Simple words like "force" and "particle" can mislead us as to what reality is actually like. Physicist Matt Strassler unpacks how to see things more clearly

Daniele Oriti’s pursuit of a theory of quantum gravity has led him to the startling conclusion that the laws of nature don’t exist independently of us – a perspective shift that could yield fresh breakthroughs

Could the universe's missing matter be hiding in a "dark" extra dimension? We now have simple ways to test this outlandish idea - and the existence of extra dimensions more generally

The symbols and mathematical operations used in the laws of physics follow a pattern that could reveal something fundamental about the universe

Antibiotics can reduce diversity in the gut microbiome, raising the risk of infections that cause diarrhoea - and the effects may last years

Title: C-Section Antibiotics Show No Link to Asthma in Childhood
Category: Health News
Created: 5/20/2022 12:00:00 AM
Last Editorial Review: 5/20/2022 12:00:00 AM

Title: It's Back to Basics to Save a Life
Category: Health News
Created: 8/23/2009 8:10:00 AM
Last Editorial Review: 8/24/2009 12:00:00 AM

Title: Antibiotics Now Recommended Before C-Sections
Category: Health News
Created: 8/25/2010 10:10:00 AM
Last Editorial Review: 8/25/2010 12:00:00 AM

Title: Most U.S. Schools Unprepared for Pandemics: Study
Category: Health News
Created: 8/30/2012 10:05:00 AM
Last Editorial Review: 8/30/2012 12:00:00 AM

Title: Some Antibiotics Linked to Serious Nerve Damage
Category: Health News
Created: 8/28/2013 11:00:00 AM
Last Editorial Review: 8/28/2013 12:00:00 AM

Title: Gene May Raise Diabetics' Chances of Heart Disease
Category: Health News
Created: 8/27/2013 4:35:00 PM
Last Editorial Review: 8/28/2013 12:00:00 AM

Title: Lack of Protective Gear Leaves Medics at Risk in Ebola Outbreak: Study
Category: Health News
Created: 8/26/2014 2:35:00 PM
Last Editorial Review: 8/27/2014 12:00:00 AM

Title: Study Counters Critics of Plainer Cigarette Packaging
Category: Health News
Created: 8/29/2014 9:35:00 AM
Last Editorial Review: 8/29/2014 12:00:00 AM

Title: Too Few Blacks, Hispanics Becoming Doctors: Study
Category: Health News
Created: 8/24/2015 12:00:00 AM
Last Editorial Review: 8/25/2015 12:00:00 AM

Title: Antibiotics Linked to Type 2 Diabetes Risk
Category: Health News
Created: 8/27/2015 12:00:00 AM
Last Editorial Review: 8/28/2015 12:00:00 AM

Title: Genes Might Explain Hispanics' Added Longevity
Category: Health News
Created: 8/19/2016 12:00:00 AM
Last Editorial Review: 8/22/2016 12:00:00 AM

Title: Mouse Study Suggests Antibiotics in Kids Might Help Spur Type 1 Diabetes
Category: Health News
Created: 8/22/2016 12:00:00 AM
Last Editorial Review: 8/23/2016 12:00:00 AM

Title: Large-Scale Pandemics Aren't as Rare as You Think: Study
Category: Health News
Created: 8/25/2021 12:00:00 AM
Last Editorial Review: 8/25/2021 12:00:00 AM

Title: Here's Why Men Should Take Probiotics
Category: Health and Living
Created: 7/27/2022 12:00:00 AM
Last Editorial Review: 7/27/2022 12:00:00 AM

Title: Pets Have Helped People With HIV Through Two Pandemics
Category: Health News
Created: 6/23/2022 12:00:00 AM
Last Editorial Review: 6/23/2022 12:00:00 AM

The poly(A) signal, together with auxiliary elements, directs cleavage of a pre-mRNA and thus determines the 3' end of the mature transcript. In many species, including humans, the poly(A) signal is an AAUAAA hexamer, but we recently found that the deeply branching eukaryote Giardia lamblia uses a distinct hexamer (AGURAA) and lacks any known auxiliary elements. Our discovery prompted us to explore the evolutionary dynamics of poly(A) signals and auxiliary elements in the eukaryotic kingdom. We use direct RNA sequencing to determine poly(A) signals for four protists within the Metamonada clade (which also contains G. lamblia) and two outgroup protists. These experiments reveal that the AAUAAA hexamer serves as the poly(A) signal in at least four different eukaryotic clades, indicating that it is likely the ancestral signal, whereas the unusual Giardia version is derived. We find that the use and relative strengths of auxiliary elements are also plastic; in fact, within Metamonada, species like G. lamblia make use of a previously unrecognized auxiliary element where nucleotides flanking the poly(A) signal itself specify genuine cleavage sites. Thus, despite the fundamental nature of pre-mRNA cleavage for the expression of all protein-coding genes, the motifs controlling this process are dynamic on evolutionary timescales, providing motivation for future biochemical and structural studies as well as new therapeutic angles to target eukaryotic pathogens.

We propose a paper that provides education on commonly used long-acting injectable antipsychotics (LAIs) to improve primary care based mental health interventions in patients with severe mental illnesses (SMIs) such as schizophrenia, schizoaffective disorder, and bipolar disorders. With the expanding interface of primary care and psychiatry across all healthcare settings, it has become increasingly important for primary care clinicians to have a broader understanding of common psychiatric treatments, including LAIs. Long-acting injectable antipsychotics have been shown to be helpful in significantly improving treatment adherence, preventing disease progression, improving treatment response, decreasing readmission rates, and reducing social impairment. We discuss evidence-based indications and guidelines for use of long-acting injectable antipsychotics. We provide an overview of the treatment of SMI with LAIs, mainly focusing on the most commonly used long-acting injectable antipsychotics, advantages and disadvantages of each, along with outlining important clinical pearls for ease of practical application. Equipped with increased familiarity and understanding of these essential therapies, primary care clinicians can better facilitate early engagement with psychiatric care, promote more widespread use, and thus significantly improve the wellbeing and quality of life of patients with severe mental illness.

BACKGROUD:Lung volume measurements are important for monitoring functional aeration and recruitment and may help guide adjustments in ventilator settings. The expiratory phase of airway pressure release ventilation (APRV) may provide physiologic information about lung volume based on the expiratory flow-time slope, angle, and time to approach a no-flow state (expiratory time [TE]). We hypothesized that expiratory flow would correlate with estimated lung volume (ELV) as measured using a modified nitrogen washout/washin technique in a large-animal lung injury model.METHODS:Eight pigs (35.2 ± 1.0 kg) were mechanically ventilated using an Engström Carescape R860 on the APRV mode. All settings were held constant except the expiratory duration, which was adjusted based on the expiratory flow curve. Abdominal pressure was increased to 15 mm Hg in normal and injured lungs to replicate a combination of pulmonary and extrapulmonary lung injury. ELV was estimated using the Carescape FRC INview tool. The expiratory flow-time slope and TE were measured from the expiratory flow profile.RESULTS:Lung elastance increased with induced lung injury from 29.3 ± 7.3 cm H2O/L to 39.9 ± 15.1cm H2O/L, and chest wall elastance increased with increasing intra-abdominal pressures (IAPs) from 15.3 ± 4.1 cm H2O/L to 25.7 ± 10.0 cm H2O/L in the normal lung and 15.8 ± 6.0 cm H2O/L to 33.0 ± 6.2 cm H2O/L in the injured lung (P = .39). ELV decreased from 1.90 ± 0.83 L in the injured lung to 0.67 ± 0.10 L by increasing IAP to 15 mm Hg. This had a significant correlation with a TE decrease from 2.3 ± 0.8 s to 1.0 ± 0.1 s in the injured group with increasing insufflation pressures (ρ = 0.95) and with the expiratory flow-time slope, which increased from 0.29 ± 0.06 L/s2 to 0.63 ± 0.05 L/s2 (ρ = 0.78).CONCLUSIONS:Changes in ELV over time, and the TE and flow-time slope, could be used to demonstrate evolving lung injury during APRV. Using the slope to infer changes in functional lung volume represents a unique, reproducible, real-time, bedside technique that does not interrupt ventilation and may be used for clinical interpretation.

BACKGROUND:PEEP is a cornerstone treatment for children with pediatric ARDS. Unfortunately, its titration is often performed solely by evaluating oxygen saturation, which can lead to inadequate PEEP level settings and consequent adverse effects. This study aimed to assess the impact of increasing PEEP on hemodynamics, respiratory system mechanics, and oxygenation in children with ARDS.METHODS:Children receiving mechanical ventilation and on pressure-controlled volume-guaranteed mode were prospectively assessed for inclusion. PEEP was sequentially changed to 5, 12, 10, 8 cm H2O, and again to 5 cm H2O. After 10 min at each PEEP level, hemodynamic, ventilatory, and oxygenation variables were collected.RESULTS:A total of 31 subjects were included, with median age and weight of 6 months and 6.3 kg, respectively. The main reasons for pediatric ICU admission were respiratory failure caused by acute viral bronchiolitis (45%) and community-acquired pneumonia (32%). Most subjects had mild or moderate ARDS (45% and 42%, respectively), with a median (interquartile range) oxygenation index of 8.4 (5.8–12.7). Oxygen saturation improved significantly when PEEP was increased. However, although no significant changes in blood pressure were observed, the median cardiac index at PEEP of 12 cm H2O was significantly lower than that observed at any other PEEP level (P = .001). Fourteen participants (45%) experienced a reduction in cardiac index of > 10% when PEEP was increased to 12 cm H2O. Also, the estimated oxygen delivery was significantly lower, at 12 cm H2O PEEP. Finally, respiratory system compliance significantly reduced when PEEP was increased. At a PEEP of 12 cm H2O, static compliance had a median reduction of 25% in relation to the initial assessment (PEEP of 5 cm H2O).CONCLUSIONS:Although it may improve arterial oxygen saturation, inappropriately high PEEP levels may reduce cardiac output, oxygen delivery, and respiratory system compliance in pediatric subjects with ARDS with low potential for lung recruitability.

Descriptive statistics (DS) play a crucial role in establishing a solid foundation for study analysis and are important for understanding the results of a study or data set. If the data from DS is used incorrectly, the study may be misinterpreted. Descriptive statistics summarizes and organizes data, making analysis easier and providing an overview of the characteristics of sampled data. This analysis is comprised of measures of central tendency, which includes the mean, median, and mode of a particular data set. Understanding how to use each metric is essential for basic statistical analysis. The purpose of this short report is to review descriptive statistics and describe how to best utilize them during data analysis. The authors aim to provide this short report as an educational resource to assist the dental hygiene research community in understanding statistical analysis through descriptive statistics.

Caenorhabditis elegans is an important model organism for human health and disease, with foundational contributions to the understanding of gene expression and tissue patterning in animals. An invaluable tool in modern gene expression research is the presence of a high-resolution ribosome structure, though no such structure exists for C. elegans. Here, we present a high-resolution single-particle cryogenic electron microscopy (cryo-EM) reconstruction and molecular model of a C. elegans ribosome, revealing a significantly streamlined animal ribosome. Many facets of ribosome structure are conserved in C. elegans, including overall ribosomal architecture and the mechanism of cycloheximide, whereas other facets, such as expansion segments and eL28, are rapidly evolving. We identify uL5 and uL23 as two instances of tissue-specific ribosomal protein paralog expression conserved in Caenorhabditis, suggesting that C. elegans ribosomes vary across tissues. The C. elegans ribosome structure will provide a basis for future structural, biochemical, and genetic studies of translation in this important animal system.

Background

Exacerbations of noncystic fibrosis bronchiectasis (bronchiectasis) are associated with reduced health-related quality of life and increased mortality, likelihood of hospitalisation and lung function decline. This study investigated patient clinical characteristics associated with exacerbation frequency.

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450’s metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug–processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes.

Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow and decreasing glomerular filtration rate (GFR) and liver blood flow, thereby altering the absorption, distribution, metabolism, and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g., muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation P = a_iHRⁱ was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. The pharmacokinetics of midazolam, quinidine, digoxin, and lidocaine during exercise were predicted by a whole-body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within the 5^th–95^th percentiles of the simulations, and the estimated peak concentrations (C_max) and area under the curve (AUC) of drugs were also within 0.5–2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time, and alterations in physiological parameters significantly affected drug pharmacokinetics and the net effect depending on drug characteristics and exercise conditions. In conclusion, the pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters.

In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference therapeutic currently in development, were investigated. OLX702A-075-16 is a novel N-acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy. We investigated the plasma concentration, tissue distribution, metabolism, and renal excretion of OLX702A-075-16 following a subcutaneous administration in mice and rats. For bioanalysis, high-performance liquid chromatography with fluorescence detection was used. The results showed rapid clearance from plasma (0.5 to 1.5 hours of half-life) and predominant distribution to the liver and/or kidney. Less than 1% of the liver concentration of OLX702A-075-16 was detected in the other tissues. Metabolite profiling using liquid chromatography coupled with high-resolution mass spectrometry revealed that the intact duplex OLX702A-075-16 was the major compound in plasma. The GalNAc moiety was predominantly metabolized from the sense strand in the liver, with the unconjugated sense strand of OLX702A-075-16 accounting for more than 95% of the total exposure in the rat liver. Meanwhile, the antisense strand was metabolized by the sequential loss of nucleotides from the 3'-terminus by exonuclease, with the rat liver samples yielding the most diverse truncated forms of metabolites. Urinary excretion over 96 hours was less than 1% of the administered dose in rats. High plasma protein binding of OLX702A-075-16 likely inhibited its clearance through renal filtration.

Over the past 20 years, quantitative proteomics has contributed a wealth of protein expression data, which are currently used for a variety of systems pharmacology applications, as a complement or a surrogate for activity of the corresponding proteins. A symposium at the 25th North American International Society for the Study of Xenobiotics meeting, in Boston, in September 2023, was held to explore current and emerging applications of quantitative proteomics in translational pharmacology and strategies for improved integration into model-informed drug development based on practical experience of each of the presenters. A summary of the talks and discussions is presented in this perspective alongside future outlook that was outlined for future meetings.

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.

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.

ABSTRACTPolitics is one of the critical factors that influence health policy agendas. However, scholarly efforts, especially in low- and middle-income countries, rarely focus on how politics influence health policy agenda-setting. We conducted a qualitative document review to examine the factors that led to developing the free primary health care policy for maternal health in Papua New Guinea. We also discuss mechanisms through which national politics, as an overriding factor, influenced the development of the policy. The review draws on Kingdon’s multiple-stream model for agenda-setting and incorporates theoretical insights from Fox and Reich’s framework for analyzing the politics of health reform for universal health coverage in low- and middle-income countries.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

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.

Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO₂ were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics.

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.

Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for BRAF rearrangement but harboring a BRAF p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-yr-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing. Whole-genome and RNA-seq analysis identified an internal tandem duplication in FGFR1 and RAS pathway activation. Future management options include FGFR1 inhibitors. These cases demonstrate the importance of escalating molecular diagnostics for pediatric brain cancer, advocating for early reflexing to integrative whole-genome sequencing and transcriptomic profiling when targeted panels are uninformative. Identifying molecular drivers can significantly impact treatment decisions and improve patient outcomes.

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.

Anna Marie Privitere gets de-wormed but has to tell Chris to stop helping. Phil Willis is not at all biased about musous. Kelley Ryan is all about the DMCAs. But Alex Fuller saw all of this coming.

The post RPG Cast – Episode 566: “Unsolicited Dik-Dik Pics” appeared first on RPGamer.

Kelley "accidentally" barbecues her horse. Josh slaps "Trails" onto Horizon: Forbidden West to get Americans to play it. Jason has to go get a tako taco.

The post RPG Cast – Episode 677: “My Parents Thought Final Fantasy Tactics Was a Strategy Guide” appeared first on RPGamer.

Chris sits in a time loop watching Vegeta backhand a guy. Kelley buys solar panels for her Red XIII werewolf. Were you into RPGs before they were cool? Now slide, slide, baby, slide.

The post RPG Cast – Episode 714: “Thirsty for Tactics” appeared first on RPGamer.

Kelley makes a Morgen Wonk. Chris loves the smell of Gundam in the morning. Phil plays some Mathfinder while listening to his favorite new band, Creepy Lego Waifus. The cake has arrived.

The post RPG Cast – Episode 728: “Cats With Jiggle Physics” appeared first on RPGamer.

Chris is unmasked as The Corporate Body. Tam talks about anime and waifus. Kelley is excited about text size. Josh explains the meaning of "time to shipwreck." Subscribe to our latest offering, The Monthly Litterbox.

The post RPG Cast – Episode 744: “11.5-Bit Graphics” appeared first on RPGamer.

Twitch have introduced a new "Politics and Sensitive Social Issues" label for streams that "focus" on topics like "elections, civic integrity, and war or military conflict". As with the streaming giant's existing labels for M-rated material, sexual themes or depictions of gambling, the idea is that viewers can filter out such streams in advance by altering their settings.

Advertisers, similarly, can "make better choices about the content they want to advertise next to" - in other words, pull their ads from a whole swathe of material if they don't want to be associated with anything controversial. Twitch's hope is that "the labels will allow advertisers to have more context to inform which types of streams they show their ads alongside, which we expect to increase brands’ confidence in running ads on Twitch, and could bring new advertisers to our service."

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I would never have predicted there'd be an isometric tactics game based on run-and-gun series Metal Slug, yet here Metal Slug Tactics is, and I am here for it. We've been following its development for a while but it's out now on Steam, and seemingly as strong as its demo suggested.

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WASHINGTON — After her Army son died in an armored vehicle rollover in Syria in May, Sheila Murphy says, she got no call or letter from President Donald Trump, even as she waited months for his condolences, wrote to him to say “some days I don’t want to live,” and still heard nothing.

In contrast, Trump called to comfort Eddie and Aldene Lee about 10 days after their Army son was killed in an explosion while on patrol in Iraq in April. “Lovely young man,” Trump said, according to Aldene. She thought that was a beautiful word to hear about her boy, “lovely.”

Like presidents before him, Trump has made personal contact with some families of the fallen, not all. What’s different is that Trump, alone among them, has picked a political fight over who’s done better to honor the war dead and their families.

He placed himself at the top of this pantheon, boasting Tuesday that “I think I’ve called every family of someone who’s died” while past presidents didn’t place such calls.

But The Associated Press found relatives of two soldiers who died overseas during Trump’s presidency who said they never received a call or a letter from him, as well as relatives of a third who did not get a call. And proof is plentiful that Barack Obama and George W. Bush — saddled with far more combat casualties than the roughly two dozen so far under Trump, took painstaking steps to write, call or meet bereaved military families.

The subject arose because nearly two weeks passed before Trump called the families of four U.S. soldiers who were killed in Niger nearly two weeks ago. He made the calls Tuesday.

READ MORE: Trump ignites furor with claim past presidents didn’t console military families by phone

Meanwhile, Rep. Frederica Wilson said late Tuesday that Trump told the widow of a slain soldier that he “knew what he signed up for.” Early Wednesday, the president called Wilson’s version of the conversation a fabrication.

The Florida Democrat said she was in the car with Myeshia Johnson on the way to Miami International Airport to meet the body of Johnson’s husband, Sgt. La David Johnson, when Trump called. Wilson says she heard part of the conversation on speakerphone.

When asked by Miami station WPLG if she indeed heard Trump say that she answered: “Yeah, he said that. To me, that is something that you can say in a conversation, but you shouldn’t say that to a grieving widow.” She added: “That’s so insensitive.”

Trump took strong issue with that recounting early Wednesday.

“Democrat Congresswoman totally fabricated what I said to the wife of a soldier who died in action (and I have proof). Sad!” he said on Twitter.

Sgt. Johnson was among four servicemen killed in the Niger ambush.

Wilson said that she didn’t hear the entire conversation and Myeshia Johnson told her she couldn’t remember everything that was said.

The White House didn’t immediately comment.

READ MORE: Trump’s claim about predecessors, fallen troops disputed

Trump’s delay in publicly discussing the men lost at Niger did not appear to be extraordinary, judging from past examples, but his politicization of the matter is. He went so far Tuesday as to cite the death of chief of staff John Kelly’s son in Afghanistan to question whether Obama had properly honored the war dead.

Kelly was a Marine general under Obama when his Marine son Robert died in 2010. “You could ask General Kelly, did he get a call from Obama?” Trump said on Fox News radio.

Democrats and some former government officials were livid, accusing Trump of “inane cruelty” and a “sick game.”

Democratic Sen. Tammy Duckworth of Illinois, an Iraq veteran who lost both legs when her helicopter was attacked, said: “I just wish that this commander in chief would stop using Gold Star families as pawns in whatever sick game he’s trying to play here.”

For their part, Gold Star families, which have lost members in wartime, told AP of acts of intimate kindness from Obama and Bush when those commanders in chief consoled them.

Trump initially claimed that only he among presidents made sure to call families. Obama may have done so on occasion, he said, but “other presidents did not call.”

He equivocated Tuesday as the record made plain that his characterization was false. “I don’t know,” he said of past calls. But he said his own practice was to call all families of the war dead.

But that hasn’t happened:

No White House protocol demands that presidents speak or meet with the families of Americans killed in action — an impossible task in a war’s bloodiest stages. But they often do.

Altogether some 6,900 Americans have been killed in overseas wars since the Sept. 11, 2001, attacks, the overwhelming majority under Bush and Obama.

Despite the much heavier toll on his watch — more than 800 dead each year from 2004 through 2007 — Bush wrote to all bereaved military families and met or spoke with hundreds if not thousands, said his spokesman, Freddy Ford.

Veterans groups said they had no quarrel with how presidents have recognized the fallen or their families.

“I don’t think there is any president I know of who hasn’t called families,” said Rick Weidman, co-founder and executive director of Vietnam Veterans of America. “President Obama called often and President Bush called often. They also made regular visits to Walter Reed and Bethesda Medical Center, going in the evenings and on Saturdays.”

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Bynum reported from Savannah, Georgia. Jonathan Drew in Raleigh, North Carolina, Kristen de Groot in Philadelphia, Jennifer McDermott in Providence, Rhode Island, Michelle Price in Salt Lake City, and Hope Yen and Robert Burns in Washington contributed to this report.

The post Trump and the new politics of honoring war dead appeared first on PBS NewsHour.