Longitudinal tracking of human plasma oxytocin suggests complex responses to moral elevation.

Positive social experiences may induce oxytocin release. However, previous studies of moral elevation have generally utilized cross-sectional and simple modeling approaches to establish the relationship between oxytocin and emotional stimuli. Utilizing a cohort of 30 non-lactating women (aged 23.6 ± 5.7 years), we tested whether exposure to a video identified as capable of eliciting moral elevation could change plasma oxytocin levels. Uniquely, we utilized a high-frequency longitudinal sampling approach and multilevel growth curve modeling with landmark registration to test physiological responses. The moral elevation stimulus, versus a control video, elicited significantly greater reports of being "touched/inspired" and "happy/joyful". However, the measured plasma oxytocin response was found to be markedly heterogeneous. While the moral elevation stimulus elicited increased plasma oxytocin as expected, this increase was only modestly larger than that seen following the control video. This increase was also only present in some individuals. We found no relationship between plasma oxytocin and self-report responses to the stimulus. From these data, we argue that future studies of the relationship between oxytocin and emotion need to anticipate heterogeneous responses and thus incorporate comprehensive individual psychological data; these should include evidence-based variables known to be associated with oxytocin such as a history of trauma, and the individual's psychological and emotional state at the time of testing. Given the complexity of physiological oxytocin release, such studies also need to incorporate frequent biological sampling to properly examine the dynamics of hormonal release and response.

An Exploratory Mixed Methods Study of Experiences of Interprofessional Teams Who Received Coaching to Simultaneously Redesign Primary Care Education and Clinical Practice.

INTRODUCTION/OBJECTIVES: Coaching is emerging as a form of facilitation in health professions education. Most studies focus on one-on-one coaching rather than team coaching. We assessed the experiences of interprofessional teams coached to simultaneously improve primary care residency training and interprofessional practice. METHODS: This three-year exploratory mixed methods study included transformational assistance from 9 interprofessional coaches, one assigned to each of 9 interprofessional primary care teams that included family medicine, internal medicine, pediatrics, nursing, pharmacy and behavioral health. Coaches interacted with teams during 2 in-person training sessions, an in-person site visit, and then as requested by their teams. Surveys administered at 1 year and end study assessed the coaching relationship and process. RESULTS: The majority of participants (82% at end of Year 1 and 76.6% at end study) agreed or strongly agreed that their coach developed a positive working relationship with their team. Participants indicated coaches helped them: (1) develop as teams, (2) stay on task, and (3) respond to local context issues, with between 54.3% and 69.2% agreeing or strongly agreeing that their coaches were helpful in these areas. Cronbach's alpha for the 15 coaching survey items was 0.965. Challenges included aligning the coach's expertise with the team's needs. CONCLUSIONS: While team coaching was well received by interprofessional teams of primary care professionals undertaking educational and clinical redesign, the 3 primary care disciplines have much to learn from each other regarding how to improve inter- and intra-professional collaborative practice among clinicians and staff as well as with interprofessional learners rotating through their outpatient clinics.

The impact of hospital boarding on the emergency department waiting room.

BACKGROUND: Patient boarding in the emergency department (ED) is a significant issue leading to increased morbidity/mortality, longer lengths of stay, and higher hospital costs. We examined the impact of boarding patients on the ED waiting room. Additionally, we determined whether facility type, patient acuity, time of day, or hospital occupancy impacted waiting rooms in 18 EDs across a large healthcare system. METHODS: This was a retrospective multicenter study that included all ED encounters between January 1, 2018, and September 30, 2019. Encounters with missing Emergency Severity Index (ESI) level were excluded. ESI levels were defined as high (ESI 1,2), middle (ESI 3), and low (ESI 4,5). Spearman correlation coefficients measured the relationship between boarded patients and number of patients in ED waiting room. A multivariable mixed effects model identified drivers of this relationship. RESULTS: A total of 1,134,178 encounters were included. Spearman correlation coefficient was significant between number of patients in the ED waiting room and patient boarding (0.54). For every additional patient boarded/hour, the number of patients waiting/hour in the waiting room increased by 8% (95% confidence interval [CI] = 1.08-1.09). The number of patients waiting for a room/hour was 2.28 times higher for middle than for high acuity. The number of patients in waiting room slightly decreased as hospital occupancy increased (95% CI = 0.997-0.997). CONCLUSION: Number of patients in ED waiting room are directly related to boarding times and hospital occupancy. ED waiting room times should be considered as not just an ED operational issue, but an aspect of hospital throughput.

Can an age-adjusted D-dimer level be adopted in managing venous thromboembolism in the emergency department? A retrospective cohort study.

INTRODUCTION: Patients suspected of having venous thromboembolism (VTE), with a low pretest probability, undergo D-dimer testing. A negative D-dimer, in a low-risk patient rules out VTE with a high degree of certainty because of its high sensitivity. It is, however, a poorly specific test, and the absolute value increases with age. The aim of this study was to establish whether an age-adjusted D-dimer could be safely used instead of a standard cut-off level in low-risk patients over the age of 50 years. PATIENTS AND METHODS: This was a retrospective review of 1649 patients with suspected VTE whose D-dimer levels were analysed. In low-risk patients (defined as 'VTE unlikely' using the dichotomized Wells' scores), the outcomes in terms of confirmed VTE diagnosis, hospital admission and investigations using an age-adjusted D-dimer level (measured in D-dimer units) of 5× the age for patients over 50 years of age and 250 ng/ml for patients younger than 50 years of age, was compared with the cut-off standard level (230 ng/ml in all patients). RESULTS: Of the total group of patients in the VTE unlikely group, the proportion of patients with a negative D-dimer when using the standard cut-off was 64.9% (859/1324). A further 130 patients had a negative D-dimer when the age-adjusted cut-off was used, increasing the proportion of all patients in whom VTE could be excluded without imaging to 74.7% (989/1324).For those patients of 75 years or older, the proportion of patients in whom VTE could be excluded without imaging increased from only 91/242 (37.6%) when using the standard D-dimer cut-off to 154/242 (63.6%) when the age-adjusted cut-off was used.These changes occurred without any additional false-negative findings. CONCLUSION: For patients over the age of 50 years suspected of having VTE with a low pretest probability, increasing the D-dimer cut-off level to 5× the age increases the proportion of patients in whom VTE can safely be excluded without radiological imaging.

Retrospective validation of the pulmonary embolism rule-out criteria rule in 'PE unlikely' patients with suspected pulmonary embolism.

INTRODUCTION: Patients presenting to emergency departments (EDs) with suspected pulmonary embolism (PE) can be risk stratified and those who are deemed to be at low risk for PE usually undergo D-dimer testing. A negative D-dimer in this low-risk group rules out PE with a high degree of certainty because of its high sensitivity. The D-dimer is, however, a poorly specific test and positive results often lead to unnecessary radiological imaging (notably computed tomography pulmonary angiography). The Pulmonary Embolism Rule-Out Criteria (PERC) rule has been suggested as an alternative to D-dimer testing in these patients. This study looked at whether the PERC rule could safely replace the use of D-dimer in patients suspected of PE, but deemed 'PE unlikely' by the dichotomized Wells score in a UK ED setting. PATIENTS AND METHODS: This was a retrospective review of 986 patients with suspected PE who had a blood sample for D-dimer level taken. In patients deemed 'PE unlikely' (using the dichotomized Wells score), the diagnostic performance of the PERC rule was compared with a standard D-dimer level in the detection of PE at index presentation and up to 3 months afterwards. RESULTS: Of the 986 patients, 940 patients were deemed 'PE unlikely' using the dichotomized Wells score. Three patients with confirmed PE would have been missed by the PERC rule compared with only one missed by the D-dimer test. In these patients, the sensitivity of the PERC rule for detecting PE was 91.4% [95% confidence interval (CI): 76.9-98.2%], with a negative likelihood ratio of 0.25 (95% CI: 0.08-0.73). However, the negative predictive value of the PERC rule was 99.1% (95% CI: 97.3-99.8%). In comparison, the sensitivity for the standard D-dimer test was 97.1% (95% CI: 85.1-99.9%), with a negative likelihood ratio of 0.04 (95% CI: 0.01-0.27). The negative predictive value for the standard D-dimer test was 99.8% (95% CI: 99.2-100%). CONCLUSION: The PERC rule has a high negative predictive value for excluding PE in patients presenting with suspected PE to the ED. However, the PERC rule may still miss around 8% of confirmed PE in patients who are deemed 'PE unlikely' by a dichotomized Wells score. Caution is advised in using the PERC rule as a substitute for the standard D-dimer test in all these patients.

Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists.

Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending on N6 substitution, small 5'-alkylamide modification maintained 5HT2BR affinity, which was enhanced upon ribose substitution with rigid bicyclo[3.1.0]hexane (North (N)-methanocarba), e.g., N6-dicyclopropylmethyl 4'-CH2OH derivative 14 (Ki 11 nM). 5'-Methylamide 23 was 170-fold selective as antagonist for 5HT2BR vs 5HT2CR. 5'-Methyl 25 and ethyl 26 esters potently antagonized 5HT2Rs with moderate selectivity in comparison to ARs; related 6-N,N-dimethylamino analogue 30 was 5HT2R-selective. 5' position flexibility of substitution was indicated in 5HT2BR docking. Both 5'-ester and 5'-amide derivatives displayed in vivo t1/2 of 3-4 h. Thus, we used G protein-coupled receptor modeling to repurpose nucleoside scaffolds in favor of binding at nonpurine receptors as novel 5HT2R antagonists, with potential for cardioprotection, liver protection, or central nervous system activity.

Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists.

Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis. Pharmacological assays were carried out at three AR subtypes for 13 ribosides. Nine compounds displayed significant activity at the ARs, and several of these represented atypical agonist scaffolds. The discovered ligands also provided insights into receptor activation and revealed unknown interactions of endogenous and clinical compounds with the ARs. The results demonstrate that virtual compound databases provide access to bioactive matter from regions of chemical space that are sparsely populated in commercial libraries, an approach transferrable to numerous drug targets.

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists.

Purine (N)-methanocarba-5'-N-alkyluronamidoriboside A3 adenosine receptor (A3AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 µmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site.

Structure-Based Design, Synthesis by Click Chemistry and in Vivo Activity of Highly Selective A3 Adenosine Receptor Agonists.

2-Arylethynyl derivatives of (N)-methanocarba adenosine 5'-uronamides are selective A3AR (adenosine receptor) agonists. Here we substitute a 1,2,3-triazol-1-yl linker in place of the rigid, linear ethynyl group to eliminate its potential metabolic liability. Docking of nucleosides containing possible short linker moieties at the adenine C2 position using a hybrid molecular model of the A3AR (based on the A2AAR agonist-bound structure) correctly predicted that a triazole would maintain the A3AR selectivity, due to its ability to fit a narrow cleft in the receptor. The analogues with various N6 and C2-aryltriazolyl substitution were synthesized and characterized in binding (Ki at hA3AR 0.3 - 12 nM) and in vivo to demonstrate efficacy in controlling chronic neuropathic pain (chronic constriction injury). Among N6-methyl derivatives, a terminal pyrimidin-2-yl group in 9 (MRS7116) increased duration of action (36% pain protection at 3 h) in vivo. N6-Ethyl 5-chlorothien-2-yl analogue 15 (MRS7126) preserved in vivo efficacy (85% protection at 1 h) with short duration. Larger N6 groups, e.g. 17 (MRS7138, >90% protection at 1 and 3 h), greatly enhanced in vivo activity. Thus, we have combined structure-based methods and phenotypic screening to identify nucleoside derivatives having translational potential.

Reporting and Using Near-miss Events to Improve Patient Safety in Diverse Primary Care Practices: A Collaborative Approach to Learning from Our Mistakes.

PURPOSE: Near-miss events represent an opportunity to identify and correct errors that jeopardize patient safety. This study was undertaken to assess the feasibility of a near-miss reporting system in primary care practices and to describe initial reports and practice responses to them. METHODS: We implemented a web-based, anonymous near-miss reporting system into 7 diverse practices, collecting and categorizing all reports. At the end of the study period, we interviewed practice leaders to determine how the near-miss reports were used for quality improvement (QI) in each practice. RESULTS: All 7 practices successfully implemented the system, reporting 632 near-miss events in 9 months and initiating 32 QI projects based on the reports. The most frequent events reported were breakdowns in office processes (47.3%); of these, filing errors were most common, with 38% of these errors judged by external coders to be high risk for an adverse event. Electronic medical records were the primary or secondary cause of the error in 7.8% and 14.4% of reported cases, respectively. The pattern of near-miss events across these diverse practices was similar. CONCLUSIONS: Anonymous near-miss reporting can be successfully implemented in primary care practices. Near-miss events occur frequently in office practice, primarily involve administrative and communication problems, and can pose a serious threat to patient safety; they can, however, be used by practice leaders to implement QI changes.

Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy.

Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in place of ribose, which adopts a receptor-preferred conformation. N (6)-Small alkyl derivatives were newly optimized for A3AR affinity and the effects of a 1-deaza-adenine modification probed. 1-Deaza-N (6)-ethyl alkyne 20 (MRS7144, K i 1.7 nM) and 1-aza N (6)-propyl alkyne 12 (MRS7154, K i 1.1 nM) were highly efficacious in vivo. Thus, the presence of N1 is not required for nanomolar binding affinity or potent, long-lasting functional activity. Docking of 1-deaza compounds to a receptor homology model confirmed a similar binding mode as previously reported 1-aza derivatives. This is the first demonstration in nonribose adenosine analogues that the 1-deaza modification can maintain high A3AR affinity, selectivity, and efficacy.

Two disparate ligand-binding sites in the human P2Y1 receptor.

In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 Å resolution, and with a non-nucleotide antagonist BPTU at 2.2 Å resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Should we use an age adjusted D-dimer threshold in managing low risk patients with suspected pulmonary embolism?

A shortcut review was carried out to establish whether a higher age related threshold can be used when using d-dimer as a rule out test for pulmonary embolism. 29 papers were found of which 13 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that in older patients suspected of having a Pulmonary Embolus (PE), with a low pretest possibility, an age-adjusted D-dimer increases specificity with minimal change in the sensitivity, thereby increasing the number of patients who can be safely discharged without further investigations.

Financing Residency Training Redesign.

BACKGROUND: Redesign in the health care delivery system creates a need to reorganize resident education. How residency programs fund these redesign efforts is not known. METHODS: Family medicine residency program directors participating in the Preparing Personal Physicians for Practice (P(4)) project were surveyed between 2006 and 2011 on revenues and expenses associated with training redesign. RESULTS: A total of 6 university-based programs in the study collectively received $5,240,516 over the entire study period, compared with $4,718,943 received by 8 community-based programs. Most of the funding for both settings came from grants, which accounted for 57.8% and 86.9% of funding for each setting, respectively. Department revenue represented 3.4% of university-based support and 13.1% of community-based support. The total average revenue (all years combined) per program for university-based programs was just under $875,000, and the average was nearly $590,000 for community programs. The vast majority of funds were dedicated to salary support (64.8% in university settings versus 79.3% in community-based settings). Based on the estimated ratio of new funding relative to the annual costs of training using national data for a 3-year program with 7 residents per year, training redesign added 3% to budgets for university-based programs and about 2% to budgets for community-based programs. CONCLUSIONS: Residencies undergoing training redesign used a variety of approaches to fund these changes. The costs of innovations marginally increased the estimated costs of training. Federal and local funding sources were most common, and costs were primarily salary related. More research is needed on the costs of transforming residency training.

Reducing utilization by uninsured frequent users of the emergency department: combining case management and drop-in group medical appointments.

BACKGROUND: Patients with complex behavioral health and medical problems can have a disproportionate impact on emergency departments. METHODS: We identified a cohort of 255 low-income, uninsured patients who had used inpatient or emergency department services more than 6 times in the previous 12 months. Between July 2010 and June 2011 we enrolled 36 of these high-risk patients to participate in a twice-weekly drop-in group medical appointment staffed by an interdisciplinary team of a family physician, behavioral health professional, and nurse case manager. The team provided 705 patient visits in a group setting (a total of 108 group sessions) and 652 case manager phone calls. The average number of clients per drop-in group medical appointment was 6.5. RESULTS: Emergency department use dropped from a rate of 0.58 per patient per month to 0.23 (P < .001), and hospital charges dropped from $1167 per patient per month to $230 (P < .001). Employment status increased from 4 to 14 among the 36 patients enrolled. Total annualized cost of the program was $66,000. CONCLUSIONS: Team-based drop-in group medical appointments coupled with case management seem to be a cost-effective model to reduce emergency department visits by some patients with complex behavioral health and medical needs.