Advances in preeclampsia testing.

Preeclampsia is a multisystem hypertensive disorder and one of the leading causes of maternal and fetal morbidity and mortality. The clinical hallmarks such as hypertension and proteinuria, and additional laboratory tests currently available including liver enzyme testing, are neither specific nor sufficiently sensitive. Therefore, biomarkers for timely and accurate identification of patients at risk of developing preeclampsia are extremely valuable to improve patient outcomes and safety. In this chapter, we will first discuss the clinical characteristics of preeclampsia and current evidence of the role of angiogenic factors, such as placental growth factor (PlGF) and soluble FMS like tyrosine kinase 1 (sFlt-1) in the pathogenesis of preeclampsia. Second, we will review the clinical practice guidelines for preeclampsia diagnostic criteria and their recommendations on laboratory testing. Third, we will review the currently available PlGF and sFlt-1 assays in terms of their methodologies, analytical performance, and clinical diagnostic values. Finally, we will discuss the future research needs from both an analytical and clinical perspective.

Comprehensive Cardiovascular Magnetic Resonance Tissue Characterization and Cardiotoxicity in Women With Breast Cancer.

Importance: There is a growing interest in understanding whether cardiovascular magnetic resonance (CMR) myocardial tissue characterization helps identify risk of cancer therapy-related cardiac dysfunction (CTRCD). Objective: To describe changes in CMR tissue biomarkers during breast cancer therapy and their association with CTRCD. Design, Setting, and Participants: This was a prospective, multicenter, cohort study of women with ERBB2 (formerly HER2)-positive breast cancer (stages I-III) who were scheduled to receive anthracycline and trastuzumab therapy with/without adjuvant radiotherapy and surgery. From November 7, 2013, to January 16, 2019, participants were recruited from 3 University of Toronto-affiliated hospitals. Data were analyzed from July 2021 to June 2022. Exposures: Sequential therapy with anthracyclines, trastuzumab, and radiation. Main Outcomes and Measures: CMR, high-sensitivity cardiac troponin I (hs-cTnI), and B-type natriuretic peptide (BNP) measurements were performed before anthracycline treatment, after anthracycline and before trastuzumab treatment, and at 3-month intervals during trastuzumab therapy. CMR included left ventricular (LV) volumes, LV ejection fraction (EF), myocardial strain, early gadolinium enhancement imaging to assess hyperemia (inflammation marker), native/postcontrast T1 mapping (with extracellular volume fraction [ECV]) to assess edema and/or fibrosis, T2 mapping to assess edema, and late gadolinium enhancement (LGE) to assess replacement fibrosis. CTRCD was defined using the Cardiac Review and Evaluation Committee criteria. Fixed-effects models or generalized estimating equations were used in analyses. Results: Of 136 women (mean [SD] age, 51.1 [9.2] years) recruited from 2013 to 2019, 37 (27%) developed CTRCD. Compared with baseline, tissue biomarkers of myocardial hyperemia and edema peaked after anthracycline therapy or 3 months after trastuzumab initiation as demonstrated by an increase in mean (SD) relative myocardial enhancement (baseline, 46.3% [16.8%] to peak, 56.2% [18.6%]), native T1 (1012 [26] milliseconds to 1035 [28] milliseconds), T2 (51.4 [2.2] milliseconds to 52.6 [2.2] milliseconds), and ECV (25.2% [2.4%] to 26.8% [2.7%]), with P <.001 for the entire follow-up. The observed values were mostly within the normal range, and the changes were small and recovered during follow-up. No new replacement fibrosis developed. Increase in T1, T2, and/or ECV was associated with increased ventricular volumes and BNP but not hs-cTnI level. None of the CMR tissue biomarkers were associated with changes in LVEF or myocardial strain. Change in ECV was associated with concurrent and subsequent CTRCD, but there was significant overlap between patients with and without CTRCD. Conclusions and Relevance: In women with ERBB2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy, CMR tissue biomarkers suggest inflammation and edema peaking early during therapy and were associated with ventricular remodeling and BNP elevation. However, the increases in CMR biomarkers were transient, were not associated with LVEF or myocardial strain, and were not useful in identifying traditional CTRCD risk.

Clinical Validation of the sFlt-1:PlGF Ratio as a Biomarker for Preeclampsia Diagnosis in a High-Risk Obstetrics Unit.

BACKGROUND: Preeclampsia is a multisystem disorder defined by new onset of hypertension with proteinuria after 20 weeks gestation. In part due to dysregulation of pro-angiogenic factors (e.g., placental growth factor [PlGF]) and anti-angiogenic factors (e.g., soluble fms-like tyrosine kinase 1 [sFlt-1]), preeclampsia results in decreased placental perfusion. An increased sFlt-1:PlGF ratio is associated with increased risk of preeclampsia. In this study, we evaluated sFlt-1:PlGF cutoffs and evaluated the clinical performance of sFlt-1:PlGF for predicting preeclampsia. METHODS: sFlt-1:PlGF results from 130 pregnant females with clinical suspicion of preeclampsia were used to evaluate the diagnostic accuracy of different sFlt-1:PlGF cutoffs and to compare the clinical performance of sFlt-1:PlGF to traditional preeclampsia markers (proteinuria and hypertension). Serum sFlt-1 and PlGF were measured using Elecsys immunoassays (Roche Diagnostics) and preeclampsia diagnosis was verified by expert chart review. RESULTS: A sFlt-1:PlGF cutoff of >38 yielded the greatest diagnostic accuracy of 90.8% (95% CI, 85.8%-95.7%). Using a cutoff of >38, sFlt-1:PlGF exhibited a greater diagnostic accuracy than traditionally used parameters such as new or worsening proteinuria or hypertension (71.9% and 68.6%, respectively). sFlt-1:PlGF >38 exhibited a negative predictive value (NPV) of 96.4% for rule-out of preeclampsia within 7 days, and a positive predictive value (PPV) of 84.8% for predicting preeclampsia within 28 days. CONCLUSIONS: Our study shows the superior clinical performance of sFlt-1:PlGF over hypertension and proteinuria alone to predict preeclampsia at a high-risk obstetrical unit.

Evaluation and comparison of four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy.

BACKGROUND: Semi-quantitative and quantitative immunoassays are the most commonly used methodology to evaluate immunity post immunization. OBJECTIVES: To compare four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy. STUDY DESIGN: 210 serological samples from COVID-19 infection and vaccination cohorts were used to create a serological sample repository. Serological methods from four manufacturers, namely Euroimmun, Roche, Abbott, and DiaSorin, were evaluated for quantitative, semi-quantitative, and qualitative antibody measurements. All four methods measure IgG antibodies against the SARS-CoV-2 spike receptor-binding domain and report the results in Binding Antibody Unit/mL (BAU/mL). A Total Error Allowable (TEa) of ±25% was chosen as the criteria to determine whether two methods are clinically equivalent quantitatively. Semi-quantitative results (titers) were derived using numeric antibody concentration divided by the cut-off value for each method. RESULTS: All paired quantitative comparisons demonstrated unacceptable performance. With ±25% as TEa, the best agreement was 74 (35.2% out of 210 samples) between Euroimmun and DiaSorin, whereas the lowest agreement was 11 (5.2% out of 210 samples) between Euroimmun and Roche. Antibody titers amongst all four methods were significantly different (p < 0.001). The highest titer difference from the same sample is between Roche and DiaSorin with a 1392-fold difference. On qualitative comparison, none of the paired comparison showed acceptable comparison (p < 0.001). CONCLUSIONS: Poor correlation exists between four evaluated assays, quantitatively, semi-quantitatively, and qualitatively. Further harmonization of assays is required to achieve comparable measurements.

A Multimodal Intervention for Reducing Unnecessary Repeat Glycated Hemoglobin Testing.

OBJECTIVES: Reducing unnecessary tests that do not enhance quality can promote health-care value. Glycated hemoglobin (A1C) is often ordered at a frequency exceeding the recommendation of once every 3 months. We conducted a quality improvement (QI) initiative aimed to reduce unnecessary repeat testing by 75% at a tertiary care academic hospital. METHODS: A retrospective baseline analysis was conducted on laboratory data from 2019 that enumerated unnecessary A1C tests, defined as repeat tests ordered within 60 days. A multifaceted change intervention with iterative plan-do-study-act cycles was introduced in March 2019 to educate providers and to automatically cancel A1C tests requested within 60 days. Monthly totals of A1C testing processed were plotted on statistical process control charts. RESULTS: In 2019, 11% of all A1C tests ordered were unnecessary. Between March 2020 and January 2021, 11% of the tests (N=14,247 tests) were unnecessary, of which 84% were cancelled with our intervention. Providers in cardiology and nephrology accounted for over half (55%) of the unnecessary tests ordered. CONCLUSIONS: A 2-pronged approach informed by root-cause analysis, and comprised of gatekeeping and provider education, can effectively promote resource stewardship for reducing unnecessary A1C testing.

Associations Among Biomarkers of Inflammation, Tubular Injury and Lipid Metabolism With Gestational Diabetes Mellitus Status, Microalbuminuria and Retinopathy in the Microalbuminuria and Retinopathy in Gestational Diabetes Study.

OBJECTIVES: Pregnancy may be complicated by gestational diabetes mellitus (GDM) and/or microvascular complications like albuminuria, retinopathy and pre-eclampsia. In this study we aimed to identify whether mechanistic pathways associated with microvascular complications are active in pregnant women with GDM or microvascular disease. METHODS: Urinary albumin excretion and biomarkers of inflammation, lipoprotein metabolism and tubular injury were quantified in 355 pregnant women with and without GDM. Participants underwent fundus photography graded for retinopathy. Adjusted associations between individual biomarkers and each outcome variable of interest, including GDM status, albuminuria and retinopathy, were performed using logistic regression. RESULTS: After adjusting for age, systolic blood pressure, body mass index and ethnicity, significant associations between GDM status and apolipoprotein A1, interleukin (IL)-6, IL-8, soluble tumour necrosis factor receptor-I and -II (sTNFR-I and -II), vascular endothelial growth factor and von Willebrand factor were observed. Increased high-sensitivity C-reactive protein (hsCRP) and sTNFR-II were associated with higher levels of albuminuria. hsCRP and previous GDM were associated with retinopathy. CONCLUSION: Mechanistic pathways associated with microvascular complications appear to be active in pregnant women with GDM or microvascular disease.

HPV Vaccination Intentions of Female Students in Chinese Universities: A Systematic Literature Review and Meta-Analysis.

OBJECTIVE: To systematically evaluate the human papillomavirus (HPV) vaccination intentions among female university students in China and establish a basis for improving HPV vaccination coverage. METHODS: We searched CNKI, EBSCO, JSTOR, MESH or Emtree, Weipu Information Chinese Journal Service Platform, Wanfang Data, China Biomedical Literature Database, PubMed, Embase, Web for the Web of Science, and the Cochrane Library to identify peer-reviewed published research on intentions by female college students in China to receive the HPV vaccination. RESULTS: A preliminary search of 408 papers resulted in the inclusion of 12 studies, all cross-sectional, of moderate or high quality, with a sample size of 12,600. The HPV vaccination intention rate among Chinese female university students was 16.67% (95% CI: 12.38% to 21.24%). The vaccination intention rates of medical students, non-medical students, and Tibetan students were 30.37% (95% CI: 28.80-34.12%), 15.53% (95% CI: 11.2-20.22%), and 14.12% (95 % CI: 10.59-18.04%), respectively. The vaccination intention rates of the participants with parental education of junior high school and below, high school, and bachelor's degree and above were 15.36% (95 % CI: 11.59 to 17.54%), 17.18% (95 % CI: 12.33% to 19.61%), and 19.81% (95 % CI: 15.61% to 22.25%), respectively. The intention rates of vaccination among residents of first-tier, second-tier, and third-tier cities were 17.64% (95% CI: 12.76-21.63%), 15.39% (95% CI: 11.74-19.82%), and 13.87% (95% CI: 9.36-15.65%), respectively. The results of the meta-analysis were relatively stable with little publication bias. CONCLUSION: The intention rate of HPV vaccination among female university students in China is low and varies among different populations. There is a need to increase HPV vaccination promotion efforts to improve the intention of female university students to receive the vaccine.

Midlife suicide: A systematic review and meta-analysis of socioeconomic, psychiatric and physical health risk factors.

Suicide is an increasing contributing cause of mortality in middle-aged adults; however, knowledge to guide prevention is limited. This first systematic review and meta-analysis of studies on midlife suicide has provided an overview of published research on this issue and synthesized the evidence on socioeconomic and physical and mental health factors associated with this mortality. Using PRISMA guidelines MEDLINE, Embase, PsycINFO, Scopus and Web of Science were searched for English-language publications that involved persons aged 35 to 65, used individual-level data, and reported prevalence of exposure(s) or relative risks. The search identified 62 studies on midlife suicides and associated factors (28 for SES, 22 for psychiatric disorder and 23 for physical illness). All studies were from high income countries, and most (80.6%) used data from population registries. Meta-analyses showed that the pooled prevalence of exposure in suicide decedents was 57.8% for psychiatric disorder, 56.3% for low income, 43.2% for unemployment, and 27.3% for physical illness. The associated pooled risk ratio was 11.68 (95% confidence intervals: 5.82-23.47) for psychiatric illness of any type, 12.59 (8.29-19.12) for mood disorders, 3.91 (2.72-5.59) for unemployment, 3.18 (2.72-3.72) for being separated or divorced, 2.64 (2.26-3.10) for cancer, 2.50 (0.96-6.38) for central nervous system illness, and 2.26 (1.16-4.41) for low income. In conclusion, midlife suicide is strongly associated with socioeconomic difficulties and physical and psychiatric illnesses that are common in this age population. Future investigations should consider the interactions between risk factors, the intersectionality of sex and ethnicity, and include data from low- and middle-income countries.

Analytical Performance and Quality Indicators of Fully Automated Immunoassays for sFlt-1 and PlGF.

BACKGROUND: The ratio of the antiangiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt-1), to the proangiogenic factor, placental growth factor (PlGF), is associated with increased risk of preeclampsia. Here, we describe an analytical evaluation of the Elecsys sFlt-1 and PlGF assays at the first North American site in which they were clinically implemented. METHODS: The analytical evaluation included short- and long-term imprecision, method comparison, accuracy, linearity, sample stability, limit of quantification verification, and measurement uncertainty. Quality indicators were also evaluated, including turnaround time and repeat test frequency. RESULTS: Short-term (13-day) and long-term (12-month) imprecision for sFlt-1 and PlGF were <4% CV. Method comparison (n = 40) between Roche cobas e602 and e411 exhibited r > 0.99 and bias <10%. sFlt-1/PlGF ratio rule-out cutoffs (≤33 and ≤38) and rule-in cutoffs (>38, >85, and >110) exhibited negative percent agreement and positive percent agreement of 100%, respectively (n = 40). During the first 12 months, 257 orders were placed, repeat test frequency was 17.5%, mean time between repeat orders was 23 days, and 72.0% of results were reported within 2 h from sample receipt when quality control was run continuously. CONCLUSIONS: We describe analytical performance parameters and quality indicators of the Elecsys sFlt-1 and PlGF assays, which was the first North American clinical laboratory site to implement these assays in support of the institution's high-risk obstetrical unit.