Evaluation of Age and Sex Differences in Contemporary versus High-Sensitivity Troponin I Measurement in Hospitalized Patients.

Background: With the transition from the contemporary (cTnI) to high-sensitivity troponin assay (hs-cTnI), concerns have arisen regarding the diagnostic differences between these two assays due to analytical distinctions. This study aims to evaluate the age and sex differences between these two assays, as well as the differences resulting from using two different 99th percentile values of the high-sensitivity troponin assay. Method: A retrospective observational study was conducted at an academic medical center, encompassing a total of 449 lithium heparin plasma samples included in the dataset. Both contemporary and high-sensitivity troponin were simultaneously measured using Siemens ADVIA Centaur analyzers. Two sets of sex-specific 99th percentile URLs from the Siemens study (cutoff-1) and Universal Sample Bank data (cutoff-2) were used for the data analysis. Results: The use of cutoff-1 or cutoff-2 had a negligible impact on troponin classification. Troponin elevation significantly increased in individuals > 50 years old for males and >40 years old for females, with both troponin assays. A receiver operating characteristic analysis did not find significant differences between the two assays. The Kaplan-Meier curves showed no differences in survival in cTnI according to the non-sex-specific 99th URL or hs-cTnI (cutoff-2) but showed a slight difference in survival in hs-cTnI (cutoff-1). Conclusions: Overall, there were no significant differences in age and sex in the diagnostic performance between the contemporary and high-sensitivity troponin assays. Selection criteria for the establishment of the 99th percentile URL should be standardized to avoid the misinterpretation of the troponin results.

Challenges of insulin-like growth factor-1 testing.

Insulin-like growth factor 1 (IGF-1), primarily synthesized in the liver, was initially discovered due to its capacity to replicate the metabolic effects of insulin. Subsequently, it emerged as a key regulator of the actions of growth hormone (GH), managing critical processes like cell proliferation, differentiation, and apoptosis. Notably, IGF-1 displays a longer half-life compared to GH, making it less susceptible to factors that may affect GH concentrations. Consequently, the measurement of IGF-1 proves to be more specific and sensitive when diagnosing conditions such as acromegaly or GH deficiency. The recognition of the existence of IGFBPs and their potential to interfere with IGF-1 immunoassays urged the implementation of various techniques to moderate this issue and provide accurate IGF-1 results. Additionally, in response to the limitations associated with IGF-1 immunoassays and the occurrence of discordant IGF-1 results, modern mass spectrometric methods were developed to facilitate the quantification of IGF-1 levels. Taking advantage of their ability to minimize the interference caused by IGF-1 variants, mass spectrometric methods offer the capacity to deliver robust, reliable, and accurate IGF-1 results, relying on the precision of mass measurements. This also enables the potential detection of pathogenic mutations through protein sequence analysis. However, despite the analytical challenges, the discordance in IGF-1 reference intervals can be attributed to a multitude of factors, potentially leading to distinct interpretations of results. The establishment of reference intervals for each assay is a demanding task, and it requires nationwide multicenter collaboration among laboratorians, clinicians, and assay manufacturers to achieve this common goal in a cost-effective and resource-efficient manner. In this comprehensive review, we examine the challenges associated with the standardization of IGF-1 measurement methods, the minimization of pre-analytical factors, and the harmonization of reference intervals. Particular emphasis will be placed on the development of IGF-1 measurement techniques using "top-down" or "bottom-up" mass spectrometric methods.

A novel role of RNase L in the development of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and affects about 25% of the population globally. NAFLD has the potential to cause significant liver damage in many patients because it can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis, which substantially increases disease morbidity and mortality. Despite the key role of innate immunity in the disease progression, the underlying molecular and pathogenic mechanisms remain to be elucidated. RNase L is a key enzyme in interferon action against viral infection and displays pleiotropic biological functions such as control of cell proliferation, apoptosis, and autophagy. Recent studies have demonstrated that RNase L is involved in innate immunity. In this study, we revealed that RNase L contributed to the development of NAFLD, which further progressed to NASH in a time-dependent fashion after RNase L wild-type (WT) and knockout mice were fed with a high-fat and high-cholesterol diet. RNase L WT mice showed significantly more severe NASH, evidenced by widespread macro-vesicular steatosis, hepatocyte ballooning degeneration, inflammation, and fibrosis, although physiological and biochemical data indicated that both types of mice developed obesity, hyperglycemia, hypercholesterolemia, dysfunction of the liver, and systemic inflammation at different extents. Further investigation demonstrated that RNase L was responsible for the expression of some key genes in lipid metabolism, inflammation, and fibrosis signaling. Taken together, our results suggest that a novel therapeutic intervention for NAFLD may be developed based on regulating the expression and activity of RNase L.

Relationship between TSH and free thyroxine in outpatient cancer patient population.

BACKGROUND: The inverse log-linear relationship between Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is well established and reliably used for evaluation of hypothalamus-pituitary-thyroid (HPT) axis function. However, there are limited data regarding oncologic states in the TSH-FT4 relationship. The purpose of this study was to evaluate thyroid pituitary hypothalamic feedback regulation by the inverse log TSH and FT4 relationship in the cancer patient population at the Ohio State University Comprehensive Cancer Center (OSUCCC-James). METHODS: This retrospective study analyzed the correlation between TSH and FT4 results from 18846 outpatient subjects collected in August 2019-November 2021 at the Department of Family Medicine (OSU Wexner Medical Center), Department of Oncology (OSUCCC-James). Patients with diagnoses related to cancers were included in the oncology group. Patients with diagnoses not related to cancers were included in the non-oncology group. Patients of the Department of Endocrinology, Department of Cardiology, Department of Obstetrics & Gynecology and Department of Hematology were excluded from this study. Time of collection for TSH and FT4 was from 7am to 7 pm. Data were analyzed by morning (7am-12pm) and afternoon (12pm-7pm). Spearman correlation and non-linear fit were used for data analysis. Sex differences were analyzed as well in each group. RESULTS: Overall, an inverse correlation was observed between TSH and FT4 in both groups (non-oncology and oncology) regardless of sample collection time and sex differences. Further analysis by linear model in log TSH and FT4 showed a significant inverse fit in males compared with females in the group of oncology, both in the afternoon (p < 0.05). Data were further analyzed by ranges of FT4, as lower or higher (pathophysiology) or within (physiology) the reference interval of FT4. There was no statistical significance between the non-oncology and oncology groups, but relatively good correlation in non-oncology group in either physiologic or pathophysiologic FT4 levels and sample collection time. Interestingly, the best correlation between TSH and FT4 was found in the non-oncology group at pathophysiologic FT4 concentrations (abnormally high). In addition, at pathophysiologic FT4 concentrations (abnormally low), the oncology group demonstrated a significant TSH response in the morning than in the afternoon (p < 0.05). CONCLUSIONS: Though overall the TSH-FT4 curves showed an inverse relationship, there are variations of TSH-FT4 relationship for collection times when considering FT4 in physiologic or pathophysiologic states. The results advance understanding of TSH response, which is beneficial for the interpretation of thyroid disease. We recommend re-evaluation for interpretation of pituitary hypothalamic axis by TSH results when FT4 is abnormally high in oncology patients or low in non-oncology patients, due to poor predictability and the potential for misdiagnosis. A better understanding of the complex nature of the TSH-FT4 relationship may need further study with better defining subclinical states of cancer patients.

Autoverification-based algorithms to detect preanalytical errors: Two examples.

The preanalytical phase of testing accounts for the majority of the errors. Software-based quality rules, such as autoverification, can assist in preanalytical error detection; therefore, preventing erroneous results from being reported. Two autoverification rules, turbidity/lipemia, and pseudohypoglycemia/pseudohyperkalemia alarms, are highlighted. Increased sample turbidity may arise from several causes outside of lipemia. Typically, this can be resolved by clarifying the sample with standard centrifugation. Truly lipemic specimens typically require higher centrifugation speeds and greater centrifugation time. At our facility, 96% of direct bilirubin (DBIL), 95% of aspartate transaminase (AST), and 98% of alanine transaminase (ALT) turbidity/lipemia alarms were found to be from sample turbidity versus lipemia. Secondly, a pseudohypoglycemia/pseudohyperkalemia rule was employed for specimens with delayed separation from cellular material. Of the total potassium results >6.0 mmol/L or glucose results <40 mg/dL (2.2 mmol/L), 30% and 50% respectively were noted to have delayed sample separation.

The Androstenedione Roche Elecsys immunoassay has superior comparability to the LC-MS/MS assay than the Siemens Immulite immunoassay.

Androstenedione (ASD) is a biomarker used in the diagnostic workup of hyperandrogenism, congenital adrenal hyperplasia, premature adrenarche, and polycystic ovary syndrome (PCOS). The Elecsys ASD competitive electrochemiluminescence immunoassay (Roche Diagnostics, Indianapolis, IN) is a new assay recently available in the US. Objective: This study evaluated the analytical and clinical performance of the Elecsys ASD assay. Design & Methods: We evaluated the linearity/analytical measuring range (AMR), precision, and accuracy of the Elecsys ASD assay on the cobas e601 analyzer. ASD was measured in serum/plasma in the Elecsys ASD, Immulite (Siemens Medical Solutions USA, Inc. Malvern, PA), and LC-MS/MS assays. Reference intervals (RI) were evaluated across genders, menopausal status, and in children. Statistical analysis was performed using EP evaluator and R program. Results: The Elecsys ASD assay had a linear response across the AMR. The intra- and inter-assay coefficients of variation at various concentrations were ≤4.5%. The Elecsys ASD assay had a mean difference of -0.04 ng/mL (-1.7%) with the LC-MS/MS assay, whereas the Immulite assay had a mean difference of 1.17 ng/mL (66%) and -1.22 ng/mL (-38%) compared to the LC-MS/MS and Elecsys ASD assays, respectively. The Roche recommended RIs for healthy men (0.280-1.52 ng/mL) and postmenopausal women (0.187-1.07 ng/mL) were successfully verified. The RIs for children were adopted from published data. For pre-menopausal women, a RI of <1.60 ng/mL was established. The ASD concentrations in women with and without PCOS overlapped. Conclusions: The Elecsys ASD assay has superior comparability to the LC-MS/MS assay than the Immulite assay.

Evaluation of the Clinical Performance of 7 Serological Assays for SARS-CoV-2 for Use in Clinical Laboratories.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays have emerged as a response to the global pandemic, warranting studies evaluating their clinical performance. This study investigated 7 commercially available SARS-CoV-2 serological assays in samples from noninfected individuals and hospitalized patients. METHODS: SARS-CoV-2 qualitative serological assays by Abbott (IgG), Beckman (IgG), DiaSorin (IgG), EUROIMMUN (IgG and IgA), Roche and Bio-Rad (Total) were evaluated using specimens collected pre-December 2019 (n = 393), from nucleic acid amplification testing (NAAT) negative patients (n = 40), and from 53 patients with COVID-19 by NAAT collected 3-21 days post-onset of symptoms (POS) (N = 83). Negative agreement (NA), positive agreement (PA), and positive and negative predictive values (PPV and NPV) at prevalences of 5% and 10% were calculated. RESULTS: The overall %NA; 95% CI in the negative samples were: Roche 99.8%; 99.3-100.2, Beckman 99.8%; 98.7-100.0, Abbott and Bio-Rad 99.3%; 98.0-99.9, DiaSorin 98.4; 97.2-99.6, EUROIMMUN IgG 97.5%; 95.5-98.7, and EUROIMMUN IgA 79.7%; 75.9-83.5), accounting for positive/equivocal results as false positives. The %PA; 95% CI in samples collected 14+ days POS (n = 24) were: Bio-Rad 83.3%; 68.4-98.2, Abbott and Roche 79.2%; 62.9-95.4, EUROIMMUN IgA 70.8%; 52.6-89.0, Beckman 58.3%; 38.6-78.1, DiaSorin 54.2; 34.2-74.1, and EUROIMMUN IgG 50.0%; 30.0-70.0, accounting for negative/equivocal results as false negatives. NPVs ranged from 97.4%-98.9% and 94.7%-97.7% for prevalences 5% and 10%, respectively. PPVs ranged from 15.5%-94.8% and 27.9%-97.4% for prevalences 5% and 10%, respectively. CONCLUSION: The Roche and Beckman assays resulted in fewer false positives, followed by the Bio-Rad and Abbott assays. While the Bio-Rad assay demonstrated higher antibody detection in COVID-19-positive patients, PA claims cannot be established with a high level of confidence in our sample population.

RNase L Is Involved in Liposaccharide-Induced Lung Inflammation.

RNase L mediates interferon (IFN) function during viral infection and cell proliferation. Furthermore, the role of RNase L in the regulation of gene expression, cell apoptosis, autophagy, and innate immunity has been well established in the last decade. Tissue distribution reveals that RNase L is highly expressed in the lung and other organs. However, the physiological roles of RNase L in the lung are largely unknown. In this study, we found that polysaccharide (LPS)-induced acute lung injury (ALI) was remarkably intensified in mice deficient in RNase L compared to wild type mice under the same condition. Furthermore, we found that RNase L mediated the TLR4 signaling pathway, and regulated the expression of various pro- and anti-inflammatory genes in the lung tissue and blood. Most importantly, RNase L function in macrophages during LPS stimulation may be independent of the 2-5A system. These findings demonstrate a novel role of RNase L in the immune response via an atypical molecular mechanism.

Cobalt(II) Diphenylazodioxide Complexes Induce Apoptosis in SK-HEP-1 Cells.

The cobalt(II) complex salts [Co(bpy)(az)2](PF6)2 and [Co(az)4](PF6), each bearing the unusual cis-N,N'-diphenylazodioxide ligand, were both screened as possible anticancer agents against SK-HEP-1 liver cancer cells. Both compounds were found to induce substantial apoptosis as an increasing function of concentration and time. Measurement of apoptosis-related proteins indicated that both the extrinsic and intrinsic pathways of apoptosis were activated. The apoptotic activity induced by these salts is not displayed either by simple cobalt(II) salts or complexes or by the free nitrosobenzene ligand. Additionally, these compounds did not induce apoptosis, as assessed by poly(adenosine diphosphate-ribose) polymerase cleavage, in several other cell lines.

Transcutaneous electric nerve stimulation over acupoints for patients with diarrhea-predominant irritable bowel syndrome: Protocol for systematic review and meta-analysis.

BACKGROUND: At present, drug therapy for diarrhea-predominant irritable bowel syndrome (IBS-D) has made great progress; however, it does not often produce a satisfying curative effect. Transcutaneous electric nerve stimulation over acupoints (Acu-TENS) might be more effective in improving patient's symptoms and producing fewer side-effects as a result.Although with a great progress of the drug therapy for IBS-D, it is often hard to achieve its satisfactory curative effect. Acu-TENS that may be effective to improve patients' symptoms and fewer side-effects will be sought. There is no systematic review concerning the efficacy of Acu-TENS for IBS-D published. Therefore, this review aims to systematically evaluate the efficacy of Acu-TENS on IBS-D. METHODS: Four English (PubMed, EMBASE, The Cochrane Library, Web of Science) and 4 Chinese electronic databases (Biomedical Literature Database, CNKI, VIP, Wanfang Database) will be searched from their inception to November 26, 2018. Randomized controlled trials that evaluated the effect of Acu-TENS on patients with IBS-D will be included. The primary outcome measures will include average weekly stool frequency, visual analog scale (VAS), and the Bristol scale. The secondary outcome measures will include the MOS 36-item short-form health survey (SF-36), IBS Quality of Life Questionnaire (IBS-QOL), severity of IBS symptoms (IBS-SSS), and rectal perception. Quality evaluation and data extraction will be independently undertaken, respectively. The data from the eligible trials will be analyzed by RevMan5.3. RESULTS: For patients with IBS-D, this systematic review will provide evidences related to the efficacy of Acu-TENS in these evaluation aspects, stool frequency, VAS and the Bristol scale, SF-36, IBS-QOL, IBS-SSS, and rectal perception. CONCLUSION: This evidence may be useful to medical workers with regard to the use of Acu-TENS in the treatment of IBS-D.PROSPERO registration number: PROSPERO CRD442018109294.

1H NMR-Based Metabonomic Study of Functional Dyspepsia in Stressed Rats Treated with Chinese Medicine Weikangning.

1H NMR-based metabolic profiling combined with multivariate data analysis was used to explore the metabolic phenotype of functional dyspepsia (FD) in stressed rats and evaluate the intervention effects of the Chinese medicine Weikangning (WKN). After a 7-day period of model establishment, a 14-day drug administration schedule was conducted in a WKN-treated group of rats, with the model and normal control groups serving as negative controls. Based on 1H NMR spectra of urine and serum from rats, PCA, PLS-DA, and OPLS-DA were performed to identify changing metabolic profiles. According to the key metabolites determined by OPLS-DA, alterations in energy metabolism, stress-related metabolism, and gut microbiota were found in FD model rats after stress stimulation, and these alterations were restored to normal after WKN administration. This study may provide new insights into the relationship between FD and psychological stress and assist in research into the metabolic mechanisms involved in Chinese medicine.

Weikangning therapy in functional dyspepsia and the protective role of Nrf2.

Functional dyspepsia (FD) is a non-organic gastrointestinal disorder that has a marked negative impact on quality of life. Compared with conventional pharmacological therapies, the traditional Chinese medicine weikangning (WKN) is a safe and effective treatment for FD. The present study aimed to determine the molecular mechanisms underlying the efficacy of WKN. The effect of different concentrations of WKN on the proliferation of the human gastric mucosal epithelial cell line GES-1 was assessed. The optimal WKN concentration to promote cell proliferation was determined, and this concentration was used to examine the effect of WKN compared with a domperidone-treated positive control group on the antioxidant capacity of GES-1 cells. The effect of WKN treatment on the growth and antioxidant activity of GES-1 cells was also assessed following nuclear factor erythroid 2 like 2 (Nrf2) knockdown. The optimal WKN dose for promoting cell growth was determined to be 0.025 mg/ml; at this concentration the expression of the antioxidant proteins glutathione S-transferase P and superoxide dismutase 2 (SOD2) were significantly elevated (P<0.0001). Furthermore, the amount of reduced glutathione and activity of SOD2 were significantly increased (P<0.0001 and P<0.01, respectively), and malondialdehyde content was significantly decreased, compared with the controls (P<0.001). With WKN treatment, the transcription of Nrf2 and its downstream genes were significantly upregulated (P<0.01), and the level and nuclear distribution of Nrf2 protein was also markedly increased. Following Nrf2 silencing, the protective antioxidant effects of WKN treatment were impaired and GES-1 cell proliferation decreased. The results of the present study suggest that the efficacy of WKN in protecting gastric mucosal epithelial cells in FD is antioxidant-dependent and mediated by Nrf2 activation.

Acupuncture for the treatment of gastro-oesophageal reflux disease: a systematic review and meta-analysis.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is one of the most common diseases presenting to gastroenterology clinics. Acupuncture is widely used as a complementary and alternative treatment for patients with GORD. OBJECTIVE: To explore the effectiveness of acupuncture for the treatment of GORD. METHODS: Four English and four Chinese databases were searched through June 2016. Randomised controlled trials investigating the effectiveness of manual acupuncture or electroacupuncture (MA/EA) for GORD versus or as an adjunct to Western medicine (WM) were selected. Data extraction and quality evaluation were performed by two authors independently and RevMan 5.2.0 was used to analyse data. RESULTS: A total of 12 trials involving 1235 patients were included. Meta-analyses demonstrated that patients receiving MA/EA combined with WM had a superior global symptom improvement compared with those receiving WM alone (relative risk (RR) 1.17, 95% CI 1.09 to 1.26; p=0.03; six studies) with no significant heterogeneity (I2=0%, p=0.41). Recurrence rates of those receiving MA/EA alone were lower than those receiving WM (RR 0.42,95% CI 0.29 to 0.61; p<0.001; three studies) with low heterogeneity (I2=7%, p=0.34), while global symptom improvement (six studies) and symptom scores (three studies) were similar (both p>0.05). Descriptive analyses suggested that acupuncture also improves quality of life in patients with GORD. CONCLUSION: This meta-analysis suggests that acupuncture is an effective and safe treatment for GORD. However, due to the small sample size and poor methodological quality of the included trials, further studies are required to validate our conclusions. TRIAL REGISTRATION NUMBER: PROSPERO Systematic review registration no. CRD42016041916.

Efficacy of Chinese Herbal Medicine for Diarrhea-Predominant Irritable Bowel Syndrome: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials.

Objective. To explore the efficacy of Chinese herbal medicine in treating diarrhea-predominant irritable bowel syndrome (D-IBS). Methods. Four English and four Chinese databases were searched through November, 2015. Randomized, double-blind and placebo-controlled trials were selected. Data extraction and quality evaluation were performed by two authors independently. RevMan 5.2.0 software was applied to analyze the data of included trials. Results. A total of 14 trials involving 1551 patients were included. Meta-analysis demonstrated superior global symptom improvement (RR = 1.62; 95% CI 1.31, 2.00; P < 0.00001; number needed to treat = 3.6), abdominal pain improvement (RR = 1.95; 95% CI 1.61, 2.35; P < 0.00001), diarrhea improvement (RR = 1.87; 95% CI 1.60, 2.20; P < 0.00001), pain threshold assessment (MD = 54.53; 95% CI 38.76, 70.30; P < 0.00001), and lower IBS Symptom Severity Score (SMD = -1.01; 95% CI -1.72, -0.30; P = 0.005), when compared with placebo, while for defecation threshold assessment, quality of life, and adverse events, no differences were found between treatment groups and controlled groups. Conclusion. This meta-analysis shows that Chinese herbal medicine is an effective and safe treatment for D-IBS. However, due to the small sample size and high heterogeneity, further studies are required.

[Effect of Shen warming Pi strengthening method on the expression of serum T cell subsets in IBS-D rats].

OBJECTIVE: To observe the effect of Shen warming Pi strengthening method on expressions of serum T cell subsets (C045+%, C03+%, and C04 +/COB+) in diarrhea-predominant irritable bowel syndrome (IBS-0) rats. Methods An IBS-0 rat model was established referring to AL-Chaer's modeling method combined with tail clamp and intragastric administration of sanna leaf. After modeling 30 SO rats were randomly divided into 6 groups according to random digit table, i.e., the model group, the high, middle, low dose Wenshen Jianpi Recipe (WJR) groups, and the Sishen Pill control group, 6 in each group. A normal control group consisting of 6 SO rats were also set up. Rats in high, middle, low dose WJ R groups were administered by gastrogavage with boil-free WJ R at the daily dose of 3. 100, 1. 550, 0. 775 g/kg, respectively. Rats in the Sis hen Pill control group were administered by gastrogavage with boil-free Sis hen Pill at the daily dose of 0. 736 g/kg. Equal volume of normal saline was given by gastrogavage to rats in the model group and the normal control group. All medication lasted for 2 successive weeks. Rats' general state, expressions of T cell subsets (CD45+%, CD3+%, and CD4+ /CDB+) changes were observed. RESULTS: Compared with the normal control group, expressions of CD45+% and CD3+% increased, but CD4+ /CDB+ decreased with statistical difference (P < 0. 05). Compared with the model group, expressions of CD45+% and CD3+% decreased, but CD4+ ICDB+ increased with statistical difference in high, middle, low dose WJR groups, and the Sis hen Pill control group (P <0. 05). Compared with the Sis hen Pill control group, there was statistical difference in all indices except CD45+ value in the low dose SWPSM group (P <0. 05). Compared with the low dose WJ R group, the expression of CD3+% decreased in high and middle dose WJR groups, and the Sis hen Pill control group; CD4+ /CD8+ increased in the Sishen Pill control group and the high dose SWPSM group (all P < 0. 05). CONCLUSIONS: WJR showed better treatment effect. The mechanism of Shen warming Pi strengthening method might be achieved by regulating expressions of CD45+% and CD3+%, and CD4+ /CD8+ ratios.