Plasma Values Research Articles

Circulating tumor DNA analysis for prediction of prognosis and molecular insights in patients with resectable gastric cancer: results from a prospective study.

This study aimed to evaluate the prognostic value of plasma circulating tumor DNA (ctDNA) level in patients with resectable gastric cancer (GC). A total of 59 patients were prospectively enrolled, with their ctDNA detected and paired tumor tissue collectedat various peri-operative time points. Patients with higher 1-month post-operative ctDNA levels demonstrated shorter overall survival status (hazard ratio [HR]=5.30, p=0.0022) and a higher risk of recurrence (HR=3.85, p=0.011).The model combining ctDNA with conventional serum tumor markers for GC, including carcinoembryonic antigen, carbohydrate antigen 19-9, and CA72-4, shows high predictive effectiveness for GC prognosis with an area under the curve of 0.940 (p=0.002), which is higher than net ctDNA and other models without ctDNA. Patients with lower ctDNA levels were more likely to have positive stromal programmed cell death ligand 1 expression (p=0.046). Additionally, DCAF4L2 mutation was identified as the crucial gene mutation in ctDNA suggesting poor prognosis of patients with GC. Overall, this study highlights that post-operative ctDNA can serve as an effective biomarker for prognostic prediction and recurrence surveillance in resectable GC.

Clinical value of saliva therapeutic drug monitoring of newer antiseizure medications.

Saliva is a promising option for therapeutic drug monitoring, with studies since the 1970s indicating a good correlation between plasma and saliva levels for early anti-seizure medications, although limited data exist for newer generation drugs. To evaluate the reliability and predictive power of saliva as a minimally invasive surrogate marker of plasma concentration for the routine therapeutic drug monitoring (TDM) of newer anti-seizure medications (ASM). We collected blood samples at steady state in patients at least 6 h post-dose, paired with unstimulated saliva samples. We evaluated the correlation between plasma and saliva drug levels and the positive and negative predictive value for plasma values extrapolation from saliva levels. A very low saliva level was defined as below half the plasma lower reference limit. 294 adult patients (53 % male) with a mean age of 40 (SD: 16) were enrolled and 589 paired saliva-plasma samples were quantified. The highest significant correlations between saliva and plasma were observed for zonisamide (R2: 0.92) perampanel (0.91), brivaracetam (0.87), followed by topiramate, lamotrigine, lacosamide (0.76-0.68), and rufinamide, levetiracetam, pregabalin (0.63-0.55). No significant correlation was found for the active mono-hydroxy derivative of oxcarbazepine. Despite a good correlation coefficient, the correlations between saliva and plasma levels were generally loose, resulting in a broad predicted range of plasma levels for a given saliva level. Nonetheless, very low saliva levels exhibited strong specificity in predicting low plasma levels, with 87 % to 100 % accuracy, and when saliva levels fell below the limit of quantification, all corresponding plasma levels were below reference ranges. This large newer ASM paired plasma-saliva collection allows to precise the potential use of saliva in the management of epilepsy, especially for commonly used ASM such as lamotrigine and levetiracetam. Although they correlate well, extrapolating plasma levels from saliva samples is still an imprecise approximation, making it inadequate for fine dosage adjustments. Yet, a very low saliva level has an appreciable discriminative ability for low plasma level. Unstimulated saliva represents a convenient non-invasive alternative to plasma, to readily identify compliance issues or major drug-drug interactions.

Characterizing the plasma protein binding profiles of chemistry diversified antisense oligonucleotides in human and mouse plasma using an ultrafiltration method

IntroductionPlasma protein binding plays a significant role in influencing the pharmacokinetic and pharmacodynamic properties of drugs. This study focuses on examining two pairs of sequence-matched ASOs: phosphorodiamidate morpholino oligomers (PMOs) and 2’-O-methoxyethyl/phosphorothioate (MOE/PS)-modified ASOs, to assess their plasma protein binding profiles.MethodsThe binding of both PMO and MOE/PS-modified ASOs was investigated using an ultrafiltration method combined with hybridization electrochemiluminescence, allowing for the measurement of the unbound fraction (fu) in both mouse and human plasma. To further characterize the interaction between ASOs and plasma proteins, individual binding measurements were taken for five major proteins in human plasma: human serum albumin, α1-acid glycoprotein, human γ-globulin, low-density lipoprotein, and high-density lipoprotein.ResultsThe results showed a notable difference in plasma protein binding between the two types of ASOs, with MOE/PS-modified ASOs exhibiting significantly higher binding compared to PMOs. The fu, plasma values revealed no significant species difference between mouse and human plasma. Additionally, a saturation point for fu, plasma was observed in MOE/PS-modified ASOs at concentrations above 1 μM, whereas PMOs did not show saturation even at concentrations up to 10 μM. Notably, human γ-globulins were found to have a predominant binding affinity for both MOE/PS and PMO ASOs at physiological concentrations, surpassing human serum albumin, the most abundant plasma protein.DiscussionThe results suggest that the chemistries of the ASOs, particularly their modifications, are key determinants of their binding profiles. The study also highlights the important, though previously overlooked, role of human γ-globulins in the plasma protein binding of ASOs. This could have implications for understanding ASO distribution and tissue disposition, which may inform the development and optimization of ASO-based therapies.

Ion acoustic solitons and periodic waves with dynamical features around the supercritical values in relativistic unmagnetized plasmas

Ion acoustic solitons and periodic waves with dynamical features around the supercritical values in relativistic unmagnetized plasmas

Pharmacokinetics and Tissue Distribution of Albendazole and Its Three Metabolites in Yellow River Carp (Cyprinus carpio haematopterus) after Single Oral Administration.

This study aimed to evaluate the pharmacokinetics and tissue distribution of albendazole (ABZ) and its three metabolites─albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO2), and albendazole-2-aminosulfone (ABZ-2-NH2-SO2)─in Yellow River carp (Cyprinus carpio haematopterus) reared at 17.2 ± 1.1 °C after single oral administration of 12 mg/kg body weight (BW) ABZ. The concentrations of ABZ and its metabolites in different samples were measured using high performance liquid chromatography (HPLC). Pharmacokinetic parameters for ABZSO2 and ABZ-2-NH2-SO2 were not estimated due to their low levels. Pharmacokinetic analysis of ABZ and ABZSO was conducted using average concentration-time data with Phoenix software. The Cmax values (μg/mL or μg/g) of ABZ in skin-on muscle, plasma, bile, kidney, gills, liver, and intestine were 0.65, 0.70, 1.01, 1.61, 1.71, 2.42, and 3.34, respectively. The elimination half-life (t1/2λZ) of ABZ was longest in skin-on muscle (37.92 h), followed by the liver (32.07 h), gills (31.92 h), bile (31.51 h), kidney (26.96 h), intestine (20.81 h), and plasma (19.86 h). For ABZSO, the Cmax values (μg/mL or μg/g) in plasma, skin-on muscle, gills, intestine, liver, kidney, and bile were 0.46, 0.76, 0.89, 1.13, 1.54, 1.89, and 3.78, respectively. These findings indicate that ABZ and ABZSO are widely distributed and metabolized slowly in Yellow River carp after single oral administration. The higher ABZ concentrations in the liver and kidney suggest that these are the main metabolic organs for ABZ, while the elevated levels of ABZSO in bile indicate that bile excretion is the main pathway of ABZSO elimination. Based on the marker residue (ABZ-2-NH2-SO2) and its maximum residue limit (MRL) of 0.1 μg/g in skin-on muscle recommended by China, no withdrawal period was required for ABZ in Yellow River carp after a single oral dose of 12 mg/kg BW. However, using the marker residue (the sum of ABZ and its three metabolites) and the MRL of 0.1 μg/g for ruminants recommended by the EU, the withdrawal period was calculated to be 7 days or 118 °C-day under the same dosing regimen.

Bacteriophage treatment is effective against carbapenem-resistant Klebsiella pneumoniae (KPC) in a neutropenic murine model of gastrointestinal translocation and renal infection.

Carbapenemase-producing Klebsiella pneumoniae (KPC) are globally emerging pathogens that cause life-threatening infections. Novel treatment alternatives are urgently needed. We therefore investigated the effectiveness of three novel bacteriophages (Spivey, Pharr, and Soft) in a neutropenic murine model of KPC gastrointestinal colonization, translocation, and disseminated infection. Bacteriophage efficacy was determined by residual bacterial burden of KPC (CFU/g) in kidneys. Parallel studies were conducted of bacteriophage pharmacokinetics and resistance. Treatment of mice with 5 × 109 PFU of phage cocktail via intraperitoneal injection was effective in significantly reducing renal KPC CFU by 100-fold (P < 0.01) when administered every 24 h and 1000-fold (P < 0.01) every 12 h. Moreover, a combination of bacteriophage and ceftazidime-avibactam produced a synergistic effect, resulting in a 105-fold reduction in bacterial burden in cecum and kidney (P < 0.001 in both tissues). Prophylactic administration of bacteriophages via oral gavage did not prevent KPC translocation to the kidneys. Bacteriophage decay determined by linear regression of the ln of mean concentrations demonstrated R2 values in plasma of 0.941, kidney 0.976, and cecum 0.918, with half-lives of t1/2 = 2.5 h. Furthermore, a phage-resistant mutant displayed increased sensitivity to serum killing in vitro, but did not show significant defects in renal infection in vivo. A combination of bacteriophages demonstrated significant efficacy alone and synergy with ceftazidime/avibactam in the treatment of experimental disseminated KPC infection in neutropenic mice.

Pre-Clinical Assessment of Bupivacaine-Loaded Poly(ester urea) Thin Films for Controlled Drug Release and Effective Pain Management After Surgery.

Safe, effective pain management remains one of the biggest challenges following surgical procedures. Despite widespread recognition of this problem and advances in the mechanistic understanding of pain signaling, post-surgical pain is often undermanaged, with opioid use remaining the clinical standard. As an alternative to current oral, systemic treatments, a degradable bupivacaine-loaded poly(ester urea) (PEU) thin film has been developed to deliver bupivacaine directly to the site of injury over an extended duration. The dose and duration of bupivacaine delivery is controlled using polymer composition and bupivacaine concentration. Systemic bupivacaine concentrations are more than an order of magnitude lower when delivered locally versus intravenous injection. Tissue analysis showed that the majority of bupivacaine is deposited into subcutaneous tissue directly surrounding the implant. Bupivacaine concentration in soft tissue around the implant are 30-fold higher than plasma values, indicating that release from PEU implants remains localized. Bupivacaine-loaded PEU films are assessed into two established mouse models for diabetic neuropathic pain and post-surgical incisional pain. In each model, bupivacaine eluting PEU films effectively block pain for 3-5 days before returning to baseline levels without loss of motor function and without signs of neurotoxicity.

Clinical application value of simultaneous plasma and bronchoalveolar lavage fluid metagenomic next generation sequencing in patients with pneumonia-derived sepsis

BackgroundDespite the increasing use of metagenomic next-generation sequencing (mNGS) in sepsis, identifying clinically relevant pathogens remains challenging. This study was aimed to evaluate the clinical utility of simultaneous plasma and bronchoalveolar lavage fluid (BALF) detection using mNGS.MethodsThis retrospective study enrolled 95 patients with pneumonia-derived sepsis (PDS) admitted to the intensive care unit (ICU) between October 2021 and January 2023. Patients were divided into two groups: mNGS group (n = 60) and the non-mNGS group (n = 35), based on whether simultaneous plasma and BALF mNGS were conducted. All patients underwent conventional microbiological tests (CMT), including bacterial/fungal culture of peripheral blood and BALF, as well as sputum culture, detection of 1, 3-beta-D- glucan in BALF and RT-PCR testing. The clinical data of the enrolled patients were collected, and the detection performance and prognosis of plasma mNGS, BALF mNGS and CMT were compared.ResultsThe mNGS group exhibited a lower mortality rate than the non-mNGS group (35.0% vs. 57.1%, P = 0.034). Simultaneous detection in dual-sample resulted in a higher proportion of microorganisms identified as definite causes of sepsis alert compared to detection in either plasma or BALF alone (55.6% vs. 20.8% vs. 18.8%, P<0.001). Acinetobacter baumannii, Stenotrophomonas maltophilia, Candida albicans, and human mastadenovirus B were the primary strains responsible for infections in PDS patients. Patients with lower white blood cells and neutrophil indices had a greater consistency in dual-sample mNGS. Patients in the mNGS group had more antibiotic adjustments compared to the non-mNGS group (85.71% vs. 33.33%, P<0.001). The percentage of neutrophils was a risk factor for mortality in PDS patients (P = 0.002).ConclusionDual sample mNGS has the advantage of detecting and determining the pathogenicity of more pathogens and has the potential to improve the prognosis of patients with PDS.

Lipaemic plasma: An objective non-invasive photometric method to classify plasma turbidity and its association with red cell haemolysis.

Plasma components are visually inspected, and non-transparent, turbid units are rejected for transfusion and fractionation. Additionally, in case a plasma component is deemed lipaemic, there is conflicting data on the accompanying red cell concentrate (RCC) in vitro quality. As visual inspection of plasma turbidity is a subjective method, we aimed to devise an objective measurement using a quick, non-invasive, table-top spectrophotometry-based method. Using this method, the correlation between spectrophotometric data and its predictive value on haemolysis of the accompanying RCC during storage was assessed. A total of 365 plasma units were visually inspected for turbidity and analysed for light reflection parameters (L*, a* and b*) and triglyceride (TG) levels. Leukoreduced RCCs in saline-adenine-glucose-mannitol (SAGM), prepared from the accompanying lipaemic whole blood, were stored for up to 6 weeks and analysed for quality parameters. The light reflection L* value was the most discriminating between clear and turbid/lipaemic plasma. Also, a correlation was found between TG levels and L* values (R2 = 0.703). Plasma with TG ≥ 2.5 mmol/L showed an L* value >50 with >90% specificity and sensitivity. RCC from donations with a plasma L* value ≥68 showed significantly higher haemolysis levels (p < 0.05) during storage. The non-invasive photometric analysis of plasma turbidity correlated both with visual inspection and plasma TG levels. Measurement of L* values of plasma may be helpful in identifying donations with high TG levels and higher risk for increased haemolysis during RCC storage.

Perioperative administration of albumin in adult patients undergoing liver transplantation: A systematic review.

Hypoalbuminemia is a risk factor for mortality in patients with end-stage liver disease (ESLD) and in those undergoing orthotopic liver transplantation (OLT), since it represents a biomarker of post-operative delayed functional recovery of the graft. Despite albumin infusion during and after OLT is frequently adopted in recipients with hypoalbuminemia, it remains unclear whether this procedure could improve post OLT clinical outcomes. Observational studies indicated that treatment with albumin after OLT might be beneficial in reducing ascites and acute kidney injury (AKI) development. However, considering potential complications and the cost of albumin therapy, the decision to use albumin after OLT should be based on careful consideration of patient's individual needs and risks. In addition, the threshold plasma value of albumin below which it could be clinically useful to infuse albumin has not been clearly defined. This systematic review, prepared in accordance with the PRISMA 2020 guidelines, aimed to assess the efficacy of albumin infusion in patients undergoing OLT, in the prevention or treatment of ascites, AKI, and ischemia reperfusion syndrome, as well as its potential impact on patient survival. Furthermore, this review aimed to illustrate the pathophysiological bases justifying the use of albumin infusion in a subset of patients receiving OLT.

Determination of functional relationships between calciuria and plasma calcium metabolism indices

In the presented work, the authors propose to use for the differential diagnosis of factors contributing to calciuria in personal observations the method of visualization of multidimensional relationships using a panel of ratios of laboratory parameters of water-electrolyte metabolism. The calculation of the ratio panel included plasma values: HCT (hematocrit), MSNS (hemoglobin concentration in erythrocyte), Na (sodium), K (potassium), Caобщ (total calcium), Cl (chlorides), F (phosphates), Kr (creatinine), Ur (urea). Along with these parameters, the following plasma parameters were determined: B-CrossLaps (osteolysis index), TP1NP (osteosynthesis index), VitD, parathyroid hormone, as well as urine pH and calcium. The results obtained, according to the authors, demonstrate the informativeness of the proposed method, which makes it possible to identify the leading complexes of bonds associated with calciuria in individual observations. At the same time, these complexes can differ significantly in their structure in different patients, finding their description in literary sources, thereby demonstrating their differential significance. The authors note that the different “images” of the connections accompanying calciuria established in this study do not exhaust all possible variants of the connections of laboratory parameters associated with the dynamics of calciuria, but as additional laboratory data of patients with various pathologies accumulate, the base of the general array can be significantly expanded. Based on the results obtained and their analysis, the authors conclude that the proposed approach is promising to use in the expert assessment of laboratory parameters as an auxiliary method in analyzing the obtained laboratory data in supporting decision-making and determining the goals of pharmacological correction of calcium metabolism disorders.

Verification of electromagnetic simulation capabilities in global gyrokinetic particle-in-cell code GTS

Recently, the numerical scheme presented by Mishchenko et al. [Phys. Plasmas 21, 052113 (2014); 21, 092110 (2014)] enabled explicit gyrokinetic simulations of low-frequency electromagnetic instabilities in tokamaks at experimentally relevant values of plasma β. This scheme resolved the long-standing cancellation problem that previously hindered gyrokinetic particle-in-cell code simulations of magnetohydrodynamic phenomena with inherently small parallel electric fields. Moreover, the scheme did not employ approximations that eliminate critical tearing-type instabilities. Here, we report on the implementation of this numerical scheme in the global gyrokinetic particle-in-cell code GTS. This implementation allows for a more complete and accurate picture of interaction between small scale turbulence and MHD modes in tokamaks. Additionally, we present a comprehensive set of verification simulations of numerous electromagnetic instabilities relevant to present-day tokamaks. These simulations encompass the kinetic ballooning mode, the internal kink mode, the tearing mode, the micro-tearing mode, and the toroidal Alfven eigenmode destabilized by energetic ions, which are all instrumental in understanding tokamak physics. We will also showcase the preliminary nonlinear simulations of kinetic ballooning instabilities and (2,1) island formation due to tearing mode instability. These simulations validate the accuracy of the scheme implementation and pave the way for studying how these instabilities affect plasma confinement and performance.

Reference values for plasma and urine trace elements in a Swiss population-based cohort.

Trace elements (TEs) are ubiquitous. TE concentrations vary among individuals and countries, depending on factors such as living area, workplaces and diet. Deficit or excessive TEs concentrations have consequences on the proper functioning of human organism so their biomonitoring is important. The aim of this project was to provide reference values for TEs concentrations in the Swiss population. The 1,078 participants to the SKiPOGH cohort included in this study were aged 18-90 years. Their 24-h urine and/or plasma samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to determine 24 TEs concentrations: Ag, Al, As, Be, Bi, Cd, Co, Cr, Cu, Hg, I, Li, Mn, Mo, Ni, Pb, Pd, Pt, Sb, Se, Sn, Tl, V and Zn. Statistical tests were performed to evaluate the influence of covariates (sex, age, BMI, smoking) on these results. Reference intervals for the Swiss adult population were also defined. TEs concentrations were obtained for respectively 994 and 903 persons in plasma and urine matrices. It was possible to define percentiles of interest (P50 and P95) for almost all the TEs. Differences in TEs distribution between men and women were noticed in both matrices; age was also a cofactor. This first Swiss biomonitoring of a large TEs-panel offers reference values in plasma and in urine for the Swiss population. The results obtained in this study were generally in line with clinical recommendations and comparable to levels reported in other population-based surveys.

Correlation of Plasma Fibroblast Growth Factor 23 with the Risk of Cardiovascular Disease in a Group of Iraqi Patients with Type 2 Diabetes Mellitus

Since it is the largest cause of death globally, cardiovascular disease (CVD) poses a serious health issue. Whether or whether they are changeable, several risk factors exist for the onset of CVD. Conventional and most often used approach to estimate cardiovascular risk is Framingham risk score. Still, ongoing research is looking for alternative markers that can better estimate this risk. One of these producers under increasing research attention is fibroblast growth factor 23 (FGF-23). The aim of this work is to investigate in patients with type 2 diabetes mellitus a possible prognostic value of plasma and urine FGF-23 for CVD. Two groups—the patients' group and the control group—will be formed out of the 200 participants split equally. The group of patients will include those with type 2 diabetes mellitus of more than five years. Using the Framingham risk score, all participants will be evaluated for their 10-year CVD risk; the outcomes will be statistically linked to both plasma and urine FGF-23. Our present work revealed a positive association between Framingham risk and cholesterol, TG, LDL, HDL, VLDL, non-VLDL. and also showed favorable link in Atherogentic index and BMI,HDL,LDL,VLDL and non LDL. In Dm.patient group and farmingham risk, the FGF23 in current study show greater signifcant.

Extracellular Vesicle Characteristics in Local Fluid and Plasma Measured by Nanoparticle Tracking Analysis Can Help Differentiate High-Grade Serous Carcinoma from Benign Ovarian Pathology

Background: High-grade serous carcinoma (HGSC) is the most lethal of gynecological cancers in developed countries. It usually presents late with non-specific symptoms and most cases are diagnosed at an advanced stage, with 5-year overall survival being around 40%. Biomarkers for screening and early diagnosis of this aggressive disease are, thus, a research priority. Extracellular vesicles (EVs) that reflect the cell of origin and that can be isolated from local fluid and plasma by minimally invasive liquid biopsy are such promising biomarkers. Besides EV concentration and molecular profile, which have been the main focus of research for many years, recent studies have also called attention to EV size distribution. The aim of our study was to evaluate the potential of EV concentration and size distribution in local fluid and plasma as diagnostic biomarkers for HGSC. Methods: Paired pretreatment ascites and plasma samples from 37 patients with advanced HGSC and paired pretreatment free peritoneal fluid (FPF) and plasma samples from 40 controls with benign ovarian pathology (BOP) were analyzed using nanoparticle tracking analysis (NTA). Results: We observed a significant difference in EV concentration in local fluid, but not in plasma, between HGSC patients and the control group. We also found a significant difference in EV size distribution in both local fluid and plasma between HGSC patients and the control group. The receiver operating characteristics (ROC) curve analysis of EV characteristics showed excellent diagnostic performance for the mode, D10, and D50 in local fluid and acceptable diagnostic performance for EV concentration and mean EV size in local fluid, as well as for the mode and D10 value in plasma. Conclusions: The results of our study show that EV concentration in local fluid and more importantly EV size distribution in both local fluid and plasma are significantly changed in the presence of HGSC. Future research of size-dependent molecular profiling of EVs could help identify novel diagnostic biomarkers for HGSC.

A-337 The Utility of Urinary Human Chorionic Gonadotropin Testing in the Emergency Department

Abstract Background Human chorionic gonadotropin (hCG) levels are measured in both urine and blood as an indication of suspected pregnancy, and assessment of progress of conception. It is also measured in the investigation of patients presenting with acute abdomen and suspected of ectopic or molar pregnancy. This study reviewed the utility of urine pregnancy test in a large university teaching hospital. Methods Results of all urinary hCG tests (using hCG Combo Pregnancy kit, MEDLINE, IL) performed as point of care in the emergency department during the year 2023 were obtained. Corresponding plasma hcG levels performed (Total β-HCG Alinity immunoassay, Abbott Diagnostics, IL) were also obtained. Analysis of hCG testing outcomes were assessed. Results A total of 2848 urinary hCG tests were performed during the study period. The majority 2113 (74.2%) of samples were negative for hCG whereas 835 samples (29.3) were positive. Among the positive hCG urine samples, 401 patients (48%) had plasma hCG requested and performed. Plasma hCG values ranged from &amp;lt; 2.4 (26.5) to 219,462.5 mIU/mL (median 16,872.35 mIU/mL). One plasma sample with corresponding positive urinary hCG result had plasma hCG level &amp;lt;2.4 mIU/mL which is below the detection limit of the assay suggesting a false positive urinary hCG result. Among the 13 patients with serial plasma hCG values, only one patient exhibited doubling (48 hours) hCG values when less than 13,000 mIU/mL. One patient had a declining serial hCG plasma values suggesting failing conception. The remaining patients with consecutive plasma hCG values cannot be assessed as either the time gap was excessive or hCG values were markedly elevated (&amp;gt; 30,000 mIU/mL). Conclusions Although the utility of urinary hCG testing in the emergency department appeared appropriate, unnecessary repeat analysis with appropriate plasma request represented 3.2%. An electronic test request duplicate notification may help resolve this unnecessary repeat.

Interpretation of TSH results can be improved by reference values fluctuating in time.

The secretion of thyroid stimulating hormone (thyrotropin, TSH), is characterized by a marked circadian rhythm. Plasma or serum TSH values are significantly lower in the afternoon and in the evening as compared to the early morning. As in clinical practice, blood sampling time shows an important variation, a reliable assessment of thyroid status is often not an easy task for the clinician. The biological variation of TSH plays a major role in the intra-individual variability of TSH results in serum or plasma. The observed intra-day variation largely exceeds the reported inter-vendor variation and the coefficient of variation of clinical TSH assays. Therefore, a mathematical solution was sought for correcting interpretation of TSH results for sampling time. We have developed a cosinor model which allows to compensate TSH decision values for the fluctuating serum or plasma TSH concentrations throughout the day. The following mathematical function could be derived: corrected TSH cutoff_value (mIU/L)=0.40+0.24*cos(((π/12) *T)+6) in which T represents the time (hours). This mathematical function can be easily implemented into a laboratory's informatics system and furthermore allows a better tailored diagnosis of (subclinical) hyperthyroidism, regardless the blood sampling time. Implementing the corrected cut-off values result in a marked reduction of apparent (false positive) hyperthyroidism diagnosis, in particular in the afternoon.

Diagnostic Value of Plasma Methylated Septin 9 in Detection of Hepatocellular Carcinoma in Egyptian Patient with post Hepatitis C Liver Cirrhosis in Comparison to Serum Level of Alphafeto Protein

Abstract Background Egypt has the highest hepatitis C virus (HCV) prevalence worldwide. Cirrhosis secondary to HCV is associated with the highest annual risk for developing hepatocellular carcinoma. The burden of HCC has been increasing in Egypt with a doubling in the incidence rate in the past 10 years. HCC contributes to 14.8% of all cancer mortality in Egypt. Most HCCs (80%) arise in a cirrhotic liver, a situation where there has been longstanding hepatocyte damage and chronic inflammation leading to fibrosis. Aim of the Work This study aims to evaluate the diagnostic value of plasma mSEPT9 assay in detection of HCC in Egyptian patients with post hepatitis C liver cirrhosis in comparison to serum level of α-fetoprotein (AFP). Patients and Methods This is a prospective case-control study conducted at the Gastroenterology department in Ain Shams University Hospital. The study population consisted of 80 subjects, divided into three groups: 40 patients with hepatocellular carcinoma, 20 patients with liver cirrhosis, and 20 healthy subjects as controls with matched age and gender. Results The study found that hepatocellular carcinoma (HCC) was more frequent in male patients and that the age of HCC patients was statistically significantly higher than patients with cirrhosis and healthy controls. Patients with HCC and cirrhosis had a higher Child Pugh score than healthy controls. Portal hypertension and portal vein thrombosis were more frequent in HCC and cirrhosis patients than in the control group. Liver enzymes were higher in patients with HCC and cirrhosis compared to healthy controls, while hemoglobin and platelet levels were lower in patients with HCC. Hepatitis C antibody and PCR were positive in HCC and cirrhosis patient groups. AFP and Methylated Septin 9 levels were higher in patients with HCC and cirrhosis than in healthy controls, and AFP had better diagnostic accuracy than Methylated Septin 9. Both AFP and Methylated Septin 9 levels were positively correlated with age, Child Score, liver enzymes, and coagulation profile and negatively correlated with platelet count and hemoglobin level. AFP level was positively correlated with the number of focal lesions and liver size. Conclusion This study demonstrated that plasma Methylated Septin 9 can be a promising noninvasive and circulating epigenetic biomarker for HCC diagnosis at the individual level. However, our results showed that AFP was superior than Methylated Septin 9 in the detection of HCC, Methylated Septin 9 has higher Sensitivity. It was suggested that the combination of plasma mSEPT9 and AFP could enhance the sensitivity of Methylated Septin 9 or AFP alone in the diagnosis of HCC. Further comparative studies with larger sample size and longer follow-up are needed to confirm our results and to identify risk factors of adverse events.

A Practical In Silico Method for Predicting Compound Brain Concentration-Time Profiles: Combination of PK Modeling and Machine Learning.

Given the aging populations in advanced countries globally, many pharmaceutical companies have focused on developing central nervous system (CNS) drugs. However, due to the blood-brain barrier, drugs do not easily reach the target area in the brain. Although conventional screening methods for drug discovery involve the measurement of (unbound fraction of drug) brain-to-plasma partition coefficients, it is difficult to consider nonequilibrium between plasma and brain compound concentration-time profiles. To truly understand the pharmacokinetics/pharmacodynamics of CNS drugs, compound concentration-time profiles in the brain are necessary; however, such analyses are costly and time-consuming and require a significant number of animals. Therefore, in this study, we attempted to develop an in silico prediction method that does not require a large amount of experimental data by combining modeling and simulation (M&S) with machine learning (ML). First, we constructed a hybrid model linking plasma concentration-time profile to the brain compartment that takes into account the transit time and brain distribution of each compound. Using mouse plasma and brain time experimental values for 103 compounds, we determined the brain kinetic parameters of the hybrid model for each compound; this case was defined as scenario I (a positive control experiment) and included the full brain concentration-time profile data. Next, we built an ML model using chemical structure descriptors as explanatory variables and rate parameters as the target variable, and we then input the predicted values from 5-fold cross-validation (CV) into the hybrid model; this case was defined as scenario II, in which no brain compound concentration-time profile data exist. Finally, for scenario III, assuming that the brain concentration is obtained at only one time point, we used the brain kinetic parameters from the result of the 5-fold CV in scenario II as the initial values for the hybrid model and performed parameter refitting against the observed brain concentration at that time point. As a result, the RMSE/R2-values of the brain compound concentration-time profiles over time were 0.445/0.517 in scenario II and 0.246/0.805 in scenario III, indicating the method provides high accuracy and suggesting that it is a practical method for predicting brain compound concentration-time profiles.

Is It Enough to Diagnose Pheochromocytoma by Measuring Urine Metanephrines Levels?

This study aimed to evaluate the diagnostic value of plasma and urinary metanephrines and determine their sensitivity, specificity, and correlation among patients with adrenal lesions, which required a multidisciplinary approach because of size, functional state, or malign appearance. This retrospective study of 152 patientswith adrenal lesions was conducted at the Outpatient Clinics of Ankara Bilkent City Hospital at the Department of Endocrinology and Metabolism Diseases betweenAugust 2019and February 2022. These patients were discussed at the Endocrinology and Surgery multidisciplinary council because of their adrenal lesions.Among them, 94 patients underwent adrenal surgery. Thirty patients with histologically proven pheochromocytoma, 36 with cortical nodular hyperplasia, four cases of adrenocortical carcinoma and 24 cases with angiomyolipoma were detected. According to the analysis, the most sensitive test in diagnosing pheochromocytoma was urinary fractionated metanephrine (90%), followed by plasma free metanephrines at 84 %. Conversely, the most specific test was plasma free normetanephrine (91.4%).A statistically significant correlation exists between plasma and urinary metanephrine; plasma normetanephrine levels were alsosignificantly correlated with urine normetanephrine. These findings indicate that plasma and urine metanephrines are sensitive for detecting pheochromocytoma and can be used interchangeably.