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As the number of trans people seeking gender-affirming care (GAC) continues to increase globally, it is increasingly important to understand the experiences of this patient population to improve healthcare delivery and ensure identified needs are being met. This qualitative descriptive study describes the experiences and perspectives of trans people (age 18-34) accessing GAC in Manitoba, Canada based on data obtained from semi-structured focus groups and individual interviews ( N = 10). Three major themes were identified to capture key elements of seeking GAC: (1) the transition decision, (2) the transition process, and (3) barriers to receiving desired care. In each major theme, subthemes were described. In addition to providing insight into critical aspects of this journey, this study also highlights the importance of including a diverse variety of perspectives when considering the design of healthcare services for the trans community., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: The International Federation for Emergency Medicine (IFEM) published its model curriculum for medical student education in emergency medicine in 2009. Because of the evolving principles of emergency medicine and medical education, driven by societal, professional, and educational developments, there was a need for an update on IFEM recommendations. The main objective of the update process was creating Intended Learning Outcomes (ILOs) and providing tier-based recommendations., Method: A consensus methodology combining nominal group and modified Delphi methods was used. The nominal group had 15 members representing eight countries in six regions. The process began with a review of the 2009 curriculum by IFEM Core Curriculum and Education Committee (CCEC) members, followed by a three-phase update process involving survey creation [The final survey document included 55 items in 4 sections, namely, participant & context information (16 items), intended learning outcomes (6 items), principles unique to emergency medicine (20 items), and content unique to emergency medicine (13 items)], participant selection from IFEM member countries and survey implementation, and data analysis to create the recommendations., Results: Out of 112 invitees (CCEC members and IFEM member country nominees), 57 (50.9%) participants from 27 countries participated. Eighteen (31.6%) participants were from LMICs, while 39 (68.4%) were from HICs. Forty-four (77.2%) participants have been involved with medical students' emergency medicine training for more than five years in their careers, and 56 (98.2%) have been involved with medical students' training in the last five years. Thirty-five (61.4%) participants have completed a form of training in medical education. The exercise resulted in the formulation of tiered ILO recommendations. Tier 1 ILOs are recommended for all medical schools, Tier 2 ILOs are recommended for medical schools based on perceived local healthcare system needs and/or adequate resources, and Tier 3 ILOs should be considered for medical schools based on perceived local healthcare system needs and/or adequate resources., Conclusion: The updated IFEM ILO recommendations are designed to be applicable across diverse educational and healthcare settings. These recommendations aim to provide a clear framework for medical schools to prepare graduates with essential emergency care capabilities immediately after completing medical school. The successful distribution and implementation of these recommendations hinge on support from faculty and administrators, ensuring that future healthcare professionals are well-prepared for emergency medical care., (© 2024. The Author(s).)

Aromatic amino acids and their derivatives are diverse primary and secondary metabolites with critical roles in protein synthesis, cell structure and integrity, defense and signaling. All de novo aromatic amino acid production relies on a set of ancient and highly conserved chemistries. Here we introduce a new enzymatic transformation for L-tyrosine synthesis by demonstrating that the β-subunit of tryptophan synthase-which natively couples indole and L-serine to form L-tryptophan-can act as a latent 'tyrosine synthase'. A single substitution of a near-universally conserved catalytic residue unlocks activity toward simple phenol analogs and yields exclusive para carbon-carbon bond formation to furnish L-tyrosines. Structural and mechanistic studies show how a new active-site water molecule orients phenols for a nonnative mechanism of alkylation, with additional directed evolution resulting in a net >30,000-fold rate enhancement. This new biocatalyst can be used to efficiently prepare valuable L-tyrosine analogs at gram scales and provides the missing chemistry for a conceptually different pathway to L-tyrosine., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

With advances in machine learning (ML)-assisted protein engineering, models based on data, biophysics, and natural evolution are being used to propose informed libraries of protein variants to explore. Synthesizing these libraries for experimental screens is a major bottleneck, as the cost of obtaining large numbers of exact gene sequences is often prohibitive. Degenerate codon (DC) libraries are a cost-effective alternative for generating combinatorial mutagenesis libraries where mutations are targeted to a handful of amino acid sites. However, existing computational methods to optimize DC libraries to include desired protein variants are not well suited to design libraries for ML-assisted protein engineering. To address these drawbacks, we present DEgenerate Codon Optimization for Informed Libraries (DeCOIL), a generalized method that directly optimizes DC libraries to be useful for protein engineering: to sample protein variants that are likely to have both high fitness and high diversity in the sequence search space. Using computational simulations and wet-lab experiments, we demonstrate that DeCOIL is effective across two specific case studies, with the potential to be applied to many other use cases. DeCOIL offers several advantages over existing methods, as it is direct, easy to use, generalizable, and scalable. With accompanying software (https://github.com/jsunn-y/DeCOIL), DeCOIL can be readily implemented to generate desired informed libraries.

Reaching zero-dose (ZD) children, operationally defined as children who have not received a first dose of the diphtheria, tetanus, and pertussis (DTP1) vaccine, is crucial to increase equitable immunisation coverage and access to primary health care. However, little is known about the approaches already taken by countries to improve immunisation equity. We reviewed all Health System Strengthening (HSS) proposals submitted by Gavi-supported countries from 2014 to 2021 inclusively and extracted information on interventions favouring equity. Pro-equity interventions were mapped to an analytical framework representing Gavi 5.0 programmatic guidance on reaching ZD children and missed communities. Data from keyword searches and manual screening were extracted into an Excel database. Open format responses were analysed using inductive and deductive thematic coding. Data analysis was conducted using Excel and R. Of the 56 proposals included, 51 (91%) included at least one pro-equity intervention. The most common interventions were conducting outreach sessions, tailoring the location of service delivery, and partnerships. Many proposals had "bundles" of interventions, most often involving outreach, microplanning and community-level education activities. Nearly half prioritised remote-rural areas and only 30% addressed gender-related barriers to immunisation. The findings can help identify specific interventions on which to focus future evidence syntheses, case studies and implementation research and inform discussions on what may or may not need to change to better reach ZD children and missed communities moving forward.

Purpose: The purpose of this study was to determine the effect of prolonged high-intensity interval (INT) and moderate-intensity continuous (CONT) treadmill exercise in the heat on markers of enterocyte injury and bacterial endotoxin translocation., Methods: Nine males completed 2 h of work-matched exercise in the heat (40 °C and 15% RH) as either INT (2 min at 80% VO 2 max and 3 min at 30% VO 2 max) or CONT (~ 50% of VO 2 max). Blood samples collected pre- and post-exercise were assayed for intestinal fatty acid-binding protein (I-FABP), claudin-3 (CLDN-3), and lipopolysaccharide-binding protein (LBP)., Results: I-FABP was significantly increased from pre- to post-exercise in CONT (913.96 ± 625.13 to 1477.26 ± 760.99 pg•mL -1 ; p = 0.014, d = 0.766) and INT (714.59 ± 470.27 to 1547.93 ± 760.99 pg•mL -1 ; p = 0.001, d = 1.160). Pre- to post-exercise changes in I-FABP were not different between CONT and INT (p = 0.088, d = 0.414). LBP was significantly increased from pre- to post-exercise in INT (15.94 ± 2.90 to 17.35 ± 3.26 μg•mL -1 ; p = 0.028, d = 0.459) but not CONT (18.11 ± 5.35 to 16.93 ± 5.39 μg•mL -1 ; p = 0.070, d = 0.226), and pre- to post-exercise changes in LBP were higher in the INT compared to CONT (p < 0.001, d = 1.160). No significant changes were detected from pre- to post-exercise for CLDN-3 in CONT (14.90 ± 2.21 to 15.30 ± 3.07 μg•mL -1 ) or INT (15.55 ± 1.63 to 16.41 ± 2.11 μg•mL -1 ) (p > 0.05)., Conclusions: We conclude that prolonged exercise in the heat induces enterocyte injury, but interval (or intermittent) exercise may cause greater bacterial endotoxin translocation which may increase the risk for local and systemic inflammation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To examine the effect of high-intensity interval work (HIIW) and moderate-intensity continuous work (MICW) on markers of acute kidney injury (AKI) and kidney function in a hot environment., Methods: Nine males completed 2 h of work (2 × 60 min with 10 min passive rest) in a hot environment (40 °C and 15% relative humidity) as either HIIW [2 min at 80% peak oxygen consumption (VO 2 peak) and 3 min at 30% VO 2 peak] or MICW (matched for total work of HIIW). Blood and urine samples were collected immediately before (Pre), after (Post), 1 h (1 h Post), and 24 h after (24 h Post) the trials. Urine flow rate (UFR), creatinine clearance, insulin-like growth factor binding protein 7 (IGFBP7), urinary neutrophil gelatinase-associated lipocalin (uNGAL), and urinary kidney injury marker 1 (uKIM-1) were measured to assess kidney function and injury., Results: Log IGFBP7 (p < 0.01), log uNGAL (p < 0.01), and log uKIM-1 (p = 0.01) all displayed a main effect for time after both HIIW and MICW. IGFBP7 (p = 0.01) and uKIM-1 (p < 0.01), corrected for Uosm, were higher after HIIW compared to MICW at Post, while IGFBP7 was also higher 1 h Post after HIIW compared to MICW (p = 0.02). UFR significantly decreasing from Pre to Post (p < 0.01) and 1 h Post (p < 0.01), but no main effect for condition (p = 0.53)., Conclusion: Both HIIW and MICW in a hot environment caused an increase in biomarkers of kidney injury (IGFBP7, KIM-1, and NGAL), but HIIW may have a greater impact on biomarkers related to AKI., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To investigate the effect of repetition tempo on cardiovascular and metabolic stress when time under tension (TUT) and effort are matched during sessions of lower body resistance training (RT)., Methods: In a repeated-measures, cross-over design, 11 recreationally trained females (n = 5) and males (n = 6) performed 5 sets of belt squats under the following conditions: slow-repetition tempo (SLOW; 10 reps with 4-s eccentric and 2-s concentric) and traditional-repetition tempo (TRAD; 20 reps with 2-s eccentric and 1-s concentric). TUT (60 s) was matched between conditions and external load was adjusted so that lifters were close to concentric muscular failure at the end of each set. External load, total volume load (TVL), impulse (IMP), blood lactate, ratings of perceived exertion (RPE), HR, and muscle oxygenation were measured., Results: Data indicated that TVL (p < 0.001), blood lactate (p = 0.017), RPE (p = 0.015), and HR (p < 0.001) were significantly greater during TRAD while external load (p = 0.030) and IMP (p = 0.002) were significantly greater during SLOW. Whether it was expressed as minimal values or change scores, muscle oxygenation was not different between protocols., Conclusion: When TUT is matched, TVL, cardiovascular stress, metabolic stress, and perceived exertion are greater when faster repetition tempos are used. In contrast, IMP and external load are greater when slower repetition tempos are used., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: The purpose of this study was to investigate the effects of surgical mask use during high intensity interval exercise (HIIE) on physiological and perceptual responses in hot and temperate environments., Methods: In a randomized fashion, 10 healthy participants completed two HIIE sessions in a 36°C hot (HUE-HOT) and two HIIE sessions in a 23°C temperate environment (HIIE-TEMP) while wearing (MASK) and not wearing a surgical mask (CON)., Results: No differences in physiological variables were found between MASK and CON during HIIE. An increase in perceived dyspnea and average RPE was found comparing MASK and CON. Interaction effects showed the greatest changes in perceived dyspnea and average RPE occurred in the HIIE-HOT/MASK condition., Conclusion: Wearing a surgical mask during HIIE increases the perception of dyspnea and exertion with the greatest effect occurring in hot environments., Competing Interests: Conflicts of interest: None declared., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Purpose: The purpose of the study was to investigate the combined effect of downhill running and heat stress on muscle damage, as well as on heat strain and kidney stress during subsequent running in the heat., Methods: In a randomized cross-over study, ten non-heat-acclimated, physically active males completed downhill running in temperate (EIMD in Temp) and hot (EIMD in Hot) conditions followed by an exercise-heat stress (HS) test after 3-h seated rest. Blood and urine samples were collected immediately pre- and post-EIMD and HS, and 24 h post-EIMD (post-24 h). Core temperature and thermal sensation were measured to evaluate heat strain. Serum creatine kinase (CK), maximal voluntary isometric contraction of the quadriceps (MVC) and perceived muscle soreness were measured to evaluate muscle damage. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) levels were measured to indicate acute kidney stress., Results: CK, MVC and perceived soreness were not different between conditions at any timepoints. In the EIMD in Hot condition, urinary NGAL was significantly elevated from pre- to post-HS (pre-HS: 6.56 {1.53-12.24} ng/min, post-HS: 13.72 {7.67-21.46} ng/min, p = 0.034). Such elevation of NGAL or KIM-1 was not found in the EIMD in Temp condition., Conclusions: As compared with downhill running in a temperate environment, downhill running in a hot environment does not appear to aggravate muscle damage. However, elevated NGAL levels following EIMD in a hot environment suggest such exercise may increase risk of mild acute kidney injury during subsequent endurance exercise in the heat., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Our aim was to determine the effect of repeated sprint exercise in hypoxia on HIF-1 and HIF-1-regulated genes involved in glycolysis, mitochondrial turnover and oxygen transport. We also determined whether genes upregulated by exercise in hypoxia were dependent on the activation of HIF-1 in an in vitro model of exercise in hypoxia., Methods: Eight endurance athletes performed bouts of repeated sprint exercise in control and hypoxic conditions. Skeletal muscle was sampled pre, post and 3 h post-exercise. HIF-1α protein and HIF1A, PDK1, GLUT4, VEGFA, BNIP3, PINK1 and PGC1A mRNA were measured. C2C12 myotubes were exposed to hypoxia and muscle contraction following treatment with a HIF-1α inhibitor to determine whether hypoxia-sensitive gene expression was dependent on HIF-1α., Results: Sprint exercise in hypoxia increased HIF-1α protein expression immediately post-exercise [fold change (FC) = 3.5 ± 2.0]. Gene expression of PDK1 (FC = 2.1 ± 1.2), BNIP3 (FC = 2.4 ± 1.4) and VEGFA (FC = 2.7 ± 1.7) increased 3 h post-exercise in hypoxia but not control. PGC1A mRNA increased 3 h post-exercise in control (FC = 5.16) and hypoxia (FC = 5.7 ± 4.1) but there was no difference between the trials. Results from the in vitro experiment showed that hypoxia plus contraction also increased PDK1, BNIP3, and VEGFA gene expression. These responses were inhibited when HIF-1 protein activity was suppressed., Conclusion: Repeated sprint exercise in hypoxia upregulates some genes involved in glycolytic metabolism, mitochondrial turnover, and oxygen transport. HIF-1α is necessary for the expression of these genes in skeletal muscle cells., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The purpose of this study was to compare the acute physiological, perceptual, and enjoyment responses between bodyweight high-intensity interval exercise (BW-HIIE) and treadmill running high-intensity interval exercise HIIE (RUN-HIIE)., Methods: Twelve adults [age: 29.5 ± 5.3 years; weight: 70.9 ± 15.0 kg; height: 167.9 ± 8.9 cm; peak oxygen consumption (VO 2 peak): 48.7 ± 6.5 ml min -1 ·kg -1 ] performed both RUN-HIIE and BW-HIIE. RUN-HIIE consisted of two sets of 5, 60-s (s) run intervals at 100% of the speed achieved during VO 2 peak testing followed by 60s of walking at 4.02 km/h. BW-HIIE consisted of two sets of 5, 60s 'all-out' effort calisthenic exercises followed by 60s of marching in place at 100 steps per minute. Oxygen consumption (VO 2 ), blood lactate (B lac ), heart rate (HR), and rating of perceived exertion (RPE) were measured during exercise. Physical activity enjoyment (PACES) was assessed post-exercise. Creatine Kinase (CK) was measured before exercise and 48-h post-exercise. Muscle soreness was assessed before exercise, post-exercise, and 48-h post-exercise., Results: Oxygen consumption relative to VO 2 peak was higher ( p  < 0.001) during RUN-HIIE (88 ± 3%) compared to BW-HIIE (77 ± 4%). HR relative to HRpeak was higher ( p  = 0.002) for RUN-HIIE (93 ± 1%) compared to BW-HIIE (88 ± 2%). B lac was higher ( p  < 0.001) after BW-HIIE (11.2 ± 3.2 mmol/l) compared to RUN-HIIE (6.9 ± 2.0 mmol/l). Average RPE achieved was higher ( p  = 0.003) during BW-HIIE (16 ± 2) than RUN-HIIE (14 ± 2). PACES was similar for RUN-HIIE and BW-HIIE ( p  > 0.05). No differences ( p  > 0.05) in CK were observed between RUN-HIIE and BW-HIIE., Conclusion: Our results indicate 'all-out' calisthenic exercise can elicit vigorous cardiorespiratory, B lac , and RPE responses. Implementing this style of exercise into training requires minimal space, no equipment, and may elicit cardiometabolic adaptations seen with traditional forms of high-intensity exercise., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bellissimo, Ducharme, Mang, Millender, Smith, Stork, Little, Deyhle, Gibson, de Castro Magalhaes and Amorim.)

Cytochrome P450 3A4 (CYP3A4) is the most important drug-metabolizing enzyme in humans and has been associated with harmful drug interactions. The activity of CYP3A4 is known to be modulated by several compounds and by the electron transfer partner, cytochrome P450 reductase (CPR). The underlying mechanism of these effects, however, is poorly understood. We have used hydrogen-deuterium exchange mass spectrometry to investigate the impact of binding of CPR and of three different substrates (7-benzyloxy-4-trifluoromethyl-coumarin, testosterone, and progesterone) on the conformational dynamics of CYP3A4. Here, we report that interaction of CYP3A4 with substrates or with the oxidized or reduced forms of CPR leads to a global rigidification of the CYP3A4 structure. This was evident from the suppression of deuterium exchange in several regions of CYP3A4, including regions known to be involved in protein-protein interactions (helix C) and substrate binding and specificity (helices B' and E, and loop K/β1). Furthermore, the bimodal isotopic distributions observed for some CYP3A4-derived peptides were drastically impacted upon binding to CPR and/or substrates, suggesting the existence of stable CYP3A4 conformational populations that are perturbed by ligand/CPR binding. The results have implications for understanding the mechanisms of ligand binding, allostery, and catalysis in CYP enzymes.

We report a novel approach to study allostery which combines the use of carefully selected bioconjugates and hydrogen-deuterium exchange mass spectrometry (HDX-MS). This strategy avoids issues related to weak substrate binding and ligand relocalization. The utility of our method is demonstrated using human cytochrome P450 3A4 (CYP3A4), the most important drug-metabolizing enzyme. Allosteric activation and inhibition of CYP3A4 by pharmaceuticals is an important mechanism of drug interactions. We performed HDX-MS analysis on several CYP3A4-effector bioconjugates, some of which mimic the allosteric effect of positive effectors, while others show activity enhancement even though the label does not occupy the allosteric pocket (agonistic) or do not show activation while still blocking the allosteric site (antagonistic). This allowed us to better define the position of the allosteric site, the protein structural dynamics associated with allosteric activation, and the presence of coexisting conformers.

Objectives : To determine what constitutes inclusive practices toward LGBT older adults in healthcare and social services and the supportive competencies of these practices. Methods: A comprehensive scoping review of the existing literature was conducted. Results : To be competent when addressing LGBT elder needs, personnel must have knowledge on LGBT realities, openness and be able to put certain skills into practice. Conclusions : Given the limited powers conferred on them by their respective positions, institutions must also play a role in encouraging the inclusion of LGBT older adults. Beyond the importance of taking into account the three dimensions of competence in staff training, changes must be made at all levels of the organizational structures. Clinical implications : Inclusive practices require 1) Educating personnel on the diversity of the life journeys of LGBT older adults; 2) Promoting relational and communication skills and open, friendly attitudes toward the diversity of LGBT identities; 3) Developing policies and procedures to create and maintain inclusive and safe environments for LGBT older adults.

Purpose: To test the efficacy of a plateau in heart rate (HR plat ) as an effective indicator for confirming [Formula: see text]max attainment in a middle-aged to older sample., Methods: Nine men and eleven women (age 60 ± 8.5 years, [Formula: see text]max 35.9 ± 9.4 ml/kg/min, N = 20) completed a single [Formula: see text]max test on both the treadmill and cycle ergometer.[Formula: see text]max was confirmed using a plateau in [Formula: see text] ([Formula: see text] plat ) of ≤ 150 ml/min, a verification bout, and HR plat (≤ 4 bpm)., Results: [Formula: see text] plat occurred in 100% and 95% of participants on the treadmill and cycle ergometer, respectively. Verification criteria ([Formula: see text]max during verification ≤ 2% of [Formula: see text]max during incremental test) were met by 80% of participants on both modalities. HR plat was achieved by 90% and 70% of participants on the treadmill and cycle ergometer, respectively., Conclusion: These results suggest that a verification bout is reliable for confirming [Formula: see text]max in older adults on both modalities. In our sample of middle-aged and older adults, [Formula: see text] plat was the most robust method to assess [Formula: see text]max when indirect calorimetry is available. Although more research is warranted, when indirect calorimetry is not available, a HR plat of ≤ 4 bpm may be a useful alternative to get an accurate representation of maximal effort in middle-aged and older adults.

Current diagnostics are insufficient for diagnosis and prognosis of acute infections and sepsis. Clinical decisions including prescription and timing of antibiotics, ordering of additional diagnostics and level-of-care decisions rely on understanding etiology and implications of a clinical presentation. Host mRNA signatures can differentiate infectious from noninfectious etiologies, bacterial from viral infections, and predict 30-day mortality. The 29-host-mRNA blood-based InSep TM test (Inflammatix, Burlingame, CA, formerly known as HostDx TM Sepsis) combines machine learning algorithms with a rapid point-of-care platform with less than 30 min turnaround time to enable rapid diagnosis of acute infections and sepsis, as well as prediction of disease severity. A scientific advisory panel including emergency medicine, infectious disease, intensive care and clinical pathology physicians discussed technical and clinical requirements in preparation of successful introduction of InSep into the market. Topics included intended use; patient populations of greatest need; patient journey and sample flow in the emergency department (ED) and beyond; clinical and biomarker-based decision algorithms; performance characteristics for clinical utility; assay and instrument requirements; and result readouts. The panel identified clear demand for a solution like InSep, requirements regarding test performance and interpretability, and a need for focused medical education due to the innovative but complex nature of the result readout. Innovative diagnostic solutions such as the InSep test could improve management of patients with suspected acute infections and sepsis in the ED, thereby lessening the overall burden of these conditions on patients and the healthcare system.

Development of a successful research program can seem daunting when looked at from the starting line. It will take years if not decades to succeed and become sustainable. It requires local partnerships and mentoring; it mandates the establishment of review boards; it requires national health policies to allow for protected time for research in salaries and for fund granting agencies to be set up; it requires training of researchers and support staff as well as a change in the mindset of clinical staff on the floor. It will almost inevitably require international support of some kind for low- and middle-income country researchers, be it university programs or other academic or private institutions. Success can occur; most likely it will occur by partnering with local research experts outside of emergency medicine in some combination with international networks and mentoring. Perhaps the most critical elements to success are intellectual curiosity and a burning flame of passion - and neither of those carry a financial cost., Competing Interests: The authors declared no conflicts of interest., (© 2020 African Federation for Emergency Medicine. Publishing services provided by Elsevier.)

Objectives: With regionalized trauma care, medical transport times can be prolonged, requiring paramedics to manage patient care and symptoms. Our objective was to evaluate pain management during air transport of trauma patients., Methods: We conducted a 12-month review of electronic paramedic records from a provincial critical care transport agency. Patients were included if they were ≥18 years old and underwent air transport to a trauma centre, and excluded if they were Glasgow Coma Scale score <14, intubated, or accompanied by a physician or nurse. Demographics, injury description, and transportation parameters were recorded. Outcomes included pain assessment via 11-point numerical rating scale, patterns of analgesia administration, and analgesia-related adverse events. Results were reported as mean ± standard deviation, [range], (percentage)., Results: We included 372 patients: 47.0 years old; 262 males; 361 blunt injuries. Transport duration was 82.4 ± 46.3 minutes. In 232 (62.4%) patients who received analgesia, baseline numerical rating scale was 5.9 ± 2.5. Fentanyl was most commonly administered at 44.3 [25-60] mcg. Numerical rating scale after first analgesia dose decreased by 1.1 [-2-7]. Thereafter, 171 (73.7%) patients received 2.4 [1-18] additional doses. While 44 (23.4%) patients had no change in numerical rating scale after first analgesia dose, subsequent doses resulted in no change in numerical rating scale in over 65% of patients. There were 43 adverse events recorded, with nausea the most commonly reported (39.5%)., Conclusions: Initial and subsequent dose(s) of analgesic had minimal effect on pain as assessed via numerical rating scale, likely due in part to inadequate dosing. Future research is required to determine and address the barriers to proper analgesia.

Objective: The management of pain is an important component of care in the prehospital and transport setting. However, recent evidence suggests that pain control is infrequently achieved in these settings. The objective of the current study was to determine the proportion and frequency of opioid analgesia provided to intubated patients during interfacility transport by an air medical transport system., Methods: This was a health records review examining electronic records of intubated patients transported by Ornge from July 2015 to November 2015. Cases were identified using Ornge database, and intubated patients were selected based on the inclusion criteria. A standardized data extraction form was piloted and used by a single trained data extractor. The primary outcome was whether analgesia was provided. Secondary outcomes included the frequency of administration and dose adequacy of an opioid analgesia; the analgesic used; adverse events; and the impact of age, sex, past medical history of chronic pain, or reason for transfer on pain management., Results: Of the 500 potential patient transports, 448 met our inclusion criteria. Among the 448 patients, 295 (65.8%) were men, 327 (73.0%) received analgesia, and 211 (64.3%) received more than 1 dose during transport (median frequency of 2 doses, interquartile range = 1 to 3). The average transport time was 135 minutes, and repeated dosing (> 1 repeat dose) occurred primarily (45.5%) in transports of over 180 minutes. Fentanyl was the most commonly used analgesic (97.9%), and the most common dose was 50 µg (51.8%). Adverse events occurred in 8 patients (2.5%), most commonly new hypotension (mean arterial pressure < 65 mm Hg, n = 5). There was no significant difference in the administration of analgesia based on the patient's age or sex (68.0% of female patients and 75.6% of male patients received analgesia). Interestingly, only 30.8% of patients repatriated to their originating hospital received analgesia compared with 72.3% of patients undergoing their initial transfer to a higher level of care., Conclusion: Seventy-three percent of intubated patients transported by Ornge received an opioid analgesic, most commonly fentanyl. We found no clinically relevant difference in the administration of analgesics based on age, sex, past medical history of chronic pain, or reason for transfer other than repatriation to the originating hospital., (Copyright © 2019 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Defining time frames throughout cardiac rehabilitation (CR) to progress exercise workloads may lead to improve functional capacity outcomes. The purpose of this study was to investigate the role of exercise progression on functional capacity among cardiac patients enrolled in CR. This was a retrospective database analysis study. Extracted data included: Demographic, functional capacity (in METs), and exercise intensity during exercise sessions 2, 12, 24, and 36 of CR from 150 patients who completed a 36-session program. Progression of exercise was determined by calculating percent change in treadmill exercise workload within predefined time frames of CR. The time frames were percent change from exercise session 2 to 12 ("%ΔS2-S12), 12 to 24 (%ΔS12-S24), and 24 to 36 (%ΔS24-S36). A multiple linear regression model was developed to predict change in functional capacity (ΔMETs). A significant proportion (21%) of total variation in ΔMETs was predicted by %ΔS2-12, %ΔS12-24, %ΔS24-36, age, sex, and body mass index (BMI). Percent changes between sessions 12 to 24 (%ΔS12-24; β = 0.17, p = 0.03) and 24 to 36 (%ΔS24-36; β = 0.23, p < 0.01) were significant predictors. Progressing patients between sessions 12 to 24 and 24 to 36 predicted significant changes in functional capacity and reinforced the importance of exercise progression across all 36 sessions of CR.

Background : Canadian specialty clinics offering gender-affirming care to trans and gender diverse children and youth have observed a significant increase in referrals in recent years, but there is a lack of information about the experiences of young people receiving care. Furthermore, treatment protocols governing access to gender-affirming medical interventions remain a topic of debate. Aims: This qualitative research aims to develop a deeper understanding of experiences of trans youth seeking and receiving gender-affirming care at Canadian specialty clinics, including their goals in accessing care, feelings about care and medical interventions they have undergone, and whether they have any regrets about these interventions. Methods : The study uses an adapted Grounded Theory methodology from social determinants of health perspective. Thirty-five trans and gender diverse young people aged 9 to 17 years were recruited to participate in semi-structured interviews through the specialty clinics where they had received or were waiting for gender-affirming medical interventions such as puberty blockers, hormone therapy, and surgery. Results: Young people felt positively overall about the care they had received and the medical interventions they had undergone, with many recounting an improvement in their well-being since starting care. Most commonly shared frustrations concerned delays in accessing interventions due to clinic waiting lists or treatment protocols. Some youth described unwanted medication side-effects and others said they had questioned their transition trajectory at certain moments in the past, but none regretted their choice to undergo the interventions. Discussion : The results suggest that trans youth and gender diverse children are benefiting from medical gender-affirming care they receive at specialty clinics, providing valuable insight into their decision-making processes in seeking care and specific interventions. Providers might consider adjusting aspects of treatment protocols (such as age restrictions, puberty stage, or mental health assessments) or applying them on a more flexible, case-by-case basis to reduce barriers to access., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Opioid use disorder risk assessment tools cannot be used in isolation. In combination with standardized clinical examination, and, when indicated, urine drug screening, a validated risk assessment tool, improves the ability to detect opioid misuse. Even though no single tool has been shown to have both high interobserver reliability and high sensitivity, the standardized approach has still been shown to be superior to subjective care giver assessment. This article will provide a global approach to risk assessment in addition to reviewing the available tools.

Because of its exceptional substrate promiscuity, human P450 3A4 (CYP3A4) is arguably the most important drug-metabolizing enzyme. CYP3A4 also has the particularity of binding multiple ligands simultaneously, which is associated with heterotropic or homotropic, positive or negative, cooperativity or allostery. Solving the kinetics of such complex systems remains challenging, and so is identifying the binding pockets involved. Progesterone (PRG) is a known allosteric activator of CYP3A4-catalyzed 7-benzyloxy-4-trifluoromethylcoumarin (BFC) debenzylation. We report herein the use of bioconjugation as a successful strategy to identify this PRG allosteric site. A progesterone analogue (PGM) was covalently attached, separately at several locations, near a peripheral binding pocket previously proposed to be an allosteric site. Studies of BFC debenzylation in the presence of free PRG revealed that two of the bioconjugates successfully positioned the covalently attached PGM moiety in a way that mimics the allosteric activation observed with free PRG. Interestingly, the PGM bioconjugate with the better fit yielded a higher permanent activation of the enzyme.

This review article provides an overview of acute pain management. It highlights the need to provide balanced pain care while limiting harm from opioids as per the World Health Organization (WHO) recommendations for balanced pain care. Opiophobia and its impact on the use of opioids for acute severe pain are discussed. Interventions that can improve global pain care and the role of pain scales in the management of acute pain are discussed. Newer trends in acute pain management in the emergency department (ED) are also reviewed and include: low dose ketamine, intravenous lidocaine, ultra-sound guided regional anesthesia, intravenous paracetamol, and patient controlled analgesia., (Copyright © 2018 by Taiwan Society of Emergency Medicine & Ainosco Press. All Rights Reserved.)

Objectives: To describe the paediatric transgender population accessing health care through the Manitoba Gender Dysphoria Assessment and Action for Youth (GDAAY) program, and report youth's experiences accessing health care in Manitoba., Methods: Demographic, medical, surgical and mental health information was extracted from the medical records of youth referred to the GDAAY program (n=174). A 77-item online survey was conducted with a subset of those youth (n=25) to identify common health care experiences and perceptions of trans youth in Manitoba., Results: Chart review of 122 natal females and 52 natal males, ranging in age from 4.7 to 17.8 years (mean 13.9 years), found 66 patients (46.8%) with a pre-existing or current mental health diagnosis, of which anxiety and depression were the most common (n=43, 30.5%). Qualitative self-reports revealed all patients had negative interactions with health care providers at some point, many having experienced lack of engagement with the medical system due to reported lack of knowledge by the provider on trans-related health services., Conclusion: Transgender youth in Manitoba seeking GDAAY services have high rates of anxiety and depression. These youth face adversity in health care settings and are distressed over long wait times for mental health services. Recommendations to improve care include increasing general health care providers' education on gender affirmative care, providing gender sensitivity training for health care providers, gathering preferred names and pronouns during triage, increasing visibility of support for LGBT+ persons in clinics, increasing resource allocation to this field and creating policies so all health care settings are safe places for trans youth.

Bioconjugation, defined as chemical modification of biomolecules, is widely employed in biological and biophysical studies. It can expand functional diversity and enable applications ranging from biocatalysis, biosensing and even therapy. This review summarizes how chemical modifications of cytochrome P450 enzymes (P450s or CYPs) have contributed to improving our understanding of these enzymes. Genetic modifications of P450s have also proven very useful but are not covered in this review. Bioconjugation has served to gain structural information and investigate the mechanism of P450s via photoaffinity labeling, mechanism-based inhibition (MBI) and fluorescence studies. P450 surface acetylation and protein cross-linking have contributed to the investigation of protein complexes formation involving P450 and its redox partner or other P450 enzymes. Finally, covalent immobilization on polymer surfaces or electrodes has benefited the areas of biocatalysis and biosensor design. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A fundamental difference? A heme protein known to catalyze electron transfers was engineered into an enzyme that catalyzes the formation of C-Si bonds with >99 % ee. The new enzyme uses diazoesters as carbene donors for the insertion of various silanes into the Si-H bond. This is the first reported organosilicon-producing enzyme., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To explore bibliometric markers in a worldwide sample of emergency physician investigators to define global, continental and individual patterns over time., Methods: We evaluated the number of papers published, citations received, cumulative impact factor and h-index of editorial board members of six international emergency medicine journals. We calculated the individual values for every year of each author's career to evaluate their dynamic evolution. We analysed the results by researcher world area and growth rate., Results: We included 107 researchers (76 American, 21 European and 10 Australasian; 46 slow-rate -group C-, 43 medium-rate -group B- and 18 fast-rate growth -group A-). The median experience was 18 (IQR: 12) years, without subgroups differences. Dynamic analysis over time showed good fit with quadratic function in all individual researchers and for all bibliometric markers (R 2 : 0.505-0.997), with the h-index achieving the best R 2 . The combined analysis of the h-index of the 107 investigators also fit the quadratic model (R 2 =0.49). Analysis by predefined continental and growth-rate subgroups allowed defining specific patterns (R 2 between 0.46-0.54 and 0.80-0.86, respectively): by continents, American researchers' h-index increased 0.632 points per year, European 0.417 and Australasian 0.341; by growth rate, researchers from group A, B and C increased 1.239, 0.683 and 0.320, respectively., Conclusions: Dynamic analysis of every individual author indicator over time has a very good fit with a quadratic model, with the h-index achieving the best R 2 . It is also possible to construct models based on continent and rate of growth that could help to predict future expected outcomes of researchers in a particular subgroup and to classify new emerging researchers by growth rate., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: We assessed the relationship between the size of the 39 Journal Citation Reports (JCR) medical categories and impact factor (IF) of journals in these categories, and the implications that it might have for emergency medicine (EM) journals., Materials and Methods: Using the 2010 JCR database, we calculated the mean IF, 5-year IF (5y-IF), Eigenfactor (EF), and Article Influence (AI) scores including all journals for each category. We also calculated a 'weighted IF' for all journals by dividing each journal IF by the mean IF of its category. We ranked EM journals according to IF and 'weighted IF' into all the journals included in the 39 categories. We assessed the relationship between category size and bibliometric scores by linear regression., Results: Category size varied from 252 journals (Pharmacology and Pharmacy) to 14 (Primary Healthcare), EM category occupying the 36th position (23 journals). The mean IF of EM category ranked in 34th position, 5-yIF in 32nd, EF in 34th, and AI in 34th position. Category size had a direct and significant association with mean IF, 5y-IF, and AI but not with mean EF. When the EM journals were ranked among all the journals according to their IF, only two (9%) were placed into the first quartile and raised up to eight (35%) when 'weighted IF' was considered., Conclusion: There is a negative relationship between JCR size category and IF achieved by the journals. This places EM journals at a clear disadvantage because they represent one of the smallest clinical medical research disciplines.

Objective: The purpose of this study was to identify the association of premedication with the adverse drug reaction (ADR) rate in infliximab infusions., Design: A retrospective chart review of 684 patients who received 4077 infusions in a network of community clinics over 16.5 months. Data collected included age, weight, sex, diagnosis, dose, premedications and ADR information, which was coded for time of onset, severity and outcome., Setting: Community infusion clinics located in Ontario, Canada., Patients: Patients aged 12-91 years who receive regular infliximab infusions to treat their autoimmune condition, mainly either Crohn's disease or rheumatoid arthritis., Main Outcome Measures: The number of infusions to the occurrence of an acute ADR by presence of premedication., Results: ADRs are not significantly different (χ 2 (1, n=644, p=0.651)=0.204) between those who always received premedications and those who never did. When controlling for age, sex, weight and diagnosis, patients receiving premedications were just as likely to experience an ADR as patients who never received any (OR 1.1, 95% CI 0.7 to 1.9, p=0.5). When assessing the number of infusions to the occurrence of an ADR using the Kaplan-Meier method, no significant difference was found between the two groups., Conclusions: The use of premedications is not associated with a decreased risk of ADR in patients receiving infliximab. This held true for patients who had never had an ADR prior to receiving premedications and while controlling for age, sex, weight and diagnosis., Competing Interests: Competing interests: None.

Objective: This project was designed to increase readiness for change for long-stay state hospital residents who were unwilling to move to the community., Methods: Project staff designed customized strategies to build relationships, increase awareness of personal and environmental influences on deciding if, when, and where to relocate, and increase commitment to making a change., Results: Of 10 participants, eight successfully relocated to the community in less than two years., Conclusion and Implications for Practice: Readiness development strategies designed specifically for individuals can be effective in facilitating change. Staff expertise in readiness assessment and creativity in designing interventions, as well as staff commitment to this program, were critical to success.

Purpose: A matched case-control study was performed to assess the relationship between metformin use and the degree of F-18 fluorodeoxyglucose (FDG) bowel activity in diabetic patients., Materials and Methods: Seventy-seven diabetic patients referred to our department for a positron emission tomography/computed tomography study, including 45 on metformin, were compared with nondiabetic controls matched for sex, age, and body mass index. Positron emission tomography studies were obtained in a standard manner and reviewed in a blinded fashion. F-18 FDG uptake in the GI tract was evaluated quantitatively using maximal standardized uptake values and visually using a previously published semiquantitative scale., Results: F-18 FDG uptake in small and large bowel was significantly increased in metformin patients compared with nondiabetic controls both visually and quantitatively (all P < 0.0001), as well as compared with nonmetformin patients with diabetes. Control sites (liver, fat, muscle) showed similar uptake. Multiple regression analysis confirmed that metformin was the variable most strongly associated with bowel uptake., Conclusion: Physiologic accumulation of F-18 FDG in bowel is increased in diabetic patients maintained on metformin.

Background: Tumour necrosis factor-alpha (TNFalpha) has an important role in the pathogenesis of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, ulcerative colitis and psoriasis. Infliximab, a chimeric anti-TNFalpha monoclonal antibody, has been shown to reduce the severity of symptoms or induces remission of active disease. Infusions have generally been limited to the hospital setting due to cost and concerns for patient safety. Studies defining its efficacy and safety have, therefore, originated almost exclusively from hospital settings., Objective: To evaluate the safety of infliximab in a community clinic environment, across all types of patients., Methods: A retrospective chart review of 3161 patients who received a combined 20,976 infusions at a network of community clinics over 16.5 months was conducted. Adverse drug reaction (ADR) information was retrieved and coded for time of onset, severity and outcome. Only ADRs that occurred during or within the first 24 h of the infusion were included., Results: A total of 524 (2.5% of all infusions) acute ADRs in 353 patients (11.2%) were recorded. Most reactions (ie, ADRs) were mild (n=263 [50.2%, 1.3% of all infusions]) or moderate (n=233 [44.5%, 1.1% of all infusions]). Twenty-eight reactions (5.3%, 0.1% of all infusions) were severe. Emergency medical services were called to transport patients to hospital for seven of the severe reactions, of which none required admission. As per pre-established medical directives, adrenaline was administered three times., Conclusions: Infliximab infusions are safe in the community setting. Severe ADRs were rare. None required active physician intervention; nurses were able to treat all reactions by following standardized medical directives.

Objective: To compare the effects of two furosemide administration protocols on bladder activity during 18F-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) imaging., Methods: A total of 109 consecutive patients with known or suspected malignancy, meeting our inclusion criteria, were chosen over a discrete time period. Group 1 (n=39) received furosemide 20 mg intravenous 15 min before PET/CT imaging (i.e. approximately 45 min after 18F-FDG administration). Group 2 (n=45) received furosemide 20 mg intravenous 15 min after 18F-FDG. Group 3 (n=25) did not receive furosemide and served as controls. Bladder standard uptake values (SUVs) and volume, and liver SUV data were collected., Results: Relative to the control group, both furosemide groups showed significantly lower mean and maximum SUV bladder activities (P<0.001), lower mean bladder-to-liver SUV ratios (P<0.001), larger mean bladder volumes (P<0.001) and higher proportions of bladder PET/CT image mis-registration. Patients tolerated earlier administration of furosemide (group 2) better relative to urinary urgency during imaging., Conclusion: The use of a relatively simple diuretic protocol can significantly lower bladder FDG activity and potentially improve image quality by reducing bladder activity artifacts and avoid invasive bladder catheterization. Administering furosemide earlier after FDG injection (i.e. 15 min) versus later (i.e. 15 min before imaging) appears to be better tolerated by patients.

Unlabelled: With PET becoming more widely used, there is an increase in the number of imaging centers being forced to rely on distant suppliers of (18)F-FDG. Because of the large distances between major urban centers, this is particularly true for PET centers in Canada., Methods: Our PET center, located in Winnipeg, Manitoba, Canada, currently purchases (18)F-FDG from a commercial vendor located more than 1,000 km from Winnipeg, necessitating transport by commercial airline cargo. This dependence on air transport and a distant supplier creates a situation in which our (18)F-FDG supply is less reliable than it would be with onsite production. In this article, we offer insight into the obstacles we have encountered in imaging with a distant supplier of (18)F-FDG and the solutions we have implemented to minimize the disruption to our patients and maximize the number of scans performed each year., Results: The development of contingency plans and protocols designed to suit our operating environment has allowed us to increase the number of patient scans obtained from 659 in year 1 to 993 in year 3, an increase of 51%, despite an increase in our actual number of scan days of only 24%. (18)F-FDG injection timetables are presented for a variety of scenarios including normal delivery, low shipped activity, and delayed delivery., Conclusion: Through the careful establishment of contingency protocols and management of (18)F-FDG shipments, patient throughput can be increased and disruptions minimized.

In a project funded by the Ontario Ministry of Health and Long-Term Care, MedEmerg facilitated the introduction of three new providers into six emergency departments. A managed change process that included team development was carried out. Increased team awareness and a higher acceptance of the provider roles were some of the key successes. Challenges included role confusion and the learning curve for the new providers. While overall the project was a success, lessons learned included the need for physician buy-in, communication, planning for unintended consequences and management of expectations. The project emphasized the importance of a managed process, including team development, in the implementation of change.

Objectives: The aim of the study was to examine the association between triage scoring systems and triage priority scores on time to initial emergency department (ED) analgesic administration., Methods: An observational, multicenter, prospective, cohort study was conducted at 20 US and Canadian EDs. Centers from the United States used the Emergency Severity Index triage system or 1 of 3 unvalidated triage systems. Canadian centers used the Canadian Triage and Acuity Scale. Patients aged 8 years or older who presented to the ED with a chief complaint of moderate to severe pain (>3 on a 10-point numerical rating scale) and who were ultimately discharged home were eligible for study enrollment. Triage score, triage system, pain rating on arrival, and time of initial analgesic administration were recorded., Results: Among 842 enrolled subjects, 506 (60%) received an analgesic while in the ED. Lower-acuity patients consistently waited longer for analgesics. On multivariate modeling, presenting pain intensity, total time spent in the ED, white ethnicity, and triage system were associated with time to initial analgesic administration. Emergency departments using the Canadian Triage and Acuity Scale triage system exhibited the lowest rates of analgesic use and displayed longer median times to initial analgesic administration., Conclusions: Although there were some differences between triage systems, all sites and systems demonstrated unacceptably long times to analgesic provision. Many patients with moderate to severe pain received no analgesic during their ED stay. Future studies should examine whether ED overcrowding impacts timeliness of analgesic administration and identify specific strategies to improve pain management practices in this challenging environment.

Objective: To determine the prevalence and correlates of low bone mineral density (BMD) in ambulatory outpatients with end-stage heart failure who were awaiting cardiac transplantation., Methods: Fifty-five cardiac transplant candidates with end-stage heart failure were enrolled in this study. Bone mineral density at the lumbar spine and proximal femur was determined by dual-energy x-ray absorptiometry. Laboratory studies included serum alkaline phosphatase, calcium, intact parathyroid hormone, and 25-hydroxyvitamin D., Results: The mean proximal femur and lumbar spine Z scores were 0.3 +/- 1.1 and 0.3 +/- 1.5, respectively. The mean BMD was not lower than that of the age-and sex-matched reference population. Z scores were less than -1 in 23% at the lumbar spine and 15% at the proximal femoral neck. On the basis of T scores, osteopenia (T scores between -1 and -2.5) was present in 24% (confidence interval, 13% to 35%) of patients at the lumbar spine and in 20% (confidence interval, 10% to 30%) at the proximal femur; osteoporosis (T scores of less than -2.5) was present in 4% of the study population. Half of the patients in this study sample had elevated intact parathyroid hormone levels, and a third of the patients had low 25-hydroxyvitamin D levels., Conclusion: Lumbar spine and hip BMD measurements were not significantly low relative to age and sex in ambulatory patients with heart failure awaiting cardiac transplantation.

Study Objective: We explore perceptions surrounding use of portable inhalers and holding chambers (spacers) for delivery of beta-agonist respiratory medications to children in the emergency department (ED) and factors influencing practice change., Methods: This was a qualitative study guided by principles of grounded theory. Data were collected through focus groups and individual interviews at 2 sites in eastern Canada: Hospital A, where inhalers and holding chambers are used routinely; and Hospital B, where prevailing practice is the use of nebulization. Participant encounters were transcribed verbatim and analyzed for emerging themes., Results: At Hospital A, 6 physicians and 7 nurses participated in separate focus groups. Four interviews were conducted with physician, nurse, respiratory therapy, and pharmacy leaders. At Hospital B, 4 physicians and 3 nurses participated in focus groups, and 6 leaders were interviewed. Perceptions negatively influencing the adoption of inhalers and holding chambers included increased workload, increased equipment costs, myths about the superiority of nebulization, and interprofessional conflict. Health professionals reported that their most prominent concern about administering medications with inhalers and holding chambers was the time demand. Nurses especially seemed to think this way, tipping the balance in favor of nebulization despite knowledge of evidence to the contrary and affecting physician decisionmaking as well. Professional territorialism appeared to hinder efforts to ameliorate workload issues through the use of respiratory therapists in the ED., Conclusion: Findings from this study could be used to inform a change program to close the gap between evidence and practice with respect to use of inhalers and holding chambers in the ED.

This study was initiated to characterize the metabolism and pharmacokinetics of SNC80 in rats and to evaluate the impact of Freund's complete adjuvant (FCA)-induced inflammation on its body disposition. In vitro, the disappearance and intrinsic clearance (CL(int)) of SNC80 were measured following incubations in recombinant rat CYPs and in phenotyped liver microsomes from naive and 24-h FCA-treated rats. The unbound fraction (f(u)) was assessed by ultrafiltration. Based on the Clint values, in vivo blood clearance of 3.35 and 2.48 L/h/kg were predicted in naive and FCA-treated rats. In vivo, SNC80 was administered to naive and 24-h FCA-treated rats at 10 micromol/kg i.v. and 50 micromol/kg p.o. The naive animals showed high plasma clearance (3.1 L/h/kg), low renal clearance (<0.02 L/h/kg) and poor bioavailability (<4%). Following i.v. administration, plasma clearance was lower (22%) in FCA-treated vs. untreated rats. Despite the decreases in f(u) (approximately 30%) and CL(int) (approximately 40%) in vitro, in vivo the apparent bioavailability and oral clearance were not significantly different between FCA-treated and naive rats. Hepatic and possibly intestinal losses contribute to the low bioavailability of SNC80. Non-hepatic mechanisms may compensate for the decrease in plasma clearance found in FCA-treated rats, preventing an increase in the oral bioavailability of SNC80.