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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
BACKGROUND
Cryopreservation extends platelet (PLT) shelf life from 5 to 7 days to 2 to 4 years. However, only 73 patients have been transfused cryopreserved PLTs in published randomized controlled ...trials (RCTs), making safety data insufficient for regulatory approval.
STUDY DESIGN AND METHODS
The Cryopreserved vs. Liquid Platelet (CLIP) study was a double‐blind, pilot, multicenter RCT involving high‐risk cardiothoracic surgical patients in four Australian hospitals. The objective was to test, as the primary outcome, the feasibility and safety of the protocol. Patients were allocated to study group by permuted block randomization, with patients and clinicians blinded by use of an opaque shroud placed over each study PLT unit. Up to 3 units of cryopreserved or liquid‐stored PLTs were administered per patient. No other aspect of patient care was affected. Adverse events were actively sought.
RESULTS
A total of 121 patients were randomized, of whom 23 received cryopreserved PLTs and 18 received liquid‐stored PLTs. There were no differences in blood loss (median, 715 mL vs. 805 mL at 24 hr; difference between groups 90 mL 95% CI, –343.8 to 163.8 mL, p = 0.41), but the Bleeding Academic Research Consortium criterion for significant postoperative hemorrhage in cardiac surgery composite bleeding endpoint occurred in nearly twice as many patients in the liquid‐stored group (55.6% vs. 30.4%, p = 0.10). Red blood cell transfusion requirements were a median of 3 units in the cryopreserved group versus 4 units with liquid‐stored PLTs (difference between groups, 1 unit 95% CI, –3.1 to 1.1 units; p = 0.23). Patients in the cryopreserved group were more likely to be transfused fresh‐frozen plasma (78.3% vs. 27.8%, p = 0.002) and received more study PLT units (median, 2 units vs. 1 unit; difference between groups, 1 unit 95% CI, –0.03 to 2.0 units; p = 0.012). There were no between‐group differences in potential harms including deep venous thrombosis, myocardial infarction, respiratory function, infection, and renal function. No patient had died at 28 days, and postoperative length of stay was similar in each group.
CONCLUSION
In this pilot RCT, compared to liquid‐stored PLTs, cryopreserved PLTs were associated with no evidence of harm. A definitive study testing safety and hemostatic effectiveness is warranted.
See editorial on page 2759–2762, in this issue
This quantitative study was conducted at a private international high school. The study purpose was to investigate United States college trends comparing International Baccalaureate Diploma Program ...candidates and International Baccalaureate Non-Diploma Program candidates from the same school in Asia. Data was collected for the Classes of 2007-2012 and the two groups were compared based on the number of college acceptances and the eventual collegiate success of the two groups once they matriculated to college, as measured by college persistence and graduation rates. The information analyzed provides data to explore the final educational outcomes for International Baccalaureate graduates and determine if there is a significant difference in the college success of the two groups.
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