The CYP3A7 enzyme accounts for ~50% of the total cytochrome P450 (P450) content in fetal and neonatal livers and is the predominant P450 involved in neonatal xenobiotic metabolism. Additionally, it is a key player in healthy birth outcomes through the oxidation of dehydroepiandrosterone (DHEA) and DHEA-sulfate. The amount of the other hepatic CYP3A isoforms, CYP3A4 and CYP3A5, expressed in neonates is low but highly variable, and therefore the activity of individual CYP3A isoforms is difficult to differentiate due to their functional similarities. Consequently, a better understanding of the contribution of CYP3A7 to drug metabolism is essential to identify the risk that drugs may pose to neonates and developing infants. To distinguish CYP3A7 activity from CYP3A4/5, we sought to further characterize the selectivity of the specific CYP3A inhibitors CYP3cide, clobetasol, and azamulin. We used three substrate probes, dibenzylfluorescein, luciferin-PPXE, and midazolam, to determine the IC₅₀ and metabolism-dependent inhibition (MDI) properties of the CYP3A inhibitors. Probe selection had a significant effect on the IC₅₀ values and P450 inactivation across all inhibitory compounds and enzymes. CYP3cide and azamulin were both identified as MDIs and were most specific for CYP3A4. Contrary to previous reports, we found that clobetasol propionate (CP) was not an MDI of CYP3A5 but was more selective for CYP3A5 over CYP3A4/7. We further investigated CYP3cide and CP’s ability to differentiate CYP3A7 activity in an equal mixture of recombinant CYP3A4, CYP3A5, and CYP3A7, and our results provide confidence of CYP3cide’s and CP’s ability to distinguish CYP3A7 activity in the presence of the other CYP3A isoforms.

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.

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy.

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.

Aberrant type 2 inflammatory responses are the underlying cause of the pathophysiology of allergic asthma, allergic rhinitis, and other atopic diseases, with an alarming prevalence in relevant parts of the Western world. A bulk of evidence points out the important role of the DP2 receptor in these inflammation processes. A screening of different polyunsaturated fatty acids at a fluorescence resonance energy transfer–based DP2 receptor conformation sensor expressed in human embryonic kidney (HEK) cells revealed an agonistic effect of the prostaglandin (PG)-D₂ precursor arachidonic acid on DP2 receptor activity of about 80% of the effect induced by PGD₂. In a combination of experiments at the conformation sensor and using a bioluminescence resonance energy transfer–based G protein activation sensor expressed together with DP2 receptor wild type in HEK cells, we found that arachidonic acid acts as a direct activator of the DP2 receptor, but not the DP1 receptor, in a concentration range considered physiologically relevant. Pharmacological inhibition of cyclooxygenases and lipoxygenases as well as cytochrome P450 did not lead to a diminished arachidonic acid response on the DP2 receptor, confirming a direct action of arachidonic acid on the receptor.

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.

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.

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.

ABSTRACTMore than half of births among Indigenous women in Guatemala are still being attended at home by providers with no formal training. We describe the incorporation of comadronas (traditional midwives) into casas maternas (birthing centers) in the rural highlands of western Guatemala. Although there was initial resistance to the casa, comadronas and clients have become increasingly enthusiastic about them. The casas provide the opportunity for comadronas to continue the cultural traditions of prayers, massages, and other practices that honor the vital spiritual dimension of childbirth close to home in a home-like environment with extended family support while at the same time providing a safer childbirth experience in which complications can be detected by trained personnel at the casa, managed locally, or promptly referred to a higher-level facility. Given the growing acceptance of this innovation in an environment in which geographical, financial, and cultural barriers to deliveries at higher-level facilities lead most women to deliver at home, casas maternas represent a feasible option for reducing the high level of maternal mortality in Guatemala.This article provides an update on the growing utilization of casas and provides new insights into the role of comadronas as birthing team members and enthusiastic promotors of casas maternas as a preferable alternative to home births. Through the end of 2023, these casas maternas had cared for 4,322 women giving birth. No maternal deaths occurred at a casa, but 4 died after referral.The Ministry of Health of Guatemala has recently adopted this approach and has begun to implement it in other rural areas where home births still predominate. This approach deserves consideration as a viable and feasible option for reducing maternal mortality throughout the world where home births are still common, while at the same time providing women with respectful and culturally appropriate care.

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.

In nuclear medicine, estimating the number of radioactive decays that occur in a source organ per unit administered activity of a radiopharmaceutical (i.e., the time-integrated activity coefficient [TIAC]) is an essential task within the internal dosimetry workflow. TIAC estimation is commonly derived by least-squares fitting of various exponential models to organ time–activity data (radiopharmaceutical biodistribution). Rarely, however, are methods used to objectively determine the model that best characterizes the data. Additionally, the uncertainty associated with the resultant TIAC is generally not evaluated. As part of the MIRDsoft initiative, MIRDfit has been developed to offer a biodistribution fitting software solution that provides the following essential features and advantages for internal dose assessment: nuclear medicine–appropriate fit functions; objective metrics for guiding best-fit selection; TIAC uncertainty calculation; quality control and data archiving; integration with MIRDcalc software for dose calculation; and a user-friendly Excel-based interface. For demonstration and comparative validation of MIRDfit’s performance, TIACs were derived from serial imaging studies involving ¹⁸F-FDG and ¹⁷⁷Lu-DOTATATE using MIRDfit. These TIACs were then compared with TIAC estimates obtained using other software. In most cases, the TIACs agreed within approximately 10% between MIRDfit and the other software. MIRDfit has been endorsed by the MIRD Committee of the Society of Nuclear Medicine and Molecular Imaging and has been integrated into the MIRDsoft suite of free dosimetry software; it is available for download at no user cost (https://mirdsoft.org/).

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.

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.

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.

BACKGROUND AND PURPOSE:

Mechanical thrombectomy is a fundamental intervention for acute ischemic stroke treatment. While conventional techniques are effective, cyclic aspiration (CyA) shows potential for better recanalization rates. We aim to investigate factors affecting CyA and compare them with static aspiration (StA).

BACKGROUND AND PURPOSE:

Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement.

We present a unique case of a single patient presenting with two mutationally distinct, PD-L1⁺ diffuse large B-cell lymphomas (DLBCLs). One of these DLBCLs demonstrated exceptionally high mutational burden (eight disease-associated variants and 41 variants of undetermined significance) with microsatellite instability (MSI) and an acquired PMS2 mutation with loss of PMS2 protein expression, detected postchemotherapy. This report, while highlighting the extent of possible tumor heterogeneity across separate clonal expansions as well as possible syndromic B-cell neoplasia, supports the notion that, although rare, PD-L1 expression and associated states permissive of high mutational burden (such as mismatch repair gene loss of function/MSI) should be more routinely considered in DLBCLs. Appropriate testing may be predictive of outcome and inform the utility of targeted therapy in these genetically diverse and historically treatment-refractory malignancies.

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

Sleep is a fundamental feature of life for virtually all multicellular animals, but many questions remain about how sleep is regulated and what biological functions it plays. Substantial headway has been made in the study of both circadian rhythms and sleep in the fruit fly Drosophila melanogaster, much of it through studies of individual fly activity using beam break counts from Drosophila activity monitors (DAMs). The number of laboratories worldwide studying sleep in Drosophila has grown from only a few 20 years ago to hundreds today. The utility of these studies is limited by the quality of the metrics that can be extracted from the data. Many software options exist to help analyze DAM data; however, these are often expensive or have significant limitations. Therefore, we describe here a method for analyzing DAM-based data using the sleep and circadian analysis MATLAB program (SCAMP). This user-friendly software has an advantage of combining several analyses of both sleep and circadian rhythms in one package and produces graphical outputs as well as spreadsheets of the outputs for further statistical analysis. The version of SCAMP described here is also the first published software package that can analyze data from multibeam DAM5Ms, enabling determination of positional preference over time.

Sleep is a fundamental feature of life for virtually all multicellular animals, but many questions remain about how sleep is regulated by circadian rhythms, homeostatic sleep drive that builds up with wakefulness, and modifying factors such as hunger or social interactions, as well as about the biological functions of sleep. Substantial headway has been made in the study of both circadian rhythms and sleep in the fruit fly Drosophila melanogaster, much of it through studies of individual fly activity using Drosophila activity monitors (DAMs). Here, we describe approaches for the activation of specific neurons of interest using optogenetics (involving genetic modifications that allow for light-based neuronal activation) and thermogenetics (involving genetic modifications that allow for temperature-based neuronal activation) so that researchers can evaluate the roles of those neurons in controlling rest and activity behavior. In this protocol, we describe how to set up a rig for simultaneous optogenetic or thermogenetic stimulation and activity monitoring for analysis of sleep and circadian rhythms in Drosophila, how to raise appropriate flies, and how to perform the experiment. This protocol will allow researchers to assess the causative role in the regulation of sleep and activity rhythms of any genetically tractable subset of cells.

The Respiratory Intensive Care Assembly of the European Respiratory Society gathered in Berlin to organise the third Respiratory Failure and Mechanical Ventilation Conference in February 2024. The conference covered key points of acute and chronic respiratory failure in adults. During the 3-day conference ventilatory strategies, patient selection, diagnostic approaches, treatment and health-related quality of life topics were addressed by a panel of international experts. In this article, lectures delivered during the event have been summarised by early career members of the Assembly and take-home messages highlighted.

There is conflicting evidence regarding the use of steroids in severe community-acquired pneumonia (CAP), with previous randomised controlled trials limited by small sample sizes. ESCAPe and CAPE COD are two recently published large trials on steroids in severe CAP. ESCAPe assessed the initiation of methylprednisolone within 72–96 h of hospital admission, while CAPE COD studied the use of hydrocortisone within 24 h of the development of severe CAP. ESCAPe did not show any differences in all-cause 60-day mortality or any of its secondary outcomes. CAPE COD showed that hydrocortisone improved all-cause 28-day mortality and reduced the risk of intubation or vasopressor-dependent shock. Important differences between the trials included the steroid regimens used, timing of steroid administration and baseline characteristics, with more diabetic patients included in ESCAPe. The results of CAPE COD support the initiation of hydrocortisone within 24 h of developing severe CAP, but more research is needed to evaluate long-term outcomes and optimum dosing regimens for steroids in severe CAP.

The respiratory literature, both written and in online formats, is growing exponentially. Capturing quality content, to meet the learning needs of those working in all fields of respiratory medicine and delivering it in a palatable, accessible format is challenging but paramount. In this article we discuss ways to determine the information content and review different methods of delivering this content to those who need it.

Palliative care pertains to the holistic multidimensional concept of "patient-centred" care. It is an interprofessional specialty, primarily aiming to improve quality of care for cancer patients and their families, from the time of diagnosis of malignant disease, over the continuum of cancer care, and extending after the patient's death to the period of bereavement to support the patient's family. There are various complex and frequently unmet needs of lung cancer patients and their families/caregivers, not only physical but also psychological, social, spiritual and cultural. Systematic monitoring of patients’ symptoms using validated questionnaires and patient-reported outcomes (PROs), on a regular basis, is highly encouraged and recommended in recent guidelines on the role of PRO measures in the continuum of cancer clinical care. It improves patient–physician communication, physician awareness of symptoms, symptom control, patient satisfaction, health-related quality of life and cost-effectiveness. This implies that all treating physicians should improve their skills in communication with lung cancer patients/relatives and become more familiar with this multidimensional assessment, repeatedly screening patients for palliative care needs. Therefore, they should receive education and training to develop palliative care knowledge, skills and attitudes. This review is dedicated to lung cancer palliative care essentials that should be within the competences of treating physicians, i.e. pneumologists/thoracic oncologists.

A nudibranch from the midnight zone has fingers on its tail, collects food with a hood, and glows.

The leak caught national intelligence officials by surprise and led to an embarrassing Air Force Inspector General investigation.

The current growth and consumption based economy is not sustainable. The world must move towards a circular economy and sustainability.

The post Degrowth, green energy, social equity, and circular economy appeared first on rabble.ca.

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HARI SREENIVASAN: The desire of the Kurds along Iraq’s northern border to govern themselves is receiving more resistance from Iraq’s central government. Iraqi army forces are demanding Kurdish troops withdraw from oil fields and military bases around Kirkuk, a city in the Kurdistan region that voted for independence last month. Kirkuk also has 10% of Iraq’s known oil reserves. Washington Post’s Loveday Morris is in Baghdad covering this standoff joins me now via Skype. First of all the significance of this. Why is it so important?

LOVEDAY MORRIS: There’s been a longtime conflict between Baghdad and Kurdistan over these disputed territories. Most significant of which is Kirkuk because of the oil reserves. But the referendum last month has really sharpened these disputes because you have Baghdad opposing independence and so it feels like they have to restate its territorial claims these areas. So that’s why we’re seeing a lot of tension right now.

HARI SREENIVASAN: And just to give people a little bit of a brief timeline – Iraqi forces control this area for a while and then in June ISIS took over the area and now it’s kind of back in Kurdish hands?

LOVEDAY MORRIS: Right. So in June 2014 Iraq lost control of a lot of the areas and we have this huge collapse in the face of an ISIS offensive. Over 100,000 soldiers fled and Kurdish forces moved in some of these areas – some of them maybe took from ISIS and others just moved into into the vacuum. And so Iraqi forces have been in these areas since June 2014. And that’s their main demand that they return to the areas.

HARI SREENIVASAN: What’s the likelihood that this standoff right now turns violent? Into some sort of a civil war?

LOVEDAY MORRIS:: I think at this point both sides don’t want violence. Al-Abadi, the prime minister, is really trying to defuse the situation by saying there’s going to be no military attack. But at the same time there is this buildup of forces so that I think they are trying to, in a way, intimidate the Kurds to withdraw from some areas but they don’t want to see a fight per say. But in this really tense situation there can be a small spark and things can turn violent quite easily.

HARI SREENIVASAN: Thank you.

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WASHINGTON — Secretary of State Rex Tillerson says diplomatic efforts aimed at resolving the North Korean crisis “will continue until the first bomb drops.”

That statement comes despite President Donald Trump’s tweets a couple of weeks ago that his chief envoy was “wasting his time” trying to negotiate with “Little Rocket Man,” a mocking nickname Trump has given the nuclear-armed nation’s leader, Kim Jong Un.

“I think he does want to be clear with Kim Jong Un and that regime in North Korea that he has military preparations ready to go and he has those military options on the table. And we have spent substantial time actually perfecting those,” Tillerson told CNN’s “State of the Union” on Sunday. “But be clear: The president has also made clear to me that he wants this solved diplomatically. He’s not seeking to go to war.”

Recent mixed messaging from the top of the U.S. government has raised concerns about the potential for miscalculation amid the increasingly bellicose exchange of words by Trump and the North Korean leader.

Trump told the U.N. General Assembly last month that if the U.S. is “forced to defend itself or its allies, we will have no choice but to totally destroy North Korea.” Trump also tweeted that Korea’s leadership “won’t be around much longer” if it continued its provocations, a declaration that led the North’s foreign minister to assert that Trump had “declared war on our country.”

Tillerson acknowledged during a recent trip to Beijing that the Trump administration was keeping open direct channels of communications with North Korea and probing the North’s willingness to talk. He provided no elaboration about those channels or the substance of any discussions.

Soon after, Trump took to Twitter, saying he had told “our wonderful Secretary of State, that he is wasting his time trying to negotiate with Little Rocket Man … Save your energy Rex, we’ll do what has to be done!” Trump offered no further explanation, but he said all military options are on the table for dealing with North Korea’s nuclear and missile programs.

Analysts have speculated about whether the president and his top diplomat were playing “good cop, bad cop” with North Korea, and how China might interpret the confusing signals from Washington. Beijing is the North’s main trading partner, and the U.S. is counting on China to enforce U.N. sanctions.

“Rest assured that the Chinese are not confused in any way what the American policy towards North Korea (is) or what our actions and efforts are directed at,” Tillerson said.

Asked if Trump’s tweets undermined Tillerson, the secretary said: “I think what the president is doing is he’s trying to motivate action on a number of people’s part, in particular the regime in North Korea. I think he does want to be clear with Kim Jong Un and that regime in North Korea that he has military preparations ready to go and he has those military options on the table and we have spent substantial time perfecting those.”

He added that Trump “has made it clear to me to continue my diplomatic efforts, which we are, and I’ve told others those diplomatic efforts will continue until the first bomb drops.”

North Korea has launched missiles that potentially can strike the U.S. mainland and recently conducted its largest ever underground nuclear explosion. It has threatened to explode another nuclear bomb above the Pacific.

The post Rex Tillerson says continue diplomacy with North Korea ‘until first bomb drops’ appeared first on PBS NewsHour.

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JUDY WOODRUFF: Longstanding rivalries were re-ignited in Iraq today between vital American allies.

Iraqi military forces and militia moved to push Kurdish forces out of the disputed city of Kirkuk in the country’s north.

Lisa Desjardins begins our coverage.

MAN (through interpreter): The commander in chief of the armed forces, Dr. Haider al-Abadi, gave orders to protect the people of Kirkuk and to impose security in the city.

LISA DESJARDINS: After months of simmering tensions, Iraqi federal troops moved to retake the disputed city of Kirkuk from Kurdish forces.

The effort launched before dawn. By midday, Iraqi soldiers, along with state-backed militias, quickly took control of several massive oil fields north of the city. Iraqis also captured Kirkuk’s military airport and various government buildings. They lowered what had been a symbolic Kurdish flag at the governor’s compound.

Journalist Rebecca Collard in Irbil was in Kirkuk this morning.

REBECCA COLLARD, Journalist: You could hear some clashes, some gunfire in the distance, but for the most part, the city seemed more or less abandoned. Now, the Iraqi army, by the end of today, was essentially in control of the whole city and many of the outskirts of Kirkuk.

LISA DESJARDINS: The spokesman for an Iraqi Shiite militia said they achieved all their goals with little resistance.

AHMED AL-ASSADI,  Spokesman for al-Hashed al-Shaabi (through translator): As the troops approached the area, they were confronted by some rebels, who tried to hinder the progress of the advancing units. Our troops returned fire and silenced its source.

LISA DESJARDINS: This comes three weeks after the Kurds held a nonbinding independence referendum that included the disputed province of Kirkuk.

More than 90 percent of the Kurdish region’s residents voted to split from Iraq. The Iraqi federal government, Turkey, Iran and the U.S. all rejected the independence drive.

The multiethnic region of Kirkuk lies just outside of the autonomous Kurdish region in Iraq’s north. Called the country’s oil capital, Kirkuk produces around 500,000 barrels a day.

In 2014, amid the ISIS onslaught across Northern Iraq, the Kurds took control of Kirkuk, as the Iraqi military fled the city. In the three years since, the Kurds, led by their president, Massoud Barzani, sought to cement their hold, despite tensions with the central government.

Today, Kurdish officials accused Iraq of carrying out a major multipronged attack.

MAJ. GEN. AYOUB YUSUF SAID, Peshmerga Commander (through interpreter): I don’t know what is happening exactly, because we have been in this fight since 4:00 in the morning. We have suffered casualties, including martyrs, and now we have withdrawn to this position. Some of the other Kurdish forces have pulled out. They didn’t fire a single shot.

LISA DESJARDINS: While Kurdish forces withdrew from posts south of the city, some residents vowed to die fighting. Thousands of others fled north.

REBECCA COLLARD: For the last few years, the Iraqi forces, these primarily Shia militia, the Hashed Shaabi, and the Kurdish forces have been focused on fighting ISIS. Now that fight is coming to an end, and what the fear is that now these internal division in Iraq are going to become more apparent and possibly more violent.

LISA DESJARDINS: These clashes pit one substantially American-armed military force against another. Both the Kurdish forces and Iraqi government troops are part of the coalition fighting ISIS. The U.S. sought to downplay the fighting, labeling the exchange of gunfire a misunderstanding.

And, in the Rose Garden, President Trump tried to stay neutral.

PRESIDENT DONALD TRUMP: We don’t like the fact that they’re clashing. We’re not taking sides. But we don’t like the fact that they’re clashing.

LISA DESJARDINS: For the PBS NewsHour, I’m Lisa Desjardins.

JUDY WOODRUFF: For more, I’m joined now by Emma Sky. She served as an adviser to General David Petraeus while he was commander of U.S. forces in Iraq from 2007 to 2010, and by Feisal Istrabadi. He’s a former Iraqi ambassador to the United Nations and he helped write Iraq’s interim constitution.

Welcome to both of you.

Let me start with you, Emma Sky.

This has happened so quickly. What exactly has the Iraqi government done?

EMMA SKY, Yale University: The Iraqi government has deployed its forces back up north into Kirkuk.

And since 2003, the Kurds have made it clear that they want to include Kirkuk within their territory in order to proceed with gaining independence, which has always been their goal. But Kirkuk is important to Iraq itself, and no Iraqi prime minister can afford to lose Kirkuk.

So you can see this reaction that has taken place following the referendum on independence, which happened September the 25th, and also included the disputed territories and the city of Kirkuk.

JUDY WOODRUFF: Feisal Istrabadi, what can you add to why the Iraqi government is so set on taking over the city?

FEISAL ISTRABADI, Former Deputy UN Ambassador, Iraq: Well, a couple of reasons.

First, as Emma just said, it is a part of the disputed territories, which are legally and constitutionally under the jurisdiction of the federal government in Baghdad. The KRG expanded into these disputed territories at the time when ISIL was expanding its territory, and then began to take steps to unilaterally declare that these areas were now incorporated into the Kurdistan region, including when it held the referendum that Emma talked about.

It included holding the referendum in these disputed territories. Now, so long as Iraq — so long as we’re talking about a single country, it matters a little less who controls Kirkuk, but once the referendum was held, this gave rise then to the second reason for Baghdad choosing to act now.

As Emma said, Kirkuk is an important oil-producing zone in Iraq. And it is vital for the economic viability of an independent Kurdish state and an important part of the economic viability of the Iraqi state. So there was never going to be a scenario, I think, in which Baghdad would allow a unilateral exercise of control by Kurds to occur over Kirkuk, so long as independence is on the table.

JUDY WOODRUFF: Emma Sky, we heard President Trump say today the U.S. is not taking sides in this.

Is that accurate, that the U.S. isn’t taking sides? What is the U.S. role here?

EMMA SKY: Well, the U.S. has stipulated over and over again that its policy is to support a united Iraq.

So you can see the U.S. has given support to Iraqi security forces, but also to the Kurdish Peshmerga, to fight against ISIS. The U.S. policy for the last few years has really been focused on ISIS and not on the day after ISIS.

But what we’re witnessing at the moment is that different groups are already moving to the day after, which is the power struggle for control of different territories in Iraq.

And Barzani believed that during the fight against ISIS, he became stronger because he got weapons directly from the international community. And, as Feisal said, he was able to extend his control over the disputed territories.

He’s also facing domestic problems within Kurdistan. There are tensions between the different Kurdish groups, and some believe that Barzani has overstayed his term as president.

JUDY WOODRUFF: Which reminds us just how complicated this is, Feisal Istrabadi.

What does the Iraqi central government want here? They’re not going to get rid of the Kurds. What is it that they want?

FEISAL ISTRABADI: Oh, well, I mean, the Kurds of course are a vital part of Iraq. They’re a vital part of the political process, and they have been represented in Baghdad. The president of Iraq is a Kurd and has been since 2005.

I think what needs to occur and I hope what the government of Iraq wants is a negotiated settlement, in which no party dictates terms to the other, but a negotiated settlement.

Look, Irbil has some legitimate agreements with respect to Baghdad. Baghdad has some legitimate agreements with respect to Irbil. I think we need a mediator perhaps or somebody to convene a roundtable — the United States is who I’m thinking of, of course — to address some of those issues.

Most of the issues are, from the Irbil side, economic issues of payments, and from Baghdad’s side, transparency of how much oil Irbil is producing and exporting, which Irbil has never accounted for to Baghdad.

I think if those issues are resolved, perhaps hopefully some of these other issues can at least be delayed for another day. But at the end of the day, neither government — neither the regional government nor the federal government in Baghdad can really tolerate dictation of terms to it by the other side. My hope is that a negotiated settlement obtains.

JUDY WOODRUFF: Emma Sky, where do you see this going from here? Do you see the peace that different sides have worked to hard to create in Iraq unraveling as a result of this?

EMMA SKY: I think there is an opportunity for a deal, and I think the sort of deal that could be negotiated is one that looks at a special status for the city of Kirkuk and negotiated terms for Kurdistan’s separate, whether that be towards confederation or towards independence.

But there needs to be negotiation. There needs to be a look at where should the border between Iraqi Kurdistan and the rest of Iraq actually be, and that requires mediation district by district through those territories.

JUDY WOODRUFF: Well, we know there are other players who are playing an important role here in Iran and Turkey, and this is all very much playing out as we watch, watch it happen in Iraq.

Emma Sky, Feisal Istrabadi, thank you very much.

FEISAL ISTRABADI: Thank you.

EMMA SKY: Thank you.

The post Why a power struggle has broken out over Kirkuk appeared first on PBS NewsHour.

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