Search

Background: Surrogate Decision-Makers (surrogates) are frequently employed in decision-making for critically ill adults. There are insufficient data considering the surrogate experience, stress, and potential for mitigation. Methods: An anonymous online survey queried (1) medical situation (2) total stress (3) demographics (4) potential factors, including sources of information about patient wishes, external sources of support or competing stressors, and their interactions with the medical team through the experience. Results: 108 respondents were included; 91 completed all items. Most respondents ranked their experience as a surrogate as one of the most stressful experiences of their lives; this was associated with whether it was an end-of-life decision (P =.003), Respondent Religion (P =.015), or religious or spiritual beliefs (P =.024), and having their own health problems (P =.008). On individual Likert responses, surrogates reported significant stress mitigation when they felt they had been helpful (P <.001), knew the patient's wishes (P =.0011), specifically discussed patient wishes (P <.001), or patient's wishes were documented (P <.001). Items about surrogate-team interaction also met significance, including the physician being communicative and available (P <.001), respectful (P =.007), honest (P <.001), and validating (P =.001). Conclusions: Surrogate stress is an evolving area for research. Significant factors included relationship with the medical team, making this an important area for HPM to play a key role in mitigating surrogate stress. [ABSTRACT FROM AUTHOR]

The Saccharomyces cerevisiae polo-like kinase Cdc5 promotes adaptation to the DNA damage checkpoint, in addition to its numerous roles in mitotic progression. The process of adaptation occurs when cells are presented with persistent or irreparable DNA damage and escape the cell-cycle arrest imposed by the DNA damage checkpoint. However, the precise mechanism of adaptation remains unknown. We report here that CDC5 is dose-dependent for adaptation and that its overexpression promotes faster adaptation, indicating that high levels of Cdc5 modulate the ability of the checkpoint to inhibit the downstream cell-cycle machinery. To pinpoint the step in the checkpoint pathway at which Cdc5 acts, we overexpressed CDC5 from the GAL1 promoter in damaged cells and examined key steps in checkpoint activation individually. Cdc5 overproduction appeared to have little effect on the early steps leading to Rad53 activation. The checkpoint sensors, Ddc1 (a member of the 9-1-1 complex) and Ddc2 (a member of the Ddc2/Mec1 complex), properly localized to damage sites. Mec1 appeared to be active, since the Rad9 adaptor retained its Mec1 phosphorylation. Moreover, the damage-induced interaction between phosphorylated Rad9 and Rad53 remained intact. In contrast, Rad53 hyperphosphorylation was significantly reduced, consistent with the observation that cell-cycle arrest is lost during adaptation. Thus, we conclude Cdc5 acts to attenuate the DNA damage checkpoint through loss of Rad53 hyperphosphorylation to allow cells to adapt to DNA damage. Polo-like kinase homologs have been shown to inhibit the ability of Claspin to facilitate the activation of downstream checkpoint kinases, suggesting that this function is conserved in vertebrates.

Background: Spermatozoa with the highest motility retain a superior genomic integrity, and elevated sperm chromatin fragmentation (SCF) has been linked to a lower ability of the conceptus to develop and implant. Therefore, the utilization of a sperm selection method, such as microfluidic sperm selection (MFSS), is capable of reducing the SCF by yielding the most motile fraction of spermatozoa with the highest embryo developmental competence. What remains unclear, however, is the causal mechanism that links SCF to an impaired embryo development. Objectives: To identify a relationship between SCF and an unexpectedly high proportion of embryo aneuploidy, while addressing treatment options. Materials and methods: We identified couples with a high incidence of embryo aneuploidy in a previous intracytoplasmic sperm injection (ICSI) cycle with pre‐implantation genetic testing for aneuploidy (PGT‐A), utilizing spermatozoa selected by density gradient (DG). Terminal deoxynucleotidyl dUTP transferase nick‐end labeling (TUNEL) and neutral Comet assays were carried out on the semen specimens to assess total SCF and double‐stranded DNA (dsDNA) fragmentation, respectively. These couples underwent subsequent ICSI/PGT‐A cycles with MFSS. Total SCF and dsDNA fragmentation were compared between the two sperm selection methods. Embryo aneuploidy, implantation, clinical pregnancy, delivery, and pregnancy loss rates were compared between the couples' historical DG and subsequent MFSS cycles. Results: In 57 couples undergoing 71 ICSI/PGT‐A cycles, where DG sperm selection was carried out, a high incidence of aneuploid embryos (74.7%) resulted in poor implantation and no viable pregnancies. Testing for SCF, inclusive of dsDNA breaks, evidenced a SCF of 26.2% and dsDNA break of 3.6% in the raw specimen, that decreased to 18.0% (p < 0.001) and 3.1%, respectively, in the DG processed specimen. Following MFSS, total SCF and dsDNA fragmentation decreased to 1.9% and 0.3%, respectively (p < 0.001). The embryo euploidy rate remarkable improved from 25.3% in the DG cycles to 42.9% in the MFSS cycles (p < 0.001). The 6.7% implantation rate in the DG cycles increased to 65.5% in the MFSS cycles (p < 0.001). Similarly, the clinical pregnancy rate rose from 10.5% (DG) to 64.6% (MFSS), resulting in a 62.5% delivery rate (p < 0.001). Discussion and conclusions: In couples with a relatively young female partner with a negative infertility workup, and a male partner with semen parameters adequate for ICSI, presenting with a high rate of embryo aneuploidy, an additional subtle male factor component may be the culprit. Thus, it is crucial to assess the SCF and test for the dsDNA breaks, which can eventually contribute to embryo chromosomal abnormalities. Given the inverse relationship between SCF and motility, a selection of the most motile gamete by MFSS enhanced the proportion of spermatozoa with an intact genome, contributing to the generation of more euploid embryos that are capable of implanting and yielding increased term pregnancies. [ABSTRACT FROM AUTHOR]