Clinical Laboratory Measurements Research Articles

Clinical application of an optimized reference measurement procedure for serum digoxin using bracketing calibration method by ID-LC-MS/MS.

Digoxin, a cardiac glycoside, is widely used in the treatment of cardiovascular diseases. Due to its narrow therapeutic range, precise monitoring of its blood concentration is essential. Areference measurement procedure (RMP) is pivotal for ensuring result accuracy and comparability. The RMP for serum digoxin by ID-LC-MS/MS was optimized with sample pre-treatment and detection processes, and the bracketing calibration method was used, which facilitates more accurate measurement, especially for extreme concentrations. The performance of this optimized RMP was thoroughly evaluated. The limit of detection (LoD) was 0.05 ng/mL (0.06 nmol/L) and the lowest limit of quantification (LLoQ) was 0.10 ng/mL (0.13 nmol/L). The intra- and inter-assay imprecisions were 2.24%, 2.51%, 1.40% and 1.72%, 1.65%, 0.97% at 0.5, 2.0, 5.0 ng/mL, respectively. Recoveries were 99.63 to 101.42% and thelinear response ranged from 0.1 to 10.0 ng/mL. The relative bias was 0.41% and 2.00% of our results compared with the median of all participating reference laboratories for IFCC-RELA (External Quality Assessment Scheme for Reference Laboratories in Laboratory Medicine) 2023A and 2023B. The uncertainty, calibration and measurement capability (CMC) of this method were also evaluated. The optimized RMP was applied in the Trueness Verification Plan of Southern China, which indicates significant differences among clinical systems, highlighting the need for standardization efforts. In addition, two commonly used clinical systems which employed immunoassay methods were compared with this optimized RMP, and 26 individual serum samples were analyzed. The good correlations indicate the feasibility of standardization for serum digoxin. The optimized RMP serves as an accurate reference baseline for routine methods, aiming to enhance the accuracy and precision of measurements in clinical laboratories.

6651 A Traceable Clinical Free Thyroxine Assay Based on Equilibrium Dialysis ID-LC/MS/MS

Abstract Disclosure: D. Spector: None. L. Zhang: None. A. Ribera: None. A. Doty: None. C. Tse: None. O. Sugahara: None. N. Vazquez: None. U. Danilenko: None. H.W. Vesper: None. Accurate diagnosis and effective treatment of thyroid diseases rely on reliable thyroid function tests. Serum free thyroxine (FT4) immunoassays (IAs) are most commonly used for FT4 measurements in clinical practice. However, FT4 IAs have not been standardized with large variations between different assay platforms. A reference measurement procedure (RMP) for FT4 based on well-defined equilibrium dialysis (ED) of serum has been established for CDC standardization program to support the standardization of clinical assays for patient care. In the current study, we aim to develop a routine clinical FT4 assay based on ED-LC/MS/MS that is traceable to the RMP. ED-LC/MS/MS analysis was performed using a commercially available micro-ED plate. FT4 in dialysate was extracted with a 96-well C18 SPE plate. FT4 in the samples was quantitated by using LC/MS/MS in positive ion mode. The assay was calibrated with the certified primary reference material. By using RMP as a reference, we compared the analysis of 40 single donor sera between the ED-LC/MS/MS assay and FT4 IA on Roche e401platform. ED-LC/MS/MS assay could resolve T4, T3, reverse triiodothyronine (rT3), and other interferences in the samples with C18 chromatography in 4 min. The linear range of the routine FT4 assay was from 0.5-100 pg/mL covering clinically relevant FT4 concentrations including hypo-, hyperthyroid patient samples. The intra and inter-run CV% of the assay in 20 days was 3.72 and 5.25%, respectively. The effect of minor changes to the method conditions was studied. It was determined that serum/buffer ratios from 1:1 to 1:2 in the ED inserts, speeds of shaker for ED, and ED incubation time, did not influence the FT4 measurement. However, elevated ED temperature at 38°C could result in a more than 10% increase in FT4 values. A microplate format for the procedures of ED and SPE is amiable to the application of an automation system which significantly improves the throughput of the procedure. Method comparison showed good agreement between ED-LC/MS/MS assay and RMP in Deming regression analysis with a slope close to 1, while there was significant bias of IA from RMP. ED-LC/MS/MS assay was also applied for pregnancy serum samples with minimal difference on the FT4 measurement from RMP. We have developed a routine clinical FT4 assay that is traceable to RMP. The accuracy, precision, and sensitivity of the assay are suitable for high-throughput FT4 measurements in clinical laboratories and large epidemiologic studies. We demonstrate that the developed method can provide accurate FT4 measurements in patients including pregnant women. Presentation: 6/3/2024

A-105 Cherry-red plasma: unraveling the impact of PV-10 on chemistry assays

Abstract Background The accuracy of clinical laboratory measurements can be compromised by laboratory test interferences. PV-10 (Rose Bengal), a chemotherapy medication used in the treatment of metastatic melanoma, was observed to cause a cherry-red discoloration in plasma. This plasma color change, resembling hemolysis, raises serious concerns about potential interference in clinical laboratory tests. Our study focused on understanding the potential interference of PV-10, particularly the impact on the hemolysis index (H index) and various chemistry assays to ensure result accuracy in cancer treatment. Methods To investigate the potential interference of PV-10, pooled normal and high baseline bilirubin plasma samples were spiked with a gradient of PV-10 concentrations (0 to 22 µg/100µL). Samples were analyzed on Roche Cobas 8000 analyzer with H index and all the chemistry assays measured. Results The presence of PV-10 in plasma significantly increased the H index, in a dose-dependent manner. Specifically, the H index increased from 14 (control plasma) to 2643 at the highest PV-10 concentration (22 µg/100µL) in pooled plasma. Among all chemistry assays, most of them were not affected by PV-10. However, certain assays like IRON have dose dependent increase with PV-10 concentration. CHO2A (Total Cholesterol), TP (Total Protein), and TRIG (Triglycerides) have shown a consistent increase trend. In contrast, the DBILI values decreased with increasing PV-10 concentrations, from 6.7 mg/dL to 0.2 mg/dL. TBIL levels also demonstrated a gradual decline from 9.6 mg/dL to 8.4 mg/dL as PV-10 concentration increased in pooled high baseline bilirubin plasma. Conclusions This study provides insights into the potential interference of PV-10 in clinical chemistry assays. The elevated H index by PV-10 is not attributed to hemolysis. It is imperative for both laboratory professionals and care providers to recognize the implications of PV-10-induced plasma discoloration and its potential interference in laboratory tests.

A-092 Siemens Healthineers Commitment to Quality - A Focus on Continuous Improvement and Customer Experience

Abstract Background It is necessary that each step of in vitro diagnostic assay development and manufacturing processes be documented and executed in alignment with established quality management systems. Here, we describe how Siemens Healthineers (SHS) maintains assay traceability and focus on continuous improvement using the Atellica® CH A-LYTE® Integrated Multisensor Technology (IMT) assays measuring electrolytes sodium (Na), potassium (K), and chloride (Cl) as a prime example. Methods Establishing an unbroken chain of comparison from the National Institute of Standards and Technology (NIST) higher standard references to the product calibrators ensures accurate value assignment within stated measurement uncertainties. Traceability and standardization are achieved by creating a panel of 10 serum anchor pools spanning the analytical measuring interval for each electrolyte: Na, K, and Cl. The concentrations of the anchor pools are determined at a reference laboratory using methods calibrated with standard solutions derived from NIST reference material. These serum anchor pools are used by SHS, assigning values to product calibrator material which maintains the chain of traceability to the primary reference methods. In addition to traceability, onboard stability for the A-LYTE® IMT multisensor is continuously monitored and evaluated against allowable drift limits for each electrolyte. Although observed drift was within allowable limits, a design change was implemented to improve recovery drift over the use life of the sensor. Results To ensure consistent, robust, and accurate performance of the A-LYTE IMT, a strict set of testing procedures are used to verify the accuracy of value assignments for each manufactured lot of master standards. The recovery of the NIST standard reference material must fall within manufacturer established acceptable bias limits. Consistency over nine master lots is shown with bias ranging from -0.9% to +1.9%, -2.4% to +1.8% and -1.8 to +0.5%, for Na, K and Cl, respectively. By further optimizing the amount of Na ionophore and the polymer matrix of the Na sensor, drift over the use life was minimized and onboard stability improved. Prior to making the sensor change, customer Na QC data at 116 mmol/L showed an SD of 1.1 mmol/L (n=585), whereas the precision improved to an SD of 0.6 mmol/L (n=470) post-optimization. As Manufacturers optimize assay performance, it may become necessary for laboratories to re-evaluate reference intervals for their patient populations. For example, one large integrated delivery network established a new reference interval for patient anion gap (AG). A re-evaluation of the historical AG reference interval which was 5-15 mmol/L identified the need for an update. AG values were calculated from 16,948 healthy patients and used to establish a new reference interval of 2-10 mmol/L. Conclusions Accurate clinical laboratory measurements are critical for diagnosing, monitoring, and treating diseases. A-LYTE assays have an unbroken chain of traceability to NIST reference material and minimal drift over the life of the multisensor. Continuous monitoring to identify improvement projects and rigorous control systems ensure sensor performance over time. This provides confidence that the patient results produced by the laboratory are accurate and consistent over time and across different laboratory locations.

Proteogenomic analysis integrated with electronic health records data reveals disease-associated variants in Black Americans.

Most genome wide association studies (GWAS) of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry enriched protein quantitative loci (pQTL). We conducted a discovery GWAS of ~3,000 plasma proteins measured by the antibody based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS), and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs were further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome wide association study (PheWAS) across two large multi-ethnic electronic health record (EHR) systems in All of Us and BioMe. We identified 1002 pQTLs for 925 proteins. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for Cathepsin L (CTSL) and Siglec-9 that were linked with sarcoidosis and non-Hodgkin's lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, white blood cell count, and multiple sclerosis. Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.

Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort.

There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). To investigate clinical laboratory markers of SARS-CoV-2 and PASC. Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). 83 enrolling sites. RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. Participants completed questionnaires and standard clinical laboratory tests. Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. National Institutes of Health.

Zinc Deficiency and the Severity of Pneumonia in Vietnamese Children: A Hospital-Based Study.

Background Pneumonia is a critical global health concern that often results in severe complications and fatalities, especially among young children. Zinc plays a crucial role in immune function and maintaining respiratory epithelial integrity. Despite its importance, data on the prevalence of zinc deficiency and its impact on pneumonia severity in Vietnamese children are limited. Objectives This study aimed to investigate the prevalence of zinc deficiency and its association with pneumonia severity in Vietnamese children under five years old. The findings could significantly contribute to our understanding of the role of zinc in pneumonia severity, guiding future public health interventions, nutritional policies, and clinical practices to prevent zinc deficiency and reduce pneumonia morbidity and mortality in children. Methods An analytical cross-sectional study was conducted at a major pediatric center in Southwestern Vietnam from December 2022 to February 2024, involving 222 children aged 2 to 59 months diagnosed with pneumonia. Clinical assessments and laboratory measurements, including serum zinc levels, were performed. Statistical analyses were conducted to compare clinical characteristics and outcomes between zinc-deficient and non-deficient groups. Multivariable logistic regression was used to assess the association between zinc deficiency and pneumonia severity, with statistical significance set at p<0.05. Results The prevalence of zinc deficiency among children with pneumonia was 74.3%. Zinc-deficient children showed a significantly higher proportion of severe pneumonia (57.6% vs. 8.8%, p<0.001), as well as a higher proportion of high fever, poor feeding, vomiting, and respiratory distress compared to non-deficient children (p<0.001). Multivariable logistic regression identified zinc deficiency as an independent predictor of severe pneumonia (aOR=13.1, 95% CI: 4.7-36.8, p<0.001). Conclusion Zinc deficiency was prevalent among Vietnamese children with pneumonia and was associated with an increased risk of severe pneumonia.

Effectiveness of oral methylprednisolone as adjuvant therapy for clinical improvement, biochemical markers, and inflammation in infants with cholestasis

AimsThis study analyzed the effectiveness of methylprednisolone in improving jaundice, bilirubin levels, liver function tests, and inflammatory biomarkers in infants with cholestasis. MethodsThe randomized, actively controlled, parallel‐group trial (ISRCTN45080388 registry) was conducted from November 2022 to May 2023 in Dr. Soetomo General Academic Hospital, Surabaya, Indonesia, on infants with cholestasis. The ethics committee of Dr. Soetomo General Academic Hospital, Surabaya approved the study protocol. Infants 14 days to 3 months old, with cholestasis followed by acholic stool, dark urine, and hepatomegaly were included in the trial. Participants were randomly assigned to methylprednisolone 2 mg/kg/day twice daily or to placebo twice daily for two weeks. Ursodeoxycholic acid (10 mg/kg) was administered to all patients thrice daily. Clinical examination and laboratory measurements (direct and total bilirubin, Aspartate aminotransferase (AST), Alanine transaminase (ALT), Gamma-glutamyl transferase (GGT), and inflammatory biomarker) were performed at baseline and after 2‐week treatment. Measurement of inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, IFN-γ, TGF-β, and ANCA) was performed using enzyme-linked immunoassays. Data distribution was checked for normality. Analysis was carried out using SPSS ver. 21 with p significant <0.05. ResultsIn total, 40 participants were randomized to methylprednisolone (n = 20; mean age 8.39 ± 3.11 weeks) and placebo (n = 18; 2 drop out; mean age 8.98 ± 2.80 weeks) groups. At baseline, the methylprednisolone treatment and placebo groups significantly differed in gender (p = 0.02) but not in clinical, laboratory examination, or inflammatory biomarker levels. The methylprednisolone group had direct bilirubin 8.36 ± 4.84 mg/dL; total bilirubin 10.40 (2.70–33.25) mg/dL; AST 187.05 (42.00–911.00) U/L; ALT 170.43 ± 134.43 U/L; IL-2 171.29 (73.70–378.57) ng/L; IL-4 119.57 ± 59.69 ng/L; IL-6 71.74 ± 29.83 ng/L; IL-10 138.15 ± 70.62 ng/L; IFN-γ 42.54 ± 12.17 ng/L; TGF-β 316.58 (163.68–606.16) ng/L; ANCA 1.70 (0.66–3.25) ng/L. After two weeks of treatment, direct bilirubin, total bilirubin, AST, IL-10, and IFN-γ levels were significantly lower in the methylprednisolone group (p < 0.05) than those in the placebo group. No serious adverse events were reported. ConclusionMethylprednisolone was efficacious in reducing 2‐week bilirubin levels. These results support the hypothesis that the immunological process is involved in cholestasis. Further studies with larger sample sizes are needed to confirm the bile duct anti-inflammatory effect of methylprednisolone in cholestasis as an opportunity for new therapies to prevent the immunopathological process of cholestasis to biliary atresia.

Evaluation for serum glucose standardization in clinical laboratories of Southern China by consecutive 6 years proficiency testing based on JCTLM-recommended reference methods

Abstract Objectives The accuracy of blood glucose measurement in clinical laboratories is vital for diabetes diagnosis. Trueness Verification Plan was carried out and analyzed for evaluating the standardization of serum glucose among clinical laboratories. Methods Trueness verification samples were distributed to clinical laboratories for three days measurement, and their target values were assigned by two certified reference laboratories. The relative bias, coefficient of variation (CV), and total error (TE) for each clinical laboratory were calculated and analyzed. Moreover, the Six Sigma metrics and Quality Goal Index were utilized to reflect the measurement quality of the clinical laboratories. Results The pass rates evaluated by bias, CV, and TE ranged from 45.2 % to 64.8 %, 96.8 %–98.9 %, and 83.9 %–97.1 % over the six years. The matched systems used in clinical laboratories demonstrated better accuracy than the un-matched systems. The pass rate by bias of hexokinase method is 53.1 %–78.6 %, while the glucose oxidase method is 29.2 %–52.2 %. Overall, 74.2 %–85.7 % of clinical laboratories achieved an acceptable level (both σ&gt;3), and 35.2 %–61.4 % of laboratories reached a “world-class” level (both σ&gt;6). Conclusions The quality for serum glucose measurement has been greatly improved. However, standardization among clinical systems still needs to be further promoted.

Prediction of post-delivery hemoglobin levels with machine learning algorithms

Predicting postpartum hemorrhage (PPH) before delivery is crucial for enhancing patient outcomes, enabling timely transfer and implementation of prophylactic therapies. We attempted to utilize machine learning (ML) using basic pre-labor clinical data and laboratory measurements to predict postpartum Hemoglobin (Hb) in non-complicated singleton pregnancies. The local databases of two academic care centers on patient delivery were incorporated into the current study. Patients with preexisting coagulopathy, traumatic cases, and allogenic blood transfusion were excluded from all analyses. The association of pre-delivery variables with 24-h post-delivery hemoglobin level was evaluated using feature selection with Elastic Net regression and Random Forest algorithms. A suite of ML algorithms was employed to predict post-delivery Hb levels. Out of 2051 pregnant women, 1974 were included in the final analysis. After data pre-processing and redundant variable removal, the top predictors selected via feature selection for predicting post-delivery Hb were parity (B: 0.09 [0.05–0.12]), gestational age, pre-delivery hemoglobin (B:0.83 [0.80–0.85]) and fibrinogen levels (B:0.01 [0.01–0.01]), and pre-labor platelet count (B*1000: 0.77 [0.30–1.23]). Among the trained algorithms, artificial neural network provided the most accurate model (Root mean squared error: 0.62), which was subsequently deployed as a web-based calculator: https://predictivecalculators.shinyapps.io/ANN-HB. The current study shows that ML models could be utilized as accurate predictors of indirect measures of PPH and can be readily incorporated into healthcare systems. Further studies with heterogenous population-based samples may further improve the generalizability of these models.

OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank with balanced sex representation, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Furthermore, both DNAmEMRAge and OMICmAge exhibit greater accuracy (average ROC = 0.88) in predicting 5-year and 10-year mortality than current biological age predictors. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process. This work was funded in part by TruDiagnostic for data generation and manuscript writing. Efforts for RK, KM, YC, SB, and JALS are supported by R01HL123915 from the NIH/NHLBI; PK is supported by K99HL159234 from the NIH/NHLBI; RSK is supported by K01HL146980 from the NIH/NHLBI; SHC is supported by K01HL153941 from the NIH/NHLBI; YC and JAILS are supported by R01HL141826 from the NIH/NHLBI; AD is supported by K01HL130629 from the NIH/NHLBI; AD and JALS are supported by 1R01HL152244 from the NIH/NHLBI; MM and JALS are supported by R01HL155742 from the NIH/NHLBI; MM is supported by R01HL139634 from the NIH/NHLBI; JALS, STW, EWK are supported by the NIH U01HG008685; VNG is supported by NIH AG065403 and AG064223; CEW is supported by the JSPS KAKENHI Grant (JP19K21239), the Japanese Environment Research and Technology Development Fund (No. 5- 1752), JPJ SBP-1201854), HLF 20180290, HLF 20200693), and the Swedish Research Council (2016-02798); NJWR is supported by MR/Y010736/1 and IF\R1\231034; EM is supported by the NIH (ZICTR000410-03). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Plasma levels of Sirtuin 7 are decreased in patients with essential hypertension

BackgroundSirtuin 7 (SIRT7), as a nicotinamide adenine dinucleotide-dependent protein/histone deacetylase, has been implicated in the pathogenesis of cardiovascular diseases. However, whether SIRT7 is related to hypertension remains largely unclear. Thus, this study aims to explore the effects and correlation between SIRT7 and hypertension. MethodsA total of 72 patients with essential hypertension and 82 controls with non-hypertension were recruited at Beijing Tongren Hospital Affiliated with Capital Medical University from July 2022 to June 2023. Plasma SIRT7 expression was measured using enzyme-linked immunosorbent assay analysis. Clinical baseline characteristics, laboratory measurements, echocardiographic data, and medical therapy were collected. ResultsPlasma levels of SIRT7 were lower in hypertensive patients compared with non-hypertensive patients [0.97 (0.58–1.30) vs. 1.24 (0.99–1.46) ng/mL, P < 0.001, respectively]. Furthermore, compared with the low SIRT7 group, there were lower levels of systolic blood pressure, hyperlipidemia, and the ultrasonic electrocardiogram parameters left ventricular end-diastolic diameter and left atrial in diastole in the high SIRT7 group (P < 0.05, respectively). More importantly, multivariate logistic regression analyses indicated that plasma SIRT7 was a predictor of hypertension [OR: 0.06, 95 % CI (0.02–0.19), P < 0.001]. Receiver operating characteristics curve analysis revealed that the optimal cutoff value for plasma SIRT7 levels in detecting hypertension was determined as 0.85 ng/mL with a sensitivity of 73.6 % and a specificity of 89.0 %. The area under the curve for SIRT7 was 0.821 (95 % CI, 0.751–0.878; P < 0.001). ConclusionPlasma levels of SIRT7 are decreased in patients with essential hypertension, implying its potential as a biomarker for diagnosing essential hypertension..

MANAGEMENT OF DIABETES INSIPIDUS AFTER SUBLABIAL TRANSSPHENOIDAL HYPOPHYSECTOMY SURGERY

MANAGEMENT OF DIABETES INSIPIDUS AFTER SUBLABIAL TRANSSPHENOIDAL HYPOPHYSECTOMY SURGERY

Evaluation of imprecision in the different detection methods of Zn based on 5 years of data from an external quality assessment program in China

BackgroundThis study examines the imprecision of zinc (Zn) measurements across various clinical detection methods by analyzing the external quality assessment (EQA) data from 2018 to 2022. The findings of this study aim to offer recommendations for enhancing Zn measurements. MethodsParticipating laboratories were grouped into peer categories based on the detection methods. The robust mean and coefficient of variation (CV) of the samples were calculated following ISO 13528 guidelines. The evaluation criteria for optimal, desirable, and minimum allowable imprecision in Zn estimation are 2.50%, 5.05%, and 7.55%, respectively, based on biological variation. Furthermore, the study examined inter-lab CVs, inter-method bias, and the passing rate. The impact of sample concentration on CVs and the pass rate was also investigated. ResultsOver the past five years, 4283 laboratories participated in the EQA program, showing a high pass rate that improved as sample concentration increased. Differential pulse polarography (DPP) demonstrated stable and low CVs (0.61–1.86%). Although differential pulse stripping (DPS) was less stable than DPP, it still exhibited a low CV (0.71–3.10%). Graphite furnace atomic absorption spectrometry (GFAAS) and flame atomic absorption spectrometry (FAAS) performed similarly and displayed stable CVs (2.39–4.42%) within the acceptable range of desirable imprecision (5.05%). However, the CVs for ICP-MS were unacceptable in three out of the five years (5.28–6.20%). In 2022, the number of participating laboratories for DDP, DPS, GFAAS, FAAS and ICP-MS is 131, 35, 35, 820 and 72, respectively. ConclusionThis study provides reliable insights into the imprecision of Zn measurements in clinical laboratories. The findings indicate that additional efforts are required to reduce the imprecision of ICP-MS in Zn measurements.

Uncovering genetic associations in the human diseasome using an endophenotype-augmented disease network.

Many diseases, particularly cardiometabolic disorders, exhibit complex multimorbidities with one another. An intuitive way to model the connections between phenotypes is with a disease-disease network (DDN), where nodes represent diseases and edges represent associations, such as shared single-nucleotide polymorphisms (SNPs), between pairs of diseases. To gain further genetic understanding of molecular contributors to disease associations, we propose a novel version of the shared-SNP DDN (ssDDN), denoted as ssDDN+, which includes connections between diseases derived from genetic correlations with intermediate endophenotypes. We hypothesize that a ssDDN+ can provide complementary information to the disease connections in a ssDDN, yielding insight into the role of clinical laboratory measurements in disease interactions. Using PheWAS summary statistics from the UK Biobank, we constructed a ssDDN+ revealing hundreds of genetic correlations between diseases and quantitative traits. Our augmented network uncovers genetic associations across different disease categories, connects relevant cardiometabolic diseases, and highlights specific biomarkers that are associated with cross-phenotype associations. Out of the 31 clinical measurements under consideration, HDL-C connects the greatest number of diseases and is strongly associated with both type 2 diabetes and heart failure. Triglycerides, another blood lipid with known genetic causes in non-mendelian diseases, also adds a substantial number of edges to the ssDDN. This work demonstrates how association with clinical biomarkers can better explain the shared genetics between cardiometabolic disorders. Our study can facilitate future network-based investigations of cross-phenotype associations involving pleiotropy and genetic heterogeneity, potentially uncovering sources of missing heritability in multimorbidities. The generated ssDDN+ can be explored at https://hdpm.biomedinfolab.com/ddn/biomarkerDDN.

Evaluation of the Relationship Between Vitamin D Deficiency and Subclinical Cardiac Dysfunction Using 2D/3D Strain Echocardiography in Healthy People.

Vitamin D deficiency has a high prevalence in the population and is highly associated with cardiovascular diseases. The aim of this study was to evaluate subclinical left ventricular (LV) function using strain analysis in healthy individuals with vitamin D deficiency. 113 healthy volunteers were enrolled in the study (age, 44.1±7 yrs, 34 male). All volunteers underwent two-dimensional (2D) and three-dimensional (3D) speckle tracking echocardiography after conventional echocardiographic evaluation. The subjects were divided into two groups according to their vitamin D concentrations. 61 subjects with vitamin D less than 20 ng / ml were included in the vitamin D deficiency group. The baseline clinical characteristics, laboratory measurements, echocardiographic data, including 2D and 3D global longitudinal strain (GLS) values, were compared between the groups. The 2D GLS values of the subjects with vitamin D deficiency were lower (mathematically less negative) than subjects with normal vitamin D (-16.1±3.4 vs -19.3±4.2, p&lt;0.001). Similarly, the 3D GLS results were lower in subjects with vitamin D deficiency (-18.3±5.2 vs -24.1±6.9, p&lt;0.001). A significant correlation was detected between the vitamin D concentrations and the 2D and 3D GLS measurements. (r=0.765 and r=0.628, respectively, p&lt;0.001). Vitamin D was found to be an independent predictor of impaired 2D and 3D LV GLS (p=0.031, p=0.023, respectively). Subclinical LV dysfunction in healthy individuals with vitamin D deficiency was demonstrated by 3D and 2D strain analysis. Due to potential negative effects of vitamin D deficiency on cardiac function, more attention should be paid to healthy individuals with vitamin D deficiency.

Autoantibody evaluation in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM), generally referred to as myositis is a heterogeneous group of diseases characterized by muscle inflammation and/or skin involvement, diverse extramuscular manifestations with variable risk for malignancy and response to treatment. Contemporary clinico-serologic categorization identifies 5 main clinical groups which can be further stratified based on age, specific clinical manifestations and/or risk for cancer. The serological biomarkers for this classification are generally known as myositis-specific (MSAs) and myositis-associated antibodies. Based on the use of these antibodies, IIM patients are classified into anti-synthetase syndrome, dermatomyositis, immune-mediated necrotizing myopathy, inclusion body myositis, and overlap myositis. The current classification criteria for IIM requires clinical findings, laboratory measurements, and histological findings of the muscles. However, the use MSAs and myositis-associated autoantibodies as an adjunct for disease evaluation is thought to provide a cost-effective personalized approach that may not only guide diagnosis but aid in stratification and/or prognosis of patients. This review provides a comprehensive overview of contemporary autoantibodies that are specific or associated myositis. In addition, it highlights possible pathways for the detection and interpretation of these antibodies with limitations for routine clinical use.

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa

Hidradenitis suppurativa is a painful immune-mediated disorder with limited treatment options; hence, a need exists for new treatments. To evaluate the feasibility of heat shock protein 90 inhibition by RGRN-305 as a novel mechanism of action in treating moderate to severe hidradenitis suppurativa. This was a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial conducted between September 22, 2021, and August 29, 2022, at the Department of Dermatology, Aarhus University Hospital in Denmark. The study included a 1- to 30-day screening period, a 16-week treatment period, and a 4-week follow-up period. Eligibility criteria included age 18 years or older and moderate to severe hidradenitis suppurativa with 6 or more inflammatory nodules or abscesses in at least 2 distinct anatomic regions. Of 19 patients screened, 15 patients were enrolled in the study. Intention-to-treat analysis was performed. Patients were randomly assigned (2:1) to receive oral RGRN-305, 250-mg tablet, or matching placebo once daily for 16 weeks. The primary efficacy end point was the percentage of patients achieving Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) at week 16. Secondary efficacy end points included HiSCR-75 or HiSCR-90, Hidradenitis Suppurativa Physician's Global Assessment, Dermatology Life Quality Index scores, and a pain numeric rating scale. Safety was assessed by adverse events, physical examinations, clinical laboratory measurements, and electrocardiograms. A total of 15 patients were enrolled, completed the study, and were included in all analyses (10 [67%] female; median age, 29 [IQR, 23-41] years). The primary end point HiSCR-50 at week 16 was achieved by a higher percentage in the RGRN-305 group (60% [6 of 10]) than in the placebo group (20% [1 of 5]). Improvements were also observed across all secondary end points at week 16, including higher rates of the harder-to-reach HiSCR levels; 50% (5 of 10) achieved HiSCR-75 and 30% (3 of 10) achieved HiSCR-90, whereas none of the placebo-treated patients achieved HiSCR-75 or HiSCR-90. RGRN-305 was well tolerated, with no deaths or serious adverse events, and treatment-emergent adverse events were similarly frequent between the RGRN-305 and placebo groups. The findings of this trial suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials. ClinicalTrials.gov Identifier: NCT05286567.

The current status of lipoprotein (a) measurement in clinical biochemistry laboratories in the UK: Results of a 2021 national survey.

Lipoprotein(a) (Lp(a)) is now established as a causal risk factor for cardiovascular disease (CVD) and accurate laboratory measurement is of pivotal importance in reducing Lp(a) associated risk. The consensus statement by HEART UK in 2019 included recommendations to improve standardisation of clinical laboratory measurement and reporting of Lp(a). A 16 question, electronic audit survey was circulated to 190 accredited clinical biochemistry laboratories to assess the adoption of these recommendations in the UK. Responses were received from 65 of 190 laboratories (34%). Only 5 (8%) did not offer Lp(a) measurement. Of those providing the test, 23% (n = 14) offered an in-house service (IHS), the remaining laboratories (77%; n = 46) used an external referral service (ERS). The majority (10 of 14 or 71%) of IHS laboratories responded with details of their method, stating whether it minimised sensitivity to the effect of Lp(a) isoform size and used calibrators certified for traceability to the WHO/IFCC reference material, however, only a minority ERS laboratories (13 of the 46 or 28%) were able to specify the method used by their referral laboratory. Of the laboratories who specified their reporting units, 6 of 10 IHS and 7 of 23 ERS laboratories reported in nmol/L. Among the 60 laboratories who responded, the HEART UK recommendations appear to have been adopted in full by only 3 IHS laboratories. Further efforts are needed to standardise the measurement and reporting of Lp(a) so that results and interpretation are comparable across clinical biochemistry laboratories in the UK.

Rigorous evaluation of genetic and epigenetic effects on clinical laboratory measurements using Japanese monozygotic twins.

The investigation of environmental effects on clinical measurements using individual samples is challenging because their genetic and environmental factors are different. However, using monozygotic twins (MZ) makes it possible to investigate the influence of environmental factors as they have the same genetic factors within pairs because the difference in the clinical traits within the MZ mostly reflect the influence of environmental factors. We hypothesized that the within-pair differences in the traits that are strongly affected by genetic factors become larger after genetic risk score (GRS) correction. Using 278 Japanese MZ pairs, we compared the change in within-pair differences in each of the 45 normalized clinical measurements before and after GRS correction, and we also attempted to correct for the effects of genetic factors to identify Cytosine-phosphodiester-Guanine (CpG) sites in DNA sequences with epigenetic effects that are regulated by genetic factors. Five traits were classified into the high heritability group, which was strongly affected by genetic factors. CpG sites could be classified into three groups: regulated only by environmental factors, regulated by environmental factors masked by genetic factors, and regulated only by genetic factors. Our method has the potential to identify trait-related methylation sites that have not yet been discovered.