Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension.

Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc-but not with a vasodilator-strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.

Structures of activin ligand traps using natural sets of type I and type II TGFß receptors.

The 30+ unique ligands of the TGFß family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one "type II-type I-Fc" fusion, ActRIIB-Alk4-Fc, in complex with two TGFß family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform.

Functionally diverse heteromeric traps for ligands of the transforming growth factor-ß superfamily.

Ligands of the transforming growth factor-ß (TGF-ß) superfamily are important targets for therapeutic intervention but present challenges because they signal combinatorially and exhibit overlapping activities in vivo. To obtain agents capable of sequestering multiple TGF-ß superfamily ligands with novel selectivity, we generated soluble, heterodimeric ligand traps by pairing the extracellular domain (ECD) of the native activin receptor type IIB (ActRIIB) alternately with the ECDs of native type I receptors activin receptor-like kinase 4 (ALK4), ALK7, or ALK3. Systematic analysis of these heterodimeric constructs by surface plasmon resonance, and comparison with their homodimeric counterparts, revealed that each type I receptor partner confers a distinct ligand-binding profile to the heterodimeric construct. Additional characterization in cell-based reporter gene assays confirmed that the heterodimeric constructs possessed different profiles of signaling inhibition in vitro, which translated into altered patterns of pharmacological activity when constructs were administered systemically to wild-type mice. Our results detail a versatile platform for the modular recombination of naturally occurring receptor domains, giving rise to inhibitory ligand traps that could aid in defining the physiological roles of TGF-ß ligand sets or be directed therapeutically to human diseases arising from dysregulated TGF-ß superfamily signaling.

ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders.

Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-ß superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects - concordant with SPR results - on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.

Naloxone counseling: Confidence and attitudes of student pharmacists after a volunteer syringe exchange experience.

INTRODUCTION: Our objective was to assess how a naloxone counseling experience impacted student pharmacists' confidence in counseling patients on naloxone use and their attitudes towards people who use drugs. METHODS: Students who completed a naloxone counseling experience at a syringe exchange program were recruited to conduct individual interviews. Investigators asked student participants open-ended questions to identify their perceptions in the following domains: experiences with naloxone, reported impact of naloxone counseling experience on confidence, experiences with people who use drugs, value of the experience, and suggestions for improvement for the experience. RESULTS: Fifteen student pharmacists participated in semi-structured interviews. Fourteen of these students reported the experience as extremely valuable in developing their confidence with naloxone. The average change in confidence was 5.2 points on a 1 through 10 scale, and seven of the student pharmacists independently suggested that a naloxone counseling experience be incorporated the required doctor of pharmacy curriculum. The qualitative themes that emerged from student feedback were breaking down the stigma of addiction and feeling useful during this experience. CONCLUSIONS: Participation in a naloxone counseling experience at a syringe exchange program was perceived as helpful in improving student pharmacist confidence in counseling patients on naloxone use. Incorporation of required experiential learning about naloxone and people who use drugs may positively impact student pharmacists by giving them more confidence and experience with this underserved population.

Beta-lactam antibiotic test doses in the emergency department.

BACKGROUND: Facilitating beta-lactam antibiotic use in patients reporting beta-lactam allergies in acute care settings is important to individual patient outcomes and public health; however, few initiatives have targeted the Emergency Department (ED) setting. METHODS: We implemented pathways for patients reporting prior penicillin and/or cephalosporin hypersensitivity as part of a hospital guideline in the ED of a large academic medical center in the United States. We described beta-lactam test doses, pathway compliance, hypersensitivity reactions (HSRs), and allergy record updating associated with ED-administered beta-lactam test doses from October 2016 to June 2018. RESULTS: 310 beta-lactam antibiotic test doses were administered to patients with penicillin and/or cephalosporin allergy histories in the study period (average volume 15/month [standard deviation 4]). Test doses were to cephalosporins (85%), penicillins (12%), and carbapenems (4%). 219 (71%) of test doses were compliant with the pathways. Ten patients (3.2%; 95% CI 1.6%-5.9%) had HSRs; five HSR patients (50%) had beta-lactams administered that were not pathway compliant. The allergy record was updated in 146 (47%) of patients, with improvement over the study period (p < 0.001). CONCLUSIONS: Inpatient approaches to prescribing beta-lactams in patients reporting beta-lactam allergies can be operationalized in the ED. Additional efforts are required to ensure guideline compliance and appropriate allergy documentation.

Thromboembolic Risk of 4-Factor Prothrombin Complex Concentrate versus Fresh Frozen Plasma for Urgent Warfarin Reversal in the Emergency Department.

INTRODUCTION: Warfarin is a potent anticoagulant used for the prevention and treatment of venous and arterial thrombosis. Occasionally, patients require emergent warfarin reversal due to active bleeding, supratherapeutic international normalized ratio, or emergent diagnostic or therapeutic interventions. Various agents can be used for emergent warfarin reversal, including fresh frozen plasma (FFP) and 4-factor prothrombin complex concentrate (4F-PCC). Both FFP and 4F-PCC are generally considered safe; however, both agents contain coagulation factors and have the potential to provoke a thromboembolic event. Although clinical trials have compared the efficacy and safety of FFP and 4F-PCC, data are limited comparing the risk of thromboembolism between the two agents. METHODS: A retrospective chart review was performed at a single, urban, academic medical center comparing the incidence of thromboembolism with FFP or 4F-PCC for warfarin reversal during a three-year period in the emergency department (ED) at Massachusetts General Hospital. Patients were included in the study if they were at least 18 years of age and were on warfarin per electronic health records. Patients were excluded if they had received both FFP and 4F-PCC during the same visit. The primary outcome was the frequency of thromboembolism within 30 days of 4F-PCC or FFP. Secondary outcomes included time to thromboembolic event and in-hospital mortality. RESULTS: Three hundred and thirty-six patients met the inclusion criteria. Thromboembolic events within 30 days of therapy occurred in seven patients (2.7%) in the FFP group and 14 patients (17.7%) in the 4F-PCC group (p=<0.001). Death occurred in 39 patients (15.2%) who received FFP and 18 patients (22.8%) who received 4F-PCC (p=0.115). Since the 4F-PCC group was treated disproportionately for central nervous system (CNS) bleeding, a subgroup analysis was performed including patients requiring reversal due to CNS bleeds that received vitamin K. The primary outcome remained statistically significant, occurring in four patients (4.1%) in the FFP group and nine patients (14.1%) in the 4F-PCC group (p=0.02). CONCLUSION: Our study found a significantly higher risk of thromboembolic events in patients receiving 4F-PCC compared to FFP for urgent warfarin reversal. This difference remained statistically significant when controlled for CNS bleeds and administration of vitamin K.

Alternatives to opioids for pain management in the emergency department decreases opioid usage and maintains patient satisfaction.

OBJECTIVE: The objective of this study was to assess opioid use in an emergency department following the development and implementation of an alternative to opioids (ALTO)-first approach to pain management. The study also assessed how implementation affected patient satisfaction scores. METHODS: This study compared data collected from October to December of 2015 (prior to implementation) to data collected between October and December of 2016 (after the intervention had been implemented). Emergency department visits during the study timeframe were included. Opioid reduction was measured in morphine equivalents (ME) administered per visit. Secondary outcomes on patient satisfaction were gathered using the Press Ganey survey. RESULTS: Intravenous (IV) opioid administration during the study period decreased by >20%. The predicted mean ME use in 2016 was 0.25 ME less when compared to 2015 (95% CI -0.27 to -0.23). Estimated use for patients in the pre-implementation period was 1.45 ME mgs (SD 0.88), and 1.13 ME mg (SD 0.69) for patients in the post-implementation period. Patient satisfaction scores using the Press Ganey Scale also were assessed. There was no significant difference in the scores between 2015 and 2016 when patients were asked "How well was you pain controlled?" (-0.94, 95% CI -5.29 to 3.4) and "How likely are you to recommend this emergency department?" (-1.55, 95% CI -5.26 to 2.14). CONCLUSION: In conclusion, by using an ALTO-first, multimodal treatment approach to pain management, participating clinicians were able to significantly decrease the use of IV opioids in the emergency department. Patient satisfaction scores remained unchanged following implementation.

A naloxone and harm reduction educational program across four years of a doctor of pharmacy program.

BACKGROUND AND PURPOSE: Naloxone distribution is an increasing service provided by pharmacists as more states enact laws enabling pharmacists to dispense naloxone without a prescription or per protocol to individuals in the wake of an opioid overdose epidemic. Education and training programs are necessary to ensure students and practicing pharmacists are able to effectively provide the service. EDUCATIONAL ACTIVITY AND SETTING: All first, second, and third year students in the doctor of pharmacy (PharmD) program at The Ohio State University College of Pharmacy (OSUCOP) participated in a pilot naloxone and harm reduction educational program. The program consisted of a three-part recorded lecture and a hands-on interactive workshop. Fourth-year students had the opportunity to participate. Students completed a ten-question assessment based on the content of the recorded lecture. Following the workshop, self-reflection and feedback were solicited. FINDINGS: Qualitative data indicated students felt the naloxone educational program was beneficial. Inclusion of harm reduction strategies, a mock counseling session, hands-on practice with naloxone delivery devices, and patient case discussions were valued. DISCUSSION AND SUMMARY: OSUCOP was able to develop and deliver a naloxone and harm reduction educational program across all four years of the PharmD curriculum within one year of passage of laws increasing pharmacist dispensing of naloxone.

Banned and discouraged-use ingredients found in weight loss supplements.

OBJECTIVES: To identify banned and discouraged-use ingredients, such as ephedra, 1,3-dimethylamylamine, and beta-methyl-phenylethylamine, in readily available weight loss dietary supplements within a 10-mile radius of Regis University. METHODS: A list of banned and discouraged-use ingredients was compiled with the use of the Food and Drug Administration (FDA) dietary supplement website which provides information on supplement ingredients that are no longer legal or are advised against owing to adverse event reporting. Investigators visited all retail outlet stores within a 10-mile radius of Regis University in Denver, Colorado. Retail chains were not duplicated and only one of each chain was evaluated. RESULTS: A total of 51 weight loss supplement products from retail stores were found with banned or discouraged-use substances listed on their labels. At least one banned ingredient was found to be listed on the product labels in 17 of the 51 studied supplements (33%). At least one discouraged-use ingredient was found in 46 of the 51 products (90%). Retail outlet stores dedicated to supplements and sports nutrition alone were found to have the greatest number of weight loss supplements that included banned and discouraged-use ingredients. CONCLUSION: The FDA has taken action to remove some weight loss supplements from the market that contain banned ingredients. Unfortunately, based on the findings of this study, it is evident that products containing these ingredients remain on the market today.

Unexpected deaths of children and young people in the UK.

Aims and method To review the deaths of children and young people who took their own life. We conducted a retrospective analysis of serious incident reports from a National Health Service trust and reviews by the child death overview panels of the local safeguarding children boards. Results We identified 23 deaths, with annual rates varying considerably between local authorities and over time. Over half of the children (n = 13, 56%) were not known to specialist child and adolescent mental health services, with 11 having no contact with any agency at the time of their death. Hanging was the most common method (n = 20, 87%) and of these, half (n = 11, 55%) were low-level hangings. Clinical implications Training is required to improve awareness, recognition and the assessment of children at risk of taking their own life. Specialist child mental health services should directly assess plans or attempts at hanging and offer advice about the seriousness of attempting this. National data (by age) on children and young people who take their own life should be routinely published to inform clinical and preventive services.

Impact of an Elective Course in Community and Ambulatory Care Pharmacy Practices on Student Perception of Patient Care.

Objective. To determine the impact of an elective course on students' perception of opportunities and of their preparedness for patient care in community and ambulatory pharmacy settings. Design. Each course meeting included a lecture and discussion to introduce concepts and active-learning activities to apply concepts to patient care or practice development in a community or ambulatory pharmacy setting. Assessment. A survey was administered to students before and after the course. Descriptive statistics were used to assess student responses to survey questions, and Wilcoxon signed rank tests were used to analyze the improvement in student responses with an alpha level set at 0.05. Students felt more prepared to provide patient care, develop or improve a clinical service, and effectively communicate recommendations to other health care providers after course completion. Conclusion. This elective course equipped students with the skills necessary to increase their confidence in providing patient care services in community and ambulatory settings.

Implementation of targeted medication adherence interventions within a community chain pharmacy practice: The Pennsylvania Project.

OBJECTIVE: To identify facilitators and barriers to implementing targeted medication adherence interventions in community chain pharmacies, and describe adaptations of the targeted intervention and organizational structure within each individual pharmacy practice. DESIGN: Qualitative study. SETTING: Central and western Pennsylvania from February to April 2012. PARTICIPANTS: Rite Aid pharmacists staffed at the 118 Pennsylvania Project intervention sites. MAIN OUTCOME MEASURES: Qualitative analysis of pharmacists' perceptions of facilitators and barriers experienced, targeted intervention and organizational structure adaptations implemented, and training and preparation prior to implementation. RESULTS: A total of 15 key informant interviews were conducted from February to April 2012. Ten pharmacists from "early adopter" practices and five pharmacists from "traditionalist" practices were interviewed. Five themes emerged regarding the implementation of targeted interventions, including all pharmacists' need to understand the relationship of patient care programs to their corporation's vision; providing individualized, continual support and mentoring to pharmacists; anticipating barriers before implementation of patient care programs; encouraging active patient engagement; and establishing best practices regarding implementation of patient care services. CONCLUSION: This qualitative analysis revealed that there are a series of key steps that can be taken before the execution of targeted interventions that may promote successful implementation of medication therapy management in community chain pharmacies.

A clinically significant interaction between tacrolimus and multiple proton pump inhibitors in a kidney transplant recipient.

The shared metabolism of PPIs and tacrolimus through the CYP enzyme system has been associated with clinically significant drug interactions, especially in patients who are classified as CYP 2C19 PMs. However, existing data are conflicting, indicating that a single mechanism does not account for all interactions. A drug interaction between tacrolimus and omeprazole, esomeprazole, but not lansoprazole, occurred in an 18-yr-old female kidney transplant recipient classified as a CYP 2C19 extensive (normal) metabolizer. This case suggests that further research is needed to establish the definitive mechanism of this potentially serious drug-drug interaction. Physicians prescribing PPIs in organ transplant recipients with tacrolimus immunosuppression should consider close pharmacokinetic monitoring of tacrolimus when starting or switching a PPI.

Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme.

MAP KAP kinase 2 (MK2), a Ser/Thr kinase, plays a crucial role in the inflammatory process. We have determined the crystal structures of a catalytically active C-terminal deletion form of human MK2, residues 41-364, in complex with staurosporine at 2.7 A and with ADP at 3.2 A, revealing overall structural similarity with other Ser/Thr kinases. Kinetic analysis reveals that the K(m) for ATP is very similar for MK2 41-364 and p38-activated MK2 41-400. Conversely, the catalytic rate and binding for peptide substrate are dramatically reduced in MK2 41-364. However, phosphorylation of MK2 41-364 by p38 restores the V(max) and K(m) for peptide substrate to values comparable to those seen in p38-activated MK2 41-400, suggesting a mechanism for regulation of enzyme activity.