Quantitative assessment of coronary plaque volume change related to triglyceride glucose index: The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry.

BACKGROUND: The association between triglyceride glucose (TyG) index and coronary atherosclerotic change remains unclear. We aimed to evaluate the association between TyG index and coronary plaque progression (PP) using serial coronary computed tomography angiography (CCTA). METHODS: A total of 1143 subjects (aged 60.7 ± 9.3 years, 54.6% male) who underwent serial CCTA with available data on TyG index and diabetic status were analyzed from The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. PP was defined as plaque volume (PV) (mm3) at follow-up minus PV at index > 0. Annual change of PV (mm3/year) was defined as PV change divided by inter-scan period. Rapid PP was defined as the progression of percent atheroma volume (PV divided by vessel volume multiplied by 100) ≥ 1.0%/year. RESULTS: The median inter-scan period was 3.2 (range 2.6-4.4) years. All participants were stratified into three groups based on TyG index tertiles. The overall incidence of PP was 77.3%. Baseline total PV (group I [lowest]: 30.8 (0.0-117.7), group II: 47.2 (6.2-160.4), and group III [highest]: 57.5 (8.4-154.3); P < 0.001) and the annual change of total PV (group I: 5.7 (0.0-20.2), group II: 7.6 (0.5-23.5), and group III: 9.4 (1.4-27.7); P = 0.010) were different among all groups. The risk of PP (odds ratio [OR] 1.648; 95% confidence interval [CI] 1.167-2.327; P = 0.005) and rapid PP (OR 1.777; 95% CI 1.288-2.451; P < 0.001) was increased in group III compared to that in group I. TyG index had a positive and significant association with an increased risk of PP and rapid PP after adjusting for confounding factors. CONCLUSION: TyG index is an independent predictive marker for the progression of coronary atherosclerosis. Clinical registration ClinicalTrials.gov NCT02803411.

Incremental role of resting myocardial computed tomography perfusion for predicting physiologically significant coronary artery disease: A machine learning approach.

BACKGROUND: Evaluation of resting myocardial computed tomography perfusion (CTP) by coronary CT angiography (CCTA) might serve as a useful addition for determining coronary artery disease. We aimed to evaluate the incremental benefit of resting CTP over coronary stenosis for predicting ischemia using a computational algorithm trained by machine learning methods. METHODS: 252 patients underwent CCTA and invasive fractional flow reserve (FFR). CT stenosis was classified as 0%, 1-30%, 31-49%, 50-70%, and >70% maximal stenosis. Significant ischemia was defined as invasive FFR < 0.80. Resting CTP analysis was performed using a gradient boosting classifier for supervised machine learning. RESULTS: On a per-patient basis, accuracy, sensitivity, specificity, positive predictive, and negative predictive values according to resting CTP when added to CT stenosis (>70%) for predicting ischemia were 68.3%, 52.7%, 84.6%, 78.2%, and 63.0%, respectively. Compared with CT stenosis [area under the receiver operating characteristic curve (AUC): 0.68, 95% confidence interval (CI) 0.62-0.74], the addition of resting CTP appeared to improve discrimination (AUC: 0.75, 95% CI 0.69-0.81, P value .001) and reclassification (net reclassification improvement: 0.52, P value < .001) of ischemia. CONCLUSIONS: The addition of resting CTP analysis acquired from machine learning techniques may improve the predictive utility of significant ischemia over coronary stenosis.

Diagnostic Performance of a Novel Coronary CT Angiography Algorithm: Prospective Multicenter Validation of an Intracycle CT Motion Correction Algorithm for Diagnostic Accuracy.

OBJECTIVE: Motion artifact can reduce the diagnostic accuracy of coronary CT angiography (CCTA) for coronary artery disease (CAD). The purpose of this study was to compare the diagnostic performance of an algorithm dedicated to correcting coronary motion artifact with the performance of standard reconstruction methods in a prospective international multicenter study. SUBJECTS AND METHODS: Patients referred for clinically indicated invasive coronary angiography (ICA) for suspected CAD prospectively underwent an investigational CCTA examination free from heart rate-lowering medications before they underwent ICA. Blinded core laboratory interpretations of motion-corrected and standard reconstructions for obstructive CAD (≥ 50% stenosis) were compared with ICA findings. Segments unevaluable owing to artifact were considered obstructive. The primary endpoint was per-subject diagnostic accuracy of the intracycle motion correction algorithm for obstructive CAD found at ICA. RESULTS: Among 230 patients who underwent CCTA with the motion correction algorithm and standard reconstruction, 92 (40.0%) had obstructive CAD on the basis of ICA findings. At a mean heart rate of 68.0 ± 11.7 beats/min, the motion correction algorithm reduced the number of nondiagnostic scans compared with standard reconstruction (20.4% vs 34.8%; p < 0.001). Diagnostic accuracy for obstructive CAD with the motion correction algorithm (62%; 95% CI, 56-68%) was not significantly different from that of standard reconstruction on a per-subject basis (59%; 95% CI, 53-66%; p = 0.28) but was superior on a per-vessel basis: 77% (95% CI, 74-80%) versus 72% (95% CI, 69-75%) (p = 0.02). The motion correction algorithm was superior in subgroups of patients with severely obstructive (≥ 70%) stenosis, heart rate ≥ 70 beats/min, and vessels in the atrioventricular groove. CONCLUSION: The motion correction algorithm studied reduces artifacts and improves diagnostic performance for obstructive CAD on a per-vessel basis and in selected subgroups on a per-subject basis.

Physiological serum copper concentrations found in malignancies cause unfolding induced aggregation of human serum albumin in vitro.

Malignancies are characterized by several drastic metabolic changes, one of which is a progressive rise in the levels of serum copper. This rise in serum copper is documented across all malignancies and across malignancies in several species. This study aims to explore in vitro the effect of increased copper levels on the structure of the blood protein human serum albumin. Exposure of human serum albumin to physiologically relevant copper concentrations for 21 days resulted in structural modifications in the protein which were evident by changes in the intrinsic florescence. A loss of the predominantly alpha helical structure of human serum albumin was recorded along with a tendency to form protein aggregates. This aggregation was characterized by Thioflavin T and Congo Red assays. Rayleigh light scattering and turbidity assays confirmed aggregation. The aggregates were visually confirmed using transmission electron microscopy. This is the first report implicating increased copper levels as a cause of aggregation of blood proteins in malignancies. The physiological and biochemical implications of this phenomenon are discussed.

Calcitriol-copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma.

Calcitriol is the metabolically active form of Vitamin D and is known to kill cancer cells. Using the rat model of DEN induced hepatocellular carcinoma we show that there is a marked increase in cellular levels of copper in hepatocellular carcinoma and that calcitriol-copper interaction leads to reactive oxygen species mediated DNA breakage selectively in hepatocellular carcinoma cells. In vivo studies show that calcitriol selectively induces severe fluctuations in cellular enzymatic and non enzymatic scavengers of reactive oxygen species in the malignant tissue. Lipid peroxidation, a well established marker of oxidative stress, was found to increase, and substantial cellular DNA breakage was observed. We propose that calcitriol is a proxidant in the cellular milieu of hepatocellular carcinoma cells, and this copper mediated prooxidant action of calcitriol causes selective DNA breakage in malignant cells, while sparing normal (non malignant) cells.

Rationale and design of the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry: A comprehensive exploration of plaque progression and its impact on clinical outcomes from a multicenter serial coronary computed tomographic angiography study.

BACKGROUND: The natural history of coronary artery disease (CAD) in patients with low-to-intermediate risk is not well characterized. Although earlier invasive serial studies have documented the progression of atherosclerotic burden, most were focused on high-risk patients only. The PARADIGM registry is a large, prospective, multinational dynamic observational registry of patients undergoing serial coronary computed tomographic angiography (CCTA). The primary aim of PARADIGM is to characterize the natural history of CAD in relation to clinical and laboratory data. DESIGN: The PARADIGM registry (ClinicalTrials.govNCT02803411) comprises ≥2,000 consecutive patients across 9 cluster sites in 7 countries. PARADIGM sites were chosen on the basis of adequate CCTA volume, site CCTA proficiency, local demographic characteristics, and medical facilities to ensure a broad-based sample of patients. Patients referred for clinically indicated CCTA will be followed up and enrolled if they had a second CCTA scan. Patients will also be followed up beyond serial CCTA performance to identify adverse CAD events that include cardiac and noncardiac death, myocardial infarction, unstable angina, target vessel revascularization, and CAD-related hospitalization. SUMMARY: The results derived from the PARADIGM registry are anticipated to add incremental insight into the changes in CCTA findings in accordance with the progression or regression of CAD that confer prognostic value beyond demographic and clinical characteristics.

Warranty Period of Zero Coronary Artery Calcium Score for Predicting All-Cause Mortality According to Cardiac Risk Burden in Asymptomatic Korean Adults.

BACKGROUND: The aim of this study was to examine whether zero coronary artery calcium (CAC) score is associated with favorable prognosis of all-cause mortality (ACM) according to a panel of conventional risk factors (RF) in asymptomatic Korean adults.Methods and Results:A total of 48,215 individuals were stratified according to presence/absence of CAC, and the following RF were examined: hypertension, diabetes, current smoking, high low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol. The RF were summed on composite score as 0, 1-2, or ≥3 RF present. The warranty period was defined as the time to cumulative mortality rate >1%. Across a median follow-up of 4.4 years (IQR, 2.7-6.6), 415 (0.9%) deaths occurred. Incidence per 1,000 person-years for ACM was consistently higher in subjects with any CAC, irrespective of number of RF. The warranty period was substantially longer (eg, 9 vs. 5 years) for CAC=0 compared with CAC >0. The latter observation did not change materially according to pre-specified RF, but difference in warranty period according to presence/absence of CAC reduced somewhat when RF burden increased. CONCLUSIONS: In asymptomatic Korean adults, the absence of CAC evoked a strong protective effect against ACM as reflected by longer warranty period, when no other RF were present. The usefulness of zero CAC score and its warranty period requires further validation in the presence of multiple RF. (Circ J 2016; 80: 2356-2361).

Rationale and Design of the CREDENCE Trial: computed TomogRaphic evaluation of atherosclerotic DEtermiNants of myocardial IsChEmia.

BACKGROUND: Coronary computed tomography angiography (CCTA) allows for non-invasive assessment of obstructive coronary artery disease (CAD) beyond measures of stenosis severity alone. This assessment includes atherosclerotic plaque characteristics (APCs) and calculation of fractional flow reserve (FFR) from CCTA (FFRCT). Similarly, stress imaging by myocardial perfusion scintigraphy (MPS) provides vital information. To date, the diagnostic performance of integrated CCTA assessment versus integrated MPS assessment for diagnosis of vessel-specific ischemia remains underexplored. METHODS: CREDENCE will enroll adult individuals with symptoms suspicious of CAD referred for non-emergent invasive coronary angiography (ICA), but without known CAD. All participants will undergo CCTA, MPS, ICA and FFR. FFR will be performed for lesions identified at the time of ICA to be ≥40 and <90 % stenosis, or those clinically indicated for evaluation. Study analyses will focus on diagnostic performance of CCTA versus MPS against invasive FFR reference standard. An integrated stenosis-APC-FFRCT metric by CCTA for vessel-specific ischemia will be developed from derivation cohort and tested against a validation cohort. Similarly, integrated metric by MPS for vessel-specific ischemia will be developed, validated and compared. An FFR value of ≤0.80 will be considered as ischemia causing. The primary endpoint will be the diagnostic accuracy of vessel territory-specific ischemia of integrated stenosis-APC-FFRCT measure by CCTA, compared with perfusion or perfusion-myocardial blood flow stress imaging testing, against invasive FFR. DISCUSSION: CREDENCE will determine the performance of integrated CCTA metric compared to integrated MPS measure for diagnosis of vessel-specific ischemia. If proven successful, this study may reduce the number of missed diagnoses and help to optimally predict ischemia-causing lesions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02173275 . Registered on June 23, 2014.

Calcitriol induced redox imbalance and DNA breakage in cells sharing a common metabolic feature of malignancies: Interaction with cellular copper (II) ions leads to the production of reactive oxygen species.

Calcitriol is known to selectively kill malignant cells, however, not much is known about the mechanism by which it kills malignant cells and spares the "normal" cells. Since elevation of cellular copper is a metabolic condition common to all malignancies, we developed a mouse model to mimic this condition and treated the animals with calcitriol. It was observed that calcitriol-copper interaction in vivo causes severe fluctuations in cellular enzymatic and nonenzymatic scavengers of reactive oxygen species (ROS). Lipid peroxidation, a well-established marker of oxidative stress, was found to increase, and a substantial cellular DNA breakage was observed. Calcitriol-copper interaction in vivo was observed to lead the cells to an apoptosis like cell death. We propose that the interaction of calcitriol and copper within malignant cells and the consequent redox scavenger fluctuations and ROS-mediated DNA breakage may be one of the several mechanisms by which calcitriol causes selective cell death of malignant cells, while sparing normal cells.

Cu(II)-vitamin D interaction leads to free radical-mediated cellular DNA damage: a novel putative mechanism for its selective cytotoxic action against malignant cells.

Vitamin D (vit D) is a known anticancer molecule, and cancer cells are reported to have elevated levels of Cu(II) ions. In this study, we show that interaction of vit D and Cu(II) leads to the formation of hydroxyl free radicals, superoxide anion and hydrogen peroxide, which causes severe oxidative stress, selectively in malignant cells. We show that the production of these reactive oxygen species causes cellular DNA fragmentation which may cause cell death. A novel putative chemical mechanism explaining how vit D causes cell death by DNA damage, selectively in malignant cells, is proposed.

Targeting increased copper levels in diethylnitrosamine induced hepatocellular carcinoma cells in rats by epigallocatechin-3-gallate.

We have earlier elucidated a pathway for the anticancer action of plant polyphenolic compounds against malignant cells involving mobilisation of endogenous copper ions and the consequent prooxidant action. To further confirm our hypothesis in vivo, we induced hepatocellular carcinoma (HCC) in rats by diethylnitrosamine (DEN). We show that in such carcinoma cells, there is a progressive elevation in copper levels at various intervals after DEN administration. Concurrently with increasing copper levels, epigallocatechin-3-gallate (EGCG; a potent anticancer plant polyphenol found in green tea) mediated DNA breakage in malignant cells is also increased. The cell membrane permeable copper chelator neocuproine inhibited the EGCG-mediated cellular DNA degradation, whereas the membrane impermeable chelator bathocuproine was ineffective. Iron and zinc specific chelators desferoxamine mesylate and histidine, respectively, were also ineffective in inhibiting EGCG mediated DNA breakage. Through the use of specific scavengers, the mechanism of DNA breakage was determined to be mediated by reactive oxygen species. In summary, we provide an in vivo evidence of accumulating copper in hepatocellular carcinoma that is targeted by EGCG, leading to its anticancer role in a prooxidant manner. Our findings confirm a novel mechanism of anticancer activity of EGCG in particular and plant derived nutraceuticals in general.

Synthesis, characterisation, and in vitro antiparasitic activity of new flavanoidal tetrazinan-6'-ones and their binding study with calf thymus DNA using molecular modelling and spectroscopic techniques.

With the developing resistance to traditional antiparasitic medications, the purpose of this study was to efficiently develop a series of six noble flavanoidal tetrazinane-6'-one derivatives by a one-pot reaction pathway. FT-IR, 1HNMR, 13CNMR, and Mass spectra were employed for the structural elucidation of the synthesized compounds (7-12). Clinostomum complanatum, a parasite infection model that has been well-established, demonstrated that all the synthesized compounds are potent antiparasitic agents. DNA is the main target for various medicinal compounds. As a result, thestudy of how small molecules attach to DNA has received a lot of attention. In the present study, we have performed various biophysical techniques to determine the mode of binding of synthesized compounds (7-12) with calf thymus DNA (ct-DNA). It was observed from the UV-visible absorbance and fluorescence spectra that all synthesized compounds (7-12) form complexes with the ct-DNA. The value of binding constant (Kb) was obtained to be in the range of 4.36---24.50 × 103 M - 1 at 298 K. Competitive displacement assay with ethidium bromide (EB), CD spectral analysis, viscosity measurements, and in silico molecular docking confirmed that ligands (7-12) incorporate with ct-DNA through groove binding only. Molecular docking studies were performed for all synthesized compounds with the calf thymus DNA and it was found that all the newly synthesized compounds strongly bind with the chain B of DNA in the minor groove with the value of binding energy in the range of -8.54 to -9.04 kcal per mole and several hydrogen bonding interactions.

Nickel-induced oxidative stress causes cell death in testicles: implications for male infertility.

Aligarh region is well known for its lock industry. This lock industry utilises nickel for electroplating. There have been informal reports of infertility in men and women living near the lock industry. We analysed field water samples to investigate this link, and the results showed considerable nickel contamination. To further validate our results, we exposed male rats to relevant nickel levels in drinking water. This experimental exposure resulted in abnormal sperm morphology, decline in sperm count, significant change in activities of antioxidant enzymes, pronounced oxidative stress in the rat spermatocytes and decrease in serum testosterone level, as well as damage in the hypothalamus and pituitary (in all cases, the changes were most significant at the highest concentration used i.e 2.5 mg/l). The breeding experiments showed decline in live birth rate, while pups did not survive post birth in cages where males were given 2 and 2.5 mg/l concentrations of nickel in drinking water prior to mating. Our data strongly indicate a link between industrial nickel exposure and male infertility.

Dietary Polyphenols, Plant Metabolites, and Allergic Disorders: A Comprehensive Review.

Given the ongoing rise in the occurrence of allergic disorders, alterations in dietary patterns have been proposed as a possible factor contributing to the emergence and progression of these conditions. Currently, there is a significant focus on the development of dietary therapies that utilize natural compounds possessing anti-allergy properties. Dietary polyphenols and plant metabolites have been intensively researched due to their well-documented anti-inflammatory, antioxidant, and immunomodulatory characteristics, making them one of the most prominent natural bioactive chemicals. This study seeks to discuss the in-depth mechanisms by which these molecules may exert anti-allergic effects, namely through their capacity to diminish the allergenicity of proteins, modulate immune responses, and modify the composition of the gut microbiota. However, further investigation is required to fully understand these effects. This paper examines the existing evidence from experimental and clinical studies that supports the idea that different polyphenols, such as catechins, resveratrol, curcumin, quercetin, and others, can reduce allergic inflammation, relieve symptoms of food allergy, asthma, atopic dermatitis, and allergic rhinitis, and prevent the progression of the allergic immune response. In summary, dietary polyphenols and plant metabolites possess significant anti-allergic properties and can be utilized for developing both preventative and therapeutic strategies for targeting allergic conditions. The paper also discusses the constraints in investigating and broad usage of polyphenols, as well as potential avenues for future research.

Physiotypic variations lead to variations within the normal range for red blood cells and haemoglobin levels in a healthy human population: An evaluation using generalised additive modelling and hierarchical structure analysis.

OBJECTIVES: Haematological parameters have been used for a long time for clinical evaluations, however the dynamics of these parameters has not been studied at length, in healthy populations. We aim to understand the dependence of haematological parameters on human physiotypes. DESIGN AND METHODS: Using an age and gender restricted healthy human (male) population (n = 100), we attempt to analyse the dynamics of haemoglobin and red blood cells, with reference to age, height and weight of individuals. Using advanced generalised additive modelling and classical hierarchical structural analysis we aim to establish relationships between these parameters and human physiotypes. RESULTS: We demonstrate that definitive relationships can be established for number of red blood cells, haemoglobin levels, RDW-CV, RDW-SD and weight, height and age of individuals. CONCLUSION: This study provides a proof of principle, that haematological parameters are dependent on physiotypic variation, within the normal ranges in a healthy population. It may also be noted that there is a definitive influence of height, weight and age on normal ranges and stratification by these factors might therefore make reference intervals narrower, in turn, possibly allowing more precise clinical decisions based on the complete blood count (CBC).

Calcitriol-induced DNA damage: toward a molecular mechanism of selective cell death.

Calcitriol, the biologically active form of vitamin D, is known to function as an important anticancer agent. The exact mechanism by which calcitriol exerts its effects remains unknown. Recent evidence suggests a link between calcitriol-induced, free-radical-mediated DNA damage and cell death, in the presence of elevated levels of copper, such as those observed in malignant cells. As calcitriol is a lipid-soluble molecule, its interaction with DNA and copper would require a "chaperone"-like molecule, which binds the relatively hydrophobic calcitriol and polar DNA. A candidate protein is the vitamin D receptor (VDR), which binds both molecules. Using the recently elucidated full-length structure of the VDR molecule, we present and discuss three possible mechanisms to explain the interaction between calcitriol and DNA, as mediated by VDR.

The Pharmacological Properties of Red Grape Polyphenol Resveratrol: Clinical Trials and Obstacles in Drug Development.

Resveratrol is a stilbenoid from red grapes that possesses a strong antioxidant activity. Resveratrol has been shown to have anticancer activity, making it a promising drug for the treatment and prevention of numerous cancers. Several in vitro and in vivo investigations have validated resveratrol's anticancer capabilities, demonstrating its ability to block all steps of carcinogenesis (such as initiation, promotion, and progression). Additionally, resveratrol has been found to have auxiliary pharmacological effects such as anti-inflammatory, cardioprotective, and neuroprotective activity. Despite its pharmacological properties, several obstacles, such as resveratrol's poor solubility and bioavailability, as well as its adverse effects, continue to be key obstacles to drug development. This review critically evaluates the clinical trials to date and aims to develop a framework to develop resveratrol into a clinically viable drug.

Current Understanding of Flavonoids in Cancer Therapy and Prevention.

Cancer is a major cause of death worldwide, with multiple pathophysiological manifestations. In particular, genetic abnormalities, inflammation, bad eating habits, radiation exposure, work stress, and toxin consumption have been linked to cancer disease development and progression. Recently, natural bioactive chemicals known as polyphenols found in plants were shown to have anticancer capabilities, destroying altered or malignant cells without harming normal cells. Flavonoids have demonstrated antioxidant, antiviral, anticancer, and anti-inflammatory effects. Flavonoid type, bioavailability, and possible method of action determine these biological actions. These low-cost pharmaceutical components have significant biological activities and are beneficial for several chronic disorders, including cancer. Recent research has focused primarily on isolating, synthesizing, and studying the effects of flavonoids on human health. Here we have attempted to summarize our current knowledge of flavonoids, focusing on their mode of action to better understand their effects on cancer.

Synthesis, characterization, computational studies and in vitro antiparasitic activity of novel flavanoidal-1,2,4,5-tetrazinane-6'-thione.

Keeping in view the growing resistance of conventional antiparasitic drugs, this study aimed to synthesize a series of six noble flavanoidal tetrazinane-6'-thione derivatives by employing a facile one pot reaction pathway. Structural characterizations of synthesized compounds were performed by using IR, 1HNMR, 13CNMR and LC-MS spectra. Molecular docking study showed that one of the newly synthesized compounds strongly bind with the amino residues of BSA with two hydrogen bonding interactions. Physiological properties, pharmacokinetic properties (ADME) and toxicity of all synthesized compounds was carried out using Molinspiration and pkCSM softwares. DFT calculations were performed for all synthesized compounds using B3LYP method to obtain various molecular properties. Using a previously established model for parasitic infections, Clinostomum complanatum we showed that the newly synthesized compounds have a very potent parasitic activity. To elucidate the possible mechanisms, we tested the exposed parasites and observed a perturbation in lipid peroxidation and the antioxidant enzyme superoxide dismutase. Implications of this are discussed in the light of development of these molecules as antiparasitic drugs. HIGHLIGHTSSix noble flavanoidal-1,2,4,5-tetrazinane-6'-thiones (7-12) were synthesized using flavanone derivatives and thiocarbohydrazide in acetic acid as a reagent in ethanol employing one-pot synthesis.Structural characterization of synthesized compounds was done using IR, 1HNMR, 13CNMR and LC-MS spectra.Physicochemical analysis determined that all synthesized compounds are efficiently absorbed and have good permeability.In silico ADME and Toxic properties were determined for all synthesized compounds.In vitro antiparasitic activity was performed for all synthesized compounds against Clinostomum complanatum.Molecular Docking studies demonstrated the binding interaction with BSA enzyme through hydrogen bonding.Density functional theory (DFT) have been performed to estimate the various molecular properties of the synthesized compounds.Communicated by Ramaswamy H. Sarma.

Kidney Allograft Monitoring by Combining Donor-Derived Cell-Free DNA and Molecular Gene Expression: A Clinical Management Perspective.

Donor-derived cell-free DNA (dd-cfDNA) may safely assess kidney allograft rejection. Molecular Microscope (MMDx®) gene expression may offer increased precision to histology. This single-center retrospective study monitored kidney transplant recipients for rejection at specified time intervals by utilizing creatinine (SCr), proteinuria, donor-specific antibodies (DSAs), and dd-cfDNA. A clinically indicated biopsy sample was sent for histopathology and MMDx®. Patients were categorized into rejection (Rej) and non-rejection (NRej) groups, and further grouped according to antibody-mediated rejection (ABMR) subtypes. Rej and NRej groups included 52 and 37 biopsies, respectively. Median follow-up duration was 506 days. DSAs were positive in 53% and 22% of patients in both groups, respectively (p = 0.01). Among these groups, pre- and post-intervention median SCr, proteinuria, and dd-cfDNA at 1 month, 2 months, and at the last follow-up revealed significant difference for dd-cfDNA (all p = 0.01), however, no difference was found for SCr and proteinuria (p > 0.05). The AUC was 0.80 (95% CI: 0.69-0.91), with an optimal dd-cfDNA criterion of 2.2%. Compared to histology, MMDx® was more likely to diagnose ABMR (79% vs. 100%) with either C4d positivity or negativity and/or DSA positivity or negativity. Hence, a pre- and post-intervention allograft monitoring protocol in combination with dd-cfDNA, MMDx®, and histology has aided in early diagnosis and timely individualized intervention.