Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in the mouse uterus.

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.

Simultaneous heart-kidney transplant compared with heart transplant alone in patients with borderline renal function who are not dialysis dependent.

OBJECTIVE: This study assessed characteristics and outcomes of patients who are not dependent on dialysis receiving simultaneous heart kidney transplantation versus heart transplantation alone (HTA) to identify optimal eGFR threshold where combined transplant strategy may be superior. METHODS: This study retrospectively analyzed 7896 adult patients with estimated glomerular filtration rate (eGFR) <60 mL/minute from the United Network for Organ Sharing database who received HTA or simultaneous heart kidney transplant between 2005 and 2021, excluding those who received pretransplant dialysis. Subjects were further stratified into 3 groups based on chronic kidney disease stage at time of transplant: Stage 3A (eGFR 45-59 mL/minute; n = 5044), Stage 3B (eGFR 30-44 mL/minute; n = 2193), and Stage 4 or 5 (eGFR <30 mL/minute; n = 659). Outcomes of interest were all-cause mortality, cardiac allograft failure, and freedom from chronic dialysis or renal transplant following heart transplant. RESULTS: Simultaneous heart kidney transplant and HTA recipients differed in various baseline characteristics. Simultaneous heart kidney transplant recipients with eGFR <45 mL/minute had greater short- and long-term overall survival and cardiac allograft survival compared with HTA, as well as greater long-term freedom from chronic dialysis or renal transplant. These results were consistent with both propensity matched analyses and multivariable Cox regression analysis of 10 year outcomes. Optimal cutoff value for pretransplant eGFR in predicting elevated risk of renal failure in recipients of heart transplant alone was found to be eGFR ∼45 mL/minute. CONCLUSIONS: Similar to patients with eGFR <30 mL/minute, patients with eGFR 30 to 44 mL/minute who underwent simultaneous heart kidney transplant had superior outcomes compared with HTA, suggesting possible benefit of combined transplant strategy for this subset of heart transplant candidates.

Do age and functional dependence affect outcomes of simultaneous heart-kidney transplantation?

Objective: This study assessed characteristics and outcomes of younger (18-65) versus older (>65) recipients of simultaneous heart-kidney (SHK) transplantation with varying functional dependence. Methods: This study retrospectively analyzed 1398 patients from the United Network for Organ Sharing database who received SHK between 2010 and 2021. Patients who were <18 year old, underwent transplant of additional organs simultaneously, or had previous heart transplant were excluded. The primary end point was all-cause mortality, and secondary end points included adverse events and cause of death. Outcomes were also evaluated by propensity score-matched comparison. Results: The number of annual SHK transplantation in the United States has significantly increased among both age groups over the past 2 decades (P < .0001). After propensity score matching of recipients aged 18 to 65 years (n = 1162) versus age >65 years (n = 236), baseline characteristics were similar and well-balanced between the 2 cohorts. Between matched cohorts, older recipients did not have increased posttransplant mortality compared with younger recipients (90-day survival, P = .85; 7-year survival, P = .61). Multivariable Cox regression analysis found that age (hazard ratio [HR], 1.039 [0.975-1.106], P = .2415) and pretransplant functional status with interaction term for age (some assistance, HR, 0.965 [0.902-1.033], P = .3079; total assistance, HR, 0.976 [0.914-1.041], P = .4610) were not significant risk factors for 7-year post-SHK transplantation mortality. Conclusions: Older and more functionally dependent recipients in this study did not have increased post-SHK transplantation mortality. These findings have important implications for organ allocation among elderly patients, as they support the need for thorough assessment of SHK candidates in terms of comorbidities, rather than exclusion solely based on age and functional dependence.

Chromatin remodeling of prostaglandin signaling in smooth muscle enables mouse embryo passage through the female reproductive tract.

Early mammalian development occurs during embryo transit of the female reproductive tract. Transport is orchestrated by secreted oviduct fluid, unidirectional beating of epithelial cilia, and smooth muscle contractions. Using gene-edited mice, we document that conditional disruption of a component of the SWI/SNF chromatin remodeling complex in smooth muscle cells prevents transport through the oviduct without perturbing embryogenesis. Analysis with RNA sequencing (RNA-seq), transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunocleavage sequencing (ChIC-seq), and pharmacologic rescue experiments implicated prostaglandin signaling pathways. In comparison with controls, gene-edited mice had compromised chromatin accessibility at enhancer/promoters of Ptgs2, Pla2g16, Pla2r1, and Ptger3 (EP3) as well as decreased enhancer-promoter interactive looping critical for Ptgs2 (aka Cox-2) expression in a SWI/SNF complex-dependent manner. Treatment of wild-type mice with prostaglandin inhibitors phenocopied the genetically induced defect.

Germ cell-specific eIF4E1b regulates maternal mRNA translation to ensure zygotic genome activation.

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 remain unknown. Using gene-edited mice, we document that the oocyte-specific eukaryotic translation initiation factor 4E family member 1b (eIF4E1b) is the regulator of maternal mRNA expression that ensures subsequent reprogramming of the zygotic genome. In oocytes, eIF4E1b binds to transcripts encoding translation machinery proteins, chromatin remodelers, and reprogramming factors to promote their translation in zygotes and protect them from degradation. The protein products are thought to establish an open chromatin landscape in one-cell zygotes to enable transcription of genes required for cleavage stage development. Our results define a program for rapid resetting of the zygotic epigenome that is regulated by maternal mRNA expression and provide new insights into the mammalian maternal-to-zygotic transition.

GLUT1 overexpression enhances glucose metabolism and promotes neonatal heart regeneration.

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.

Access to oral health care for people living with HIV/AIDS attending a community-based program.

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. Audiorecordings 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 difficulté à accéder à des services de santé buccodentaire, principalement en raison de la stigmatisation et de la discrimination associées au VIH. En 2011, le Programme de baccalauréat en hygiène dentaire de l'Université de la Colombie-Britannique (UBC) a mis en place un programme de services de santé buccodentaire préventifs à la Positive Living Society of British Columbia (PLSBC), un organisme sans but lucratif soutenant les GVAVS. La présente étude vise à évaluer la perception de la façon dont ce type de prestation de service a influencé l'accès aux soins de santé buccodentaire pour les membres de la PLSBC. Méthodologie: Des entrevues personnelles ont été menées avec 10 membres et un groupe de discussion comprenant 12 membres du personnel. Les enregistrements sonores ont été transcrits mot à mot et codés par thème. Des thèmes émergents ont été ciblés au moyen de l'approche phénoménologique et interprétative, fondée sur la théorie sur l'accès de Penchansky et Thomas. Résultats: Le programme a aidé les membres à maximiser leur couverture dentaire afin de pouvoir recevoir d'autres types de services dentaires. Les membres qui ont été influencés par des expériences traumatiques précédentes ont été reconnaissants que les services aient été fournis de façon sécuritaire et dans un milieu exempt de stigmatisation. Les membres ont aimé avoir l'occasion d'éduquer les futurs professionnels dentaires en vue de réduire la stigmatisation liée au VIH. Cependant, les besoins dentaires qui ne pouvaient pas être satisfaits par le programme sont demeurés non traités pour certains membres qui ont continué à faire face à des obstacles en matière de soins aux cliniques de renvois. Conclusion: Ce programme dentaire préventif offert en milieu communautaire fournit des soins dentaires à prix abordables, un milieu libre de stigmatisation, des soins offerts de manière sécuritaire, une occasion de formation et un emplacement accessible, qui semblent tous avoir une influence positive sur l'accès aux soins de santé buccodentaire des membres de la PLSBC. Cependant, l'accessibilité limitée du programme a empêché plusieurs membres d'avoir accès à des soins de santé buccodentaire complets et cela est un élément qui doit être abordé.

Evaluating Point-of-Care HIV Screening in Dental Hygiene Education Settings: Patient, Faculty, and Student Perspectives.

Although HIV screening is needed at a wider range of sites, dentists have shown reluctance to incorporate screening in their practices, but dental hygiene settings may be better suited for such screenings. The aim of this mixed-methods study was to determine the feasibility and acceptability of point-of-care (POC) HIV screening in dental hygiene education community settings from the patient, faculty, and student perspectives. After training, dental hygiene students and faculty at a Canadian dental school offered POC HIV screening to patients as part of routine dental hygiene care over 36 weeks at four sites in 2015-16. Of the 199 patients offered screening, 78 agreed; no positive results were found. Of the 199 patients, 97 completed an 11-item survey (49% response rate), with 80 (82%) agreeing HIV screening was within the scope of practice of a dental professional. Of the 57 patients who were screened, 48 (84%) agreed POC HIV screening should be part of regular dental check-ups, and 52 (91%) perceived dental settings were appropriate sites for screening. The main reasons for patients' agreeing to screening were that it was free and convenient and the results were delivered quickly. Those who refused screening had been tested recently or did not perceive themselves at risk for HIV. In two focus groups with 12 dental hygiene students, one focus group with five faculty members, and individual interviews with five other faculty members, participants agreed on the importance of offering POC HIV screening in the dental setting as a public health service. Faculty members thought students were well prepared and increased in confidence with testing. Students expressed a desire to offer screening throughout their careers and to educate patients about the importance of HIV testing.