Labial artery pseudoaneurysm following preterm vaginal delivery treated with ultrasound-guided thrombin injection: A case report.

This case describes the diagnosis and management of a pseudoaneurysm of the right labial artery. A 25-year-old primigravida woman at 33 weeks and 4 days of gestation delivered a live infant vaginally. A large vulvovaginal haematoma was diagnosed and was managed in theatre with an incision and drainage. A recurrence of the haematoma was suspected postoperatively given ongoing pain. Doppler ultrasonography and computerised tomography angiography confirmed the diagnosis of a vulvovaginal haematoma with an associated pseudoaneurysm. The arterial pseudoaneurysm was successfully managed prior to rupture using ultrasound-guided direct thrombin injection to promote local thrombosis. There were no immediate complications following the procedure.

Validation of ctDNA Quality Control Materials Through a Precompetitive Collaboration of the Foundation for the National Institutes of Health.

We report the results from a Foundation for the National Institutes of Health Biomarkers Consortium project to address the absence of well-validated quality control materials (QCMs) for circulating tumor DNA (ctDNA) testing. This absence is considered a cause of variance and inconsistencies in translating ctDNA results into clinical actions. METHODS: In this phase I study, QCMs with 14 clinically relevant mutations representing single nucleotide variants, insertions or deletions (indels), translocations, and copy number variants were sourced from three commercial manufacturers with variant allele frequencies (VAFs) of 5%, 2.5%, 1%, 0.1%, and 0%. Four laboratories tested samples in quadruplicate using two allele-specific droplet digital polymerase chain reaction and three (amplicon and hybrid capture) next-generation sequencing (NGS) panels. RESULTS: The two droplet digital polymerase chain reaction assays reported VAF values very close to the manufacturers' claimed concentrations for all QCMs. NGS assays reported most single nucleotide variants and indels, but not translocations, close to the expected VAF values. Notably, two NGS assays reported lower VAF than expected for all translocations in all QCM mixtures, possibly related to technical challenges detecting these variants. The ability to call ERBB2 copy number amplifications varied across assays. All three QCMs provided valuable insight into assay precision. Each assay across all variant types demonstrated dropouts at 0.1%, suggesting that the QCM can serve for testing of an assay's limit of detection with confidence claims for specific variants. CONCLUSION: These results support the utility of the QCM in testing ctDNA assay analytical performance. However, unique designs and manufacturing methods for the QCM, and variations in a laboratory's testing configuration, may require testing of multiple QCMs to find the best reagents for accurate result interpretation.

International liquid biopsy standardization alliance white paper.

The promise of precision medicine as a model to customize health care to the individual patient is heavily dependent upon new genetic tools to classify and characterize diseases and their hosts. Liquid biopsies serve as a safe alternative to solid biopsies and are thus a useful and critical component to fully realizing personalized medicine. The International Liquid Biopsy Standardization Alliance (ILSA) comprises organizations and foundations that recognize the importance of working towards the global use of liquid biopsy in oncology practice to support clinical decision making and regulatory considerations and seek to promote it in their communities. This manuscript provides an overview of the independent liquid biopsy- and standardization-based programs engaged with ILSA, their objectives and progress to date, and the tools and resources each is developing to contribute to the field. It also describes the unique areas of effort as well as synergy found within the group.

Opportunities and Challenges in Implementation of Multiparameter Single Cell Analysis Platforms for Clinical Translation.

The high-content interrogation of single cells with platforms optimized for the multiparameter characterization of cells in liquid and solid biopsy samples can enable characterization of heterogeneous populations of cells ex vivo. Doing so will advance the diagnosis, prognosis, and treatment of cancer and other diseases. However, it is important to understand the unique issues in resolving heterogeneity and variability at the single cell level before navigating the validation and regulatory requirements in order for these technologies to impact patient care. Since 2013, leading experts representing industry, academia, and government have been brought together as part of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium to foster the potential of high-content data integration for clinical translation.

Competition between intercellular adhesion molecule-1 and a small-molecule antagonist for a common binding site on the alphal subunit of lymphocyte function-associated antigen-1.

The lymphocyte function-associated antigen-1 (LFA-1) binding of a unique class of small-molecule antagonists as represented by compound 3 was analyzed in comparison to that of soluble intercellular adhesion molecule-1 (sICAM-1) and A-286982, which respectively define direct and allosteric competitive binding sites within LFA-1's inserted (I) domain. All three molecules antagonized LFA-1 binding to ICAM-1-Immunoglobulin G fusion (ICAM-1-Ig) in a competition ELISA, but only compound 3 and sICAM-1 inhibited the binding of a fluorescein-labeled analog of compound 3 to LFA-1. Compound 3 and sICAM-1 displayed classical direct competitive binding behavior with ICAM-1. Their antagonism of LFA-1 was surmountable by both ICAM-1-Ig and a fluorescein-labeled compound 3 analog. The competition of both sICAM-1 and compound 3 with ICAM-1-Ig for LFA-1 resulted in equivalent and linear Schild plots with slopes of 1.24 and 1.26, respectively. Cross-linking studies with a photoactivated analog of compound 3 localized the high-affinity small-molecule binding site to the N-terminal 507 amino acid segment of the alpha chain of LFA-1, a region that includes the I domain. In addition, cells transfected with a variant of LFA-1 lacking this I domain showed no significant binding of a fluorescein-labeled analog of compound 3 or ICAM-1-Ig. These results demonstrate that compound 3 inhibits the LFA-1/ICAM-1 binding interaction in a directly competitive manner by binding to a high-affinity site on LFA-1. This binding site overlaps with the ICAM-1 binding site on the alpha subunit of LFA-1, which has previously been localized to the I domain.

Cooperative learning effects on teamwork attitudes in clinical laboratory science students.

OBJECTIVE: To evaluate clinical laboratory science (CLS) student attitudes toward teamwork when using cooperative learning (CL) as compared to individual learning (IL) in a course and to determine if learning method affects student attitudes toward the course itself. DESIGN/SETTING/PARTICIPANTS: This was a multi-institutional study involving eight classrooms in seven states. The effects of CL and IL on student attitudes were compared for 216 student participants. INTERVENTION: One group of students learned the course material through a CL approach while a second group of students learned via a traditional IL approach. For each course, the instructor, class material, and examination content was identical for the CL and IL students; the only variable was learning method. MAIN OUTCOME MEASURE: Student attitudes toward teamwork and toward the course were evaluated with a 35-item Attitude Questionnaire administered as a posttest. Mean scores for the CL and IL groups were compared using the Student t-test for independent samples. RESULTS: No significant difference was seen between the CL and IL students when assessing the first 30 questions on student attitudes toward teamwork (means = 98.42 and 98.22, respectively) when all institutions were combined. Comparable results were seen for each of the eight institutions. For the five questions comparing attitudes toward the course itself, there usually was no significant difference in attitude between CL and IL students. The only classrooms where CL students had more positive attitudes were those with instructors who had more than 10 years experience with CL. CONCLUSION: Results suggest that CL produces similar student attitudes toward teamwork and toward a CLS course as does IL.

Selective alpha4beta7 integrin antagonists and their potential as antiinflammatory agents.

The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin alpha4beta7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of alpha4beta7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that alpha4beta7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective alpha4beta7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded alpha4beta7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for alpha4beta7 by more than 500-fold to afford a potent and selective alpha4beta1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for alpha4beta7 compared to other integrins.

Evidence of clinical utility: an unmet need in molecular diagnostics for patients with cancer.

This article defines and describes best practices for the academic and business community to generate evidence of clinical utility for cancer molecular diagnostic assays. Beyond analytical and clinical validation, successful demonstration of clinical utility involves developing sufficient evidence to demonstrate that a diagnostic test results in an improvement in patient outcomes. This discussion is complementary to theoretical frameworks described in previously published guidance and literature reports by the U.S. Food and Drug Administration, Centers for Disease Control and Prevention, Institute of Medicine, and Center for Medical Technology Policy, among others. These reports are comprehensive and specifically clarify appropriate clinical use, adoption, and payer reimbursement for assay manufacturers, as well as Clinical Laboratory Improvement Amendments-certified laboratories, including those that develop assays (laboratory developed tests). Practical criteria and steps for establishing clinical utility are crucial to subsequent decisions for reimbursement without which high-performing molecular diagnostics will have limited availability to patients with cancer and fail to translate scientific advances into high-quality and cost-effective cancer care. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development."

Lack of antenatal care in far north Queensland.

OBJECTIVE: To examine reasons for women not accessing antenatal care, and subsequent pregnancy outcomes for this group of women. DESIGN: Retrospective observational study between 1992 and 2001. SETTING: Large public provincial referral obstetric unit. SAMPLE: A total of 226 of 16 176 women (1.4%) who gave birth had not accessed antenatal care in the index pregnancy. RESULTS: The women who did not access antenatal care were more likely to be highly parous or young, indigenous, and users of alcohol than the women who did access antenatal care; women who lived in remote communities and women who significant medical conditions complicating their pregnancy were less likely to default on antenatal care. The women who did not access antenatal care had a higher incidence of preterm birth and post-partum haemorrhage; their babies were more likely to be of low birthweight, to be born with 5-min Apgar scores less than 5, and had a higher incidence of perinatal death. CONCLUSIONS: Lack of antenatal care is associated with a significant number of poor pregnancy outcomes, which are not explained by the basic epidemiological characteristics of women. As the women not accessing antenatal care tend to be from the most disadvantaged or marginalised groups in our society, a better understanding of their reasons for not accessing antenatal care is necessary so that care options can be provided which this high-risk group of women may find acceptable and use.

Solid-phase synthesis of dual alpha4beta1/alpha4beta7 integrin antagonists: two scaffolds with overlapping pharmacophores.

Two structural classes of dual alpha4beta1/alpha4beta7 integrin antagonists were investigated via solid-phase parallel synthesis. Using an acylated amino acid backbone, lead compounds containing biphenylalanine or tyrosine carbamate scaffolds were optimized for inhibition of alpha4beta1/VCAM and alpha4beta7/MAdCAM. A comparison of the structure-activity relationships in the inhibition of the alpha4beta7/MAdCAM interaction for substituted amines employed in both scaffolds suggests a similar binding mode for the compounds.