Background:

Discharge communication between hospitalists and primary care clinicians is essential to improve care coordination, minimize adverse events, and decrease unplanned health services use. Health-related social needs are key drivers of health, and hospitalists and primary care clinicians value communicating social needs at discharge.

The SARS-CoV-2 frameshifting element (FSE) has been intensely studied and explored as a therapeutic target for coronavirus diseases, including COVID-19. Besides the intriguing virology, this small RNA is known to adopt many length-dependent conformations, as verified by multiple experimental and computational approaches. However, the role these alternative conformations play in the frameshifting mechanism and how to quantify this structural abundance has been an ongoing challenge. Here, we show by DMS and dual-luciferase functional assays that previously predicted FSE mutants (using the RAG graph theory approach) suppress structural transitions and abolish frameshifting. Furthermore, correlated mutation analysis of DMS data by three programs (DREEM, DRACO, and DANCE-MaP) reveals important differences in their estimation of specific RNA conformations, suggesting caution in the interpretation of such complex conformational landscapes. Overall, the abolished frameshifting in three different mutants confirms that all alternative conformations play a role in the pathways of ribosomal transition.

Background

Halm's clinical stability criteria have long guided antibiotic treatment and hospital discharge decisions for patients hospitalised with community-acquired pneumonia (CAP). Originally introduced in 1998, these criteria were established based on a relatively small and select patient population. Consequently, our study aims to reassess their applicability in the management of CAP in a contemporary real-world setting.

Hepatocyte nuclear factor 4 alpha antisense 1 (HNF4A-AS1) is a long noncoding RNA (lncRNA) gene physically located next to the transcription factor HNF4A gene in the human genome. Its transcription products have been reported to inhibit the progression of hepatocellular carcinoma (HCC) and negatively regulate the expression of cytochrome P450s (CYPs), including CYP1A2, 2B6, 2C9, 2C19, 2E1, and 3A4. By altering CYP expression, lncRNA HNF4A-AS1 also contributes to the susceptibility of drug-induced liver injury. Thus, HNF4A-AS1 lncRNA is a promising target for controlling HCC and modulating drug metabolism. However, HNF4A-AS1 has four annotated alternative transcripts in the human genome browsers, and it is unclear which transcripts the small interfering RNAs or small hairpin RNAs used in the previous studies are silenced and which transcripts should be used as the target. In this study, four annotated and two newly identified transcripts were confirmed. These six transcripts showed different expression levels in different liver disease conditions, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and obesity. The expression patterns of all HNF4A-AS1 transcripts were further investigated in liver cell growth from human embryonic stem cells to matured hepatocyte-like cells, HepaRG differentiation, and exposure to rifampicin treatment. Several HNF4A-AS1 transcripts highly displayed correlations with these situations. In addition, some of the HNF4A-AS1 transcripts also showed a strong correlation with CYP3A4 during HepaRG maturation and rifampicin exposure. Our findings provide valuable insights into the specific roles of HNF4A-AS1 transcripts, paving the way for more targeted therapeutic strategies for liver diseases and drug metabolism.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small-molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99- to 1.31-fold from clinical trial results for inhibition with itraconazole, whereas exposure predictions for the induction with rifampicin were less accurate, with deviations of 0.22- to 0.48-fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method.

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures of CYP-sensitive substrates coadministered with cytokine modulators as reported in the University of Washington Drug Interaction Database were extracted and examined for each of the CYPs. Coadministration of cytochrome P450 family 3 subfamily A (CYP3A) (midazolam/simvastatin), cytochrome P450 subfamily 2C19 (omeprazole), or cytochrome P450 subfamily 1A2 (caffeine/tizanidine) substrates with anti-interleukin-6 and with anti-interleukin-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ –58% to ~35%; no significant trends were observed for cytochrome P450 subfamily 2D6 (dextromethorphan) and cytochrome P450 subfamily 2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when coadministered with tocilizumab, suggest a ~six- to sevenfold increase in midazolam clearance, suggesting potential implications of cytokine–CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of nonclinical and clinical assessments of cytokine–CYP drug interactions in drug discovery and development.

Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including carboxylesterase (CES)-1 CES2, arylacetamide deacetylase (AADAC), paraoxonase (PON)-1 PON3, and cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared with other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases.

ABSTRACTIntroduction:Since the health information system (HIS) in public health care services in Serbia was introduced in 2009, it has gradually expanded. However, it is unclear how well the HIS components have developed and the whole system’s stage of maturity.Method:In June–September 2021, a maturity assessment of the Serbian HIS was conducted for the first time using the HIS Stages of Continuous Improvement (SOCI) toolkit. The toolkit measures HIS status across 5 HIS domains: leadership and governance, management and workforce, information and communication technology (ICT), standards and interoperability, and data quality and use. The domains were further divided into 13 components and 39 subcomponents whose maturity stage was assessed on a 5-point Likert scale, indicating the level of development: (1) emerging/ad hoc; (2) repeatable; (3) defined; (4) managed; and (5) optimized. The toolkit was applied in a working group of 32 professionals and experts who were engaged in developing the new national eHealth strategy and action plan.Results:The overall maturity score of the Serbian HIS was 1.6, which indicates a low level. The highest baseline score (2) was given to the standards and interoperability domain, and the lowest (1.1) was given to ICT infrastructure. The remaining 3 domains (leadership and governance, Management and Workforce, and Data Quality and Use) were similarly rated (1.7, 1.7, and 1.6, respectively).Conclusion:A baseline assessment of the maturity level of Serbian HIS indicates that the majority of components are between the emerging/ad hoc stage and repeatable, which represent isolated, ad hoc efforts, with some basic processes in place and existing and accessible policies. This exercise provided an opportunity to address identified weaknesses in the upcoming national eHealth strategy.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7–10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain.

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [¹¹C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60–90 or 70–90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD.

Neuroendocrine tumor (NET) metastases to the heart are found in 1%–4% of NET patients and have been reported primarily in the form of individual cases. We investigated the prevalence, clinical characteristics, imaging features, and outcomes of NET patients with cardiac metastases on ⁶⁸Ga-DOTATATE PET/CT. Methods: ⁶⁸Ga-DOTATATE PET/CT of 490 consecutive patients from a single institution were retrospectively reviewed for sites of metastases. The cumulative cardiovascular event rate and overall survival of patients with cardiac NET metastases (CNMs) were compared with those of a control group of metastatic NET patients without cardiac metastases. In patients with CNMs, the cardiac SUV_max with and without normalization to the myocardial background uptake was compared with a separate cohort of 11 patients with active cardiac sarcoidosis who underwent ⁶⁸Ga-DOTATATE PET/CT for research purposes. Results: In total, 270 patients with metastatic NETs were identified, 9 (3.3%) of whom had CNMs. All 9 patients had grade 1–2 gastroenteropancreatic NETs, most commonly from the small intestine (7 patients). The control group consisted of 140 patients with metastatic grade 1–2 gastroenteropancreatic NETs. On Kaplan–Meier analysis, there was no significant difference in the risk of cardiovascular adverse events (P = 0.91 on log-rank test) or mortality (P = 0.83) between the metastatic NET patients with and without cardiac metastases. The degree of cardiac DOTATATE uptake was significantly higher in CNMs than in patients with cardiac sarcoidosis without overlap, in terms of both cardiac SUV_max (P = 0.027) and SUV_max–to–myocardial background ratio (P = 0.021). Conclusion: Routine ⁶⁸Ga-DOTATATE PET/CT can be used to identify CNMs in 3% of patients with metastatic NETs. CNMs do not confer added cardiovascular or mortality risk. A distinguishing feature of CNMs is their high degree of DOTATATE uptake compared with focal myocardial inflammation.

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders.

BACKGROUND AND PURPOSE:

World Health Organization (WHO) grade 2 and 3 diffuse gliomas account for approximately 5% of primary brain tumors. They are invasive and infiltrative tumors and have considerable morbidity, causing progressive neurologic deterioration. The mean survival time is <10 years from diagnosis. Surgical debulking represents first-line management. The extent of resection is associated with progression-free and overall survival. Radiologic assessment of the extent of resection is challenging. This can be underestimated on early postoperative MRI, meaning that accurate assessment may be achieved only on delayed follow-up imaging. We hypothesized that DWI may help facilitate more reliable estimates of the extent of resection on early postoperative MRI. This study aimed to assess the utility of DWI in early postoperative MRI to evaluate the extent of resection.

BACKGROUND AND PURPOSE:

Gadolinium-based contrast agents are widely used for meningioma imaging; however, concerns exist regarding their side effects, cost, and environmental impact. At the standard gadolinium dose, most meningiomas show avid contrast enhancement, suggesting that administering a smaller dose may be feasible. The purpose of this study was to evaluate the impact of a lower gadolinium dose on the differentiation between meningiomas and adjacent intracranial tissues.

BACKGROUND AND PURPOSE:

Preoperative assessment of meningioma consistency is beneficial for optimizing surgical strategy and prognosis of patients. We aim to develop a noninvasive prediction model for meningioma consistency utilizing MR elastography and DTI.

Central sleep apnoea (CSA) is characterised by recurrent episodes of airway cessation or reduction in the absence of respiratory effort. Although CSA is less common than obstructive sleep apnoea, it shares similar symptoms. CSA can be secondary to various medical conditions, high altitude and medication exposure. CSA can also emerge during obstructive sleep apnoea therapy. There are a range of treatment options and selecting the right therapy requires an understanding of the pathophysiology of CSA. This review explores the aetiology, pathophysiology and clinical management of non-hypercapnic CSA.

Pitched as a mix of ‘Blade Runner’ and ‘Jurassic Park,’ Neom is the world’s biggest construction project. Twenty-one thousand people have died so far to make it happen.

Tim Miller hopes Amazon's anthology series will help viewers appreciate the "blood, sweat, and tears" Firewalk Studios put into the scrapped game.

Watch Video | Listen to the Audio

The United Nations says South Sudan’s four-year-old civil war has left half of the nation’s population — 6 million people — in need of humanitarian aid. The conflict began when South Sudan’s army split between factions loyal to President Salva Kiir and former Vice President Riek Machar. The two men mobilized their respective tribes, the Dinka and the Nuer. The war has caused what is now one of the world’s worst refugee crises.

SIMONA FOLTYN: Civil war is emptying huge swaths of South Sudan. The violence has uprooted four million people, including two million who’ve fled to neighboring countries. In the last year, more than a million South Sudanese have poured into northern Uganda alone, crossing makeshift bridges like this one to flee fighting, hunger, and brutal attacks on civilians.

SEME LUPAI, REFUGEE: They started fighting very, very severely. So that made us to escape with our properties to this side.

SIMONA FOLTYN: When Seme Lupai’s family went to one of the refugee camps, initially, he stayed behind to look after the family’s most precious commodity — their cattle. He hid for a year to escape the violence. The refugees carry whatever they can salvage — mattresses, pots, clothes, notebooks — remnants of once peaceful lives turned upside down. At checkpoints, Ugandan soldiers search their belongings for weapons, before the refugees proceed to reception centers. After entering Uganda, the refugees sign in at small waystations. For many, it’s the first night spent in safety after walking for days to escape fighting. Levi Arike fled with his wife and four children.

LEVI ARIKE, REFUGEE: When the gunshots started, we laid under a tree with the whole family, because there was nowhere else to hide. We waited for the fighting to stop, and then we got up and started walking to Uganda.

SIMONA FOLTYN: Uganda now shoulders most of the burden of Africa’s biggest refugee crisis, managing a constellation of camps which require food, water, healthcare, and policing. At Imvepi Camp, now home to more than 120,000 South Sudanese, new arrivals receive vaccinations, hot meals, and basic items such as soap and plastic tarps to build a house. The government also gives each refugee family a small plot of land, about a twentieth of an acre, where they can build a tent shelter and grow crops to eat or sell. But the land often proves too rocky for farming.

SIMONA FOLTYN, IMVEPI REFUGEE CAMP, NORTHERN UGANDA: After completing the registration process, the new arrivals will receive their plot, to start a new life as refugees in Uganda. While they are safe here, there are many challenges ahead, not least processing the trauma of what they experienced back home.

This woman, who we’ll call “Agnes,” agreed to tell us about her harrowing experience. She says four government soldiers from President Salva Kiir’s Dinka tribe stopped her as she was fleeing South Sudan and raped her right in front of her family.

AGNES (translated to English): When they started raping me, they told me not to raise alarm, otherwise they would shoot me. Still when I’m sleeping, I’m dreaming of the Dinka, that they are coming to rape me again.

SIMONA FOLTYN: How often do you have those dreams?

AGNES: Daily, every time I lie down, those dreams come.

SIMONA FOLTYN: A recent Human Rights Watch report on South Sudan found “…a clear pattern of government forces unlawfully targeting civilians for killings, rapes, torture…and destruction of property..” The victims are from ethnic groups suspected to support the rebels.

AGNES: They are doing it, because they know very well that those soldiers are our brothers. So they do it to punish them..

SIMONA FOLTYN: Although the rebels, known as the Sudan People’s Liberation Army In Opposition, purport to protect local communities, there are also reports of their fighters assaulting civilians near the Ugandan border. Josephine Yanya told us she didn’t feel safe in the presence of either side’s soldiers. Her family and neighbors fled their village after government soldiers killed her uncle.

They hid in the mountains only to find themselves under attack again, this time by opposition fighters from the Nuer tribe loyal to former vice president Riek Machar. Yanya says ethnic Nuer soldiers from the SPLA-IO rebel group raped a member of her group and stole her father’s’ cattle.

JOSEPHINE YANYA (translated to English): Before we were thinking that the rebels would protect us, but if they are lacking food, they just come and take things by force.

SIMONA FOLTYN: With nowhere left to hide, Yanya fled to Uganda with her son.
But instead of finding a place to rebuild their lives, they are in limbo. And aid groups don’t have enough food to distribute.

JOSEPHINE YANYA (translated to English):We are getting small food rations. I know it won’t be enough even for one month.

SIMONA FOLTYN: According to the United Nations, the international community has given less than a-third of the $1.4 billion dollars needed for the refugee response in South Sudan’s neighboring countries. These refugees foresee more hardship and have no idea when they might return home.

JOSEPHINE YANYA (translated to English): I’m always praying for peace in South Sudan, and until then, I’ll just stay here.

The post South Sudan civil war causes Africa’s worst refugee crisis appeared first on PBS NewsHour.

Up to 650 houses could be built on land at the golf club

Kelley watches DVDs like a caveman. Josh chews on all the expensive things. Meanwhile, Chris stands by some barrels.

The post RPG Cast – Episode 609: “Throwing Corpses at the Door Till You Let Me In” appeared first on RPGamer.

Kelley starts a Reddit fight. Robert learns about purrkour gaming. Pascal makes plans to be a booth babe. Chris eats the mic like it's meat flavored cereal. Mung beans.

The post RPG Cast – Episode 732: “Excited PoE Noises” appeared first on RPGamer.

Sony president Hiroki Totoki in a Q&A session with investors was asked about the failure of Concord, which was shut down less than two weeks after it released.

"Currently, we are still in the process of learning," said Totoki (via VideoGamesChronicle). "And basically, with regards to new IP, of course, you don’t know the result until you actually try it.

"So for us, for our reflection, we probably need to have a lot of gates, including user testing or internal evaluation, and the timing of such gates. And then we need to bring them forward, and we should have done those gates much earlier than we did.

"Also, we have a siloed organisation, so going beyond the boundaries of those organisations in terms of development, and also sales, I think that could have been much smoother.

"And then going forward, in our own titles and in third-party titles, we do have many different windows. And we want to be able to select the right and optimal window so that we can deploy them on our own platform without cannibalization, so that we can maximize our performance in terms of title launches. That’s all I have."

Sony senior vice president for finance and IR Sadahiko Hayakawa discussed the success of Helldivers 2 and the failure of Concord.

"We launched two live-service games this year," he said. "Helldivers 2 was a huge hit, while Concord ended up being shut down. We gained a lot of experience and learned a lot from both.

"We intend to share the lessons learned from our successes and failures across our studios, including in the areas of title development management as well as the process of continually adding expanded content and scaling the service after its release so as to strengthen our development management system.

"We intend to build on an optimum title portfolio during the current mid-range plan period that combines single-player games – which are our strengths and which have a higher predictability of becoming hits due to our proven IP – with live-service games that pursue upside while taking on a certain amount of risk upon release."

Concord released for the PlayStation 5 and PC on August 23, and it was shut down on September 6.

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 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463026/sony-discusses-what-lessons-can-be-learned-from-the-failure-of-concord/

Publisher Kasedo Games and developer Beard Envy have announced he roguelite spaceship repair simulation game, Uncle Chop's Rocket Shop, has been delayed to December 5. It will launch for the PlayStation 5, Xbox Series X|S, Nintendo Switch, and PC via Steam and Epic Games Store.

View the release date trailer below:

Read details on the game below:

Come on down to Uncle Chop’s Rocket Shop, for all your roguelite spaceship repair simulation needs! Wake up, clock in, fix ships, make friends and enemies, pay R.E.N.T., upgrade your workshop, ponder the futility of your existence, go to bed and then do it all over again the next day.

On an asteroid-bound service station in an unfrequented space lane, Wilbur carves out a paltry living as a mechanic, repairing as many ships as he can to afford the ever-rising R.E.N.T payments to his corporate overlord, Uncle Chop. Where most of his customers find meaning in pastimes like worshipping deranged space gods, feeding random crap to a sentient black hole, endlessly digging for The Treasure™ or mentally enslaving donut shop workers, Wilbur lives a more humble life, fixing the galaxy’s ills one broken ship module at a time.

Fix Stuff

Using a range of tools, diagnostic devices, parts and workshop appliances, you’ll be correcting faults in the modules of procedurally generated spaceships. From simple refuel jobs to total overhauls, get ready to frantically fumble, slice, loosen, tighten, grab and drop as you try to complete as many jobs as you can within each daily time limit. With a huge variety of ships and modules, your hands are gonna get real dirty real fast, in some real unusual places.

Read Stuff

Flaunt your basic literacy by consulting manual pages for guidance on diagnosing and correcting faults in spaceship modules, as well as operating workshop appliances. And if basic literacy isn’t your bag, then at least you’ve got pretty diagrams to gawp at! All your IKEA furniture-assembly training has led to this moment.

Upgrade Stuff

Using whatever hard-earned pennies Uncle Chop doesn’t take from you, expand your workshop and kit it out with a range of workstations. From industrial devices to esoteric altars, these workstations will allow you to fix bigger and more lucrative ships.

Talk About Stuff

Interact with a diverse range of oddballs as you engage with both anthology-style storytelling and a multiple-ending, overarching narrative. The lore is (*consults notes*) “deep and rich and good,” with different factions you can choose to ingratiate yourself with – each with their own inane agendas.

Discover Stuff

Narrative and random events, hidden puzzles and upgrades, secret lore—we got all that goodness that ensures each day and gameplay run will feel substantially different from the last.

Do All That Stuff Again, But Better

Meeting those escalating R.E.N.T payments ain’t gonna be easy, but chin up, champ – certain station upgrades will persist across gameplay runs, making life a little more tolerable every time around. You’ll also get faster and smarter the more you do the thing, so keep doing the thing!

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 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463037/uncle-chops-rocket-shop-releases-december-5-for-ps5-xbox-series-xs-switch-and-pc/

The PlayStation 5 was the best-selling console in the UK in October, according to GfK Entertainment data reported by GamesIndustry. 

The Xbox Series X|S was the second best-selling console for the month, followed by the Nintendo Switch in third. The Xbox Series X|S has also surpassed the Switch in year-to-date sales.

Sales for the PS5 are up 27 percent month-on-month and down 18 percent year-on-year. Sales for the Switch are up 13 percent month-on-month and down 18 percent year-on-year. Sales for the Xbox Series X|S are down seven percent month-on-month and down 17 percent year-on-year. 

Overall, there were just under 144,000 video game consoles sold (NielsenIQ/GfK panel data) in the UK in October 2024. This is down 18 percent year-on-year.

GSD data shows there were 2.9 million games sold in October 2024, which is up 3.2 percent year-on-year. 

Call of Duty: Black Ops 6 debuted in first place on the software charts (digital and physical combined). Sales are 11 percent lower than the launch month of 2023's 2023's Call of Duty: Modern Warfare III, however, this is most likely due to the number of people playing the game via Xbox Game Pass.

Sales of Call of Duty: Black Ops 6 are up 24 percent year-on-year on PlayStation consoles, while sales dropped on Xbox consoles and PC. 75 percent of total sales were on PlayStation consoles, followed by 15 percent on PC, and just under 11 percent on Xbox consoles.

Dragon Ball: Sparking! Zero debuted in third place with the first four week of sales up 80 percent compared to 2020's Dragon Ball Z: Kakarot.

Undisputed debuted in fourth place and had the second biggest launch for a sports title in 2024. Only EA Sports FC 24 had a bigger launch.

The remake of Silent Hill 2 debuted in fifth place. Launch sales are 32 percent lower than the remake of Dead Space and 62 percent lower than the remake of Resident Evil 4.

Super Mario Party Jamboree debuted in ninth place. Sales are 11 percent higher than 2018's Super Mario Party, but are four percent lower than 2021's Mario Party Superstar. It should be noted Nintendo doesn't share digital sales with these charts.

Sonic X Shadows Generations debuted in 10th place. Sales for the game are 150 percent compared to 2023's Sonic Superstars, but are down 21 percent compared to 2022's Sonic Frontiers.

Metaphor: Refantazio debuted in 12th place and the new version of Until Dawn debuted in 30th place.

EA Sports FC 25 came in second place with sales down 14 percent year-on-year.

There were over 681,000 accessories and add-on products sold in the UK in October, which is up nearly 16 percent year-over-year, but is down over eight percent month-on-month.

The White DualSense controller was the best-selling accessory, followed by the Midnight Black DualSense controller. The PlayStation Portal Remote Player is up four spots to take fourth place.

Here are the top 10 best-selling games in the UK (Digital + Physical):

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 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463042/ps5-best-seller-in-the-uk-in-october-black-ops-6-leads-strong-month-of-new-releases/

Publisher indie.io and developer Maple Powered Games announced G.I. Joe: Wrath of Cobra will launch for PlayStation 5, Xbox Series X|S, and Nintendo Switch on November 21.

The game is currently available for PC Steam, Epic Games Store, and GOG.

View the console reveal date trailer below:

Read details on the game below:

Cobra rears its ugly head yet again and it’s up to G.I. Joe to save the world! Embracing the 1980s era of the iconic universe, Wrath of Cobra is a retro side-scrolling beat ’em up. Play as one of the legendary G.I. Joe characters, including Duke, Scarlett, Roadblock, Snake Eyes, and more. Defeat hordes of Cobra troopers, Vipers, Crimson Guards and more of Cobra’s malevolent machinations.

Bring Cobra down, striking back at the likes of Destro, Serpentor, Baroness, and Cobra Commander himself! Fight your own way: Rely on your fists and get up close and personal using each character’s unique combos and special moves or keep your foes at a distance with a variety of weapons!

Retro Gameplay in a Modern Era

Wrath of Cobra takes the classic arcade beat ’em up and brings it into the modern age: Easy to play, hard to master, and smoother than a ride in a H.I.S.S. Want to play with your friends? The game supports local multiplayer (eg. from your couch) and online co-op!

Play as Classic Heroes

Fight Cobra as your favorite G.I. Joe heroes, painstakingly recreated in beautiful pixel art. The differences between characters aren’t just cosmetic: Each hero has different movesets and unique abilities. From the fast and nimble Snake Eyes to the rough and tumble Roadblock, each character is true to form!

Battle Iconic Villains

Cobra isn’t just the Cobra Commander, it’s also its legions! Face hordes of troopers, armored Alley Vipers, artificial B.A.T.s, armed with some of the most iconic weapon systems in the franchise, including the H.I.S.S., C.L.A.W., and the notorious Trubble Bubble.

Retro-Infused Soundtrack

Foil the Commander’s plot to the beat of classic G.I. Joe themes, reimagined by industry veterans at Kid Katana Records, bringing a modern twist to classic arcade music!

Post-Launch Support

Like Destro’s plots, Wrath of Cobra will continue with extensive post-launch support, bringing more G.I. Joe heroes into the fray, adding new game modes, levels, and more to keep the G.I. Joe legacy alive!

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 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463047/gi-joe-wrath-of-cobra-releases-november-21-for-ps5-xbox-series-xs-and-switch/

Journalists at CNN, including some of the network’s biggest personalities, are living in fear of “inevitable” layoffs and pay cuts as its new CEO looks to shore up finances amid declining ratings.

That’s according to The Ankler, which reported Wednesday that 77-year-old Chris Wallace—whose already been relegated to a weekend program—is among the network’s most well-known names whose future is in limbo.

Wallace’s $8.5 million contract, signed by the ex-CNN boss Jeff Zucker to recruit him away from Fox News three years ago, is reportedly up and he was spotted in CEO Mark Thompson’s office on Tuesday.

Read more at The Daily Beast.

Disaster was averted at a Kentucky hospital when an ostensibly deceased organ donor began “thrashing” around in the operating theater, a preservationist tells NPR.

“He was moving around,” Natasha Miller recalled of the patient, whom NPR identified as Anthony Thomas “TJ” Hoover II. “He was crying visibly.”

The two surgeons assigned to the transplant naturally refused to go through with the procedure, which was reportedly scheduled to take place at Baptist Health Richmond Hospital in October 2021. But when her colleague called Kentucky Organ Donor Affiliates, which coordinated the harvest, Miller said the supervisor told them they “were going to do the case” and needed to “find another doctor.”

Read more at The Daily Beast.

Like a plague doctor delicately administering another handful of leeches, Ice Pick Lodge have shared a bit more about the recently announced Pathologic 3, explaining how their plans for the cult epidemic-battling series have progressed since the release of Pathologic 2.

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I was excited for Slitterhead, an action adventure game by Bokeh Studio, a studio founded by none other than your boy Keiichiro Toyama: the creator of Silent Hill, Gravity Rush, and the Siren series. And within that first hour, Slitterhead's body-possessing and Hong Kong-inspired streets had me thinking, "Is this it, the sleeper hit of 2024?!"

No, sadly not. It's no doubt built a compelling universe filled with brain-sucking aliens that masquerade as humans, and it attempts plenty else besides: bouncing between bodies as you stealth around dingy apartment blocks, fighting with blood katanas, and gorging on pools of red plasma to refuel skills, many of which require more body-flitting. Thing is, they are ultimately just attempts, attempts that fall victim to an emptiness and jitteriness that quickly reveals Slitterhead's true, irritating form.

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Call Of Duty: Black Ops 6 has been out for a little while already, what with me giving its multiplayer largely a thumbs up. Still, it's an ever-evolving thing and Activision have announced the game's first seasonal drop. It's a hefty one with a lot of additions, so I'll try my best to break down the good stuff. TLDR: there's some new maps for multiplayer and zombies, new modes, and a few extra bits. I'm mildly excited for more. More in this case is good.

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HARI SREENIVASAN: In the day’s other news: Attorney General Jeff Sessions insisted he never lied to the Senate Judiciary Committee about his conversations with the Russian ambassador during the presidential campaign. At a hearing today, he bridled at Democratic Senator Al Franken’s accusation that he’d — quote — “moved the goalposts” on the nature of his discussions.

SEN. AL FRANKEN, D-Minn.: First it was, I didn’t have communications with Russians, which wasn’t true. Then it was, I never met with any Russians to discuss any political campaign, which may or may not be true.

Now it’s, I didn’t discuss interference in the campaign.

JEFF SESSIONS, Attorney General: Well, let me just say without hesitation, that I conducted no improper discussions with the Russians at any time regarding the campaign or any other item facing this country.

HARI SREENIVASAN: Sessions has recused himself from the Justice Department’s investigation into Russia’s election meddling.

President Trump had new criticism today for former FBI Director James Comey over the Hillary Clinton e-mail probe. He complained again that Comey decided to clear Clinton before she was even interviewed. That’s based on newly released draft statements by Comey from May of 2016. FBI officials say it was already clear that no charges were warranted.

On another issue, the president faced fallout over the death of Army Sergeant La David Johnson in Niger this month. Congresswoman Frederica Wilson says she was with Mrs. Johnson when the president called. The Florida Democrat told The Washington Post that Mr. Trump said — quote — “He knew what he was signing up for, but I guess it hurts anyway.”

The sergeant’s mother confirmed it, but the president denied it, and White House Press Secretary Sarah Huckabee Sanders went after Wilson.

SARAH SANDERS, White House Press Secretary: This is a president who loves our country very much, who has the greatest level of respect for men and women in uniform and wanted to call and offer condolences to the family, and I think to try to create something from that, that the congresswoman is doing, is, frankly, appalling and disgusting.

HARI SREENIVASAN: The Post also reported on another incident today. It quoted the father of a soldier killed in Afghanistan as saying the president offered $25,000 from his personal account, but never followed through.

We will get more detail on all of this after the news summary.

The death toll in Northern California’s wildfires rose to 42 today. Officials in Sonoma County found the remains of the latest victim, as they searched hundreds of burned homes. Meanwhile, fire crews made new gains overnight with the help of cooler weather and low winds.

A two-time Olympic medalist says the former team doctor for U.S. women’s gymnastics sexually abused her for years. McKayla Maroney is the highest profile athlete to come forward in the scandal. In a statement today, she said Dr. Larry Nassar began molesting her when she was just 13. He’s awaiting sentencing on a child pornography charge, but has denied any sexual abuse.

More questions tonight about drug pricing. A new study finds the costs of injectable cancer drugs, approved since 1996, rose an average of 25 percent over eight years. That’s far higher than the rate of inflation. The study was based at Emory University and published in “The Journal of Clinical Oncology.”

And on Wall Street, health insurers and IBM fueled a surge in stocks today. The Dow Jones industrial average gained 160 points, more than half-a-percent, to close above 23000 for the first time. The Nasdaq rose just a fraction, and the S&P 500 was up two points.

The post News Wrap: Sessions insists he didn’t lie about Russian contacts to Senate appeared first on PBS NewsHour.

October marked the "biggest" sales month for supermarkets in the UK so far despite food price hikes.

A Labour minister confirmed that the application process for Personal Independence Payment is being 'kept under review'

NASA is investigating a strange noise coming through the speaker on Boeing’s Starliner capsule, which has been beset with technical issues

See the world's best space images from the Astronomy Photographer of the Year 2024 award

Moin Hussain's debut feature film Sky Peals sees a man discover his father may be from outer space. Part sci-fi, part family drama, part coming-of-age tale, it is odd and otherworldly

An artificial intelligence model that can identify the calls of eight whale species is helping researchers track the elusive whale behind a perplexing sound in the Pacific

What happens if AI is trained to write choral music by feeding it a specially created vocal dataset? Moving new exhibition The Call tackles some thorny questions about AI and creativity – and stirs the soul with music

Can we trust whatever is going on with Becky Minkoff?

Gary Lineker is the longest-serving Match of the Day host since the BBC first aired the show in 1964.

November and December will nominally be about confirming judges and kicking the can on must-pass bills. More ambitious efforts probably aren't happening.

From Goats to airplanes, Xbox Game Pass has another bumper month in store for subscribers. Here's everything you need to know about what is heading to PC and console this November 2024