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Early gestational loss occurs in approximately 20% of all clinically recognized human pregnancies and is an important cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. We report that the switch/sucrose nonfermentable (SWI/SNF) remodeling complex containing polybromo-1 (PBRM1) and Brahma-related gene 1 (BRG1) is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although preimplantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathways and uterine receptivity. Heart and neural crest derivatives expressed 2 (Hand2) encodes a basic helix-loop-helix (bHLH) transcription factor required for embryo implantation. We identify an enhancer of the Hand2 gene in stromal cells that requires PBRM1 for epigenetic histone modifications/coactivator recruitment and looping with the promoter. In Pbrm1cKO mice, perturbation of chromatin assembly at the promoter and enhancer sites compromises Hand2 transcription, adversely affects fibroblast growth factor signaling pathways, prevents normal stromal-epithelial crosstalk, and disrupts embryo implantation. The mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.

The mammalian heart switches its main metabolic substrate from glucose to fatty acids shortly after birth. This metabolic switch coincides with the loss of regenerative capacity in the heart. However, it is unknown whether glucose metabolism regulates heart regeneration. Here, we report that glucose metabolism is a determinant of regenerative capacity in the neonatal mammalian heart. Cardiac-specific overexpression of Glut1, the embryonic form of constitutively active glucose transporter, resulted in an increase in glucose uptake and concomitant accumulation of glycogen storage in postnatal heart. Upon cryoinjury, Glut1 transgenic hearts showed higher regenerative capacity with less fibrosis than non-transgenic control hearts. Interestingly, flow cytometry analysis revealed two distinct populations of ventricular cardiomyocytes: Tnnt2-high and Tnnt2-low cardiomyocytes, the latter of which showed significantly higher mitotic activity in response to high intracellular glucose in Glut1 transgenic hearts. Metabolic profiling shows that Glut1-transgenic hearts have a significant increase in the glucose metabolites including nucleotides upon injury. Inhibition of the nucleotide biosynthesis abrogated the regenerative advantage of high intra-cardiomyocyte glucose level, suggesting that the glucose enhances the cardiomyocyte regeneration through the supply of nucleotides. Our data suggest that the increase in glucose metabolism promotes cardiac regeneration in neonatal mouse heart.

Early gestational loss occurs in approximately 20% of all clinically recognized human pregnancies and is an important cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. We report that the switch/sucrose nonfermentable (SWI/SNF) remodeling complex containing polybromo-1 (PBRM1) and Brahma-related gene 1 (BRC1) is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although preimplantation development is unaffected, conditional ablation of Pbrml in uterine stromal cells disrupts progesterone pathways and uterine receptivity. Heart and neural crest derivatives expressed 2 (Hand2) encodes a basic helix-loop-helix (bHLH) transcription factor required for embryo implantation. We identify an enhancer of the Hand2 gene in stromal cells that requires PBRM1 for epigenetic histone modifications/coactivator recruitment and looping with the promoter. In PbrmTK0 mice, perturbation of chromatin assembly at the promoter and enhancer sites compromises Hand2 transcription, adversely affects fibroblast growth factor signaling pathways, prevents normal stromalepithelial crosstalk, and disrupts embryo implantation. The mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.

Objective: People living with HIV/AIDS (PLWHA) have difficulty accessing oral health services primarily due to HIV-related stigma and discrimination. In 2011, the University of British Columbia (UBC) Dental Hygiene Degree Program implemented a preventive oral health services program at the Positive Living Society of British Columbia (PLSBC), a non-profit organization supporting PLWHA. This study aims to assess the perception of how this type of service delivery influenced access to oral health care for members of PLSBC. Methods: Personal interviews with 10 members and one focus group comprising 12 staff were conducted. Audio-recordings were transcribed verbatim and coded thematically. Emerging themes were identified using the interpretative phenomenology approach following Penchansky and Thomas' theory of access. Results: The program helped members maximize their dental coverage to receive other types of dental services. Members who were influenced by past traumatic experiences appreciated that services were delivered in a safe manner and in a stigma-free setting. Members valued the opportunity to educate future dental professionals to reduce HIV-related stigma. However, dental needs that could not be addressed by the program remained untreated for some members who continued to face barriers to care at referral clinics. Conclusion: This community-based preventive dental program provided affordable dental care, a stigma-free setting, care delivered in a safe manner, an educational opportunity, and accessible location, which all seemed to have a positive influence on access to oral health care for members of PLSBC. However, the limited availability of the program prevented many members from accessing comprehensive oral health care and is a factor that should be addressed. Objectif: Les gens qui vivent avec le VIH/SIDA (GVAVS) ont de la difficulte a acceder a des services de sante buccodentaire, principalement en raison de la stigmatisation et de la discrimination associees au VIH. En 2011, le Programme de baccalaureat en hygiene dentaire de l'Universite de la Colombie-Britannique (UBC) a mis en place un programme de services de sante buccodentaire preventifs a la Positive Living Society of British Columbia (PLSBC), un organisme sans but lucratif soutenant les GVAVS. La presente etude vise a evaluer la perception de la facon dont ce type de prestation de service a influence l'acces aux soins de sante buccodentaire pour les membres de la PLSBC. Methodologie: Des entrevues personnelles ont ete menees avec 10 membres et un groupe de discussion comprenant 12 membres du personnel. Les enregistrements sonores ont ete transcrits mot a mot et codes par theme. Des themes emergents ont ete cibles au moyen de l'approche phenomenologique et interpretative, fondee sur la theorie sur l'acces de Penchansky et Thomas. Resultats: Le programme a aide les membres a maximiser leur couverture dentaire afin de pouvoir recevoir d'autres types de services dentaires. Les membres qui ont ete influences par des experiences traumatiques precedentes ont ete reconnaissants que les services aient ete fournis de facon securitaire et dans un milieu exempt de stigmatisation. Les membres ont aime avoir l'occasion d'eduquer les futurs professionnels dentaires en vue de reduire la stigmatisation liee au VIH. Cependant, les besoins dentaires qui ne pouvaient pas etre satisfaits par le programme sont demeures non traites pour certains membres qui ont continue a faire face a des obstacles en matiere de soins aux cliniques de renvois. Conclusion: Ce programme dentaire preventif offert en milieu communautaire fournit des soins dentaires a prix abordables, un milieu libre de stigmatisation, des soins offerts de maniere securitaire, une occasion de formation et un emplacement accessible, qui semblent tous avoir une influence positive sur l'acces aux soins de sante buccodentaire des membres de la PLSBC. Cependant, l'accessibilite limitee du programme a empeche plusieurs membres d'avoir acces a des soins de sante buccodentaire complets et cela est un element qui doit etre aborde. Keywords: access, community-based preventive dental program, HIV/AIDS, oral health care, people living with HIV/AIDS, stigma CDHA Research Agenda category: access to care and unmet needs

Abstract OBJECTIVES This study sought to demonstrate outcomes of veno-arterial extracorporeal life support (VA-ECLS) in non-intubated (‘awake’) patients with cardiogenic shock, as very few studies have investigated safety and feasibility in this population. METHODS This was a retrospective review of 394 consecutive VA-ECLS patients at our institution from 2017 to 2021. We excluded patients cannulated for indications definitively associated with intubation. Patients were stratified by intubation status at time of cannulation and baseline differences were balanced by inverse probability of treatment weighting. The primary outcome was in-hospital mortality while secondary outcomes included adverse events during ECLS and destination at discharge. RESULTS Out of 135 patients in the final cohort, 79 were intubated and 56 were awake at time of cannulation. All awake patients underwent percutaneous femoral cannulation with technical success of 100% without intubation. Indications for VA-ECLS in awake patients included acute decompensated heart failure (64.3%), pulmonary hypertension or massive pulmonary embolism (12.5%), myocarditis (8.9%) and acute myocardial infarction (5.4%). After adjustment, awake and intubated patients had similar ECLS duration (7 vs 6 days, P = 0.19), in-hospital mortality (39.6% vs 51.7%, P = 0.28), and rates of various adverse events. Intubation status was not a significant risk factor for 90-day mortality (hazard ratio [95% confidence interval]: 1.26 [0.64, 2.45], P = 0.51) in multivariable analysis. Heart transplantation (15.1% vs 4.9%) and ventricular assist device (17.4% vs 2.2%) were more common destinations at discharge in awake patients than intubated patients (P = 0.02). CONCLUSIONS Awake VA-ECLS is safe and feasible with comparable outcomes as intubated counterparts in select cardiogenic shock patients. Veno-arterial extracorporeal life support (VA-ECLS) has increasingly become an important tool in the treatment of patients with refractory cardiogenic shock (RCS) [1]. Graphical abstract

Translation of maternal mRNAs is detected before transcription of zygotic genes and is essential for mammalian embryo development. How certain maternal mRNAs are selected for translation instead of degradation and how this burst of translation affects zygotic genome activation remains unknown. Using gene-edited mice, we document that the eukaryotic translation initiation factor 4E family member 1B (eIF4E1B) is the regulator of maternal mRNA translation that ensures subsequent reprogramming of the zygotic genome. In oocytes, the germ-cell specific eIF4E1B binds to mRNAs encoding chromatin remodeling complexes as well as reprogramming factors to protect them from degradation and promote their translation in zygotes. These protein products establish an open chromatin landscape in one-cell zygotes and enable transcription. Our results define a program for rapid resetting of the zygotic epigenome that is regulated by maternal mRNA translation and provides new insight into the mammalian maternal-to-zygotic transition. Competing Interest Statement The authors have declared no competing interest.

The mammalian heart switches its main metabolic substrate from glucose to fatty acids shortly after birth. This metabolic switch coincides with the loss of regenerative capacity in the heart. However, it is unknown whether glucose metabolism itself regulates heart regeneration. Here, we report that glucose metabolism is a determinant of regenerative capacity in the neonatal mammalian heart. Cardiac-specific overexpression of Glut1, the embryonic form of constitutively active glucose transporter, resulted in an increase in glucose uptake and concomitant glycogen storage in postnatal heart. Upon cryoinjury, Glut1 transgenic hearts showed higher regenerative capacity with less fibrosis than non-transgenic control hearts. Interestingly, flow cytometry analysis revealed two distinct populations of ventricular cardiomyocytes: Tnnt2-high and Tnnt2-low cardiomyocytes, the latter of which showed significantly higher mitotic activity in response to high intracellular glucose in Glut1 transgenic hearts. Metabolic profiling shows that Glut1-transgenic hearts have a significant increase in the glucose metabolites upon injury, and inhibition of the nucleotide biosynthesis abrogated the regenerative advantage of high intra-cardiomyocyte glucose level. Our data suggest that the increased in glucose metabolism promotes cardiac regeneration in neonatal mouse heart.