Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network.

Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.

Crystal Structure and Mechanistic Molecular Modeling Studies of Mycobacterium tuberculosis Diterpene Cyclase Rv3377c.

Terpenes make up the largest class of natural products, with extensive chemical and structural diversity. Diterpenes, mostly isolated from plants and rarely prokaryotes, exhibit a variety of important biological activities and valuable applications, including providing antitumor and antibiotic pharmaceuticals. These natural products are constructed by terpene synthases, a class of enzymes that catalyze one of the most complex chemical reactions in biology: converting simple acyclic oligo-isoprenyl diphosphate substrates to complex polycyclic products via carbocation intermediates. Here we obtained the second ever crystal structure of a class II diterpene synthase from bacteria, tuberculosinol pyrophosphate synthase (i.e., Halimadienyl diphosphate synthase, MtHPS, or Rv3377c) from Mycobacterium tuberculosis (Mtb). This enzyme transforms (E,E,E)-geranylgeranyl diphosphate into tuberculosinol pyrophosphate (Halimadienyl diphosphate). Rv3377c is part of the Mtb diterpene pathway along with Rv3378c, which converts tuberculosinol pyrophosphate to 1-tuberculosinyl adenosine (1-TbAd). This pathway was shown to exist only in virulent Mycobacterium species, but not in closely related avirulent species, and was proposed to be involved in phagolysosome maturation arrest. To gain further insight into the reaction pathway and the mechanistically relevant enzyme substrate binding orientation, electronic structure calculation and docking studies of reaction intermediates were carried out. Results reveal a plausible binding mode of the substrate that can provide the information to guide future drug design and anti-infective therapies of this biosynthetic pathway.

Enlarged hippocampal fissure in psychosis of epilepsy.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase.

The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined "pseudolaratriene." Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono- and sesqui-terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene.

The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.

The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. Acute evaluation with blood, imaging and electroencephalographic monitoring will be performed and then patients will be tracked for 2 years to determine the incidence of PTE. Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies.

Outcomes of complex Descemet Stripping Endothelial Keratoplasty performed by cornea fellows.

BACKGROUND: A major obstacle that academic institutions face is the steep learning curve for cornea fellows initially learning to perform Descemet Stripping Endothelial Keratoplasty (DSEK). The purpose of this study is to evaluate the outcomes of complex DSEK performed by cornea fellow supervised by an attending surgeon at an academic institution. METHODS: Patients who underwent a complex DSEK procedure performed by a cornea fellow during the years 2009-2013 were included. All the surgeries were supervised by the same cornea attending. All patients had a minimum follow-up of 6 months. Charts were reviewed for demographic data, intraoperative and postoperative complications and clinical outcomes. Corneal graft survival was calculated using the Kaplan-Meier analysis. RESULTS: Fifty-seven eyes of 55 patients (mean age 77.5 ± 8.5 years) were included in the study with a mean follow-up time of 16.4 ± 15.6 months. Previous graft failure, presence of a tube and history of trabeculectomy were the leading diagnoses to define the surgery as complex. No intraoperative complications occurred. In 21.1% of cases a corneal graft detachment was documented in the first postoperative day. Mean visual acuity improved from 1.06 LogMAR (20/230) preoperatively to 0.39 LogMAR (20/50, p < 0.001) by the sixth postoperative month and to 0.52 LogMAR (20/65, p < 0.001) at the last follow-up visit. Graft failure rate was 29.8%. Kaplan-Meier analysis found a 67.2% graft survival rate at 20 months. CONCLUSIONS: Complex DSEK can be performed successfully with an acceptable postoperative complication rate by cornea fellows during their training period when supervised by an experienced attending.

Comparison of graft survival following penetrating keratoplasty and Descemet's stripping endothelial keratoplasty in eyes with a glaucoma drainage device.

PURPOSE: To compare corneal graft survival rates after penetrating keratoplasty (PK) and Descemet's stripping endothelial keratoplasty (DSEK) in patients with a glaucoma drainage device (GDD) or medically managed glaucoma. METHODS: A retrospective chart review was conducted on consecutive patients who underwent primary PK or primary DSEK. Inclusion criteria consisted of eyes with a diagnosis of glaucoma prior to corneal transplantation and a minimum of 6 months of follow-up. Graft failure was defined as an edematous cornea with failure to maintain deturgescence lasting beyond a period of 1 month of intense steroid therapy or vascularization and scarring resulting in irreversible loss of central graft clarity. Corneal graft survival was calculated using Kaplan-Meier survival analysis. Patients were divided into four groups: GDD-PK, GDD-DSEK, medical-PK and medical-DSEK. RESULTS: Fifty-six eyes of 56 patients were identified as meeting inclusion criteria. Among eyes with a GDD, there was no difference in the proportion of failures between PK grafts (48%) and DSEK grafts (50%) (p = 0.90). Failure occurred earlier in DSEK recipients compared to PK recipients, 5.82 ± 6.77 months versus 14.40 ± 7.70 months, respectively (p = 0.04). A Kaplan-Meier analysis did not identify a difference between the four groups with respect to graft failure (p = 0.52). CONCLUSION: There is no significant difference in graft survival rates between medically and surgically treated glaucoma patients for either PK or DSEK grafts. In patients with GDD, graft failure occurs earlier in DSEK compared to PK.

Interleukin-1ß has trophic effects in microglia and its release is mediated by P2X7R pore.

BACKGROUND: Enhanced expression of the purinergic P2X7 receptor (P2X7R) occurs in several neuroinflammatory conditions where increased microglial activation is a co-existing feature. P2X7 receptors can function either as a cation channel or, upon continued stimulation, a large pore. P2X7R-over-expression alone is sufficient to drive microglial activation and proliferation in a process that is P2X7R pore dependent, although the biological signaling pathway through which this occurs remains unclear. Once activated, microglia are known to release a number of bioactive substances that include the proinflammatory cytokine interleukin-1ß (IL-1ß). Previous studies have linked P2X7R stimulation to the processing and release of IL-1ß, but whether the channel or pore state of P2X7R is predominant in driving IL-1ß release is unknown and is a major aim of this study. In addition, we will determine whether IL-1ß has trophic effects on surrounding microglia. METHODS: Electron microscopy and immunohistochemistry were used to delineate the sub-cellular localization of P2X7R and IL-1ß in primary hippocampal rat cultures. FM1-43 fluorescent dye and confocal microscopy were used to quantify vesicular exocytosis from microglia expressing the pore-forming P2X7R versus a non-pore-forming point mutant, P2X7RG345Y. IL-1ß in culture was quantified with an enzyme-linked immunosorbent assay (ELISA). IL-1ß intracellular processing was blocked with inhibition of caspase 1 (with a synthetic peptide antagonist), and its extracellular form was neutralized with an IL-1ß neutralizing antibody. Microglial activation and proliferation was quantified immunohistochemically with confocal microscopy. RESULTS: P2X7R and IL-1ß were co-localized in lysosomes. Vesicular exocytosis was higher in microglia expressing the pore-forming P2X7R compared to those expressing the non-pore-forming mutant. There was increased IL-1ß in cultures expressing the pore-forming P2X7R, and this proinflammatory cytokine was found to mediate the trophic effects of P2X7R pore in microglia. Inhibition of IL-1ß production and function resulted in a significant decrease in P2X7R-mediated microglial activation and proliferation. CONCLUSIONS: IL-1ß is a mediator of microglial activation and proliferation, and its release/production is P2X7R pore dependent. Blockade of P2X7R pore could serve as a therapeutic target in alleviating the degree of inflammation seen in neurodegenerative and neoplastic conditions.

Antiepileptic drug combinations not involving valproate and the risk of fetal malformations.

OBJECTIVE: To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined. METHODS: An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999-2014). RESULTS: Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64%; odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14-3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23-5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025). SIGNIFICANCE: The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.

How we developed a comprehensive resuscitation-based simulation curriculum in emergency medicine.

Over the past decade, simulation-based education has emerged as a new and exciting adjunct to traditional bedside teaching and learning. Simulation-based education seems particularly relevant to emergency medicine training where residents have to master a very broad skill set, and may not have sufficient real clinical opportunities to achieve competence in each and every skill. In 2006, the Emergency Medicine program at Queen's University set out to enhance our core curriculum by developing and implementing a series of simulation-based teaching sessions with a focus on resuscitative care. The sessions were developed in such as way as to satisfy the four conditions associated with optimum learning and improvement of performance; appropriate difficulty of skill, repetitive practice, motivation, and immediate feedback. The content of the sessions was determined with consideration of the national training requirements set out by the Royal College of Physicians & Surgeons of Canada. Sessions were introduced in a stepwise fashion, starting with a cardiac resuscitation series based on the AHA ACLS guidelines, and leading up to a more advanced resuscitation series as staff became more adept at teaching with simulation, and as residents became more comfortable with this style of learning. The result is a longitudinal resuscitation curriculum that begins with fundamental skills of resuscitation and crisis resource management (CRM) in the first 2 years of residency and progresses through increasingly complex resuscitation cases where senior residents are expected to play a leadership role. This paper documents how we developed, implemented, and evaluated this resuscitation-based simulation curriculum for Emergency Medicine postgraduate trainees, with discussion of some of the challenges encountered.

The efficacy of the newer antiepileptic drugs in controlling seizures in pregnancy.

OBJECTIVES: To assess the effectiveness of the newer antiepileptic drugs (AEDs)-in particular lamotrigine, topiramate, and levetiracetam-in controlling epileptic seizures in pregnant women. METHODS: Analysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy concerning seizure control in 1,534 pregnancies in women with AED-treated epilepsies. RESULTS: In AED monotherapy (1,111 pregnancies), use of levetiracetam in pregnancies in the Australian Register was associated with levels of seizure control similar to those that applied for the major older AEDs carbamazepine and valproate, but with levels of seizure control superior to those associated with use of lamotrigine and topiramate. SIGNIFICANCE: Levetiracetam shows promise as a satisfactory drug for controlling seizures in pregnancy.

Computer-Selected Antiviral Compounds: Assessing In Vitro Efficacies against Rift Valley Fever Virus.

Rift Valley fever is a zoonotic viral disease transmitted by mosquitoes, impacting both humans and livestock. Currently, there are no approved vaccines or antiviral treatments for humans. This study aimed to evaluate the in vitro efficacy of chemical compounds targeting the Gc fusion mechanism. These compounds were identified through virtual screening of millions of commercially available small molecules using a structure-based artificial intelligence bioactivity predictor. In our experiments, a pretreatment with small molecule compounds revealed that 3 out of 94 selected compounds effectively inhibited the replication of the Rift Valley fever virus MP-12 strain in Vero cells. As anticipated, these compounds did not impede viral RNA replication when administered three hours after infection. However, significant inhibition of viral RNA replication occurred upon viral entry when cells were pretreated with these small molecules. Furthermore, these compounds exhibited significant inhibition against Arumowot virus, another phlebovirus, while showing no antiviral effects on tick-borne bandaviruses. Our study validates AI-based virtual high throughput screening as a rational approach for identifying effective antiviral candidates for Rift Valley fever virus and other bunyaviruses.

Docking carbocations into terpene synthase active sites using chemically meaningful constraints-The TerDockin approach.

Terpenes are a diverse class of natural products which have long been sought after for their chemical properties as medicine, perfumes, and for food flavoring. Computational docking studies of terpene mechanisms have been a challenge due to the lack of strong directing groups which many docking programs rely on. In this chapter, we dive into our computational method Terdockin (Terpene-Docking) as a successful methodology in modeling terpene synthase mechanisms. This method could also be used as inspiration for any multi-ligand docking project.

Graph Signal Processing, Graph Neural Network and Graph Learning on Biological Data: A Systematic Review.

Graph networks can model data observed across different levels of biological systems that span from population graphs (with patients as network nodes) to molecular graphs that involve omics data. Graph-based approaches have shed light on decoding biological processes modulated by complex interactions. This paper systematically reviews graph-based analysis methods of Graph Signal Processing (GSP), Graph Neural Networks (GNNs) and graph topology inference, and their applications to biological data. This work focuses on the algorithms of graph-based approaches and the constructions of graph-based frameworks that are adapted to a broad range of biological data. We cover the Graph Fourier Transform and the graph filter developed in GSP, which provides tools to investigate biological signals in the graph domain that can potentially benefit from the underlying graph structures. We also review the node, graph, and interaction oriented applications of GNNs with inductive and transductive learning manners for various biological targets. As a key component of graph analysis, we provide a review of graph topology inference methods that incorporate assumptions for specific biological objectives. Finally, we discuss the biological application of graph analysis methods within this exhaustive literature collection, potentially providing insights for future research in biological sciences.

Reduced total number of enlarged perivascular spaces in post-traumatic epilepsy patients with unilateral lesions - a feasibility study.

BACKGROUND: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE+) from chronic TBI patients without PTE (PTE-) in a feasibility study. METHODS: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived. RESULTS: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE+ cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE- cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE+ (M=1.21e-4, IQR [8.89e-5]) and PTE- cases (M=2.79e-4, IQR [6.25e-5]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups. CONCLUSION: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker.

Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

Remodeling of the peripheral cardiac conduction system in response to pressure overload.

How chronic pressure overload affects the Purkinje fibers of the ventricular peripheral conduction system (PCS) is not known. Here, we used a connexin (Cx)40 knockout/enhanced green fluorescent protein knockin transgenic mouse model to specifically label the PCS. We hypothesized that the subendocardially located PCS would remodel after chronic pressure overload and therefore analyzed cell size, markers of hypertrophy, and PCS-specific Cx and ion channel expression patterns. Left ventricular hypertrophy with preserved systolic function was induced by 30 days of surgical transaortic constriction. After transaortic constriction, we observed that PCS cardiomyocytes hypertrophied by 23% (P < 0.05) and that microdissected PCS tissue exhibited upregulated markers of hypertrophy. PCS cardiomyocytes showed a 98% increase in the number of Cx40-positive gap junction particles, with an associated twofold increase in gene expression (P < 0.05). We also identified a 50% reduction in Cx43 gap junction particles located at the interface between PCS cardiomyocytes and the working cardiomyocyte. In addition, we measured a fourfold increase of an ion channel, hyperpolarization-activated cyclic nucleotide-gated channel (HCN)4, throughout the PCS (P < 0.05). As a direct consequence of PCS remodeling, we found that pressure-overloaded hearts exhibited marked changes in ventricular activation patterns during normal sinus rhythm. These novel findings characterize PCS cardiomyocyte remodeling after chronic pressure overload. We identified significant hypertrophic growth accompanied by modified expression of Cx40, Cx43, and HCN4 within PCS cardiomyocytes. We found that a functional outcome of these changes is a failure of the PCS to activate the ventricular myocardium normally. Our findings provide a proof of concept that pressure overload induces specific cellular changes, not just within the working myocardium but also within the specialized PCS.

Coronary CT angiography versus conventional cardiac angiography for therapeutic decision making in patients with high likelihood of coronary artery disease.

PURPOSE: To assess the efficacy of coronary computed tomographic (CT) angiography for therapeutic decision making in patients with high likelihood of coronary artery disease (CAD)-specifically the ability of coronary CT angiography to help differentiate patients without and patients with a need for revascularization and determine the appropriate revascularization procedure. MATERIALS AND METHODS: The study protocol was approved by institutional review board, with written informed consent from all patients. The study was conducted in compliance with HIPAA. One hundred eighty-five consecutive symptomatic patients (121 men; mean age, 59.4 years±9.7) with a positive single photon emission computed tomography (SPECT) myocardial perfusion study underwent coronary CT angiography and conventional cardiac angiography (hereafter, cardiac catheterization). The management strategy (conservative treatment vs revascularization) and revascularization procedure (percutaneous coronary intervention [PCI] vs coronary artery bypass graft surgery [CABG]) were prospectively selected on the basis of a combination of coronary CT angiography and SPECT. In addition, the authors calculated the accuracy, sensitivity, specificity, and negative and positive predictive values of coronary CT angiography in the detection of obstructive CAD and the selection of a revascularization strategy. Cardiac catheterization was used as the standard of reference. RESULTS: Of the 185 patients, 113 (61%) did not undergo revascularization and 42 (23%) were free of CAD. In 178 patients (96%), the same therapeutic strategy (conservative treatment vs revascularization) was chosen on the basis of coronary CT angiography and catheterization. All patients in need of revascularization were identified with coronary CT angiography. When revascularization was indicated, the same procedure (PCI vs CABG) was chosen in 66 of 72 patients (92%). CONCLUSION: In patients with high likelihood of CAD, the performance of coronary CT angiography in the differentiation of patients without and patients with a need for revascularization and the selection of a revascularization strategy was similar to that of cardiac catheterization; accordingly, coronary CT angiography has the potential to limit the number of patients without obstructive CAD who undergo cardiac catheterization and to inform decision making regarding revascularization.

Scheimpflug Corneal Densitometry Values and Severity of Guttae in Relation to Visual Acuity in Fuchs Endothelial Corneal Dystrophy.

PURPOSE: The purpose of this study was to investigate the association between corneal densitometry (CD) values from Scheimpflug tomography imaging, severity of guttae, and visual acuity in eyes with Fuchs endothelial corneal dystrophy (FECD). METHODS: This was a retrospective, cross-sectional study. Patients with FECD were examined at the Bascom Palmer Eye Institute from January 2015 to September 2019. We extracted CD values at central annuli of 0-2, 2-6, 6-10 and 10-12 mm from Scheimpflug tomography images. We investigated the association of corrected distance visual acuity (CDVA) with CD values, severity of guttae, central corneal thickness (CCT), cataract grade, refractive error, corneal edema grade, age, and gender using multivariate generalized estimating equation regression models. RESULTS: One hundred ninety-two eyes from 110 patients were included in this study. Increase in central CD values at the 0 to 2 mm zone (P < 0.001), severity of guttae (P = 0.046), age (P < 0.001), cataract grade (P < 0.001), corneal edema grade (P < 0.001), and type of refractive error (P = 0.008) were significantly associated with decreased CDVA. Central corneal thickness, sex, and the peripheral CD values (2-6, 6-10, and 10-12 mm) were not significantly associated with CDVA (P > 0.05) in the final multivariate regression model. CONCLUSIONS: Our study demonstrates that central CD values at 0 to 2 mm and severity of guttae are each associated with decreased CDVA in FECD. These findings carry implications for patients with FECD considering surgical intervention for phacoemulsification alone, Descemet stripping only, or endothelial cell transplantation and provide a multifactorial perspective on vision loss in FECD.