Studying Nonlinear Change in Music Therapy Applying Dynamic Systems Theory.

Change in music therapy is often modeled linearly. In linear analysis, change is represented as the difference between the scores recorded before and after treatment, where changes in the input are proportional to the output. However, changes in complex systems are often not linear and depend on time. We propose Dynamic Systems Theory (DST) as a means to overcome the shortcomings of linear analysis and enrich the study of change in music therapy. This article aims to introduce and critically discuss the applications of DST in music therapy, focusing on its theoretical and methodological aspects. DST offers a meta-framework to model nonlinear change in music therapy, considering time as continuous. The application of DST can further enhance the understanding of how music therapy works, the shape of the change, and how the relevant therapeutic processes within music therapy support therapeutic change. An introduction to DST theory is provided along with its history, implications, assessment methods, statistical analyses, mathematical modeling, and implementation examples in music therapy research.

Economic and cost considerations of delivering and using mobile X-ray services in residential aged care facilities: A qualitative study.

OBJECTIVE: To describe the economic and cost considerations of mobile X-ray services (MXS) in residential aged care facilities (RACFs), according to stakeholders (involved in residents' healthcare), residents living in RACFs and informal carers (ICs) of residents. METHODS: Semistructured interviews were conducted with 20 residents and 27 ICs recruited from six RACFs across metropolitan Adelaide (South Australia, Australia), and 22 stakeholders, on their perspectives of using MXS in RACFs. Data relating to economic and cost considerations were extracted and analysed using thematic analysis. RESULTS: Residents' mean age was 85 years, 60% were women and 40% had experienced an MXS in the last 12 months. Most ICs were daughters (70%) and wives (11%) and 30% had a family member who had experienced an MXS in the last 12 months. Stakeholders included RACF staff, GPs, a hospital avoidance program clinician, paramedics, emergency department clinicians, MXS radiographers and manager, and a radiologist. Four themes were presented: (1) business considerations, where private providers found it necessary to charge residents a co-payment to deliver MXS; (2) cost and payment process as a potential barrier to using MXS, with varied willingness and ability to pay for an MXS co-payment, and equity concerns; (3) overcoming cost and payment barriers, with staff and consumers sometimes using strategies to overcome cost barriers; and (4) perceived cost benefits of MXS to the healthcare system, residents and ICs. CONCLUSIONS: Mobile X-ray services providers charge residents an upfront co-payment for business viability, which can be a barrier to some residents wishing to access MXS.

Mobile X-ray services in nursing homes as an enabler to healthcare-in-place for residents: informal carers' views.

BACKGROUND: Informal carers (ICs) of residents living in nursing homes (NH) have a key role in the care of residents, including making decisions about and providing care. As radiology has a role in decision making about care, it is important to understand IC's perspectives about resident's use of mobile X-ray services (MXS). The aim was to explore the perspectives of ICs of residents living in nursing homes about the use of MXS. METHODS: From November 2020 to February 2021, twenty ICs of residents living in four nursing homes in different areas of one Australian city participated. Their perspectives of MXS, including benefits and barriers, were explored in semi-structured interviews. Data were analysed using thematic analysis. RESULTS: ICs were resident's children (80%) and spouses (20%). One resident had received a MXS. Four themes were developed: (1) a priority for resident well-being, where ICs were positive about using MXS, because residents could receive healthcare without transfer; (2) MXS could reduce carer burden; (3) economic considerations, where MXS could reduce health system burden but the MXS call-out fee could result in health inequities; and (4) pathways to translation, including the need to improve consumer awareness of MXS, ensure effective processes to using MXS,, consider nursing home staff levels to manage MXS and ICs expectations about quality and availability of MXS. CONCLUSIONS: ICs consider MXS can benefit resident well-being by potentially reducing transfers to hospital or radiology facilities and advocated equitable access. ICs cautioned that the quality and safety of healthcare delivered in nursing homes should equal what they would receive in hospitals.

Evaluation of the Delivery of a Live Attenuated Porcine Reproductive and Respiratory Syndrome Virus as a Unit Solid Dose Injectable Vaccine.

Solid dose vaccine formulation and delivery systems offer potential advantages over traditional liquid vaccine formulations. In addition to enhanced thermostability, needle-free delivery of unit solid dose injectable (USDI) vaccines offers safe, rapid, and error-free administration, with applicability to both human and animal health. Solid dose formulation technologies can be adapted for delivery of different vaccine formats including live attenuated vaccines, which remain the 'gold standard' for many disease targets. Porcine reproductive and respiratory syndrome viruses (PRRSV) cause one of the most economically important diseases affecting the global pig industry. Despite several shortcomings, live attenuated vaccines are widely used to control PRRSV. We optimised a freeze-dried USDI formulation of live attenuated PRRSV-1, which fully retained infectious titre, and evaluated its immunogenicity in comparison to virus delivered in liquid suspension via intramuscular and subcutaneous needle inoculation. Pigs vaccinated with the USDI formulation displayed vaccine viraemia, and PRRSV-specific antibody and T cell responses comparable to animals immunised with the liquid vaccine. The USDI vaccine formulation was stable for at least 6 months when stored refrigerated. These data demonstrate the potential for a solid dose vaccine delivery system as an alternative to conventional needle-syringe delivery of live attenuated PRRSV vaccines.

Stakeholders' perspectives of mobile x-ray services in support of healthcare-in-place in residential aged care facilities: a qualitative study.

BACKGROUND: There is interest in reducing avoidable emergency department presentations from residential aged care facilities (RACF). Mobile x-ray services may enable the delivery of healthcare in residential aged care facilities. Accordingly, the Australian Government in November 2019 introduced a Medicare Benefit Schedule rebate providing for a 'call-out' fee payable to radiology service providers. This study aims to understand stakeholder perspectives on the benefits of mobile x-ray services and the factors influencing their adoption by RACFs. DESIGN, SETTING, PARTICIPANTS: Twenty-two semi-structured interviews were conducted between October 2020 and February 2021 with a range of stakeholders involved in healthcare delivery to residents: a) general practitioners; b) emergency department clinicians; c) paramedic clinicians; d) a hospital avoidance clinician; e) radiology clinicians and managers; and f) aged care clinicians and managers. Thematic analysis was conducted. RESULTS: Mobile x-ray services were considered valuable for RACF residents. Lack of timely general practitioner in-person assessment and referral, as well as staffing deficits in residential aged care facilities, reduces optimal use of mobile x-ray services and results in potentially unnecessary hospital transfers. CONCLUSIONS: The use of mobile x-ray services, as a hospital avoidance strategy, depends on the capacity of RACFs to provide more complex healthcare-in-place. However, this requires greater access to general practitioners for in-person assessment and referral, adequate staffing numbers and appropriately skilled nursing staff within residential aged care facilities.

Residents' perspectives of mobile X-ray services in support of healthcare-in-place in residential aged care facilities: a qualitative study.

BACKGROUND: Mobile X-ray services (MXS) could be used to investigate clinical issues in aged care residents within familiar surroundings, reducing transfers to and from emergency departments and enabling healthcare to be delivered in residential aged care facilities. There is however little research exploring consumer perspectives about such services. The objective of this research was to explore the perspectives and preferences of residents about the provision of MXS in residential aged care facilities, including their knowledge about the service, perceived benefits, and factors that require consideration for effective implementation. METHODS: A qualitative study design was used. The setting for the study included four residential aged care facilities of different sizes from different parts of a South Australian city. Purposive sampling was used to recruit participants. 16 residents participated in semi-structured interviews that were audio-recorded and transcribed verbatim. Data were inductively derived using thematic analysis. RESULTS: Participants had a mean age of 85 years, 56% were female, 25% had dementia and 25% had had a mobile X-ray in the last 12 months. Four themes were developed. Participants preferred mobile X-rays, provided as healthcare-in-place, to improve accessibility to them and minimize physical and psychological discomfort. Participants had expectations about the processes for receiving mobile X-rays. Costs of X-rays to people, family and society were a consideration. Decision making required residents be informed about mobile X-rays. CONCLUSIONS: Residents have positive views of MXS as they can receive healthcare-in-place, with familiar people and surroundings. They emphasised that MXS delivered in residential aged care facilities need to be of equivalent quality to those found in other settings. Increased awareness of mobile X-ray services is required.

Nobiletin Prevents High-Fat Diet-Induced Dysregulation of Intestinal Lipid Metabolism and Attenuates Postprandial Lipemia.

OBJECTIVE: Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout (Ldlr-/-), and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol (HFHC) diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT (protein kinase B) and FoxO1 (forkhead box O1) and normal Srebf1c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by HFHC feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in HFHC-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. CONCLUSIONS: Nobiletin opposed the effects of the HFHC diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.

Activation of Dendritic Cells in Tonsils Is Associated with CD8 T Cell Responses following Vaccination with Live Attenuated Classical Swine Fever Virus.

Classical swine fever (CSF) is a highly contagious disease caused by the classical swine fever virus (CSFV). The live attenuated C-strain vaccine is highly efficacious, initiating protection within several days of delivery. The vaccine strain is detected in the tonsil early after inoculation, yet little is known of the role that tonsillar immune cells might play in initiating protection. Comparing the C-strain vaccine with the pathogenic CSFV Alfort-187 strain, changes in the myeloid cell compartment of the tonsil were observed. CSFV infection led to the emergence of an additional CD163+CD14+ cell population, which showed the highest levels of Alfort-187 and C-strain infection. There was also an increase in both the frequency and activation status (as shown by increased MHC-II expression) of the tonsillar conventional dendritic cells 1 (cDC1) in pigs inoculated with the C-strain. Notably, the activation of cDC1 cells coincided in time with the induction of a local CSFV-specific IFN-γ+ CD8 T cell response in C-strain vaccinated pigs, but not in pigs that received Alfort-187. Moreover, the frequency of CSFV-specific IFN-γ+ CD8 T cells was inversely correlated to the viral load in the tonsils of individual animals. Accordingly, we hypothesise that the activation of cDC1 is key in initiating local CSFV-specific CD8 T cell responses which curtail early virus replication and dissemination.

Inactivation of African Swine Fever Virus by reagents commonly used in containment laboratories.

Rapid and effective virus inactivation is an essential step for safe diagnostic testing and for research and vaccine development using infectious viruses. We characterised the reduction of African Swine Fever Virus (ASFV) infectivity using Virkon™ S (Lanxess) 1% w/v disinfectant, FACS™ Lysing buffer (BD), and AVL™ buffer (Qiagen), using porcine cell culture. No virus was detected following a 30 s 20:1 v/v mixing ratio of Virkon™ S 1% with high titre ASFV, supporting its effective use as a laboratory surface disinfectant. FACS™ Lysing and AVL™ buffers also inactivated ASFV, permitting safe removal of treated infected samples from high containment facilities.

A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses.

There is need for effective and affordable vaccines against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a protein nanoparticle vaccine against SARS-CoV-2. The vaccine is based on the display of coronavirus spike glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle (VLP) platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology. Low doses of RBD-SpyVLP in a prime-boost regimen induce a strong neutralising antibody response in mice and pigs that is superior to convalescent human sera. We evaluate antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we show that RBD-SpyVLP induces a polyclonal antibody response that recognises key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. Moreover, RBD-SpyVLP is thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence. The data suggests that RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic.

Evaluation of a population health strategy to reduce distracted driving: Examining all "Es" of injury prevention.

BACKGROUND: Cell phone use while driving (CPWD) increases the risk of crashing and is a major contributor to injuries and deaths. The objective of this study was to describe the evaluation of a multifaceted, evidence-based population health strategy for the reduction of distracted driving. METHODS: A multipronged campaign was undertaken from 2014 to 2016 for 16- to 44-year-olds, based on epidemiology, focused on personal stories and consequences, using the "Es" of injury prevention (epidemiology, education, environment, enforcement, and evaluation). Education consisted of distracted driving videos, informational cards, a social media AdTube campaign, and a movie theater trailer, which were evaluated with a questionnaire regarding CPWD attitudes, opinions, and behaviors. Spatial analysis of data within a geographic information system was used to target advertisements. A random sample telephone survey evaluated public awareness of the campaign. Increased CPWD enforcement was undertaken by police services and evaluated by ARIMA time series modeling. RESULTS: The AdTube campaign had a view rate of >10% (41,101 views), slightly higher for females. The top performing age group was 18- to 24-year-olds (49%). Our survey found 61% of respondents used handheld CPWD (14% all of the time) with 80% reporting our movie trailer made them think twice about future CPWD. A stakeholder survey and spatial analysis targeted our advertisements in areas of close proximity to high schools, universities, near intersections with previous motor vehicle collisions, high traffic volumes, and population density. A telephone survey revealed that 41% of the respondents were aware of our campaign, 17% from our print and movie theater ads and 3% from social media. Police enforcement campaign blitzes resulted in 160 tickets for CPWD. Following campaign implementation, there was a statistically significant mean decrease of 462 distracted driving citations annually (p = 0.001). CONCLUSION: A multifaceted, evidence-based population health strategy using the Es of injury prevention with interdisciplinary collaboration is a comprehensive method to be used for the reduction of distracted driving. LEVEL OF EVIDENCE: Therapeutic, level IV.

Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19.

Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.

Substitution of warthog NF-κB motifs into RELA of domestic pigs is not sufficient to confer resilience to African swine fever virus.

African swine fever virus (ASFV) causes a lethal, haemorrhagic disease in domestic swine that threatens pig production across the globe. Unlike domestic pigs, warthogs, which are wildlife hosts of the virus, do not succumb to the lethal effects of infection. There are three amino acid differences between the sequence of the warthog and domestic pig RELA protein; a subunit of the NF-κB transcription factor that plays a key role in regulating the immune response to infections. Domestic pigs with all 3 or 2 of the amino acids from the warthog RELA orthologue have been generated by gene editing. To assess if these variations confer resilience to ASF we established an intranasal challenge model with a moderately virulent ASFV. No difference in clinical, virological or pathological parameters were observed in domestic pigs with the 2 amino acid substitution. Domestic pigs with all 3 amino acids found in warthog RELA were not resilient to ASF but a delay in onset of clinical signs and less viral DNA in blood samples and nasal secretions was observed in some animals. Inclusion of these and additional warthog genetic traits into domestic pigs may be one way to assist in combating the devastating impact of ASFV.

Naringenin enhances the regression of atherosclerosis induced by a chow diet in Ldlr-/- mice.

BACKGROUND AND AIMS: Naringenin is a citrus-derived flavonoid with lipid-lowering and insulin-sensitizing effects leading to athero-protection in Ldlr-/- mice fed a high-fat diet. However, the ability of naringenin to promote atherosclerosis regression is unknown. In the present study, we assessed the capacity of naringenin to enhance regression in Ldlr-/- mice with diet-induced intermediate atherosclerosis intervened with a chow diet. METHODS: Male Ldlr-/- mice were fed a high-fat, cholesterol-containing (HFHC) diet for 12 weeks to induce intermediate atherosclerosis and metabolic dysfunction. Subsequently, a group of these mice were sacrificed for baseline analyses and the remainder either 1) continued on the HFHC diet, 2) switched to a chow diet or 3) switched to chow diet supplemented with naringenin. RESULTS: After 12 weeks induction, intermediate lesions developed in the aortic sinus. Intervention with chow alone slowed lesion growth, while intervention with naringenin-supplemented chow completely halted lesion growth. Lesions were characterized by features of improved morphology. Compared to chow alone, naringenin reduced plaque macrophages and modestly increased smooth muscle cells. Investigating processes that contributed to improved plaque morphology, we showed naringenin further reduced plasma triglycerides and cholesterol compared to chow alone. Furthermore, elevated monocytosis and myelopoiesis were further corrected by intervention with naringenin compared to chow alone. Metabolically, naringenin enhanced the correction of insulin resistance, hepatic steatosis and obesity compared to chow alone, potentially contributing to enhanced regression. CONCLUSIONS: Naringenin supplementation to chow enhances atherosclerosis regression in male Ldlr-/- mice. These studies further underscore the potential therapeutic utility of naringenin.

Naringenin Supplementation to a Chow Diet Enhances Energy Expenditure and Fatty Acid Oxidation, and Reduces Adiposity in Lean, Pair-Fed Ldlr-/- Mice.

SCOPE: Naringenin is a citrus-derived flavonoid that has potent lipid-lowering and insulin-sensitizing effects in obese mouse models of metabolic dysfunction. However, in these models, a significant effect of naringenin supplementation is the prevention of weight gain, which in itself can confer metabolic protection. Therefore, in the present study, the effect of naringenin supplementation in lean, chow-fed Ldlr-/- mice is investigated. METHODS AND RESULTS: In Ldlr-/- mice with isocaloric food consumption, treatment with naringenin for 8 weeks reduces body weight and adiposity compared to littermate controls pair-fed the chow diet alone. Furthermore, naringenin treatment reduces plasma lipids and enhances insulin sensitivity compared to chow-fed controls. Metabolic cage studies reveal that naringenin-treated mice have elevated energy expenditure with no change in ambulatory activity. Additionally, naringenin-treated mice have an increased respiratory exchange ratio and food consumption during the dark cycle. Treatment increases the expression of fatty acid oxidation genes in liver, and increased ß-hydroxybutyrate concentrations in plasma, indicating that one mechanism through which naringenin mediates metabolic improvement is enhanced hepatic fatty acid oxidation. CONCLUSIONS: These studies highlight the potential therapeutic utility of naringenin and suggest that this flavonoid maintains potent metabolic properties in the absence of obesity or a high-fat diet.

Counseling and Psychology Student Experiences of Personal Therapy: A Critical Interpretive Synthesis.

Background: Committing to attendance at personal therapy sessions is frequently either mandated or encouraged in many different types of therapeutic trainings across allied health, psychotherapy, social work and counseling. The small number of published accounts have indicated that student experiences of personal therapy can be mixed. Methods: The project examined contemporary interview based research about student experience of personal therapy during training using Critical Interpretive Synthesis method. Ten papers were found which met the search criteria. The papers included a total of 89 participants (75 F). Results: The results comprised 12 themes derived from 89 meaning units gleaned from student experiences presented in the research studies. These were used to inform a synthesizing statement here truncated as follows: Beginning therapy is challenging for some students, especially when attendance is mandatory. However, students can experience transformative change by the end of the process, even if they commence the work in a guarded way. Multiple problems can arise in the process of attending therapy as a student, and it can be difficult for a student to know what to do if these challenges are overwhelming. Attending personal therapy brings rich learnings which can be applied in clinical work but can also positively impact learning in the course, and lifelong personal development. The process can enhance the student's understanding of what the client may experience in the therapeutic journey. Conclusions: Attending personal therapy during training is not a straightforward process for all students. Course leaders and trainers need to be mindful of the possibility that students will struggle with the personal therapy requirement. Course and professional bodies should regularly review personal therapy requirements, being clear about the aims; remaining attuned to the student experience.

Characterization of the Myeloid Cell Populations' Resident in the Porcine Palatine Tonsil.

The palatine tonsil is the portal of entry for food and air and is continuously subjected to environmental challenges, including pathogens, which use the tonsil and pharynx as a primary site of replication. In pigs, this includes the viruses causing porcine respiratory and reproductive syndrome, and classical and African swine fever; diseases that have impacted the pig production industry globally. Despite the importance of tonsils in host defense, little is known regarding the phenotype of the myeloid cells resident in the porcine tonsil. Here, we have characterized five myeloid cell populations that align to orthologous populations defined in other mammalian species: a CD4+ plasmacytoid dendritic cell (DC) defined by expression of the conserved markers E2.2 and IRF-7, a conventional dendritic cell (cDC1) population expressing CADM1highCD172alow and high levels of XCR1 able to activate allogeneic CD4 and CD8 T cells; a cDC2 population of CADM1dim cells expressing FLT3, IRF4, and CSF1R with an ability to activate allogeneic CD4 T cells; CD163+ macrophages (MÏ´s) defined by high levels of endocytosis and responsiveness to LPS and finally a CD14+ population likely derived from the myelomonocytic lineage, which showed the highest levels of endocytosis, a capacity for activation of CD4+ memory T cells, combined with lower relative expression of FLT3. Increased knowledge regarding the phenotypic and functional properties of myeloid cells resident in porcine tonsil will enable these cells to be targeted for future vaccination strategies to current and emerging porcine viruses.

Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr-/- mice.

Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in Ldlr-/- mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in Ldlr-/- mice with diet-induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease.

Strategies for Successful Nurse-Student Preceptorships.

Being a preceptor for a new nurse or a student is a great way to promote the future of nursing. However, most nurses have not been taught how to be an effective preceptor. Eight strategies for effective precepting are presented. Servant leadership is discussed as a theoretical basis for serving as a preceptor.

Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient (LDLR+/- and LDLR-/-) Yucatan Miniature Pigs.

OBJECTIVE: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia. APPROACH AND RESULTS: Gene targeting has been used to generate Yucatan miniature pigs heterozygous (LDLR+/-) or homozygous (LDLR-/-) for LDL receptor deficiency (ExeGen). LDLR+/- and LDLR-/- pigs were fed a high-fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or BemA for 160 days. In LDLR+/- pigs, compared with placebo, BemA decreased plasma cholesterol and LDL-C up to 40% and 61%, respectively. In LDLR-/- pigs, in which plasma cholesterol and LDL-C were 5-fold higher than in LDLR+/- pigs, BemA decreased plasma cholesterol and LDL-C up to 27% and 29%, respectively. Plasma levels of triglycerides and high-density lipoprotein cholesterol, fasting glucose and insulin, and liver lipids were unaffected by treatment in either genotype. In the aorta of LDLR+/- pigs, BemA robustly attenuated en face raised lesion area (-58%) and left anterior descending coronary artery cross-sectional lesion area (-40%). In LDLR-/- pigs, in which lesions were substantially more advanced, BemA decreased aortic lesion area (-47%) and left anterior descending coronary artery lesion area (-48%). CONCLUSIONS: In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both LDLR+/- and LDLR-/- miniature pigs.