Isomerization of BRCA1-BARD1 promotes replication fork protection.

The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection.

Maternal exposure to intimate partner violence and breastfeeding practices in 51 low-income and middle-income countries: A population-based cross-sectional study.

BACKGROUND: Intimate partner violence (IPV) against women is a major global health issue, particularly in low- and middle-income countries (LMICs), that is associated with poor physical and mental health, but its association with breastfeeding practices is understudied. Both the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recommend that children initiate breastfeeding within the first hour of birth and be exclusively breastfed for the first 6 months of life. Breastfeeding within the first hour of birth is critical to newborn survival, and exclusive breastfeeding for 6 months is recognised to offer significant health benefits to mothers and their infants. We examined the association of maternal exposure to IPV with early initiation of breastfeeding (within 1 hour of birth) and exclusive breastfeeding in the first 6 months. METHODS AND FINDINGS: We assessed population-based cross-sectional Demographic and Health Surveys (DHS) from 51 LMICs. Data from the most recent DHS in each country (conducted between January 2000 and January 2019) with data available on IPV and breastfeeding practices were used. By WHO region, 52.9% (27/51) were from Africa, 11.8% (6/51) from the Americas, 7.8% (4/51) from the Eastern Mediterranean, 11.8% (6/51) from Europe, 11.8% (6/51) from South-East Asia, and 3.9% (2/51) from the Western Pacific. We estimated multilevel logistic regression models for any IPV and each type of IPV separately (physical violence, sexual violence, and emotional violence), accounting for demographic and socioeconomic factors. Depending on specification, the sample size varied between 95,320 and 102,318 mother-infant dyads. The mean age of mothers was 27.5 years, and the prevalence of any lifetime exposure to IPV among mothers was 33.3% (27.6% for physical violence, 8.4% for sexual violence, and 16.4% for emotional violence). Mothers exposed to any IPV were less likely to initiate breastfeeding early (adjusted odds ratio [AOR]: 0.88 [95% CI 0.85-0.97], p < 0.001) and breastfeed exclusively in the first 6 months (AOR: 0.87 [95% CI 0.82-0.92], p < 0.001). The associations were similar for each type of IPV and were overall consistent across infant's sex and WHO regions. After simultaneously adjusting for all 3 types of IPV, all 3 types of IPV were independently associated with decreased likelihood of early breastfeeding initiation, but only exposure to physical violence was independently associated with a decreased likelihood of exclusively breastfeeding in the first 6 months. The main limitations of this study included the use of cross-sectional datasets, the possibility of residual confounding of the observed associations by household wealth, and the possibility of underreporting of IPV experiences attenuating the magnitude of observed associations. CONCLUSIONS: Our study indicates that mothers exposed to any form of IPV (physical, sexual, or emotional violence) were less likely to initiate breastfeeding early and breastfeed exclusively in the first 6 months. These findings may inform the argument for antenatal screening for IPV in LMICs and the provision of services to not only improve mothers' safety and well-being, but also support them in adopting recommended breastfeeding practices.

Applying implementation science in the field of transplant and cellular therapy.

Implementation science (IS) is a systematic way to approach the broader adoption of evidence-based practices and has as its goal to understand and address the gap between research and practice, ensuring that research findings are effectively translated into practice and policy to improve health outcomes and service. We describe the various facets of IS and their relevance to the field of hematopoietic cell transplantation and cellular therapy (HCT/CT) with an emphasis on health equity, community engagement, and systems approach. We also review the similarities and differences among clinical research, quality improvement, and implementation science. Additionally, we describe how CIBMTR applies IS across various phases: dissemination, analyzing current practices, and developing implementation intervention strategies. This includes designing studies and evaluation, scaling up operations, and ensuring sustainability. Lastly, we discuss further applications of IS in HCT/CT including the application to prospective research studies, collaboration across the field, and standardization and adoption of best practices. The application of IS in HCT/CT is pivotal to bringing research benefits directly to all patients. Through partnership, open-mindedness, and a commitment to evidence-based practice, we can collectively ensure the greatest impact of research on improving patient outcomes following HCT/CT.

Reducing barriers of access and care related to hematopoietic cell transplantation and cellular therapy: The mission-driven role of the national marrow donor program.

The treatment of malignant and nonmalignant hematologic disorders continues to benefit from significant scientific advancement and progress in the use of hematopoietic cell transplantation and cellular therapies. However, barriers associated with receiving these lifesaving treatments and care remain, which necessitate innovative approaches to overcome, so all persons in need can receive these therapies. This article reviews barriers to receiving hematopoietic cell transplantation and cellular therapies, and highlights novel approaches taken by the National Marrow Donor Program in reducing barriers for all patients in need.

Enhancing Administrative Claims Data: Feasibility, Validation and Application of Linking Medicare Claims Data and National Marrow Donor Program Search Data.

PURPOSE: Administrative claims data provide real-world service utilization of acute myeloid leukemia (AML) treatment, but lacks insight into treatment delays or barriers. The National Marrow Donor Program (NMDP)/Be The Match Search (Search) data contains information on donor search, but lacks information on treatment received if allogeneic hematopoietic cell transplant (HCT) is not performed. We hypothesized that linking these two data sets would create a rich resource to define factors associated with receiving HCT that could not be evaluated with either data set alone. METHODS: A subset of 2010-2016 Medicare administrative claims data was linked with Search data. A total of 5,351 patients with AML age 65-74 years (HCT = 607, no HCT = 4,744) were identified using Medicare. These patients were then linked to 93,800 records with a donor search between 2009 and 2016. Patient date of birth, sex, disease, ZIP code, transplant center/hospital, and diagnosis date were used for matching. Exploratory analysis was conducted to identify predictors associated with receiving HCT for patients with AML who received a search. RESULTS: The data sets were successfully linked, showing high sensitivity and specificity. The final cohort included 5,085 patients with AML (HCT = 533, no HCT = 4,552). Of 97 patients who received HCT without a matched search, more than 85% received a related donor HCT. Of those not receiving HCT, 609 had a matched NMDP search and 3,943 did not have a matched NMDP search. Multivariate analysis showed time to search, age, diagnosis year, race/ethnicity, and neighborhood education status associated with receiving HCT. CONCLUSION: Methods herein demonstrate the feasibility of linking Search and Medicare data. Similar methods may be applied to answer critical questions regarding barriers to HCT, thereby identifying areas to improve access to care.

Prospective observational study of mechanical cardiopulmonary resuscitation, extracorporeal membrane oxygenation and early reperfusion for refractory cardiac arrest in Sydney: the 2CHEER study.

BACKGROUND: Patients with prolonged cardiac arrest that is not responsive to conventional cardiopulmonary resuscitation have poor outcomes. The use of extracorporeal membrane oxygenation (ECMO) in refractory cardiac arrest has shown promising results in carefully selected cases. We sought to validate the results from an earlier extracorporeal cardiopulmonary resuscitation (ECPR) study (the CHEER trial). METHODS: Prospective, consecutive patients with refractory in-hospital (IHCA) or out-of-hospital cardiac arrest (OHCA) who met predefined inclusion criteria received protocolised care, including mechanical cardiopulmonary resuscitation, initiation of ECMO, and early coronary angiography (if an acute coronary syndrome was suspected). RESULTS: Twenty-five patients were enrolled in the study (11 OHCA, 14 IHCA); the median age was 57 years (interquartile range [IQR], 39-65 years), and 17 patients (68%) were male. ECMO was established in all patients, with a median time from arrest to ECMO support of 57 minutes (IQR, 38-73 min). Percutaneous coronary intervention was performed on 18 patients (72%). The median duration of ECMO support was 52 hours (IQR, 24-108 h). Survival to hospital discharge with favourable neurological recovery occurred in 11/25 patients (44%, of which 72% had IHCA and 27% had OHCA). When adjusting for lactate, arrest to ECMO flow time was predictive of survival (odds ratio, 0.904; P = 0.035). CONCLUSION: ECMO for refractory cardiac arrest shows promising survival rates if protocolised care is applied in conjunction with predefined selection criteria.

AMPA-induced dark cell degeneration is associated with activation of caspases in pyramidal neurons of the rat hippocampus.

Various neurons in the central nervous system (CNS) exhibit selective vulnerability to AMPA-induced delayed neurotoxicity known as dark cell degeneration. Hippocampal pyramidal neurons in the CA1 and CA3 regions display such vulnerability that encompasses morphological changes including cytoplasmic and nuclear condensation, neuronal shrinkage, formation of cytoplasmic vacuoles, and general failure of physiology. The present study was undertaken to ascertain the potential involvement of initiator (caspase-9) and executor (caspase-3) caspases in AMPA-receptor-induced dark cell degeneration in pyramidal neurons. Immunohistochemical analyses revealed that immunoreactivity of the active form of caspase-9 and -3 was increased in pyramidal neurons in CA1 and CA3 regions of the hippocampus following AMPA (100 microM). Elevated levels of active caspase-9 immunoreactivity generally preceded elevations in active caspase-3 immunoreactivity. The pan caspase inhibitor FK011 effectively attenuated AMPA-induced dark cell degeneration in both CA1 and CA3 regions. Collectively, the data suggest a role for these caspases in mediating AMPA-induced toxicity in pyramidal neurons of the rat hippocampus.