Towards understanding and improving medication safety for patients with mental illness in primary care: A multimethod study.

INTRODUCTION: Medication safety incidents have been identified as an important target to improve patient safety in mental healthcare. Despite this, the causes of preventable medication safety incidents affecting patients with mental illness have historically been poorly understood, with research now addressing this knowledge gap through a healthcare professional lens. However, patients and carers can also provide complimentary insight into safety issues, and as key stakeholders in healthcare, it is vital to consider their needs when designing effective interventions. METHODS: A two-stage approach was adopted by (i) conducting three focus groups (FG) comprising 13 patients with mental illness and their carers to develop a holistic picture of medication safety in primary care with extraction of themes guided by the P-MEDS framework; (ii) conducting two separate nominal group consensus workshops with seven patients with mental illness/carers and seven healthcare professionals to identify priority areas for targeted interventions. RESULTS: Seven themes were identified in the FGs: communication; trust, involvement and respect; continuity and support; access; the healthcare professional; the patient and carer; and the organisation. Priority areas identified for intervention by key stakeholders included improving communication within and between clinical services, enhancing patient support with holistic continuity of care, maximising shared decision-making and empowerment, ensuring timely access to medicines and services, strengthening healthcare professional knowledge regarding mental illnesses and associated medications, and increasing patient dignity and respect. CONCLUSION: This study has developed a holistic picture of contributors to medication safety incidents affecting patients with mental illness in primary care. This theory was then used by key stakeholders to inform and generate priority recommendations for targeted interventions. These findings can be used to inform future intervention research, as they consider the needs of those who access or work within primary care services. PATIENT OR PUBLIC CONTRIBUTION: An advisory group consisting of three expert patients with lived experience of mental illness was consulted on the design of both stages of this study. Patients with mental illness and/or their carers were recruited and participated in both stages of this study. Patients/carers aided with data analysis and interpretation during the patient/carer nominal group consensus workshop.

Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series.

AIMS AND METHOD: A series of eleven patients prescribed intramuscular clozapine at five UK sites is presented. Using routinely collected clinical data, we describe the use, efficacy and safety of this treatment modality. RESULTS: We administered 188 doses of intramuscular clozapine to eight patients. The remaining three patients accepted oral medication. With the exception of minor injection site pain and nodules, side-effects were as expected with oral clozapine, and there were no serious untoward events. Nine patients were successfully established on oral clozapine with significant improvement in their clinical presentations. CLINICAL IMPLICATIONS: Although a novel formulation in the UK, we have shown that intramuscular clozapine can be used safely and effectively when the oral route is initially refused.

Investigation into the effects of varying frequency of mechanical stimulation in a cycle-by-cycle manner on engineered cardiac construct function.

Mechanical stimulation has been used extensively to improve the function of cardiac engineered tissue, as it mimics the physical environment in which the tissue is situated during normal development. However, previous mechanical stimulation has been carried out under a constant frequency that more closely resembles a diseased heart. The goal of this study was to create a bioreactor system that would allow us to control the mechanical stimulation of engineered cardiac tissue on a cycle-by-cycle basis. This unique system allows us to determine the effects on cardiac construct function of introducing variability to the mechanical stretch. To test our bioreactor system, constructs created from neonatal rat cardiomyocytes entrapped in fibrin hydrogels were stimulated under various regimes for 2 weeks and then assessed for functional outcomes. No differences were observed in the final cell number in each condition, indicating that variability in frequency did not have a negative effect on viability. The forces were higher for all mechanical stimulation groups compared to static controls, although no differences were observed between the mechanically stimulated conditions, indicating that variable frequency on a cycle-by-cycle basis has limited effects on the resulting force. Although differences in the observed twitch force were not observed, differences in the protein expression indicate that variable-frequency mechanical stimulation had an effect on cell-cell coupling and growth pathway activation in the constructs. Thus, this bioreactor system provides a valuable tool for further development and optimization of engineered myocardial tissue as a repair or replacement strategy for patients undergoing heart failure. Copyright © 2014 John Wiley & Sons, Ltd.

Multi-Material Tissue Engineering Scaffold with Hierarchical Pore Architecture.

Multi-material polymer scaffolds with multiscale pore architectures were characterized and tested with vascular and heart cells as part of a platform for replacing damaged heart muscle. Vascular and muscle scaffolds were constructed from a new material, poly(limonene thioether) (PLT32i), which met the design criteria of slow biodegradability, elastomeric mechanical properties, and facile processing. The vascular-parenchymal interface was a poly(glycerol sebacate) (PGS) porous membrane that met different criteria of rapid biodegradability, high oxygen permeance, and high porosity. A hierarchical architecture of primary (macroscale) and secondary (microscale) pores was created by casting the PLT32i prepolymer onto sintered spheres of poly(methyl methacrylate) (PMMA) within precisely patterned molds followed by photocuring, de-molding, and leaching out the PMMA. Pre-fabricated polymer templates were cellularized, assembled, and perfused in order to engineer spatially organized, contractile heart tissue. Structural and functional analyses showed that the primary pores guided heart cell alignment and enabled robust perfusion while the secondary pores increased heart cell retention and reduced polymer volume fraction.

Poly(Limonene Thioether) Scaffold for Tissue Engineering.

A photocurable thiol-ene network polymer, poly(limonene thioether) (PLT32o), is synthesized, characterized, fabricated into tissue engineering scaffolds, and demonstrated in vitro and in vivo. Micromolded PLT32o grids exhibit compliant, elastomeric mechanical behavior similar to grids made of poly(glycerol sebacate) (PGS), an established biomaterial. Multilayered PL32o scaffolds with regular, geometrically defined pore architectures support heart cell seeding and culture in a manner similar to multilayered PGS scaffolds. Subcutaneous implantation of multilayered PLT32o scaffolds with cultured heart cells provides long-term 3D structural support and retains the exogenous cells, whereas PGS scaffolds lose both their structural integrity and the exogenous cells over 31 d in vivo. PLT32o membrane implants retain their dry mass, whereas PGS implants lose 70 percent of their dry mass by day 31. Macrophages are initially recruited to PLT32o and PGS membrane implants but are no longer present by day 31. Facile synthesis and processing in combination with the capability to support heart cells in vitro and in vivo suggest that PLT32o can offer advantages for tissue engineering applications where prolonged in vivo maintenance of 3D structural integrity and elastomeric mechanical behavior are required.

It's all in the timing: modeling isovolumic contraction through development and disease with a dynamic dual electromechanical bioreactor system.

This commentary discusses the rationale behind our recently reported work entitled "Mimicking isovolumic contraction with combined electromechanical stimulation improves the development of engineered cardiac constructs," introduces new data supporting our hypothesis, and discusses future applications of our bioreactor system. The ability to stimulate engineered cardiac tissue in a bioreactor system that combines both electrical and mechanical stimulation offers a unique opportunity to simulate the appropriate dynamics between stretch and contraction and model isovolumic contraction in vitro. Our previous study demonstrated that combined electromechanical stimulation that simulated the timing of isovolumic contraction in healthy tissue improved force generation via increased contractile and calcium handling protein expression and improved hypertrophic pathway activation. In new data presented here, we further demonstrate that modification of the timing between electrical and mechanical stimulation to mimic a non-physiological process negatively impacts the functionality of the engineered constructs. We close by exploring the various disease states that have altered timing between the electrical and mechanical stimulation signals as potential future directions for the use of this system.

Creation of a bioreactor for the application of variable amplitude mechanical stimulation of fibrin gel-based engineered cardiac tissue.

This chapter details the creation of three-dimensional fibrin hydrogels as an engineered myocardial tissue and introduces a mechanical stretch bioreactor system that allows for the cycle-to-cycle variable amplitude mechanical stretch of the constructs as a method of conditioning the constructs to be more similar to native tissue. Though mechanical stimulation has been established as a standard method of improving construct development, most studies have been performed under constant frequency and constant amplitude, even though variability is a critical aspect of healthy cardiac physiology. The introduction of variability in other organ systems has demonstrated beneficial effects to cell function in vitro. We hypothesize that the introduction of variability in engineered cardiac tissue could have a similar effect.

Mimicking isovolumic contraction with combined electromechanical stimulation improves the development of engineered cardiac constructs.

Electrical and mechanical stimulation have both been used extensively to improve the function of cardiac engineered tissue as each of these stimuli is present in the physical environment during normal development in vivo. However, to date, there has been no direct comparison between electrical and mechanical stimulation and current published data are difficult to compare due to the different systems used to create the engineered cardiac tissue and the different measures of functionality studied as outcomes. The goals of this study were twofold. First, we sought to directly compare the effects of mechanical and electrical stimulation on engineered cardiac tissue. Second, we aimed to determine the importance of the timing of the two stimuli in relation to each other in combined electromechanical stimulation. We hypothesized that delaying electrical stimulation after the beginning of mechanical stimulation to mimic the biophysical environment present during isovolumic contraction would improve construct function by improving proteins responsible for cell-cell communication and contractility. To test this hypothesis, we created a bioreactor system that would allow us to electromechanically stimulate engineered tissue created from neonatal rat cardiac cells entrapped in fibrin gel during 2 weeks in culture. Contraction force was higher for all stimulation groups as compared with the static controls, with the delayed combined stimulation constructs having the highest forces. Mechanical stimulation alone displayed increased final cell numbers but there were no other differences between electrical and mechanical stimulation alone. Delayed combined stimulation resulted in an increase in SERCA2a and troponin T expression levels, which did not happen with synchronous combined stimulation, indicating that the timing of combined stimulation is important to maximize the beneficial effect. Increases in Akt protein expression levels suggest that the improvements are at least in part induced by hypertrophic growth. In summary, combined electromechanical stimulation can create engineered cardiac tissue with improved functional properties over electrical or mechanical stimulation alone, and the timing of the combined stimulation greatly influences its effects on engineered cardiac tissue.

Neurophysiologic assessment of neonatal sleep organization: preliminary results of a randomized, controlled trial of skin contact with preterm infants.

BACKGROUND: Sleep is important to brain organization, but few strategies to promote sleep among premature infants have been tested. Behaviorally based measures of sleep have shown increased quiet sleep (QS) and decreased active sleep (AS) during skin-to-skin contact (SSC) with the mother, but these results have not been confirmed with objective electroencephalographic/polysomnographic measures of sleep organization. Important differences exist between behavioral and electroencephalographic/polysomnographic definitions of sleep state. METHODS: Data for the first 28 relatively healthy, preterm subjects of an ongoing randomized trial of one 2- to 3-hour session of SSC or incubator care between feedings are reported here. Infants were positioned prone, inclined, and nested in an incubator during the 2- to 3-hour pretest period, were fed, and then went into the test period of SSC or incubator care. Infants were left largely undisturbed throughout testing. A mixed-model regression analysis compared the test-pretest differences in outcome measures within and between groups. RESULTS: Results showed that arousals were significantly lower in the SSC group, compared with the control group, for the entire study period and for test-pretest matched segments of QS and AS. Rapid eye movement was significantly lower for the SSC group for the study period and AS segments. Indeterminate sleep was significantly lower for the SSC group when confounding environmental variables were included in the regression analysis. When 4 subjects who experienced excessive ambient light levels during SSC were removed from analysis, QS increased during SSC. CONCLUSIONS: The patterns demonstrated by the SSC group are analogous to more-mature sleep organization. SSC may be used as an intervention to improve sleep organization in this population of preterm infants.

Breast and infant temperatures with twins during shared Kangaroo Care.

Kangaroo Care has been shown to keep a singleton preterm infant warm by body heat generated in maternal breasts that is conducted to the infant. No studies have examined whether twins simultaneously receiving Kangaroo Care, called Shared Kangaroo Care, are sufficiently warm and how the breasts respond to twin presence. Two case studies were done to determine the temperatures of twins being simultaneously kangarooed and the temperatures of maternal breasts during Shared Kangaroo Care. Two sets of premature twins were held in Shared Kangaroo Care for 1.5 hours. Infant temperatures were recorded from incubators; breast temperatures were recorded from thermistors. Infant temperatures remained warm and increased during Kangaroo Care, and each breast appeared to respond to the thermal needs of the infant on that breast. Physiological explanations for thermal synchrony exist. These data suggest that twins can be simultaneously held in Kangaroo Care without thermal compromise because each breast responds individually to the infant's thermal needs.