The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population.We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro–B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, β-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A_1c [Hb A_1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016–2017; age 71–94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors.In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44–3.22]; no diabetes: OR, 2.31 [95%CI, 1.76–3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08–1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22–1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A_1c (OR, 1.76 [95% CI, 1.22–2.54]), fructosamine (OR, 1.71 [95% CI, 1.19–2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03–2.03]) with PN were significant only among participants with diabetes.Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain.We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk.We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR.We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

Dramatically rising costs in drug development are in large part because of the high failure rates in clinical phase trials. The poor correlation of animal studies to human toxicity and efficacy have led many developers to question the value of requiring animal studies in determining which drugs should enter in-human trials. Part 1 of this 2-part series examined some of the data regarding the lack of concordance between animal toxicity studies and human trials, as well as some of the potential reasons behind it. This second part of the series focuses on some alternatives to animal trials (hereafter referred to as animal research) as well as current regulatory discussions and developments regarding such alternatives.

Recognizing that guideline-directed histologic grading of endomyocardial biopsy tissue samples for rejection surveillance has limited diagnostic accuracy, quantitative, in situ characterization was performed of several important immune cell types in a retrospective cohort of clinical endomyocardial tissue samples. Differences between cases were identified and were grouped by histologic grade versus clinical rejection trajectory, with significantly increased programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cells suppressed in clinically evident rejections, especially cases with marked clinical-histologic discordance. Programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cell proportions are also significantly higher in "never-rejection" when compared with "future-rejection." These findings suggest that in situ immune modulators regulate the severity of cardiac allograft rejection.

Intrathecal administration of anti-infectives is indicated in central nervous system infections by multiresistant pathogens when drugs that can reach adequate cerebrospinal fluid (CSF) concentrations by systemic therapy are not available. Antibiotics that readily pass the blood-brain and blood-CSF barriers and/or that have low toxicity allowing an increase in the daily dosage should not be used for intrathecal therapy. Intrathecal therapy is accompanied by systemic treatment. Antibacterials indispensable for intrathecal therapy include aminoglycosides, colistin, daptomycin, tigecycline, and vancomycin. Limited experience suggests the utility of the antifungals amphotericin B and caspofungin. Intraventricular administration ensures distribution throughout the CSF compartment, whereas intralumbar dosing often fails to attain adequate antibiotic concentrations in the ventricles. The individual dose is determined by the estimated size of the CSF space and by the estimated clearance from CSF. For moderately lipophilic anti-infectives with a molecular weight above approximately 1,000 g/mol, as well as for hydrophilic drugs with a molecular weight above approximately 400 g/mol, one daily dose is normally adequate. The ventricular drain should be clamped for 15 to 120 min to facilitate the distribution of the anti-infective in the CSF space. Therapeutic drug monitoring of the trough levels is necessary only in cases of therapeutic failure.

Purpose:

The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the cerebrospinal fluid (CSF) from patients with LMM to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells.

Experimental Design:

A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (<4 months) and one was an extraordinary responder (still alive with survival >35 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells that were subjected to RNA sequencing (RNA-seq) analysis. Functional assays were performed to validate the pathways identified.

Results:

Mass spectrometry analyses showed the CSF of most patients with LMM to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anticorrelated in the extraordinary responder. RNA-seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGFβ, and oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGFβ expression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays.

Conclusions:

These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from patients with LMM has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.

See related commentary by Glitza Oliva and Tawbi, p. 2083

Purpose:

Using standard-of-care CT images obtained from patients with a diagnosis of non–small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity of tumors to nivolumab, docetaxel, and gefitinib.

Experimental Design:

Data were collected prospectively and analyzed retrospectively across multicenter clinical trials [nivolumab, n = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, n = 50, CheckMate017; gefitinib, n = 46, (NCT00588445)]. Patients were randomized to training or validation cohorts using either a 4:1 ratio (nivolumab: 72T:20V) or a 2:1 ratio (docetaxel: 32T:18V; gefitinib: 31T:15V) to ensure an adequate sample size in the validation set. Radiomics signatures were derived from quantitative analysis of early tumor changes from baseline to first on-treatment assessment. For each patient, 1,160 radiomics features were extracted from the largest measurable lung lesion. Tumors were classified as treatment sensitive or insensitive; reference standard was median progression-free survival (NCT01642004, NCT01721759) or surgery (NCT00588445). Machine learning was implemented to select up to four features to develop a radiomics signature in the training datasets and applied to each patient in the validation datasets to classify treatment sensitivity.

Results:

The radiomics signatures predicted treatment sensitivity in the validation dataset of each study group with AUC (95 confidence interval): nivolumab, 0.77 (0.55–1.00); docetaxel, 0.67 (0.37–0.96); and gefitinib, 0.82 (0.53–0.97). Using serial radiographic measurements, the magnitude of exponential increase in signature features deciphering tumor volume, invasion of tumor boundaries, or tumor spatial heterogeneity was associated with shorter overall survival.

Conclusions:

Radiomics signatures predicted tumor sensitivity to treatment in patients with NSCLC, offering an approach that could enhance clinical decision-making to continue systemic therapies and forecast overall survival.

Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the core protein. Core is a potential target for new antiviral therapies, the capsid assembly modulators (CAMs). JNJ-56136379 (JNJ-6379) is a novel and potent CAM currently in phase II trials. We evaluated the mechanisms of action (MOAs) and antiviral properties of JNJ-6379 in vitro. Size exclusion chromatography and electron microscopy studies demonstrated that JNJ-6379 induced the formation of morphologically intact viral capsids devoid of genomic material (primary MOA). JNJ-6379 accelerated the rate and extent of HBV capsid assembly in vitro. JNJ-6379 specifically and potently inhibited HBV replication; its median 50% effective concentration (EC₅₀) was 54 nM (HepG2.117 cells). In HBV-infected primary human hepatocytes (PHHs), JNJ-6379, when added with the viral inoculum, dose-dependently reduced extracellular HBV DNA levels (median EC₅₀ of 93 nM) and prevented covalently closed circular DNA (cccDNA) formation, leading to a dose-dependent reduction of intracellular HBV RNA levels (median EC₅₀ of 876 nM) and reduced antigen levels (secondary MOA). Adding JNJ-6379 to PHHs 4 or 5 days postinfection reduced extracellular HBV DNA and did not prevent cccDNA formation. Time-of-addition PHH studies revealed that JNJ-6379 most likely interfered with postentry processes. Collectively, these data demonstrate that JNJ-6379 has dual MOAs in the early and late steps of the HBV life cycle, which is different from the MOA of nucleos(t)ide analogues. JNJ-6379 is in development for chronic hepatitis B treatment and may translate into higher HBV functional cure rates.

KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC_50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.

Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the bla_KPC family) is one of the most common transmissible carbapenem resistance mechanisms worldwide. The dissemination of bla_KPC historically has been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the United Kingdom, bla_KPC has represented a large-scale, persistent management challenge for some hospitals, particularly in North West England. The dissemination of bla_KPC has evolved to be polyclonal and polyspecies, but the genetic mechanisms underpinning this evolution have not been elucidated in detail; this study used short-read whole-genome sequencing of 604 bla_KPC-positive isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 isolates for characterization. We observed the dissemination of bla_KPC (predominantly bla_KPC-2; 573/604 [95%] isolates) across eight species and more than 100 known sequence types. Although there was some variation at the transposon level (mostly Tn4401a, 584/604 [97%] isolates; predominantly with ATTGA-ATTGA target site duplications, 465/604 [77%] isolates), bla_KPC spread appears to have been supported by highly fluid, modular exchange of larger genetic segments among plasmid populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates), and IncR (252/604 isolates) replicons. The subset of reconstructed plasmid sequences (21 isolates, 77 plasmids) also highlighted modular exchange among non-bla_KPC and bla_KPC plasmids and the common presence of multiple replicons within bla_KPC plasmid structures (>60%). The substantial genomic plasticity observed has important implications for our understanding of the epidemiology of transmissible carbapenem resistance in Enterobacterales for the implementation of adequate surveillance approaches and for control.

Omadacycline is an aminomethylcycline antibiotic with in vitro activity against pathogens causing community-acquired bacterial pneumonia (CABP). This study investigated the activity of omadacycline against Legionella pneumophila strains isolated between 1995 and 2014 from nosocomial or community-acquired respiratory infections. Omadacycline exhibited extracellular activity similar to comparator antibiotics; intracellular penetrance was found by day 3 of omadacycline exposure. These results support the utility of omadacycline as an effective antibiotic for the treatment of CABP caused by L. pneumophila.

We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC₅₀] ≤ 10 μM), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC₅₀ of ≤1 μM, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizont-ring transition (with ≥50% parasites failing to proceed to the next stage) at 1 μM. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.

A 4-year surveillance of carbapenem-resistant Acinetobacter spp. isolates in Argentina identified 40 strains carrying bla_NDM-1. Genome sequencing revealed that most were Acinetobacter baumannii, whereas seven represented other Acinetobacter spp. The A. baumannii genomes were closely related, suggesting recent spread. bla_NDM-1 was located in the chromosome of A. baumannii strains and on a plasmid in non-A. baumannii strains. A resistance gene island carrying bla_PER-7 and other resistance determinants was found on a plasmid in some A. baumannii strains.

Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with noncoding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies.

Significance:

We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies.

See related commentary by van Galen, p. 646.

This article is highlighted in the In This Issue feature, p. 627

The MaMTH-DS assay detected inhibitors of mutant EGFR in non–small cell lung cancer cells.

Background:

The impact of light-intensity physical activity (LPA) in preventing cancer mortality has been questioned. To address this concern, the present meta-analysis aimed to quantify the association between objectively-measured LPA and risk of cancer mortality.

Methods:

We conducted a systematic literature search in PubMed and Scopus to January 2020. Prospective cohort studies reporting the association between objectively-measured LPA using activity monitors (e.g., accelerometers) and risk of cancer mortality in the general population were included. The summary hazard ratios (HR) per 30 min/day of LPA and 95% confidence intervals (CI) were obtained using a random-effects model. Dose–response analysis was used to plot their relationship.

Results:

Five prospective cohort studies were included, in which the definition of LPA based on accelerometer readings was mainly set within 100 to 2,100 counts/min. The summary HR for cancer mortality per 30 min/day of LPA was 0.86 (95% CI, 0.79–0.95; I² < 1%), and the association between LPA and risk reduction in cancer mortality was linearly shaped (P_nonlinearity = 0.72). LPA exhibited a comparable magnitude of risk reduction in cancer mortality of moderate-to-vigorous physical activity regardless of equal time-length (0.87 per 30 min/day vs. 0.94 per 30 min/day, P_interaction = 0.46) or equal amount (0.74 vs. 0.94 per 150 metabolic equivalents-min/day, P_interaction = 0.11). Furthermore, replacing sedentary time by LPA of 30 min/day decreased the risk of cancer mortality by 9%.

Conclusions:

Objectively-measured LPA conferred benefits in decreasing the risk of cancer mortality.

Impact:

LPA should be considered in physical activity guidelines to decrease the risk of cancer mortality.

Ovarian cancer imposes a substantial health and economic burden. We systematically reviewed current health-economic evidence for ovarian cancer early detection or prevention strategies. Accordingly, we searched relevant databases for cost-effectiveness studies evaluating ovarian cancer early detection or prevention strategies. Study characteristics and results including quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were summarized in standardized evidence tables. Economic results were transformed into 2017 Euros. The included studies (N = 33) evaluated ovarian cancer screening, risk-reducing interventions in women with heterogeneous cancer risks and genetic testing followed by risk-reducing interventions for mutation carriers. Multimodal screening with a risk-adjusted algorithm in postmenopausal women achieved ICERs of 9,800–81,400 Euros/QALY, depending on assumptions on mortality data extrapolation, costs, test performance, and screening frequency. Cost-effectiveness of risk-reducing surgery in mutation carriers ranged from cost-saving to 59,000 Euros/QALY. Genetic testing plus risk-reducing interventions for mutation carriers ranged from cost-saving to 54,000 Euros/QALY in women at increased mutation risk. Our findings suggest that preventive surgery and genetic testing plus preventive surgery in women at high risk for ovarian cancer can be considered effective and cost-effective. In postmenopausal women from the general population, multimodal screening using a risk-adjusted algorithm may be cost-effective.

It is well established that African Americans exhibit higher incidence, higher mortality, and more aggressive forms of some cancers, including those of breast, prostate, colon, stomach, and cervix. Here we examine the ancestral haplotype of the TRPV6 calcium channel as a putative genomic factor in this racial divide. The minor (ancestral) allele frequency is 60% in people of African ancestry, but between 1% and 11% in all other populations. Research on TRPV6 structure/function, its association with specific cancers, and the evolutionary-ecological conditions that impacted selection of its haplotypes are synthesized to provide evidence for TRPV6 as a germline susceptibility locus in cancer. Recently elucidated mechanisms of TRPV6 channel deactivation are discussed in relation to the location of the allele favored in selection, suggesting a reduced capacity to inactivate the channel in those who have the ancestral haplotype. This could result in an excessively high cellular Ca²⁺, which has been implicated in cancer, for those in settings where calcium intake is far higher than in their ancestral environment. A recent report associating increasing calcium intake with a pattern of increase in aggressive prostate cancer in African-American but not European-American men may be related. If TRPV6 is found to be associated with cancer, further research would be warranted to improve risk assessment and examine interventions with the aim of improving cancer outcomes for people of African ancestry.

BACKGROUND AND PURPOSE:

Endovascular treatment of petrous dural AVFs may carry a risk of iatrogenic facial nerve palsy if the facial nerve arterial arcade, an anastomotic arterial arch that supplies the geniculate ganglion, is not respected or recognized. Our purpose was to demonstrate that the use of a treatment strategy algorithm incorporating detailed angiographic anatomic assessment allows identification of the facial nerve arterial arcade and therefore safe endovascular treatment.

MATERIALS AND METHODS:

This was a retrospective cohort study of consecutive petrous dural AVF cases managed at Toronto Western Hospital between 2006 and 2018. Our standard of care consists of detailed angiographic assessment followed by multidisciplinary discussion on management. Arterial supply, primary and secondary treatments undertaken, angiographic outcomes, and clinical outcomes were assessed by 2 independent fellowship-trained interventional neuroradiologists.

RESULTS:

Fifteen patients had 15 fistulas localized over the petrous temporal bone. Fistulas in all 15 patients had direct cortical venous drainage and received at least partial supply from the facial nerve arterial arcade. Following multidisciplinary evaluation, treatment was performed by endovascular embolization in 8 patients (53%) and microsurgical disconnection in 7 patients (47%). All patients had long-term angiographic cure, and none developed iatrogenic facial nerve palsy.

CONCLUSIONS:

By means of our treatment strategy based on detailed angiographic assessment and multidisciplinary discussion, approximately half of our patients with petrous AVFs were cured by endovascular treatment, half were cured by an operation, and all had preserved facial nerve function.

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According to Deputy Minister of Construction Nguyen Viet Sinh, Vietnam will have at least 3 smart cities in 3 key economic regions: North, Central and South. Thus, by the next 6 years, Hanoi, Da Nang and Ho Chi Minh City will become smart cities.

Real estate insiders and experts said it is essential to develop strict penalties to combat those operating fraudulent property businesses to protect the legitimate rights of consumers and legitimate enterprises.

Three marketing experts share their unconventional means of capturing the attention of potential homeowners of today.

Premier industry experts also share an overview of the first quarter of the year, as well as brief market forecasts.

पंजाब में पेट्रोल और डीजल बुधवार सुबह छह बजे से दो रुपये महंगा हो जाएगा।

शनि कर्म के देवता हैं और आपके किए गए कार्य का फल जरूर देते हैं। शनिदेव को मनाने के लिए किए जाने वाले सनातनी उपाय को करके आप कुंडली के उन दोषों को दूर कर सकते हैं जिनके कारण आपको कष्ट उठाने पड़ते हैं।

लग्जरी कार बनाने वाली जर्मनी की दिग्गज ऑटोमोबाइल कंपनी BMW (बीएमडब्ल्यू) ने अपनी BMW 8 Series Gran Coupe (8-सीरीज ग्रैन कूपे) और BMW M8 Coupe (एम-8 कूपे) भारतीय बाजार में लॉन्च कर दिया है।

Microsoft has announced it will share new information on the Xbox Series X every month in 2020 starting with the May 7th episode of Inside Xbox, which will showcase gameplay from third-party partners. Microsoft is calling it "Xbox 20/20." The event starts at 8am PT / 11am ET. 

"These monthly moments will take place throughout the rest of the year and will be a way for us to engage, connect and celebrate with you about what’s in store for the next generation of gaming, including what’s next for Xbox Series X, Xbox Game Studios, Xbox Game Pass and Project xCloud," said Microsoft. "Every month will bring something different. Stay tuned to Xbox Wire for more details."

The company did reveal the July event will be focused on upcoming first-party games from Xbox Game Studios. 

"A number of our studio teams are looking forward to sharing first looks at new gameplay, insights from development teams being optimized for Xbox Series X, and brand-new game announcements," said Microsoft.  "We cannot wait to share this initial look at what some of those teams are working on."

A new teaser video of the May 7 Inside Xbox event has been posted online and the closed captions reveals it is the "New Xbox Sound." It is possible it is the new bootup screen for the Xbox Series X. View the video below:

The Inside Xbox event for May 7 can be watched from multiple streaming sites:

• Facebook
• Mixer
• Twitch
• Twitter
• YouTube (4K stream)

Read more information below:

This is a momentous year for Xbox, with our next-gen console paving the way for all our games and services to come together in even better ways. Here’s what 2020 looks like, just to start:

• Our goal remains to launch Xbox Series X and Halo Infinite this Holiday
• All 15 Xbox Game Studios teams are hard at work on next-generation games for Xbox Series X and Xbox Game Pass
• The best development teams around the world are working hard to have their games ready to play on Xbox Series X this holiday
• For PC players, we plan to support the community by making all our major releases at launch available with Xbox Game Pass for PC, including Halo Infinite, Wasteland 3, Minecraft Dungeons and of course, Microsoft Flight Simulator.
• We have new updates and titles lined up for Xbox Game Pass for console and PC
• We’re expanding Project xCloud into new countries and on new devices—and later this year Project xCloud and Xbox Game Pass will come together, enabling you and your friends to play together in more ways.

It’s a lot – and that’s saying something in 2020, a year which could be summed up as “a lot.” With all this in mind, we set out to create new touchpoints to celebrate gaming and share what’s next with our global community.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443394/xbox-series-x-news-planned-for-every-month-of-2020-starts-with-inside-xbox-gameplay-reveals-on-may-7/

Microsoft earlier announced it will share new information on the Xbox Series X every month in 2020 calling it "Xbox 20/20." The first event will be held on May 7th at 8am PT / 11am ET and will focus on gameplay from third-party partners. 

The event in June has now been revealed it will focus on platform and services, according to Bloomberg.

It is possible the June event will see the unveiling of the long rumored weaker next generation Xbox, codenamed Lockhart, with an expected official name of Xbox Series S. The price and launch date for the Xbox Series X is also possible, as well as information on Game Pass, Xbox Live Gold and Project xCloud. 

The July event will be focused on upcoming first-party games from Xbox Game Studios. 

"These monthly moments will take place throughout the rest of the year and will be a way for us to engage, connect and celebrate with you about what’s in store for the next generation of gaming, including what’s next for Xbox Series X, Xbox Game Studios, Xbox Game Pass and Project xCloud," said Microsoft. "Every month will bring something different. Stay tuned to Xbox Wire for more details."

The Xbox Series X will launch in Holiday 2020.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443395/xbox-series-x-june-event-to-focus-on-platform-and-services/

Microsoft and Sony are both hard at working preparing their next generation consoles, the Xbox Series X and PlayStation 5, for launch this holiday season. 

A key factor in getting as many consoles shipped for both companies will be from AMD, who will be providing the latest Zen 2-powered CPU and matching Navi GPU.

AMD is ramping up production as they expect semi-custom revenue to grow in the second quarter and have a big increase in the second half of 2020 as they provide parts for the Xbox Series X and PS5. 

"We expect semi-custom revenue to increase in the second quarter and be heavily weighted towards the second-half of the year, as we ramp production to support the holiday launches of the new PlayStation 5 and Xbox Series X consoles," said AMD CEO Dr. Lisa Su. 

Thanks Tom's Hardware.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443398/amd-ramping-up-cpu-production-for-xbox-series-x-and-playstation-5/

Publisher Raw Fury and developer Out of the Blue have announced adventure game, Call of the Sea, for the Xbox Series X, Xbox One and Windows PC via Steam. It will launch in late 2020.

View the reveal trailer below:

Here is an overview of the game:

It is 1934, in the far reaches of the South Pacific. Norah has crossed the ocean following the trail of her missing husband’s expedition and finds herself on a lush island paradise—a nameless, forgotten place, dotted with the remnants of a lost civilization.

What strange secrets does it hold, and what might Norah unearth in her quest for the truth?

Key Features:

• Explore the Beauty – Explore a stunning tropical island (meticulously modeled in Unreal Engine 4), brimming with fantastic sights, lost ruins and occult mysteries.
• Meet Norah – Experience an emotional, charming character study of a woman on a journey of self-discovery, fully voiced by Cissy Jones (Firewatch, The Walking Dead: Season 1).’
  Dive into the Deep – Immerse yourself in a story-driven adventure full of suspense and surreal surprises.
• Search for Meaning – Investigate the clues left by a previous voyage, piece together what happened, and solve a variety of clever puzzles.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443418/call-of-the-sea-announced-for-xbox-series-x-xbox-one-and-pc/

Publisher Deep Silver and developer Fishlabs have announced Chorus: Rise as One for the Xbox Series X, PlayStation 4, PlayStation 4, Xbox One, and Windows PC. It will launch in 2021.

View the announcement trailer below:

Here is an overview of the game:

Take control of Nara, once the Circle’s deadliest warrior, now their most wanted fugitive, on a quest to destroy the dark cult that created her. Unlock devastating weapons and mind-bending abilities in a true evolution of the space-combat shooter. Along with Forsaken, her sentient starfighter, explore ancient temples, engage in exhilarating zero-g combat, and venture beyond our waking reality.

Key Features:

• Journey of Redemption – Lead Nara, an ace pilot facing her haunted past, and Forsaken, her sentient ship on a quest for redemption across the galaxy.
• Venture Beyond the Void – Enter a dark new universe, teeming with mystery that balances the scale and spectacle of exploration with fast-paced action.
• One Pilot, One Ship, One Living Weapon – Attain unique weapons. Unlock deadly abilities. Chain powers together to become the ultimate living weapon.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443419/chorus-rise-as-one-announced-for-xbox-series-x-ps5-ps4-xbox-one-and-pc/

Bloober Team has announced psychological horror game, The Medium, for Xbox Series X and Windows PC via Steam. It will launch this holiday season and be available on Xbox Game Pass.

"Every one of our games has a central theme that drives its creative and technological design," said Bloober Team CEO Piotr Babieno.

"In The Medium, we focus on perspective and perception. When you change your point of view, you discover that things are more complicated and nuanced than you initially thought. The Medium is our most ambitious game ever and we can’t wait to show you how we’re translating this vision into a psychological horror."

View the reveal trailer below:

Here is an overview of the game:

Become a medium living in two different worlds: the real one and the spirit one. Haunted by the vision of a child’s murder, you travel to an abandoned hotel resort, which many years ago became the stage of an unthinkable tragedy. There you begin your search for difficult answers.

As a medium with access to both worlds, you have a wider perspective and can see more clearly that there’s no one simple truth to what others perceive. Nothing is what it seems, everything has another side.

The Medium features a “dual” soundtrack by Bloober Team’s Arkadiusz Reikowski and legendary composer Akira Yamaoka of Silent Hill fame.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443420/psychological-horror-game-the-medium-announced-for-xbox-series-x-and-pc/

ebb software has released a new trailer for the Xbox Series X version of the atmospheric first-person horror adventure, Scorn. The game is in development for the Xbox Series X and Windows PC via Steam and Windows Store.

View the Xbox Series X trailer below:

Here is an overview of the game:

Scorn is set in a nightmarish universe of odd forms and somber tapestry. It is designed around the idea of "being thrown into the world". Isolated and lost inside this dream-like world, you will explore different interconnected regions in a non-linear fashion. Every location contains its own theme, puzzles and characters that are integral in creating a cohesive world.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443422/horror-adventure-game-scorn-xbox-series-x-trailer-released/

Codemasters during the latest Inside Xbox event announced Dirt 5 for the Xbox Series X. The game will also launch for the PlayStation 5, PlayStation 4, Xbox One, and Google Stadia. It will release in October 2020.

View the announcement trailer below:

Read an overview of the game via Xbox below:

Fresh out of the box from the latest Inside Xbox, myself and the whole Codemasters team are delighted to reveal Dirt 5 to the world (but especially you), launching this year on both Xbox One and Xbox Series X.

For a while now, our dedicated development team in Cheshire, UK has been under the hood of this machine, turning a concept into reality. Well, gaming reality. You get what I mean. That concept? To make the boldest, bravest, most stylish off-road racing game ever made, where intense, competitive action is just the beginning of what blows you away in Dirt 5.

To the uninitiated who may not be clued up on the legacy of Dirt, let’s go for a drive, all the way back to 1998, when Colin McRae Rally brought the world of off-road racing into gaming and into the mainstream. With the series morphing into Dirt in 2007, it’s delivered high-impact extreme racing ever since – most recently through the brutal, ultra-realistic Dirt Rally 2.0. This time around with Dirt 5, we’re doing things a little… differently.

Take a peek at our announce trailer, first revealed exclusively during Inside Xbox, and you’ll see what we mean – from the stunning locations, to the epic racing, to the variety of vehicles and surfaces. We’re putting you behind the wheel of incredible off-road machines, in iconic real-world settings, to race through dynamic routes and extreme conditions. But don’t forget the concept. All that racing action is only part of the story.

We wanted to go bigger, in all possible ways. Take Career, which hands you a deep story-based mode with a star-studded cast, led by the legendary Troy Baker and Nolan North. These legendary voices of gaming, and some familiar names from the car culture world, lay out a story with decision-based changes and a proper narrative to get your teeth into.

There’s the franchise’s deepest livery editor and in-race Photo Mode, where you can show off your creative side. Then you’ve got the 12-player multiplayer action with playful objective-based modes, the four-player split-screen for offline frolics with your pals, and even more brand new features we’ll be revealing more on soon… I’m basically listing stuff at this point, but there’s so much going on here!

And not to forget: Everything we’re laying out here is raised up a notch through the, quite frankly, intimidating power of Xbox Series X. The team here has made use of the tools to create an unprecedented level of graphical fidelity and optimized performance. What does that mean for you in Dirt 5? Constant action, greater potential in gameplay, and seeing every spec of mud kick up and splat onto your windscreen. Ah, bliss.

Before I leave you, I wanted to give you a pro tip; a little pocket of knowledge to store away until Dirt 5 bursts onto the scene this Autumn. When you jump into this game, forget the norm. Forget expectations. Forget the ‘regular’ way of playing. Dirt 5 dares you – and rewards you – for being creative, stylish, and sometimes for being a straight-up lunatic.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443421/dirt-5-announced-coming-to-xbox-series-x-ps5-ps4-xbox-one/

Developer Systemic Reaction has announced three-player, online cooperative shooter, Second Extinction, for the Xbox Series X, Xbox One and Windows PC via Steam.

"I’m very proud of what our team has created," said Systemic Reaction managing director Tobias Andersson. "As a live game, we plan to support Second Extinction long-term, as we do with all our titles. We can’t wait for players to team up, start playing, and become part of our community."

Lead producer Brynley Gibson added, "Second Extinction is a real passion project for our tight-knit team, and we’re just getting started. It’s incredible how far we’ve come in this short time, and I’m super excited to reveal more details, including our live roadmap, in the coming months."

View the announcement trailer below:

Here is an overview of the game:

Second Extinction is an intense three-player cooperative shooter, where your goal is to wipe out the mutated dinosaurs that have taken over the planet. Teamwork is  vital as you adopt the role of one of the survivors, using a unique combination of  weapons, abilities and skills to take on the vast number of enemies. Fight through  a maelstrom of bullets, bombs, teeth, claws and gore, it’s up to you to reclaim  Earth!

Key Features:

• Intense Three-Player Co-Op – Earth is overrun by mutated dinosaurs! Team up with up to two other resistance fighters to take it back in short but intense combat operations.
• Battle Mutated Monstrosities – These dinos are nothing like the ones in your history books! From electric raptors  to behemoth T-Rexes that tower over the horizon, these deadly creatures have evolved into the ultimate killing machines.
• Experience Spectacular Action – Combine your fireteam’s unique weapons and abilities for explosive results  against overwhelming opposition in challenging combat set pieces.
• Take Part in a Joint Effort – Your actions, together with the rest of the community, will shape the course of  the war against the dinosaurs.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443423/fps-second-extinction-announced-for-xbox-series-x-xbox-one-and-pc/

It was confirmed at the Inside Xbox event today Vampire: The Masquerade - Bloodlines 2 will be getting a next generation release on the Xbox Series X. It was already confirmed the game will release on the PlayStation 4, Xbox One and Windows PC.

View the latest trailer below:

Here is an overview of the game:

Enter the World of Darkness and rise through vampire society. Experience Seattle - a city full of alluring, dangerous, characters and factions. You are dead now but stronger, quicker, more alluring and with potential for so much more. Choose to be brutal and unflinching or cultured and seductive. Use charm, cunning, terror and sheer will to rise through vampire society. What monster will you be?

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443424/vampire-the-masquerade-bloodlines-2-confirmed-for-xbox-series-x/

Bandai Namco has announced a new RPG, Scarlet Nexus, for the Xbox Series X and Xbox One. It will feature Smart Delivery. A release date was not announced. 

"The next generation of video game home consoles lets the development team realize the full potential of Scarlet Nexus," said producer Keita Iizuka. "Players can expect visuals and psychic battles with high resolution and frame rate along with fully interactive real-time battles with dynamic animation. Utilizing Smart Delivery on Xbox Series X also means players can enjoy the best version of Scarlet Nexus regardless of whether they are playing on the next generation with Xbox Series X or Xbox One."

Bandai Namco America senior brand manager Stephen Akana added, "Scarlet Nexus aims to change the way gamers view Japanese RPGs with a powerful futuristic aesthetic as well as a streamlined combat system that balances fast-paced action with strategic planning. Lead by an extremely talented team at Bandai Namco Studios, including members from fan-favorite title Tales of Vesperia, Scarlet Nexus combines years of game development experience with the excitement and creative freedom of the power behind the next generation of home console systems."

View the announcement trailer below:

Here is an overview of the game:

Scarlet Nexus takes place in the far distant future, where a psionic hormone was discovered in the human brain, granting people extra-sensory powers and changed the world as we knew it. As humanity entered this new era, deranged mutants known as Others began to descend from the sky with a hunger for human brains. Impervious to conventional weapons, those with acute extra-sensory abilities, known as psionics, were our only chance to fight the onslaught from above and preserve humanity. Since then, psionics have been scouted for their talents and recruited to the Other Suppression Force, humanity’s last line of defense.

In Scarlet Nexus, players will take on the role of Yuito Sumeragi, armed with a talent in psycho-kinesis, and explore the futuristic city of New Himuka and uncover the mysteries of a Brain Punk future caught between technology and physic abilities. With these psycho-kinetic powers, the world becomes an important ally. Lift, break, and hurl pieces of the environment to build attack combos and lay waste to enemies.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443425/bandai-namco-announces-rpg-scarlet-nexus-for-xbox-series-x-and-xbox-one/

Publisher Playism and developer FYQD-Studio announced Bright Memory: Infinite will launch for Xbox Series X alongside the previously announced PlayStation 4, Xbox One and Windows PC versions.

View the Xbox Series X trailer below:

Here is an overview of the game:

A Rich Sci-fi Story

Bright Memory: Infinite is set in a sprawling, futuristic metropolis in the year 2036.

The player will take on the role of Shelia, a member of the Supernatural Science Research Organization (SRO), an organization in possession of more advanced science and technology than even the military. Bright Memory: Infinite is full of breathtaking fun and exciting action, such as navigating a spaceship that can travel through time, battling ancient samurai displaced from 1000 years ago to the present, and exploring a wormhole that has appeared on Earth.

High-Speed 3D Combat

By now I’m sure everyone has seen Bright Memory: Infinite‘s appearance on Inside Xbox. In addition to the deep and rich story, another main feature of the game is its adrenaline-pumping gameplay design. With the way I’ve designed the battle system, players can experience lightning-fast combat using a variety of skills to create their own personalized style of fighting. Basically, any skills can be combined and will generate different effects when utilized and it’s up to the player to figure out how to best use these skills both in and out of battle. Some skills can be used to overcome certain obstacles or solve certain puzzles, be it in combat or while exploring the futuristic world.

Stunning Visual Effects

The quality of the graphics of Bright Memory: Infinite for the Xbox Series X is the aspect I focused most on throughout the game’s development, in order to truly harness and show off the abilities of the next-gen system. This can particularly be seen in the wormholes appearing in the game. I’ve also made use of the dramatic visual effects made possible by the Xbox Series X, which can be seen in dynamic scenes in which wind, rain, leaves, and pebbles are visibly sucked toward a wormhole as the player explores their surroundings. These stunning visual effects are all possible thanks to DirectX Raytracing (DXR) on the Xbox Series X.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443426/bright-memory-infinite-headed-to-xbox-series-x/

The Ascent is a new solo and co-op action RPG set in a cyberpunk world from developer Neon Giant and publisher Curve Digital. It was announced today during Microsoft's Inside Xbox showcase for the Xbox Series X and Xbox One. It will feature Smart Delivery. The Ascent will launch in Holiday 2020.

View the reveal trailer below:

Here is an overview of the game:

The Ascent is a solo and co-op action RPG set in a cyberpunk world. The mega corporation that owns you and everyone, The Ascent Group, has just collapsed. Confusion and chaos ensue, security and order are in disarray, and without protection, everyone is left to fend for themselves. Stop gangs and hostile corporations from taking over and discover what really happened.

Explore the Ascent Group arcology

Make allies as well as enemies as you explore the brimming arcology and its wide range of districts, from the deep slums to the higher luxury spheres.

Shoot and Loot

Consider enemies' height and weaknesses into account when fighting, making the most out of every opportunity. Take down even the worst opponents to find the rarest loot.

Customization and Augmentations

Modify your body with cyberware and gear up with weapons and equipment that suit your playstyle. Take a slick and precise approach or arm yourself to the teeth and go full chrome.

Solo or Co-op

Play the entire game alone or work together with up to three friends in local or online co-op.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443427/the-ascent-is-a-cyberpunk-action-rpg-announced-for-xbox-series-x-and-xbox-one/

Ubisoft has released the first look gameplay trailer for Assassin’s Creed Valhalla. The gameplay is "representative of Xbox Series X gameplay."

"As developers, we’re always excited to work with new hardware because it gives us a greater ability to express our creative vision," said Assassin’s Creed Valhalla creative director Ashraf Ismail. "Assassin’s Creed has always been committed to exploring new technologies and leveraging new consoles’ abilities to deliver the most immersive experience possible. We are excited to be collaborating closely with Microsoft to bring Assassin’s Creed Valhalla to the Xbox Series X."

View the Assassin’s Creed Valhalla gameplay trailer below:

Here is an overview of the game:

In Assassin’s Creed Valhalla, you are Eivor, a fierce Viking warrior raised on tales of battle and glory. Explore a dynamic and beautiful open world set against the brutal backdrop of England’s Dark Ages. Raid your enemies, grow your settlement, and build your political power in your quest to earn your place among the gods in Valhalla.

Key Features:

• Write Your Viking Saga – Advanced RPG mechanics allow you to shape the growth of your character and influence the world around you. With every choice you make, from political alliances and combat strategy to dialogue and gear progression, you will carve your own path to glory.
• Visceral Combat System – Dual-wield powerful weapons such as axes, swords, and even shields to relive the ruthless fighting style of the Viking warriors. Brutally decapitate your foes, vanquish them from afar, or stealthily assassinate targets with your hidden blade. Challenge yourself with the most varied collection of deadly enemies ever found in an Assassin’s Creed game.
• A Dark Age Open World – Sail from the harsh and mysterious shores of Norway to the beautiful but forbidding kingdoms of England and beyond. Immerse yourself in the Viking way of life through fishing, hunting, drinking games, and more.
• Lead Epic Raids – Launch massive assaults against Saxon troops and fortresses throughout England. Lead your clan in surprise attacks from your longship and pillage enemy territories to bring riches and resources back to your people.
• Grow Your Settlement – Construct and upgrade buildings that allow for deep customization, including a barracks, blacksmith, tattoo parlor, and more. Recruit new members to your clan and personalize your Viking experience.
• Mercenary Vikings – Create and customize a unique Viking raider within your clan and share it online with friends to use during their own raids.

Assassin’s Creed Valhalla will launch for Xbox Series X, PlayStation 5, PlayStation 4, Xbox One, Windows PC, and Google Stadia in Holiday 2020. The game will support Smart Delivery on the Xbox. This means if you purchase the game on the Xbox One or Xbox Series X, you will automatically gain access to the other version of the game. 

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443428/assassins-creed-valhalla-gets-xbox-series-x-first-look-gameplay-trailer/

SEGA announced Yakuza: Like a Dragon will be a launch title for the Xbox Series X, and it will also be coming to the Xbox One and Windows PC via Steam. The game has previously been confirmed to launch in the west for the PlayStation 4. 

The Xbox Series X and Xbox One version of the game will support Smart Delivery and cross-save functionality.

View the Yakuza: Like a Dragon Xbox Series X cinematic trailer below:

Here is an overview of the game:

The Story Begins…

Yakuza: Like a Dragon is, at its core, an underdog story about fighting for what you believe in, even when you’re at rock bottom. Our new main protagonist, Ichiban Kasuga, a low-ranking grunt of a low-ranking yakuza family, takes the fall for a crime he didn’t commit in order to protect his patriarch and father-figure, Masumi Arakawa. After serving an 18-year prison sentence, he returns to society to discover that the clan he once belonged to has been destroyed, its few remaining members are being hunted in the streets, and learns that his former patriarch may be the man responsible for it all. Facing an unimaginable sense of betrayal, loss, and confusion, he sets out to discover the truth. This is where Yakuza: Like a Dragon’s story begins.

A Truly Outrageous RPG Like You’ve Never Seen Before

Along with the all-new cast and setting, Yakuza: Like a Dragon introduces a new dynamic RPG combat system that takes the genre somewhere it’s never been before – present-day Japan. Ichiban is a diehard RPG fan, so to help him stay focused in fights, he imagines the battlefield as if he was living in one of his favorite games. In Yakuza: Like a Dragon, players will level up 19 different ‘Jobs’ far from traditional RPG fare – not Warriors or Mages, but Bodyguards and Musicians, with completely unique strengths and skills. Get ready to step into Ichiban’s shoes and crack some skulls in style!

Welcome to the Underworld Playground

Even with so many changes, Yakuza: Like a Dragon still retains the core Yakuza experience, and a large part of that is the seemingly endless supply of hilarious minigames and substories spread throughout the city. Over 50 substories and a collection of never-before-seen minigames, as well as the return of fan-favorites like Karaoke and SEGA Arcades will ensure that players will enjoy their time in Yokohama to the fullest.

Yakuza: Like a Dragon is everything that fans know and love about the series, with several over the top twists for the next generation. Featuring an entirely-new cast of characters and taking place in the brand new and beautifully-realized setting of Yokohama, players can jump right into the drama, action, and hilarity that Yakuza is known for.

Character Introductions

• Ichiban Kasuga (voiced by Kazuhiro Nakaya) – Of the Arakawa Family, a Tojo Clan subsidiary. A low-ranking member of a low-ranking family, Kasuga is asked by his patriarch and father-figure, Masumi Arakawa, to turn himself in for a murder committed by the family captain, Jo Sawashiro. He is released after serving 18 years in prison, only to discover that the Tojo Clan has been eradicated from Kamurocho and in its place is the Omi Alliance of Kansai—and that Masumi Arakawa may be behind all of it. Seeking the truth, he heads to meet with his former patriarch.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443429/yakuza-like-a-dragon-is-a-launch-title-for-xbox-series-x/

A centenarian who tested positive for COVID-19 has become the oldest local resident to die from the virus. The woman in her 100s was a resident of a long-term care or retirement home. She died on Thursday, the Windsor-Essex County Health Unit reported during its end-of-week epidemic data summary on Friday. “I would like to […]

City of Windsor payouts on personal injury and property damage claims totaled $2.1 million in 2019, the lowest number in eight years. The total — for settlements as well as court decisions — was well below the $3 million budgeted for the hundreds of claims made each year against the city for everything from trip-and-falls, […]

We have to capture carbon dioxide to slow climate change, but instead of simply burying it we could first use it to extract useful metals from old electrical equipment