Projected land ice contributions to twenty-first-century sea level rise.

The land ice contribution to global mean sea level rise has not yet been predicted1 using ice sheet and glacier models for the latest set of socio-economic scenarios, nor using coordinated exploration of uncertainties arising from the various computer models involved. Two recent international projects generated a large suite of projections using multiple models2-8, but primarily used previous-generation scenarios9 and climate models10, and could not fully explore known uncertainties. Here we estimate probability distributions for these projections under the new scenarios11,12 using statistical emulation of the ice sheet and glacier models. We find that limiting global warming to 1.5 degrees Celsius would halve the land ice contribution to twenty-first-century sea level rise, relative to current emissions pledges. The median decreases from 25 to 13 centimetres sea level equivalent (SLE) by 2100, with glaciers responsible for half the sea level contribution. The projected Antarctic contribution does not show a clear response to the emissions scenario, owing to uncertainties in the competing processes of increasing ice loss and snowfall accumulation in a warming climate. However, under risk-averse (pessimistic) assumptions, Antarctic ice loss could be five times higher, increasing the median land ice contribution to 42 centimetres SLE under current policies and pledges, with the 95th percentile projection exceeding half a metre even under 1.5 degrees Celsius warming. This would severely limit the possibility of mitigating future coastal flooding. Given this large range (between 13 centimetres SLE using the main projections under 1.5 degrees Celsius warming and 42 centimetres SLE using risk-averse projections under current pledges), adaptation planning for twenty-first-century sea level rise must account for a factor-of-three uncertainty in the land ice contribution until climate policies and the Antarctic response are further constrained.

Framework of the strengths and challenges of clinically integrated trials: An expert panel report.

The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems. The operational and design features of clinically integrated trials include a focused scope, simplicity in design and requirements, the leveraging of existing data structures, and patient participation in the entire trial process. These features are designed to minimize barriers to participation and trial execution and reduce additional research burdens for participants and clinicians alike. Broad adoption and scalability of clinically integrated trials are dependent, in part, on continuing regulatory, healthcare system, and payer support. This analysis presents a framework of the strengths and challenges of clinically integrated trials and is based on a multidisciplinary expert "Think Tank" panel discussion that included representatives from patient populations, academia, non-profit funding agencies, the U.S. Food and Drug Administration, and industry.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Absorption pharmacokinetics and feasibility of intranasal dexmedetomidine in patients under general anaesthesia.

BACKGROUND: The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics. METHODS: We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 µg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (CMAX) and time (TMAX) were estimated using simulation (n = 1000) with parameter estimates and their associated variability. RESULTS: There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) µg kg-1. CMAX 0.273 µg L-1 was achieved at 98 min after intranasal administration (TMAX). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (TABS = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable. CONCLUSIONS: Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after TMAX for several hours.

Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

How many kinases are druggable? A review of our current understanding.

There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases are tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible to discover a drug for each individual kinase? For every human kinase, we gathered data on their citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. Analysis of these factors highlights which kinase groups have a wealth of information available, and which groups still have room for progress. The data suggest a disproportionate focus on the more well characterized kinases while much of the kinome remains comparatively understudied. It is noteworthy that tool compounds for understudied kinases have already been developed, and there is still untapped potential for further development in this chemical space. Finally, this review discusses many of the different strategies employed to generate selectivity between kinases. Given the large volume of information available and the progress made over the past 20 years when it comes to drugging kinases, we believe it is possible to develop a tool compound for every human kinase. We hope this review will prove to be both a useful resource as well as inspire the discovery of a tool for every kinase.

Developing an initial set of quality indicators for chiropractic care: a scoping review.

BACKGROUND: Quality indicators are standardized, evidence-based measures of health care quality. Currently, there is no basic set of quality indicators for chiropractic care published in peer-reviewed literature. The goal of this research is to develop a preliminary set of quality indicators, measurable with administrative data. METHODS: We conducted a scoping review searching PubMed/MEDLINE, CINAHL, and Index to Chiropractic Literature databases. Eligible articles were published after 2011, in English, developing/reporting best practices and clinical guidelines specifically developed for, or directly applicable to, chiropractic care. Eligible non-peer-reviewed sources such as quality measures published by the Centers for Medicare and Medicaid Services and the Royal College of Chiropractors quality standards were also included. Following a stepwise eligibility determination process, data abstraction identified specific statements from included sources that can conceivably be measured with administrative data. Once identified, statements were transformed into potential indicators by: 1) Generating a brief title and description; 2) Documenting a source; 3) Developing a metric; and 4) Assigning a Donabedian category (structure, process, outcome). Draft indicators then traversed a 5-step assessment: 1) Describes a narrowly defined structure, process, or outcome; 2) Quantitative data can conceivably be available; 3) Performance is achievable; 4) Metric is relevant; 5) Data are obtainable within reasonable time limits. Indicators meeting all criteria were included in the final set. RESULTS: Literature searching revealed 2562 articles. After removing duplicates and conducting eligibility determination, 18 remained. Most were clinical guidelines (n = 10) and best practice recommendations (n = 6), with 1 consensus and 1 clinical standards development study. Data abstraction and transformation produced 204 draft quality indicators. Of those, 57 did not meet 1 or more assessment criteria. After removing duplicates, 70 distinct indicators remained. Most indicators matched the Donabedian category of process (n = 35), with 31 structure and 4 outcome indicators. No sources were identified to support indicator development from patient perspectives. CONCLUSIONS: This article proposes a preliminary set of 70 quality indicators for chiropractic care, theoretically measurable with administrative data and largely obtained from electronic health records. Future research should assess feasibility, achieve stakeholder consensus, develop additional indicators including those considering patient perspectives, and study relationships with clinical outcomes. TRIAL REGISTRATION: Open Science Framework, https://osf.io/t7kgm.

Pediatric anesthesia in Australia and New Zealand and health inequity among First Nations and Maori children.

Australia and New Zealand are two countries in the Southern Pacific region. They share many pediatric anesthesia similarities in terms of medical organizational systems, education, training, and research, however there are important differences between the two nations in relation to geography, the First Nations populations and the history of colonization. While the standards for pediatric anesthesia and the specialty training requirements are set by the Australian and New Zealand College of Anesthetists and the Society for Pediatric Anesthesia in New Zealand and Australia, colonization has created distinct challenges that each nation now faces in order to improve the anesthetic care of its pediatric population. Australia generally has a high standard of living and good access to health care; disparities exist for First Nations People and for those living in rural or remote areas. Two influences have shaped training within New Zealand over the past 40 years; establishment of a national children's hospital in 1990 and, more importantly, acknowledgement that the First Nations people of New Zealand (Maori) have suffered because of failure to recognize their rights consequent to establishing a partnership treaty between Maori and the British Crown in 1840. Health inequities among Maori in New Zealand and First Nations People in Australia have implications for the health system, culturally appropriate approaches to treatment, and the importance of having an appreciation of First Nations people's history and culture, language, family structure, and cultural safety. Trainees in both countries need to be adequately supported in these areas in order for the sub-specialty of pediatric anesthesia to develop further and improve the anesthetic and surgical outcomes of our children.

Feasibility and Acceptability of Using Wireless Limited Polysomnography to Capture Sleep Before, During, and After Hospitalization for Patients With Planned Cardiothoracic Surgery.

BACKGROUND: Sleep disruption, a common symptom among patients requiring cardiovascular surgery, is a potential risk factor for the development of postoperative delirium. Postoperative delirium is a disorder of acute disturbances in cognition associated with prolonged hospitalization, cognitive decline, and mortality. OBJECTIVE: The aim of this study was to evaluate the feasibility and acceptability of using polysomnography (PSG) to capture sleep in patients with scheduled cardiothoracic surgery. METHODS: Wireless limited PSG assessed sleep at baseline (presurgery at home), postoperatively in the intensive care unit, and at home post hospital discharge. Primary outcomes were quality and completeness of PSG signals, and acceptability by participants and nursing staff. RESULTS: Among 15 patients, PSG data were of high quality, and mean percentage of unscorable data was 5.5% ± 11.1%, 3.7% ± 5.4%, and 3.7% ± 8.4% for baseline, intensive care unit, and posthospitalization measurements, respectively. Nurses and patients found the PSG monitor acceptable. CONCLUSIONS: Wireless, limited PSG to capture sleep across the surgical continuum was feasible, and data were of high quality. Authors of future studies will evaluate associations of sleep indices and development of postoperative delirium in this high-risk population.

Filtering distractors is costly.

To find a target in visual search, it is often necessary to filter out task-irrelevant distractors. People find the process of distractor filtering effortful, exerting physical effort to reduce the number of distractors that need to be filtered on a given search trial. Working memory demands are sufficiently costly that people are sometimes willing to accept aversive heat stimulation in exchange for the ability to avoid performing a working memory task. The present study examines whether filtering distractors in visual search is similarly costly. The findings reveal that individuals are sometimes willing to accept an electric shock in exchange for the ability to skip a single trial of visual search, increasingly so as the demands of distractor filtering increase. This was true even when acceptance of shock resulted in no overall time savings, although acceptance of shock was overall infrequent and influenced by a plurality of factors, including boredom and curiosity. These findings have implications for our understanding of the mental burden of distractor filtering and why people seek to avoid cognitive effort more broadly.

Restricting angles of incidence to improve super resolution in time reversal focusing that uses metamaterial properties of a resonator array.

Focusing waves with a spatial extent smaller than a half wavelength (i.e., super resolution or sub diffraction limit) is possible using resonators placed in the near field of time reversal (TR) focusing. While a two-dimensional (2D) Helmholtz resonator array in a three-dimensional reverberant environment has limited ability to produce a high-resolution spatial focus in the TR focusing of audible sound, it is shown that acoustic waves propagating out-of-plane with the resonator array are not as strongly affected by the smaller effective wavelength induced by the resonator array, partially negating the effect of the resonators. A physical 2D waveguide is shown to limit the out-of-plane propagation, leading to improved resolution. It is also shown that post processing using an orthogonal particle velocity decomposition of a spatial scan of the focusing can filter out-of-plane particle motion in the near field of the array, which bypasses the effect of the unwanted third spatial dimension of propagation. The spatial resolution in a reverberant environment is shown to improve in the presence of a 2D Helmholtz resonator array and then further improve by adding a 2D waveguide. The resolution among the resonator array is better still without using a waveguide and instead using the partial-pressure reconstruction.

Observational learning of threat-related attentional bias.

Attentional bias to threat has been almost exclusively examined after participants experienced repeated pairings between a conditioned stimulus (CS) and an aversive unconditioned stimulus (US). This study aimed to determine whether threat-related attentional capture can result from observational learning, when participants acquire knowledge of the aversive qualities of a stimulus without themselves experiencing aversive outcomes. Non-clinical young-adult participants (N = 38) first watched a video of an individual (the demonstrator) performing a Pavlovian conditioning task in which one colour was paired with shock (CS+) and another colour was neutral (CS-). They then carried out visual search for a shape-defined target. Oculomotor measures evidenced an attentional bias toward the CS+ colour, suggesting that threat-related attentional capture can ensue from observational learning. Exploratory analyses also revealed that this effect was positively correlated with empathy for the demonstrator. Our findings extend empirical and theoretical knowledge about threat-driven attention and provide valuable insights to better understand the formation of anxiety disorders.

Perceptions on and roadblocks to implementation of standardized nomenclature in radiation oncology: A survey from TG-263U1.

PURPOSE: AAPM Task Group No. 263U1 (Update to Report No. 263 - Standardizing Nomenclatures in Radiation Oncology) disseminated a survey to receive feedback on utilization, gaps, and means to facilitate further adoption. METHODS: The survey was created by TG-263U1 members to solicit feedback from physicists, dosimetrists, and physicians working in radiation oncology. Questions on the adoption of the TG-263 standard were coupled with demographic information, such as clinical role, place of primary employment (e.g., private hospital, academic center), and size of institution. The survey was emailed to all AAPM, AAMD, and ASTRO members. RESULTS: The survey received 463 responses with 310 completed survey responses used for analysis, of whom most had the clinical role of medical physicist (73%) and the majority were from the United States (83%). There were 83% of respondents who indicated that they believe that having a nomenclature standard is important or very important and 61% had adopted all or portions of TG-263 in their clinics. For those yet to adopt TG-263, the staffing and implementation efforts were the main cause for delaying adoption. Fewer respondents had trouble adopting TG-263 for organs at risk (29%) versus target (44%) nomenclature. Common themes in written feedback were lack of physician support and available resources, especially in vendor systems, to facilitate adoption. CONCLUSIONS: While there is strong support and belief in the benefit of standardized nomenclature, the widespread adoption of TG-263 has been hindered by the effort needed by staff for implementation.  Feedback from the survey is being utilized to drive the focus of the update efforts and create tools to facilitate easier adoption of TG-263.

Dabigatran pharmacokinetic-pharmacodynamic in sheep: Informing dose for anticoagulation during cardiopulmonary bypass.

BACKGROUND: The effect of the anticoagulant, dabigatran, and its antagonist, idarucizumab, on coagulation remains poorly quantified. There are few pharmacokinetic-pharmacodynamic data available to determine dabigatran dose in humans or animals undergoing cardiopulmonary bypass. METHODS: Five sheep were given intravenous dabigatran 4 mg/kg. Blood samples were collected for thromboelastometric reaction time (R-time) and drug assay at 5, 15, 30, 60, 120, 240, 480 min, and 24 h. Plasma dabigatran concentrations and R-times were analyzed using an integrated pharmacokinetic-pharmacodynamic model using non-linear mixed effects. The impact of idarucizumab 15 mg/kg administered 120 min after dabigatran 4 mg/kg and its effect on R-time was observed. RESULTS: A 2-compartment model described dabigatran pharmacokinetics with a clearance (CL 0.0453 L/min/70 kg), intercompartment clearance (Q 0.268 L/min/70 kg), central volume of distribution (V1 2.94 L/70 kg), peripheral volume of distribution (V2 9.51 L/70 kg). The effect compartment model estimates for a sigmoid EMAX model using Reaction time had an effect site concentration (Ce50 64.2 mg/L) eliciting half of the maximal effect (EMAX 180 min). The plasma-effect compartment equilibration half time (T1/2keo) was 1.04 min. Idarucizumab 15 mg/kg reduced R-time by approximately 5 min. CONCLUSIONS: Dabigatran reversibly binds to the active site on the thrombin molecule, preventing activation of coagulation factors. The pharmacologic target concentration strategy uses pharmacokinetic-pharmacodynamic information to inform dose. A loading dose of dabigatran 0.25 mg/kg followed by a maintenance infusion of dabigatran 0.0175 mg/kg/min for 30 min and a subsequent infusion dabigatran 0.0075 mg/kg/min achieves a steady state target concentration of 5 mg/L in a sheep model.

A Nationwide Network of Health AI Assurance Laboratories.

Importance: Given the importance of rigorous development and evaluation standards needed of artificial intelligence (AI) models used in health care, nationwide accepted procedures to provide assurance that the use of AI is fair, appropriate, valid, effective, and safe are urgently needed. Observations: While there are several efforts to develop standards and best practices to evaluate AI, there is a gap between having such guidance and the application of such guidance to both existing and new AI models being developed. As of now, there is no publicly available, nationwide mechanism that enables objective evaluation and ongoing assessment of the consequences of using health AI models in clinical care settings. Conclusion and Relevance: The need to create a public-private partnership to support a nationwide health AI assurance labs network is outlined here. In this network, community best practices could be applied for testing health AI models to produce reports on their performance that can be widely shared for managing the lifecycle of AI models over time and across populations and sites where these models are deployed.

Ablative Margins of Colorectal Liver Metastases Using Deformable CT Image Registration and Autosegmentation.

Background Confirming ablation completeness with sufficient ablative margin is critical for local tumor control following colorectal liver metastasis (CLM) ablation. An image-based confirmation method considering patient- and ablation-related biomechanical deformation is an unmet need. Purpose To evaluate a biomechanical deformable image registration (DIR) method for three-dimensional (3D) minimal ablative margin (MAM) quantification and the association with local disease progression following CT-guided CLM ablation. Materials and Methods This single-institution retrospective study included patients with CLM treated with CT-guided microwave or radiofrequency ablation from October 2015 to March 2020. A biomechanical DIR method with AI-based autosegmentation of liver, tumors, and ablation zones on CT images was applied for MAM quantification retrospectively. The per-tumor incidence of local disease progression was defined as residual tumor or local tumor progression. Factors associated with local disease progression were evaluated using the multivariable Fine-Gray subdistribution hazard model. Local disease progression sites were spatially localized with the tissue at risk for tumor progression (<5 mm) using a 3D ray-tracing method. Results Overall, 213 ablated CLMs (mean diameter, 1.4 cm) in 124 consecutive patients (mean age, 57 years ± 12 [SD]; 69 women) were evaluated, with a median follow-up interval of 25.8 months. In ablated CLMs, an MAM of 0 mm was depicted in 14.6% (31 of 213), from greater than 0 to less than 5 mm in 40.4% (86 of 213), and greater than or equal to 5 mm in 45.1% (96 of 213). The 2-year cumulative incidence of local disease progression was 72% for 0 mm and 12% for greater than 0 to less than 5 mm. No local disease progression was observed for an MAM greater than or equal to 5 mm. Among 117 tumors with an MAM less than 5 mm, 36 had local disease progression and 30 were spatially localized within the tissue at risk for tumor progression. On multivariable analysis, an MAM of 0 mm (subdistribution hazard ratio, 23.3; 95% CI: 10.8, 50.5; P < .001) was independently associated with local disease progression. Conclusion Biomechanical deformable image registration and autosegmentation on CT images enabled identification and spatial localization of colorectal liver metastases at risk for local disease progression following ablation, with a minimal ablative margin greater than or equal to 5 mm as the optimal end point. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Sofocleous in this issue.

The Influence of Social Determinants on Receiving Outpatient Treatment with Monoclonal Antibodies, Disease Risk, and Effectiveness for COVID-19.

BACKGROUND: Limited research has studied the influence of social determinants of health (SDoH) on the receipt, disease risk, and subsequent effectiveness of neutralizing monoclonal antibodies (nMAbs) for outpatient treatment of COVID-19. OBJECTIVE: To examine the influence of SDoH variables on receiving nMAb treatments and the risk of a poor COVID-19 outcome, as well as nMAb treatment effectiveness across SDoH subgroups. DESIGN: Retrospective observational study utilizing electronic health record data from four health systems. SDoH variables analyzed included race, ethnicity, insurance, marital status, Area Deprivation Index, and population density. PARTICIPANTS: COVID-19 patients who met at least one emergency use authorization criterion for nMAb treatment. MAIN MEASURE: We used binary logistic regression to examine the influence of SDoH variables on receiving nMAb treatments and risk of a poor outcome from COVID-19 and marginal structural models to study treatment effectiveness. RESULTS: The study population included 25,241 (15.1%) nMAb-treated and 141,942 (84.9%) non-treated patients. Black or African American patients were less likely to receive treatment than white non-Hispanic patients (adjusted odds ratio (OR) = 0.86; 95% CI = 0.82-0.91). Patients who were on Medicaid, divorced or widowed, living in rural areas, or living in areas with the highest Area Deprivation Index (most vulnerable) had lower odds of receiving nMAb treatment, but a higher risk of a poor outcome. For example, compared to patients on private insurance, Medicaid patients had 0.89 (95% CI = 0.84-0.93) times the odds of receiving nMAb treatment, but 1.18 (95% CI = 1.13-1.24) times the odds of a poor COVID-19 outcome. Age, comorbidities, and COVID-19 vaccination status had a stronger influence on risk of a poor outcome than SDoH variables. nMAb treatment benefited all SDoH subgroups with lower rates of 14-day hospitalization and 30-day mortality. CONCLUSION: Disparities existed in receiving nMAbs within SDoH subgroups despite the benefit of treatment across subgroups.

The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian α-linked glycosylceramides.

Glycosylceramides in mammalian species are thought to be present in the form of ß-anomers. This conclusion was reinforced by the identification of only one glucosylceramide and one galactosylceramide synthase, both ß-transferases, in mammalian genomes. Thus, the possibility that small amounts of α-anomers could be produced by an alternative enzymatic pathway, by an unfaithful enzyme, or spontaneously in unusual cellular compartments has not been examined in detail. We approached the question by taking advantage of the exquisite specificity of T and B lymphocytes and combined it with the specificity of catabolic enzymes of the sphingolipid pathway. Here, we demonstrate that mammalian immune cells produce constitutively very small quantities of α-glycosylceramides, which are the major endogenous ligands of natural killer T cells. Catabolic enzymes of the ceramide and glycolipid pathway tightly control the amount of these α-glycosylceramides. The exploitation of this pathway to manipulate the immune response will create new therapeutic opportunities.

Intravenous Dabigatran Provides Adequate Anticoagulation for Cardiopulmonary Bypass Using a Rabbit Model.

BACKGROUND: Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. METHODS: Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. RESULTS: The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 µg/ml at 5 min of CPB to 428 ± 150 µg/ml at 60 min, and 295 ± 35 µg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. CONCLUSIONS: In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model.

Reward history modulates visual attention in an avian model.

Attention can be biased towards previously reward-associated stimuli even when they are task-irrelevant and physically non-salient, although studies of reward-modulated attention have been largely limited to primate (including human and nonhuman) models. Birds have been shown to have the capacity to discriminate reward and spatial cues in a manner similar to primates, but whether reward history involuntarily affects their attention in the same way remains unclear. We adapted a spatial cueing paradigm with differential rewards to investigate how reward modulates the allocation of attention in peafowl (Pavo cristatus). The birds were required to locate and peck a target on a computer screen that was preceded by a high-value or low-value color cue that was uninformative with respect to the location of the upcoming target. All birds exhibited a validity effect (performance enhanced on valid compared to invalid cue), and an interaction effect between value and validity was evident at the group level, being particularly pronounced in the birds with the greatest amount of reward training. The time course of reward learning was conspicuously incremental, phenomenologically slower compared to primates. Our findings suggest a similar influence of reward history on attention across phylogeny despite a significant difference in neuroanatomy.