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Social policy questions in the U.S. are often framed in terms of individual rights, valorizing individual freedom and self-determination. But this focus obscures the social and economic bases of health and disease. U.S. bioethics, as its counterparts in Africa and Asia have done, needs to restructure its philosophical framework and expand its moral criteria to consider how to define a global ethics. [ABSTRACT FROM AUTHOR]

Poly- and perfluoroalkyl substances (PFAS) are a group of compounds with uses in industry and many consumer products. Concerns about the potential health effects of these compounds resulted in regulation by the Stockholm Convention on the use of three of the most common PFAS, including perfluorooctanoic acid (PFOA). Thousands of PFAS remain in production that are unregulated and for which their toxicity is unknown. Our group recently identified a new class of PFAS, fluorotelomer ethoxylates (FTEOs), in indoor dust and industrial wastewater. In this study, we investigated the effect of PFAS on placental metabolism by exposing healthy, pregnant CD-1 mice to PFOA or FTEOs at one of three concentrations (0 ng/L (controls), 5 ng/L, 100 ng/L) (n = 7-8/group). While PFOA is banned and PFOA concentrations in human blood are decreasing, we hypothesize that FTEOs will cause adverse pregnancy outcomes similar to PFOA, the compounds they were meant to replace. Placental tissue samples were collected at embryonic day 17.5 and 1 H solid-state magic angle spinning nuclear magnetic resonance spectroscopy was used to determine the relative concentration of placental metabolites (n = 18-20/group). At the highest concentration, the relative concentrations of glucose and threonine were increased and the relative concentration of creatine was decreased in the PFOA-exposed placentas compared to controls (p < 0.05). In contrast, the relative concentrations of asparagine and lysine were decreased and the relative concentration of creatine was increased in the FTEOs-exposed placentas compared to controls (p < 0.05). Partial least squares - discriminant analysis showed the FTEOs-exposed and control groups were significantly separated (p < 0.005) and pathway analysis found four biochemical pathways were perturbed following PFOA exposure, while one pathway was altered following FTEOs exposure. Maternal exposure to PFOA and FTEOs had a significant impact on the placental metabolome, with the effect depending on the pollutant. This work motivates further studies to determine exposure levels and evaluate associations with adverse outcomes in human pregnancies., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Combination antiretroviral therapy (ART) use in pregnancy has been pivotal in improving maternal health and reducing perinatal HIV transmission. However, children born HIV-exposed uninfected fall behind their unexposed peers in several areas including neurodevelopment. The contribution of in utero ART exposure to these deficits is not clear. Here we present our findings of neurocognitive outcomes in adult mice exposed in utero to ART., Methods: Dams were treated with a combination of ritonavir-boosted atazanavir with either abacavir plus lamivudine (ABC/3TC + ATV/r) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC + ATV/r), or water as a control, administered daily from day of plug detection to birth. Offspring underwent a battery of behavioral tests that investigated motor performance and cognition starting at 6-weeks of age and ending at 8 months. Changes in brain structure were assessed using magnetic resonance imaging and immunohistochemistry. Expression of genes involved in neural circuitry and synaptic transmission were assessed in the hippocampus, a region strongly associated with memory formation, using qPCR., Findings: Pups exposed to TDF/FTC + ATV/r showed increased motor activity and exploratory drive, and deficits in hippocampal-dependent working memory and social interaction, while pups exposed to ABC/3TC + ATV/r showed increased grooming, and deficits in working memory and social interaction. Significant volumetric reductions in the brain were seen only in the ABC/3TC + ATV/r group and were associated with reduced neuronal counts in the hippocampus. Altered neurotransmitter receptor mRNA expression as well as changes in expression of the neurotrophic factor BDNF and its receptors were observed in both ART-exposed groups in a sex-dependent manner., Interpretation: In our model, in utero ART exposure had long-term effects on brain development and cognitive and motor outcomes in adulthood. Our data show that neurological outcomes can be influenced by the type of nucleoside reverse transcriptase inhibitor backbone of the regimen and not just the base drug, and display sex differences., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dhume, Balogun, Sarkar, Acosta, Mount, Cahill, Sled and Serghides.)

Maternal exposure to microplastics and nanoplastics has been shown to result in fetal growth restriction in mice. In this study, we investigated the placental and fetal hemodynamic responses to plastics exposure in mice using high-frequency ultrasound. Healthy, pregnant CD-1 dams were given either 106 ng/L of 5 μm polystyrene microplastics or 106 ng/L of 50 nm polystyrene nanoplastics in drinking water throughout gestation and were compared with controls. Maternal exposure to both microplastics and nanoplastics resulted in evidence of placental dysfunction that was highly dependent on the particle size. The umbilical artery blood flow increased by 48% in the microplastic-exposed group and decreased by 25% in the nanoplastic-exposed group compared to controls (p < 0.05). The microplastic- and nanoplastic-exposed fetuses showed a significant decrease in the middle cerebral artery pulsatility index of 10% and 13%, respectively, compared to controls (p < 0.05), indicating vasodilation of the cerebral circulation, a fetal adaptation that is part of the brain sparing response to preserve oxygen delivery. Hemodynamic markers of placental dysfunction and fetal hypoxia were more pronounced in the group exposed to polystyrene nanoplastics, suggesting nanoplastic exposure during human pregnancy has the potential to disrupt fetal brain development, which in turn may cause suboptimal neurodevelopmental outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While microplastics have been recently detected in human blood and the placenta, their impact on human health is not well understood. Using a mouse model of environmental exposure during pregnancy, our group has previously reported that exposure to polystyrene micro- and nanoplastics throughout gestation results in fetal growth restriction. While polystyrene is environmentally relevant, polyethylene is the most widely produced plastic and amongst the most commonly detected microplastic in drinking water and human blood. In this study, we investigated the effect of maternal exposure to polyethylene micro- and nanoplastics on fetal growth and placental function. Healthy, pregnant CD-1 dams were divided into three groups: 10 6  ng/L of 740-4990 nm polyethylene with surfactant in drinking water (n = 12), surfactant alone in drinking water (n = 12) or regular filtered drinking water (n = 11). At embryonic day 17.5, high-frequency ultrasound was used to investigate the placental and fetal hemodynamic responses following exposure. While maternal exposure to polyethylene did not impact fetal growth, there was a significant effect on placental function with a 43% increase in umbilical artery blood flow in the polyethylene group compared to controls (p < 0.01). These results suggest polyethylene has the potential to cause adverse pregnancy outcomes through abnormal placental function., (© 2024. The Author(s).)

Implementation of evidence-informed rehabilitation of the upper limb is variable, and outcomes for stroke survivors are often suboptimal. We established a national partnership of clinicians, survivors of stroke, researchers, healthcare organizations, and policy makers to facilitate change. The objectives of this study are to increase access to best-evidence rehabilitation of the upper limb and improve outcomes for stroke survivors. This prospective pragmatic, knowledge translation study involves four new specialist therapy centers to deliver best-evidence upper-limb sensory rehabilitation (known as SENSe therapy) for survivors of stroke in the community. A knowledge-transfer intervention will be used to upskill therapists and guide implementation. Specialist centers will deliver SENSe therapy, an effective and recommended therapy, to stroke survivors in the community. Outcomes include number of successful deliveries of SENSe therapy by credentialled therapists; improved somatosensory function for stroke survivors; improved performance in self-selected activities, arm use, and quality of life; treatment fidelity and confidence to deliver therapy; and for future implementation, expert therapist effect and cost-effectiveness. In summary, we will determine the effect of a national partnership to increase access to evidence-based upper-limb sensory rehabilitation following stroke. If effective, this knowledge-transfer intervention could be used to optimize the delivery of other complex, evidence-based rehabilitation interventions.

Objective: To examine the relationship between umbilical cord insertion site, placental pathology and adverse pregnancy outcome in a cohort of normal and complicated pregnancies., Methods: Sonographic measurement of the cord insertion and detailed placental pathology were performed in 309 participants. Associations between cord insertion site, placental pathology and adverse pregnancy outcome (pre-eclampsia, preterm birth, small-for-gestational age) were examined., Results: A total of 93 (30%) participants were identified by pathological examination to have a peripheral cord insertion site. Only 41 of the 93 (44%) peripheral cords were detected by prenatal ultrasound. Peripherally inserted cords were associated significantly (P < 0.0001) with diagnostic placental pathology (most commonly with maternal vascular malperfusion (MVM)); of which 85% had an adverse pregnancy outcome. In cases of isolated peripheral cords, without placental pathology, the incidence of adverse outcome was not statistically different when compared to those with central cord insertion and no placental pathology (31% vs 18%; P = 0.3). A peripheral cord with an abnormal umbilical artery (UA) pulsatility index (PI) corresponded to an adverse outcome in 96% of cases compared to 29% when the UA-PI was normal., Conclusions: This study demonstrates that peripheral cord insertion is often part of the spectrum of findings of MVM disease and is associated with adverse pregnancy outcome. However, adverse outcome was uncommon when there was an isolated peripheral cord insertion and no placental pathology. Therefore, additional sonographic and biochemical features of MVM should be sought when a peripheral cord is observed. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Concerns regarding the persistence, bioaccumulation behaviour, and toxicity of perfluorooctanoic acid and perfluorooctane sulfonic acid have resulted in the creation of thousands of replacement perfluoroalkyl substances (PFAS). This study reports on the discovery of fluorotelomer ethoxylates (FTEO) in indoor dust (9/15 samples), and industrial effluents (14/37 samples) using gas chromatographic cyclic ion mobility mass spectrometry (GC-cIMS). By filtering the detected unknowns by mass and collision-cross section, a series of FTEO homologues were revealed with the formula F-(CF 2 ) n (C 2 H 4 O) x H, where n = 6,8,10, and x = 4-12. The highest concentrations were observed in samples collected from healthcare facilities, consistent with the potential use of these compounds in anti-fog products, sprays used to prevent condensation on eyeglasses. FTEOs were also detected in c. 40 % of industrial effluent samples, with the highest concentrations in electroplating facilities, manufacturers of cosmetics and personal care products, and linen cleaning services for healthcare and work uniforms. These results suggest that FTEOs may well be widespread pollutants that are more persistent than previously thought, underlining the need for further study of their occurrence and potential impact to human health and the environment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Endothelial nitric oxide synthase (eNOS) produces nitric oxide, which is essential for a variety of physiological functions in the brain. Previous work has demonstrated the detrimental effects of eNOS deficiency on brain function in male eNOS knockout (eNOS KO) mice. However, the effect of eNOS deficiency on brain structure and any association between these effects and sex is unknown., Methods: This study used three-dimensional high-resolution ex vivo magnetic resonance imaging and behavioral tests of anxiety and cognitive performance to investigate structure-function relationships in the brain of female and male eNOS KO mice in young adulthood., Results: While there were no differences in anxiety-like behavior or locomotion, there was a sex-specific deficit in contextual fear memory retention in male, but not in female, eNOS mice compared to wild-type controls. Moreover, we found that eNOS deficiency induced changes in multiple brain regions that are involved in learning and fear memory including the hippocampus, amygdala, hypothalamus, and areas of the cortex. Several of these MRI-detectable neuroanatomical changes were dependent on sex., Conclusion: The observation that eNOS deficiency impacts brain structure at an early age demonstrates the importance of eNOS for healthy brain development., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Fetal growth and maturation are highly intertwined with placental development during pregnancy. Here we used placental vascular morphology measurements (depth and span) as well as the umbilical artery (UA) diameter of previously published studies on three different mouse strains (C57BL6/J, CD-1 and BALB/c), which were exposed to different conditions (combination antiretroviral therapy, chronic maternal hypoxia and malaria infection) at different embryonic days, to test the hypothesis that placental vascularization and specifically the UA size affect conceptus weight. Interaction of each study parameter with embryonic day, strain and exposure to treatments are studied to investigate the stability of the scaling relationships across and/or within strains and conditions. In addition, the effect of UA diameter on the placental growth measurements (depth and span) is studied. These results show that the power-law scaling relationship of conceptus weight and placental depth with the UA diameter is conserved across strains and conditions with the scaling exponent of approximately 3/8 and 5/8, respectively. By contrast, the relationship between conceptus weight and either the placental span or depth is different between strains and conditions, suggesting multiple mechanisms of vascular adaptation.

Per- and polyfluoroalkyl substances (PFASs) such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are persistent in the environment and bioaccumulate in wildlife and humans, potentially causing adverse health effects at all stages of life. Studies from human pregnancy have shown that exposure to these contaminants are associated with placental dysfunction and fetal growth restriction; however, studies in humans are confounded by genetic and environmental factors. Here, we synthesize the available results from mouse models of pregnancy to show the causal effects of prenatal exposure to PFOA and PFOS on placental and fetal development and on neurocognitive function and metabolic disorders in offspring. We also propose gaps in the present knowledge and provide suggestions for future research studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes., Methods: Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1 +/- mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes., Findings: Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1 +/- ), to worsen birth outcomes by impeding vascular remodeling required for placental function., Interpretation: Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes., Funding: This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

In hypoplastic left heart syndrome (HLHS), the mechanisms leading to left heart hypoplasia and their associated fetal abnormalities are largely unknown. Current animal models have limited utility in resolving these questions as they either do not fully reproduce the cardiac phenotype, do not survive to term and/or have very low disease penetrance. Here, we report the development of a surgically induced mouse model of HLHS that overcomes these limitations. Briefly, we microinjected the fetal left atrium of embryonic day (E)14.5 mice with an embolizing agent under high-frequency ultrasound guidance, which partially blocks blood flow into the left heart and induces hypoplasia. At term (E18.5), all positively embolized mice exhibit retrograde aortic arch flow, non-apex-forming left ventricles and hypoplastic ascending aortas. We thus report the development of the first mouse model of isolated HLHS with a fully penetrant cardiac phenotype and survival to term. Our method allows for the interrogation of previously intractable questions, such as determining the mechanisms of cardiac hypoplasia and fetal abnormalities observed in HLHS, as well as testing of mechanism-based therapies, which are urgently lacking., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Background: The umbilical artery (UA) Doppler pulsatility index is used clinically to detect elevated feto-placental vascular resistance. However, this metric is confounded by variation in fetal cardiac function and is only moderately predictive of placental pathology. Our group developed a novel ultrasound methodology that measures wave reflections in the UA, thereby isolating a component of the Doppler signal that is specific to the placenta. The present study examined whether wave reflections in the UA are predictive of placental vascular pathology., Methods: Standard clinical Doppler ultrasound of the UAs was performed in 241 pregnant women. Of these, 40 women met narrowly defined preset criteria for the control group, 36 had maternal vascular malperfusion (MVM) and 16 had fetal vascular malperfusion (FVM). Using a computational procedure, the Doppler waveforms were decomposed into a pair of forward and backward propagating waves., Findings: Compared to controls, wave reflections were significantly elevated in women with either MVM (p<0.0001) or FVM pathology (p = 0.02). In contrast, the umbilical and uterine artery pulsatility indices were only elevated in the MVM group (p<0.0001) and there were no differences between women with FVM and the controls., Interpretation: The measurement of wave reflections in the UA, combined with standard clinical ultrasound parameters, has the potential to improve the diagnostic performance of UA Doppler to detect placental vascular pathology. Identifying women with FVM pathology is particularly challenging prenatally and future investigations will determine if women at risk of this specific placental disease could benefit from this novel diagnostic technique., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy., Methods: A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex., Results: While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively)., Conclusions: Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.

The cervix is responsible for maintaining pregnancy, and its timely remodeling is essential for the proper delivery of a baby. Cervical insufficiency, or "weakness", may lead to preterm birth, which causes infant morbidities and mortalities worldwide. We used a mouse model of pregnancy and term labor, to examine the cervical structure by histology (Masson Trichome and Picrosirius Red staining), immunohistochemistry (Hyaluronic Acid Binding Protein/HABP), and ex-vivo MRI (T 2 -weighted and diffusion tensor imaging), focusing on two regions of the cervix (i.e., endocervix and ectocervix). Our results show that mouse endocervix has a higher proportion of smooth muscle cells and collagen fibers per area, with more compact tissue structure, than the ectocervix. With advanced gestation, endocervical changes, indicative of impending delivery, are manifested in fewer smooth muscle cells, expansion of the extracellular space, and lower presence of collagen fibers. MRI detected three distinctive zones in pregnant mouse endocervix: (1) inner collagenous layer, (2) middle circular muscular layer, and (3) outer longitudinal muscular layer. Diffusion MRI images detected changes in tissue organization as gestation progressed suggesting the potential application of this technique to non-invasively monitor cervical changes that precede the onset of labor in women at risk for preterm delivery.

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor that functions to maintain metabolic homeostasis, regulate cell growth, and limit the development of excessive inflammation during immune responses. Previously, we reported that PPAR-δ-deficient mice develop a more severe clinical course of experimental autoimmune encephalomyelitis (EAE); however, it was difficult to delineate the role that microglia played in this disease phenotype since PPAR-δ-deficient mice exhibited a number of immune defects that enhanced CNS inflammation upstream of microglia activation. Here, we specifically investigated the role of PPAR-δ in microglia during EAE by using mice where excision of a floxed Ppard allele was driven by expression of a tamoxifen (TAM)-inducible CX3C chemokine receptor 1 promoter-Cre recombinase transgene ( Cx3cr1 CreERT2 : Ppard fl/fl ). We observed that by 30 days of TAM treatment, Cx3cr1 CreERT2 : Ppard fl/fl mice exhibited Cre-mediated deletion primarily in microglia and this was accompanied by efficient knockdown of Ppard expression in these cells. Upon induction of EAE, TAM-treated Cx3cr1 CreERT2 : Ppard fl/fl mice presented with an exacerbated course of disease compared to TAM-treated Ppard fl/fl controls. Histopathological and magnetic resonance (MR) studies on the spinal cord and brains of EAE mice revealed increased Iba-1 immunoreactivity, axonal injury and CNS tissue loss in the TAM-treated Cx3cr1 CreERT2 : Ppard fl/fl group compared to controls. In early EAE, a time when clinical scores and the infiltration of CD45 + leukocytes was equivalent between Cx3cr1 CreERT2 : Ppard fl/fl and Ppard fl/fl mice, Ppard -deficient microglia exhibited a more reactive phenotype as evidenced by a shorter maximum process length and lower expression of genes associated with a homeostatic microglia gene signature. In addition, Ppard -deficient microglia exhibited increased expression of genes associated with reactive oxygen species generation, phagocytosis and lipid clearance, M2-activation, and promotion of inflammation. Our results therefore suggest that PPAR-δ has an important role in microglia in limiting bystander tissue damage during neuroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Doroshenko, Drohomyrecky, Gower, Whetstone, Cahill, Ganguly, Spring, Yi, Sled and Dunn.)

Background: The adoption of research evidence to improve client outcomes may be enhanced using the principles of implementation science. This systematic review aimed to understand the effect of involving consumers to change health professional behaviours and practices. The barriers and enablers to consumer engagement will also be examined., Methods: We searched Medline, CINAHL, Embase, the Cochrane Central Register of Controlled Trials and PDQ-Evidence from 2004 to February 2019. Implementation studies involving consumers in at least one phase (development, intervention or facilitation) of an intervention that aimed to change health professional behaviour to align with evidence-based practice were included. Studies in the areas of paediatrics and primary care were excluded. Two review authors independently screened studies for inclusion, and one author extracted data and conducted quality assessments with review of a second author. Knowledge translation interventions were categorized using the Effective Practice and Organisation of Care taxonomy. The primary outcome was measures of change in health professional behaviour., Results: Sixteen articles met the inclusion criteria. Meta-analysis of three studies found support for consumer involvement in changing healthcare professionals' behaviour (Hedges' g = 0.41, 95% CI [0.27, 0.57], P < 0.001). Most knowledge translation studies involved consumers during the development phase only (n = 12). Most studies (n = 9) included one type of knowledge translation intervention. Professional interventions (including education of health professionals, educational outreach, and audit and feedback) were described in 13 studies., Conclusions: Consumer involvement rarely moves beyond the design phase of knowledge translation research in healthcare settings. Further research of the barriers to and effect of increased consumer engagement across all stages of knowledge translation interventions is needed., Systematic Review Registration: PROSPERO CRD42019119179., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Somatosensory loss is common after stroke with one-in-two individuals affected. Although clinical practice guidelines recommend providing somatosensory rehabilitation, this impairment often remains unassessed and untreated. To address the gap between guideline recommendations and clinical practice, this study sought to understand the factors influencing delivery of evidence-based upper limb sensory rehabilitation after stroke., Design: Qualitative study involving focus groups and interviews. Data analysis used an inductive approach (thematic analysis) and deductive analysis using implementation theory (the Theoretical Domains Framework and Normalisation Process Theory)., Setting: Eight healthcare organisations in metropolitan and regional areas of Victoria and New South Wales, Australia., Participants: Eighty-seven rehabilitation therapists (79% occupational therapists and 21% physiotherapists) were purposively sampled and participated in a knowledge translation study with staggered recruitment from 2014 to 2018., Results: Three types of factors influenced therapists' delivery of upper limb somatosensory rehabilitation: individual ('The uncertain, unskilled therapist'), patient ('Patient understanding and priorities ' ) and organisational ('System pressures and resources ' ). Deductive analysis using implementation theory identified key determinants of practice change, such as opportunities to consolidate new skills, the anticipated benefits of upskilling as a therapy team and the work anticipated by therapists to incorporate a new somatosensory rehabilitation approach., Conclusions: Occupational therapists and physiotherapists hold valuable insights towards practice change in somatosensory rehabilitation from the 'frontline'. Therapists experience barriers to change including a lack of knowledge and skills, lack of resources and organisational pressures. Facilitators for change were identified, including social support and therapists' perceived legitimacy in using new somatosensory rehabilitation approaches. Results will inform the design of a tailored implementation strategy to increase the use of evidence-based somatosensory rehabilitation in Australia., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12615000933550)., Competing Interests: Competing interests: LMC is the lead author of the SENSe approach to sensory rehabilitation, the focus of knowledge translation in the SENSe Implement project. A SENSe training package (manual and DVD) has been developed and is available for purchase from a Not for Profit organisation. SENSe assessment and training equipment are also available for purchase. LMC has no personal financial interest in the sale of these resources. There is no patent, or intended application for a patent, associated with these resources. LMC has conducted workshops on the SENSe approach and been invited to give lectures and conference presentations on the approach., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies., Methods: A prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope., Results: While the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p < 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p < 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation., Conclusions: The uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation.

Objective: To evaluate the feasibility of using umbilical artery (UA) Doppler waveforms to measure fetal heart rate (FHR) short-term variation (STV) across gestation., Methods: This was a prospective longitudinal study, conducted at two study sites, of 195 pregnancies considered low risk. Pulsed-wave Doppler of the UAs was performed at 4-weekly intervals, between 14 and 40 weeks of gestation, using a standardized imaging protocol. Up to 12 consecutive UA Doppler waveforms were analyzed using offline processing software. FHR STV was calculated using average R-R intervals extracted from the waveforms and baseline corrected for FHR., Results: Baseline-corrected FHR STV increased significantly with gestational age (conditional R 2  = 0.37; P < 0.0001) and was correlated inversely with FHR (conditional R 2  = 0.54; P < 0.0001). The STV ranged (median (interquartile range)) from 3.5 (2.9-4.1) ms at 14-20 weeks' gestation to 6.3 (4.8-7.7) ms at 34-40 weeks' gestation. The change in heart rate STV did not differ between study sites or individual sonographers., Conclusions: UA Doppler waveforms offer a robust and feasible method to derive STV of the FHR. It should be emphasized that the UA Doppler-derived STV is not interchangeable with measurements derived with computerized cardiotocography. Accordingly, further investigations are needed to validate associations with outcome, in order to determine the value of concurrent fetal cardiovascular and heart rate evaluations that are possible with the technique described here. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Dolutegravir (DTG) is a preferred regimen for all people with HIV including pregnant women, but its effects on the fetus are not fully understood. Periconceptional exposure to DTG has been associated with increased rates of neural tube defects (NTDs), although it is unknown whether this is a causal relationship. This has led to uncertainty around the use of DTG in women of reproductive potential., Methods: Pregnant C57BL/6J mice were randomly allocated to control (water), 1x-DTG (2.5 mg/kg-peak plasma concentration ~3000 ng/ml - therapeutic level), or 5x-DTG (12.5 mg/kg-peak plasma concentration ~12,000 ng/ml - supratherapeutic level), once daily from gestational day 0.5 until sacrifice. DTG was administered with 50 mg/kg tenofovir+33.3 mg/kg emtricitabine. Fetal phenotypes were determined, and maternal and fetal folate levels were quantified by mass-spectrometry., Findings: 352 litters (91 control, 150 1x-DTG, 111 5x-DTG) yielding 2776 fetuses (747 control, 1174 1x-DTG, 855 5x-DTG) were assessed. Litter size and viability rates were similar between groups. Fetal and placenta weights were lower in the 1x-DTG vs. control. Placental weight was higher in the 5x-DTG vs. control. Five NTDs were observed, all in the 1x-DTG group. Fetal defects, including microphthalmia, severe edema, and vascular/bleeding defects were more frequent in the 1x-DTG group. In contrast, defect rates in the 5x-DTG were similar to control. Fetal folate levels were similar between control and 1x-DTG, but were significantly higher in the 5x-DTG group., Interpretation: Our findings support a causal relationship of DTG at therapeutic doses with increased risk for fetal defects, including NTDs at a rate that is similar that reported in the Tsepamo study for women exposed to DTG-based ART from conception. The non-monotonic dose-response relationship between DTG and fetal anomalies could explain the previous lack of fetal toxicity findings from pre-clinical DTG studies. The fetal folate levels suggest that DTG is unlikely to be an inhibitor of folate uptake., Funding: This project has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I., Competing Interests: Declaration of Competing Interest The authors have no competing interests relating to this study. AJC acts as consultant for ViiV Healthcare Limited, with any fees going to support his research program. LS received personal support for participating in a ViiV organized Think Tank., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Elevated umbilical artery pulsatility is a widely used biomarker for placental pathology leading to intra-uterine growth restriction and, in severe cases, still-birth. It has been hypothesized that placental pathology modifies umbilical artery pulsatility by altering the degree to which the pulse pressure wave, which originates from the fetal heart, is reflected from the placental vasculature to interfere with the incident wave. Here we present a method for estimating the reflected pulse wave in the umbilical artery of human fetuses using asynchronously acquired Doppler ultrasound measurements from the two ends of the umbilical cord. This approach assumes non-dispersive and loss-less propagation of the waves along the artery and models the reflection process as a linear system with a parameterized impulse response. Model parameters are determined from the measured Doppler waveforms by constrained optimization. Velocity waveforms were obtained from 142 pregnant volunteers where 123 met data quality criteria in at least one umbilical artery. The reflection model was consistent with the measured waveforms in 183 of 212 arteries that were analyzed. The analysis method was validated by applying it to simulated datasets and comparing solutions to ground-truth. With measurement noise levels typical of clinical ultrasound, parameters describing the reflected wave were accurately determined.

Background: Rehabilitation based upon research evidence gives stroke survivors the best chance of recovery. There is substantial research to guide practice in stroke rehabilitation, yet uptake of evidence by healthcare professionals is typically slow and patients often do not receive evidence-based care. Implementation interventions are an important means to translate knowledge from research to practice and thus optimise the care and outcomes for stroke survivors. A synthesis of research evidence is required to guide the selection and use of implementation interventions in stroke rehabilitation., Objectives: To assess the effects of implementation interventions to promote the uptake of evidence-based practices (including clinical assessments and treatments recommended in evidence-based guidelines) in stroke rehabilitation and to assess the effects of implementation interventions tailored to address identified barriers to change compared to non-tailored interventions in stroke rehabilitation., Search Methods: We searched CENTRAL, MEDLINE, Embase, and eight other databases to 17 October 2019. We searched OpenGrey, performed citation tracking and reference checking for included studies and contacted authors of included studies to obtain further information and identify potentially relevant studies., Selection Criteria: We included individual and cluster randomised trials, non-randomised trials, interrupted time series studies and controlled before-after studies comparing an implementation intervention to no intervention or to another implementation approach in stroke rehabilitation. Participants were qualified healthcare professionals working in stroke rehabilitation and the patients they cared for. Studies were considered for inclusion regardless of date, language or publication status. Main outcomes were healthcare professional adherence to recommended treatment, patient adherence to recommended treatment, patient health status and well-being, healthcare professional intention and satisfaction, resource use outcomes and adverse effects., Data Collection and Analysis: Two review authors independently selected studies for inclusion, extracted data, and assessed risk of bias and certainty of evidence using GRADE. The primary comparison was any implementation intervention compared to no intervention., Main Results: Nine cluster randomised trials (12,428 patient participants) and three ongoing trials met our selection criteria. Five trials (8865 participants) compared an implementation intervention to no intervention, three trials (3150 participants) compared one implementation intervention to another implementation intervention, and one three-arm trial (413 participants) compared two different implementation interventions to no intervention. Eight trials investigated multifaceted interventions; educational meetings and educational materials were the most common components. Six trials described tailoring the intervention content to identified barriers to change. Two trials focused on evidence-based stroke rehabilitation in the acute setting, four focused on the subacute inpatient setting and three trials focused on stroke rehabilitation in the community setting. We are uncertain if implementation interventions improve healthcare professional adherence to evidence-based practice in stroke rehabilitation compared with no intervention as the certainty of the evidence was very low (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.53 to 2.64; 2 trials, 39 clusters, 1455 patient participants; I 2 = 0%). Low-certainty evidence indicates implementation interventions in stroke rehabilitation may lead to little or no difference in patient adherence to recommended treatment (number of recommended performed outdoor journeys adjusted mean difference (MD) 0.5, 95% CI -1.8 to 2.8; 1 trial, 21 clusters, 100 participants) and patient psychological well-being (standardised mean difference (SMD) -0.02, 95% CI -0.54 to 0.50; 2 trials, 65 clusters, 1273 participants; I 2 = 0%) compared with no intervention. Moderate-certainty evidence indicates implementation interventions in stroke rehabilitation probably lead to little or no difference in patient health-related quality of life (MD 0.01, 95% CI -0.02 to 0.05; 2 trials, 65 clusters, 1242 participants; I 2 = 0%) and activities of daily living (MD 0.29, 95% CI -0.16 to 0.73; 2 trials, 65 clusters, 1272 participants; I 2 = 0%) compared with no intervention. No studies reported the effects of implementation interventions in stroke rehabilitation on healthcare professional intention to change behaviour or satisfaction. Five studies reported economic outcomes, with one study reporting cost-effectiveness of the implementation intervention. However, this was assessed at high risk of bias. The other four studies did not demonstrate the cost-effectiveness of interventions. Tailoring interventions to identified barriers did not alter results. We are uncertain of the effect of one implementation intervention versus another given the limited very low-certainty evidence., Authors' Conclusions: We are uncertain if implementation interventions improve healthcare professional adherence to evidence-based practice in stroke rehabilitation compared with no intervention as the certainty of the evidence is very low., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Traumatic brain injury (TBI) can induce changes in vascular architecture. Although ultrasound metrics such as pulsatility index (PI) are sensitive to changes in hemodynamic resistance downstream from major arteries, these metrics depend on features unrelated to vessel architecture, such as blood pressure and heart rate. In contrast, input impedance and reflection coefficient that are derived from wave reflection theory seek to minimize the effects of altered cardiac output or heart rate. In this article, we investigate the use of ultrasound to assess changes in vascular impedance and wave reflection in the common carotid arteries of mice exposed to a controlled cortical impact. Focusing on the first harmonics of the reflected waves, the impedance phase was increased ipsilaterally in impacted mice compared with shams, whereas the magnitude of the impedance was unchanged. In contrast, PI was reduced bilaterally. Interestingly, PI and the first harmonic magnitude of input impedance in the carotid artery were correlated on the contralateral but not ipsilateral side. We investigated the use of these metrics to classify mice as sham or TBI, finding an area under the receiver operating characteristic curve ipsilaterally of 0.792 (confidence interval [CI]: 0.648-0.936) for correct classification with first harmonic impedance magnitude and phase as predictors and 0.716 (CI: 0.553-0.879) using carotid artery PI and diameter as predictors. Overall, the findings support the use of wave reflection analysis as a more specific measure of vascular changes following TBI and motivate the translation of this approach for monitoring vascular changes in humans affected by TBI.

An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. Using in vivo magnetic resonance imaging and behavioral testing to study male and female decrepit mice, we found a stereotypical neuroanatomical pattern of progression of the lesion along the limbic system network and an associated memory impairment. Using structural variant analysis, we identified an intronic mutation in a mitochondrial-associated gene ( Mrpl3 ) that is responsible for the decrepit phenotype. While the function of this gene is unknown, embryonic lethality in Mrpl3 knock-out mice suggests it is critical for early development. The observation that a mutation linked to energy metabolism precipitates a pattern of neurodegeneration via cell death across disparate but linked brain regions may explain how stereotyped patterns of neurodegeneration arise in humans or define a not yet identified human disease. SIGNIFICANCE STATEMENT The development of novel therapies for adult-onset neurodegenerative disease has been impeded by the limitations of available animal models in reproducing many of the clinical features. Here, we present a novel spontaneous mutation in a mitochondrial-associated gene in a mouse (termed decrepit) that results in adult-onset neurodegeneration with a stereotypical neuroanatomical pattern of progression and an associated memory impairment. The decrepit mouse model may represent a heretofore undiagnosed human disease and could serve as a new animal model to study neurodegenerative disease., (Copyright © 2020 the authors.)

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2 + mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS., Competing Interests: The authors declare no competing interest.

Antenatal corticosteroids are often administered to women at risk of preterm birth to accelerate fetal lung development; however, there is evidence that this treatment may adversely affect placental function in some fetuses. Our group has recently demonstrated that wave reflections in the umbilical artery (UA), measured using high-frequency ultrasound, are sensitive to placental vascular abnormalities. In the present study, we used this approach to investigate the effect of maternal administration of betamethasone, a clinically relevant corticosteroid, on the feto-placental vasculature of the mouse. Fetuses were assessed at embryonic day (E)15.5 and E17.5 in C57BL6/J mice. At both gestational ages, the UA diameter, UA blood flow, and the wave reflection coefficient were significantly elevated in the betamethasone-treated mice compared to vehicle-treated controls. These observations support the interpretation that placental vascular resistance dropped with betamethasone treatment to an extent that could not be explained by vasodilation of the UA alone. Consistent with clinical studies, the effect of betamethasone on UA end-diastolic velocity was heterogeneous. Our results suggest that UA wave reflections are more sensitive to acute changes in placental vascular resistance compared with the UA pulsatility index, and this technique may have clinical application to identify a favorable placental vascular response to fetal therapies such as antenatal corticosteroids, where the fetal heart rate is likely to vary., (© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Offspring of preeclamptic pregnancies have cognitive alterations. Placental growth factor (PGF), is low in preeclampsia; reduced levels may affect brain development. PGF-null mice differ from normal congenic controls in cerebrovasculature, neuroanatomy and behavior. Using brain imaging and behavioral testing, we asked whether developmentally asynchronous (i.e. neonatal) PGF supplementation alters the vascular, neuroanatomic and/or behavioral status of Pgf -/- mice at adulthood. C57BL/6-Pgf -/- pups were treated intraperitoneally on postnatal days 1-10 with vehicle or PGF at 10 pg/g, 70 pg/g or 700 pg/g. These mice underwent behavioral testing and perfusion for MRI and analysis of retinal vasculature. A second cohort of vehicle- or PGF-treated mice was perfused for micro-CT imaging. 10 pg/g PGF-treated mice exhibited less locomotor activity and greater anxiety-like behavior relative to vehicle-treated mice. Depressive-like behavior showed a sex-specific, dose-dependent decrease and was lowest in 700 pg/g PGF-treated females relative to vehicle-treated females. Spatial learning did not differ. MRI revealed smaller volume of three structures in the 10 pg/g group, larger volume of seven structures in the 70 pg/g group and smaller volume of one structure in the 700 pg/g group. No cerebral or retinal vascular differences were detected. Overall, neonatal PGF replacement altered behavior and neuroanatomy of adult Pgf -/- mice.

Hypoxic stress is a common occurrence during human pregnancy, yet little is known about its effects on the fetal brain. This study examined the fetal hemodynamic responses to chronic hypoxia in an experimental mouse model of chronic maternal hypoxia (11% O 2 from E14.5 to E17.5). Using high-frequency Doppler ultrasound, we found fetal cerebral and ductus venosus blood flow were both elevated by 69% and pulmonary blood flow was decreased by 62% in the fetuses exposed to chronic hypoxia compared to controls. This demonstrates that brain sparing persists during chronic fetal hypoxia and is mediated by "streaming," where highly oxygenated blood preferentially flows through the ductus venosus towards the cerebral circulation, bypassing the liver and the lungs. Consistent with these changes in blood flow, the fetal brain volume measured by MRI is preserved, while the liver and lung volumes decreased compared to controls. However, hypoxia exposed fetuses were rendered vulnerable to an acute hypoxic challenge (8% O 2 for 3 min), demonstrating global blood flow decreases consistent with imminent fetal demise rather than elevated cerebral blood flow. Despite this vulnerability, there were no differences in adult brain morphology in the mice exposed to chronic maternal hypoxia compared to controls.

The pulsatile pattern of blood motion measured by Doppler ultrasound within the umbilical artery is known to contain useful diagnostic information and is widely used to monitor pregnancies at risk of fetal growth restriction or stillbirth. Animal studies have identified reflected pressure waves traveling counter to the direction of blood flow as an important factor in the shape of these waveforms. In the present study, we establish a method to measure reflected waves in the human umbilical artery and assess their influence on blood velocity pulsation. Ninety-five pregnant women were recruited from a general obstetrics clinic between 26 and 37 wk of gestation and examined by Doppler ultrasound. Blood velocity waveforms were recorded for each umbilical artery at three locations along the umbilical cord. With the use of a computational procedure, a pair of forward and reverse propagating waves was identified to explain the variation in observed Doppler ultrasound waveforms along the cord. Among the data sets that met data quality requirements, waveforms in 93 of the 130 arteries examined agreed with the wave reflection model to within 1.5% and showed reflections ranging in magnitude from 3 to 52% of the forward wave amplitude. Strong reflections were associated with large differences in pulsatility between the fetal and placental ends of the cord. As reflections arise from transitions in the biomechanical properties of blood vessels, these observations provide a plausible mechanism for the link between abnormal waveforms and clinically significant placental pathology and could lead to more precise screening methods for detecting pregnancies complicated by placental disease. NEW & NOTEWORTHY The pulsatile pattern of blood motion measured by Doppler ultrasound within the umbilical artery is known to contain useful diagnostic information and is widely used to monitor pregnancies at risk of fetal growth restriction. We demonstrate based on a study of 95 pregnant women that the shape of these umbilical artery waveforms is explained by the presence of a reflected pressure wave traveling counter to the direction of blood flow.

Current methods to detect placental vascular pathologies that monitor Doppler ultrasound changes in umbilical artery (UA) pulsatility have only moderate diagnostic utility, particularly in late gestation. In fetal mice, we recently demonstrated that reflected pressure waves propagate counter to the direction of flow in the UA and proposed the measurement of these reflections as a means to detect abnormalities in the placental circulation. In the present study, we used this approach in combination with microcomputed tomography to investigate the relationship between altered placental vascular architecture and changes in UA wave reflection metrics. Fetuses were assessed at embryonic day (E) 15.5 and E17.5 in control C57BL6/J mice and dams treated with combination antiretroviral therapy (cART), a known model of fetal growth restriction. Whereas the reflection coefficient was not different between groups at E15.5, it was 27% higher at E17.5 in cART-treated mice compared with control mice. This increase in reflection coefficient corresponded to a 36% increase in the total number of vessel segments, a measure of overall architectural complexity. Interestingly, there was no difference in UA pulsatility index between groups, suggesting that the wave reflections convey information about vascular architecture that is not captured by conventional ultrasound metrics. The wave reflection parameters were found to be associated with the morphology of the fetoplacental arterial tree, with the area ratio between the UA and first branch points correlating with the reflection coefficient. This study highlights the potential for wave reflection to aid in the noninvasive clinical assessment of placental vascular pathology. NEW & NOTEWORTHY We used a novel ultrasound methodology based on detecting pulse pressure waves that propagate along the umbilical artery to investigate the relationship between changes in wave reflection metrics and altered placental vascular architecture visualized by microcomputed tomography. Using pregnant mice treated with combination antiretroviral therapy, a model of fetal growth restriction, we demonstrated that reflections in the umbilical artery are sensitive to placental vascular abnormalities and associated with the geometry of the fetoplacental tree.

Preeclampsia, a hypertensive syndrome occurring in 3-5% of human pregnancies, has lifelong health consequences for fetuses. Cognitive ability throughout life is altered, and adult stroke risk is increased. One potential etiological factor for altered brain development is low concentrations of proangiogenic placental growth factor (PGF). Impaired PGF production may promote an antiangiogenic fetal environment during neural and cerebrovascular development. We previously reported delayed vascularization of the hindbrain, altered retinal vascular organization, and less connectivity in the circle of Willis in Pgf -/- mice. We hypothesized Pgf -/- mice would have impaired cognition and altered brain neuroanatomy in addition to compromised cerebrovasculature. Cognitive behavior was assessed in adult Pgf -/- and Pgf +/+ mice by four paradigms followed by postmortem high-resolution MRI of neuroanatomy. X-ray microcomputed tomography imaging investigated the three-dimensional cerebrovascular geometry in another cohort. Pgf -/- mice exhibited poorer spatial memory, less depressive-like behavior, and superior recognition of novel objects. Significantly smaller volumes of 10 structures were detected in the Pgf -/- compared with Pgf +/+ brain. Pgf -/- brain had more total blood vessel segments in the small-diameter range. Lack of PGF altered cognitive functions, brain neuroanatomy, and cerebrovasculature in mice. Pgf -/- mice may be a preclinical model for the offspring effects of low-PGF preeclampsia gestation.

Key Points: Chronic fetal hypoxia is one of the most common complications of pregnancy and is known to cause fetal growth restriction. The structural adaptations of the placental vasculature responsible for growth restriction with chronic hypoxia are not well elucidated. Using a mouse model of chronic maternal hypoxia in combination with micro-computed tomography and scanning electron microscopy, we found several placental adaptations that were beneficial to fetal growth including capillary expansion, thinning of the interhaemal membrane and increased radial artery diameters, resulting in a large drop in total utero-placental vascular resistance. One of the mechanisms used to achieve the rapid increase in capillaries was intussusceptive angiogenesis, a strategy used in human placental development to form terminal gas-exchanging villi. These results contribute to our understanding of the structural mechanisms of the placental vasculature responsible for fetal growth restriction and provide a baseline for understanding adaptive physiological responses of the placenta to chronic hypoxia., Abstract: The fetus and the placenta in eutherian mammals have a unique set of compensatory mechanisms to respond to several pregnancy complications including chronic maternal hypoxia. This study examined the structural adaptations of the feto- and utero-placental vasculature in an experimental mouse model of chronic maternal hypoxia (11% O 2 from embryonic day (E) 14.5-E17.5). While placental weights were unaffected by exposure to chronic hypoxia, using micro-computed tomography, we found a 44% decrease in the absolute feto-placental arterial vascular volume and a 30% decrease in total vessel segments in the chronic hypoxia group compared to control group. Scanning electron microscopy imaging showed significant expansion of the capillary network; consequently, the interhaemal membrane was 11% thinner to facilitate maternal-fetal exchange in the chronic hypoxia placentas. One of the mechanisms for the rapid capillary expansion was intussusceptive angiogenesis. Analysis of the utero-placental arterial tree showed significant increases (24%) in the diameter of the radial arteries, resulting in a decrease in the total utero-placental resistance by 2.6-fold in the mice exposed to chronic maternal hypoxia. Together these adaptations acted to preserve placental weight whereas fetal weight was decreased., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Moderate anemia is associated with increased mortality and morbidity, including acute kidney injury (AKI), in surgical patients. A red blood cell (RBC)-specific antibody model was utilized to determine whether moderate subacute anemia could result in tissue hypoxia as a potential mechanism of injury. Cardiovascular and hypoxic cellular responses were measured in transgenic mice capable of expressing hypoxia-inducible factor-1α (HIF-1α)/luciferase activity in vivo. Antibody-mediated anemia was associated with mild intravascular hemolysis (6 h) and splenic RBC sequestration ( day 4), resulting in a nadir hemoglobin concentration of 89 ± 13 g/l on day 4. At this time point, renal tissue oxygen tension (P t O 2 ) was decreased in anemic mice relative to controls (13.1 ± 4.3 vs. 20.8 ± 3.7 mmHg, P < 0.001). Renal tissue hypoxia was associated with an increase in HIF/luciferase expression in vivo ( P = 0.04) and a 20-fold relative increase in renal erythropoietin mRNA transcription ( P < 0.001) but no increase in renal blood flow ( P = 0.67). By contrast, brain P t O 2 was maintained in anemic mice relative to controls (22.7 ± 5.2 vs. 23.4 ± 9.8 mmHg, P = 0.59) in part because of an increase in internal carotid artery blood flow (80%, P < 0.001) and preserved cerebrovascular reactivity. Despite these adaptive changes, an increase in brain HIF-dependent mRNA levels was observed (erythropoietin: P < 0.001; heme oxygenase-1: P = 0.01), providing evidence for subtle cerebral tissue hypoxia in anemic mice. These data demonstrate that moderate subacute anemia causes significant renal tissue hypoxia, whereas adaptive cerebrovascular responses limit the degree of cerebral tissue hypoxia. Further studies are required to assess whether hypoxia is a mechanism for acute kidney injury associated with anemia.

Background: The treatment of somatosensory loss in the upper limb after stroke has been historically overshadowed by therapy focused on motor recovery. A double-blind randomized controlled trial has demonstrated the effectiveness of SENSe (Study of the Effectiveness of Neurorehabilitation on Sensation) therapy to retrain somatosensory discrimination after stroke. Given the acknowledged prevalence of upper limb sensory loss after stroke and the evidence-practice gap that exists in this area, effort is required to translate the published research to clinical practice. The aim of this study is to determine whether evidence-based knowledge translation strategies change the practice of occupational therapists and physiotherapists in the assessment and treatment of sensory loss of the upper limb after stroke to improve patient outcomes., Method/design: A pragmatic, before-after study design involving eight (n = 8) Australian health organizations, specifically sub-acute and community rehabilitation facilities. Stroke survivors (n = 144) and occupational therapists and physiotherapists (~10 per site, ~n = 80) will be involved in the study. Stroke survivors will be provided with SENSe therapy or usual care. Occupational therapists and physiotherapists will be provided with a multi-component approach to knowledge translation including i) tailoring of the implementation intervention to site-specific barriers and enablers, ii) interactive group training workshops, iii) establishing and fostering champion therapists and iv) provision of written educational materials and online resources. Outcome measures for occupational therapists and physiotherapists will be pre- and post-implementation questionnaires and audits of medical records. The primary outcome for stroke survivors will be change in upper limb somatosensory function, measured using a standardized composite measure., Discussion: This study will provide evidence and a template for knowledge translation in clinical, organizational and policy contexts in stroke rehabilitation., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) retrospective registration ACTRN12615000933550 .

Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation, during which blood vessels elongate. However, the cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase G9a, also known as Ehmt2, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand owing to decreased endothelial cell proliferation and increased trophoblast proliferation. Moreover, G9a deficiency altered the transcriptional switch initiating placental maturation and caused downregulation of Notch pathway effectors including Rbpj Importantly, Notch pathway activation in G9a-deficient endothelial progenitors extended embryonic life and rescued placental vascular expansion. Thus, G9a activates the Notch pathway to balance endothelial cell and trophoblast proliferation and coordinates the transcriptional switch controlling placental vascular maturation. Accordingly, G9A and RBPJ were downregulated in human placentae from IUGR-affected pregnancies, suggesting that G9a is an important regulator in placental diseases caused by defective vascular maturation., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Abnormally pulsatile umbilical artery (UA) Doppler ultrasound velocity waveforms are a hallmark of severe or early onset placental-mediated intrauterine growth restriction (IUGR), whereas milder late onset IUGR pregnancies typically have normal UA pulsatility. The diagnostic utility of these waveforms to detect placental pathology is thus limited and hampered by factors outside of the placental circulation, including fetal cardiac output. In view of these limitations, we hypothesized that these Doppler waveforms could be more clearly understood as a reflection phenomenon and that a reflected pulse pressure wave is present in the UA that originates from the placenta and propagates backward along the UA. To investigate this, we developed a new ultrasound approach to isolate that portion of the UA Doppler waveform that arises from a pulse pressure wave propagating backward along the UA. Ultrasound measurements of UA lumen diameter and flow waveforms were used to decompose the observed flow waveform into its forward and reflected components. Evaluation of CD1 and C57BL/6 mice at embryonic day (E)15.5 and E17.5 demonstrated that the reflected waveforms diverged between the strains at E17.5, mirroring known changes in the fractal geometry of fetoplacental arteries at these ages. These experiments demonstrate the feasibility of noninvasively measuring wave reflections that originate from the fetoplacental circulation. The observed reflections were consistent with theoretical predictions based on the area ratio of parent to daughters at bifurcations in fetoplacental arteries suggesting that this approach could be used in the diagnosis of fetoplacental vascular pathology that is prevalent in human IUGR. Given that the proposed measurements represent a subset of those currently used in human fetal surveillance, the adaptation of this technology could extend the diagnostic utility of Doppler ultrasound in the detection of placental vascular pathologies that cause IUGR. NEW & NOTEWORTHY Here, we describe a novel approach to noninvasively detect microvascular changes in the fetoplacental circulation using ultrasound. The technique is based on detecting reflection pulse pressure waves that travel along the umbilical artery. Using a proof-of-principle study, we demonstrate the feasibility of the technique in two strains of experimental mice., (Copyright © 2017 the American Physiological Society.)

Aerobic activity has been shown highly beneficial to brain health, yet much uncertainty still surrounds the effects of exercise on the functioning of cerebral microvasculature. This study used two-photon fluorescence microscopy to examine cerebral hemodynamic alterations as well as accompanying geometric changes in the cortical microvascular network following five weeks of voluntary exercise in transgenic mice endogenously expressing tdTomato in vascular endothelial cells to allow visualization of microvessels irrespective of their perfusion levels. We found a diminished microvascular response to a hypercapnic challenge (10% FiCO 2 ) in running mice when compared to that in nonrunning controls despite commensurate increases in transcutaneous CO 2 tension. The flow increase to hypercapnia in runners was 70% lower than that in nonrunners (p = 0.0070) and the runners' arteriolar red blood cell speed changed by only half the amount seen in nonrunners (p = 0.0085). No changes were seen in resting hemodynamics or in the systemic physiological parameters measured. Although a few unperfused new vessels were observed on visual inspection, running did not produce significant morphological differences in the microvascular morphometric parameters, quantified following semiautomated tracking of the microvascular networks. We propose that voluntary running led to increased cortical microvascular efficiency and desensitization to CO 2 elevation.

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.