Solution Structure and Dynamics of Hf-Al and Hf-Zn Heterobimetallic Adducts Mimicking Relevant Intermediates in Chain Transfer Reactions.

Cationic cyclometalated hafnocenes [CpPrCpCH2CH2CH2Hf][B(C6F5)4] (4Pr) and [CpiBuCpCH2CH(Me)CH2Hf][B(C6F5)4] (4aiBu and 4biBu) were synthesized from the corresponding [(CpPr)2HfMe][B(C6F5)4] (1Pr) and [(CpiBu)2HfMe][B(C6F5)4] (1iBu) complexes via C-H activation. 4aiBu, 4biBu, and 4Pr, mimicking a propagating M-polymeryl species (M = transition metal) with or without a ß-methyl branch on the metalated chains, serve to investigate whether and how the nature of the last inserted olefin molecules changes the structure, stability, and reactivity of the corresponding heterobimetallic complexes, formed in the presence of aluminum- or zinc-alkyl chain transfer agents (CTAs), which are considered relevant intermediates in coordinative chain transfer polymerization (CCTP) and chain shuttling polymerization (CSP) technologies. NMR and DFT data indicate no major structural difference between the resulting heterobridged complexes, all characterized by the presence of multiple α-agostic interactions. On the contrary, thermodynamic and kinetic investigations, concerning the reversible formation and breaking of heterobimetallic adducts, demonstrate that isomer 4aiBu, in which the ß-Me is oriented away from the reactive coordination site on Hf, but not 4biBu, having the ß-Me pointing in the opposite direction, is capable of reacting with CTAs. Quantification of kinetic rate constants highlights that the formation process is rate limiting and that the nature of the last inserted α-olefin unit modulates transalkylation kinetics. The reaction of 4aiBu, 4biBu, and 4Pr with diisobutylaluminum hydride (DiBAlH) allows the interception and characterization of new heterobinuclear and heterotrinuclear species, featuring both hydride and alkyl bridging moieties, which represent structural models of elusive intermediates in CCTP and CSP processes, capturing the instant when an alkyl chain has just transferred from a transition metal to a main group metal, while the two metals remain engaged in a single heterobimetallic intermediate.

Food waste tectonics: Points of friction between policy push and practice pull in council-led household-food-waste interventions in Australia.

Household food waste is increasingly recognised as a global wicked problem for its greenhouse gas emissions, economic damage, and resource loss. Although targeted in the UN's Sustainable Development Goals, countries can only respond according to their capacity. For Australia, national policy has put the pressure on states and territories to divert food waste away from landfill into a nascent circular economy. For councils, this increasingly means implementing a FOGO (Food Organics/Garden Organics) kerbside collection. Despite funding and infrastructure development, many are resisting. Framed by the tenets of policy diffusion, this paper presents the results of a nationwide exploratory survey aimed at identifying how and why council-based waste services staff resist, emulate or lead FOGO implementation. By assessing participants current kerbside systems and their attitudes towards household food waste management, the survey found costs, contamination, and capacity and were key concerns. However, responses to these varied considerably despite similarities of situation, often relating more to collaborative attitudes across waste services, council, and councillors. This paper recognises that a conducive environment for change is urgently needed for Australia to achieve organics diversion targets and shift household food towards a circular economy. It provides a starting point for further research into the complex and nuanced dynamics between council waste services and FOGO implementations, from external drivers and council paradigms to individual attitudes and perceptions.

Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies.

Iptacopan (LNP023) is an oral, small-molecule, first-in-class, highly potent proximal complement inhibitor that specifically binds factor B and inhibits the alternative complement pathway. Iptacopan is currently in development as a targeted treatment of paroxysmal nocturnal hemoglobinuria and multiple other complement-mediated diseases. In this study, the absorption, distribution, metabolism, and excretion (ADME) of iptacopan was characterized in six healthy volunteers after a single 100 mg oral dose of [14C]iptacopan. This was supplemented with an in vivo rat ADME study and metabolite exposure comparisons between human, rat, and dog, in addition to in vitro assays, to better understand the clearance pathways and enzymes involved in the metabolism of iptacopan. The fraction of [14C]iptacopan absorbed was estimated to be about 71%, with a time to maximum concentration of 1.5 hours and elimination half-life from plasma of 12.3 hours. Following a single dose of [14C]iptacopan, 71.5% of the radioactivity was recovered in feces and 24.8% in urine. [14C]iptacopan was primarily eliminated by hepatic metabolism. The main biotransformation pathways were oxidative metabolism via CYP2C8, with M2 being the major oxidative metabolite, and acyl glucuronidation via UGT1A1. The two acyl glucuronide metabolites in human plasma, M8 and M9, each accounted for ≤ 10% of the total circulating drug-related material; systemic exposure was also observed in toxicology studies in rat and dog, suggesting a low risk associated with these metabolites. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan. SIGNIFICANCE STATEMENT: We characterized the pharmacokinetics, excretion, metabolism and elimination of [14C]iptacopan (an oral, selective small-molecule inhibitor of factor B) in healthy human subjects. [14C]iptacopan was primarily eliminated by metabolism. The primary biotransformation pathways were oxidative metabolism via CYP2C8 and acyl glucuronidation via UGT1A1. Direct secretion of iptacopan into urine and potentially bile represented additional elimination mechanisms. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan.

Multidisciplinary perceptions on robotic surgical training: the robot is a stimulus for surgical education change.

BACKGROUND: It is unclear how to best establish successful robotic training programs or if subspecialty robotic program principles can be adapted for general surgery practice. The objective of this study is to understand the perspectives of high-volume robotic surgical educators on best practices in robotic surgery training and to provide recommendations transferable across surgical disciplines. METHODS: This multi-institutional qualitative analysis involved semi-structured interviews with high-volume robotic educators from academic general surgery (AGS), community general surgery (CGS), urology (URO), and gynecology (GYN). Purposeful sampling and snowballing ensured high-volume status and geographically balanced representation across four strata. Interviews were transcribed, deidentified, and independently, inductively coded. A codebook was developed and refined using constant comparative method until interrater reliability kappa reached 0.95. A qualitative thematic, framework analysis was completed. RESULTS: Thirty-four interviews were completed: AGS (n = 9), CGS (n = 8), URO (n = 9), and GYN (n = 8) resulting in 40 codes and four themes. Theme 1: intangibles of culture, resident engagement, and faculty and administrative buy-in are as important as tangibles of robot and simulator access, online modules, and case volumes. Theme 2: robotic OR integration stresses the trainee-autonomy versus patient-safety balance. Theme 3: trainees acquire robotic skills along individual learning curves; benchmark assessments track progress. Theme 4: AGS can learn from URO and GYN through multidisciplinary collaboration but must balance pre-existing training program use with context-specific curricular needs. CONCLUSIONS: Robotic surgical experts emphasize the importance of universal training paradigms, such as a strong educational culture that balances autonomy and patient safety, collaboration between disciplines, and routine assessments for continuous growth. Often, introduction and acceptance of the robot serves as a stimulus to discuss broader surgical education change.

Why people are bad at leftover food management? A systematic literature review and a framework to analyze household leftover food waste generation behavior.

Food waste is a significant global problem. In the Global North, households are a major driver of food waste generation and also a key enabler of solutions to address the issue. Leftover food management is identified as one of the key areas that can be targeted to reduce food waste at home. Although a large body of literature exists on household food waste and its drivers, managing food leftovers has received less attention. This state-of-the-art review focuses on leftover food management practices with the view of supporting practitioners in designing and prioritizing behavioral interventions to reduce leftover food waste in households. It uses the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework to select articles for the review. Based on 42 primary studies, this systematic review identifies a range of psycho-social, socio-demographic and lifestyle factors influencing leftover food waste generation behavior at home. Moreover, household food handling skills and knowledge, and availability and accessibility to infrastructure facilities affect leftover food waste generation behavior. Based on the synthesized literature, Leftover Food Waste Generation Behavior (LFWGB) Framework has been developed. The framework conceptualizes psycho-social, personal and lifestyle factors driving leftover food management behaviors at home. Reducing food leftovers must be given top priority along with consumer meal planning and food preparation skills in household food waste reduction interventions and campaigns.

Has the COVID-19 pandemic changed household food management and food waste behavior? A natural experiment using propensity score matching.

Household food management behavior changed considerably during the COVID-19 pandemic. A growing body of work has quantified the impact of lockdowns on household food waste. Yet, previous studies used a retrospective study design which undermines the accuracy of the causal effect on household food waste. This paper investigates the causal impact of the COVID-19 pandemic on household food management and food waste using a natural experiment approach. Using two large national-scale longitudinal data sets (n = 8157), this study quantifies the impact of COVID-19 on food waste and food behavior of Australian households. Propensity score matching (PSM) was carried out to address potential endogeneity issues and to select control and treatment groups for analysis. Findings reveal that Australian households reduced food waste by 9% on average in 2020 (during COVID-19) compared to the pre-pandemic (2019) level. The use of a grocery list, discount purchases, and 'just-in-case' purchases, and food refrigeration have recorded a marked increase during the pandemic compared to pre-pandemic times. The changes to food management and food discard behavior during the pandemic offer important insights for behavior change campaigns to reduce household food waste. Interventions to sustain good food planning and storage practices and involving food retailers are promising entry points in addressing household food waste. The study also highlights the considerable challenge in achieving SDG 12.3 target by 2030.

A case of VEXAS syndrome associated with EBV-associated hemophagocytic lymphohistiocytosis.

Vacuoles, E1, X-linked, autoimmunity, somatic (VEXAS) syndrome is characterized by a pathogenic mutation in UBA1, which leads to protean complications including autoimmunity and myelodysplasia. A 56-year-old man with steroid-dependent, later steroid-refractory cutaneous polyarteritis nodosa and Sweet syndrome developed recurrent daily fever, macrocytic anemia, thrombocytopenia, acute hypoxic respiratory failure, and anasarca. He was eventually diagnosed with Epstein-Barr virus (EBV) viremia and hemophagocytic lymphohistiocytosis (HLH). He improved clinically with rituximab, ruxolitinib, and increased glucocorticoids before expiring from Pseudomonas sepsis. UBA1 exon 3 mutational analysis in myeloid enriched peripheral blood revealed a c.122T>C (p.Met41Thr) pathogenic variant, consistent with VEXAS syndrome. We describe the first case of EBV-associated HLH in a patient diagnosed with VEXAS syndrome. Early identification of this syndrome will be important in order to offer potential therapies before life-threatening complications arise.

Human Pharmacokinetics of LYS006, an Oral Leukotriene A4 Hydrolase Inhibitor Displaying Target-Mediated Drug Disposition.

LYS006 is a potent leukotriene A4 hydrolase inhibitor currently in clinical development for long-term treatment of various neutrophil-driven inflammatory conditions. Here, we present pharmacokinetics from the first-in-human study with complementary metabolism and transporter profiling data. The randomized first-in-human study included nine cohorts receiving 5-2*100 mg of LYS006 or placebo, a crossover food-effect part, and a multiple-dose part consisting of two fasted (5 mg and 15 mg once daily) and three fed cohorts (20-80 mg twice a day) of LYS006 or placebo. LYS006 and metabolites were assessed in plasma and urine, and transporters involved in LYS006 disposition were analyzed in vitro. Systemic plasma exposure increased with dose; steady-state exposure was dose proportional up to 40 mg twice a day. Steady state was achieved after ∼3 days, with mean accumulation of 2.1-fold for 5 mg once daily and ≤1.4-fold for all higher doses. Despite limited accumulation, a long terminal half-life (T1/2) was observed. The long T1/2 and saturable binding to blood cells, which causes a highly nonlinear blood-to-plasma distribution, reflect a strong impact of target binding on drug distribution at lower concentrations. Skin biopsy and blister fluid concentration data indicated saturable binding in the former but not the latter, suggesting saturable binding in tissues beyond blood. Major excretion of LYS006 (∼90% of dose) through urine at steady state triggered renal transporter investigations that identified LYS006 as a substrate of organic anion transporter (OAT)3, OAT4, breast cancer resistance protein, and multidrug resistance-associated protein 4. Seven metabolites were identified in human plasma and urine, comprising only 4% of the dose recovered in urine at steady state. SIGNIFICANCE STATEMENT: Pharmacokinetic data from a first-in-human study combined with in vitro work support dose and regimen selection for patient studies with LYS006 and provide guidance on drug interaction investigations and other clinical pharmacology work needed for further development. Mass balance information at steady state without the use of a radiolabel, skin concentrations, and identification of the major clearance pathway, as well as the transporters driving elimination, make this a particularly conclusive early study despite nonlinear pharmacokinetics impacted by target binding.

Species-dependent hepatic and intestinal metabolism of selective oestrogen receptor degrader LSZ102 by sulphation and glucuronidation.

LSZ102 is an orally bioavailable selective oestrogen receptor degrader in clinical development for the treatment of breast cancer. Preclinical studies showed efficacy in xenograft models on oral dosing. However, oral bioavailability was relatively low in several preclinical species (7-33%), and was associated with first-pass metabolism, particularly intestinal first-pass.To investigate metabolism and first-pass effects, metabolites were analysed in human plasma samples after oral dosing of LSZ102 to patients, rat plasma samples after oral dosing of [14C]LSZ102, and in vitro incubations of [14C]LSZ102 with human and rat hepatocytes and intestinal S9 fractions. The kinetics of human sulfotransferase (SULT) enzymes potentially involved in metabolism of LSZ102 was characterised.Sulphate metabolites were found to be the major components in human plasma, as well as in human hepatocytes and intestinal S9 fractions. Contrastingly, glucuronidation was predominant in rat plasma, hepatocytes and intestinal S9. LSZ102 was found to be metabolised by several human SULTs expressed in liver and intestine. The combined metabolism data in rat and human provide supporting evidence for an extensive intestinal first-pass metabolism effect via sulphation in human but glucuronidation in rat.As LSZ102 is metabolised by a number of different SULTs, drug-drug interactions resulting from the inhibition of one SULT are unlikely.Despite the observed species difference in metabolism, the major human metabolites of LSZ102, sulphate M5, glucuronide M4, and secondary glucuronide/sulphate metabolite M12, have no or weak pharmacological activity and are not considered a toxicity risk as they are phase II conjugative metabolites.

High-throughput mechanobiology: Force modulation of ensemble biochemical and cell-based assays.

Mechanobiology is focused on how the physical forces and mechanical properties of proteins, cells, and tissues contribute to physiology and disease. Although the response of proteins and cells to mechanical stimuli is critical for function, the tools to probe these activities are typically restricted to single-molecule manipulations. Here, we have developed a novel microplate reader assay to encompass mechanical measurements with ensemble biochemical and cellular assays, using a microplate lid modified with magnets. This configuration enables multiple static magnetic tweezers to function simultaneously across the microplate, thereby greatly increasing throughput. We demonstrate the broad applicability and versatility through in vitro and in cellulo approaches. Overall, our methodology allows, for the first time (to our knowledge), ensemble biochemical and cell-based assays to be performed under force in high-throughput format. This approach substantially increases the availability of mechanobiology measurements.

Cutaneous T-cell lymphoma is associated with increased risk of lymphoma, melanoma, lung cancer, and bladder cancer.

BACKGROUND: Patients with cutaneous T-cell lymphoma (CTCL) are at a higher risk of developing second malignancies. However, rates of incidence vary significantly across studies. METHODS: A systematic review and meta-analysis of articles published between 1950 and 2019 was performed to evaluate the risk of second malignancies in patients with CTCL. RESULTS: We identified 10 eligible studies, including 12 patient cohorts, with 5.9% to 16.8% of patients developing second malignancies. All studies showed a male predominance for patients developing second malignancies. The mean age across the studies ranged from 44.6 to 68.0 years. The time between the diagnosis of CTCL and second malignancy ranged from 2.1 to 5.4 years (mean, 3.29 y; 95% confidence interval [CI], 2.69-5.15). Meta-analysis showed a standardized incidence ratio of 2.18 (95% CI, 1.43-2.93) for all malignancies. The standardized incidence ratios were 15.25 (95% CI, 7.70-22.79) for Hodgkin lymphoma, 4.96 (95% CI, 3.58-6.33) for non-Hodgkin lymphoma, 1.69 (95% CI, 1.18-2.21) for lung cancer, 1.72 (95% CI, 1.18-2.21) for bladder cancer, and 3.09 (95% CI, 1.77-6.43) for melanoma. CONCLUSIONS: We find that patients with CTCL are at increased risk of second malignancies, especially Hodgkin and non-Hodgkin lymphoma, lung cancer, bladder cancer, and melanoma. These findings provide evidence of a population at increased risk of malignancy. Early detection may decrease the morbidity burden of second malignancies, thus providing a strong rationale for prospective screening studies.

Multidisciplinary Approach to Robotic Resection of Abdominal Wall Endometriosis and Mesh Repair.

STUDY OBJECTIVE: To demonstrate a technique for robot-assisted laparoscopic excision of abdominal wall endometriosis and mesh reinforcement of the subsequent defect. DESIGN: Description and demonstration of surgical technique. SETTING: Abdominal wall endometriosis most commonly takes hold after seeding of a previous cesarean scar [1-5]. As of 2018, 31.9% of deliveries in the United States were accomplished by cesarean section [6]. With endometriosis at an estimated incidence of 11% in the United States, evaluation for, and minimally invasive management of, abdominal wall endometriosis is becoming an essential skillset for the gynecologic surgeon [7]. INTERVENTIONS: Robot-assisted laparoscopic evaluation of size and location of lesion in relation to anatomic landmarks. Demonstration of techniques to identify borders of endometriotic lesion including clinical and microscopic. Minimally invasive resection of lesion with preservation of vital structures. Placement of abdominal wall mesh for reinforcement of rectus muscle and fascial defect. Peritoneal closure to minimize adhesions and herniation into defect. Brief review of alternative approaches to surgical management. CONCLUSION: Minimally invasive resection of abdominal wall endometriosis with subsequent mesh reinforcement provides a surgical option with less morbidity while still accomplishing successful treatment.

Prehospital ECG with ST-depression and T-wave inversion are associated with new onset heart failure in individuals transported by ambulance for suspected acute coronary syndrome.

BACKGROUND: Prehospital electrocardiogram(s) (ECG) can improve early detection of acute coronary syndrome (ST-segment elevation myocardial infarction [STEMI], non-STEMI, and unstable angina) and inform prehospital activation of cardiac catheterization lab; thus, reducing total ischemic time and improving patient outcomes. Less is known, however, about the association of prehospital ECG ischemic findings and long term adverse clinical events. With this in mind, this study was designed to examine the: 1) frequency of prehospital ECGs for acute myocardial ischemia (ST-elevation, ST-depression, and/or T-wave inversion); and, 2) whether any of these specific ECG features are associated with adverse clinical events within 30 day of initial presentation to the emergency department (ED). METHODS: We included consecutive patients ≥ 21 years during a five-year period (2013-2017), who were transported by ambulance to the ED with non-traumatic chest pain and/or anginal equivalent(s) and had a prehospital 12­lead ECG. Two cardiologists (LG, EC), blinded to clinical data, interpreted the 12­lead ECGs applying current guideline based ischemia criteria. Adverse clinical events, return to ED, and rehospitalization evaluated at 30-days. RESULTS: We identified 3646 patients (mean age, 59.7 years ±15.7; 45% female) with ECGs, of which N = 3587 had data on the three ischemic markers of interest. Of these, 1762 (49.1%) had ECG evidence of ischemia. In adjusted logistic regression models, those with T-wave inversion had a higher odds (OR = 1.59) of new onset heart failure, while ST-elevation was associated with lower odds (OR = 0.69). Patients with ST-depression had higher odds of new onset heart failure and death within 30 days (OR = 1.29, 1.49 respectively), but this association attenuated after controlling for other ECG features. CONCLUSIONS: ST-depression and/or T-wave inversion are independent predictors of new onset heart failure, within 30 days of initial ED presentation. Our study in a large cohort of patients, suggests that using ECG ST-elevation alone may not capture patients with ischemia who may benefit from aggressive anti-ischemic therapies to reduce myocardial damage with resultant heart failure.

Malignancy in dermatomyositis: A retrospective study of 201 patients seen at the University of Pennsylvania.

BACKGROUND: There is an increased incidence of malignancy in patients with dermatomyositis. It is unknown if the risk differs between the subtypes of dermatomyositis. OBJECTIVE: To (1) compare the prevalence of malignancy-associated dermatomyositis between patients with classic and clinically amyopathic disease and (2) determine factors associated with an increased risk of malignancy-associated disease. METHODS: Retrospective cohort study of 201 patients with adult-onset dermatomyositis prospectively enrolled in a longitudinal dermatomyositis database between July 2008 and April 2018 at an outpatient dermatology urban tertiary referral center. The main outcome measure was a diagnosis of malignancy, excluding nonmelanoma skin cancer. RESULTS: There were 201 patients with adult-onset dermatomyositis: 142 (71%) classic and 59 (29%) clinically amyopathic. Within 2 years of diagnosis, the prevalences of malignancy-associated classic and clinically amyopathic dermatomyositis were 9.9% and 1.7%, respectively. In this time period, patients who were older at dermatomyositis diagnosis (P = .01) and had the classic subtype (P = .04) were significantly more likely to have an underlying malignancy on multivariable regression analysis. LIMITATIONS: This was a retrospective study of prospectively collected data at a single tertiary referral center. CONCLUSION: Older age and classic dermatomyositis are independent risk factors for malignancy-associated dermatomyositis within 2 years of disease onset.

Sensitivity of tropical carbon to climate change constrained by carbon dioxide variability.

The release of carbon from tropical forests may exacerbate future climate change, but the magnitude of the effect in climate models remains uncertain. Coupled climate-carbon-cycle models generally agree that carbon storage on land will increase as a result of the simultaneous enhancement of plant photosynthesis and water use efficiency under higher atmospheric CO(2) concentrations, but will decrease owing to higher soil and plant respiration rates associated with warming temperatures. At present, the balance between these effects varies markedly among coupled climate-carbon-cycle models, leading to a range of 330 gigatonnes in the projected change in the amount of carbon stored on tropical land by 2100. Explanations for this large uncertainty include differences in the predicted change in rainfall in Amazonia and variations in the responses of alternative vegetation models to warming. Here we identify an emergent linear relationship, across an ensemble of models, between the sensitivity of tropical land carbon storage to warming and the sensitivity of the annual growth rate of atmospheric CO(2) to tropical temperature anomalies. Combined with contemporary observations of atmospheric CO(2) concentration and tropical temperature, this relationship provides a tight constraint on the sensitivity of tropical land carbon to climate change. We estimate that over tropical land from latitude 30° north to 30° south, warming alone will release 53 ± 17 gigatonnes of carbon per kelvin. Compared with the unconstrained ensemble of climate-carbon-cycle projections, this indicates a much lower risk of Amazon forest dieback under CO(2)-induced climate change if CO(2) fertilization effects are as large as suggested by current models. Our study, however, also implies greater certainty that carbon will be lost from tropical land if warming arises from reductions in aerosols or increases in other greenhouse gases.

19F-NMR-based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers.

1. Leniolisib is a novel oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor, currently in clinical development for the treatment of inflammatory and autoimmune diseases. 2. We investigated the absorption, metabolism, and excretion of leniolisib in healthy subjects after a single oral 400 mg dose as part of a first-in-human clinical study. The parent drug and metabolites were quantified by 19F-NMR in plasma, urine and faeces after liquid chromatography separation, and structures were determined by liquid chromatography coupled to tandem mass spectrometry. 3. Drug-related material was mainly excreted as oxidative metabolites in urine and faeces, providing evidence that elimination occurs mainly by metabolism. No metabolites were abundant in plasma relative to the parent drug. An average mass balance of 66% was obtained, demonstrating that relatively extensive elimination/excretion data can be obtained by 19F-NMR in a first in human clinical study without the use of a radiolabeled drug.

Team-focused Cardiopulmonary Resuscitation: Prehospital Principles Adapted for Emergency Department Cardiac Arrest Resuscitation.

BACKGROUND: Out-of-hospital cardiac arrest has high rates of morbidity and mortality, and a growing body of evidence is redefining our approach to the resuscitation of these high-risk patients. OBJECTIVES: Team-focused cardiopulmonary resuscitation (TFCPR), most commonly deployed and described by prehospital care providers, is a focused approach to cardiac arrest care that emphasizes early defibrillation and high-quality, minimally interrupted chest compressions while de-emphasizing endotracheal intubation and intravenous drug administration. TFCPR is associated with statistically significant increases in survival to hospital admission, survival to hospital discharge, and survival with good neurologic outcome; however, the adoption of similar streamlined resuscitation approaches by emergency physicians has not been widely reported. In the absence of a deliberately streamlined approach, such as TFCPR, other advanced therapies and procedures that have not shown similar survival benefit may be prioritized at the expense of simpler evidence-based interventions. DISCUSSION: This review examines the current literature on cardiac arrest resuscitation. The recent prehospital success of TFCPR is highlighted, including the associated improvements in multiple patient-centered outcomes. The adaptability of TFCPR to the emergency department (ED) setting is also discussed in detail. Finally, we discuss advanced interventions frequently performed during ED cardiac arrest resuscitation that may interfere with early defibrillation and effective high-quality chest compressions. CONCLUSION: TFCPR has been associated with improved patient outcomes in the prehospital setting. The data are less compelling for other commonly used advanced resuscitation tools and procedures. Emergency physicians should consider incorporating the TFCPR approach into ED cardiac arrest resuscitation to optimize delivery of those interventions most associated with improved outcomes.

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro.

Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.