My daughter's daughter: the tragedy of late stage miscarriage.

This article sets out my observations of my daughter's difficult pregnancy and late-stage miscarriage. I share this information to raise awareness that the specialist support for women going through this is not always in place and doesn't fully prepare women for this experience. Even though this can be uncomfortable for maternity professionals, the care that women receive, especially during labour and birth, has a massive impact on them and their families. There are many opportunities for midwives to make a positive difference at this difficult time. My granddaughter, Jess, died at five months gestation and was later confirmed to have Turner Syndrome. Turner Syndrome is a chromosomal abnormality that only affects girls and is related to the partial or complete deletion of the X chromosome. Not all affected girls are miscarried and an estimated one in 2000 girls born in the UK has Turner Syndrome.

Robotic Cytoreductive Surgery With Heated Intraperitoneal Chemotherapy.

Cytoreductive surgery with heated intraperitoneal chemotherapy (CRS-HIPEC) is traditionally an open operation given the dissection required during cytoreduction. There are reports of minimally invasive HIPECs, but CRS to an accepted completeness of cytoreduction (CCR) has been described less frequently. We report a patient with metastatic low-grade mucinous appendiceal neoplasm (LAMN) to the peritoneum treated with robotic CRS-HIPEC. A 49-year-old male presented to our center following a laparoscopic appendectomy at an outside facility with final pathology showing LAMN. He had a peritoneal cancer index (PCI) score of 5 determined by diagnostic laparoscopy. Given the small amount of peritoneal disease, he was deemed a candidate for robotic CRS-HIPEC. Cytoreduction was completed robotically with a CCR score of 0. He then received HIPEC with mitomycin C. This case shows the feasibility of robotic-assisted CRS-HIPEC for select LAMNs. When appropriately selected, we advocate for the continued use of this minimally invasive approach.

Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC. SIGNIFICANCE: To improve the efficacy of immunotherapy in PDAC, there is a great need to understand the PDAC TIL landscape. This study represents a reference of PDAC TIL subpopulations and their relationships and provides a foundation upon which to base future immunotherapeutic efforts. This article is highlighted in the In This Issue feature, p. 2221.

A review on the motivations, decision-making factors, attitudes and experiences of couples using pre-implantation genetic testing for inherited conditions.

BACKGROUND: In pre-implantation genetic testing (PGT), fertile couples undergo IVF with genetic testing of embryos to avoid conceptions with a genetic condition. There is an exponentially increasing uptake with over 600 applications listed by the Human Fertilisation and Embryology Authority in the UK. The psychological aspects of the decision-making process and the experience of PGT, however, are relatively underevaluated, with the potential to leave patients unsupported in their journeys. OBJECTIVE AND RATIONALE: In this review, we aim to comprehensively report on every aspect of couples' experiences of PGT. We consider what motivates users, the practical and ethical decisions involved and how couples navigate the decision-making process. Additionally, we report on the social and psychological impact on couples who are actively undergoing or have completed the PGT process. SEARCH METHODS: A systematic search of English peer-reviewed journals of three computerized databases was undertaken following PRISMA guidelines. Studies that examined the motivations, attitudes, decision-making factors and experiences of patients who have been actively engaged in the PGT process were included. No restrictions were placed on study design or date of publication. Studies examining patients using PGT in a hypothetical context or solely using PGT for aneuploidy were excluded. Qualitative data were extracted using thematic analysis. OUTCOMES: The main outcomes were patient motivations, deciding factors and attitudes, as well as the patient experience of coming to a decision and going through PGT.Patients were primarily motivated by the desire to have a healthy child and to avoid termination of pregnancy. Those with a sick child or previous experience of termination were more likely to use PGT. Patients also felt compelled to make use of the technology available, either from a moral responsibility to do so or to avoid feelings of guilt if not. The main factors considered when deciding to use PGT were the need for IVF and the acceptability of the technology, the financial cost of the procedure and one's ethical standpoint on the creation and manipulation of embryos. There was a general consensus that PGT should be applied to lethal or severe childhood disease but less agreement on use for adult onset or variable expression conditions. There was an agreement that it should not be used to select for aesthetic traits and a frustration with the views of PGT in society. We report that couples find it difficult to consider all of the benefits and costs of PGT, resulting in ambivalence and prolonged indecision. After deciding on PGT use, we found that patients find the process extremely impractical and psychologically demanding. WIDER IMPLICATIONS: This review aimed to summarize the current knowledge on how patients decide to use and experience PGT and to make suggestions to incorporate the findings into clinical practice. We cannot stress enough the importance of holistic evaluation of patients and thorough counselling prior to and during PGT use from a multidisciplinary team that includes geneticists, IVF clinicians, psychologists and also patient support groups. Large prospective studies using a validated psychological tool at various stages of the PGT process would provide an invaluable database for professionals to better aid patients in their decision-making and to improve the patient experience.

Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/ß-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and ß-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis. SIGNIFICANCE: Oncogenic KRAS and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic KRAS effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis.This article is highlighted in the In This Issue feature, p. 1861.

Implementing a patient assessment framework in acute care.

This article describes the secondment of a critical care practitioner to an acute medicine unit. The aim was to develop the acute assessment skills of the unit's nurses and to implement a new assessment framework. The secondment took place over four months from December 2007 to March 2008 at the Heart of England NHS Foundation Trust, Birmingham. There were several stages to the project, commencing with exploration of existing practice and culminating with evaluation of the project's effect on practice. A review of the multi-professional patient records was conducted six months after the conclusion of the secondment. This revealed that the assessment framework continued to be used in practice. The secondment demonstrated that supporting nurses to embrace new skills resulted in a change in practice. However, a permanent change cannot be assured unless practice is revisited and supported on a continual basis.

Social support during adolescent pregnancy: piecing together a quilt.

OBJECTIVE: To investigate pregnant adolescents' experiences of receiving support, including variations by age. DESIGN: The study was guided by feminist theory. SETTING: An alternative, public school for pregnant and parenting adolescents in an urban area of the Southern United States. PARTICIPANTS: Participants (n = 30) consisted of 6 early (13-14), 19 middle (15-16), and 5 late (17-18) adolescents. Nineteen of the participants were African American, 10 European American, and 1 Asian American. METHOD: A qualitative research design based on feminist theory with data collected through focus groups. The focus groups were audio-taped, transcribed verbatim, and checked against the first author's field notes, then analyzed using principles of analytic induction. Group interaction and influence were considered. RESULTS: The metaphor of a patchwork quilt emerged from the data and represented how adolescents "piece together" the support they need from adults, peers, and partners who are often unreliable. Affecting receipt of social support were the adolescents' relationships with their families and their babies' fathers, threats to their safety, and their socioeconomic status. CONCLUSIONS: These findings can be used by nurses, educators, and community leaders as they develop programs to meet the needs of these young women.