The Importance of Cultural Awareness in the Management of Heart Failure: A Narrative Review.

Heart failure is a commonly encountered clinical syndrome arising from a range of etiologic cardiovascular diseases and manifests in a phenotypic spectrum of varying degrees of systolic and diastolic ventricular dysfunction. Those affected by this life-limiting illness are subject to an array of burdensome symptoms, poor quality of life, prognostic uncertainty, and a relatively onerous and increasingly complex treatment regimen. This condition occurs in epidemic proportions worldwide, and given the demographic trend in societal ageing, the prevalence of heart failure is only likely to increase. The marked upturn in international migration has generated other demographic changes in recent years, and it is evident that we are living and working in ever more ethnically and culturally diverse communities. Professionals treating those with heart failure are now dealing with a much more culturally disparate clinical cohort. Given that the heart failure disease trajectory is unique to each individual, these clinicians need to ensure that their proposed treatment options and responses to the inevitable crises intrinsic to this condition are in keeping with the culturally determined values, preferences, and worldviews of these patients and their families. In this narrative review, we describe the importance of cultural awareness across a range of themes relevant to heart failure management and emphasize the centrality of cultural competence as the basis of appropriate care provision.

Application of Raman Spectroscopy to Dynamic Binding Capacity Analysis.

Protein A affinity chromatography is a key step in isolation of biotherapeutics (BTs) containing fragment crystallizable regions, including monoclonal and bispecific antibodies. Dynamic binding capacity (DBC) analysis assesses how much BT will bind to a protein A column. DBC reduces with column usage, effectively reducing the amount of recovered product over time. Drug regulatory bodies mandate chromatography resin lifetime for BT isolation, through measurement of parameters including DBC, so this feature is carefully monitored in industrial purification pipelines. High-performance affinity chromatography (HPAC) is typically used to assess the concentration of BT, which when loaded to the column results in significant breakthrough of BT in the flowthrough. HPAC gives an accurate assessment of DBC and how this changes over time but only reports on protein concentration, requires calibration for each new BT analyzed, and can only be used offline. Here we utilized Raman spectroscopy and revealed that this approach is at least as effective as both HPAC and ultraviolet chromatogram methods at monitoring DBC of protein A resins. In addition to reporting on protein concentration, the chemical information in the Raman spectra provides information on aggregation status and protein structure, providing extra quality controls to industrial bioprocessing pipelines. In combination with partial least square (PLS) analysis, Raman spectroscopy can be used to determine the DBC of a BT without prior calibration. Here we performed Raman analysis offline in a 96-well plate format, however, it is feasible to perform this inline. This study demonstrates the power of Raman spectroscopy as a significantly improved approach to DBC monitoring in industrial pipelines.

Culture, ethnicity, and socio-economic status as determinants of the management of patients with advanced heart failure who need palliative care: A clinical consensus statement from the Heart Failure Association (HFA) of the ESC, the ESC Patient Forum, and the European Association of Palliative Care.

The delivery of effective healthcare entails the configuration and resourcing of health economies to address the burden of disease, including acute and chronic heart failure, that affects local populations. Increasing migration is leading to more multicultural and ethnically diverse societies worldwide, with migration research suggesting that minority populations are often subject to discrimination, socio-economic disadvantage, and inequity of access to optimal clinical support. Within these contexts, the provision of person-centred care requires medical and nursing staff to be aware of and become adept in navigating the nuances of cultural diversity, and how that can impact some individuals and families entrusted to their care. This paper will examine current evidence, provide practical guidance, and signpost professionals on developing cultural competence within the setting of patients with advanced heart failure who may benefit from palliative care.

Causes of Industrial Protein A Column Degradation, Explored Using Raman Spectroscopy.

Monoclonal antibodies (mAbs) are used extensively as biotherapeutics for chronic and acute conditions. Production of mAbs is lengthy and expensive, with protein A affinity capture the most costly step, due both to the nature of the resin and its marked reduction in binding capacity with repeated use. Our previous studies using in situ ATR-FTIR spectroscopy indicated that loss in protein A binding capacity is not the result of leaching or degradation of protein A ligand, suggesting fouling is the principal cause. Here we explore binding behavior and resin capacity loss using Raman spectroscopy. Our data reveal a distinct Raman spectral fingerprint for mAb bound to the protein A ligand of MabSelect SuRe. The results show that the drop in static binding capacity (SBC) previously observed for used protein A resin is discernible by Raman spectroscopy in combination with partial least-squares regression. The SBC is lowest (35.76 mg mL-1) for used inlet resin compared to used outlet (40.17 mg mL-1) and unused resin samples (70.35 mg mL-1). Depth profiling by Raman spectroscopy indicates that at below saturating concentrations (∼18 mg mL-1), binding of mAb is not homogeneous through used resin beads with protein binding preferentially to the outer regions of the bead, in contrast to fully homogeneous distribution through unused control MabSelect SuRe resin beads. Analysis of the Raman spectra indicates that one foulant is irreversibly bound mAb. The presence of irreversibly bound mAb and host cell proteins was confirmed by mass spectrometric analysis of used resin beads.

Implementation of the Mental Capacity Act: a national observational study comparing resultant trends in place of death for older heart failure decedents with or without comorbid dementia.

BACKGROUND: Heart failure (HF) is increasingly prevalent in the growing elderly population and commonly associated with cognitive impairment. We compared trends in place of death (PoD) of HF patients with/without comorbid dementia around the implementation period of the Mental Capacity Act (MCA) in October 2007, this legislation supporting patient-centred decision making for those with reduced agency. METHODS: Analyses of death certification data for England between January 2001 and December 2018, describing the PoD and sociodemographic characteristics of all people ≥ 65 years registered with HF as the underlying cause of death, with/without a mention of comorbid dementia. We used modified Poisson regression with robust error variance to determine the prevalence ratio (PR) of the outcome in dying at home, in care homes or hospices compared to dying in hospital. Covariates included year of death, age, gender, marital status, comorbidity burden, index of multiple deprivation and urban/rural settings. RESULTS: One hundred twenty thousand sixty-eight HF-related death records were included of which 8199 mentioned dementia as a contributory cause. The overall prevalence proportion of dementia was 6.8%, the trend significantly increasing from 5.6 to 8.0% pre- and post-MCA (Cochran-Armitage trend test p < 0.0001). Dementia was coded as unspecified (78.2%), Alzheimer's disease (13.5%) and vascular (8.3%). Demented decedents were commonly older, female, and with more comorbidities. Pre-MCA, PoD for non-demented HF patients was hospital 68.2%, care homes 20.2% and 10.7% dying at home. Corresponding figures for those with comorbid dementia were 47.6%, 48.0% and 4.2%, respectively. Following MCA enforcement, PoD for those without dementia shifted from hospital to home, 62.5% and 17.2%, respectively; PR: 1.026 [95%CI: 1.024-1.029]. While home deaths also rose to 10.0% for those with dementia, with hospital deaths increasing to 50.4%, this trend was insignificant, PR: 1.001 [0.988-1.015]. Care home deaths reduced for all, with/without dementia, PR: 0.959 [0.949-0.969] and PR: 0.996 [0.993-0.998], respectively. Hospice as PoD was rare for both groups with no appreciable change over the study period. CONCLUSIONS: Our analyses suggest the MCA did not materially affect the PoD of HF decedents with comorbid dementia, likely reflecting difficulties implementing this legislation in real-life clinical practice.

Insight into purification of monoclonal antibodies in industrial columns via studies of Protein A binding capacity by in situ ATR-FTIR spectroscopy.

Therapeutic monoclonal antibodies (mAbs) are effective treatments for a range of cancers and other serious diseases, however mAb treatments cost on average ∼$100 000 per year per patient, limiting their use. Currently, industry favours Protein A affinity chromatography (PrAc) as the key step in downstream processing of mAbs. This step, although highly efficient, represents a significant mAb production cost. Fouling of the Protein A column and Protein A ligand leaching contribute to the cost of mAb production by shortening the life span of the resin. In this study, we assessed the performance of used PrAc resin recovered from the middle inlet, center and outlet as well as the side inlet of a pilot-scale industrial column. We used a combination of static binding capacity (SBC) analysis and Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) spectroscopy to explore the used resin samples. SBC analysis demonstrated that resin from the inlet of the column had lower binding capacity than resin from the column outlet. ATR-FTIR spectroscopy with PLS (partial least square) analysis confirmed the results obtained from SBC analysis. Importantly, in situ ATR-FTIR spectroscopy also allowed both measurement of the concentration and assessment of the conformational state of the bound Protein A. Our results reveal that PrAc resin degradation after use is dependent on column location and that neither Protein A ligand leaching nor denaturation are responsible for binding capacity loss.

The COVID-19 pandemic: challenges in providing supportive care to those with cardiovascular disease in a time of plague.

PURPOSE OF REVIEW: COVID-19 has permeated the very essence of human existence and society and disrupted healthcare systems. The attrition stemming from this highly contagious disease particularly affects those rendered vulnerable by age and infirmity, including those with underlying cardiovascular disease. This article critically reviews how best to integrate supportive care into the management of those affected. RECENT FINDINGS: Numerous studies have described the pathophysiology of COVID-19, including that specifically arising in those with cardiovascular disease. Potential treatment strategies have emerged but there is limited guidance on the provision of palliative care. A framework for implementation of this service needs to be developed, perhaps involving the training of non-specialists to deliver primary palliative care in the community, bolstered by the use of telemedicine. The appropriate use of limited clinical resources has engendered many challenging discussions and complex ethical decisions. Prospective implementation of future policies requires the incorporation of measures to assuage moral distress, burnout and compassion fatigue in healthcare staff who are psychologically and physically exhausted. SUMMARY: Further research based on patient-centred decision making and advance care planning is required to ensure the supportive needs of COVID-19 patients with cardiovascular disease are adequately met. This research should focus on interventions applicable to daily healthcare practice and include strategies to safeguard staff well-being.

Palliative Care in Acute Heart Failure.

PURPOSE OF REVIEW: Palliative care is increasingly acknowledged as beneficial in supporting patients and families affected by heart failure, but policy documents have generally focused on the chronic form of this disease. We examined palliative care provision for those with acute heart failure, based on the recently updated National Consensus Project Clinical Practice Guidelines for Quality Palliative Care. RECENT FINDINGS: The commonest reason for hospitalization in those > 65 years, acute heart failure admissions delineate crisis points on the unpredictable disease trajectory. Palliative care is underutilized, often perceived as limited to end-of-life care rather than determined by regular systematic needs assessment. No dominant paradigm of palliative care provision has emerged from the nascent evidence base related to this clinical cohort, underscoring the need for further research. Embedding palliative support as mainstream to heart failure care from the point of diagnosis may better ensure treatment strategies for those admitted with acute heart failure remain consistent with patients' preferences and values.

Integration of a palliative approach into heart failure care: a European Society of Cardiology Heart Failure Association position paper.

The Heart Failure Association of the European Society of Cardiology has published a previous position paper and various guidelines over the past decade recognizing the value of palliative care for those affected by this burdensome condition. Integrating palliative care into evidence-based heart failure management remains challenging for many professionals, as it includes the identification of palliative care needs, symptom control, adjustment of drug and device therapy, advance care planning, family and informal caregiver support, and trying to ensure a 'good death'. This new position paper aims to provide day-to-day practical clinical guidance on these topics, supporting the coordinated provision of palliation strategies as goals of care fluctuate along the heart failure disease trajectory. The specific components of palliative care for symptom alleviation, spiritual and psychosocial support, and the appropriate modification of guideline-directed treatment protocols, including drug deprescription and device deactivation, are described for the chronic, crisis and terminal phases of heart failure.

Iron deficiency in 78 805 people admitted with heart failure across England: a retrospective cohort study.

Objectives: Iron deficiency (ID), with or without anaemia (IDA), is an important comorbidity in people with chronic heart failure (HF), but the prevalence and significance in those admitted with HF is uncertain. We assessed the prevalence of ID or IDA in adults (age ≥21 years) hospitalised with a primary diagnosis of HF, and examined key metrics associated with these secondary diagnoses. Methods: A retrospective cohort study of Hospital Episode Statistics describing all adults admitted to National Health Service (NHS) hospitals across England from April 2015 through March 2016 with primary diagnostic discharge coding as HF, with or without subsidiary coding for ID/IDA. Results: 78 805 adults were admitted to 177 NHS hospitals with primary coding as HF: 26 530 (33.7%) with secondary coding for ID/IDA, and 52 275 (66.3%) without. Proportionately more patients coded ID/IDA were admitted as emergencies (94.8% vs 87.6%; p<0.0001). Tending to be older and female, they required a longer length of stay (15.8 vs 12.2 days; p<0.0001), with higher per capita costs (£3623 vs £2918; p<0.0001), the cumulative excess expenditure being £21.5 million. HF-related (8.2% vs 5.2%; p<0.0001) and all-cause readmission rates (25.8% vs 17.7%; p<0.05) at ≤30 days were greater in those with ID/IDA against those without, and they manifested a small but statistically significant increased inpatient mortality (13.5% v 12.9%; p=0.009). Conclusions: For adults admitted to hospitals in England, principally with acute HF, ID/IDA are significant comorbidities and associated with adverse outcomes, both for affected individuals, and the health economy.

Determining the efficacy of camera traps, live capture traps, and detection dogs for locating cryptic small mammal species.

Metal box (e.g., Elliott, Sherman) traps and remote cameras are two of the most commonly employed methods presently used to survey terrestrial mammals. However, their relative efficacy at accurately detecting cryptic small mammals has not been adequately assessed. The present study therefore compared the effectiveness of metal box (Elliott) traps and vertically oriented, close range, white flash camera traps in detecting small mammals occurring in the Scenic Rim of eastern Australia. We also conducted a preliminary survey to determine effectiveness of a conservation detection dog (CDD) for identifying presence of a threatened carnivorous marsupial, Antechinus arktos, in present-day and historical locations, using camera traps to corroborate detections. 200 Elliott traps and 20 white flash camera traps were set for four deployments per method, across a site where the target small mammals, including A. arktos, are known to occur. Camera traps produced higher detection probabilities than Elliott traps for all four species. Thus, vertically mounted white flash cameras were preferable for detecting the presence of cryptic small mammals in our survey. The CDD, which had been trained to detect A. arktos scat, indicated in total 31 times when deployed in the field survey area, with subsequent camera trap deployments specifically corroborating A. arktos presence at 100% (3) indication locations. Importantly, the dog indicated twice within Border Ranges National Park, where historical (1980s-1990s) specimen-based records indicate the species was present, but extensive Elliott and camera trapping over the last 5-10 years have resulted in zero A. arktos captures. Camera traps subsequently corroborated A. arktos presence at these sites. This demonstrates that detection dogs can be a highly effective means of locating threatened, cryptic species, especially when traditional methods are unable to detect low-density mammal populations.

Corrigendum: Insulin- like Growth Factor-Binding Protein Action in Bone Tissue: A Key Role for Pregnancy- Associated Plasma Protein-A.

[This corrects the article DOI: 10.3389/fendo.2018.00031.].

A characteristic signature of insulin-like growth factor (IGF) axis expression during osteogenic differentiation of human dental pulp cells (hDPCs): Potential co-ordinated regulation of IGF action.

The IGF axis is represented by two growth factors (IGF1 and IGF2), two cognate cell surface receptors (IGF1R and IGF2R), six soluble high affinity IGF binding proteins (IGFBP1-6) and several IGFBP proteases. IGF1 and IGF2 are present at high concentrations in bone and play a crucial role in the maintenance and differentiation of both foetal and adult skeleton. In order to understand the role of the IGF axis in bone and other tissues it is necessary to profile the expression and activity of all genes in the axis together with the activity of relevant ancillary proteins (including IGFBP proteases). In the current report we used differentiating human dental pulp cells (hDPC) to examine the expression and activity of the IGF axis during osteogenic differentiation of these cells. We found that, with the exception of IGF1 and IGFBP1, all components of the IGF axis are expressed in hDPCs. IGFBP-4 is the most abundantly expressed IGFBP species at both mRNA and protein levels under both basal and osteogenic conditions. Although we found no difference in IGFBP-4 expression under osteogenic conditions, we report increased expression and activity of pregnancy associated plasma protein-A (PAPP-A - an IGFBP-4 proteinase) leading to increased IGFBP-4 proteolysis in differentiating cell cultures. Further to this we report increased expression of IGF-2 (an activator of PAPP-A), and decreased expression of stanniocalcin-2 (STC2- a recently discovered inhibitor of PAPP-A) under osteogenic conditions. We also demonstrate that STC2 and PAPP-A are able to form complexes in hDPC conditioned medium indicating the potential for regulation of IGFBP-4 proteolysis through this mechanism. We suggest that these changes in the expression and activity of the IGF axis may represent part of an osteogenic signature characteristic of differentiating hDPCs.

CaMKIIδ interacts directly with IKKß and modulates NF-κB signalling in adult cardiac fibroblasts.

Calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) acts as a molecular switch regulating cardiovascular Ca2+ handling and contractility in health and disease. Activation of CaMKIIδ is also known to regulate cardiovascular inflammation and is reported to be required for pro-inflammatory NF-κB signalling. In this study the aim was to characterise how CaMKIIδ interacts with and modulates NF-κB signalling and whether this interaction exists in non-contractile cells of the heart. Recombinant or purified CaMKIIδ and the individual inhibitory -κB kinase (IKK) proteins of the NF-κB signalling pathway were used in autoradiography and Surface Plasmon Resonance (SPR) to explore potential interactions between both components. Primary adult rat cardiac fibroblasts were then used to study the effects of selective CaMKII inhibition on pharmacologically-induced NF-κB activation as well as interaction between CaMKII and specific IKK isoforms in a cardiac cellular setting. Autoradiography analysis suggested that CaMKIIδ phosphorylated IKKß but not IKKα. SPR analysis further supported a direct interaction between CaMKIIδ and IKKß but not between CaMKIIδ and IKKα or IKKγ. CaMKIIδ regulation of IκΒα degradation was explored in adult cardiac fibroblasts exposed to pharmacological stimulation. Cells were stimulated with agonist in the presence or absence of a CaMKII inhibitor, autocamtide inhibitory peptide (AIP). Selective inhibition of CaMKII resulted in reduced NF-κB activation, as measured by agonist-stimulated IκBα degradation. Importantly, and in agreement with the recombinant protein work, an interaction between CaMKII and IKKß was evident following Proximity Ligation Assays in adult cardiac fibroblasts. This study provides new evidence supporting direct interaction between CaMKIIδ and IKKß in pro-inflammatory signalling in cardiac fibroblasts and could represent a feature that may be exploited for therapeutic benefit.