Clinical chemistry最新文献

Background: Prenatal cell-free DNA (cfDNA) screening is primarily designed to detect fetal chromosomal abnormalities, but can also identify aneuploidies derived from other tissues, including cancer. The identification of aneuploidies of unknown origin during prenatal cfDNA screening can lead to time-consuming multistage investigations and anxiety for the expecting mother.

Methods: To expedite the identification of the origin of copy-number aberrations and guide clinical management of such profiles suggestive of maternal malignancy, we developed a methylation and aneuploidy-aware prenatal screening pipeline. Plasma cfDNA is enzymatically converted to identify the methylated cytosines during sequencing. The tissue of origin is predicted by leveraging a cell-type-specific methylome atlas into our methylation-based deconvolution algorithm, MetDecode.

Results: We demonstrate that aneuploidy profiling on enzymatically converted cfDNA enables the identification of placental and cancer-derived aneuploidies with similar accuracy compared with conventional prenatal cfDNA screening. The methylation-based deconvolution pinpointed the tumor origin correctly in 91.67% of the pregnant women with a tumor fraction >3%.

Conclusion: Methylome and aneuploidy-aware cfDNA screening could substantially improve the diagnostic processes, pinpoint the origins of aneuploidy and improve cancer management during pregnancy.

Background: Diagnosis of tuberculosis (TB) and multidrug-resistant tuberculosis (MDR-TB) is increasingly performed using molecular tools that detect Mycobacterium tuberculosis DNA. To ensure accurate and reliable results from the molecular tests, appropriate quality assessment is required. This involves implementing reference measurement procedures (RMPs) to characterize material standards that are representative of the clinical specimen. These material standards should address drug resistance and mixtures of drug-resistant and -susceptible bacteria. However, currently these RMPs and materials standards do not exist, which can hamper the accuracy and precision of routine clinical testing. To address this, we applied digital PCR (dPCR) as a RMP to MDR-TB material standards.

Methods: Four standards were prepared and characterized using dPCR to quantify drug-resistant and -susceptible genotypes. We investigated the performance of existing molecular tests via an interlaboratory study including 9 laboratories from Africa and Europe, assessing 3 methods for MDR-TB detection and 2 methods for TB-only detection.

Results: All tests correctly identified M. tuberculosis, and 2 out of 3 tests identified the associated drug resistance (one test failed to identify drug resistance in one of the materials). Generally, discrepancies occurred with the more challenging samples bearing lower concentrations and mixed genotypes.

Conclusions: The approaches used in this study will enhance the quality assessment of MDR-TB and can be applied to afford test manufacturers and clinical laboratories more accurate results to guide test development, selection, and regulation. Such an approach can improve confidence in MDR-TB testing, enabling physicians to guide treatment, potentially leading to better patient outcomes.

Background: Pregnancy is characterized by dynamic physiological changes that alter the concentrations of many maternal blood biomarkers. Reporting results against nonpregnant reference values can lead to misinterpretation, diagnostic error, and inappropriate clinical management. The use and reporting of pregnancy-specific reference intervals (RIs) by laboratories is not yet routine practice.

Content: This review underscores the critical need for pregnancy RIs to support accurate diagnosis, effective patient care, and optimal clinical decision-making in pregnancy and highlights unique considerations and challenges specific to pregnancy RI studies. Aspects such as defining inclusion/exclusion criteria and participant engagement are more complex in pregnant cohorts. Logistical and resource constraints must be anticipated when undertaking these studies. The current landscape of pregnancy RIs is summarized, drawing upon the literature, which shows substantial heterogeneity in study designs, populations, analytical methods, and partitioning strategies, with important details often missing or insufficient. These issues limit the comparability of findings between studies and the application of published RIs to other pregnant populations. Indirect RI approaches combined with clinical databases provide promising alternatives to traditional direct studies, which help overcome some of the barriers, particularly around recruitment. Experience and lessons learned from the authors' own involvement in prospective and retrospective studies for chemistry and hematology biomarkers are shared.

Summary: The challenges associated with developing pregnancy RIs require coordinated and uniform efforts. The discussion herein will help guide future work and knowledge translation to ensure high-quality, standardized studies generate pregnancy RIs that are widely applicable and support maternity care providers and patients alike.

Background: Hypertensive disorders of pregnancy (HDPs) complicate 8% to 9% of all pregnancies. They are a leading cause of maternal and neonatal morbidity and mortality and contribute to over $2.2 billion of health care expenditures annually. In 2023, the FDA first approved a soluble fms-like tyrosine kinase 1 to placental growth factor ratio system for HDP risk stratification; however, little is known about the implementation of such biomarker testing outside of research contexts.

Content: HDP severity drives clinical management and adverse perinatal outcomes. Placental biomarker testing aims to determine which patients are at risk for developing or progressing to the most severe HDPs. Widespread implementation of biomarker testing may increase access though it may not be cost-efficient or practice-changing for individual institutions. Accordingly, further attention must be paid to restrictive testing situations (e.g., low-resource settings) or even off-label uses (e.g., multiple gestations) that may solidify the role of biomarker testing in routine practice.

Summary: This review aims to outline clinical and institutional considerations for placental biomarker utilization in the context of their FDA-approved uses and to highlight the potential advantages and disadvantages of various testing strategies.

Background: Pregnancy induces a series of physiological adaptations, making accurate interpretation of clinical laboratory tests essential for maternal and fetal health. However, significant knowledge gaps persist in understanding how gestation affects circulating blood biochemistry, leading to potential clinical misinterpretations and underscoring the need for updated reference intervals in contemporary obstetric populations.

Methods: A cohort of approximately 135 healthy pregnant individuals was recruited with informed consent. Participants were excluded based on the use of prescribed medications, multiple gestations, age above 40 years, a history of chronic illness, or presence of acute illness during pregnancy. Blood samples were collected at 4 time points: 0 to 13 weeks, 14 to 27 weeks, 28 to 42 weeks, and 1 to 3 months postpartum. A total of 24 biochemical markers were analyzed. Statistically significant differences across gestational and early postpartum periods were assessed, and trimester-specific reference intervals were established.

Results: Of the 24 biochemical markers assessed, 17 exhibited statistically significant variations across gestation and the early postpartum period. Notably, albumin, total protein, creatinine, urea, uric acid, free thyroxine (FT4), and anemia markers showed significant decreases in late gestation compared to postpartum. Conversely, alkaline phosphatase, cholesterol, and triglycerides demonstrated substantial increases during gestation, followed by a marked decrease in the postpartum period.

Conclusion: This study provides comprehensive biochemical profiling of healthy pregnant individuals in Canada across gestation and the postpartum period. The findings highlight substantial alterations in circulating blood biochemistry during pregnancy, emphasizing the need for trimester-specific reference intervals to ensure accurate clinical test interpretation. Without such gestational age-specific benchmarks, maternal-fetal care standards remain suboptimal.

Background: Childhood cancers comprise a variety of liquid and solid tumors that display different patterns of incidence than adult cancers. Most have distinct molecular subtypes characterized by specific genomic driver events. The mutational processes that influence the somatic landscape of cancers also generate distinctive mutational signatures (mutSig). While these signatures are often inert, they do represent a fingerprint of the insult(s) present during mutagenesis. Associating mutSig with putatively causal exposures for pediatric cancer could inform future etiologic studies and elucidate the exposure pathways underlying risk.

Content: Here we review the epidemiology of pediatric cancers. We then summarize the knowledge around mutSig seen in pediatric cancer to date, discuss observed geographic and subtype-related variability, and discuss future efforts to characterize mutSig with unknown etiologies.

Summary: The diversity of childhood cancers and their molecular subtypes suggest etiologic heterogeneity. Detection of mutSig in childhood cancers has promoted hypothesis generation; e.g., the enrichment of UV-related signatures in aneuploid B-acute lymphoblastic leukemia has inspired new studies. Although the Mutographs projects were developed to investigate geographical variation in incidence, mutational epidemiology studies should also be employed to understand why certain mutSig are enriched in particular childhood cancers or subtypes. As pediatric cancers have lower mutational burdens than adult cancers, studying childhood cancer may also help determine the causes of mutSig with unknown etiologies. Given persistent differences in pediatric cancer risk by ancestry and socioeconomics, as well as the shifting global burden of childhood cancer, there is a need for studies with patients from diverse populations.

Background: Uterus transplantation (UTx) is uniquely positioned at the transition from experimental to clinical reality for women with absolute uterine factor insufficiency. As the technique gains wider clinical adoption, there is a growing need for standardization in both protocols and diagnostics.

Content: This review describes the current evaluation, monitoring, and emerging diagnostics in UTx across the main phases of care: (a) preoperative evaluation, which includes fertility evaluation and in vitro fertilization, surgical, psychosocial, and donor assessments, as well as donor-recipient matching considerations; (b) perioperative management, which focuses on acute surgical care, initiation of immunosuppression, and early graft evaluation; (c) posttransplant and pregnancy monitoring, which encompasses ongoing immunosuppression evaluation, biopsy interpretation, management of acute rejection, and detection and management of pregnancy and maternal complications; and (d) long-term follow-up, which addresses the potential for repeat pregnancies and planned graft hysterectomy to facilitate immunosuppression withdrawal.The review further explores future directions for clinical diagnostics in UTx, drawing on broader solid organ transplantation experiences. This includes molecular and allele-level human leukocyte antigen matching for recipient-donor compatibility, strategies for immunosuppression minimization, and the development of noninvasive rejection monitoring tools such as donor-derived cell-free DNA and novel blood and urine transcriptomics approaches.

Summary: Standardization of protocols and diagnostics is essential as UTx transitions to routine clinical practice. Emerging molecular diagnostics and noninvasive monitoring tools hold promise for improving graft outcomes and patient care in this evolving field.