Healthcare-related errors cause patient morbidity and mortality. Despite fear of reprimand, laboratory personnel have a professional obligation to rapidly report major medical errors when they are identified. Well-defined protocols regarding how and when to disclose a suspected error by a colleague do not exist.We describe a woman with a well documented allergy to sulfamethoxazole who was treated with sulfadiazine that led to toxic epidermal necrolysis. After the patient's death, the laboratory medicine resident was asked by one of the patient's physicians to measure serum sulfadiazine, but only if the results were not reported in the patient's electronic medical record. The case was brought to the attention of a laboratory medicine faculty member and the hospital risk management team.Laboratorians are patient fiduciaries and are responsible for reporting errors. Most medical associations have codes of ethics that address disclosure of incompetence and errors, although the AACC's Guide to Ethics does not. New types of error, risk management, and root-cause analyses help to shift the focus to system errors and away from individuals' errors. This can lead to a healthcare environment that encourages truth and disclosure rather than fear and reprimand. Disposition: The individuals involved in the presented case fulfilled their fiduciary duty to the patient by reporting this incident. An extensive investigation showed that, in fact, no medical errors or misconducts had occurred in the care of the patient.
Genetic testing has uncovered rare variants in complement proteins associated with thrombotic microangiopathy (TMA) and C3 glomerulopathy (C3G). Approximately 50% are classified as variants of uncertain significance (VUS). Clinical risk assessment of patients carrying a VUS remains challenging primarily due to a lack of functional information, especially in the context of multiple confounding factors in the setting of kidney transplantation. Our objective was to evaluate the clinicopathologic significance of genetic variants in TMA and C3G in a kidney transplant cohort. We used whole exome next-generation sequencing to analyze complement genes in 76 patients, comprising 60 patients with a TMA and 16 with C3G. Ten variants in complement factor H ( CFH ) were identified; of these, four were known to be pathogenic, one was likely benign and five were classified as a VUS (I372V, I453L, G918E, T956M, L1207I). Each VUS was subjected to a structural analysis and was recombinantly produced; if expressed, its function was then characterized relative to the wild-type (WT) protein. Our data indicate that I372V, I453L, and G918E were deleterious while T956M and L1207I demonstrated normal functional activity. Four common polymorphisms in CFH (E936D, N1050Y, I1059T, Q1143E) were also characterized. We also assessed a family with a pathogenic variant in membrane cofactor protein ( MCP ) in addition to CFH with a unique clinical presentation featuring valvular dysfunction. Our analyses helped to determine disease etiology and defined the recurrence risk after kidney transplant, thereby facilitating clinical decision making for our patients. This work further illustrates the limitations of the prediction models and highlights the importance of conducting functional analysis of genetic variants particularly in a complex clinicopathologic scenario such as kidney transplantation.
Abstract Clear cell carcinomas (CCCs) of the gynecologic tract are aggressive tumors with high resistance rate to conventional platinum‐based chemotherapies. Currently, the molecular features of these tumors remain largely unknown and there is no targeted therapy available. The aim of our study was to identify anaplastic lymphoma kinase ( ALK ) translocations, a potential molecular target for therapy. Ninety‐seven patients with gynecologic CCC (62 ovarian, 27 uterine corpus and 8 uterine cervical) were screened for ALK rearrangement and ALK copy number gain using an ALK break‐apart fluorescence in situ hybridization probe. The genomic landscape of all cases with ALK rearrangements and 10 random cases with ALK copy number gain was queried using a hybrid capture‐based DNA next‐generation sequencing assay and an Illumina Fusion RNA assay. Findings were then correlated with ALK immunohistochemistry (clone D5F3) expression. ALK rearrangement was detected in 5% (5/97) and ALK copy number gain in 79% (77/97) of gynecologic CCCs. Next‐generation sequencing in ALK ‐rearranged CCCs identified a novel BABAM2 ‐ ALK fusion in one case. ALK translocation partners were not identified in the remaining cases. Our findings show that ALK fusion, which is targetable in other cancers, may be a pathogenetic mechanism in a small number of gynecologic CCCs.
In 2017, AMP, ASCO and CAP jointly published the first formalized classification system for the interpretation and reporting of sequence variants in cancer. The challenges of incorporating new variant interpretation guidelines into existing, validated workflows have likely hampered adoption and implementation in labs with classification methods in place. Ambiguity in assigning clinical significance across guidelines is grounded in differential weighting of evidence used in variant assessment. Therefore, we undertook an internal process-improvement exercise to correlate the two classification schemes using historical laboratory data.Existing clinical variant assignments from 40 consecutive oncology cases comprising 150 somatic variants were re-assessed according to the 2017 AMP/ASCO/CAP scheme. Approximately 50% of these were cancers of the gynecologic tract.Our laboratory-developed (GPS) classifications for 'actionable' variants and variants of uncertain clinical significance mapped consistently with the AMP/ASCO/CAP Tiers I-III. The majority of Level 1 variants were reclassified to Tier I (21/25; 84%) while all Level 2 and Level 4 variants were assigned to Tier II (9/9; 100%) and Tier III (17/17; 100%), respectively. The greatest variability was seen for GPS Level 3 variants, which was strongly influenced by TP53 interpretations. Ultimately, we found that most GPS Level 3 variants were classified as Tier III (77/99; 77.8%).Our internally developed 5-level classifications mapped consistently with the proposed AMP/ASCO/CAP 4-Tiered system. As a result of this analysis, we can provide a framework for other labs considering a similar transition to the 2017 AMP/ASCO/CAP guidelines and a rationale for explaining specific discrepancies.
Fatty acid (FA) metabolism is tightly regulated across several tissues and impacts insulin sensitivity. CD36 facilitates cellular FA uptake, and CD36 genetic variants associate with lipid abnormalities and susceptibility to metabolic syndrome. The objective of this study was to gain insight regarding the in vivo metabolic influence of muscle and adipose tissue CD36. For this, we determined the relationships between CD36 alternative transcripts, which can reflect tissue-specific CD36 regulation, and measures of FA metabolism and insulin resistance.The relative abundance of alternative CD36 transcripts in adipose tissue and skeletal muscle from 53 nondiabetic obese subjects was measured and related to insulin sensitivity and FA metabolism assessed by hyperinsulinemic-euglycemic clamps and isotopic tracers for glucose and FA.Transcript 1C, one of two major transcripts in adipose tissue, that is restricted to adipocytes predicted systemic and tissue (adipose, liver, and muscle) insulin sensitivity, suggesting adipocyte CD36 protects against insulin resistance. Transcripts 1B and 1A, the major transcripts in skeletal muscle, correlated with FA disposal rate and triglyceride clearance, supporting importance of muscle CD36 in clearance of circulating FA. Additionally, the common CD36 single nucleotide polymorphism rs1761667 selectively influenced CD36 transcripts and exacerbated insulin resistance of glucose disposal by muscle.Alternative CD36 transcripts differentially influence tissue CD36 and consequently FA homeostasis and insulin sensitivity. Adipocyte CD36 appears to be metabolically protective, and its selective upregulation might have therapeutic potential in insulin resistance.
Single nucleotide polymorphisms (SNPs) within the hepatocyte nuclear factor 4alpha (HNF4alpha) gene are associated with type 2 diabetes in Finns and Ashkenazi Jews. Previous studies in both populations have reported linkage to type 2 diabetes near the HNF4alpha locus on chromosome 20q12-13. To investigate whether HNF4alpha is a diabetes susceptibility gene in Pima Indians, a population with the highest reported prevalence of type 2 diabetes but with no evidence for linkage of the disease on chromosome 20q, 19 SNPs across the promoter and coding region of HNF4alpha were genotyped for association analysis. In a group of 1,037 Pima Indians (573 diabetic and 464 nondiabetic subjects), three SNPs in HNF4alpha (rs3212183 and rs2071197 located in introns 3 and 1, respectively, and rs6031558, an extremely rare SNP located in the P2 promoter region) were modestly associated with type 2 diabetes (rs3212183 odds ratio [OR] 1.34 [95% CI 1.07-1.67], P = 0.009; rs2071197 1.34 [1.07-1.66], P = 0.008; and rs6031558 3.18 [1.03-9.84], P = 0.04, adjusted for age, sex, birth year, heritage, and family membership). We conclude that variants in HNF4alpha do not appear to be major determinants for type 2 diabetes in Pima Indians; however, HNF4alpha may have a minor role in type 2 diabetes susceptibility within this Native American population.
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