Palliation of heart failure: value-based supportive care.

OBJECTIVES: Heart failure (HF) is a prevalent condition associated with poor quality-of-life and high symptom burden. As patients reach ceilings of survival-extending interventions, their priorities may be more readily addressed through the support of palliative care services; however, the best model of care remains unestablished.We aimed to create and evaluate a cospeciality cross-boundary service model for patients with HF that better provides for their palliative care needs in the latter stages of life, while delivering a more cost-effective patient journey. METHODS: In 2016, the Heart Failure Supportive Care Service (HFSCS) was established to provide patient-centred holistic support to patients with advanced HF. Patient experience questionnaires were developed and distributed in mid-2018 and end-of-2020. Indexed hospital admission data (in-patient bed days pre-referral/post-referral) were used allowing statistical comparisons by paired t-tests. RESULTS: From 2016-2020, 236 patients were referred to the HFSCS. Overall, 75/118 questionnaires were returned. Patients felt that the HFSCS delivered compassionate care (84%) that improved symptoms and quality of life (80% and 65%). Introduction of the HFSCS resulted in a reduction in HF-related admissions: actual days 18.3 to 4 days (p<0.001), indexed days 0.05 to 0.032 days (p=0.03). Cost mapping revealed an estimated average saving of at least £10 218.36 per referral and a total estimated cost saving of approximately £2.4 million over 5 years. CONCLUSION: This service demonstrates that a cospeciality cross-boundary method of care delivery successfully provides the benefits of palliative care to patients with HF in a value-based manner, while meeting the priorities of care that matter to patients most.

Leaving No One Behind: Interventions and Outcomes of the COVID-19 Vaccine Maximising Uptake Programme.

The devastating impact of COVID-19 on individuals and communities has accelerated the development of vaccines and the deployment of ambitious vaccination programmes to reduce the risks of infection, infection transmission and symptom severity. However, many people delay or refuse to get vaccinated against COVID-19, for many complex reasons. Vaccination programmes that are tailored to address individual and communities' COVID-19 concerns can improve vaccine uptake rates and help achieve the required herd-immunity threshold. The Maximising Uptake Programme has led to the vaccination of 7979 people from February-August 2021 in the South West of England, UK, who are at high risk of severe illness from COVID-19 and/or may not access the COVID-19 vaccines through mass vaccination centres and general practices. These include: people experiencing homelessness; non-English-speaking people; people from minority ethnic groups; refugees and asylum seekers; Gypsy, Roma, Travelers and boat people; and those who are less able to access vaccination centres, such as people with learning difficulties, serious mental illness, drug and alcohol dependence, people with physical and sensory impairment, and people with dementia. Outreach work coupled with a targeted communication and engagement campaign, co-designed with community leaders and influencers, have led to significant engagement and COVID-19 vaccine uptake among the target populations.

The healthcare resource impact of maternal mental illness on children and adolescents: UK retrospective cohort study.

BACKGROUND: The general health of children of parents with mental illness is overlooked. AIMS: To quantify the difference in healthcare use of children exposed and unexposed to maternal mental illness (MMI). METHOD: This was a retrospective cohort study of children aged 0-17 years, from 1 April 2007 to 31 July 2017, using a primary care register (Clinical Practice Research Datalink) linked to Hospital Episodes Statistics. MMI included non-affective/affective psychosis and mood, anxiety, addiction, eating and personality disorders. Healthcare use included prescriptions, primary care and secondary care contacts; inflation adjusted costs were applied. The rate and cost was calculated and compared for children exposed and unexposed to MMI using negative binomial regression models. The total annual cost to NHS England of children with MMI was estimated. RESULTS: The study included 489 255 children: 238 106 (48.7%) girls, 112 741 children (23.0%) exposed to MMI. Compared to unexposed children, exposed children had a higher rate of healthcare use (rate ratio 1.27, 95% CI 1.26-1.28), averaging 2.21 extra contacts per exposed child per year (95% CI 2.14-2.29). Increased healthcare use among exposed children occurred in inpatients (rate ratio 1.37, 95% CI 1.32-1.42), emergency care visits (rate ratio 1.34, 95% CI 1.33-1.36), outpatients (rate ratio 1.30, 95% CI 1.28-1.32), prescriptions (rate ratio 1.28, 95% CI 1.26-1.30) and primary care consultations (rate ratio 1.24, 95% CI 1.23-1.25). This costs NHS England an additional £656 million (95% CI £619-£692 million), annually. CONCLUSIONS: Children of mentally ill mothers are a health vulnerable group for whom targeted intervention may create benefit for individuals, families, as well as limited NHS resources.

Long-term adaptive versus maladaptive remodelling of the pulmonary autograft after the Ross operation.

OBJECTIVES: Following the Ross operation, the pulmonary autograft undergoes structural changes (remodelling). We sought to determine the extent, nature and possible determinants of long-term remodelling in the different components of the pulmonary autograft. METHODS: Ten pulmonary autografts and 12 normal control valves (6 pulmonary and 6 aortic) were examined by conventional histology, immunocytochemistry and electron microscopy. The structural changes were quantified by morphometry. RESULTS: The leaflets from free-standing root replacement valves demonstrated thickening to levels comparable to the normal aortic leaflets, largely due to the addition of a thin layer of 'neointima' formed of radial elastic fibres, collagen bundles and glycoaminoglycans, on the ventricular aspect of the leaflets. The leaflets of valves from sub-coronary implantation demonstrated a significantly thicker fibroelastic layer on the ventricularis and calcium deposition in the fibrosa. The media of the explanted valves showed increased number of lamellar units to levels comparable to normal aortic roots. Electron microscopy of valves inserted as free-standing roots showed increased organization into continuous layers. However, intralamellar components showed varying degrees of 'disorganization' in comparison to those in the normal aortic media. In addition, there was a marked increase in the number of vasa vasorum with thickened arteriolar wall in the outer media and adventitia. CONCLUSIONS: Following the Ross operation, in the very long term, all components of the autograft showed varying degrees of remodelling, which was judged to be largely adaptive. Defining the type, determinants and possible functional effects of remodelling could help in understanding and optimizing the results of the Ross operation.

Platelet-derived transforming growth factor-ß1 promotes keratinocyte proliferation in cutaneous wound healing.

Platelets are a recognised potent source of transforming growth factor-ß1 (TGFß1), a cytokine known to promote wound healing and regeneration by stimulating dermal fibroblast proliferation and extracellular matrix deposition. Platelet lysate has been advocated as a novel personalised therapeutic to treat persistent wounds, although the precise platelet-derived growth factors responsible for these beneficial effects have not been fully elucidated. The aim of this study was to investigate the specific role of platelet-derived TGFß1 in cutaneous wound healing. Using a transgenic mouse with a targeted deletion of TGFß1 in megakaryocytes and platelets (TGFß1fl/fl .PF4-Cre), we show for the first time that platelet-derived TGFß1 contributes to epidermal and dermal thickening and cellular turnover after excisional skin wounding. In vitro studies demonstrate that human dermal fibroblasts stimulated with platelet lysate containing high levels of platelet-derived TGFß1 did not exhibit enhanced collagen deposition or proliferation, suggesting that platelet-derived TGFß1 is not a key promoter of these wound healing processes. Interestingly, human keratinocytes displayed enhanced TGFß1-driven proliferation in response to platelet lysate, reminiscent of our in vivo findings. In summary, our novel findings define and emphasise an important role of platelet-derived TGFß1 in epidermal remodelling and regeneration processes during cutaneous wound healing.

Understanding quality of life and well-being for people living with advanced dementia.

AIM: To investigate the quality of life (QoL) and well-being of people living with advanced dementia in care homes. METHOD: A mixed-methods approach was taken combining participant observations, interviews with the participants' families and carers, and quantitative measurements. The quantitative measures included AwareCare assessments, QoL in Late-Stage Dementia scale ratings and semi-structured interviews with relatives and staff members. Ryff's psychological well-being framework, the Fairness, Respect, Equality, Identity, Dignity, Autonomy principles, and Kitwood's indicators of well-being, were examined to attempt to identify contributors to QoL for people living with advanced dementia. RESULTS: Participants had limited verbal abilities, but used non-vocal behaviours to communicate. These behaviours influenced their QoL and well-being. CONCLUSION: The indicators of well-being in Kitwood's personhood model were helpful in describing how relatives and staff perceived the QoL of the person with dementia.

Early identification of severe community-acquired pneumonia: a retrospective observational study.

Background: Community-acquired pneumonia (CAP) is a leading cause of sepsis worldwide. Prompt identification of those at high risk of adverse outcomes improves survival by enabling early escalation of care. There are multiple severity assessment tools recommended for risk stratification; however, there is no consensus as to which tool should be used for those with CAP. We sought to assess whether pneumonia-specific, generic sepsis or early warning scores were most accurate at predicting adverse outcomes. Methods: We performed a retrospective analysis of all cases of CAP admitted to a large, adult tertiary hospital in the UK between October 2014 and January 2016. All cases of CAP were eligible for inclusion and were reviewed by a senior respiratory physician to confirm the diagnosis. The association between the CURB65, Lac-CURB-65, quick Sequential (Sepsis-related) Organ Failure Assessment tool (qSOFA) score and National Early Warning Score (NEWS) at the time of admission and outcome measures including intensive care admission, length of hospital stay, in-hospital, 30-day, 90-day and 365-day all-cause mortality was assessed. Results: 1545 cases were included with 30-day mortality of 19%. Increasing score was significantly associated with increased risk of poor outcomes for all four tools. Overall accuracy assessed by receiver operating characteristic curve analysis was significantly greater for the CURB65 and Lac-CURB-65 scores than qSOFA. At admission, a CURB65 ≥2, Lac-CURB-65 ≥moderate, qSOFA ≥2 and NEWS ≥medium identified 85.0%, 96.4%, 40.3% and 79.0% of those who died within 30 days, respectively. A Lac-CURB-65 ≥moderate had the highest negative predictive value: 95.6%. Conclusion: All four scoring systems can stratify according to increasing risk in CAP; however, when a confident diagnosis of pneumonia can be made, these data support the use of pneumonia-specific tools rather than generic sepsis or early warning scores.

A Collaborative Approach: Care Staff and Families Working Together to Safeguard the Quality of Life of Residents Living With Advanced Dementia.

OBJECTIVES: This study aimed to explore the quality of life and well-being of care home residents living with advanced dementia, how personalised care can be achieved where the person is completely dependent on others for care and how individuals' choices and human rights were upheld. METHODS: The study design used a qualitative approach, with data collected through in-depth, semi-structured interviews with 8 family members, all of whom visited daily, and 8 care staff. RESULTS: Emerging themes highlighted the importance of family involvement, signs of well-being, communication and the valued role of direct care staff. DISCUSSION: Participants were able to identify factors of residents' well-being in residents living with advanced dementia. Family members who visited daily saw themselves working collaboratively with care staff to maintain the quality of life of their relatives and engage in proxy decision making. Regarding human rights, the emphasis was on avoiding abuse, rather than promoting well-being.

ICS Use May Modify FEV1 Decline in α1-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils.

BACKGROUND: α1-Antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease (COPD). In COPD unrelated to AATD, the role of a higher blood eosinophil count in disease and subsequent personalization of therapy has recently received much attention. We sought to investigate this concept in patients with AATD-associated COPD. OBJECTIVES: The study aims to evaluate eosinophilia status against outcomes including mortality and FEV1 decline in patients with AATD. METHODS: All patients with PiSZ and PiZZ genotypes were identified from the UK AATD registry. The participants were substratified according to inhaled corticosteroid (ICS) use. Blood eosinophil counts were assessed from baseline and annually during follow-up (range 1-18 years). Eosinophilia was defined as a level >0.2 × 109/L, and classified by the frequency of such counts into "always," "intermittent," or "never present." Univariate and multivariate analyses were conducted. RESULTS: In total, 646 participants were included, 53.9% of whom demonstrated intermittent and 7.4% persistent eosinophilia. Survival did not differ according to eosinophilic group (p > 0.05). Those with persistent eosinophilia showed a slower FEV1 decline (p < 0.001). There was no clear association with exacerbation frequency. Patients on ICS at baseline were more likely to be eosinophilic (p = 0.002) and having a lower FEV1 (p < 0.001) and greater pack-year exposure (16.5 vs. 7.8 pack-years, p < 0.001). When the multivariate analyses of FEV1 decline were stratified for baseline ICS use, the association of persistent eosinophilia with slower decline persisted in those on ICS. CONCLUSIONS: Blood eosinophil levels persistently >0.2 × 109/L may be an indication for ICS use in PiZZ AATD in order to reduce FEV1 decline.

Maximal mid-expiratory flow detects early lung disease in α1-antitrypsin deficiency.

Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all α1-antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk.Maximal mid-expiratory flow (MMEF), forced expiratory volume in 1 s (FEV1), ratio of FEV1/forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV1 were assessed in 196 AATD patients.FEV1/FVC, FEV1 % predicted and lung densitometry related to MMEF % pred (r2=0.778, p<0.0001; r2=0.787, p<0.0001; r2=0.594, p<0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV1/FVC and MMEF (group 1), normal FEV1/FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St George's Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09-39.63) versus 9.67 (IQR 1.83-22.35); p=0.006) and had a greater subsequent decline in FEV1 (median change in FEV1 -1.09% pred per year (IQR -1.91-0.04% pred per year) versus -0.04% pred per year (IQR -0.67-0.03% pred per year); p=0.007).A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV1.

A Rare Colocalization of Lichen Planus and Vitiligo.

We report an unusual manifestation of vitiligo colocalizing with lichen planus (LP). A 76-year-old Greek male presented with a history of a red, scaly, itchy, asymmetrical patch located at the umbilicus within a well-demarcated depigmented macule of vitiligo. Histology showed features of a lichenoid interface dermatitis, favouring a diagnosis of LP. Colocalization of LP and vitiligo has rarely been reported in the literature. After reviewing the literature, we believe that at present there is insufficient evidence to resolve the uncertainties in the aetiology of this colocalization. It seems to us that the association between LP and vitiligo is more than coincidental, but none of the theories discussed in this paper can sufficiently account for it. Rather, the association is likely to be multifactorial in its pathogenesis.

Severn School of Psychiatry education fellowships: a new way to promote educational practice and research.

This paper describes a model of training in leadership and project management skills for advanced trainees, using educational projects within the Severn School of Psychiatry. Fellowships lasting 1 year have been developed to enable trainees, working with a senior consultant trainer associated with the School of Psychiatry, to support important new educational initiatives. Linkage with the local university training and learning for health professionals research module has provided academic support for the trainees and the projects. Four examples for the first year of the programme are described and feedback from structured interviews with participants is presented. The development of the fellowships appears to have had wider benefits, in developing educational faculty in the School of Psychiatry and the trainees involved have had opportunities to extend their project management and leadership skills. The fellowship programme is continuing to develop, based on feedback from its first successful year.

Early functional and transcriptomic changes in the myocardium predict outcome in a long-term rat model of sepsis.

Myocardial function is depressed in sepsis and is an important prognosticator in the human condition. Using echocardiography in a long-term fluid-resuscitated Wistar rat model of faecal peritonitis we investigated whether depressed myocardial function could be detected at an early stage of sepsis and, if so, whether the degree of depression could predict eventual outcome. At 6 h post-insult, a stroke volume <0.17 ml prognosticated 3-day mortality with positive and negative predictive values of 93 and 80%, respectively. Subsequent fluid loading studies demonstrated intrinsic myocardial depression with poor-prognosis animals tolerating less fluid than either good-prognosis or sham-operated animals. Cardiac gene expression analysis at 6 h detected 527 transcripts significantly up- or down-regulated by the septic process, including genes related to inflammatory and cell cycle pathways. Predicted mortality was associated with significant differences in transcripts of genes expressing proteins related to the TLR2/MyD88 (Toll-like receptor 2/myeloid differentiation factor 88) and JAK/STAT (Janus kinase/signal transducer and activator of transcription) inflammatory pathways, ß-adrenergic signalling and intracellular calcium cycling. Our findings highlight the presence of myocardial depression in early sepsis and its prognostic significance. Transcriptomic analysis in heart tissue identified changes in signalling pathways that correlated with clinical dysfunction. These pathways merit further study to both better understand and potentially modify the disease process.

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: is ketamine a viable induction agent for the trauma patient with potential brain injury.

A short cut review was carried out to establish whether ketamine is a viable induction agent in trauma patients with potential brain injuries. 276 papers were found using the reported searches, of which 5 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that there is no evidence to suggest harm with Ketamine use as induction agent for the patient with potential traumatic brain injury. The drug has major advantages in those patients with associated haemodynamic compromise and should potentially be regarded as the agent of choice.

Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity.

OBJECTIVES: We sought to investigate the clinical-genetic profile of left-dominant arrhythmogenic cardiomyopathy (LDAC). BACKGROUND: In the absence of coronary disease and left ventricular (LV) systolic dysfunction, lateral T-wave inversion and arrhythmia of LV origin are often considered benign. Similarly, chest pain with enzyme release might be attributed to viral myocarditis. We hypothesized that these abnormalities might be manifestations of the "left-dominant" subtype of arrhythmogenic right ventricular cardiomyopathy. METHODS: The 42-patient cohort was established through clinical evaluation of individuals with unexplained (infero)lateral T-wave inversion, arrhythmia of LV origin, and/or proven LDAC/idiopathic myocardial fibrosis in the family. RESULTS: Patients presented from adolescence to age >80 years with arrhythmia or chest pain but not heart failure. Desmosomal mutations were identified in 8 of 24 families (15 of 33 patients). Magnetic resonance findings included LV late-enhancement in a subepicardial/midwall distribution, corresponding to fibrofatty replacement and fibrosis on histopathology. Fifty percent had previously been misdiagnosed with viral myocarditis, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy, or idiopathic ventricular tachycardia. Arrhythmic events included presentation with ventricular fibrillatory arrest in 1 patient and 2 instances of sudden cardiac death during follow-up. CONCLUSIONS: Arrhythmogenic cardiomyopathy is distinguished from DCM by a propensity towards arrhythmia exceeding the degree of ventricular dysfunction. The left-dominant subtype is under-recognized owing to misattribution to other disorders and lack of specific diagnostic criteria. Clinicians are alerted to the possibility of LDAC in patients of any age with unexplained arrhythmia of LV origin, (infero)lateral T-wave inversion, apparent DCM (with arrhythmic presentation), or myocarditis (chest pain and enzyme rise with unobstructed coronary arteries).

Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families.

AIMS: At least 4% of sudden deaths are unexplained at autopsy [sudden arrhythmic death syndrome (SADS)] and a quarter may be due to inherited cardiac disease. We hypothesized that comprehensive clinical investigation of SADS families would identify more susceptible individuals and causes of death. METHODS AND RESULTS: Fifty seven consecutively referred families with SADS death underwent evaluation including resting 12 lead, 24 h and exercise ECG and 2D echocardiography. Other investigations included signal averaged ECG, ajmaline testing, cardiac magnetic resonance imaging, and mutation analysis. First-degree relatives [184/262 (70%)] underwent evaluation, 13 (7%) reporting unexplained syncope. Seventeen (30%) families had a history of additional unexplained premature sudden death(s). Thirty families (53%) were diagnosed with inheritable heart disease: 13 definite long QT syndrome (LQTS), three possible/probable LQTS, five Brugada syndrome, five arrhythmogenic right ventricular cardiomyopathy (ARVC), and four other cardiomyopathies. One SCN5A and four KCNH2 mutations (38%) were identified in 13 definite LQTS families, one SCN5A mutation (20%) in five Brugada syndrome families and one (25%) PKP2 (plakophyllin2) mutation in four ARVC families. CONCLUSION: Over half of SADS deaths were likely to be due to inherited heart disease; accurate identification is vital for appropriate prophylaxis amongst relatives who should undergo comprehensive cardiological evaluation, guided and confirmed by mutation analysis.

Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease.

AIMS: Mutations in the desmoglein-2 (DSG2) gene have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) but clinical information regarding the associated phenotype is at present limited. In this study, we aimed to clinically characterize probands and family members carrying a DSG2 mutation. METHODS AND RESULTS: We investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands. Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Morphological abnormalities of the right ventricle were evident in 66% of gene carriers, left ventricular (LV) involvement in 25%, and classical right precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death/aborted sudden death in 66%. CONCLUSION: Mutations in DSG2 display a high degree of penetrance. Disease expression was of variable severity with LV involvement a prominent feature. The low prevalence of classical ECG changes highlights the need to expand current diagnostic criteria to take account of LV disease, childhood disease expression, and incomplete penetrance.

GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology.

Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by an unstable GAA repeat expansion mutation within intron 1 of the FXN gene. However, the origins of the GAA repeat expansion, its unstable dynamics within different cells and tissues, and its effects on frataxin expression are not yet completely understood. Therefore, we have chosen to generate representative FRDA mouse models by using the human FXN GAA repeat expansion itself as the genetically modified mutation. We have previously reported the establishment of two lines of human FXN YAC transgenic mice that contain unstable GAA repeat expansions within the appropriate genomic context. We now describe the generation of FRDA mouse models by crossbreeding of both lines of human FXN YAC transgenic mice with heterozygous Fxn knockout mice. The resultant FRDA mice that express only human-derived frataxin show comparatively reduced levels of frataxin mRNA and protein expression, decreased aconitase activity, and oxidative stress, leading to progressive neurodegenerative and cardiac pathological phenotypes. Coordination deficits are present, as measured by accelerating rotarod analysis, together with a progressive decrease in locomotor activity and increase in weight. Large vacuoles are detected within neurons of the dorsal root ganglia (DRG), predominantly within the lumbar regions in 6-month-old mice, but spreading to the cervical regions after 1 year of age. Secondary demyelination of large axons is also detected within the lumbar roots of older mice. Lipofuscin deposition is increased in both DRG neurons and cardiomyocytes, and iron deposition is detected in cardiomyocytes after 1 year of age. These mice represent the first GAA repeat expansion-based FRDA mouse models that exhibit progressive FRDA-like pathology and thus will be of use in testing potential therapeutic strategies, particularly GAA repeat-based strategies.