Analysis of pressure-activated Piezo1 open and subconductance states at a single channel level.

Mechanically activated Piezo1 channels undergo transitions from closed to open-state in response to pressure and other mechanical stimuli. However, the molecular details of these mechanosensitive gating transitions are unknown. Here, we used cell-attached pressure-clamp recordings to acquire single channel data at steady-state conditions (where inactivation has settled down), at various pressures and voltages. Importantly, we identify and analyze subconductance states of the channel which were not reported before. Pressure-dependent activation of Piezo1 increases the occupancy of open and subconductance state at the expense of decreased occupancy of shut-states. No significant change in the mean open time of subconductance states was observed with increasing negative pipette pressure or with varying voltages (ranging from -40 to -100 mV). Using Markov-chain modeling, we identified a minimal four-states kinetic scheme, which recapitulates essential characteristics of the single channel data, including that of the subconductance level. This study advances our understanding of Piezo1-gating mechanism in response to discrete stimuli (such as pressure and voltage) and paves the path to develop cellular and tissue level models to predict Piezo1 function in various cell types.

Unravelling the Mechanism of Elastin-like Polypeptide-Enzyme Fusion Stabilization in Organic Solvents.

Elastin-like polypeptides (ELP) are a class of materials that are widely used as purification tags and in potential therapeutic applications. We have used the hydrophobic nature of ELP to extract them into organic solvents and precipitate them to obtain highly pure materials. Although many different types of ELP have been rapidly purified in this manner, the underlying mechanism for this process and its ability to retain functional proteins within organic phase-rich media has been unclear. A cleavable ELP-Intein construct fused with the enzyme chorismate mutase (ELP-I-Cm2) was used to better understand the organic solvent extraction process for ELP and the factors impacting the retention of enzyme activity. Our extraction studies indicated that a cell lysis step was essential to stabilize the ELP-I-Cm2 in the organic phase, prevent intein cleavage, and extract the fusion protein with high efficiency and retained activity. Circular dichroism and infrared spectroscopic characterization of ELP-I-Cm2 in organic solvents and aqueous solutions of the extracted and precipitated material indicated that the ELP secondary structure was retained in both environments. Atomic force microscopy and negative stain transmission electron microscopy imaging of ELP-I-Cm2 in organic solvents revealed highly regular circular features that were ∼50 nm in diameter, in contrast to larger (>100 nm) irregular features found in aqueous solutions. Since reverse micelles have often been used in catalytic processes, we evaluated the enzymatic activity of the ELP-I-Cm2 reversed micelles in different organic solvent mixtures and found that Cm2-mediated reactions in organic media were of comparable rate and efficiency to those in aqueous media. Based on these findings, we report an exciting new opportunity for ELP-enzyme fusion applications by exploiting their ability to form catalytically active reverse micelles in organic media.

Transitional Care in Patients With Hirschsprung Disease: Those Left Behind.

BACKGROUND: The long-term effects of Hirschsprung disease are clinically variable. An improved understanding of challenges patients may face as adults can help inform transitional care management. OBJECTIVE: To explore the outcomes and transitional care experiences in adult patients with Hirschsprung. DESIGN: Cohort study. SETTING: Single center. PATIENTS: All patients treated for Hirschsprung between 1977 and 2001 (aged older than 18 years at the time of survey distribution in July 2018-2019). Eligible patients were sent validated multidomain surveys and qualitative questions regarding their transitional care. MAIN OUTCOME MEASURES: Status of transitional care, bowel function, and quality-of-life assessment. Qualitative analysis of transitional care experience. RESULTS: Of 139 patients, 20 had received transition care (10 had at least 1 visit but had been discharged and 10 were receiving ongoing follow-up). These patients had inferior bowel function and quality-of-life scores at follow-up. Twenty-three patients (17%) had issues with soiling at the time of discharge, and 7 patients received transitional care. Of these 23 patients, 9 (39%) had a normal Bowel Function Score (17 or more), 5 (22%) had a poor score (less than 12), and 1 had since had a stoma formation. Eighteen patients (13%) had active moderate-severe issues related to bowel function, only 5 had been transitioned, and just 2 remained under ongoing care. Importantly, when these patients were discharged from our pediatric center, at a median age of 14 (interquartile range, 12-16) years, 10 of 17 patients had no perceptible bowel issues, suggesting a worsening of function after discharge. LIMITATIONS: The retrospective design and reliance on clinical notes to gather information on discharge status as well as patient recall of events. CONCLUSIONS: There remains a small but significant proportion of Hirschsprung patients for whom bowel function either remains or becomes a major burden. These results support a need to better stratify patients requiring transitional care and ensure a clear route to care if their status changes after discharge. See Video Abstract . ATENCIN DE TRANSICIN EN PACIENTES CON ENFERMEDAD DE HIRSCHSPRUNG, LOS QUE SE QUEDAN ATRS: ANTECEDENTES:Los efectos a largo plazo de la enfermedad de Hirschsprung son clínicamente variables. Una mejor comprensión de los desafíos que los pacientes pueden enfrentar cuando sean adultos puede ayudar a informar la gestión de la atención de transición.OBJETIVO:Explorar los resultados y las experiencias de atención de transición en pacientes adultos con Hirschsprung.DISEÑO:Estudio de cohorte.AJUSTE:Unico centro.PACIENTES:Todos los pacientes tratados por Hirschsprung 1977-2001 (edad >18 años en el momento de la encuesta, Julio de 2018-2019). A los pacientes elegibles se les enviaron encuestas multidominio validadas, así como preguntas cualitativas sobre su atención de transición.PRINCIPALES MEDIDAS DE RESULTADOS:Estado de la atención de transición, función intestinal y evaluación de la calidad de vida. Análisis cualitativo de la experiencia de cuidados transicionales.RESULTADOS:De 139 pacientes, 20 habían recibido atención de transición (10 tuvieron al menos una visita pero habían sido dados de alta y 10 estaban recibiendo seguimiento continuo). Estos pacientes tenían puntuaciones inferiores de función intestinal y calidad de vida en el seguimiento. Veintitrés (17%) pacientes tuvieron problemas para ensuciarse en el momento del alta y 7 recibieron atención de transición. De estos, 9/23 (39%) tenían una puntuación de función intestinal normal (≥17), 5/23 (22%) tenían una puntuación baja (<12) y un paciente había tenido desde entonces una formación de estoma. Dieciocho (13%) pacientes tenían problemas activos de moderados a graves relacionados con la función intestinal, solo cinco habían realizado la transición y solo 2 permanecían bajo atención continua. Es importante destacar que cuando estos pacientes fueron dados de alta de nuestro centro pediátrico, a una edad promedio de 14 [RIQ 12-16] años, 10/17 no tenían problemas intestinales perceptibles, lo que sugiere un empeoramiento de la función después del alta.LIMITACIONES:El diseño retrospectivo y la dependencia de notas clínicas para recopilar información sobre el estado del alta, así como el recuerdo de los eventos por parte del paciente.CONCLUSIÓN:Sigue existiendo una proporción pequeña pero significativa de pacientes con Hirschsprung para quienes la función intestinal permanece o se convierte en una carga importante. Estos resultados respaldan la necesidad de estratificar mejor a los pacientes que requieren atención de transición y garantizar una ruta clara hacia la atención si su estado cambia después del alta. ( Traducción-Dr. Yesenia Rojas-Khalil ).

Prevention and Rehabilitation After Heart Transplantation: A Clinical Consensus Statement of the European Association of Preventive Cardiology, Heart Failure Association of the ESC, and the European Cardio Thoracic Transplant Association, a Section of ESOT.

Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.

Psychological interventions for depression and anxiety in patients with coronary heart disease, heart failure or atrial fibrillation.

BACKGROUND: Depression and anxiety occur frequently (with reported prevalence rates of around 40%) in individuals with coronary heart disease (CHD), heart failure (HF) or atrial fibrillation (AF) and are associated with a poor prognosis, such as decreased health-related quality of life (HRQoL), and increased morbidity and mortality. Psychological interventions are developed and delivered by psychologists or specifically trained healthcare workers and commonly include cognitive behavioural therapies and mindfulness-based stress reduction. They have been shown to reduce depression and anxiety in the general population, though the exact mechanism of action is not well understood. Further, their effects on psychological and clinical outcomes in patients with CHD, HF or AF are unclear. OBJECTIVES: To assess the effects of psychological interventions (alone, or with cardiac rehabilitation or pharmacotherapy, or both) in adults who have a diagnosis of CHD, HF or AF, compared to no psychological intervention, on psychological and clinical outcomes. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL databases from 2009 to July 2022. We also searched three clinical trials registers in September 2020, and checked the reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing psychological interventions with no psychological intervention for a minimum of six months follow-up in adults aged over 18 years with a clinical diagnosis of CHD, HF or AF, with or without depression or anxiety. Studies had to report on either depression or anxiety or both. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were depression and anxiety, and our secondary outcomes of interest were HRQoL mental and physical components, all-cause mortality and major adverse cardiovascular events (MACE). We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: Twenty-one studies (2591 participants) met our inclusion criteria. Sixteen studies included people with CHD, five with HF and none with AF. Study sample sizes ranged from 29 to 430. Twenty and 17 studies reported the primary outcomes of depression and anxiety, respectively. Despite the high heterogeneity and variation, we decided to pool the studies using a random-effects model, recognising that the model does not eliminate heterogeneity and findings should be interpreted cautiously. We found that psychological interventions probably have a moderate effect on reducing depression (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.65 to -0.06; 20 studies, 2531 participants; moderate-certainty evidence) and anxiety (SMD -0.57, 95% CI -0.96 to -0.18; 17 studies, 2235 participants; moderate-certainty evidence), compared to no psychological intervention. Psychological interventions may have little to no effect on HRQoL physical component summary scores (PCS) (SMD 0.48, 95% CI -0.02 to 0.98; 12 studies, 1454 participants; low-certainty evidence), but may have a moderate effect on improving HRQoL mental component summary scores (MCS) (SMD 0.63, 95% CI 0.01 to 1.26; 12 studies, 1454 participants; low-certainty evidence), compared to no psychological intervention. Psychological interventions probably have little to no effect on all-cause mortality (risk ratio (RR) 0.81, 95% CI 0.39 to 1.69; 3 studies, 615 participants; moderate-certainty evidence) and may have little to no effect on MACE (RR 1.22, 95% CI 0.77 to 1.92; 4 studies, 450 participants; low-certainty evidence), compared to no psychological intervention. AUTHORS' CONCLUSIONS: Current evidence suggests that psychological interventions for depression and anxiety probably result in a moderate reduction in depression and anxiety and may result in a moderate improvement in HRQoL MCS, compared to no intervention. However, they may have little to no effect on HRQoL PCS and MACE, and probably do not reduce mortality (all-cause) in adults who have a diagnosis of CHD or HF, compared with no psychological intervention. There was moderate to substantial heterogeneity identified across studies. Thus, evidence of treatment effects on these outcomes warrants careful interpretation. As there were no studies of psychological interventions for patients with AF included in our review, this is a gap that needs to be addressed in future studies, particularly in view of the rapid growth of research on management of AF. Studies investigating cost-effectiveness, return to work and cardiovascular morbidity (revascularisation) are also needed to better understand the benefits of psychological interventions in populations with heart disease.

Influence of soundboard modelling approaches on piano string vibration.

This work explores the influence of the dynamics of the piano soundboard on string vibration and on the force acting between the vibrating string and the bridge. Four different soundboard representations of different complexities are considered: (i) a finite element model that considers the complete dynamic behavior of the soundboard at the connection point with the string within the frequency range of interest, (ii) a reduced modal model containing only five modes, (iii) a Kelvin-Voigt system characterized by an equivalent stiffness and damping, and (iv) a rigid soundboard represented by a simply supported boundary condition. The connection between the string and the soundboard is modelled by coupling a simply supported stiff string model with the different representations of the soundboard through a contact stiffness. As well as directly accounting for the string-soundboard coupling, this approach also includes the duplex scaling segment. The latter can be left to vibrate freely or muted with a continuous distribution of dampers. Although the simplest soundboard representation is not dissimilar from the other more complex models, the dynamics of the soundboard affect the decay time of the note, the force transmitted to it, and the vibration of the radiating surface of the soundboard.

Exploring perceptions of what increased gender diversity might bring to the nursing profession.

AIMS: To explore university nursing students and academic staff's perceptions of what increased gender diversity might bring to the nursing profession. DESIGN: An exploratory study with students and academic staff from two university nursing schools. METHODS: Students and staff in two university nursing schools were invited to participate in an anonymous online survey (October-November 2022). The survey focused on gender diversity within nursing and patient care, asking respondents about existing barriers to gender diversity and inviting ideas on increasing gender diversity within nursing. The survey findings helped inform questions, which were used to further explore views and thoughts of gender diversity within nursing through semi-structured one-to-one interviews (January-February 2023). RESULTS: Nearly, two-thirds (64%, n = 69) of survey respondents strongly agreed/agreed that the lack of gender diversity in nursing negatively impacted delivering care to a gender-diverse society. Most (84%, n = 90) strongly agreed/agreed that increased gender diversity within the nursing workforce would positively contribute to nursing. Three-quarters (75%, n = 74) strongly agreed/agreed that working with a more gender-diverse nursing workforce would enrich their experience as a nurse. Three themes emerged from the interview data: shared stereotypes; improved care through knowledge, better relations and the presence of a gender-diverse workforce; a culture of welcome: suggested changes for the future. CONCLUSION: Most of those who participated in the study believe there are benefits to be gained from greater gender diversity within nursing. This study provides insight into the lack of gender diversity in the nursing environment, highlights how this might impact patient care and suggests actions to make nursing a more inclusive profession. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Practical solutions were suggested, including the greater visibility of trans and non-binary persons in advertisement and recruitment campaigns to ensure nursing is viewed as a career choice for "all". Including a space for considered pronouns on university application forms, hospital documentation and name badges. Gender-neutral titles and uniforms should be considered for all nursing staff, and more gender-neutral toilets should be made available for staff and patients in university and hospital settings. IMPACT: This study addressed the lack of gender diversity in nursing and explored what an increase in gender diversity might bring to the nursing profession. The main findings were: (i) Less than a tenth (9%, n = 12) of respondents described their team of colleagues as being "extremely gender diverse". (ii) Most (84%, n = 90) strongly agreed/agreed that increased gender diversity within the nursing workforce would be a positive attribute to nursing. (iii) Three-quarters 75% (n = 74) strongly agreed/agreed that working with a more gender-diverse nursing workforce would enrich their experience as a nurse. (iv) Many stereotypes still exist in nursing and tackling them is important to make the profession more inclusive. (v) A nurse's gender can impact the care they provide. (vi) A more gender-diverse workforce would better reflect the population it serves. (vii) This research will have an impact on the nursing profession globally. REPORTING METHOD: The consolidated criteria for reporting qualitative studies (COREQ) was used as a guide throughout data collection and analysis. PATIENT OR PUBLIC CONTRIBUTION: Every step of the study, including the survey and interview schedule, was co-constructed using an iterative approach with service users, students and staff who had personal experience of gender diversity and were a core part of the study team.

Clinical and demographic moderators of self-care and hospitalizations in pre-coronary artery bypass grafting patients: A cross-sectional study.

AIM: To examine the influence of clinical and demographic factors on self-care behaviour and hospitalization rates among patients with coronary heart disease awaiting coronary artery bypass grafting. BACKGROUND: Appropriate self-care behaviour can improve the management of patients with coronary heart disease and reduce hospitalization rates among those awaiting coronary artery bypass graft surgery. However, little is known about the influence of clinical and demographic factors on self-care or hospitalizations in this population. DESIGN: A cross-sectional study. METHODS: A convenience sample of 99 participants diagnosed with coronary heart disease awaiting coronary artery bypass grafting surgery were recruited from an outpatient clinic of a public tertiary hospital in southern Thailand. Data were collected on clinical (left ventricular ejection fraction, symptom severity and comorbid disease) and demographic (age, education level and marital status) factors, self-care behaviour and hospitalization rates. Path analysis using LISREL was performed to examine the influence of self-care on hospitalizations, with clinical and demographic factors as moderators. RESULTS: Path analysis showed that clinical and demographic factors accounted for nearly half of the variance (46%) in self-care, and that self-care accounted for nearly half of the variance (48%) in hospitalization rates. CONCLUSION: Our findings demonstrate that clinical and demographic factors play an important role in self-care behaviour, and in turn hospitalization rates of pre-coronary artery bypass graft surgery patients. It is suggested that the period pre-surgery is an ideal time to introduce programmes designed to bolster self-care and minimize uncertainty among this patient population and that nurses are well-positioned to do so. REPORTING METHOD: Study methods and results reported in adherence to the STROBE checklist. PATIENT OR PUBLIC CONTRIBUTION: Patients contributed their consent, time and data to the study.

Methods optimization for the expression and purification of human calcium calmodulin-dependent protein kinase II alpha.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a complex multifunctional kinase that is highly expressed in central nervous tissues and plays a key regulatory role in the calcium signaling pathway. Despite over 30 years of recombinant expression and characterization studies, CaMKII continues to be investigated for its impact on signaling cooperativity and its ability to bind multiple substrates through its multimeric hub domain. Here we compare and optimize protocols for the generation of full-length wild-type human calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα). Side-by-side comparison of expression and purification in both insect and bacterial systems shows that the insect expression method provides superior yields of the desired autoinhibited CaMKIIα holoenzymes. Utilizing baculovirus insect expression system tools, our results demonstrate a high yield method to produce homogenous, monodisperse CaMKII in its autoinhibited state suitable for biophysical analysis. Advantages and disadvantages of these two expression systems (baculovirus insect cell versus Escherichia coli expression) are discussed, as well as purification optimizations to maximize the enrichment of full-length CaMKII.

Neurovascular complications post bronchial artery embolisation in patients with cystic fibrosis. A 7-year single centre retrospective review.

Bronchial artery embolisation (BAE) is a treatment used to manage haemoptysis. We performed a 7-year review of BAE procedures for haemoptysis at our CF centre aiming to evaluate the incidence and outcomes of patients with neurovascular complications post-BAE. Our review suggests that whilst BAE is an effective method for controlling life-threatening haemoptysis, patients are at risk of developing neurovascular complications with long term residual symptoms, and therefore careful consideration should be given in offering BAE, especially to otherwise well patients with chronic small volume haemoptysis and managing teams should have a low threshold to image symptomatic patients.

Benefit-Risk Assessment of mRNA COVID-19 Vaccines in Children Aged 6 Months to 4 Years in the Omicron Era.

BACKGROUND: There is no risk and benefit assessment of COVID-19 vaccination for children younger than 5 years using a single health outcomes scale. The objective of this study is to compare the expected risk and benefits of the mRNA primary series of COVID-19 vaccines for children aged 6 months to 4 years in the United States using a single health outcome scale in the Omicron era. METHODS: The expected benefits and risks of the primary two-dose series of mRNA COVID-19 vaccines for children aged 6 months to 4 years were stratified by sex, the presence of underlying medical conditions, the presence of infection-induced immunity, and the type of mRNA vaccine (BNT162b2 or mRNA-1273). A scoping literature review was conducted to identify the indicators in the decision tree model. The benefit-risk ratio was the outcome of interest. RESULTS: The benefit-risk ratios ranged from 200.4 in BNT162b2 for males aged 6-11 months with underlying medical conditions and without infection-induced immunity to 3.2 in mRNA-1273 for females aged 1-4 years without underlying medical conditions and with infection-induced immunity. CONCLUSIONS: The expected benefit of receiving the primary series of mRNA vaccines outweighed the risk among children ages 6 months to 4 years regardless of sex, presence of underlying medical conditions, presence of infection-induced immunity, or type of mRNA vaccines. However, the continuous monitoring of the COVID-19 epidemiology as well as vaccine effectiveness and safety is important.

International guideline comparison of lifestyle management for acute coronary syndrome and type 2 diabetes mellitus: A rapid review.

Acute coronary syndrome (ACS) is a life-threatening condition, with ACS-associated morbidity and mortality causing substantial human and economic challenges to the individual and health services. Due to shared disease determinants, those with ACS have a high risk of comorbid Type 2 diabetes mellitus (T2DM). Despite this, the two conditions are managed separately, duplicating workload for staff and increasing the number of appointments and complexity of patient management plans. This rapid review compared current ACS and T2DM guidelines across Australia, Canada, Europe, Ireland, New Zealand, the UK, and the USA. Results highlighted service overlap, repetition, and opportunities for integrated practice for ACS-T2DM lifestyle management across diet and nutrition, physical activity, weight management, clinical and psychological health. Recommendations are made for potential integration of ACS-T2DM service provision to streamline care and reduce siloed care in the context of the health services for ACS-T2DM and similar comorbid conditions.

Accuracy of a Continuous Glucose Monitor in the Intensive Care Unit: A Proposed Accuracy Standard and Calibration Protocol for Inpatient Use.

Background and Aims: Guidelines now recommend inpatient continuous glucose monitor (CGM) use with confirmatory blood glucose measurements. However, the Food and Drug Administration has not yet officially approved CGM for inpatient use in large part because its accuracy has not been established in this setting. We tested the accuracy of the Dexcom G6 (G6) in 28 adults on an insulin infusion in a medical-surgical intensive care unit with 1064 matched CGM and arterial point-of-care pairs. Methods: The participants were on average 57.29 (SD 2.39) years, of whom 13 had a prior diagnosis of diabetes and 14 were admitted for a surgical diagnosis. The first 19 participants received the G6 without calibration and had a mean absolute relative difference (MARD) of 13.19% (IQR 5.11, 19.03) across 659 matched pairs, which just meets the critical care expert recommendation of MARD <14%. We then aimed to improve accuracy for the subsequent 9 participants using a calibration protocol. Results: The MARD for calibrated participants was 9.65% (3.03, 13.33), significantly lower than for uncalibrated participants (P < 0.001). Calibration also demonstrated excellent safety with 100% of values within the Clarke Error Grid zones A and B compared with 99.07% without calibration. Our protocol achieved the lowest MARD and safest CEG profile in the critical care setting and well exceeds the critical care expert recommendations. Our large sample of heterogenous critically ill patients also reached comparable accuracy to the MARD of 9% for G6 in outpatients. We believe our calibration protocol will allow G6 to be used with sufficient accuracy in inpatients.

What do patients want from a digital device that supports heart failure self-management?

OBJECTIVE: To assess patients' needs and the factors determining their acceptance of an e-Health intervention. METHODS: Purposive sample of patients with heart failure, attending an outpatient consultation were invited to complete a questionnaire designed to assess their needs and acceptance of an e-Health intervention. Data analysis was performed using Chi-square tests with post-hoc corrections. RESULTS: Response rate was 61 % (n = 101), with most patients (>70 %) indicating they could see themselves using an e-Health intervention to manage their heart failure. Participants with a healthy lifestyle (i.e., non-smoker and consumed alcohol < once/week) were more likely to have a positive attitude towards technology (p adj.=0.013). Those willing to use an e-Health intervention were convinced of its advantages by other patients with heart failure (p adj.=0.013). Advanced age, education level, employment or marital status did not influence patient attitudes toward health technology. CONCLUSIONS & PRACTICE IMPLICATIONS: Results indicate patients have a positive attitude towards the use of e-Health interventions to enable their self-management of heart failure. These findings will inform further development and delivery strategies of e-Health interventions.

Inhibition of Vascular Smooth Muscle Cell Proliferation by ENPP1: The Role of CD73 and the Adenosine Signaling Axis.

The Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) ectoenzyme regulates vascular intimal proliferation and mineralization of bone and soft tissues. ENPP1 variants cause Generalized Arterial Calcification of Infancy (GACI), a rare genetic disorder characterized by ectopic calcification, intimal proliferation, and stenosis of large- and medium-sized arteries. ENPP1 hydrolyzes extracellular ATP to pyrophosphate (PPi) and AMP. AMP is the precursor of adenosine, which has been implicated in the control of neointimal formation. Herein, we demonstrate that an ENPP1-Fc recombinant therapeutic inhibits proliferation of vascular smooth muscle cells (VSMCs) in vitro and in vivo. Addition of ENPP1 and ATP to cultured VSMCs generated AMP, which was metabolized to adenosine. It also significantly decreased cell proliferation. AMP or adenosine alone inhibited VSMC growth. Inhibition of ecto-5'-nucleotidase CD73 decreased adenosine accumulation and suppressed the anti-proliferative effects of ENPP1/ATP. Addition of AMP increased cAMP synthesis and phosphorylation of VASP at Ser157. This AMP-mediated cAMP increase was abrogated by CD73 inhibitors or by A2aR and A2bR antagonists. Ligation of the carotid artery promoted neointimal hyperplasia in wild-type mice, which was exacerbated in ENPP1-deficient ttw/ttw mice. Prophylactic or therapeutic treatments with ENPP1 significantly reduced intimal hyperplasia not only in ttw/ttw but also in wild-type mice. These findings provide the first insight into the mechanism of the anti-proliferative effect of ENPP1 and broaden its potential therapeutic applications beyond enzyme replacement therapy.

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301).

PURPOSE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. PATIENTS AND METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. CONCLUSION: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .

Heart failure in nursing homes: A scoping review of educational interventions for optimising care provision.

Background: Heart failure has an estimated global prevalence of 64.3 million cases, with an average age of a person living with heart failure at 75.2 years. Approximately 20% of residents living in nursing homes (a long-term residential care environment for some individuals) report living with heart failure. Residents living with heart failure in nursing home environments are often frail, have reduced quality of life, higher rates of rehospitalisation and mortality, and greater complications in heart failure management. Further, nursing home staff often lack the knowledge and skills required to provide the necessary care for those living with heart failure. Interventions for improving heart failure management in nursing homes have proven effective, yet there is a lack of understanding regarding interventions for optimising care provision. The aim of this review was to synthesise the current evidence on educational interventions to optimise care provided to people with heart failure in nursing homes. Methods: A scoping review with four databases searched: Medline, CINAHL, Web of Science, and EMBASE. Relevant reference lists were searched manually for additional records. Studies of nursing home staff or resident outcomes associated with changes in care provision (i.e., resident quality of life, staff knowledge of heart failure) were included. Results from the charting data process were collated into themes: intervention outcomes, changes to practice, and implementation and process evaluation. Results: Seven papers were deemed eligible for inclusion. Most studies (n=6) were comprised of nursing home staff only, with one comprised only of residents. Study aims were to improve heart failure knowledge, interprofessional communication, heart failure assessment and management. Positive changes in staff outcomes were observed, with improvements in knowledge, self-efficacy, and confidence in providing care reported. No difference was reported concerning nursing home resident outcomes. Interprofessional communication and staff ability to conduct heart failure assessments improved post-intervention. Changes to practice were mixed, with issues around sustainability reported. Nursing home staff highlighted their appreciation towards receiving education, recommending that videos, images, and humour could improve the intervention content. Conclusions: There is a paucity of evidence around educational interventions to support residents living with heart failure in nursing homes. However, available evidence suggests that educational interventions in nursing homes may improve care through improving staff self-efficacy and confidence in providing care, heart failure knowledge and interprofessional communication. The complexity of implementing educational interventions in the nursing home setting must be considered during the development process to improve implementation, effectiveness, and sustainability.