Cutoff Value Of Concentration Research Articles

Serum zinc concentration as a potential predictor of presarcopenia in patients with chronic liver disease: a preliminary study.

Presarcopenia is a common complication of chronic liver disease. However, the relationship between serum zinc concentration and presarcopenia in patients with chronic liver disease remains unclear. Herein, we examined whether serum zinc concentration could predict presarcopenia in patients with chronic liver disease. Between October 2015 and December 2019, 278 patients with chronic liver disease (median age, 68 years; women/men, 133/145; hepatitis B virus/hepatitis C virus/negative hepatitis B surface antigen and negative anti-hepatitis C virus antibody, 55/124/99) who underwent abdominal computed tomography (CT) and simultaneous measurement of serum zinc concentration were included. Zinc deficiency and subclinical zinc deficiency were classified using serum zinc concentration cutoff values of <60 and <80 μg/dL [based on the Japanese Society of Clinical Nutrition (JSCN) guidelines], respectively. Additionally, presarcopenia was evaluated based on the skeletal muscle mass as per the Japan Society of Hepatology (JSH)'s sarcopenia criteria. Univariate analysis revealed that the following factors were significantly associated with the presence of presarcopenia in patients with chronic liver disease: age (P<0.001), male sex (P<0.001), body mass index (BMI) (P<0.001), serum zinc concentration (P=0.005), fibrosis-4 index (P<0.001), and serum albumin concentration (P=0.03). Additionally, the median L3 skeletal muscle indices were as follows: men, non-presarcopenia group/presarcopenia group, 47.56/37.91 cm2/m2 (P<0.001); women, non-presarcopenia group/presarcopenia group, 41.64/32.88 cm2/m2 (P<0.001). Multivariate analysis using logistic regression analysis revealed that male sex [odds ratio (OR), 0.194; 95% confidence interval (CI): 0.089-0.419; P<0.001], BMI (OR, 0.666; 95% CI: 0.582-0.761; P<0.001), and serum zinc concentration <60 μg/dL (OR, 5.930; 95% CI: 1.480-23.80; P=0.01) were factors associated with presarcopenia. The OR for serum zinc concentration between 60 and 80 μg/dL was 1.910 (95% CI: 0.824-4.420; P=0.13). Low serum zinc levels may be an independent predictor of presarcopenia in patients with chronic liver disease.

Epidemiological trends of traveler's diarrhea in Japan: An analysis of imported infectious disease registry data from 2017-2022.

Traveler's diarrhea (TD) is a global problem, and identifying the causative organisms of TD is important for adequate treatment. Therefore, this study retrospectively analyzed TD cases in patients who returned to Japan after traveling abroad to determine the causative organisms by travel region. We included patients with a final diagnosis of TD registered in the Japan Registry for Infectious Diseases from Abroad database from September 25, 2017, to September 1, 2022, from 14 medical institutions. A total of 919 patients were analyzed; the causative TD pathogen was identified in 188 cases (20%), of which 154 were caused by diarrheagenic bacteria, the most common being Campylobacter spp. (64%). A 2.2 mg/dL C-reactive protein concentration cutoff value had some predictive ability for bacterial TD (negative predictive value, 89%). Therefore, the C-reactive protein level may help rule out bacterial diarrhea and prevent unnecessary antimicrobial administration when patients cannot provide a stool specimen.

Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial.

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7-18 years; 24.6% males) was treated with fluoxetine (10-40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208-328 ng/mL (transdiagnostically) and 201.5-306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose-serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.

Investigation of serum afamin concentration in pregnant women diagnosed with late fetal growth restriction or small for gestational age fetus

Objective To investigate the afamin concentration in the serum of pregnant women diagnosed with late fetal growth restriction (FGR) or small for gestational age (SGA) in the third trimester. Methods This prospective case-control study was conducted on 126 pregnant women, 42 of whom were diagnosed with late FGR in the third trimester, 43 were SGA, and 41 were healthy controls. The groups were compared in terms of maternal serum afamin concentrations. Results Three groups were similar in terms of demographic characteristics and gestational age at blood sampling for afamin (p < .05). The median afamin concentration was determined as 199 ng/mL in the late FGR group, 153 ng/mL in the SGA group, and 108 ng/mL in the control group (p = .000). In the post-hoc analysis, while maternal serum afamin concentrations were found to be significantly higher in the late FGR group and SGA group compared to the control group but, this significance could not be shown between the FGR group and the SGA group (p = .00001, p = .005, p = .137, respectively). In the ROC analysis, the optimal cutoff value of serum afamin concentration to predict late FGR was determined as 141 ng/mL, with a sensitivity of 66.6% and a specificity of 85.3%. Conclusions The serum afamin concentration in the third trimester was found to be higher in pregnant women with late FGR compared to the SGA and control groups. Although afamin is seen as a promising molecule in the clinical prediction of late FGR, this needs to be supported by large series of studies.

Use of Saliva to Assess the Adherence to Treatment with Oral Hypoglycemic Agents in Patients with Type 2 Diabetes.

The diagnosis of Type 2 Diabetes Mellitus (T2DM) is made by demonstrating the hypoglycemic condition, which involves the determination of plasma glucose, and the follow-up of hypoglycemic treatment is performed by assessing the glycated hemoglobin (HbA1c) concentration. The aim of this study was to evaluate the saliva as an alternative sample in assessing the adherence to treatment with oral hypoglycemic agents in patients with Type 2 Diabetes. We selected 68 patients with T2DM, who were subjected to venous blood and saliva collection, in addition to answering a standardized questionnaire on adherence to hypoglycemic treatment. Laboratory tests performed on saliva, whole blood, serum or plasma included assessment of glycemia, urea, creatinine, uric acid, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, and glycated hemoglobin. It was concluded that 82% of the patients adhered to hypoglycemic treatment based on glycated hemoglobin concentration (cut-off value of 7.0%). Comparing the groups that adhered to hypoglycemic treatment and those that did not adhere, statistical differences (P<0.05) were observed in the glucose, HDL-cholesterol, triglycerides, and insulin use (insulin therapy) parameters. Plasma glucose and urea serum concentration showed positive correlations when compared to saliva samples. Regarding the questionnaire, it was found that 35% of the patients presented positive screening for belief barriers and 83% positive score for recall barriers, and the positive screening correlated with glycated hemoglobin. Data have shown that it is possible to use saliva as an alternative sample to the laboratory assessment of hypoglycemic treatment adherence in T2DM patients.

The risk of venous thromboembolism and blood hyperlactatemia is associated with increased mortality among critically ill patients with Covid-19.

Coronavirus disease 2019 (Covid-19) following venous thromboembolism (VTE) and blood hyperlactatemia are associated with higher mortality. However, reliable biomarkers for this association remain to be elucidated. This study investigated the associations of VTE risk and blood hyperlactatemia with mortality among critically ill Covid-19 patients admitted to the intensive care unit (ICU). In this single-centre retrospective study, we included 171 patients aged ≥18 years with confirmed Covid-19 admitted to the ICU at a tertiary healthcare clinic in the Eastern region of Saudi Arabia between 1 March 2020 and 31 January 2021. Patients were divided into two groups: survivor and non-survivor. The survivors have been identified as the patients discharged from the ICU alive. The VTE risk was defined using a Padua prediction score (PPS) >4. The blood lactate concentration (BLC) cut-off value >2 mmol/L was used to determine the blood hyperlactatemia. Multi-factor Cox analysis showed that PPS >4 and BLC >2 mmol/L were more likely to be significantly associated with higher odds of ICU mortality in critically ill Covid-19 patients (hazard ratio [HR] = 2.80, 95% confidence interval [CI] = 1.00-8.08, p = 0.050; HR = 3.87, 95% CI = 1.12-13.45, p = 0.033, respectively). The Area under the Curve for VTE and blood hyperlactatemia were 0.62 and 0.85, respectively. VTE risk and blood hyperlactatemia have been associated with a higher mortality risk in critically ill Covid-19 patients who are hospitalized in the ICU in Saudi Arabia. According to our findings, these people needed more effective VTE prevention strategies based on a personalized assessment of their risk of bleeding. Moreover, persons without diabetes and other groups with a high risk of dying from COVID-19 may be recognized by measuring glucose as having elevated glucose and lactate jointly.

Validation of a blood gas device for ionized calcium analysis in Holstein cows.

Accurate analysis of ionized calcium (iCa) is critical for the detection of hypocalcemia or subclinical hypocalcemia. The Edan i15 Vet (EDAN) blood gas device has not been validated for iCa in dairy cows. We aimed to validate the EDAN blood gas device against the Gem Premier 3000 (GEM) analyzer by measuring iCa concentrations and evaluating the ability of these measurements, compared with serum total calcium (TCa) concentrations, to diagnose subclinical hypocalcemia. iCa concentrations were measured with the EDAN and GEM devices, and serum TCa concentrations were measured with a wet biochemistry method with blood from 125 lactating Holstein cows between calving to day 27 postpartum. Bland-Altman plots showed a mean and total bias of 0.05 and 0.24 mmol/L for the EDAN device, respectively. The intercept did not include zero, but the slope included 1.0 in the Passing-Bablok regression. The sensitivity and specificity (Se/Sp) of the EDAN device were 93/94%, 93/90%, 91/93%, and 85/95% for iCa cut-off values of <1.00, 1.05, 1.10, and 1.15 mmol/L, respectively, as determined with the GEM device. The Se/Sp were 57/82% and 72/80% for EDAN and 57/80% and 72/79% for GEM at serum TCa cut-off points <2.15 and <2.00 mmol/L, respectively. The average iCa concentrations analyzed with the GEM and EDAN devices were 1.04 ± 0.18 and 1.09 ± 0.17, respectively. The EDAN device did not have satisfactory agreement with GEM and could not be used interchangeably, but it had satisfactory Se/Sp to diagnose subclinical hypocalcemia compared with the GEM-derived iCa cut-off points. Serum TCa concentration cut-off values were not suitable for diagnosing subclinical hypocalcemia because of unsatisfactory Se/Sp compared with iCa concentrations analyzed by the GEM and EDAN devices. The iCa values analyzed using the EDAN and GEM devices were consistent with previously reported data.

The association of plasma NT-proBNP level and progression of diabetic kidney disease

Aims Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD). The identification of risk factors involved in the progression of DKD to ESKD is expected to result in early detection and appropriate intervention and improve prognosis. This study aimed to explore whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) and biopsy-proven DKD. Methods Patients with biopsy-proven DKD who were followed up at West China Hospital over 12 months were enrolled. The kidney outcome was defined as progression to ESKD. The cutoff value of plasma NT-proBNP concentration was calculated by using receiver operating characteristic (ROC) curve analysis. The influence of NT-proBNP levels on kidney outcome in patients with DKD was assessed using Cox regression analysis. Results A total of 30 (24.5%) patients reached ESKD during a median follow-up of 24.1 months. The baseline serum NT-proBNP level had a significant correlation with baseline proteinuria, kidney function, glomerular lesions, interstitial fibrosis tubular atrophy (IFTA), and arteriolar hyalinosis. Multivariate Cox regression analysis indicated that increased NT-proBNP level was significantly associated with a higher risk of progression to ESKD (HR 6.43; 95% CI (1.65–25.10, p = 0.007), and each 1 SD increase in LG (NT-proBNP) was also associated with a higher risk (HR 2.43; 95% CI 1.94–5.29, p = 0.047) of an adverse kidney outcome after adjusting for confounding factors. Conclusions A higher level of plasma NT-proBNP predicts kidney prognosis in patients with biopsy-proven DKD. This warrants further investigation into the potential mechanisms.

Aldosterone Immunoassay-Specific Cutoff Value for Seated Saline Suppression Test for Diagnosing Primary Aldosteronism.

A seated saline loading test (SLT) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is one of the most accepted confirmatory tests of primary aldosteronism. However, LC-MS/MS is time-consuming and is not widely available in diagnostic laboratories compared to immunoassay. With immunoassay, it is unknown whether SLT in the seated position is more accurate than that of the supine position, and a cutoff value of post-seated SLT plasma aldosterone concentration (PAC) must be established in the Korean population. Ninety-eight patients underwent SLT in both positions, and post-SLT PAC was measured by LC-MS/MS and radioimmunoassay. We confirmed primary aldosteronism if post-seated SLT PAC by LC-MS/MS exceeded 5.8 ng/dL. The area under the receiver operating characteristic curve was greater for seated than supine SLT (0.928 vs. 0.834, P=0.003). The optimal cutoff value of post-seated SLT by radioimmunoassay was 6.6 ng/dL (sensitivity 83.3%, specificity 92.2%).

Increased ammonium in culture medium may promote cellular apoptosis and negatively affect pluripotency of human blastocysts.

To determine the association between ammonium concentration in culture medium and blastocyst development and to assess the influence of increased ammonium concentration on the expression of Bax, Bcl-2 and Oct4. A total of 254 cleavage-stage embryos were individually cultured in 30μL G2-plus medium on Day 3, and then culture media samples were collected on Day 5 for ammonium concentration determination immediately after evaluating the embryos morphology. Poor-quality blastocysts (combined score of CC) were used for gene expression analysis. The blastocyst formation rate, good-quality blastocyst rate and relative expression levels of Bax, Bcl-2 and Oct4 were analyzed. Based on receiver operating characteristic curve, the cutoff value of ammonium concentration produced by embryos was 16.07μmol/L (AUC = 0.722, 95% CI 0.637-0.807; P = 0.000), so all embryos were assigned to two groups according to the cutoff value: normal group (< 16.07μmol/L) and increased group (≥ 16.07μmol/L). There was a significant difference in blastocyst formation rate (80.5% vs 59.0%, P < 0.01) between normal group and increased group, as well as for good-quality blastocyst rate (21.0% vs 3.4%, P < 0.01). A significantly higher expression level of Bax (P < 0.05) and considerably lower expression level of Oct4 (P < 0.01) were observed in increased group compared to normal group. Our data demonstrated for the first time that increased ammonium concentration in culture medium may promote cellular apoptosis and negatively affect pluripotency of human blastocyst.

A dried blood spot test for diagnosis of autoimmune pulmonary alveolar proteinosis

Granulocyte/macrophage colony-stimulating factor autoantibodies (GMAbs) mediate the pathogenesis of autoimmune pulmonary alveolar proteinosis (autoimmune PAP) and their quantification in serum by enzyme-linked immunosorbent assay (ELISA) – the serum GMAb test – is the ‘gold standard’ for diagnosis of autoimmune PAP. Because GMAbs are high in autoimmune PAP and low or undetectable in healthy people, we hypothesized that the ELISA could be adapted for evaluation of blood obtained from the fingertip using a dried blood spot card (DBSC) for specimen collection. Here, we report development of such a method – the DBSC GMAb test – and evaluate its ability to measure GMAb concentration in blood and to diagnose autoimmune PAP. Fresh, heparinized whole blood was obtained from 60 autoimmune PAP patients and 19 healthy people and used to measure the GMAb concentration in blood (by the DBSC GMAb test). After optimization, the DBSC GMAb test was evaluated for accuracy, precision, reliability, sensitivity, specificity, and ruggedness. The coefficient of variation among repeated measurements was low with regard to well-to-well, plate-to-plate, day-to-day, and inter-operator variation, and results were unaffected by exposure of prepared DBSC specimens to a wide range of temperatures (from -80 °C to 65 °C), repeated freeze-thaw cycles, or storage for up to 2.5 months before testing. The limit of blank (LoB), limit of detection (LoD), and lower limit of quantification (LLoQ), were 0.01, 0.21, and 3.5 μg/ml of GMAb in the blood, respectively. Receiver operating curve characteristic analysis identified 2.7 μg/ml as the optimal GMAb concentration cutoff value to distinguish autoimmune PAP from healthy people. This cutoff value was less than the LLoQ and the ranges of GMAb results for autoimmune PAP patients and healthy people were widely separated (median (interquartile range): 22.6 (13.3–43.8) and 0.23 (0.20–0.30) μg/ml, respectively). Consequently, the LLoQ is recommended as the lower limit of the range indicating a positive test result (i.e., that autoimmune PAP is present); lower values indicate a negative test result (i.e., autoimmune PAP is not present). Among the 30 autoimmune PAP patients and 19 healthy people evaluated, the sensitivity and specificity of the DBSC GMAb test were both 100% for a diagnosis of autoimmune PAP. Results demonstrate the DBSC GMAb test reliably measures GMAbs in blood and performs well in the diagnosis of autoimmune PAP.

Diagnostic value of a novel test paper detection of ECP in nasal secretion for allergic rhinitis

Objective:To explore the diagnostic value of a novel test paper, which detect eosinophil cationic protein（ECP） of nasal secretion in allergic rhinitis（AR）. Methods:Nasal secretion and serum samples from 107 patients with allergic rhinitis（AR group） and 40 healthy volunteers（control group） were selected. The nasal symptoms were also evaluated in AR group. The degree of ECP coloration was evaluated by nasal secretion eosinophil cationic protein-myeloperoxid（ECP-MPO） test paper, and the concentration of ECP in nasal secretion and the concentration of cytokines in serum were detected at the same time. The difference and correlation among these indexes were analyzed. The best cutoff value and test efficiency of ECP chromogenic grade and concentration of nasal secretion were calculated by receiver operating characteristic curve（ROC）. Results:The concentration of ECP in nasal secretion of AR patients was significantly higher than that of healthy controls（P<0.05）. The color grade of nasal secretion detected by the test paper was positively correlated with the concentration of ECP in nasal secretion（P<0.05）, and there was significant difference among different grades（P<0.05）. There was a satisfying symmetry between the ECP color grade of nasal secretion and the serum specific IgE（sIgE） level as well as a high diagnostic consistency between them（P<0.05）. The area under the curve（AUC） of ECP concentration ROC in nasal secretion was 0.807 2, corresponding to 64% sensitivity and 85% specificity when the cutoff value was set at 0.980 5; when the cutoff value was set at 1, the AUC of nasal secretion ECP color grading was 0.941 9, corresponding to 92% sensitivity and 94% specificity. No clear correlation between the concentration of ECP in nasal secretion and serum cytokines was found（P>0.05）. Conclusion:The results of this novel test paper is in good agreement with those of serological allergens. It could serve as a preliminary test to evaluate the severity of allergy with satisfactory sensitivity and specificity, and is especially suitable in clinical practice for primary hospital.

Parameters of dual-energy CT for the differential diagnosis of thyroid nodules and the indirect prediction of lymph node metastasis in thyroid carcinoma: a retrospective diagnostic study.

To further investigate the differential diagnosis of thyroid nodules using dual-energy computed tomography (DECT) and explore the relationship between DECT parameters and lymph node metastasis in thyroid carcinoma for clinical practice, especially difficult diagnosis by routine imaging examination. A total of 150 patients with thyroid nodules who underwent preoperative DECT and Thyroid Imaging Report and Data System (TIRADS) classification were enrolled in this study, including 96 patients with malignant tumors and 54 with benign tumors. The DECT parameters were got form regions of interest (ROI) by an experienced radiologist team and thyroid nodules and lymph node status of all patients were identified by cytology and histopathology. Statistical analyses were performed using Student's t-test, Chi-squared test, and receiver operating characteristic (ROC) curves. In the differential diagnosis of benign and malignant thyroid nodules, the optimal iodine concentration (IC) and normalized iodine concentration (NIC) cut-off values were ICa (2.835 mg/mL), NIC1a (0.690), and their corresponding area under the curve (AUC) were 0.940, 0.954 respectively; meantime, the optimal computed tomography (CT) value and slope of the spectral Hounsfield unit curve (λHU) cut-off values were 70 keVa (125.05 HU) and λHU2a (1.405), and their corresponding AUC were 0.955, 0.941 respectively. For lymph node status (with or without lymph node metastasis), the optimal IC and NIC thresholds were ICa (1.715 mg/mL) and NIC2a (0.155), and their corresponding AUC were 0.717, 0.720 respectively; meanwhile, the optimal CT value and λHU thresholds were 70 keVv (89.635 HU) and λHU2v (1.185), and their corresponding AUC were 0.729, 0.641 respectively. Base on our study, we think DECT is useful in differentiating malignant from benign thyroid nodules, which has potential value in the indirect prediction of lymph node metastasis in thyroid carcinoma.

Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population.

Background: Although newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity.Methods: Analytical and clinical performance was evaluated by MS/MS using 237 initially positive neonatal samples between March 2019 and March 2020 at the Newborn Screening Center of Xuzhou Maternity and Child Health Care Hospital. Additionally, second-tier testing by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with the quantification of ethylmalonate (EMA) or isobutyryl-glycine (IBG) in dried blood spots (DBSs) was performed to reduce the false-positive rate.Results: We reviewed initial MS/MS data for DBSs from 469,730 neonates, and a second-tier test was performed using 237 samples that exceeded the C4 concentration cutoff value. Eleven variants of the ACADS gene were identified, with c.1031A>G (p.E344G) being the most common. Fifteen ACAD8 mutations were identified in seven patients, and Swiss modeling and amino acid conservation analyses were conducted for the novel variants. Based on a retrospective analysis of EMA and IBG, the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening.Conclusion: A screening algorithm including EMA/IBG improves target differential testing for NBS and may eliminate unnecessary referrals while maintaining 100% sensitivity. Second-tier screening using UPLC-MS/MS as a rapid and convenient supplemental DNA sequencing method may be beneficial for differential detection.

Objective Identification of Cannabis Use Levels in Clinical Populations Is Critical for Detecting Pharmacological Outcomes.

Introduction: Cannabis is widely used for recreational and medical purposes, but its therapeutic efficacy remains unresolved for many applications as data from retrospective studies show dramatic discrepancy. We hypothesized that false self-reporting of cannabis use and lack of differentiation of heavy users from light or occasional users contribute to the conflicting outcomes. Objective: The goal of this study was to develop an objective biomarker of cannabis use and test how application of such biomarker impacts clinical study outcomes and dose-response measures. Methods and Analysis: Population pharmacokinetic (PK) models of (-)-trans-Δ9-tetrahydrocannabinol (THC) and its metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC) were developed based on published studies reporting cannabinoid disposition in individual subjects following intravenous administration or smoking of cannabis. Plasma 11-COOH-THC concentration distributions in different cannabis user groups smoking cannabis were generated via Monte Carlo simulations, and plasma concentration cutoff values of 11-COOH-THC were developed to differentiate light and heavy daily cannabis users in clinical studies. The developed cutoff value was then applied to a retrospective study that assessed the impact of cannabis use on T cell activation in subjects with HIV who self-reported as either nonuser or daily user of cannabis. Results: The developed population PK models established plasma 11-COOH-THC concentration of 73.1 μg/L as a cutoff value to identify heavy daily users, with a positive predictive value of 80% in a mixed population of equal proportions of once daily and three times a day users. The stratification allowed detection of changes in T cell activation in heavy users which was not detected based on self-reporting or detectability of plasma cannabinoids. A proof-of-concept power analysis demonstrated that implementation of such cutoff value greatly increases study power and sensitivity to detect pharmacological effects of cannabis use. Conclusions: This study shows that the use of plasma 11-COOH-THC concentration cutoff value as an objective measure to classify cannabis use in target populations is critical for study sensitivity and specificity and provides much needed clarity for addressing dose-response relationships and therapeutic effects of cannabis.

Tissue 2-Hydroxyglutarate and Preoperative Seizures in Patients With Diffuse Gliomas.

Mutant isocitrate dehydrogenase (IDH) 1/2 gene products gain a new ability to produce D-2-hydroxyglutarate (D2HG). IDH1/2 mutations are thought to be associated with seizures owing to the structural similarity between D2HG and glutamate. However, the effects of D2HG on seizures in clinical settings are not fully understood. We sought to investigate the relationship between tissue 2-hydroxyglutarate (2HG) concentration and preoperative seizures using clinical samples. We included 104 consecutive patients with diffuse glioma who underwent surgery from August 2008 to May 2016 and whose clinical presentation and IDH1/2 status were identified. The presence of preoperative seizures, tumor location, histopathologic diagnosis, IDH1/2 status, and 1p/19q codeletion were assessed from the patient charts. Tissue 2HG concentration was measured using liquid chromatography-tandem mass spectrometry. To evaluate 2HG distribution without artefactual tissue disruption, we applied matrix-assisted laser desorption/ionization high-resolution mass spectrometry imaging (MALDI-MSI) in 12 patients' surgically resected samples. We assessed the correlation of preoperative seizures with tissue 2HG concentration, IDH1/2 status, WHO grade, and 1p/19q codeletion. Tissue 2HG concentration was higher in IDH1/2 mutant tumors (IDH-Mut, n = 42) than in IDH1/2 wild-type tumors (IDH-WT, n = 62) (median 4,860 ng/mg vs 75 ng/mg) (p < 0.0001). MALDI-MSI could detect 2HG signals in IDH-Mut, but not in IDH-WT. Preoperative seizures were observed in 64.3% of patients with IDH-Mut and 21.0% patients with IDH-WT (p < 0.0001). The optimal cutoff value of tissue 2HG concentration for predicting preoperative seizures was 1,190 ng/mg, as calculated by the receiver operating characteristic curve. Increased preoperative seizure risk was only observed in tumors with 2HG concentration above the cutoff value among IDH-Mut (IDH-Mut with above the cutoff value: 71.4% vs IDH-Mut with below the cutoff value: 28.6%; p = 0.031). Multivariate analysis, including IDH1/2 mutation status, tissue 2HG concentration, WHO grade, and 1p/19q codeletion, revealed that only increased tissue 2HG concentration was associated with preoperative seizures (odds ratio 5.86, 95% confidence interval 1.02-48.5; p = 0.048). We showed that high tissue 2HG concentration was associated with preoperative seizures, suggesting that excess 2HG increases risk of preoperative seizures in IDH1/2 mutant tumors.

Increased serum PCSK9 in patients with idiopathic pulmonary arterial hypertension: insights from inflammatory cytokines.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important and major player in the pathophysiology of hypercholesterolemia and atherosclerosis. Recently, PCSK9 has been implicated in the pathogenesis of inflammatory diseases. Whether PCSK9 is involved in idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to investigate the relationship between PCSK9 and IPAH. Serum PCSK9, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and monocyte chemotactic protein-1 (MCP-1) were measured by enzyme linked immunosorbent assay. Transthoracic echocardiography was performed among 40 IPAH patients and 20 control subjects. Hemodynamic data were collected via right heart catheterization in patients with IPAH. Serum PCSK9, TNF-α, IL-6, IL-1β, and MCP-1 levels were significantly higher in IPAH patients than in control subjects (p < 0.001). Among enrolled IPAH patients, PCSK9 levels were higher in WHO-FC III/IV patients compared with those in WHO-FC I/II (p < 0.05), and were positively correlated with TNF-α, IL-6, MCP-1, N-Terminal pro-brain natriuretic peptide, pulmonary arterial systolic pressure (r = 0.653, p < 0.001), pulmonary arterial diastolic pressure (r = 0.466, p = 0.002), mean pulmonary arterial pressure (mPAP, r = 0.730, <0.001), pulmonary vascular resistance (r = 0.488, p = 0.001), and right ventricle diameter (r = 0.563, p < 0.001). In multiple regression analysis, mPAP was strongly associated with serum PCSK9 (β = 0.694, p < 0.001), independent of other variables. Receiver operating characteristic curve analysis showed the optimal cutoff value of serum PCSK9 concentration for predicting IPAH was 90.67 ng/ml, with a sensitivity of 90.0% and a specificity of 85.0%. In conclusion, IPAH patients had elevated serum PCSK9 levels which correlated the presence and severity of pulmonary hypertension. PCSK9 may be a novel potential therapeutic target.

Midkine: Utility as a Predictor of Early Diabetic Nephropathy in Children with Type 1 Diabetes Mellitus

Objective:This study aimed to assess the role of serum midkine (MK) as a biomarker for early detection of diabetic nephropathy in children with type 1 diabetes mellitus (T1DM) before microalbuminuria emerges.Methods:A total of 120 children with T1DM, comprising 60 microalbuminuric patients (Group 1), 60 normoalbuminuric patients (Group 2), and 60 healthy participants as a control group (Group 3) were included. Detailed medical history, clinical examination, and laboratory assessment of high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c percentage (HbA1c%), lipid profile, urinary albumin to creatinine ratio (ACR), serum MK and estimated glomerular filtration rate based on serum creatinine were performed in all participants.Results:Both Group 1 and Group 2 had significantly higher serum MK compared to controls (p<0.001). Additionally, significantly higher MK concentrations were present in Group 1 compared with Group 2 (p<0.001). Receiver operating characteristic curve analysis revealed that the MK concentration cutoff value of 1512 pg/mL was able to predict microalbuminuria with a sensitivity of 96% and specificity of 92%. Stepwise regression analysis revealed that HbA1c%, hs-CRP, and ACR were independently related to MK levels (p<0.001 for each).Conclusion:The results of this study suggest that serum MK is a useful, novel, practical marker for the evaluation of renal involvement in children with T1DM, especially in normoalbuminuric children.

Association of Interleukin-6 Levels with Morbidity and Mortality in Patients with Coronavirus Disease 2019 (COVID-19).

The prognostic value of interleukin-6 (IL-6) in coronavirus disease 2019 (COVID-19) needs to be clarified. In this retrospective study, COVID-19 patients treated at Renmin Hospital of Wuhan University from January 7 to February 8, 2020 with measurements of serum IL-6 levels within 1 week after admission were included. Data regarding demographics, clinical characteristics, laboratory tests, complications, and outcomes were collected and analyzed. Sixty-six patients diagnosed with COVID-19 were included in this study (31 patients were females). They were divided into a normal group (serum IL-6 <10 pg/mL, n = 35) and an abnormal group (serum IL-6 <10 pg/mL, n = 31). Compared with the normal group, the incidence of critical cases (P <0.001), acute respiratory distress syndrome (ARDS) (P = 0.001), acute cardiac injury (P = 0.002), cardiac insufficiency (P = 0.039), mechanical ventilation rate (P = 0.002), and mortality (P = 0.021) was significantly increased in the abnormal group. Serum IL-6 concentration was an independent predictor of fatal outcome (P = 0.04). The optimal cutoff value of serum IL-6 concentration for predicting fatal outcomes was 26.09 pg/mL (P <0.001). In COVID-19, elevated serum IL-6 levels were associated with critical illness, use of mechanical ventilation, and complications, including heart injury and ARDS, and could predict a fatal outcome. Early detection of serum IL-6 levels after admission should be necessary in COVID-19 patients.

Evaluation of Saccharin and Resveratrol as Extrinsic Markers of Small-Quantity Lipid-Based Nutrient Supplement Consumption in Healthy Women.

ABSTRACTBackgroundDietary supplements, like small-quantity lipid-based nutrient supplements (SQ-LNS), are used in intervention programs to prevent undernutrition among women and young children in low-income countries. An objective marker is needed to track consumption of supplements to evaluate the effectiveness of these programs.ObjectiveThe aim of this study was to evaluate saccharin and resveratrol as potential adherence markers for tracking recent consumption of a single serving of SQ-LNS in women.MethodsForty-seven healthy nonpregnant women 18–45 y of age were assigned to consume a single dose of SQ-LNS (20 g) containing either 10 mg sodium saccharin or 5 mg trans-resveratrol, under supervision. On the day before and for 2 d following SQ-LNS consumption, urine samples were collected each day for 24 h as 3 consecutive 4-h collections and one 12-h overnight collection. Urinary concentrations of saccharin and trans-resveratrol-3-O-sulfate, a resveratrol metabolite, were measured by ultra-high-performance liquid chromatography interfaced to a mass spectrometer with electrospray ionization [UHPLC-(ESI-)MS/MS]. Urinary concentrations (μmol/L urine) of saccharin and trans-resveratrol-3-O-sulfate were plotted against time, and receiver operating characteristic (ROC) curves were used to determine the discriminative capacity of each compound, at each post-consumption time point compared with baseline, to detect recent consumption of SQ-LNS. Cutoff values to differentiate supplement consumption from nonconsumption of each marker were developed using the closest-to-(0,1)-corner cut-point approach.ResultsForty-five participants were included in the analysis. Urinary concentrations of saccharin and trans-resveratrol-3-O-sulfate increased within 4 h of SQ-LNS consumption. Urinary concentration cutoff values for saccharin (13.4 µmol/L) and trans-resveratrol-3-O-sulfate (0.7 µmol/L) allowed for 78% and 89% sensitivity, respectively, and 100% specificity in detecting consumption of SQ-LNS within the first 12 h after consumption.ConclusionsUrinary concentrations of saccharin and trans-resveratrol-3-O-sulfate reflect consumption of SQ-LNS containing those compounds during the first 12 h post-consumption with high sensitivity and specificity in healthy women and may be useful objective adherence markers for tracking consumption of SQ-LNS.