Increasing postpartum family planning uptake through group antenatal care: a longitudinal prospective cohort design

Abstract Background Despite significant improvements, postpartum family planning uptake remains low for women in sub-Saharan Africa. Transmitting family planning education in a comprehensible way during antenatal care (ANC) has the potential for long-term positive impact on contraceptive use. We followed women for one-year postpartum to examine the uptake and continuation of family planning following enrollment in group versus individual ANC. Methods A longitudinal, prospective cohort design was used. Two hundred forty women were assigned to group ANC (n = 120) or standard, individual care (n = 120) at their first ANC visit. Principal outcome measures included intent to use family planning immediately postpartum and use of a modern family planning method at one-year postpartum. Additionally, data were collected on intended and actual length of exclusive breastfeeding at one-year postpartum. Pearson chi-square tests were used to test for statistically significant differences between group and individual ANC groups. Odds ratios and adjusted odds ratios were calculated using logistic regression. Results Women who participated in group ANC were more likely to use modern and non-modern contraception than those in individual care (59.1% vs. 19%, p < .001). This relationship improved when controlled for intention, age, religion, gravida, and education (AOR = 6.690, 95% CI: 2.724, 16,420). Women who participated in group ANC had higher odds of using a modern family planning method than those in individual care (AOR = 8.063, p < .001). Those who participated in group ANC were more likely to exclusively breastfeed for more than 6 months than those in individual care (75.5% vs. 50%, p < .001). This relationship remained statistically significant when adjusted for age, religion, gravida, and education (AOR = 3.796, 95% CI: 1.558, 9.247). Conclusions Group ANC has the potential to be an effective model for improving the uptake and continuation of post-partum family planning up to one-year. Antenatal care presents a unique opportunity to influence the adoption of postpartum family planning. This is the first study to examine the impact of group ANC on family planning intent and use in a low-resource setting. Group ANC holds the potential to increase postpartum family planning uptake and long-term continuation. Trial registration Not applicable. No health related outcomes reported.https://deepblue.lib.umich.edu/bitstream/2027.42/146750/1/12978_2018_Article_644.pd

A mechanism for the suppression of homologous recombination in G1 cells

DNA repair by homologous recombination (HR)(1) is highly suppressed in G1 cells(2,3) to ensure that mitotic recombination occurs solely between sister chromatids(4). Although many HR factors are cell cycle-regulated, the identity of the events that are both necessary and sufficient to suppress recombination in G1 cells is unknown. Here we report that the cell cycle controls the interaction of BRCA1 with PALB2-BRCA2 in order to constrain BRCA2 function to the S/G2 phases. We found that the BRCA1-interaction site on PALB2 is targeted by an E3 ubiquitin ligase composed of KEAP1, a PALB2-interacting protein(5), in complex with CUL3-RBX1(6). PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11, which is itself under cell cycle control. Restoration of the BRCA1-PALB2 interaction combined with the activation of DNA end resection is sufficient to induce HR in G1, as measured by RAD51 recruitment, unscheduled DNA synthesis and a CRISPR/Cas9-based gene targeting assay. We conclude that the mechanism prohibiting HR in G1 minimally consists of the suppression of DNA end resection coupled to a multi-step block to BRCA2 recruitment to DNA damage sites that involves the inhibition of BRCA1-PALB2-BRCA2 complex assembly. We speculate that the ability to induce HR in G1 cells with defined factors could spur the development of gene targeting applications in non-dividing cells

The CIP2A–TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer

BRCA1/2-mutated cancer cells adapt to the genome instability caused by their deficiency in homologous recombination (HR). Identification of these adaptive mechanisms may provide therapeutic strategies to target tumors caused by the loss of these genes. In the present study, we report genome-scale CRISPR-Cas9 synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells and identify CIP2A as an essential gene in BRCA1- and BRCA2-mutated cells. CIP2A is cytoplasmic in interphase but, in mitosis, accumulates at DNA lesions as part of a complex with TOPBP1, a multifunctional genome stability factor. Unlike PARP inhibition, CIP2A deficiency does not cause accumulation of replication-associated DNA lesions that require HR for their repair. In BRCA-deficient cells, the CIP2A-TOPBP1 complex prevents lethal mis-segregation of acentric chromosomes that arises from impaired DNA synthesis. Finally, physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient tumors, indicating that CIP2A represents an attractive synthetic lethal therapeutic target for BRCA1- and BRCA2-mutated cancers

The MMS22L-TONSL Complex Mediates Recovery from Replication Stress and Homologous Recombination

Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks

HELB Is a Feedback Inhibitor of DNA End Resection.

DNA double-strand break repair by homologous recombination is initiated by the formation of 3' single-stranded DNA (ssDNA) overhangs by a process termed end resection. Although much focus has been given to the decision to initiate resection, little is known of the mechanisms that regulate the ongoing formation of ssDNA tails. Here we report that DNA helicase B (HELB) underpins a feedback inhibition mechanism that curtails resection. HELB is recruited to ssDNA by interacting with RPA and uses its 5'-3' ssDNA translocase activity to inhibit EXO1 and BLM-DNA2, the nucleases catalyzing resection. HELB acts independently of 53BP1 and is exported from the nucleus as cells approach S phase, concomitant with the upregulation of resection. Consistent with its role as a resection antagonist, loss of HELB results in PARP inhibitor resistance in BRCA1-deficient tumor cells. We conclude that mammalian DNA end resection triggers its own inhibition via the recruitment of HELB