A prefilled syringe (PFS) should be able to be adequately and consistently extruded during injection for optimal safe drug delivery and accurate dosing. To facilitate appropriate break-loose and gliding forces (BLGFs) required during injection, certain primary packaging materials (PPMs) such as the syringe barrel and plunger are usually coated with silicone oil, which acts as a lubricant. Due to its direct contact with drug, silicone oil can increase the number of particles in the syringe, which could lead to adverse interactions. Compliance with regulatory-defined silicone oil quantities in certain drug products, such as ophthalmics, presents a trade-off with the necessity for desirable low and consistent BLGF. In addition to its siliconization, the dimensional accuracy of the PPM has an important role in controlling the BLGF. The dimensions of the PPM are individualized depending on the product and its design and have certain tolerances that must be met during manufacturing. Most studies on ophthalmics focused on the adverse interactions between silicone oil and the drug. To the authors' knowledge, there have been no public studies so far that have investigated the impact of the dimensional variability of the PPM on the BLGF in ophthalmic PFSs. In this study, we applied advanced optical shaft and tactile measuring technologies to investigate this impact. The syringes investigated were first sampled during aseptic production and tested for the BLGF. Subsequently, defined dimensions of the PPM were measured individually. The results showed that the dimensional variability of the PPM can have a negative impact on the BLGF, despite their conformity to specifications, which indicates that the currently available market quality of PPMs is improvable for critical drug products such as ophthalmics. This study could serve as an approach to define product-specific requirements for primary packaging combinations and thus appropriate specifications based on data during the development stage of drug products.

Obidoxime chloride is an antidote for nerve gas intoxication. As an emergency medicine, it is being stored by the Israel Defense Forces (IDF) scattered throughout Israel in depots without a controlled environment (field conditions), thus being exposed to high and fluctuating temperatures. These conditions do not meet the manufacturer’s requirements. In addition, due to possible supply shortages, the utilization of expired batches was suggested. The current work investigated these matters. Long-term (15 years) storage under different conditions was initiated. Chemical stability and toxicity in rats were assessed. No difference was found between field conditions vs the controlled environment. The obidoxime assay remained >95% for 5 years and >90% for 7 years. The pH remained above the lower specification limit for 7–8 years. The major degradation product, 4-pyridinealdoxime, surpassed the allowed limit at 5 years. The content of total unknown impurities reached its maximum allowed by the IDF limit at 4–5 years. Threefold higher than clinically utilized doses of valid-to-date Toxogonin batches administered to rats did not cause any abnormality. However, expired batches produced significant toxic effects. Although no difference was found between storage of obidoxime ampoules when adhering to manufacturer’s recommendations vs field conditions, accumulation of degradants over the limit allowed by the IDF at 4–5 years of storage and the toxicity of the expired batches observed in rats led the IDF to a decision to shorten the shelf-life of this product from 5 to 4 years when stored in an uncontrolled environment of the Mediterranean climate.

Background

The real-world consequences of a Philips Respironics recall for positive airway pressure (PAP) devices distributed between 2009 and 2021 are unknown.

Antifolates are important for chemotherapy in non–small cell lung cancer (NSCLC). They mainly rely on reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) to enter cells. PCFT is supposed to be the dominant transporter of the two in tumors, as it operates optimally at acidic pH and has limited transport activity at physiological pH, whereas RFC operates optimally at neutral pH. In this study, we found RFC showed a slightly pH-dependent uptake of antifolates, with similar affinity values at pH 7.4 and 6.5. PCFT showed a highly pH-dependent uptake of antifolates, with an optimum pH of 6.0 for pemetrexed and 5.5 for methotrexate. The Michaelis-Menten constant (K_m) value of PCFT for pemetrexed at pH 7.4 was more than 10 times higher than that at pH 6.5. Interestingly, we found that antifolate accumulations mediated by PCFT at acidic pH were significantly affected by the efflux transporter, breast cancer resistance protein (BCRP). The highest pemetrexed concentration was observed at pH 7.0–7.4 after a 60-minute accumulation in PCFT-expressing cells, which was further evidenced by the cytotoxicity of pemetrexed, with the IC₅₀ value of pemetrexed at pH 7.4 being one-third of that at pH 6.5. In addition, the in vivo study indicated that increasing PCFT and RFC expression significantly enhanced the antitumor efficacy of pemetrexed despite the high expression of BCRP. These results suggest that both RFC and PCFT are important for antifolates accumulation in NSCLC, although there is an acidic microenvironment and high BCRP expression in tumors.

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD_1–10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems.

BACKGROUND AND PURPOSE:

Recently, artificial intelligence tools have been deployed with increasing speed in educational and clinical settings. However, the use of artificial intelligence by trainees across different levels of experience has not been well-studied. This study investigates the impact of artificial intelligence assistance on the diagnostic accuracy for intracranial hemorrhage and large-vessel occlusion by medical students and resident trainees.

Patient expectations of receiving antibiotics for common symptoms can trigger unnecessary use. We conducted a survey (n = 564) between January 2020 to June 2021 in public and private primary care clinics in Texas to study the prevalence and predictors of patients’ antibiotic expectations for common symptoms/illnesses. We surveyed Black patients (33%) and Hispanic/Latine patients (47%), and over 93% expected to receive an antibiotic for at least 1 of the 5 pre-defined symptoms/illnesses. Public clinic patients were nearly twice as likely to expect antibiotics for sore throat, diarrhea, and cold/flu than private clinic patients. Lack of knowledge of potential risks of antibiotic use was associated with increased antibiotic expectations for diarrhea (odds ratio [OR] = 1.6; 95% CI, 1.1-2.4) and cold/flu symptoms (OR = 2.9; 95% CI, 2.0-4.4). Lower education and inadequate health literacy were predictors of antibiotic expectations for diarrhea. Future antibiotic stewardship interventions should tailor patient education materials to include information on antibiotic risks and guidance on appropriate antibiotic indications.

HUNDREDS of travellers’ holiday plans are in disarray after all Tigerair flights in and out of Bali were cancelled again today and early tomorrow.

A Dundee ice hockey player has been jailed after being found guilty of raping a teenage girl in his car.

Two thirds of Celtic fans believe the club should have an independently elected Fan Advisory Board according to new research from the University of Glasgow.

A new Nordic-style Open Kindergarten will be trialled in part of Scotland ahead of a potential roll-out across the country.

The plane is hailed as 'one of the most advanced aircraft available on the market'

The site, on the shores of a famous Scottish loch, has been acquired for a luxury lodge development

There's one cat in the mouse, but five folks on the cast. Alex apologizes for rocks. Kelley learns things by watching mew. Chris is watching RPGmaniacs. Anna Marie has started embalming ship girls. And Pascal flips coins to decide whether or not to open a site indexing body mutilation in films.

The post RPG Cast – Episode 564: “Paws Is Best Lederhosen” appeared first on RPGamer.

Anna Marie wonders why we can't be friends. Jonathan becomes a Marbula One fan. Kelley engages "pants off, games on" mode. And Chris learns that the only person he's cheating is himself...and his dire gryphon.

The post RPG Cast – Episode 584: “A Crater Sized Hole Filled with Funko Pops!” appeared first on RPGamer.

Kelley annoys her cat by looking at her feet. Chris scratches his nose with elbow spikes. Josh wonders how fast his computer can emulate Saturn. And Phil needs surgery because of Monster Hunter.

The post RPG Cast – Episode 651: “I’m Sub-Entitled” appeared first on RPGamer.

Valve has announced Steam Deck OLED: Limited Edition White.

The handheld is a limited edition white version of the Steam Deck OLED that will be available in limited quantities for $679.

Pre-orders will open up on Steam on November 18 at 3:00 pm PT / 6:00 pm ET / 11:00 pm UK.

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/463040/valve-announces-steam-deck-oled-limited-edition-white/

Nintendo has announced its Black Friday 2024 deals. 

Dozens of games will be discounted including The Legend of Zelda: Tears of the Kingdom, Super Mario Maker 2, Animal Crossing: New Horizons, Pikmin 4, Nintendo Switch Sports, Kirby and the Forgotten Land, Super Mario Odyssey, Pikmin 1 + 2, and more.

The Neon Red and Neon Blue Joy-Con controllers and the Nintendo Switch Pro Controller will be discounted by $20, while the Nintendo Switch Carrying Case & Screen Protector - The Legend of Zelda: Tears of the Kingdom Edition will be discounted by $10.

The Nintendo Switch: Mario Kart 8 Deluxe Bundle will once again return for $299.99, while the new Nintendo Switch – OLED Model: Mario Kart 8 Deluxe Bundle will be available for $349.99. Both bundles include a digital download of Mario Kart 8 Deluxe and a 12-month Nintendo Switch Online Individual Membership.

The Nintendo Switch Lite: Hyrule Edition with Bonus Nintendo Switch Online + Expansion Pack will be available for $209.99. The bundle includes a 12-month Nintendo Switch Online + Expansion Pack Individual Membership.

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/463045/nintendos-black-friday-2024-deals-revealed/

Prior to his untimely death in Argentina on Wednesday, One Direction’s Liam Payne, 31, was in the middle of a legal spat with his ex-fiancée Maya Henry.

On Monday, The Sun reported that Henry, 23, had lawyered up in an attempt to stop Payne from constantly messaging her family and friends.

“Maya Henry issued a cease and desist last week to Liam Payne following the emergence of new and concerning information…She has retained attorneys Marco Crawford and Daniel Cerna to represent her. At this time, that is her only comment on the matter,” a spokesperson for Henry told the tabloid.

Read more at The Daily Beast.

Former President Donald Trump said Wednesday that Jan. 6, 2021— the day his supporters occupied Congress in a failed insurrection to try to stop lawmakers from certifying Joe Biden’s election victory—was a “day of love.”

Trump made the baffling claim during a televised election town hall hosted by Univision.

Ramiro González, a construction worker from Tampa, told the meeting he deregistered as a Republican because he found Trump’s “inaction” during both Jan. 6 and the COVID-19 pandemic “disturbing.” He asked Trump to square his controversial behavior during the attack on the U.S. Capitol—and the fact that many of his own former administration officials don’t support him any longer—with why he should be re-elected.

Read more at The Daily Beast.

Senate Minority Leader Mitch McConnell called his party’s presidential nominee, Donald Trump, a “stupid,” “ill-tempered,” and “despicable human being,” according to his own records.

McConnell made the withering assessments in a series of private “personal oral histories” that he gave to Michael Tackett, the deputy Washington bureau chief of the Associated Press, who has a forthcoming biography about the Kentucky senator called The Price of Power. The AP conveniently reported the book’s juicy details.

McConnell’s remarks were made after the 2020 election that Trump lost, and the senator was apparently elated to see the backside of the former president, musing, “it’s not just the Democrats who are counting the days” until he leaves office.

Read more at The Daily Beast.

The Steam Deck is something of a talisman for gaming on Linux, its popularity and penguin-powered SteamOS having almost singlehandedly dragged it past MacOS as the second-most-used operating system among Steam users. Sadly, this also means the Valve handheld is the primary casualty when developers decide to stop bothering with Linux support, as Respawn Entertainment have decided to do for Apex Legends.

Read more

The trailer for Bambas! starts off innocently enough. It's an "innovative urban walking simulator" in which you play a disembodied pair of shoes, individually moved with a controller's analog sticks and trigger buttons. The first half of the trailer is all whimsy and playground fun - kicking a football, standing on a climbing frame, riding a skateboard. But then a note of darkness creeps in, as the player begins to channel the sheer nihilistic inconsequentiality of a world in which shoes have no thinking human bodies to restrain them.

Read more

The Steam Deck OLED – which is like a Steam Deck but better in almost every way – is getting a new, if potentially more smudge-susceptible Limited Edition. A successor to the translucent version that only went on sale in the US and Canada last year, the Steam Deck OLED: Limited Edition White offers both a snowy look and, for those of us outside North America, the chance to actually buy one. It’ll go on sale November 18th, in all the countries that the Steam Deck currently ships in.

Read more

Brown dwarfs could be hiding dark matter inside their cores – if they are, there would be signs that could help us track it down

‘Little red dot’ galaxies seen by JWST appear to be much more tightly packed with stars than other galaxies, raising big questions about how they came to be this way

Nearly imperceptible quantum flickers used to limit how precisely we could detect the way space-time ripples, but squeezing the laser light used in detectors overcomes this and doubles the number of gravitational waves we can see

A detector on the International Space Station found signatures of unexpectedly abundant antimatter – which may have been created in clashes of dark matter particles

Advances in generative AI mean fake images, videos, audio and bots are now everywhere. But studies have revealed the best ways to tell if something is real

Hurricane Helene hit a quartz mine in North Carolina that is key to global semiconductor production, which could impact the entire tech industry. Here is everything we know so far

There has been another shock at the Grand Slam of Darts.

Emma Raducanu struck a deal to return to one of her favourite tournaments.

An insider reveals the famed aviation company's apparent change of heart.

Overwatch 2 is bringing 6v6 gameplay back from Overwatch 1 - and fans are overjoyed. Here's all we know so far, including when you can finally play the Classic mode

Mary Earps said she felt “very honoured and humbled” to receive “the ultimate all-round sporting accolade”, after being named as the BBC’s Sports Personality of the year ahead of runner-up Stuart Broad to continue women’s sport’s strong recent run in the event.

Boeing's Starliner spacecraft landed on Earth Saturday morning, with two test pilots left behind because of NASA's concerns that their return was too risky.

Featuring the AMD Ryzen 7 PRO 5750G, this case=heatsink PC costs from $2,179.

An intricate atlas of the inner lining of the uterus could help researchers better understand conditions like endometriosis, infertility and abnormal menstruation

A meta-analysis of 137 clinical trials finds triptan drugs are among the most effective for treating migraines, while newer ditan and gepant drugs were rated less highly

CIBUS Fresh of Noblesville, IN, is recalling CIBUS Fresh products containing Glenview Farms Spreadable Brie, 2/3lb because of a supplier notification of possible Listeria monocytogenes (products are listed below).  More information regarding the recent Brie recall can be found here. The product was distributed under the following labels: CIBUS Fresh,... Continue Reading

Yu Shang Food, Inc., a Spartanburg, SC, business, over the weekend recalled 4,589 pounds of ready-to-eat (RTE) meat and poultry products, which may have been adulterated with Listeria monocytogenes, according to the U.S. Department of Agriculture’s Food Safety and Inspection Service (FSIS). The ready-to-eat meat and poultry items were produced from... Continue Reading

Sharks less likely to interact as LED lights get brighter

Ars speaks with users and partners unhappy with Broadcom's changes.

The family of the man shot and killed by Hamilton police on Saturday has identified him as Erixon Kabera — a father of three, known for his kindness and dedication to Hamilton's Rwandan community.