Clinical chemistry最新文献

英文中文

Transdermal GFR Signals a New Horizon in Renal Diagnostics. 透皮GFR信号是肾脏诊断的新领域。

IF 6.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-12-02 DOI: 10.1093/clinchem/hvaf106

Vrajesh Pandya

引用次数: 0

The Changing Face of Academic Laboratory Medicine-A Decade Later and Beyond. 学术检验医学的变化面貌——十年后及以后。

IF 9.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-19 DOI: 10.1093/clinchem/hvaf132

Khushbu Patel,Mitchell G Scott,Aasne K Aarsand,Ann M Gronowski,Shannon Haymond,Christina Lockwood,Nader Rifai,Mark D Zarella

引用次数: 0

Diagnostic Value of Serum p-tau217 in Alzheimer Disease: Equal to Plasma in Levels and Clinical Utility? 血清p-tau217对阿尔茨海默病的诊断价值：与血浆水平相等及其临床应用？

IF 9.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-13 DOI: 10.1093/clinchem/hvaf162

Andrea L Benedet, Burak Arslan, Kubra Tan, Hanna Huber, Ilaria Pola, Guglielmo Di Molfetta, Hlin Kvartsberg, Anna Orduña Dolado, Shorena Janelidze, Kaj Blennow, Henrik Zetterberg, Oskar Hansson, Pedro Rosa-Neto, Nicholas J Ashton

Background Phosphorylated tau 217 (p-tau217) has emerged as a leading blood-based biomarker for Alzheimer disease (AD). While typically measured in plasma, serum is a widely used matrix in clinical laboratories, yet few p-tau217 assays have been validated for serum. Evaluating serum p-tau217 performance is essential for expanding its use in clinical and research settings, particularly for cohorts with only serum samples available. Methods We quantified p-tau217 in plasma and serum from individuals within the AD continuum (n = 100; mean age 72.5 ± 5.0 years; 54% female) using 6 assays across 4 platforms. Spearman correlation, Passing–Bablok regression, and receiver operating characteristics analysis were used to assess intermatrix agreement and diagnostic performance. Specific validation parameters (e.g., precision, parallelism, dilution linearity, stability) were evaluated in both matrices. Results High correlations between plasma and serum were observed for most assays (ρ > 0.8), though plasma often yielded higher concentrations. Notably, the Lumipulse assay showed near-perfect correlation (ρ = 0.98) and minimal bias. Fold changes in p-tau217 levels across the AD continuum were comparable between matrices, though cutoffs for detecting AD pathology differed. Applying plasma-derived cutoffs to serum resulted in misclassification rates ranging from 16% to 47%, except for Lumipulse (10% in serum vs 5% in plasma). Not all assays performed equally in serum, as reflected in validation metrics. Conclusions Serum p-tau217, across multiple platforms, shows strong correlations with plasma p-tau217 and reflected comparable patterns across the AD continuum. However, absolute concentrations differed for most assays, thus requiring differing disease specific cutoffs. Most of the evaluated platforms demonstrated reliable quantification of p-tau217 in serum, yielding satisfactory validation performance. These findings support serum as a viable alternative to plasma for p-tau217 quantification in both research and clinical settings, provided matrix-specific validation is ensured.

磷酸化tau217 （p-tau217）已成为阿尔茨海默病（AD）的主要血液生物标志物。虽然通常在血浆中测量，但在临床实验室中，血清是一种广泛使用的基质，但很少有p-tau217测定法被用于血清。评估血清p-tau217的性能对于扩大其在临床和研究环境中的应用至关重要，特别是对于只有血清样本的队列。方法：通过4个平台的6项检测，对AD连续体个体（n = 100，平均年龄72.5±5.0岁，54%为女性）血浆和血清中的p-tau217进行定量分析。使用Spearman相关、passingbablok回归和受者操作特征分析来评估矩阵间一致性和诊断性能。在两种基质中评估特定的验证参数（例如，精密度、平行度、稀释线性度、稳定性）。结果血浆和血清之间的相关性很高（ρ > 0.8），尽管血浆中的浓度通常较高。值得注意的是，Lumipulse试验显示出接近完美的相关性（ρ = 0.98）和最小的偏差。p-tau217水平在AD连续体中的折叠变化在基质之间具有可比性，尽管检测AD病理的截止值不同。将血浆来源的截止值应用于血清导致误分类率从16%到47%不等，但Lumipulse除外（血清10% vs血浆5%）。正如验证指标所反映的那样，并非所有测定法在血清中的效果都是一样的。结论血清p-tau217在多个平台上与血浆p-tau217表现出很强的相关性，并反映了AD连续体的可比性模式。然而，大多数测定的绝对浓度不同，因此需要不同的疾病特异性截止值。大多数评估的平台显示可靠的血清中p-tau217的定量，产生令人满意的验证性能。这些发现支持在研究和临床环境中，血清作为p-tau217定量的可行替代血浆，前提是确保基质特异性验证。

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引用次数: 0

Per Se Driving Under the Influence of Cannabis Statutes and Blood Delta-9-Tetrahydrocannabinol Concentrations following Short-Term Cannabis Abstinence. 短期戒断大麻后，大麻法规和血液中δ -9-四氢大麻酚浓度影响下的自身驾驶。

IF 9.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-12 DOI: 10.1093/clinchem/hvaf121

Robert L Fitzgerald,Anya Umlauf,Raymond T Suhandynata,David J Grelotti,Marilyn A Huestis,Kyle F Mastropietro,Igor Grant,Thomas D Marcotte

BACKGROUNDSeveral US states have per se laws using 2 or 5 ng/mL of delta-9-tetrahydrocannabinol (THC) as cutpoints for driving under the influence of cannabis, while some have zero-tolerance statutes. These cutpoints are considered prima facia evidence of driving impairment.METHODSIn a cohort of people who regularly use cannabis (N = 190) we measured baseline concentrations of THC after instructing participants to abstain from cannabis for at least 48 hours. Baseline driving performance was evaluated using a driving simulator. We also measured blood THC concentrations serially following a smoking session (placebo or active cannabis).RESULTSForty-three percent of the participants exceeded zero-tolerance statutes (≥0.5 ng/mL) at baseline. Twenty-four percent had baseline blood THC concentrations that were ≥2 ng/mL and 5.3% were ≥5 ng/mL. The maximum observed baseline blood concentration was 16.2 ng/mL. Six hours after smoking active cannabis, the median (interquartile range) difference in THC concentrations compared with baseline was 0.5 (0-0.9) ng/mL; a 1-sample t-test comparing the mean change to 0 was significant (P < 0.001). There was no difference when comparing the mean change to 0 in the placebo group (P = 0.69). Simulated driving performance was not different between those who exceed zero tolerance and per se cutpoints vs those who are below these cutpoints (P > 0.05).CONCLUSIONSMany regular users of cannabis exceed zero tolerance and per se THC cutpoint concentrations days after their last use, risking legal consequences despite no evidence of impairment.

美国的几个州都有自己的法律，将2或5 ng/mL的δ -9-四氢大麻酚（THC）作为在大麻影响下驾驶的临界值，而一些州则有零容忍法规。这些交叉点被认为是驾驶障碍的初步证据。方法在一组经常使用大麻的人群中（N = 190），我们在指示参与者戒除大麻至少48小时后测量了四氢大麻酚的基线浓度。使用驾驶模拟器评估基线驾驶性能。我们还在吸烟（安慰剂或活性大麻）后连续测量了血液中四氢大麻酚的浓度。结果43%的参与者在基线时超过零容忍法规（≥0.5 ng/mL）。24%的患者基线血THC浓度≥2ng /mL， 5.3%的患者基线血THC浓度≥5ng /mL。观察到的最大基线血药浓度为16.2 ng/mL。吸食活性大麻6小时后，四氢大麻酚浓度与基线相比的中位数（四分位数范围）差异为0.5 (0-0.9)ng/mL；比较平均变化到0的单样本t检验是显著的（P < 0.001）。当将安慰剂组的平均变化与0进行比较时，没有差异（P = 0.69）。超过零容忍和本身临界值的人与低于这些临界值的人的模拟驾驶性能没有差异（P > 0.05）。结论：许多经常使用大麻的人在最后一次使用后几天内就超过了零容忍和本身的四氢大麻酚临界点浓度，尽管没有证据表明存在损害，但仍有可能承担法律后果。

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引用次数: 0

Emerging Threat of Xylazine. 新出现的噻嗪威胁。

IF 6.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-11 DOI: 10.1093/clinchem/hvaf147

Kyla M Jorgenson, Robert A Middleberg, Brandy L Young, Alex J Krotulski, Nicholas E Nacca, Tanzy M Love, Joshua Marvald, Rachel Becker, Marilyn A Huestis, Y Victoria Zhang

Background: The increasing reports of xylazine in clinical and postmortem toxicology necessitate a survey of its clinical impact. This review examines reports of xylazine across the peer-reviewed literature and grey literature (government and public health reports).

Content: Before 2005, reports of xylazine abuse primarily involved veterinary-associated accidental and intentional exposures. A notable shift occurred in 2006 with increasing xylazine exposure documented among persons with illicit drug use, including fatal and nonfatal overdoses. Xylazine prevalence continued to increase in clinical and postmortem cases. Cases of xylazine abuse began in the northeast United States and expanded nationwide, with persistent high prevalence in the East and Midwest. Xylazine has been most frequently identified with fentanyl in clinical, drug-impaired driving, and postmortem analyses.

Summary: Xylazine's rising prevalence, especially as a fentanyl adulterant, contributes to increased opioid-related morbidity and mortality. Its presence across clinical, forensic, and environmental samples underscores the urgent need for enhanced surveillance, clinician education, public awareness, and targeted policy responses.

背景：越来越多的临床和死后毒理学报告表明，有必要对其临床影响进行调查。本综述审查了同行评议文献和灰色文献（政府和公共卫生报告）中关于噻嗪的报告。内容：2005年以前，有关氯嗪滥用的报告主要涉及与兽医有关的意外和故意暴露。2006年发生了显著的变化，非法药物使用者（包括致命和非致命过量）中有记录的二嗪接触量增加。在临床和死后病例中，噻嗪的患病率继续上升。二甲肼的滥用始于美国东北部，并在全国范围内扩大，在东部和中西部地区持续高发。在临床、药物损伤驾驶和尸检分析中，Xylazine与芬太尼最常被识别。总结：氯拉嗪的流行率不断上升，特别是作为芬太尼掺杂剂，导致阿片类药物相关发病率和死亡率增加。它在临床、法医和环境样本中的存在强调了加强监测、临床医生教育、公众意识和有针对性的政策应对的迫切需要。

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引用次数: 0

Validation of a Multiplex mRNA- and gDNA-Based Droplet Digital PCR Assay in Acute Myeloid Leukemia Patients with an NPM1 Mutation NPM1突变急性髓系白血病患者多重mRNA和gdna微滴数字PCR检测的验证

IF 9.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-09 DOI: 10.1093/clinchem/hvaf142

Albertus T J Wierenga, Lucy B Hesp, Arjan Simpelaar, Linde M Morsink, Carolien M Woolthuis, Jan Jacob Schuringa, Isidor Minovic, Gerwin Huls, André B Mulder

Background NPM1 is a disease-defining gene in the diagnosis of acute myeloid leukemia (AML) and is important for measurable residual disease (MRD) assessment. Over 50 different NPM1 mutations have been described, but only the 3 most common are routinely monitored during follow-up. Methods We developed a multiplex droplet digital polymerase chain reaction (PCR) assay for measurement of both variant allele frequencies (VAF) and mRNA transcripts of 10 different NPM1 mutations, using one generic probe, one generic NPM1 reverse primer, and 10 mutation-specific NPM1 forward primers. ABL1 expression and AP3B1 VAF were used as references. The performance of the assay was tested in diagnosis and follow-up samples from patients with an NPM1-mutated AML. Results Our assay shows negligible false-positive signals and high assay precision, leading to low limits of detection of at least 0.01%. The assay can easily be expanded to cover more NPM1 mutations by adding extra mutation-specific forward primers to the primer mix. Overall, a good correlation between mutant NPM1 expression and VAF was found. However, we also observed discrepant variable ABL1 expression levels, especially in AML patients with fms-related receptor tyrosine kinase 3-internal tandem duplications co-mutations. Conclusion We developed a robust and extremely flexible mRNA- and gDNA-based multiplex droplet digital PCR NPM1 assay. Because the AML tumor load is better reflected by mutant NPM1 VAF than expression level, we recommend using the gDNA-based mutant NPM1 MRD assay with a VAF detection limit of 0.01%. For MRD signals below 0.01%, our more sensitive mRNA-based method can be used, although further research has to prove its clinical impact.

NPM1是急性髓性白血病（AML）诊断中的疾病定义基因，对可测量的残留病（MRD）评估很重要。已有超过50种不同的NPM1突变被描述，但在随访期间只有3种最常见的突变被常规监测。方法利用一个通用探针、一个通用NPM1反向引物和10个突变特异性NPM1正向引物，建立了一种多重液滴数字聚合酶链反应（PCR）方法，测定10个不同NPM1突变的变异等位基因频率（VAF）和mRNA转录本。以ABL1表达和AP3B1 VAF为参照。在npm1突变的AML患者的诊断和随访样本中测试了该检测的性能。结果本方法假阳性信号可忽略不计，检测精度高，最低检出限至少为0.01%。通过在引物混合物中添加额外的突变特异性正向引物，该分析可以很容易地扩展到覆盖更多的NPM1突变。总的来说，突变体NPM1的表达与VAF之间存在良好的相关性。然而，我们也观察到不同的可变ABL1表达水平，特别是在fms相关受体酪氨酸激酶3-内部串联重复共突变的AML患者中。结论我们建立了一种基于mRNA和gdna的多液滴数字PCR NPM1检测方法。由于突变体NPM1 VAF比表达水平更能反映AML肿瘤负荷，我们建议使用基于gdna的突变体NPM1 MRD检测，VAF检测限为0.01%。对于低于0.01%的MRD信号，我们可以使用更敏感的基于mrna的方法，尽管还需要进一步的研究来证明其临床影响。

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引用次数: 0

Integrated Genotyping Strategies for Uncovering Detailed Haplotype Structures and Characterization of DMD Duplications 揭示DMD重复的详细单倍型结构和特征的综合基因分型策略

IF 9.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-09 DOI: 10.1093/clinchem/hvaf136

Jin Sun, Jie Tang, Lu Wei, Juan Geng, Rui Xiao, Niu Li, Shuyuan Li, Jian Wang, Qihua Fu, Ruen Yao, Tingting Yu

Background Duchenne and Becker muscular dystrophies are X-linked neuromuscular disorders caused by mutations in the dystrophin gene (DMD). Duplications account for approximately 10% of pathogenic variants, but their structural complexity and variable clinical impact present significant challenges in pathogenicity interpretation. Methods We retrospectively analyzed whole exome sequencing and multiplex ligation-dependent probe amplification data from 3842 individuals, identifying 39 patients with DMD duplications. These patients underwent whole genome sequencing (WGS) to characterize duplication patterns, breakpoint features, and haplotype structures. Optical genome mapping (OGM) was additionally performed in WGS-unresolved cases to identify exact haplotypes. We also compared the diagnostic performance of different platforms and further investigated genotype–phenotype correlations. Results DMD duplications exhibited substantial structural heterogeneity and were characterized into 4 major patterns: tandem duplication (58%), duplication-normal-duplication (16%), duplication-inversion-duplication (16%), and intricate duplication (10%). Recurrent complex arrangements were associated with high-homology repeats and often extended beyond DMD, complicating haplotype interpretation. WGS alone failed to resolve haplotypes in 34% (13/38) of cases, while OGM missed certain exon duplications and small fragments in 33% of cases (2/6). Integration of WGS and OGM enabled precise haplotype reconstruction and improved genotype–phenotype correlation. Conclusions Our findings broaden the molecular spectrum of DMD duplications, highlight their widespread structural complexity, and emphasize the importance of integrating multiple technologies to precisely delineate duplication haplotype structures and assess the pathogenicity of variants with uncertain significance. These findings provide valuable insights for DMD duplication detection, pathogenicity evaluation, and genetic counseling.

Duchenne和Becker肌营养不良症是由肌营养不良蛋白基因（DMD）突变引起的x连锁神经肌肉疾病。重复约占致病变异的10%，但其结构的复杂性和可变的临床影响给致病性解释带来了重大挑战。方法回顾性分析3842例患者的全外显子组测序和多重连接依赖探针扩增数据，确定39例DMD重复患者。这些患者接受了全基因组测序（WGS）来表征复制模式、断点特征和单倍型结构。此外，在未解决的wgs病例中进行光学基因组定位（OGM）以确定确切的单倍型。我们还比较了不同平台的诊断性能，并进一步研究了基因型-表型相关性。结果DMD重复具有明显的结构异质性，主要表现为4种模式：串联重复（58%）、重复-正常重复（16%）、重复-反转重复（16%）和复杂重复（10%）。反复出现的复杂排列与高同源重复有关，并且经常延伸到DMD之外，使单倍型解释复杂化。在34%（13/38）的病例中，WGS无法解析单倍型，而在33%（2/6）的病例中，OGM遗漏了某些外显子重复和小片段。WGS和OGM的整合实现了精确的单倍型重建，并改善了基因型-表型相关性。我们的发现拓宽了DMD重复的分子谱，突出了其广泛的结构复杂性，并强调了整合多种技术精确描述重复单倍型结构和评估具有不确定意义的变异致病性的重要性。这些发现为DMD重复检测、致病性评估和遗传咨询提供了有价值的见解。

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引用次数: 0

Post-Translationally Modified Proteoforms as Biomarkers: From Discovery to Clinical Use. 翻译后修饰的蛋白质形式作为生物标志物：从发现到临床应用。

IF 6.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-04 DOI: 10.1093/clinchem/hvaf094

Ruben Y Luo, Priscilla S W Yeung, Morgan W Mann, Lichao Zhang, Yifei K Yang, Andrew N Hoofnagle

Background: Protein biomarkers are routinely measured for disease diagnosis and prognosis in clinical laboratories. Since most assays focus on protein quantity, information about proteoforms is often not acquired. Proteoforms of a protein represent the complex integration of genetic polymorphism, alternative splicing of RNA transcripts, and post-translational modifications (PTMs) on the amino-acid backbone. A detailed analysis of the post-translationally modified proteoforms (PTMPs), which are influenced by pathophysiological conditions, may lead to more precise diagnosis and prognosis.

Content: This article first discusses the methodologies used to accurately detect and characterize PTMPs, i.e., immunoassays, electrophoresis, chromatography, and intact and proteolysis-aided mass spectrometry techniques. Then it reviews specific examples of PTMP biomarkers that have been successfully translated from biomarker discovery to clinical use. The examples include β2-transferrin for cerebrospinal fluid leak diagnosis, phosphorylated tau proteoforms for Alzheimer disease diagnosis, and fucosylated alpha-fetoprotein for hepatocellular carcinoma prognosis. In addition, the article provides prospective views of novel analytical technologies and promising new PTMP biomarkers entering clinical practice.

Summary: In summary, PTMs are controlled by biochemical processes to modulate the functions of proteins by expanding their chemical diversity. PTM alterations in proteins can be indicators for pathophysiological conditions. Advances in analytical technologies are deepening our understanding of PTMPs and paving the way for their translation to clinical use. As research continues to discover the clinical meaning of PTMP biomarkers, they are poised to become valuable additions to the clinical testing menu for precision medicine.

背景：在临床实验室中，蛋白质生物标志物是疾病诊断和预后的常规测量指标。由于大多数检测的重点是蛋白质的数量，因此通常无法获得有关蛋白质形态的信息。蛋白质的蛋白质形态代表了遗传多态性、RNA转录物的选择性剪接和氨基酸主链上的翻译后修饰（PTMs）的复杂整合。详细分析受病理生理条件影响的翻译后修饰的蛋白形态（PTMPs）可能会导致更准确的诊断和预后。内容：本文首先讨论了用于准确检测和表征PTMPs的方法，即免疫分析、电泳、色谱、完整和蛋白质水解辅助质谱技术。然后回顾了PTMP生物标志物的具体例子，这些生物标志物已经成功地从生物标志物发现转化为临床应用。这些例子包括用于脑脊液漏诊断的β2-转铁蛋白，用于阿尔茨海默病诊断的磷酸化tau蛋白形态，以及用于肝癌预后的集中的甲胎蛋白。此外，文章还展望了新的分析技术和有望进入临床实践的新的PTMP生物标志物。综上所述，PTMs受生化过程控制，通过扩大蛋白质的化学多样性来调节蛋白质的功能。PTM蛋白的改变可以作为病理生理状况的指标。分析技术的进步正在加深我们对PTMPs的理解，并为其转化为临床应用铺平道路。随着研究不断发现PTMP生物标志物的临床意义，它们将成为精准医学临床检测菜单中有价值的补充。

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引用次数: 0

Excess Leading to Deficiency: An Unusual Cause of Cytopenia. 过量导致不足：细胞减少症的一个不寻常的原因。

IF 9.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-04 DOI: 10.1093/clinchem/hvaf096

Jorieke Weiden,Susan D P W M de Jonge-Peeters,Johannes M W van den Ouweland

引用次数: 0

Commentary on Excess Leading to Deficiency: An Unusual Cause of Cytopenia. 过量导致不足：细胞减少症的一个不寻常的原因。

IF 9.3 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Clinical chemistry

Pub Date : 2025-11-04 DOI: 10.1093/clinchem/hvaf107

Brian D Adkins,Sharon K Germans,Charles F Timmons,Hung S Luu

引用次数: 0

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