Implementation of a Synergistic, Complementary Pharmacy Practice Model for an Advanced Heart Failure/Heart Transplant Program.

Study Objective: A pharmacy practice model for an Advanced Heart Failure (HF)/Transplant program was designed to address gaps in medication access, medication education and transitions of care (ToC). Activities specific to these initiatives performed by a four-member pharmacy team (3 pharmacists, 1 specialty technician) are described. Methods: Data were prospectively collected in 2020 for 284 admissions involving a high-risk cohort of advanced HF/transplant patients and a similar cohort seen in an ambulatory HF clinic. Interventions including medication reconciliation, e-prescribing, patient consultation and telephone call backs were performed daily to ensure medication access on discharge and as outpatients, comprehensive medication education on a continuum, and improved ToC. Metrics specific to these interventions and revenue reflecting outpatient prescription volume were quantified. Results: Standardized discharge medication education was provided to 97% of the cohort (n = 275). Of the 51 patients newly transplanted or receiving a left ventricular assist device, 100% had medication access on discharge and received follow-up telephone consultation within 48 hours. ToC was performed on admission (97%), pre-operatively (n = 51; 100%), post-operatively (n = 51; 100%) and on discharge (97%). Outpatient prescription volume increased 42% with net revenue increasing 157%. Conclusion: A pharmacy practice model involving an integrated 4-member team improved medication access and education and allowed for ToC at multiple points in the care process thereby improving medication safety. Collaboration between pharmacists and technicians working in inpatient, outpatient and specialty pharmacy settings is encouraged to provide complementary care to high-risk patients.

A Multidisciplinary Educational Approach to Anticoagulation Management for a Percutaneous Endovascular Mechanical Circulatory Support Device.

BACKGROUND: Anticoagulation (AC) management of the Impella varies considerably among treatment centers. Published data regarding the management of complications including heparin-induced thrombocytopenia, bleeding and thrombosis are limited. OBJECTIVE: A multidisciplinary team was assembled to 1) identify baseline knowledge of nurses and pharmacists involved in Impella anticoagulation management; 2) develop an educational tool specific to Impella anticoagulation; 3) reassess knowledge following implementation of the tool. METHODS: A team consisting of pharmacists, nurses and a physician developed surveys that were subsequently distributed to 28 nurses and 17 pharmacists. Survey questions measured knowledge in 4 areas of anticoagulation management: product selection, administration, monitoring and therapeutic recommendation. A pocket card containing flow diagrams for Impella anticoagulation management was developed. Following distribution of the card and education on its application, surveys were redistributed to measure the change in knowledge. RESULTS: The frequency (%) of correct answers for all survey questions for both pharmacists and nurses significantly increased from 38% to 84% (p < 0.00001) and 63% to 93% (p < 0.00001), respectively. Substantial increases in the frequency of correct answers in the majority of question categories were observed for both pharmacists and nurses postintervention. CONCLUSION AND RELEVANCE: Using a multidisciplinary approach, an institution-specific pocket card addressing the complexities of Impella anticoagulation was developed. Following dissemination of the card and education on its application, improved knowledge across the scope of Impella anticoagulation management was observed in both pharmacists and nurses.

Drug-Induced Liver Injury (DILI) With Micafungin: The Importance of Causality Assessment.

Background: Micafungin is increasingly used in the treatment and prevention of candidiasis in hospitalized patients. Limited data are available from which to assess the risk of drug-induced liver injury (DILI) with micafungin. No studies, to date, have applied a standardized causality assessment method to the study of micafungin-associated DILI. Objective: This study aimed to identify the frequency and clinical pattern of DILI in micafungin-treated patients as determined using 2 standardized causality assessment algorithms. Methods: A retrospective analysis was conducted of micafungin-treated patients at a single center between May 15, 2017, and May 15, 2018. DILI was defined on the basis of liver test elevations and the presence of associated signs and symptoms. The Roussel UClaf Causality Assessment Method (RUCAM) and the Naranjo algorithm were applied to each case. Results: A total of 99 patients were assessed; 52 were excluded, with a final sample of 47 evaluable patients. The definition of DILI was met in 9 (19%) patients, with a clinical pattern consistent with cholestatic injury in 7 of 9 (78%) patients. No cases were associated with jaundice. Agreement between the 2 causality assessment methods occurred in 4 of 9 (44%) cases. Application of the RUCAM algorithm led to the exclusion of 4 cases, resulting in a final reported prevalence of micafungin-associated DILI of 10.6%. Conclusion and Relevance: Asymptomatic DILI was identified in 10.6% of micafungin-treated patients. The choice of a causality assessment nomogram substantially influenced the determination of DILI prevalence. Compared with the Naranjo algorithm, the RUCAM algorithm is recommended as a more precise tool of assessing the relationship between drug exposure and DILI.

Calmodulin shuttling mediates cytonuclear signaling to trigger experience-dependent transcription and memory.

Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist. However, how synapse-to-nucleus communication supports long-term plasticity and behavior has remained elusive. Among cytonuclear signaling proteins, γCaMKII stands out in its ability to rapidly shuttle Ca2+/CaM to the nucleus and thus activate CREB-dependent transcription. Here we show that elimination of γCaMKII prevents activity-dependent expression of key genes (BDNF, c-Fos, Arc), inhibits persistent synaptic strengthening, and impairs spatial memory in vivo. Deletion of γCaMKII in adult excitatory neurons exerts similar effects. A point mutation in γCaMKII, previously uncovered in a case of intellectual disability, selectively disrupts CaM sequestration and CaM shuttling. Remarkably, this mutation is sufficient to disrupt gene expression and spatial learning in vivo. Thus, this specific form of cytonuclear signaling plays a key role in learning and memory and contributes to neuropsychiatric disease.

What is memory? The present state of the engram.

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today.

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops.

Understanding the mechanisms underlying autism spectrum disorders (ASDs) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry, and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops and provide detailed commentary for exemplar genes within each module.

New developments in the treatment of acute bacterial skin and skin structure infections: considerations for the effective use of dalbavancin.

Dalbavancin, an intravenous glycopeptide, was approved by the US Food and Drug Administration in May 2014 for use in adult patients with acute bacterial skin and skin structure infections. The recommended dosing regimen for effective use of dalbavancin is 1,000 mg followed by a 500 mg dose after 1 week. Two multinational, identically designed, non-inferiority trials, DISCOVER 1 and 2, demonstrated similar early clinical success with dalbavancin compared to vancomycin with an option to switch to oral linezolid. In a recently published non-inferiority trial, a single-dose regimen of dalbavancin was compared to the traditional two-dose administration and was found to have a non-inferior clinical response. In the aforementioned trials, dalbavancin was well tolerated, with patients experiencing transient adverse events of mild to moderate severity. The prolonged half-life, excellent skin and soft tissue penetration, bactericidal activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, and convenient dosing make dalbavancin a reasonable option for the treatment of acute bacterial skin and skin structure infections in adult patients who have tried and failed other therapies.

Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice.

Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1. However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases, which are based on aberrant translation and protein expression. One such condition is fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorder (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macroorchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble-burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS, and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling.