93% in 1996, 77% in 2006, and 58% in 2016-2020. Over time, representation of women as first and senior authors increased (7% in 1996, 42% in 2016-2020, p<0.00001). There was no immediate impact of the early pandemic on gender distribution of authorship. CONCLUSIONS: Despite greater representation of women over time as authors in gynecologic oncology journals, there remains gender disparity in senior authorship and editorial board representation. This presents an opportunity for the academic publishing community to advocate for deliberate strategies to achieve gender parity. Although no impact of the early COVID-19 pandemic was found, this requires ongoing surveillance.

Evaluating the diagnostic performance of preoperative endometrial biopsies in patients diagnosed with high grade endometrial cancer: A study of the Society of Gynecologic Oncology (GOC) Community of Practice (CoP).

BACKGROUND: High grade cancers account for a disproportionate number of recurrences in patients with endometrial cancer. Accurately identifying these cases on endometrial biopsies allows for better surgical planning. This study evaluates the diagnostic accuracy of general pathologists (GP) compared to gynecological pathologists (GYNP) in interpreting preoperative biopsies. METHODS: A retrospective cohort study was conducted of patients diagnosed with high grade endometrial cancer (HGEC) between 2012 and 2016 at eight Canadian cancer centres. Data was collected from medical records. Pre-operative biopsies were categorized into groups; biopsies read by GP, GYNP and GP reviewed by GYNP. Rates of HGEC on pre-operative biopsy were calculated. Fisher exact test was used to compare differences between the groups. Univariate logistic regression analysis was conducted for HGEC prediction. RESULTS: Of 1237 patients diagnosed with HGEC, 245 (19.8%) did not have a preoperative diagnosis of high-grade disease. Discordancy was identified in 91/287 (31.71%) of biopsies reported by GP, and in 114/910 (12.53%) of biopsies reported by a GYNP (p < 0.0001). Compared to GP, GYNP were 3.24 (CI 2.36-4.45) times more likely to identify high grade disease on preoperative biopsy. Patients whose biopsy was reported by a GYNP were more likely to have a comprehensive staging procedure (OR 1.77 CI 1.33-2.38) and less likely to receive adjuvant therapy (OR 0.71 CI 0.52-0.96). CONCLUSION: GYNP are more likely to identify HGEC on pre-operative biopsies. Due to high rates of overall discordancy, it is possible that surgical staging procedures should not be based solely on preoperative biopsy. Further strategies to improve pre-operative biopsies' accuracy are needed.

Crossed Cerebellar Atrophy in Perinatal Stroke.

Background and Purpose- Perinatal stroke causes most hemiparetic cerebral palsy and lifelong disability. Crossed cerebellar atrophy (CCA) is chronic cerebellar volume loss following contralateral motor pathway injury. We hypothesized that CCA is quantifiable in perinatal stroke and associated with poor motor outcome. Methods- Term-born children with perinatal stroke, magnetic resonance imaging beyond 6 months of age, and no additional neurological disorders were recruited. Blinded scorers measured cerebellar volumes expressed as ratios (contralesional/ipsilesional), with values <1 suggesting CCA. Motor outcomes including perinatal stroke outcome measure (PSOM) motor and cognitive scores (good/poor), Assisting Hand Assessment, and Melbourne Assessment were compared with cerebellar volume measures. Results- Seventy-three children met criteria (53% male). Mean cerebellar ratios were <1.0 (0.975±0.04; range, 0.885-1.079; P<0.001) suggesting occurrence of CCA. Cerebellar ratios did not differ between stroke types or across PSOM motor outcomes. Larger ipsilesional cerebellar volume was associated with poor PSOM cognitive outcome (P=0.042), possibly with poor PSOM motor outcome (P=0.063), and overall PSOM score (P=0.034). Conclusions- CCA occurs in perinatal stroke but is not strongly associated with motor outcome. However, ipsilesional cerebellar volume is associated with poor cognitive and overall outcomes.

DNA methylation profiling in human Huntington's disease brain.

Despite extensive progress in Huntington's disease (HD) research, very little is known about the association of epigenetic variation and HD pathogenesis in human brain tissues. Moreover, its contribution to the tissue-specific transcriptional regulation of the huntingtin gene (HTT), in which HTT expression levels are highest in brain and testes, is currently unknown. To investigate the role of DNA methylation in HD pathogenesis and tissue-specific expression of HTT, we utilized the Illumina HumanMethylation450K BeadChip array to measure DNA methylation in a cohort of age-matched HD and control human cortex and liver tissues. In cortex samples, we found minimal evidence of HD-associated DNA methylation at probed sites after correction for cell heterogeneity but did observe an association with the age of disease onset. In contrast, comparison of matched cortex and liver samples revealed tissue-specific DNA methylation of the HTT gene region at 38 sites (FDR < 0.05). Importantly, we identified a novel differentially methylated binding site in the HTT proximal promoter for the transcription factor CTCF. This CTCF site displayed increased occupancy in cortex, where HTT expression is higher, compared with the liver. Additionally, CTCF silencing reduced the activity of an HTT promoter-reporter construct, suggesting that CTCF plays a role in regulating HTT promoter function. Overall, although we were unable to detect HD-associated DNA methylation alterations at queried sites, we found that DNA methylation may be correlated to the age of disease onset in cortex tissues. Moreover, our data suggest that DNA methylation may, in part, contribute to tissue-specific HTT transcription through differential CTCF occupancy.

A pooling-based approach to mapping genetic variants associated with DNA methylation.

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.

The early care environment and DNA methylome variation in childhood.

Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes.

Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained ∼25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation.

Epigenetic correlates of neonatal contact in humans.

Animal models of early postnatal mother-infant interactions have highlighted the importance of tactile contact for biobehavioral outcomes via the modification of DNA methylation (DNAm). The role of normative variation in contact in early human development has yet to be explored. In an effort to translate the animal work on tactile contact to humans, we applied a naturalistic daily diary strategy to assess the link between maternal contact with infants and epigenetic signatures in children 4-5 years later, with respect to multiple levels of child-level factors, including genetic variation and infant distress. We first investigated DNAm at four candidate genes: the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), µ-opioid receptor M1 (OPRM1) and oxytocin receptor (OXTR; related to the neurobiology of social bonds), and brain-derived neurotrophic factor (BDNF; involved in postnatal plasticity). Although no candidate gene DNAm sites significantly associated with early postnatal contact, when we next examined DNAm across the genome, differentially methylated regions were identified between high and low contact groups. Using a different application of epigenomic information, we also quantified epigenetic age, and report that for infants who received low contact from caregivers, greater infant distress was associated with younger epigenetic age. These results suggested that early postnatal contact has lasting associations with child biology.

The International Incidence of Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Understanding the epidemiology of traumatic brain injury (TBI) is essential to shape public health policy, implement prevention strategies, and justify allocation of resources toward research, education, and rehabilitation in TBI. There is not, to our knowledge, a systematic review of population-based studies addressing the epidemiology of TBI that includes all subtypes. We performed a comprehensive systematic review and meta-analysis of the worldwide incidence of TBI. METHODS: A search was conducted on May 23, 2014, in Medline and EMBASE according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Abstracts were screened independently and in duplicate to identify original research. Study quality and ascertainment bias were assessed in duplicate using a previously published tool. Demographic data and incidence estimates from each study were recorded, along with stratification by age, gender, year of data collection, and severity. RESULTS: The search strategy yielded 4944 citations. Two hundred and sixteen articles met criteria for full-text review; 144 were excluded. Hand searching resulted in ten additional articles. Eighty-two studies met all eligibility criteria. The pooled annual incidence proportion for all ages was 295 per 100,000 (95% confidence interval: 274-317). The pooled incidence rate for all ages was 349 (95% confidence interval: 96.2-1266) per 100,000 person-years. Incidence proportion and incidence rate were examined to see if associated with age, sex, country, or severity. CONCLUSIONS: We conclude that most TBIs are mild and most TBIs occur in males among the adult population. The incidence of TBI varies widely by ages and between countries. Despite being an important medical, economic, and social problem, the global epidemiology of TBI is still not well-characterized in the current literature. Understanding the incidence of TBI, particularly mild TBI, remains challenging because of nonstandardized reporting among neuroepidemiological studies.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism influences the association of the methylome with maternal anxiety and neonatal brain volumes.

Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.

A national cohort study of community belonging and its influence on premature mortality.

BACKGROUND: Community belonging, an important constituent of subjective well-being, is an important target for improving population health. Ageing involves transitioning across different social conditions thus, community belonging on health may vary across the life course. Using a nationally representative cohort, this study estimates the life stage-specific impact of community belonging on premature mortality. METHODS: Six cycles of the Canadian Community Health Survey (2000-2012) were combined and linked to the Canadian Vital Statistics Database (2000-2017). Respondents were followed for up to 5 years. Multivariable-adjusted modified Poisson regression models were used to estimate the relative risk of premature mortality for three life stages: early adulthood (18-35 years), middle adulthood (36-55 years) and late adulthood (56-70 years). RESULTS: The final analytical sample included 477 100 respondents. Most reported a 'somewhat strong' sense of belonging (45.9%). Compared with their 'somewhat strong' counterparts, young adults reporting a 'somewhat weak' sense of belonging exhibited an increased relative risk (RR) of 1.76 (95% CI 1.27 to 2.43) for premature mortality, whereas middle-aged adults reporting the same exhibited a decreased RR of 0.82 (95% CI 0.69, 0.98). Among older adults, groups reporting a 'very strong' (RR 1.10, 95% CI 1.01, 1.21) or a 'very weak' sense (RR 1.14, 95% CI 1.01, 1.28) of belonging exhibited higher RRs for premature mortality. CONCLUSION: The results demonstrate how community belonging relates to premature mortality differs across age groups underscoring the importance of considering life stage-specific perspectives when researching and developing approaches to strengthen belonging.

Cerebellar atrophy in childhood arterial ischemic stroke: acute diffusion MRI biomarkers.

BACKGROUND AND PURPOSE: Crossed cerebellar atrophy is uncommon in childhood arterial ischemic stroke. Acute corticospinal tract diffusion-weighted imaging (CST-DWI) changes occur in stroke of all ages. Contralateral CST-DWI is unexplained but approximates corticopontocerebellar pathways. We hypothesized that cerebellar atrophy can be quantified on clinical neuroimaging in childhood arterial ischemic stroke and is predicted by contralesional CST-DWI. METHODS: Consecutive children (>28 days-18 years) were included with the following features: (1) acute, unilateral, middle cerebral artery arterial ischemic stroke, (2) DWI <14 days from stroke onset, (3) anatomic T1 MRI >6 months, and (4) Pediatric Stroke Outcome Measure >12 months. Blinded scorers measured cerebellar volumes (left/right/hemisphere/vermis/total) using Osirix software. Cerebellar volumes ratios (nonstroke/stroke) were expressed as asymmetry indices (AI), with chronic/acute ratio <1.0 suggesting crossed atrophy. Acute brain stem and cerebellum (peduncle, hemisphere) DWI ratios were scored. Software measures were compared with visual inspection. Associations between AI, motor outcome (good/poor), and contralesional CST-DWI were sought. Rater reliabilities were assessed. RESULTS: Twenty-three children were studied (median age, 6.3±4.4 years; 62% male). Baseline cerebellar volumes were comparable (right=56.9 cm(3), left=57.1 cm(3)). Cerebellar atrophy was suggested across the sample with overall AI <1.0 (0.973±0.05; P=0.009). Visual atrophy detection was specific (≈100%) but insensitive (54%). Children with poor motor outcome did not have lower AI (0.983±0.027 versus 0.965±0.068; P=0.40); however, children with acute contralesional CST-DWI did (0.928±0.078 versus 986±0.040; P=0.03). Acute cerebellar DWI did not predict atrophy. Rater reliabilities were excellent (>0.92). CONCLUSIONS: Cerebellar atrophy can be demonstrated on MRI in childhood arterial ischemic stroke. Association with acute contralesional pontine DWI signal suggests early degeneration of corticopontocerebellar connections. The clinical significance of cerebellar atrophy in childhood stroke remains to be determined.

Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells.

Processing of pre-miRNA through Dicer1 generates an miRNA duplex that consists of an miRNA and miRNA* strand. Despite the general view that miRNA*s have no functional role, we further investigated miRNA* species in 10 deep-sequencing libraries from mouse and human tissue. Comparisons of miRNA/miRNA* ratios across the miRNA sequence libraries revealed that 50% of the investigated miRNA duplexes exhibited a highly dominant strand. Conversely, 10% of miRNA duplexes showed a comparable expression of both strands, whereas the remaining 40% exhibited variable ratios across the examined libraries, as exemplified by miR-223/miR-223* in murine and human cell lines. Functional analyses revealed a regulatory role for miR-223* in myeloid progenitor cells, which implies an active role for both arms of the miR-223 duplex. This was further underscored by the demonstration that miR-223 and miR-223* targeted the insulin-like growth factor 1 receptor/phosphatidylinositol 3-kinase axis and that high miR-223* levels were associated with increased overall survival in patients with acute myeloid leukemia. Thus, we found a supporting role for miR-223* in differentiating myeloid cells in normal and leukemic cell states. The fact that the miR-223 duplex acts through both arms extends the complexity of miRNA-directed gene regulation of this myeloid key miRNA.

Cervical PEComa: Challenges in diagnosis and prognosis of a rare neoplasm.

•Cervical PEComas are rare neoplasms which present a diagnostic challenge.•Large tumour size is an important clinical prognosticator in cervical PEComa.•All reported cases of cervical PEComa classified as benign by Folpe criteria behaved in benign fashion clinically.•Tumours ≤ 4 cm may be assessed with cone biopsy, and simple hysterectomy considered if no adverse pathologic features.•Molecular characterization and linkage with coordinated rare tumour registries may identify novel treatments.