Development of a paediatric triage tool for use by pharmacists to aid clinical prioritisation of patients and delivery of pharmaceutical care

Aim To gain consensus from an expert paediatric and neonatal clinical pharmacist panel on criteria to be applied in the design of a triage tool for use in paediatric and neonatal settings. Methods The ‘Delphi Technique’1 was used to identify pharmaceutical care issues, known as criteria, to aid in the prioritisation and targeting of pharmacists’ time to deliver pharmaceutical care to paediatric and neonatal patients. Criteria based ’statements’ based upon the literature2–4 were developed and put into a questionnaire format which was distributed amongst members of the Scottish Neonatal and Paediatric Pharmacy Group (SNAPP). A five point Likert-scale and option for free hand text was used to record responses. Responses were analysed and used to modify subsequent rounds of the Delphi technique. Results 18 criteria were identified for use in the triage tool and were largely characterised upon time of review. Criteria pertaining to daily review included patients prescribed high risk medicines, psychotropic medication, continuous infusions and those with severe, acute kidney injury. Criteria pertaining to 48-hourly review included patients with stable chronic renal failure and mild kidney injury. Criteria for 72-hourly review included stable patients with no acute issues. Conclusion A triage tool to aid pharmaceutical prioritisation in paediatric and neonatal patients has been developed and will be piloted for use in clinical practice

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

BACKGROUND Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (\u3c= 250 mg/m(2)), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin \u3e250 mg/m(2) were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS Thirty-one genes were differentially enriched for variants between case patients and control patients (p \u3c 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 x 10(-15)). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs

Supportive care for older people with frailty in hospital: An integrative review

BACKGROUND: Growing numbers of older people living with frailty and chronic health conditions are being referred to hospitals with acute care needs. Supportive care is a potentially highly relevant and clinically important approach which could bridge the practice gap between curative models of care and palliative care. However, future interventions need to be informed and underpinned by existing knowledge of supportive care. AIM: To identify and build upon existing theories and evidence about supportive care, specifically in relation to the hospital care of older people with frailty, to inform future interventions and their evaluation. DESIGN: An integrative review was used to identify and integrate theory and evidence. Electronic databases (Cochrane Medline, EMBASE and CIHAHL) were searched using the key term 'supportive care'. Screening identified studies employing qualitative and/or quantitative methods published between January 1990 and December 2015. Citation searches, reference checking and searches of the grey literature were also undertaken. DATA SOURCES: Literature searches identified 2733 articles. After screening, and applying eligibility criteria based on relevance to the research question, studies were subject to methodological quality appraisal. Findings from included articles (n=52) were integrated using synthesis of themes. RESULTS: Relevant evidence was identified across different research literatures, on clinical conditions and contexts. Seven distinct themes of the synthesis were identified, these were: Ensuring fundamental aspects of care are met, Communicating and connecting with the patient, Carer and family engagement, Building up a picture of the person and their circumstances, Decisions and advice about best care for the person, Enabling self-help and connection to wider support, and Supporting patients through transitions in care. A tentative integrative model of supportive care for frail older people is developed from the findings. CONCLUSION: The findings and model developed here will inform future interventions and can help staff and hospital managers to develop appropriate strategies, staff training and resource allocation models to improve the quality of health care for older people

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Regulation of fibronectin synthesis by nitric oxide dependent phosphorylation of LC3 and by a map kinase dependent mechanism

grantor: University of TorontoIntimal cushion formation in the fetal ductus arteriosus (DA) requires fibronectin (FN)-dependent smooth muscle cell (SMC) migration. Nitric Oxide (NO) mediates increased FN mRNA translation in DA SMC through phosphorylation and binding of LC3, a microtubule-associated protein, to an AU rich element in the 3' UTR of FN mRNA. To investigate the mechanism whereby NO regulates LC3 phosphorylation, we assessed the influence of kinase inhibitors on FN synthesis. While extracellular signal-regulated kinase inhibition suppressed FN synthesis, this was not related to reduced LC3-mediated FN mRNA translation. We then sought to determine the specific NO-dependent phosphorylation site using an LC3 tagged green fluorescent protein (GFP) construct, transfected into DA SMC. In contrast to the perinuclear and microtubule associated distribution of native LC3, immunofluorescence was observed in vacuoles in LC3-GFP transfected cells and was increased by NO. Western immunoblotting revealed a truncated phosphorylated LC3-GFP, explaining the vacuolar distribution.M.Sc

Upper limb motor training using a Saebo™ orthosis is feasible for increasing task-specific practice in hospital after stroke

Background/aim: Assistive technologies have the potential to increase the amount of movement practice provided during inpatient stroke rehabilitation. The primary aim of this study was to investigate the feasibility of using the Saebo-Flex™ device in a subacute stroke setting to increase task-specific practice for people with little or no active hand movement. The secondary aim was to collect preliminary data comparing hand/upper limb function between a control group that received usual rehabilitation and an intervention group that used, in addition, the Saebo-Flex™ device. Methods: Nine inpatients (mean three months (median six weeks) post-stroke) participated in this feasibility study conducted in an Australian rehabilitation setting, using a randomised pre-test and post-test design with concealed allocation and blinded outcome assessment. In addition to usual rehabilitation, the intervention group received eight weeks of daily motor training using the Saebo-Flex™ device. The control group received usual rehabilitation (task-specific motor training) only. Participants were assessed at baseline (pre-randomisation) and at the end of the eight-week study period. Feasibility was assessed with respect to ease of recruitment, application of the device, compliance with the treatment programme and safety. Secondary outcome measures included the Motor Assessment Scale (upper limb items), Box and Block Test, grip strength and the Stroke Impact Scale. Results: Recruitment to the study was very slow because of the low number of patients with little or no active hand movement. Otherwise, the study was feasible in terms of being able to apply the Saebo-Flex™ device and compliance with the treatment programme. There were no adverse events, and a greater amount of upper limb rehabilitation was provided to the intervention group. While there were trends in favour of the intervention group, particularly for dexterity, no between-group differences were seen for any of the secondary outcomes. Conclusions: This pilot feasibility study showed that the use of assistive technology, specifically the Saebo-Flex™ device, could be successfully used in a sample of stroke patients with little or no active hand movement. However, recruitment to the trial was very slow. The use of the Saebo-FlexTM device had variable results on outcomes, with some positive trends seen in hand function, particularly dexterity

Entrusting Observable Practice Activities and Milestones Over the 36 Months of an Internal Medicine Residency

Purpose Competency-based medical education and milestone reporting have led to increased interest in work-based assessments using entrustment over time as an assessment framework. Little is known about data collected from these assessments during residency. This study describes the results of entrustment of discrete work-based skills over 36 months in the University of Cincinnati internal medicine (IM) residency program. Method Attending physician and peer/allied health assessors provided entrustment ratings of resident performance on work-based observable practice activities (OPAs) mapped to Accreditation Council for Graduate Medicine Education/American Board of Internal Medicine reporting milestones for IM. These data were translated into milestones data and tracked longitudinally. The authors analyzed data from this new entrustment system's first 36 months (July 2012-June 2015). Results During the 36-month period, assessors made 364,728 milestone assessments (mapped from OPAs) of 189 residents. Residents received an annualized average of 83 assessment encounters, producing means of 3,987 milestone assessments and 4,325 words of narrative assessment. Mean entrustment ratings (range 1-5) from all assessors for all milestones rose from 2.46 for first-month residents to 3.92 for 36th-month residents (r(2) = 0.9252, P < .001). Attending physicians' entrustment ratings were lower than peer/allied health assessors' ratings. Medical knowledge and patient care milestones were rated lower than professionalism and interpersonal and communication skills milestones. Conclusions Entrustment of milestones appears to rise progressively over time, with differences by assessor type, competency, milestone, and resident. Further research is needed to elucidate the validity of these data in promotion, remediation, and reporting decisions