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.

The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental, and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport, and pharmacokinetics is reviewed. Pharmacometabolomic approaches can help describe factors mediating drug disposition, efficacy, and toxicity. While important advancements in this area have been made, there remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy.

G protein–coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of α and β subunits, to convert extracellular signals into activation of intracellular signaling pathways. Canonically, GPCR-mediated activation results in the exchange of GDP for GTP on G protein α subunits (Gα) and the dissociation of Gα-GTP and G protein β subunits (Gβ), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by Gα returns the protein to Gα-GDP and allows reassociation with Gβ to reform the inactive heterotrimer. Naturally occurring mutations in Gα have been found at conserved glutamine and arginine amino acids that disrupt the canonical G protein cycle by inhibiting GTP hydrolysis, rendering these mutants constitutively active. Interestingly, these dysregulated Gα mutants are found in many different cancers due to their ability to sustain aberrant signaling without a need for activation by GPCRs. This review will highlight an increased recognition of the prevalence of such constitutively activating Gα mutations in cancers and the signaling pathways activated. In addition, we will discuss new knowledge regarding how these constitutively active Gα are regulated, how different mutations are biochemically distinct, and how mutationally activated Gα are unique compared with GPCR-activated Gα. Lastly, we will discuss recent progress in developing inhibitors directly targeting constitutively active Gα mutants.

ABSTRACTIntroduction:Health risks associated with short interpregnancy intervals, coupled with women’s desires to avoid pregnancy following childbirth, underscore the need for effective postpartum family planning programs. The antenatal period provides an opportunity to intervene; however, evidence is limited on the effectiveness of interventions aimed at reaching women in the antenatal period to increase voluntary postpartum family planning in low- and middle-income countries (LMICs). This systematic review aimed to identify and describe interventions in LMICs that attempted to increase postpartum contraceptive use via contacts with pregnant women in the antenatal period.Methods:Studies published from January 2012 to July 2022 were considered if they were conducted in LMICs, evaluated an intervention delivered during the antenatal period, were designed to affect postpartum contraceptive use, were experimental or quasi-experimental, and were published in French or English. The main outcome of interest was postpartum contraceptive use within 1 year after birth, defined as the use of any method of contraception at the time of data collection. We searched EMBASE, Global Health, and Medline and manually searched the reference lists from studies included in the full-text screening.Results:We double-screened 771 records and included 34 reports on 31 unique interventions in the review. Twenty-three studies were published from 2018 on, with 21 studies conducted in sub-Saharan Africa. Approximately half of the study designs (n=16) were randomized controlled trials, and half (n=15) were quasi-experimental. Interventions were heterogeneous. Among the 24 studies that reported on the main outcome of interest, 18 reported a positive intervention effect, with intervention recipients having greater contraceptive use in the first year postpartum.Conclusion:While the studies in this systematic review were heterogeneous, the findings suggest that interventions that included a multifaceted package of initiatives appeared to be most likely to have a positive effect.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa. The two most abundant cannabinoids (⁹-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC.

Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRAB_eCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known. This review aims to comprehensively examine the current knowledge of these modulators and provide insights into their pharmacological properties, particularly in the context of cancer and other diseases. Notably, the prominent gp130 modulators SC144, bazedoxifene, and raloxifene are discussed in detail, with a specific focus on the discovery of SC144’s iron-chelating properties. This adds a new dimension to the understanding of its pharmacological effects and therapeutic potential in conditions where iron homeostasis is significant. Our bioinformatic analysis of gp130 and genes related to iron homeostasis reveals insightful correlations, implicating the role of iron in the gp130 signaling pathway. Overall, this review contributes to the evolving understanding of gp130 modulation and its potential therapeutic applications in various disease contexts.

Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs’ physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that "hitchhike" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future.

Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-β peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications.

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.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts, such as concentration-response curves, additive effects, and predictive models, are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. Although various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors, such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

SUMMARY:

The 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS5), introduced significant changes, impacting tumors ranging from glial to ependymal neoplasms. Ependymal tumors were previously classified and graded based on histopathology, which had limited clinical and prognostic utility. The updated CNS5 classification now divides ependymomas into 10 subgroups based on anatomic location (supratentorial, posterior fossa, and spinal compartment) and genomic markers. Supratentorial tumors are defined by zinc finger translocation associated (ZFTA) (formerly v-rel avian reticuloendotheliosis viral oncogene [RELA]), or yes-associated protein 1 (YAP1) fusion; posterior fossa tumors are classified into groups A (PFA) and B (PFB), spinal ependymomas are defined by MYCN amplification. Subependymomas are present across all these anatomic compartments. The new classification kept an open category of "not elsewhere classified" or "not otherwise specified" if no pathogenic gene fusion is identified or if the molecular diagnosis is not feasible. Although there is significant overlap in the imaging findings of these tumors, a neuroradiologist needs to be familiar with updated CNS5 classification to understand tumor behavior, for example, the higher tendency for tumor recurrence along the dural flap for ZFTA fusion-positive ependymomas. On imaging, supratentorial ZFTA-fused ependymomas are preferentially located in the cerebral cortex, carrying predominant cystic components. YAP1-MAMLD1-fused ependymomas are intra- or periventricular with prominent multinodular solid components and have significantly better prognosis than ZFTA-fused counterparts. PFA ependymomas are aggressive paramedian masses with frequent calcification, seen in young children, originating from the lateral part of the fourth ventricular roof. PFB ependymomas are usually midline, noncalcified solid-cystic masses seen in adolescents and young adults arising from the fourth ventricular floor. PFA has a poorer prognosis, higher recurrence, and higher metastatic rate than PFB. Myxopapillary spinal ependymomas are now considered grade II due to high recurrence rates. Spinal-MYCN ependymomas are aggressive tumors with frequent leptomeningeal spread, relapse, and poor prognosis. Subependymomas are noninvasive, intraventricular, slow-growing benign tumors with an excellent prognosis. Currently, the molecular classification does not enhance the clinicopathologic understanding of subependymoma and myxopapillary categories. However, given the molecular advancements, this will likely change in the future. This review provides an updated molecular classification of ependymoma, discusses the individual imaging characteristics, and briefly outlines the latest targeted molecular therapies.

Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS. Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel DPYS variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.

BackgroundMost people with type 2 diabetes receive treatment in primary care by GPs who are not specialised in diabetes. Thus, it is important to uncover the most essential information needs regarding type 2 diabetes in general practice.AimTo identify information needs related to type 2 diabetes for GPs.Design and settingSystematic review focused on literature relating to Western countries.MethodMEDLINE, Embase, PsycInfo and CINAHL were searched from inception to January 2024. Two researchers conducted the selection process, and citation searches were performed to identify any relevant articles missed by the database search. Quality appraisal was conducted with the Mixed Methods Appraisal Tool. Meaning units were coded individually, grouped into categories, and then studies were summarised within the context of these categories using narrative synthesis. An evidence map was created to highlight research gaps.ResultsThirty-nine included studies revealed eight main categories and 36 subcategories of information needs. Categories were organised into a comprehensive hierarchical model of information needs, suggesting ‘Knowledge of guidelines’ and ‘Reasons for referral’ as general information needs alongside more specific needs on ‘Medication’, ‘Management’, ‘Complications’, ‘Diagnosis’, ‘Risk factors’, and ‘Screening for diabetes’. The evidence map provides readers with the opportunity to explore the characteristics of the included studies in detail.ConclusionThis systematic review provides GPs, policymakers, and researchers with a hierarchical model of information and educational needs for GPs, and an evidence map showing gaps in the current literature. Information needs about clinical guidelines and reasons for referral to specialised care overlapped with needs for more specific information.

BackgroundBetween 2003 and 2018, incident prescriptions of beta-blockers for anxiety increased substantially, particularly for young adults. National Institute for Health and Care Excellence guidance for anxiety does not recommend beta-blockers, probably due to a lack of evidence to support such use. Recent reports have highlighted the potential risks of beta-blockers.AimTo understand when and why GPs prescribe beta-blockers for people with anxiety.Design and settingIn-depth interviews with 17 GPs in Bristol and the surrounding areas.MethodInterviews were held by telephone or video call. A topic guide was used to ensure consistency across interviews. Interviews were audio-recorded, transcribed verbatim, and analysed thematically.ResultsMany GPs viewed beta-blockers as ‘low risk’, particularly for young adults. Some GPs viewed beta-blockers as an alternative to benzodiazepines, acting quickly and not leading to dependence. GPs reflected that some patients appeared to want an ‘immediate fix’ to their symptoms, which GPs thought beta-blockers could potentially offer. This is salient in light of substantial waiting lists for talking therapies and delays in antidepressants taking effect. GPs described how some patients seemed more willing to try beta-blockers than antidepressants, as patients did not perceive them as ‘mental health drugs’ and therefore viewed them as potentially more acceptable and less stigmatising. Further, GPs viewed beta-blockers as ‘patient-led’, with patients managing their own dose and frequency, without GP input.ConclusionMany GPs believe that beta-blockers have a role to play in the management of anxiety. Given recent increases in the prescribing of these drugs in primary care, there is a need to assess their safety and effectiveness as a treatment for people with anxiety disorders.

PURPOSE

Chest pain frequently poses a diagnostic challenge for general practitioners (GPs). Utilizing risk stratification tools might help GPs to rule out acute coronary syndrome (ACS) and make appropriate referral decisions. We conducted a systematic review of studies evaluating risk stratification tools for chest pain in primary care settings, both with and without troponin assays. Our aims were to assess the performance of tools for ruling out ACS and to provide a comprehensive review of the current evidence.

BACKGROUND

For many patients with post–COVID-19 condition (long COVID), primary care is the first point of interaction with the health care system. In principle, primary care is well situated to manage long COVID. Beyond expressions of disempowerment, however, the patient’s perspective regarding the quality of long COVID care is lacking. Therefore, this study aimed to analyze the expectations and experiences of primary care patients seeking treatment for long COVID.

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.

A national review of social work in Scotland has been launched in a bid to address ‘systemic racism’ within the sector.

Audiovisual pioneers Kristina Karpysheva and Alexandr Letsius on creating colossal, mind-bending installations.

The post Interview: 404.zero appeared first on Fact Magazine.

Lyra Pramuk on how collaboration, space and healing are central to her live performance.

The post Interview: Lyra Pramuk appeared first on Fact Magazine.

Taking a hacker’s approach to create playful, subversive works of music and visual art.

The post Interview: Freeka Tet appeared first on Fact Magazine.

On heritage, identity, and what it means and looks like to be a practicing artist today.

The post Interview: Tschabalala Self appeared first on Fact Magazine.

World-building, identity and decolonising spaces in the digital and offline realms.

The post Interview: Gabriel Massan & LYZZA appeared first on Fact Magazine.

Deller on politics, music and his film Everybody in the Place, now showing at The Vinyl Factory's Reverb exhibition.

The post Interview: Jeremy Deller appeared first on Fact Magazine.

Fox News host Bret Baier recapped his Wednesday night interview with Vice President Kamala Harris, telling his colleagues that he got a sense early on that Harris “was going to be tough to redirect without me trying to interrupt.”

The interview, Harris’ first on the right-wing network since becoming the Democratic nominee, was broadcast on Special Report after being filmed in the previous hour. According to Baier, the interview had been scheduled for 5 p.m., but Harris showed up 15 minutes late. This, he complained, was like “icing the kicker” in football.

“We were supposed to start at 5 p.m. This was the time they gave us. Originally, we were going to do 25 or 30 minutes. They came in and said, ‘Well, maybe 20.’ So, it’s already getting whittled down. And then the vice president showed up at about 5:15 p.m. We were pushing the envelope to be able to turn it around for the top of the 6 p.m.. So that’s how it started,” Baier said.

Read more at The Daily Beast.

It doesn’t matter how long a play is: sometimes 75 minutes can feel like 3 hours if the play is bad, while a three-hour play may first elicit an inner groan, then flow pleasurably by if the writing and performances are in well-oiled tandem.

Kenneth Lonergan’s Hold on to Me Darling (Lucille Lortel Theatre, to Dec. 22) belongs, mostly, to the latter category: it is long, and it feels long, but that’s OK; not gold-standard wow, but far more than pleasant. This is down to Lonergan’s engaging writing and a collection of differently distinctive, carefully drawn performances, led by Adam Driver as a famous country star called Strings (real name Clarence), wondering if he could/should give up all the trappings of fame for a simpler life after his mother’s death.

It is an off-Broadway treat to see Driver, most recently seen on the big screen as the star of Francis Ford Coppola’s polarizing epic Megalopolis, here bestriding—he is so tall, he is really bestriding—the compact Lucille Lortel stage. Theater fans last saw him on Broadway in Burn This, for which he was nominated for the Tony Award for Best Actor in a Play. He is renowned for playing powder-keg personas. With characters like Adam in Girls, Charlie in Marriage Story, and Pale in Burn This, the question, the bubbling menace, was when will Adam Driver go off? Those characters memorably combusted—thrashing, shouting, snarling and occupying spaces that could barely contain them—and Driver made it so that you recoiled from their crackling fury.

Read more at The Daily Beast.

MSNBC’s Chris Hayes called out Fox News for not showing the full context of Donald Trump’s “enemy within” comments during Vice President Kamala Harris’ interview on the network earlier Wednesday.

The anchor of All In opened his broadcast by calling attention to something that Harris herself did in the sit-down with Fox’s Bret Baier. The clip that the right-wing network showed to Harris as part of Baier’s question was of Trump during his all-female town hall event in Georgia—the one where Trump bizarrely argued he was the “father of IVF.”

In the clip that Fox aired directly to Harris during her interview, Trump wasn’t heard talking about how former House Speaker Nancy Pelosi or Rep. Adam Schiff are the “enemy within.” Instead, Fox made it so Harris had to react to him talking more mildly about “phony investigations.” The network omitted Trump’s line about “the enemy within.”

Read more at The Daily Beast.

Donald Trump praised Fox News chief political anchor Bret Baier for a “great job” in his interview with Democratic 2024 presidential hopeful Kamala Harris on Wednesday night, claiming Baier had “showed how totally incompetent Kamala is” while himself demanding she undergo a cognitive ability test.

Trump joined his campaign in calling the interview a total disaster for Harris. During the interview, Harris and Baier engaged in multiple back-and-forths; at one point, on the topic of immigration, Harris clapped back at Baier as he interrupted her: “May I finish responding to you?”

Immediately after the interview aired, the campaign—notably advisers Stephen Miller and Steven Cheung—took to X to decry Harris’ responses.

Read more at The Daily Beast.

In his monologue Wednesday, Jimmy Kimmel played a montage of Fox News anchors praising Bret Baier for his interview with Kamala Harris, where they described Baier’s performance as “incredible” and “a masterful job.”

Kimmel responded, “Alright, save it for the post-show orgy, everybody! Come on now.”

The late night host was skeptical that the Fox News pundits’ praise came from a genuine place of journalistic integrity. “They all sit there in fear, imagining Donald Trump on the toilet watching them,” he said.

Read more at The Daily Beast.

Donald Trump pulled out of another mainstream interview Thursday–this time nixing a sit-down with NBC News.

The interview, CNN reported, would be in Philadelphia with NBC News' senior business correspondent, Christine Romans. CNN’s Brian Stelter said one source suggested that it had only been “postponed.”

It was the second time in a week that he had canceled a scheduled appearance outside the conservative news sphere, CNN’s Reliable Sources reported Thursday. He had canceled an in-studio appearance on the CNBC flagship show, Squawk Box, which was due on Friday.

Read more at The Daily Beast.

People have asked me, a Call Of Duty liker, "How's the new COD?" - such is the mass appeal of Call Of Duty that even a lot of my non-industry pals are invested in whether Black Ops 6's shooty really does bang. And every single time my brain clunks into gear and I turn inwards, where I struggle to come up with anything meaningful to say. So much so that a fog develops and out of the fog emerges a figure - it's me. I'm holding an M4A1 with an extended barrel and a vertical foregrip. My brain and body perform a pincer movement of physical response: 1) I shrug 2) I say, "It's like Call Of Duty".

Read more

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.

Read more

It’s tempting to frame Straftat as a throwback to an older, better time for the multiplayer FPS, when the lingo was coded in frags and gibs and sucking it down, when satisfaction was drawn entirely from performance rather than some convoluted, artificial system of progression. Not only would this be inaccurate, but it would also do a disservice to what Straftat truly is, namely a wild overcorrection in response to the direction of modern multiplayer gunfests, one that careens straight through retro stations to arrive somewhere new and exciting.

Read more

To say that Factorio: Space Age throws out the rulebook is an understatement. It'd be more fitting to say it's somehow automated the whole process: an inserter plucked out the rulebook from my brain and deposited it in hot magma, while a new rulebook was churned out in a nearby machine and plopped into my brain from the other side - only for that to be immediately plucked out and incinerated as well. With each new planet and each new phase, Space Age reinvents itself. I'm battling hyperbole here, but ah hell, I admit defeat. Factorio: Space Age is a masterpiece, the final form of perhaps the most well-crafted building game I'll ever play.

Read more

As a yearly blockbuster, Call of Duty, through sheer expense and effort, would like you to think it is the Die Hard of video games. Or, depending on the setting, the Saving Private Ryan of video games. But it is barely Black Hawk Down. This latest campaign in Call Of Duty: Black Ops 6 reminds me more of the forgettable Netflix shootfests that thumbnail their way across your TV screen as you try to find some gritty nothing to aid you in zoning out of life. Still, there is an anecdotal contingent of casual sofa sitters for whom Call Of Duty is the game. A balls-to-the-wall shooter to return to every winter and rinse through in a weekend. Ed has already gestured at its multiplayer, announcing: "yup, it's COD", like a deeply tired Captain Birdseye inspecting the day's catch, wondering when his life will change. But never mind that. How does the single player story mode hold up? Some are calling it the best campaign in years. And I guess that's true, in the sense that it is the least worst.

Read more

When I was a competitive long-distance runner at school, breath control was paramount. We were never really taught this, mind. It was an art you picked up through practice: how to breathe before the race, saturating your blood with O2 without dizzying yourself; when to permit the shorter, emergency breaths and when to apply restraint; when to deepen your inhales and charge yourself up for an attack on a hill.

And then, how to organise your body around your breath, straightening your posture to expand your lungs without tipping back too far and squandering muscle power; how to breath in time with your stride and the movement of your shoulders, so as to firm up your momentum and shave a miraculous-feeling minute off your finishing time. All this, plus various daft psychological war gambits of my own devising. When overtaking or being overtaken, I used to seal my lips shut on that side and breath through the other corner of my mouth, to make it look like I was hardly out of breath at all.

Read more

"The cool thing about bombs is that you can hide them in anything," is probably my favourite Oppenheimer quote of all time, and in the case of Ian Hitman, it does raise an important question: with so many everyday objects equal to the rubber duck in its unthreatening aura, yet more inconspicuous, why choose to put an explosive in this one?

The simplest answer is that’s it’s a recurring bit of levity, a holdover easter egg, elevated to the status of key mission item in Hitman: Codename 47 before being given pride of place as an explosive in the World Of Assassination games. But to ascribe such unassuming purpose to the duck is to ignore its revelatory power. We must go deeper.

Read more

Great God Grove is, in a word, bonkers. I’ve stopped a small community from completing a blood ritual, played the role of matchmaker to a group of lonely hearts that involved organising a date with god, and plastered a statue with paint as part of a revolutionary movement to uplift the power of art. My time with GGG has been a pick n’ mix of colourful escapades, and together with its story of godly woes, striking art style, vacuum-based puzzle-solving, and nightmare-inducing puppet work, I’m now a die-hard LimboLane devotee.

Read more

Here’s a Steam quote for you: ‘The Rise Of The Golden Idol is the best game I’ve ever played where I spent most of my time staring at the screen going “well what chuffing well is it, then?!” Fiendish but fair, this detective puzzler demands a heady mix of observation, deduction, and logic, but rewards you with a progressively engaging story, and steadily more infuriatingly brilliant puzzles. Despite teaching you everything you need to know in the tutorial, it still manages to introduce new wrinkles and twists on the formula with each fresh chapter. My verdict? Imagine me lying my floor, massaging my temple with one hand and giving a fat thumbs up with the other.

Read more

These dazzling images taken by NASA's Hubble Space Telescope are from the upcoming book Cosmos: Explore the wonders of the universe, which has a foreword by astrophysicist Becky Smethurst

The author of Sapiens has turned his attention to the information networks that shape our societies, but when you stop and think about what he's saying, it's obvious