Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are useful for scaling in vitro and animal data to humans for accurate prediction and interpretation of drug clearance and toxicity. Targeted DMET proteomics that relies on synthetic stable isotope-labeled surrogate peptides as calibrators is routinely used for the quantification of selected proteins; however, the technique is limited to the quantification of a small number of proteins. Although the global proteomics-based total protein approach (TPA) is emerging as a better alternative for large-scale protein quantification, the conventional TPA does not consider differential sequence coverage by identifying unique peptides across proteins. Here, we optimized the TPA approach by correcting protein abundance data by the sequence coverage, which was applied to quantify 54 DMETs for characterization of 1) differential tissue DMET abundance in the human liver, kidney, and intestine, and 2) interindividual variability of DMET proteins in individual intestinal samples (n = 13). Uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7), microsomal glutathione S-transferases (MGST1, MGST2, and MGST3) carboxylesterase 2 (CES2), and multidrug resistance-associated protein 2 (MRP2) were expressed in all three tissues, whereas, as expected, four cytochrome P450s (CYP3A4, CYP3A5, CYP2C9, and CYP4F2), UGT1A1, UGT2B17, CES1, flavin-containing monooxygenase 5, MRP3, and P-glycoprotein were present in the liver and intestine. The top three DMET proteins in individual tissues were: CES1>CYP2E1>UGT2B7 (liver), CES2>UGT2B17>CYP3A4 (intestine), and MGST1>UGT1A6>MGST2 (kidney). CYP3A4, CYP3A5, UGT2B17, CES2, and MGST2 showed high interindividual variability in the intestine. These data are relevant for enhancing in vitro to in vivo extrapolation of drug absorption and disposition and can be used to enhance the accuracy of physiologically based pharmacokinetic prediction of systemic and tissue concentration of drugs.

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.

ABSTRACTToxicological emergencies present a significant health challenge in Nepal. Despite the high burden, the country has inadequate formal toxicology training, medical toxicology expertise, and adequate poison control infrastructure. In recognition of this need, the Nepal Poison Information Center (PIC) was established as a collaborative effort involving local and international partners. Through a comprehensive partnership framework, the Nepal PIC provides 24 hours a day, 7 days a week expert guidance to health care workers, conducts educational webinars, and engages in research. Initial data from the pilot phase indicate successful consultation delivery. Challenges include bureaucratic hurdles and the need for sustainable funding. Despite these challenges, the Nepal PIC demonstrates early feasibility and potential for expansion into a comprehensive toxicology center, contributing to the advancement of clinical toxicology in Nepal. Long-term sustainability relies on governmental support and continued advocacy efforts.

ABSTRACTThe private health care sector is an important source of service delivery in low- and middle-income countries (LMICs). Yet, the private sector remains fragmented, making it difficult for health system actors to support and ensure the availability of quality health care services. In global health programs, social franchising is one model used to engage and organize the private health care sector. Two social franchise networks, ProFam in West Africa and Tunza in East and Central Africa, provide health care through branded networks of facilities. However, these social franchise networks include a limited number of private health care facilities, and in fragile contexts, like Burundi and Mali, they have faced challenges in integrating with national health systems. The MOMENTUM Private Healthcare Delivery (MPHD) project in Burundi and Mali sought to expand the number of health facilities it engaged beyond the existing ProFam and Tunza networks. The expansion aimed to help improve service quality in more private facilities while advancing localization and reducing fragmentation for improved stewardship by health system actors. MPHD achieved this expansion by removing barriers for private health facilities to join inclusive, nonbranded networks and engaging local partners to build and maintain these networks. We share lessons learned regarding the growing role of local organizations as actors within mixed health systems and provide insights on strengthening stewardship of the increasingly heterogeneous private health care delivery sector in LMICs, particularly in fragile settings.

ABSTRACTBackground: This analysis aimed to evaluate the effectiveness of eliciting sexual partners from HIV-positive clients using the elicitation box model (where an HIV-positive index can report sexual contacts on paper and insert in a box for a health care provider to contact at a later time) compared to the conventional model (in which a health care provider elicits sexual contacts directly from clients) in Akwa Ibom, Southern Nigeria.Methods: Between March 2021 and April 2022, data were collected from index testing registers at 4 health facilities with a high volume of HIV clients currently on treatment in 4 local government areas in Akwa Ibom State. Primary outcome analyzed was the elicitation ratio (number of partners elicited per HIV-index offered index testing services). Secondary outcomes were the index testing acceptance (index HIV-positive clients accepted index testing service), testing coverage (partners tested for HIV from a list of partners elicited from HIV-index accepted index testing services), testing yield (index partners identified HIV positive from index partners HIV-tested), and linkage rate (index partners identified HIV positive and linked to antiretroviral therapy).Results: Of the total 2,705 index clients offered index testing services, 91.9% accepted, with 2,043 and 439 indexes opting for conventional elicitation and elicitation box models, respectively. A total of 3,796 sexual contacts were elicited: 2,546 using the conventional model (elicitation ratio=1:1) and 1,250 using the elicitation box model (elicitation ratio=1:3). Testing coverage was significantly higher in the conventional compared to the elicitation box model (P<.001). However, there was no significant difference in the testing yield (P=.81) and linkage rate using the conventional compared to elicitation box models (P=.13).Conclusion: The implementation of the elicitation box model resulted in an increase in partner elicitation compared to the conventional model. Increasing the testing coverage by implementing the elicitation box model should be considered.

ABSTRACTIntroduction:Postpartum hemorrhage (PPH) remains the leading cause of maternal mortality. A new clinical intervention (E-MOTIVE) holds the potential to improve early PPH detection and management. We aimed to develop and pilot implementation strategies to support uptake of this intervention in Kenya, Nigeria, South Africa, and Tanzania.Methods:Implementation strategy development: We triangulated findings from qualitative interviews, surveys and a qualitative evidence synthesis to identify current PPH care practices and influences on future intervention implementation. We mapped influences using implementation science frameworks to identify candidate implementation strategies before presenting these at stakeholder consultation and design workshops to discuss feasibility, acceptability, and local adaptations. Piloting: The intervention and implementation strategies were piloted in 12 health facilities (3 per country) over 3 months. Interviews (n=58), case report forms (n=1,269), and direct observations (18 vaginal births, 7 PPHs) were used to assess feasibility, acceptability, and fidelity.Results:Implementation strategy development: Key influences included shortages of drugs, supplies, and staff, limited in-service training, and perceived benefits of the intervention (e.g., more accurate PPH detection and reduced PPH mortality). Proposed implementation strategies included a PPH trolley, on-site simulation-based training, champions, and audit and feedback. Country-specific adaptations included merging the E-MOTIVE intervention with national maternal health trainings, adapting local PPH protocols, and PPH trollies depending on staff needs. Piloting: Intervention and implementation strategy fidelity differed within and across countries. Calibrated drapes resulted in earlier and more accurate PPH detection but were not consistently used at the start. Implementation strategies were feasible to deliver; however, some instances of limited use were observed (e.g., PPH trolley and skills practice after training).Conclusion:Systematic intervention development, piloting, and process evaluation helped identify initial challenges related to intervention fidelity, which were addressed ahead of a larger-scale effectiveness evaluation. This has helped maximize the internal validity of the trial.

ABSTRACTWe describe the development, implementation, and evaluation of a novel twinning approach: the Twinning Partnership Network (TPN). Twinning is a well-known approach to peer learning that has been used in a variety of settings to build organizational capacity. Although twinning takes many forms, the heart of the approach is that institutions with shared characteristics collaborate via sharing information and experiences to achieve a specific goal. We adapted a twinning partnership strategy developed by the World Health Organization to create a network of like-minded health institutions. The key innovation of the TPN is the network, which ensures that an institution always has a high-performing peer with whom to partner on a specific topic area of interest. We identified 10 hospitals and 30 districts in Rwanda to participate in the TPN. These districts and hospitals participated in a kickoff workshop in which they identified capacity gaps, clarified goals, and selected twinning partners. After the workshop, districts and hospitals participated in exchange visits, coaching visits, and virtual and in-person learning events. We found that districts and hospitals that selected specific areas and worked on them throughout the duration of the TPN with their peers improved their performance significantly when compared with those that selected and worked on other areas. Accreditation scores improved by 5.6% more in hospitals selecting accreditation than those that did not. Districts that selected improving community-based health insurance coverage improved by 4.8% more than districts that did not select this topic area. We hypothesize that these results are due to senior management’s interest and motivation to improve in these specific areas, the motivation gained by learning from high-performing peers with similar resources, and context-specific knowledge sharing from peer hospitals and districts.

Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment's integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come.

Sir Andy Murray will swap Centre Court for the stage next summer as he embarks on a tour discussing his illustrious tennis career.

The concierge team at The Balmoral have helped raise awareness for a special event to raise money for charity in memory of Scotland legend Doddie Weir.

Josh is having an Ys-y time. Anna Marie ranks all the slime families. Robert gets notified every time google kills a product. And Chris tells everyone to blink on cue.

The post RPG Cast – Episode 572: “Partly Cloudy Souls With a Chance of Roguelike” appeared first on RPGamer.

Super Mario Party Jamboree (NS) has remained in first place on the retail charts in Japan with sales of 57,522 units, according to Famitsu for the week ending October 27, 2024. 

Farmagia (NS) debuted in eighth place with sales of 4,296 units.

Romancing SaGa 2: Revenge of the Seven (NS) remained in second place with sales of 14,646 units. The PS5 version fell from third to seventh place with sales of 5,097 units.

Call of Duty: Black Ops 6 (PS5) is up one spot to third place with sales of 8,620 units and Mario Kart 8 Deluxe (NS) re-entered the top 10 in fourth place with sales of 5,782 units.

Professional Baseball Spirits 2024-2025 (PS5) is up two spots to fifth with sales of 5,729, and The Legend of Zelda: Echoes of Wisdom (NS) is up two spots to sixth place with sales of 5,492 units.

The Nintendo Switch was the best-selling platform with 60,096 units sold. The PlayStation 5 sold 13,965 units, the Xbox Series X|S sold 2,610 units, and the PlayStation 4 sold 53 units.

Here are the best-selling games in Japan:

1. [NSW] Super Mario Party Jamboree (Nintendo, 10/17/24) – 57,522 (364,484)
2. [NSW] Romancing SaGa 2: Revenge of the Seven (Square Enix, 10/24/24) – 14,646 (85,013)
3. [PS5] Call of Duty: Black Ops 6 (Activision, 10/25/24) – 8,620 (35,567)
4. [NSW] Mario Kart 8 Deluxe (Nintendo, 04/28/17) – 5,782 (6,044,039)
5. [PS5] Professional Baseball Spirits 2024-2025 (Konami, 10/17/24) – 5,729 (84,989)
6. [NSW] The Legend of Zelda: Echoes of Wisdom (Nintendo, 09/26/24) – 5,492 (294,371)
7. [PS5] Romancing SaGa 2: Revenge of the Seven (Square Enix, 10/24/24) – 5,097 (37,254)
8. [NSW] Farmagia (Marvelous, 11/01/24) – 4,296 (New)
9. [NSW] Animal Crossing: New Horizons (Nintendo, 03/20/20) – 4,253 (7,943,533)
10. [NSW] Minecraft (Microsoft, 06/21/18) – 4,242 (3,666,338)

Here is the hardware breakdown (followed by lifetime sales):

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/463007/super-mario-party-jamboree-tops-the-japanese-charts/

Amplitude Studios, developers of many a game with "Endless" in the name, have split with publisher Sega to become independent again, with ownership of the studio reverting to its original founders and "other members of the team". The developers say everyone is parting "on good terms" and that the last eight years of getting published under Sega has been "amazing". But there are other businessy reasons, of course. Namely, Sega have been trying to trim down their European studios for the past year, and Amplitude is just the latest bunch of devs affected by that.

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It was the 20-year anniversary of Halo 2 at the weekend, which saw the shooter's modern counterparts celebrating with classic multiplayer maps and long-lost levels. But also emerging from the dust of time are insights to the sequel's development back in 2004. Rolling Stone interviewed two key designers of the game and made a fun discovery. The Flood (the sickly pale alien infestation that briefly turns Halo into sci-fi horror) was partly inspired by a colourful and innocent children's book about a nice elephant.

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What would it take to turn Texas, a Republican stronghold, into a blue state? According to data from SurveyMonkey, just remove all the gun owners from the Lone Star State and it would have gone to Hillary Clinton in 2016. You can do the same thing in liberal California. Remove all the non-gun owners and the state would have voted for Donald Trump.

That’s how divisive the issue of gun control is in American politics.

SurveyMonkey found that no other demographic — not race, religion or gender — so perfectly divided voters. In the 2016 election, 47 percent of Trump supporters said gun control was an issue important enough to influence their vote. That’s compared to just 27 percent of voters who supported Hillary Clinton.

But what does this divide mean? How is it impacting gun control policy, and how might this issue change in light of recent mass shootings like Las Vegas, Orlando and Newtown? To discuss the data, join a PBS NewsHour-hosted Twitter chat at 1 p.m. EDT Thursday with data journalist Dante Chinni (@Dchinni), professor and chairman of political science at the University of Kansas Don Haider-Markel (@dhmarkel), and Washington Post correspondent Philip Bump (@pbump).

Have questions? Tweet them using #NewsHourChats.

The post Twitter chat: How the gun control debate mirrors larger issues of partisanship in America appeared first on PBS NewsHour.

In Still Wakes the Deep, you play as a Glaswegian electrician on a 1970s oil rig. The well-crafted setting gives way to horror, but I wish I could linger in mundanity for longer, says Jacob Aron

Certain strains of E. coli are capable of causing severe disease, by rapidly spreading through the human digestive system, wreaking havoc throughout the bloodstream, and eventually damaging the delicate kidneys. That's the situation right now during a large outbreak in Alberta, with hundreds of children now affected.

The Health and Human Services Department employs 294 people whose jobs focus on diversity, and the department maintains seven separate "minority health" offices spread across its various agencies, according to a new report that suggests it will be tough for the incoming Trump administration to unwind it all.

A new Government Accountability Office report says that the Justice Department kept FBI employees in the dark for seven years after Congress updated whistleblower protections for bureau personnel in 2016.

President-elect Donald Trump on Tuesday announced that Tesla founder Elon Musk and businessman Vivek Ramaswamy will a new Department of Government Efficiency, a White House office given the task of cutting the federal budget.

$329/£300 graphics card is said to be "future ready" for your 1080p gaming needs.

A FEMA supervisor fired for instructing subordinates to skip over houses with Trump signs says her actions were consistent with agency guidance and were not isolated to her team alone.

President-elect Trump announced that billionaire Elon Musk and former GOP presidential candidate Vivek Ramaswamy will lead the Department of Government Efficiency.

Former Education Secretary Betsy DeVos discusses what a second Trump term could mean for U.S. education on "The Story with Martha MacCallum."

President-elect Trump announced on Tuesday that Kristi Noem is his pick for secretary of the Department of Homeland Security.

Researchers suspect the marine mammals may have been communicating across the vast distance

New NatGeo documentary was directed by the same duo who brought us the Oscar-winning Free Solo.

Trump nominated Republican South Dakota Gov. Kristi Noem to serve as his Secretary of the Department of Homeland Security (DHS).

The post Trump Nominates Kristi Noem for Secretary of Department of Homeland Security appeared first on Breitbart.

President-elect Donald Trump announced he has picked Tesla CEO and X owner Elon Musk and entrepreneur and former Republican presidential candidate Vivek Ramaswamy to "lead the Department of Government Efficiency."

The post Donald Trump Selects Elon Musk, Vivek Ramaswamy to ‘Lead the Department of Government Efficiency’ appeared first on Breitbart.

Hombale Films and Prabhas will begin their three-film partnership with ‘Salaar 2’, to be directed by Prashanth Neel

The buzz surrounding his post even caused a temporary block on his Instagram account due to a surge in user engagement

Shea Weber is member of the Hockey Hall of Fame. The former defenceman headlined the 2024 class inducted Monday, joining Pavel Datsyuk, Jeremy Roenick, Natalie Darwitz and Krissy Wendell in the player category. David Poile and Colin Campbell entered as builders.

President-elect Trump announced a "Department of Government Efficiency," or DOGE, that will be led by Tesla CEO Elon Musk and entrepreneur Vivek Ramaswamy, focused on shrinking the federal government.

NPD “restatement” shows consistent spending growth as digital sales dominate.

Rivian is teaming up with Volkswagen in a $5.8 billion joint venture for EV innovation on its R2 model, which the company says will eventually be manufactured in Georgia.

It's no secret that most technology nowadays isn't exactly built to last forever, with new product models regularly on sale on replace malfunctioning items. However, Apple, which famously announces new products each September, is taking new steps to let people repair their own devices. Apple has launched parts and tools for the iPhone 16, including the Plus, Pro and Pro Max. 

Now, if you have an iPhone 16 model that's acting up, you can go to Apple's self service repair store and — possibly — get what you need to fix it. Choose the product type and model then pick from the iPhone 16's choices of back glass, battery, camera, top speaker, TrueDepth camera, SIM tray and more. Apple's iPhone 16 should be easier to fix than its predecessor, receiving a 7/10 on the iFixit repairability scale, compared to a 4/10 for the iPhone 15. 

You can either get kits or just the necessary part with prices varying based on your phone model. For example, a battery and screw kit for the iPhone 16 Pro Max is $119, but its $99 for the regular iPhone 16. You can get quite a lot of money back on the kit prices if you return the replaced piece afterward. The iPhone 16 Pro Max, for instance, goes down to $61.88 after you send back the old battery. 

Apple created its self-service program in 2022, giving its customers access to actual Apple parts when something in their device failed. However, Apple states that the service "is intended for individuals with the knowledge and experience to repair electronic devices. If you are experienced with the complexities of repairing electronic devices." So, repairs might not be as accessible if you or someone you know isn't savvy in making the swaps. 

President-elect Donald Trump has named Elon Musk as the leader of a new “Department of Government Efficiency," that will “dismantle Government Bureaucracy, slash excess regulations, cut wasteful expenditures, and restructure Federal Agencies.” The Tesla CEO and owner of X will spearhead the effort along with former presidential candidate Vivek Ramaswamy, Trump announced in a statement on Truth Social.

The scope of the role isn’t exactly clear. Trump’s press release said that “the Department of Government Efficiency will provide advice and guidance from outside of Government, and will partner with the White House and Office of Management & Budget to drive large scale structural reform, and create an entrepreneurial approach to Government never seen before.” It also stated that “their work will conclude no later than July 4, 2026.”

Musk shared the news on X, but didn’t indicate how the role might impact his obligations at his various other companies. Musk, who poured millions of dollars into Super Pac boosting Trump’s campaign, has previously talked about his desire to work with Trump to cut government spending. He did, however, joke about potential "merch" for the operation. "Republican politicians have dreamed about the objectives of 'DOGE' for a very long time," Trump's statement said. 

C'était une nouvelle attendue.

Le Parti Québécois misera sur sa présidente, Catherine Gentilcore, pour tenter de ravir la circonscription de Terrebonne à la CAQ.

The deal secured by the Hull facility is for the East Anglia TWO project off the Suffolk coast.

The National Commission for Allied Health Professionals (NCAHP), constituted by the Union ministry of health and family welfare in the beginning of this year, will have its official representative in the National

Raising deep concern over the partnership between Swiggy Instamart and PharmEasy for a rapid drug delivery model, the All India Organization of Chemists and Druggists (AIOCD) has apprised the Drug Controller

The Embassy of India in Iraq has extended an invitation to Indian businesses to participate in the "Medico Expo," officially known as the Erbil International Health Exhibition. This prestigious event, set to be the

As part of the National Pharmacy Week (NPW) celebration, the Kerala Private Pharmacist Association (KPPA) is organizing a high─impact webinar series from November 17th to 23rd, connected by the common