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Objective: To evaluate the change in consumption of specific antibiotics in a neonatal intensive care unit after the implementation of an antimicrobial stewardship program (ASP). Design: Retrospective cohort study between January 1, 2010, and December 31,2019. Setting: The neonatal intensive care unit at British Columbia Women’s Hospital (Vancouver Canada), a tertiary-care center. Patients: Admitted neonates prescribed antibiotics. Methods: We implemented an ASP with an early implementation phase starting in January 2014 (period 2) and a later phase starting in January 2017 (period 3). Patient demographics were collected, including birth weight, gestational age, history of necrotizing enterocolitis (NEC), and surgical operations from existing databases. Interrupted time-series analysis was used, and comparison of antibiotic days of therapy (DOT) averages were conducted across the preimplementation period (period 1), period 2, and period 3 regarding total patients and subgroups. Results: We identified 4,512 infants. There was a significant decrease in DOT from 472 (95% confidence interval [CI], 431–517) in period 1 to 405 (95% CI, 367–446) in period 2 to 313 (95% CI, 280–350) in period 3. We detected a significant decrease in the use of ampicillin, aminoglycosides, cloxacillin, and linezolid but not in vancomycin or cefotaxime. Subgroup analyses of infants Conclusions: The implementation of an ASP was associated with a significant decrease in the overall DOT and use of certain antibiotics. This study presents important targets for ongoing ASP work.

Background Multiple contraindications to combined hormonal contraceptives (CHC) use exist. The impact of these factors on contraceptive choice, particularly among women living with HIV (WLWH), is not well understood. We measured and compared the prevalence of contraceptive use and contraindications among WLWH and women not living with HIV (controls). Methods We examined cross-sectional survey and medical chart data from 83 WLWH and 62 controls, aged 16–49 and sexually active, from 2013–2017. We compared the age-adjusted prevalence and types of contraceptives used in the last month and the proportion of women with CHC contraindications, including drug interactions, medical comorbidities, and smoking at ≥ 35 years old. All WLWH received care at an interdisciplinary, women-centred HIV clinic. Results Compared to controls, WLWH were older (median [IQR)] 39 [34–43] vs 31 [23–41] years; p = 0.003), had less post-secondary education (37% vs 73%; p, Plain language summary Background There are many reasons why individuals cannot use combined hormonal contraceptives (CHC). The impact of these reasons on contraceptive choice for women living with HIV (WLWH) are poorly understood. We measured and compared the prevalence of contraceptive choice and factors that may preclude their use in WLWH. Methods We examined survey and medical chart data from 83 WLWH and 62 controls (women not living with HIV), aged 16–49 and sexually active, from 2013 to 2017. We compared the prevalence and types of contraceptives used in the last month and the proportion of women with factors that would not allow the use of CHC, including drug interactions, medical conditions, and smoking at ≥ 35 years old. All WLWH received care at a women-centred HIV clinic. Results Compared to controls, WLWH were older, had less post-secondary education, and more often had household income

The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identifiedDown syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function. Indscaml1mutant animals, hypothalamic CRH neurons had highercrhb(the CRH homolog in fish) expression, increased cell number, and reduced cell death compared to wild-type controls. Physiologically,dscaml1mutant animals had higher baseline stress hormone (cortisol) levels and attenuated responses to acute stressors. Together, these findings identifydscaml1as an essential factor for stress axis development and suggest that HPA axis dysregulation may contribute to the etiology of humanDSCAML1-linked neuropsychiatric disorders.

ObjectiveThe increased stress the globe has experienced with the COVID-19 pandemic has affected mental health, disproportionately affecting women. However, how perceived stress in the first year affected menstrual and menopausal symptoms has not yet been investigated.MethodsResidents 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 (RESPPONSE). A subgroup (n=4171) who were assigned female sex at birth (age 25-69) and were surveyed within the first 6-12 months of the pandemic (August 2020-February 2021), prior to the widespread rollout of vaccines, were retrospectively asked if they noticed changes in their menstrual or menopausal symptoms, as well as completing validated measures of stress, depression, and anxiety.ResultsWe 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 have reproductive cycle disturbances. Free text responses revealed that reasons for disturbances were perceived to be related to the pandemic.ConclusionsThe COVID-19 pandemic has highlighted the need to research women’s health issues, such as menstruation. Our data indicates that in the first year of the pandemic, almost a third of the menstruating population reported disturbances in their cycle, which is approximately two times higher than in non-pandemic situations and four times higher than any reported changes in menopausal symptoms across that first year of the pandemic.Summary SentencesWomen+ with higher anxiety, depression or perceived stress scores during the first year of the pandemic were more likely to have experienced menstrual cycle phase disturbance or menopausal status disruption. Younger women were particularly prone to disturbances in their reproductive cycles.

Background Women living with HIV (WLWH) experience higher rates of human papillomavirus (HPV) infection and cervical cancer than women without HIV. Changes in the vaginal microbiome have been implicated in HPV-related disease processes such as persistence of high-risk HPV infection but this has not been well defined in a population living with HIV. Methods Four hundred and 20 girls and WLWH, age ≥9, across 14 clinical sites in Canada were enrolled to receive three doses of quadrivalent HPV vaccine for assessment of vaccine immunogenicity. Blood, cervical cytology, and cervico-vaginal swabs were collected. Cervico-vaginal samples were tested for HPV DNA and underwent microbiota sequencing. Results Principal component analysis (PCA) and hierarchical clustering generated community state types (CSTs). Relationships between taxa and CSTs with HPV infection were examined using mixed-effects logistic regressions, Poisson regressions, or generalized linear mixed-effects models, as appropriate. Three hundred and fifty-six cervico-vaginal microbiota samples from 172 women were sequenced. Human papillomavirus DNA was detected in 211 (59%) samples; 110 (31%) contained oncogenic HPV. Sixty-five samples (18%) were taken concurrently with incident oncogenic HPV infection and 56 (16%) were collected from women with concurrent persistent oncogenic HPV infection. Conclusions No significant associations between taxa, CST, or microbial diversity and HPV-related outcomes were found. However, we observed weak associations between a dysbiotic microbiome and specific species, including Gardnerella, Porphyromonas, and Prevotella species, with incident HPV infection.

IMPORTANCE: There are limited high-quality, population-level data about the effect of SARS-CoV-2 infection on pregnancy using contemporaneous comparator cohorts. OBJECTIVES: To describe maternal and perinatal outcomes associated with SARS-CoV-2 infection in pregnancy and to assess variables associated with severe disease in the pregnant population. DESIGN, SETTING, AND PARTICIPANTS: CANCOVID-Preg is an observational surveillance program for SARS-CoV-2–affected pregnancies in Canada. This analysis presents exploratory, population-level data from 6 Canadian provinces for the period of March 1, 2020, to October 31, 2021. A total of 6012 pregnant persons with a positive SARS-CoV-2 polymerase chain reaction test result at any time in pregnancy (primarily due to symptomatic presentation) were included and compared with 2 contemporaneous groups including age-matched female individuals with SARS-CoV-2 and unaffected pregnant persons from the pandemic time period. EXPOSURE: SARS-CoV-2 infection during pregnancy. Incident infections in pregnancy were reported to CANCOVID-Preg by participating provinces/territories. MAIN OUTCOMES AND MEASURES: Maternal and perinatal outcomes associated with SARS-CoV-2 infection as well as risk factors for severe disease (ie, disease requiring hospitalization, admission to an intensive care unit/critical care unit, and/or oxygen therapy). RESULTS: Among 6012 pregnant individuals with SARS-CoV-2 in Canada (median age, 31 [IQR, 28-35] years), the greatest proportion of cases were diagnosed at 28 to 37 weeks’ gestation (35.7%). Non-White individuals were disproportionately represented. Being pregnant was associated with a significantly increased risk of SARS-CoV-2–related hospitalization compared with SARS-CoV-2 cases among all women aged 20 to 49 years in the general population of Canada (7.75% vs 2.93%; relative risk, 2.65 [95% CI, 2.41-2.88]) as well as an increased risk of intensive care unit/critical care unit admission (2.01% vs 0.37%; relative risk, 5.46 [95% CI, 4.50-6.53]). Increasing age, preexisting hypertension, and greater gestational age at diagnosis were significantly associated with worse maternal outcomes. The risk of preterm birth was significantly elevated among SARS-CoV-2–affected pregnancies (11.05% vs 6.76%; relative risk, 1.63 [95% CI, 1.52-1.76]), even in cases of milder disease not requiring hospitalization, compared with unaffected pregnancies during the same time period. CONCLUSIONS AND RELEVANCE: In this exploratory surveillance study conducted in Canada from March 2020 to October 2021, SARS-CoV-2 infection during pregnancy was significantly associated with increased risk of adverse maternal outcomes and preterm birth.

This study sought to examine how access to contraception and cervical and breast cancer screening in British Columbia, Canada, has been affected by the COVID-19 pandemic.From August 2020 to March 2021, 3691 female residents of British Columbia (age 25-69 y) participated in this study. We used generalized estimating equations to analyze the proportion of females accessing contraception and the proportion having difficulty accessing contraception across the different phases of pandemic control measures, and logistic regression to analyze attendance at cervical and breast cancer screening. We added sociodemographic and biological variables individually into the models. Self-reported barriers to accessing contraception and attending screening were summarized.During phases with the highest pandemic controls, self-reported access to contraception was lower (OR 0.94; 95% CI 0.90-0.98; P = 0.005) and difficulty with access was higher (OR 2.74; 95% CI 1.54-4.88; P = 0.001). A higher proportion of adults aged 25-34 years reported difficulty accessing contraception than those aged 35-39 years (Plt; 0.0001), and participants identifying as Indigenous had higher odds of access difficulties (OR 5.56; 95% CI 2.44-12.50; P lt; 0.001). Of those who required screening during the COVID-19 pandemic, 62% and 54.5% did not attend at least one of their cervical or breast screening appointments, respectively. Those with a history of breast cancer had significantly higher odds of self-reporting having attended their mammogram appointment compared with those without a history of breast cancer (OR 5.62; 95% CI 2.69-13.72; Plt; 0.001). The most common barriers to screening were difficulty getting an appointment and appointments being considered non-urgent.The COVID-19 pandemic has uniquely affected access to contraception and cancer screening participation for various subgroups. Self-reported data present potential avenues for mitigating barriers.

Occiput posterior is the most common malposition in labor. Deliveries in occiput posterior position have been shown to have higher rates of adverse short-term maternal and neonatal outcomes compared with deliveries in occiput anterior position. There are no guidelines providing recommendations nor summarizing risks of adverse outcomes by delivery method to inform the decision-making process in occiput posterior delivery management. Population-based studies examining the outcomes associated with various management processes of occiput posterior position at the time of labor or delivery are lacking.This study aimed to describe the current management of term singleton occiput posterior deliveries in British Columbia, Canada and to examine the association between different management strategies and adverse outcomes by describing the rates of: occiput posterior malposition; and spontaneous vaginal delivery, operative vaginal delivery, and cesarean delivery from occiput posterior malposition. We also analyzed the rates of adverse labor and delivery outcomes stratified by fetal position and delivery mode, and the interaction effect of occiput posterior position and delivery mode on the rates of adverse outcomes.This was a retrospective cohort study of cephalic term singleton deliveries in British Columbia from 2004 to 2020, using the British Columbia Perinatal Data Registry. The obstetrical adverse outcome index (a composite of 10 adverse maternal or neonatal events), adverse outcome index subcomponent rates, and adverse outcome index-derived weighted scores were compared between deliveries stratified by fetal position at delivery (occiput posterior or occiput anterior) and occiput posterior deliveries stratified by delivery method. Multivariable log-binomial logistic regression was used to model the adverse outcome index score.Of 306,237 term births, 19% had occiput posterior position during labor, 37% of which persisted in occiput posterior position at delivery. Among occiput posterior deliveries, 27% were spontaneous vaginal deliveries, 8% vacuum, 5% forceps, 1% mixed vacuum-forceps, and 59% were cesarean delivery; this distribution differed from that of occiput anterior deliveries (One in five singleton deliveries at term gestation had occiput posterior position in labor; most of these rotated to occiput anterior by delivery, which had better outcomes than persistent occiput posterior deliveries. Among the latter, spontaneous vaginal delivery and cesarean delivery had the lowest frequency of adverse outcomes, whereas forceps deliveries had the highest. This study provides a robust updated analysis of birth outcomes following different occiput posterior management strategies, which can inform provider decision-making and counseling. Its observational design may limit its use for direct recommendations for management of occiput posterior malposition, yet the study helps to define the risks associated with different modes of delivery in the setting of occiput posterior malposition. With additional studies examining success rates of intermediate occiput posterior-occiput anterior rotation, other delivery management steps, and long-term outcomes, this study helps to define safe management of occiput posterior delivery.

In contrast to traditional classifications of emotion regulation (ER) strategies as either uniformly maladaptive or adaptive, recent theoretical models emphasize that adaptability is determined by greater ERThe online version contains supplementary material available at 10.1007/s42761-022-00132-7.

Sex differences exist in many neurological and psychiatric diseases, but these have not always been addressed adequately in research. In order to address this, it is necessary to consider how sex is incorporated into the design (e.g. using a balanced design) and into the analyses (e.g. using sex as a covariate) in the published literature. We surveyed papers published in 2009 and 2019 across six journals in neuroscience and psychiatry. In this sample, we find a 30% increase in the percentage of papers reporting studies that included both sexes in 2019 compared with 2009. Despite this increase, in 2019 only 19% of papers in the sample reported using an optimal design for discovery of possible sex differences, and only 5% of the papers reported studies that analysed sex as a discovery variable. We conclude that progress to date has not been sufficient to address the importance of sex differences in research for discovery and therapeutic potential for neurological and psychiatric disease.

An emerging area of interest in Neuroscience is the cellular relationship between glia and blood vessels, as many of the presumptive support roles of glia require an association with the vasculature. These interactions are best studied in vivo and great strides have been made using mice to longitudinally image glial-vascular interactions. However, these methods are cumbersome for developmental studies, which could benefit from a more accessible system. Zebrafish (Danio rerio) are genetically tractable vertebrates, and given their translucency, are readily amenable for daily live imaging studies. We set out to examine whether zebrafish glia have conserved traits with mammalian glia regarding their ability to interact with and maintain the developing brain vasculature. We utilized transgenic zebrafish strains in which oligodendrocyte transcription factor 2 (olig2) and glial fibrillary acidic protein (gfap) identify different glial populations in the zebrafish brain and document their corresponding relationship with brain blood vessels. Our results demonstrate that olig2+ and gfap+ zebrafish glia have distinct lineages and each interact with brain vessels as previously observed in mouse brain. Additionally, we manipulated these relationships through pharmacological and genetic approaches to distinguish the roles of these cell types during blood vessel development. olig2+ glia use blood vessels as a pathway during their migration and Wnt signaling inhibition decreases their single-cell vessel co-option. By contrast, the ablation of gfap+ glia at the beginning of CNS angiogenesis impairs vessel development through a reduction in Vascular endothelial growth factor (Vegf), supporting a role for gfap+ glia during new brain vessel formation in zebrafish. This data suggests that zebrafish glia, akin to mammalian glia, have different lineages that show diverse interactions with blood vessels, and are a suitable model for elucidating glial-vascular relationships during vertebrate brain development. NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01CA22714901A1]; NIH NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01NS082851]; Fralin Biomedical Research Institute at VTC [234859, 175999] Published version This work was supported by NIH grants 1R01CA22714901A1, NIH NINDS R01NS082851 and operational funds #234859 and #175999 through the Fralin Biomedical Research Institute at VTC.

Mammalian inner ear and fish lateral line sensory hair cells depend on fluid motion to transduce environmental signals and elicit a response. In mammals, actively maintained ionic homeostasis of the cochlear and vestibular fluid (endolymph) is essential for hair cell function and numerous mammalian hearing and vestibular disorders arise from disrupted endolymph ion homeostasis. Lateral line hair cells, however, are openly exposed to the aqueous environment with fluctuating ionic composition. How sensory transduction in the lateral line is maintained during environmental changes of ionic composition is not fully understood. Using lineage labeling,in vivotime lapse imaging and scRNA-seq, we discovered highly motile skin-derived cells that invade mature mechanosensory organs of the zebrafish lateral line and differentiate into Neuromast-associated (Nm) ionocytes. Furthermore, the invasive behavior is adaptive as it is triggered by drastic fluctuations in environmental stimuli. Our findings challenge the notion of an entirely placodally-derived lateral line and identify Nm ionocytes as regulators of mechanosensory hair cell function by modulating the ionic microenvironment. The discovery of lateral line ionocytes provides an experimentally accessiblein vivosystem to study cell invasion and migration, as well as the physiological adaptation of vertebrate organs to changing environmental conditions.

Connexins are transmembrane proteins that form hemichannels allowing the exchange of molecules between the extracellular space and cell interior. Two hemichannels from adjacent cells dock and form a continuous gap junction pore, thereby permitting direct intercellular communication. Connexin 36 (Cx36), expressed primarily in neurons, is involved in the synchronous activity of neurons and may play a role in aberrant synchronous firing, as seen in seizures. To understand the reciprocal interactions between Cx36 and seizure-like neural activity, we examined three questions: a) does Cx36 deficiency affect seizure susceptibility, b) does seizure-like activity affect Cx36 expression patterns, and c) does acute blockade of Cx36 conductance increase seizure susceptibility. We utilize the zebrafish pentylenetetrazol (PTZ; a GABA(A) receptor antagonist) induced seizure model, taking advantage of the compact size and optical translucency of the larval zebrafish brain to assess how PTZ affects brain-wide neuronal activity and Cx36 protein expression. We exposed wild-type and genetic Cx36-deficient (cx35.5- /-) zebrafish larvae to PTZ and subsequently mapped neuronal activity across the whole brain, using phosphorylated extracellular-signal-regulated kinase (pERK) as a proxy for neuronal activity. We found that cx35.5-/- fish exhibited region-specific susceptibility and resistance to PTZ-induced hyperactivity compared to wild-type controls, suggesting that genetic Cx36 deficiency may affect seizure susceptibility in a region-specific manner. Regions that showed increased PTZ sensitivity include the dorsal telencephalon, which is implicated in human epilepsy, and the lateral hypothalamus, which has been underexplored. We also found that PTZ-induced neuronal hyperactivity resulted in a rapid reduction of Cx36 protein levels. 30 minutes and one-hour exposure to 20 mM PTZ significantly reduced the expression of Cx36. This Cx36 reduction persists after one-hour of recovery but recovered after 3-6 hours. This acute downregulation of Cx36 by PTZ is likely maladaptive, as acute pharmacological blockade of Cx36 by mefloquine results in increased susceptibility to PTZ-induced neuronal hyperactivity. Together, these results demonstrate a reciprocal relationship between Cx36 and seizure-associated neuronal hyperactivity: Cx36 deficiency contributes region-specific susceptibility to neuronal hyperactivity, while neuronal hyperactivity-induced downregulation of Cx36 may increase the risk of future epileptic events.

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient. This article has an associated First Person interview with the first author of the paper., Editor's choice: The functions of two endocytic adaptor proteins, PHETA1/2, are determined using zebrafish mutants and a potentially disease-causing variant of human PHETA1. Findings suggest essential roles in craniofacial and renal development.

SAD kinases regulate presynaptic vesicle clustering and neuronal polarization. A previous report demonstrated that Sada−/− and Sadb−/− double-mutant mice showed perinatal lethality with a severe defect in axon/dendrite differentiation, but their single mutants did not. These results indicated that they were functionally redundant. Surprisingly, we show that on a C57BL/6N background, SAD-A is essential for cortical development whereas SAD-B is dispensable. Sada−/− mice died within a few days after birth. Their cortical lamination pattern was disorganized and radial migration of cortical neurons was perturbed. Birth date analyses with BrdU and in utero electroporation using pCAG-EGFP vector showed a delayed migration of cortical neurons to the pial surface in Sada−/− mice. Time-lapse imaging of these mice confirmed slow migration velocity in the cortical plate. While the neurites of hippocampal neurons in Sada−/− mice could ultimately differentiate in culture to form axons and dendrites, the average length of their axons was shorter than that of the wild type. Thus, analysis on a different genetic background than that used initially revealed a nonredundant role for SAD-A in neuronal migration and differentiation.

Down syndrome cell adhesion molecules (dscamanddscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences ofdscaml1deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation ofdscaml1resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to thedscaml1mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control anddscaml1mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss ofdscaml1resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows thatdscaml1mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes indscaml1mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements fordscaml1during oculomotor behavior. These findings underscore the importance ofdscaml1in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.