CT Myocardial Perfusion and CT-FFR versus Invasive FFR for Hemodynamic Relevance of Coronary Artery Disease.

Background CT-derived fractional flow reserve (CT-FFR) and dynamic CT myocardial perfusion imaging enhance the specificity of coronary CT angiography (CCTA) for ruling out coronary artery disease (CAD). However, evidence on comparative diagnostic value remains scarce. Purpose To compare the diagnostic accuracy of CCTA plus CT-FFR, CCTA plus CT perfusion, and sequential CCTA plus CT-FFR and CT perfusion for detecting hemodynamically relevant CAD with that of invasive angiography. Materials and Methods This secondary analysis of a prospective study included patients with chest pain referred for invasive coronary angiography at nine centers from July 2016 to September 2019. CCTA and CT perfusion were performed with third-generation dual-source CT scanners. CT-FFR was assessed on-site. Independent core laboratories analyzed CCTA alone, CCTA plus CT perfusion, CCTA plus CT-FFR, and a sequential approach involving CCTA plus CT-FFR and CT perfusion for the presence of hemodynamically relevant stenosis. Invasive coronary angiography with invasive fractional flow reserve was the reference standard. Diagnostic accuracy metrics and the area under the receiver operating characteristic curve (AUC) were compared with the Sign test and DeLong test. Results Of the 105 participants (mean age, 64 years ± 8 [SD]; 68 male), 49 (47%) had hemodynamically relevant stenoses at invasive coronary angiography. CCTA plus CT-FFR and CCTA plus CT perfusion showed no evidence of a difference for participant-based sensitivities (90% vs 90%, P > .99), specificities (77% vs 79%, P > .99) and vessel-based AUCs (0.84 [95% CI: 0.77, 0.91] vs 0.83 [95% CI: 0.75, 0.91], P = .90). Both had higher participant-based specificity than CCTA alone (54%, both P < .001) without evidence of a difference in sensitivity between CCTA (94%) and CCTA plus CT perfusion (P = .50) or CCTA plus CT-FFR (P = .63). The sequential approach combining CCTA plus CT-FFR with CT perfusion achieved higher participant-based specificity than CCTA plus CT-FFR (88% vs 77%, P = .03) without evidence of a difference in participant-based sensitivity (88% vs 90%, P > .99) and vessel-based AUC (0.85 [95% CI: 0.77, 0.93], P = .78). Compared with CCTA plus CT perfusion, the sequential approach showed no evidence of a difference in participant-based sensitivity (P > .99), specificity (P = .06), or vessel-based AUC (P = .54). Conclusion There was no evidence of a difference in diagnostic accuracy between CCTA plus CT-FFR and CCTA plus CT perfusion for detecting hemodynamically relevant CAD. A sequential approach combining CCTA plus CT-FFR with CT perfusion led to improved participant-based specificity with no evidence of a difference in sensitivity compared with CCTA plus CT-FFR. ClinicalTrials.gov registration no.: NCT02810795 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Sinitsyn in this issue.

Genome-wide analysis of hepatic DNA methylation reveals impact of epigenetic aging on xenobiotic metabolism and transport genes in an aged mouse model.

Hepatic xenobiotic metabolism and transport decline with age, while intact xenobiotic metabolism is associated with longevity. However, few studies have examined the genome-wide impact of epigenetic aging on these processes. We used reduced representation bisulfite sequencing (RRBS) to map DNA methylation changes in liver DNA from mice ages 4 and 24 months. We identified several thousand age-associated differentially methylated sites (a-DMS), many of which overlapped genes encoding Phase I and Phase II drug metabolizing enzymes, in addition to ABC and SLC classes of transporters. Notable genes harboring a-DMS were Cyp1a2, Cyp2d9, and Abcc2 that encode orthologs of the human drug metabolizing enzymes CYP1A2 and CYP2D6, and the multidrug resistance protein 2 (MRP2) transporter. Cyp2d9 hypermethylation with age was significantly associated with reduced gene expression, while Abcc2 expression was unchanged with age. Cyp1a2 lost methylation with age while, counterintuitively, its expression also reduced with age. We hypothesized that age-related dysregulation of the hepatic transcriptional machinery caused down-regulation of genes despite age-related hypomethylation. Bioinformatic analysis of hypomethylated a-DMS in our sample found them to be highly enriched for hepatic nuclear factor 4 alpha (HNF4α) binding sites. HNF4α promotes Cyp1a2 expression and is downregulated with age, which could explain the reduction in Cyp1a2 expression. Overall, our study supports the broad impact of epigenetic aging on xenobiotic metabolism and transport. Future work should evaluate the interplay between hepatic nuclear receptor function and epigenetic aging. These results may have implications for studies of longevity and healthy aging.

Socioeconomic inequalities in cervical cancer mortality in Canada, 1990 and 2019: a trend analysis.

OBJECTIVE: It is increasingly recognized that those of lower socioeconomic status (SES) are disproportionately affected by cancer mortality. The association between cervical cancer mortality and SES have been reported; however, it remains poorly understood in the Canadian population. Thus, this study investigates trends in income and education inequalities in cervical cancer mortality in Canada over the last three decades. STUDY DESIGN: Trend analysis. METHODS: A dataset constructed at the census division level (n = 280), comprising the Canadian Vital Statistics Death Database, the Canadian Census of Population, and the National Household Survey was used to measure cervical cancer mortality in Canada. Income and education inequalities in cervical cancer mortality were measured using age-standardized Concentration index (C). RESULTS: Crude cervical cancer mortality rates decreased significantly during the study period. Age-standardized C values were negative for the majority of years for income and education inequalities, reaching significance in some years. Trend analyses indicated an increasing concentration of cervical cancer mortality amongst those with lower education levels. CONCLUSION: Despite recent decreases in cervical cancer mortality rates, socioeconomic inequalities in cervical cancer mortality in Canada are persistent. Notably, those of lower income and education levels are disproportionately affected, underscoring an opportunity to improve clinical outcomes by addressing these inequalities.

Ketamine Produces Antidepressant Effects by Inhibiting Histone Deacetylases and Upregulating Hippocampal Brain-Derived Neurotrophic Factor Levels in a Diisopropyl Fluorophosphate-Based Rat Model of Gulf War Illness.

Approximately one-third of Gulf War veterans suffer from Gulf War Illness (GWI), which encompasses mood disorders and depressive symptoms. Deployment-related exposure to organophosphate compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased brain-derived neurotrophic factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the Food and Drug Administration for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET's antidepressant effect in GWI-related depression. Here, we investigated whether KET's effect on histone mechanisms signals BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once daily with diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c., 5 days). At 6 months following DFP exposure, KET (10 mg/kg, i.p.) was injected, and brains were dissected 24 hours later. Western blotting was used for protein expression, and epigenetic studies used chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of histone deacetylase (HDAC) enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the Bdnf promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET's actions involve the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathologic synaptic plasticity and exerts an antidepressant effect in DFP rats. SIGNIFICANCE STATEMENT: This study offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated brain-derived neurotrophic factor expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.

Lemon extract supported green synthesis of bimetallic CuO/Ag nanoporous materials for sensitive detection of vitamin D3.

In modern era, deficiency of Vitamin D3 is predominantly due to limited exposure to sunlight and UV radiation resulting from indoor lifestyles. Several studies have revealed that vitamin D deficiency can lead to chronic vascular inflammation, diabetes mellitus, hypertension, congestive left ventricular hypertrophy, and heart failure. This study introduces a green synthesis of novel bimetallic nanoporous composite, CuO/Ag using lemon extract. The synthesized nanoporous material, CuO/Ag@lemon extract was characterized using several analytical techniques, including X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX). The CuO/Ag@lemon extract nanoparticles were immobilized on glassy carbon electrode (GCE) to prepare modified CuO/Ag@lemon extract-GCE interface. The electrocatalytic and electrochemical properties investigation was carried out on the modified electrode. using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and amperometry for detecting of Vitamin D3. The DPV method displayed a linear response range of 0.02-22.5 µM with a detection limit of 2.62 nM, while the amperometric method showed a broader linear range of 0.25-23.25 µM with a detection limit of 2.70 nM with 82% modified electrode stability. The designed electrode exhibited a positive response to the inclusion of Vitamin D3 with electro-oxidation, reaching steady-state within 3.4 s, with 87% reproducibility within a day. The proposed method offers a rapid and sensitive platform for detection of Vitamin D3 with minimal interference from other molecules. The early diagnosis of Vitamin D3 deficiency using modified electrodes allows for early treatment, thereby preventing severe health complications.

Osteoporosis and fracture as risk factors for self-harm and suicide: a systematic review and meta-analysis.

BACKGROUND: Increase in presentations of self-harm to primary care, a risk factor of suicide, has led to a growing interest in identifying at-risk populations. AIM: To examine whether osteoporosis or fractures are risk factors for self-harm, suicidal ideation, and suicide. DESIGN AND SETTING: This was a systematic review of observational studies in adults (>18 years) that had examined the role of osteoporosis and/or fractures in subsequent self-harm, suicidal ideation, and/or suicide. METHOD: Six databases were searched from inception to July 2019. Additional citation tracking of eligible studies was undertaken in November 2022. Screening, data extraction, and quality assessment of full-text articles were performed independently by at least two authors. Where possible, meta-analysis was run on comparable risk estimates. RESULTS: Fifteen studies were included: two examined the outcome of self-harm, three suicidal ideation, and 10 suicide. In approximately half of studies on osteoporosis, the risk of suicidal ideation and suicide remained significant. However, pooling of adjusted odds ratios from three studies indicated no association between osteoporosis and suicide (1.14, 95% confidence interval = 0.88 to 1.49). Nine studies examined the risk of a mixture of fracture types across different outcomes, limiting comparisons. However, all studies examining vertebral fracture (n = 3) reported a significant adjusted negative association for self-harm and suicide. CONCLUSION: Patients with vertebral fractures, a risk potential factor for suicide, may benefit from clinical case finding for mood disorders with personalised primary care management. However, because of the limited number and quality of studies and mixed findings, further examination of these associations is warranted.

Association of Migraine Headache With Depression, Anxiety, and Stress in the Population of Makkah City, Saudi Arabia: A Cross-Sectional Study.

Introduction Migraine is characterized by persistent headaches and a wide range of symptoms, such as nausea, vomiting, and photophobia. The chance of developing a chronic migraine might be increased by lifestyle variables like obesity, stress, and excessive medication use. According to previous studies in Saudi Arabia, migraines are more common there than they are globally. The study aimed to examine the migraine associations with depression, anxiety, and stress in the population of Makkah City, Saudi Arabia. Methods The study employed a descriptive cross-sectional design with a non-probability snowball sampling technique and an online questionnaire that included sociodemographic characteristics, the International Classification of Headache Disorders-3 (ICHD-3) criteria for migraine assessment, and the Depression, Anxiety, and Stress Scale-21 (DASS-21) measure for depression, anxiety, and stress. Results Our study included 418 participants, out of whom 73.7% were female and 26.3% were male. Regarding migraine, only 8.9% of participants met the ICHD-3 criteria for migraine headache screening, with a female predominance (78.4%). The study showed a high prevalence of depression, anxiety, and stress among the population (63.9%, 63.6%, and 55%, respectively), with females having a higher prevalence. Depression, anxiety, and stress had an equal prevalence of 78.4% among migraineurs, which was significantly higher than that of non-migraineurs. Conclusions The study found significant associations between migraine and depression, anxiety, and stress. This study provides insights into the association between these conditions. The study's findings suggest the need for screening and management of mental health conditions in patients with migraine. However, extensive efforts are needed to be applied in different cities and demographics for a more precise understanding of the association.

Universal pre-mixing dry-film stickers capable of retrofitting existing microfluidics.

Integrating microfluidic mixers into lab-on-a-chip devices remains challenging yet important for numerous applications including dilutions, extractions, addition of reagents or drugs, and particle synthesis. High-efficiency mixers utilize large or intricate geometries that are difficult to manufacture and co-implement with lab-on-a-chip processes, leading to cumbersome two-chip solutions. We present a universal dry-film microfluidic mixing sticker that can retrofit pre-existing microfluidics and maintain high mixing performance over a range of Reynolds numbers and input mixing ratios. To attach our pre-mixing sticker module, remove the backing material and press the sticker onto an existing microfluidic/substrate. Our innovation centers around the multilayer use of laser-cut commercially available silicone-adhesive-coated polymer sheets as microfluidic layers to create geometrically complex, easy to assemble designs that can be adhered to a variety of surfaces, namely, existing microfluidic devices. Our approach enabled us to assemble the traditional yet difficult to manufacture "F-mixer" in minutes and conceptually extend this design to create a novel space-saving spiral F-mixer. Computational fluid dynamic simulations and experimental results confirmed that both designs maintained high performance for 0.1 < Re < 10 and disparate input mixing ratios of 1:10. We tested the integration of our system by using the pre-mixer to fluorescently tag proteins encapsulated in an existing microfluidic. When integrated with another microfluidic, our pre-mixing sticker successfully combined primary and secondary antibodies to fluorescently tag micropatterned proteins with high spatial uniformity, unlike a traditional pre-mixing "T-mixer" sticker. Given the ease of this technology, we anticipate numerous applications for point-of-care devices, microphysiological-systems-on-a-chip, and microfluidic-based biomedical research.

Rapid fractionation of mitochondria from mouse liver and heart reveals in vivo metabolite compartmentation.

The compartmentation and distribution of metabolites between mitochondria and the rest of the cell is a key parameter of cell signalling and pathology. Here, we have developed a rapid fractionation procedure that enables us to take mouse heart and liver from in vivo and within ~ 30 s stabilise the distribution of metabolites between mitochondria and the cytosol by rapid cooling, homogenisation and dilution. This is followed by centrifugation of mitochondria through an oil layer to separate mitochondrial and cytosolic fractions for subsequent metabolic analysis. Using this procedure revealed the in vivo compartmentation of mitochondrial metabolites and will enable the assessment of the distribution of metabolites between the cytosol and mitochondria during a range of situations in vivo.

Wall shear stress-related plaque growth of lipid-rich plaques in human coronary arteries: an near-infrared spectroscopy and optical coherence tomography study.

AIMS: Low wall shear stress (WSS) is acknowledged to play a role in plaque development through its influence on local endothelial function. Also, lipid-rich plaques (LRPs) are associated with endothelial dysfunction. However, little is known about the interplay between WSS and the presence of lipids with respect to plaque progression. Therefore, we aimed to study the differences in WSS-related plaque progression between LRPs, non-LRPs, or plaque-free regions in human coronary arteries. METHODS AND RESULTS: In the present single-centre, prospective study, 40 patients who presented with an acute coronary syndrome successfully underwent near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) of at least one non-culprit vessel at baseline and completed a 1-year follow-up. WSS was computed applying computational fluid dynamics to a three-dimensional reconstruction of the coronary artery based on the fusion of the IVUS-segmented lumen with a CT-derived centreline, using invasive flow measurements as boundary conditions. For data analysis, each artery was divided into 1.5 mm/45° sectors. Plaque growth based on IVUS-derived percentage atheroma volume change was compared between LRPs, non-LRPs, and plaque-free wall segments, as assessed by both OCT and NIRS. Both NIRS- and OCT-detected lipid-rich sectors showed a significantly higher plaque progression than non-LRPs or plaque-free regions. Exposure to low WSS was associated with a higher plaque progression than exposure to mid or high WSS, even in the regions classified as a plaque-free wall. Furthermore, low WSS and the presence of lipids had a synergistic effect on plaque growth, resulting in the highest plaque progression in lipid-rich regions exposed to low shear stress. CONCLUSION: This study demonstrates that NIRS- and OCT-detected lipid-rich regions exposed to low WSS are subject to enhanced plaque growth over a 1-year follow-up. The presence of lipids and low WSS proves to have a synergistic effect on plaque growth.

Mitochondrial metabolism and bioenergetic function in an anoxic isolated adult mouse cardiomyocyte model of in vivo cardiac ischemia-reperfusion injury.

Cell models of cardiac ischemia-reperfusion (IR) injury are essential to facilitate understanding, but current monolayer cell models poorly replicate the in vivo IR injury that occurs within a three-dimensional tissue. Here we show that this is for two reasons: the residual oxygen present in many cellular hypoxia models sustains mitochondrial oxidative phosphorylation; and the loss of lactate from cells into the incubation medium during ischemia enables cells to sustain glycolysis. To overcome these limitations, we incubated isolated adult mouse cardiomyocytes anoxically while inhibiting lactate efflux. These interventions recapitulated key markers of in vivo ischemia, notably the accumulation of succinate and the loss of adenine nucleotides. Upon reoxygenation after anoxia the succinate that had accumulated during anoxia was rapidly oxidized in association with extensive mitochondrial superoxide/hydrogen peroxide production and cell injury, mimicking reperfusion injury. This cell model will enable key aspects of cardiac IR injury to be assessed in vitro.

Repeated exposure to chlorpyrifos is associated with a dose-dependent chronic neurobehavioral deficit in adult rats.

Organophosphate (OP) chemicals include commonly used pesticides and chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. Epidemiological studies report long-term neuropsychiatric issues, including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of an acute high-dose CPF (30-250 mg/kg) or studied sub-chronic behavioral effects, particularly the motor and cognitive effects of repeated low-dose CPF. However, studies are lacking on chronic mood and depression-related morbidities following repeated CPF doses that would mimic occupationally relevant OP exposures during adulthood. In this study, adult male rats were injected with CPF (1, 3, 5, or 10 mg/kg/d, s.c.) for 21 consecutive days. Dependent on the CPF dose, ChE activity was inhibited approximately 60-80% in the blood and about 20-50% in the hippocampus at 2-days after the end of CPF exposures. Following a 12-week washout period, a complete recovery of ChE activity was noted. However, CPF-treated rats exhibited a dose-dependent increase in signs related to anhedonia (sucrose preference test), anxiety (open-field and elevated plus-maze), and despair (forced swim test) at this stage. To the best of our knowledge, this could be the first laboratory study that demonstrates a cause-effect relationship between occupational-like CPF exposures in adult rats and the development of long-term depression-related outcomes and could provide an experimental system to study molecular mechanisms underlying environmental OP exposures and the elevated risk for chronic behavioral deficits.

Dynamic Myocardial Perfusion CT for the Detection of Hemodynamically Significant Coronary Artery Disease.

OBJECTIVES: In this international, multicenter study, using third-generation dual-source computed tomography (CT), we investigated the diagnostic performance of dynamic stress CT myocardial perfusion imaging (CT-MPI) in addition to coronary CT angiography (CTA) compared to invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR). BACKGROUND: CT-MPI combined with coronary CTA integrates coronary artery anatomy with inducible myocardial ischemia, showing promising results for the diagnosis of hemodynamically significant coronary artery disease in single-center studies. METHODS: At 9 centers in Europe, Japan, and the United States, 132 patients scheduled for ICA were enrolled; 114 patients successfully completed coronary CTA, adenosine-stress dynamic CT-MPI, and ICA. Invasive FFR was performed in vessels with 25% to 90% stenosis. Data were analyzed by independent core laboratories. For the primary analysis, for each coronary artery the presence of hemodynamically significant obstruction was interpreted by coronary CTA with CT-MPI compared to coronary CTA alone, using an FFR of ≤0.80 and angiographic severity as reference. Territorial absolute myocardial blood flow (MBF) and relative MBF were compared using C-statistics. RESULTS: ICA and FFR identified hemodynamically significant stenoses in 74 of 289 coronary vessels (26%). Coronary CTA with ≥50% stenosis demonstrated a per-vessel sensitivity, specificity, and accuracy for the detection of hemodynamically significant stenosis of 96% (95% CI: 91%-100%), 72% (95% CI: 66%-78%), and 78% (95% CI: 73%-83%), respectively. Coronary CTA with CT-MPI showed a lower sensitivity (84%; 95% CI: 75%-92%) but higher specificity (89%; 95% CI: 85%-93%) and accuracy (88%; 95% CI: 84%-92%). The areas under the receiver-operating characteristic curve of absolute MBF and relative MBF were 0.79 (95% CI: 0.71-0.86) and 0.82 (95% CI: 0.74-0.88), respectively. The median dose-length product of CT-MPI and coronary CTA were 313 mGy·cm and 138 mGy·cm, respectively. CONCLUSIONS: Dynamic CT-MPI offers incremental diagnostic value over coronary CTA alone for the identification of hemodynamically significant coronary artery disease. Generalized results from this multicenter study encourage broader consideration of dynamic CT-MPI in clinical practice. (Dynamic Stress Perfusion CT for Detection of Inducible Myocardial Ischemia [SPECIFIC]; NCT02810795).

CT-derived fractional flow reserve (FFRct) for functional coronary artery evaluation in the follow-up of patients after heart transplantation.

OBJECTIVES: Invasively measured fractional flow reserve (FFR) is associated with outcome in heart transplant (HTx) patients. Coronary computed tomography angiography (CCTA)-derived FFR (FFRct) provides additional functional information from anatomical CT images. We describe the first use of FFRct in HTx patients. METHODS: HTx patients underwent CCTA with FFRct to screen for cardiac allograft vasculopathy. FFRct was measured distal to each coronary stenosis > 30% and FFRct ≤ 0.8 indicated hemodynamically significant stenosis. FFRct was also measured at the most distal location of each vessel. Overall distal FFRct was calculated as the mean of the distal values in the left, right, and circumflex coronary artery in each patient. RESULTS: Seventy-three patients (age 56 (42-65) years, 63% males) at 11 (8-16) years after HTx were included. Eighteen (25%) patients had a focal hemodynamically significant stenosis (stenosis > 30% with FFRct ≤ 0.8). In the 55 patients without a hemodynamically significant focal FFRct stenosis (FFRct > 0.80), the distal left anterior descending artery FFRct was < 0.90 in 74% of the patients and 10 (18%) patients had ≥ 1 coronary artery with a distal FFRct ≤ 0.8, including 1 with a distal FFRct ≤ 0.8 in all coronaries. Overall distal FFRct in patients without focal stenosis was 0.88 (0.86-0.91), 0.87 (0.86-0.90), and 0.88 (0.86-0.91) (median with 25th-75th percentile) at 5-9, 10-14, or ≥ 15 years post-transplantation, respectively (p = 0.93). CONCLUSIONS: FFRct performed on CCTA scans of HTx patients demonstrated that 25% of patients had a focal coronary stenosis with FFRct ≤ 0.8. Even without a focal stenosis, FFRct values are often abnormal in HTx patients. KEY POINTS: • This is the first report describing the use of FFRct in in heart transplant patients. • FFRct identifies patients after heart transplantation with hemodynamically significant coronary stenosis. • Even without a focal stenosis, FFRct values are often abnormal in heart transplant patients.

Histone acetylation at the sulfotransferase 1a1 gene is associated with its hepatic expression in normal aging.

OBJECTIVES: Phase II drug metabolism is poorly studied in advanced age and older adults may exhibit significant variability in their expression of phase II enzymes. We hypothesized that age-related changes to epigenetic regulation of genes involved in phase II drug metabolism may contribute to these effects. METHODS: We examined published epigenome-wide studies of human blood and identified the SULT1A1 and UGT1A6 genes as the top loci showing epigenetic changes with age. To assess possible functional alterations with age in the liver, we assayed DNA methylation (5mC) and histone acetylation changes around the mouse homologs Sult1a1 and Ugt1a6 in liver tissue from mice aged 4-32 months. RESULTS: Our sample shows a significant loss of 5mC at Sult1a1 (ß = -1.08, 95% CI [-1.8, -0.2], SE = 0.38, P = 0.011), mirroring the loss of 5mC with age observed in human blood DNA at the same locus. We also detected increased histone 3 lysine 9 acetylation (H3K9ac) with age at Sult1a1 (ß = 0.11, 95% CI [0.002, 0.22], SE = 0.05, P = 0.04), but no change to histone 3 lysine 27 acetylation (H3K27ac). Sult1a1 gene expression is significantly positively associated with H3K9ac levels, accounting for 23% of the variation in expression. We did not detect any significant effects at Ugt1a6. CONCLUSIONS: Sult1a1 expression is under epigenetic influence in normal aging and this influence is more pronounced for H3K9ac than DNA methylation or H3K27ac in this study. More generally, our findings support the relevance of epigenetics in regulating key drug-metabolizing pathways. In the future, epigenetic biomarkers could prove useful to inform dosing in older adults.

Clinical implementation of coronary computed tomography angiography for routine detection of cardiac allograft vasculopathy in heart transplant patients.

Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects long-term outcomes in heart transplant (HTx) patients. We prospectively evaluated the feasibility of coronary computed tomography angiography (CCTA) for the detection of CAV during clinical implementation at our center. All consecutive HTx patients >4 years post-transplant were actively converted from myocardial perfusion imaging to CCTA for the annual assessment of CAV. Between February 2018 and May 2019, 129/172 (75%) HTx patients underwent a CCTA. Renal impairment (n = 21/43) was the most frequent reason for patients could not undergo CCTA. CCTA image quality was good-excellent in 118/129 (92%) patients, and the radiation dose was 2.1 (1.6-2.8) mSv. CCTA showed obstructive CAV in 19/129 (15%) patients. Thirteen (10%) patients underwent additional tests, of which 8 patients underwent coronary revascularization within 90 days of CCTA. After 1 year, 3 additional coronary angiograms were performed, resulting in one revascularization in a patient with known severe CAV who developed ventricular tachycardia. One myocardial infarction after coronary stenting and 2 non-cardiac deaths were observed. CCTA can be successfully implemented for routine detection of CAV with good image quality and low radiation dose. CCTA allows CAV evaluation with the limited need for additional invasive testing.

Epigenetic histone acetylation and Bdnf dysregulation in the hippocampus of rats exposed to repeated, low-dose diisopropylfluorophosphate.

AIMS: Deployment-related exposures to organophosphate (OP) compounds are implicated for Gulf War Illness (GWI) development in First GW veterans. However, reasons for the persistence of GWI are not fully understood. Epigenetic modifications to chromatin are regulatory mechanisms that can adaptively or maladaptively respond to external stimuli. These include DNA methylation and histone acetylation. DNA methylation changes have been reported in GWI but the role of histone acetylation in GWI has been less explored, despite its importance as an epigenetic mechanism for neurological disorders. MAIN METHODS: Male Sprague-Dawley rats were exposed to OP diisopropyl fluorophosphate (DFP, 0.5 mg/kg s.c., 5-d) and 6-m later brains were dissected for hippocampus. Western blotting, activity assays and chromatin immunoprecipitation (ChIP) were utilized for epigenetic analyses. Behavior was assessed using the Forced Swim Test (FST) and the Elevated Plus Maze (EPM). KEY FINDINGS: We observed a significant upregulation in HDAC1 protein along with a significant increase in HDAC enzyme activity in the hippocampus of DFP rats. A locus-specific ChIP study revealed decreases in H3K9ac at the brain derived neurotrophic factor (Bdnf) promoter IV coupled with a significant decrease in BDNF protein in DFP rat hippocampus. Treatment with HDAC inhibitor valproic acid reduced HDAC activity and decreased the FST immobility time in DFP rats. SIGNIFICANCE: Our research suggests that epigenetic alterations to histone acetylation pathways and decreased BDNF expression could represent novel mechanisms for GWI symptomatology and may provide new targets for developing effective drugs for GWI treatment.

A Phase II Study of Biodegradable Stents Plus Palliative Radiotherapy in Oesophageal Cancer.

AIMS: Self-expanding metal stents provide rapid improvement of dysphagia in oesophageal cancer but are associated with complications. The aim of the present study was to test the effectiveness of an alternative treatment of combining biodegradable stents with radiotherapy. MATERIALS AND METHODS: A Simon two-stage single-arm prospective phase II trial design was used to determine the efficacy of biodegradable stents plus radiotherapy in patients with dysphagia caused by oesophagus cancer who were unsuitable for radical treatment. Fourteen patients were recruited and data from 12 were included in the final analyses. RESULTS: Five of 12 patients met the primary end point: one stent-related patient death; four further interventions for dysphagia within 16 weeks of stenting (41.7%, 95% confidence interval 15.2-72.3%). The median time to a 10-point deterioration of quality of life was 2.7 weeks. Nine patients died within 52 weeks of registration. The median time to death from any cause was 15.0 weeks (95% confidence interval 9.6-not reached). CONCLUSION: The high re-intervention observed, which met the pre-defined early stopping criteria, meant that the suggested alternative treatment was not sufficiently effective to be considered for a larger scale trial design. Further work is needed to define the place of biodegradable stents in the management of malignant oesophageal strictures.

Molecular mechanisms for the antidepressant-like effects of a low-dose ketamine treatment in a DFP-based rat model for Gulf War Illness.

Exposure to organophosphates (OP) during the First Gulf War is among one of the factors for Gulf War Illness (GWI) development in veterans and it has been challenging to treat GWI symptoms with existing therapies. Ketamine produces a rapid-onset and sustained antidepressant response, but there is no evidence whether ketamine treatment is effective for GWI depression. Repeated, low-dose exposure to diisopropyl fluorophosphate (DFP) mimic Gulf War related OP exposures and produces a chronic depressive state in rats. In this study, DFP-exposed rats treated with ketamine (10 mg/kg, i.p.) exhibited antidepressant-like effect on the Forced Swim Test at 1-h. This effect persisted at 24-h post ketamine, a time-point by which it is eliminated from the brain suggesting involvement of mechanisms that affect long-term synaptic plasticity. Western blot analysis showed significantly lower Brain-Derived Neurotrophic Factor (BDNF) levels in DFP rat brains. Ketamine produced a nonsignificant increase in BDNF expression at 1-h but produced a larger, significant (2.2-fold) increase at 24-h in DFP rats. We previously reported chronic hippocampal calcium elevations ([Ca2+]i) in DFP rats. Ketamine-treated DFP rats exhibited significantly lower [Ca2+]i at 1-h but not at 24-h. Interestingly, treatment with ANA-12, a TrkB-BDNF receptor antagonist, in DFP rats blunted ketamine's antidepressant-like effect at 24-h but not at 1-h. These experiments suggest that in a rat model of DFP-induced depression, inhibition of the NMDAR-Ca2+ contributes to the rapid-onset antidepressant effects of ketamine while the antidepressant actions that persisted at 24-h post ketamine administration involve upregulation of BDNF signaling.