Angiographic Features of Meningiomas Predicting Extent of Preoperative Embolization.

BACKGROUND AND OBJECTIVES: Preoperative embolization is used as an endovascular adjunct to surgical resection of meningiomas. However, there is no standardized system to assess the efficacy or extent of embolization during the embolization procedure. We sought to establish a purely angiographic grading system to facilitate consistent reporting of the outcome of meningioma embolization and to characterize the anatomic and other features of meningiomas that predict the degree of devascularization achieved through preoperative embolization. METHODS: We identified patients with meningiomas who underwent preoperative cerebral angiography and subsequent resection between 2015 and 2021. Demographic, clinical, and imaging data were collected in a research registry. We defined an angiographic devascularization grading scale as follows: grade 0 for no embolization, 1 for partial embolization, 2 for majority embolization, 3 for complete external carotid artery embolization, and 4 for complete embolization. RESULTS: Eighty consecutive patients were included, 60 of whom underwent preoperative tumor embolization (20 underwent angiography with an intention to treat but ultimately not embolization). Embolized tumors were larger (59.0 vs 35.9 cc; P = .03). Gross total resection, length of stay, and complication rates did not differ among groups. The distribution of arterial feeders differed significantly across tumors in a location-specific manner. Both the tumor location and the identity of arterial feeders were predictive of the extent of embolization. Anterior midline meningiomas were associated with internal carotid (ophthalmic, ethmoidal) supply and lower devascularization grades (P = .03). Tumors fed by meningeal feeders (convexity, falcine, lateral sphenoid wing) were associated with higher devascularization grades (P < .01). The procedural complication rate for tumor embolization was 2.5%. CONCLUSION: Angiographic outcomes can be graded to indicate the extent of tumor embolization. This system may facilitate consistency of reported angiographic results. In addition, arterial feeders vary in a manner predicted by tumor location, and these patterns correlate with typical degrees of devascularization achieved in those tumor locations.

From flare to care: Dermatologists' impact on pediatric atopic dermatitis hospital admissions.

BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) is a common chronic skin disease in the pediatric population; however, rates of admissions for flares in patients established with dermatology compared to those that are not established have not been fully assessed in prior studies. METHODS: We reviewed electronic medical records of patients hospitalized (billing codes 99221-99223, 99217) with diagnoses encompassing AD, eczema, and dermatitis (ICD-10 codes L20.8-L20.9, L30.8-L30.9) between January 1, 2011, and December 31, 2021, at University Hospitals (UH) in Cleveland, Ohio. Patients were considered established with dermatology if they had been seen by a dermatology provider within 6 months prior to admission. Statistical analysis was performed using chi-square goodness of fit. RESULTS: A total of 95 patient encounters met criteria for inclusion. Fifteen (15.8%) patients were established with dermatology at the time of admission and 80 (84.2%) were not. The chi-square value (x2 = 44.74) was greater than the critical value of 10.828 at one degree of freedom (p < .001). There were 8 patients who had more than one admission for atopic dermatitis flares; 2 of these patients were established with dermatology prior to their first admission, and 4 were established at the time of the second admission. CONCLUSION: The majority of patients admitted with AD flare were not established with dermatology. Many of these patients lived in a low socioeconomic area and missed follow-up appointments. Increasing access to dermatologic care for patients with atopic dermatitis, especially in lower-income areas, could aid in decreasing atopic dermatitis-related hospitalizations.

Cryo-Fluorescence Tomography as a Tool for Visualizing Whole-Body Inflammation Using Perfluorocarbon Nanoemulsion Tracers.

PURPOSE: We explore the use of intravenously delivered fluorescent perfluorocarbon (PFC) nanoemulsion tracers and multi-spectral cryo-fluorescence tomography (CFT) for whole-body tracer imaging in murine inflammation models. CFT is an emerging technique that provides high-resolution, three-dimensional mapping of probe localization in intact animals and tissue samples, enabling unbiased validation of probe biodistribution and minimizes reliance on laborious histological methods employing discrete tissue panels, where disseminated populations of PFC-labeled cells may be overlooked. This methodology can be used to streamline the development of new generations of non-invasive, cellular-molecular imaging probes for in vivo imaging. PROCEDURES: Mixtures of nanoemulsions with different fluorescent emission wavelengths were administered intravenously to naïve mice and models of acute inflammation, colitis, and solid tumor. Mice were euthanized 24 h post-injection, frozen en bloc, and imaged at high resolution (~ 50 µm voxels) using CFT at multiple wavelengths. RESULTS: PFC nanoemulsions were visualized using CFT within tissues of the reticuloendothelial system and inflammatory lesions, consistent with immune cell (macrophage) labeling, as previously reported in in vivo magnetic resonance and nuclear imaging studies. The CFT signals show pronounced differences among fluorescence wavelengths and tissues, presumably due to autofluorescence, differential fluorescence quenching, and scattering of incident and emitted light. CONCLUSIONS: CFT is an effective and complementary methodology to in vivo imaging for validating PFC nanoemulsion biodistribution at high spatial localization, bridging the resolution gap between in vivo imaging and histology.

Cerebral blood flow in relation to peripheral endothelial function in youth bipolar disorder.

INTRODUCTION: Anomalous cerebral blood flow (CBF) is evident in bipolar disorder (BD), however the extent to which CBF reflects peripheral vascular function in BD is unknown. This study investigated endothelial function, an index of early atherosclerosis and cardiovascular disease risk, in relation to CBF among youth with BD. METHODS: Participants included 113 youth, 13-20 years old (66 BD; 47 healthy controls [HC]). CBF was measured using arterial spin labeling with 3T MRI. Region of interest analyses (ROI; global grey matter, middle frontal gyrus, anterior cingulate cortex, temporal cortex, caudate) were undertaken alongside voxel-wise analyses. Reactive hyperemia index (RHI), a measure of endothelial function, was assessed non-invasively via pulse amplitude tonometry. General linear models were used to examine RHI and RHI-by-diagnosis associations with CBF, controlling for age, sex, and body mass index. Bonferroni correction for multiple comparisons was used for ROI analyses, such that the significance level was divided by the number of ROIs (α = 0.05/5 = 0.01). Cluster-extent thresholding was used to correct for multiple comparisons for voxel-wise analyses. RESULTS: ROI findings were not significant after correction. Voxel-wise analyses found that higher RHI was associated with lower left thalamus CBF in the whole group (p < 0.001). Additionally, significant RHI-by-diagnosis associations with CBF were found in three clusters: left intracalcarine cortex (p < 0.001), left thalamus (p < 0.001), and right frontal pole (p = 0.006). Post-hoc analyses showed that in each cluster, higher RHI was associated with lower CBF in BD, but higher CBF in HC. CONCLUSION: We found that RHI was differentially associated with CBF in youth with BD versus HC. The unanticipated association of higher RHI with lower CBF in BD could potentially reflect a compensatory mechanism. Future research, including prospective studies and experimental designs are warranted to build on the current findings.

IFN-γ production by functionally reprogrammed Treg cells promotes anti-tumor efficacy of OX40/CD137 bispecific agonist therapy.

Regulatory T (Treg) cells are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Treg cells to contribute to anti-tumor immunity. OX40 and CD137 are expressed highly on Treg cells, activated and memory T cells, and NK cells. Here, using a novel tetravalent bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonists induce potent anti-tumor immunity partially dependent upon IFN-γ-production by functionally reprogrammed Treg cells. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Treg cells into both fragile Foxp3+ IFN-γ+ cells with decreased suppressive function, and lineage instable Foxp3- IFN-γ+ cells. Treg cell fragility is partially dependent upon IFN-γ signaling, whereas Treg cell instability is associated with reduced IL-2 signaling upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Treg cells and their progeny partially reverses the anti-tumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Treg cells into IFN-γ-producing cells contributes to the efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting co-stimulatory receptors highly expressed by Treg cells potentiate anti-tumor immunity in mouse models.

Cytochrome P450-soluble epoxide hydrolase oxylipins, depression and cognition in type 2 diabetes.

AIMS: This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM). METHODS: Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry. RESULTS: The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F1,101 = 6.094, p = 0.015 and F1,101 = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F1,100 = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F1,100 = 6.481, p = 0.012) and 11(12)-EpETrE (F1,100 = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F1,100 = 4.286, p = 0.041), 5(6)-EpETrE (F1,100 = 6.845, p = 0.010), 11(12)-EpETrE (F1,100 = 3.981, p = 0.049) and 14(15)-EpETrE (F1,100 = 5.019, p = 0.027). CONCLUSIONS: Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM.

Controlled Study of Metabolic Syndrome Among Offspring of Parents With Bipolar Disorder.

Objectives: Bipolar disorder (BD) is highly heritable and associated with increased rates of metabolic syndrome (MetS). However, little is known about MetS in offspring of parents with BD. We therefore examined this topic in the Pittsburgh Bipolar Offspring Study cohort.Methods: Participants included 199 parents (n = 116 BD, diagnosed using DSM-IV; n = 83 non-BD) and 330 offspring (mean age 19.9 ± 5.3 years), including 198 high-risk offspring of parents with BD (n = 80 affected with a mood disorder) and 132 control offspring. We defined MetS and its components using International Diabetes Federation (IDF) guidelines (primary) and National Cholesterol Education Program (NCEP) guidelines (secondary). Multivariable analyses controlled for age and socioeconomic status in offspring. Sensitivity analyses controlled for psychotropic medications.Results: There was higher prevalence of MetS in parents with BD as compared to controls. NCEP-defined MetS was significantly more prevalent among affected high-risk offspring (16.3%) and controls (15.2%) vs unaffected high-risk offspring (6.0%; χ2 = 6.54, P = .04). There was greater mean number of MetS components (IDF: 1.7 ± 1.1; NCEP: 1.4 ± 1.0) among affected high-risk offspring vs unaffected high-risk offspring (IDF: 1.2 ± 1.0; NCEP: 1.0 ± 1.0) and controls (IDF: 1.3 ± 1.2; NCEP: 1.1 ± 1.1; IDF: H[2] = 10.26, P = .006; NCEP: H[2] = 9.18, P = .01). Most findings became nonsignificant in multivariable analyses. Some between-group results became nonsignificant after controlling for second-generation antipsychotics.Conclusions: This preliminary study found increased risk of MetS among affected high-risk offspring, which may be attributable to socioeconomic status. Prospective studies may determine timing of MetS onset in relation to mood disorder onset, and the role of socioeconomic status in moderating this association.

Increased risk of cardiovascular disease among kidney cancer survivors: a nationwide population-based cohort study.

Background: Cardiovascular disease (CVD) is a major concern of morbidity and mortality among cancer survivors. However, few evidence exists on the short- and long-term risk of CVD in kidney cancer (KCa) survivors. Methods: In this nationwide, large population-based retrospective cohort study, we used the Korean national health insurance and medical checkup survey linkage database (2007-2021), drawn from the entire Korean population. We included adults diagnosed with KCa as the first primary cancer and matched them to an individual without KCa at a 1:5 ratio. The primary outcome was CVD incidence, including myocardial infarction, stroke, atrial fibrillation, heart failure, peripheral arterial occlusion, and venous thromboembolism (VTE). We evaluated CVD risk at 6 months, 1 year, and 5 years following cancer diagnosis, using Fine-Gray competing risk models that accounted for death as a competing factor. Results: A total of 149,232 participants were included (KCa survivors: N=20,093 and matched non-KCa individuals: N=129,139). After 6-month follow-up, KCa survivors showed an increased risk of CVD compared to the general population (subdistribution hazard ratio (HR) 2.70, 95% confidence interval (CI) 2.31-3.15). After 1 year, KCa survivors had a higher risk of CVD (HR=1.77, 95% CI: 1.56-2.00). After 5 years, this elevated CVD risk remained (HR=1.10, 95% CI: 1.03-1.18), with VTE identified as the primary contributing disease (HR=3.05, 95% CI:2.59-3.59). Conclusion: KCa survivors had an increased risk of CVD up to 5 years after cancer diagnosis compared to the general population. Our findings emphasize the importance of comprehensive healthcare management for both CVD and KCa throughout cancer survivorship.

The Utility of the Rodent Synergist Ablation Model in Identifying Molecular and Cellular Mechanisms of Skeletal Muscle Hypertrophy.

Skeletal muscle exhibits remarkable plasticity to adapt to stimuli such as mechanical loading. The mechanisms that regulate skeletal muscle hypertrophy due to mechanical overload have been thoroughly studied. Remarkably, our understanding of many of the molecular and cellular mechanisms that regulate hypertrophic growth were first identified using the rodent synergist ablation (SA) model and subsequently corroborated in human resistance exercise training studies. To demonstrate the utility of the SA model, we briefly summarize the hypertrophic mechanisms identified using the model and the following translation of these mechanism to human skeletal muscle hypertrophy induced by resistance exercise training.

Cysteamine Suppresses Cancer Cell Invasion and Migration in Glioblastoma through Inhibition of Matrix Metalloproteinase Activity.

Glioblastoma (GBM) cells are highly invasive, infiltrating the surrounding normal brain tissue, thereby limiting the efficacy of surgical resection and focal radiotherapy. Cysteamine, a small aminothiol molecule that is orally bioavailable and approved for cystinosis, has potential as a cancer treatment by inhibiting tumor cell invasion and metastasis. Here we demonstrate that these potential therapeutic effects of cysteamine are likely due to the inhibition of matrix metalloproteinases (MMPs) in GBM. In vitro assays confirmed that micromolar concentrations of cysteamine were not cytotoxic, enabling the interrogation of the cellular effects without confounding tumor cell loss. Cysteamine's inhibition of MMP activity, especially the targeting of MMP2, MMP9, and MMP14, was observed at micromolar concentrations, suggesting the mechanism of action in suppressing invasion and cell migration is by inhibition of these MMPs. These findings suggest that achievable micromolar concentrations of cysteamine effectively inhibit cancer cell invasion and migration in GBM, supporting the potential for use as an adjunct cancer treatment.

High resolution assessment of commercial fisheries activity along the US West Coast using Vessel Monitoring System data with a case study using California groundfish fisheries.

Commercial fisheries along the US West Coast are important components of local and regional economies. They use various fishing gear, target a high diversity of species, and are highly spatially heterogeneous, making it challenging to generate a synoptic picture of fisheries activity in the region. Still, understanding the spatial and temporal dynamics of US West Coast fisheries is critical to meet the US legal mandate to manage fisheries sustainably and to better coordinate activities among a growing number of users of ocean space, including offshore renewable energy, aquaculture, shipping, and interactions with habitats and key non-fishery species such as seabirds and marine mammals. We analyzed vessel tracking data from Vessel Monitoring System (VMS) from 2010 to 2017 to generate high-resolution spatio-temporal estimates of contemporary fishing effort across a wide range of commercial fisheries along the entire US West Coast. We identified over 247,000 fishing trips across the entire VMS data, covering over 25 different fisheries. We validated the spatial accuracy of our analyses using independent estimates of spatial groundfish fisheries effort generated through the NOAA's National Marine Fisheries Service Observer Program. Additionally, for commercial groundfish fisheries operating in federal waters in California, we combined the VMS data with landings and ex-vessel value data from California commercial fisheries landings receipts to generate highly resolved estimates of landings and ex-vessel value, matching over 38,000 fish tickets with VMS data that included 87% of the landings and 76% of the ex-vessel value for groundfish. We highlight fisheries-specific and spatially-resolved patterns of effort, landings, and ex-vessel value, a bimodal distribution of fishing effort with respect to depth, and variable and generally declining effort over eight years. The information generated by our study can help inform future sustainable spatial fisheries management and other activities in the marine environment including offshore renewable energy planning.

Ambient air pollution and urological cancer risk: A systematic review and meta-analysis of epidemiological evidence.

Exposure to ambient air pollution has significant adverse health effects; however, whether air pollution is associated with urological cancer is largely unknown. We conduct a systematic review and meta-analysis with epidemiological studies, showing that a 5 µg/m3 increase in PM2.5 exposure is associated with a 6%, 7%, and 9%, increased risk of overall urological, bladder, and kidney cancer, respectively; and a 10 µg/m3 increase in NO2 is linked to a 3%, 4%, and 4% higher risk of overall urological, bladder, and prostate cancer, respectively. Were these associations to reflect causal relationships, lowering PM2.5 levels to 5.8 µg/m3 could reduce the age-standardized rate of urological cancer by 1.5 ~ 27/100,000 across the 15 countries with the highest PM2.5 level from the top 30 countries with the highest urological cancer burden. Implementing global health policies that can improve air quality could potentially reduce the risk of urologic cancer and alleviate its burden.

Molecular-targeted therapy for childhood low-grade glial and glioneuronal tumors.

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.

Microbial-Derived Exerkines Prevent Skeletal Muscle Atrophy.

Regular exercise yields a multitude of systemic benefits, many of which may be mediated through the gut microbiome. Here, we report that cecal microbial transplants (CMTs) from exercise-trained vs. sedentary mice have modest benefits in reducing skeletal muscle atrophy using a mouse model of unilaterally hindlimb-immobilization. Direct administration of top microbial-derived exerkines from an exercise-trained gut microbiome preserved muscle function and prevented skeletal muscle atrophy.

Pilot study of circulating cell-free mitochondrial DNA in relation to brain structure in youth bipolar disorder.

BACKGROUND: Mitochondrial dysfunction is implicated in the neuropathology of bipolar disorder (BD). Higher circulating cell-free mitochondrial DNA (ccf-mtDNA), generally reflecting poorer mitochondrial health, has been associated with greater symptoms severity in BD. The current study examines the association of serum ccf-mtDNA and brain structure in relation to youth BD. We hypothesized that higher ccf-mtDNA will be associated with measures of lower brain structure, particularly in the BD group. METHODS: Participants included 40 youth (BD, n = 19; Control group [CG], n = 21; aged 13-20 years). Serum ccf-mtDNA levels were assayed. T1-weighted brain images were acquired using 3T-MRI. Region of interest (ROI) analyses examined prefrontal cortex (PFC) and whole brain gray matter, alongside exploratory vertex-wise analyses. Analyses examined ccf-mtDNA main-effects and ccf-mtDNA-by-diagnosis interaction effects controlling for age, sex, and intracranial volume. RESULTS: There was no significant difference in ccf-mtDNA levels between BD and CG. In ROI analyses, higher ccf-mtDNA was associated with higher PFC surface area (SA) (ß = 0.32 p < 0.001) and PFC volume (ß = 0.32 p = 0.002) in the overall sample. In stratified analyses, higher ccf-mtDNA was associated with higher PFC SA within both subgroups (BD: ß = 0.39 p = 0.02; CG: ß = 0.24 p = 0.045). Higher ccf-mtDNA was associated with higher PFC volume within the BD group (ß = 0.39 p = 0.046). In vertex-wise analyses, higher ccf-mtDNA was associated with higher SA and volume in frontal clusters within the overall sample and within the BD group. There were significant ccf-mtDNA-by-diagnosis interactions in three frontal and parietal clusters, whereby higher ccf-mtDNA was associated with higher neurostructural metrics in the BD group but lower neurostructural metrics in CG. CONCLUSIONS: Contrasting our hypothesis, higher ccf-mtDNA was consistently associated with higher, rather than lower, regional neuralstructural metrics among youth with BD. While this finding may reflect a compensatory mechanism, future repeated-measures prospective studies evaluating the inter-relationship among ccf-mtDNA, mood, and brain structure across developmental epochs and illness stages are warranted.

Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care.

During the last 100 years, the role of anesthesiologists in psychiatry has focused primarily on facilitating electroconvulsive therapy and mitigating postoperative delirium and other perioperative neurocognitive disorders. The discovery of the rapid and sustained antidepressant properties of ketamine, and early results suggesting that other general anesthetic drugs (including nitrous oxide, propofol, and isoflurane) have antidepressant properties, has positioned anesthesiologists at a new frontier in the treatment of neuropsychiatric disorders. Moreover, shared interest in understanding the biologic underpinnings of anesthetic drugs as psychotropic agents is eroding traditional academic boundaries between anesthesiology and psychiatry. This article presents a brief overview of anesthetic drugs as novel antidepressants and identifies promising future candidates for the treatment of depression. The authors issue a call to action and outline strategies to foster collaborations between anesthesiologists and psychiatrists as they work toward the common goals of repurposing anesthetic drugs as antidepressants and addressing mood disorders in surgical patients.

The impact of venous thromboembolism before open or minimally-invasive radical cystectomy in the USA: insurance claims data on perioperative outcomes and healthcare costs.

BACKGROUND: The relationship between venous thromboembolism (VTE) and solid malignancy has been established over the decades. With rising projected rates of bladder cancer (BCa) worldwide as well as increasing number of patients experiencing BCa and VTE, our aim is to assess the impact of a preoperative VTE diagnosis on perioperative outcomes and health-care costs in BCa cases undergoing radical cystectomy (RC). METHODS: Patients ≥18 years of age with BCa diagnosis and undergoing open or minimally invasive (MIS) RC were identified in the Merative™ Marketscan® Research Databases between 2007 and 2021. The association of previous VTE history with 90-day complication rates, postoperative VTE events, rehospitalization, and total hospital costs (2021 USA dollars) was determined by multivariable logistic regression modeling adjusted for patient and perioperative confounders. Sensitivity analysis on VTE degree of severity (i.e., pulmonary embolism [PE] and/or peripheral deep venous thrombosis [DVT]) was also examined. RESULTS: Out of 8759 RC procedures, 743 (8.48%) had a previous positive history for any VTE including 245 (32.97%) PE, 339 (45.63%) DVT and 159 (21.40%) superficial VTE. Overall, history of VTE before RC was strongly associated with almost any worse postoperative outcomes including higher risk for any and apparatus-specific 90-days postoperative complications (odds ratio [OR]: 1.21, 95% CI, 1.02-1.44). Subsequent incidence of new VTE events (OR: 7.02, 95% CI: 5.93-8.31), rehospitalization (OR: 1.25, 95% CI: 1.06-1.48), other than home/self-care discharge status (OR: 1.53, 95% CI: 1.28-1.82), and higher health-care costs related to the RC procedure (OR: 1.43, 95% CI: 1.22-1.68) were significantly associated with a history of VTE. CONCLUSIONS: Preoperative VTE in patients undergoing RC significantly increases morbidity, post-procedure VTE events, hospital length of stay, rehospitalizations, and increased hospital costs. These findings may help during the BCa counseling on risks of surgery and hopefully improve our ability to mitigate such risks.

Conformational Dynamics of an Amyloidogenic Intermediate of Transthyretin: Implications for Structural Remodeling and Amyloid Formation.

The aggregation pathway of transthyretin (TTR) proceeds through rate-limiting dissociation of the tetramer (a dimer of dimers) and partial misfolding of the resulting monomer, which assembles into amyloid structures through a downhill polymerization mechanism. The structural features of the aggregation-prone monomeric intermediate are poorly understood. NMR relaxation dispersion offers a unique opportunity to characterize amyloidogenic intermediates when they exchange on favorable timescales with NMR-visible ground states. Here we use NMR to characterize the structure and conformational dynamics of the monomeric F87E mutant of human TTR. Chemical shifts derived from analysis of multinuclear relaxation dispersion data provide insights into the structure of a low-lying excited state that exchanges with the ground state of the F87E monomer at a rate of 3800 s-1. Disruption of the subunit interfaces of the TTR tetramer leads to destabilization of edge strands in both ß-sheets of the F87E monomer. Conformational fluctuations are propagated through the entire hydrogen bonding network of the DAGH ß-sheet, from the inner ß-strand H, which forms the strong dimer-dimer interface in the TTR tetramer, to outer strand D which is unfolded in TTR fibrils. Fluctuations are also propagated from the AB loop in the weak dimer-dimer interface to the EF helix, which undergoes structural remodeling in fibrils. The conformational fluctuations in both regions are enhanced at acidic pH where amyloid formation is most favorable. The relaxation dispersion data provide insights into the conformational dynamics of the amyloidogenic state of monomeric TTR that predispose it for structural remodeling and progression to amyloid fibrils.

Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.

The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.