LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Effect of asthma management with exhaled nitric oxide versus usual care on perinatal outcomes.

INTRODUCTION: Asthma exacerbations in pregnancy are associated with adverse perinatal outcomes. We aimed to determine whether fractional exhaled nitric oxide (F ENO)-based asthma management improves perinatal outcomes compared to usual care. METHODS: The Breathing for Life Trial was a multicentre, parallel-group, randomised controlled trial conducted in six hospital antenatal clinics, which compared asthma management guided by F ENO (adjustment of asthma treatment according to exhaled nitric oxide and symptoms each 6-12 weeks) to usual care (no treatment adjustment as part of the trial). The primary outcome was a composite of adverse perinatal events (preterm birth, small for gestational age (SGA), perinatal mortality or neonatal hospitalisation) assessed using hospital records. Secondary outcomes included maternal asthma exacerbations. Concealed random allocation, stratified by study site and self-reported smoking status was used, with blinded outcome assessment and statistical analysis (intention to treat). RESULTS: Pregnant women with current asthma were recruited; 599 to the control group (608 infants) and 601 to the intervention (615 infants). There were no significant group differences for the primary composite perinatal outcome (152 (25.6%) out of 594 control, 177 (29.4%) out of 603 intervention; OR 1.21, 95% CI 0.94-1.56; p=0.15), preterm birth (OR 1.14, 95% CI 0.78-1.68), SGA (OR 1.06, 95% CI 0.78-1.68), perinatal mortality (OR 3.62, 95% CI 0.80-16.5), neonatal hospitalisation (OR 1.24, 95% CI 0.89-1.72) or maternal asthma exacerbations requiring hospital admission or emergency department presentation (OR 1.19, 95% CI 0.69-2.05). CONCLUSION: F ENO-guided asthma pharmacotherapy delivered by a nurse or midwife in the antenatal clinic setting did not improve perinatal outcomes.

Measuring Change in Health Status Over Time (Responsiveness): A Meta-analysis of the SF-36 in Cardiac and Pulmonary Rehabilitation.

OBJECTIVE: The purpose of this meta-analysis is to gather and investigate pooled information on the responsiveness of the main patient outcome measure in cardiac rehabilitation (CR) and pulmonary rehabilitation (PR). The main outcome measure in CR and PR has been found to be the Medical Outcomes Study Short Form-36 health survey (SF-36). DATA SOURCES: A previous systematic effectiveness review of this literature was used as the basis of this statistical analysis, with the bulk of articles being observational studies. STUDY SELECTION: This meta-analysis assessed articles on CR that used SF-36 pre and post "within" (per interventional group) mean scores and in the PR literature that used the SF-36 and the Chronic Respiratory Questionnaire (CRQ) "within" change scores. DATA EXTRACTION: Each group of patients in the chosen literature were taken to represent a single group, so that studies such as randomized controlled trials were listed twice. We undertook a correlation analysis between SF-36 pre and post "within" mean scores in the CR literature. In the PR literature, we undertook a correlation analysis between SF-36 and the CRQ "within" change scores; this involved Spearman correlation coefficients. DATA SYNTHESIS: The SF-36 Mental Composite Score domain is the most responsive of the composite SF-36 domains, with the Physical Composite Score showing less ability to discriminate in the higher SF-36 scores. In the individual domains, Role Emotional scored r=0.52, P≤.001 with only 27% of the variance explained, and Role Physical with r=0.49, P≤.005 had only 24% of the variance explained. In the PR literature Spearman rank correlation coefficient shows that SF-36 Physical Composite Score has a weaker correlation to the CRQ at 0.39 than the SF-36 Mental Composite Score, which was 0.63. CONCLUSIONS: This suggests that the SF-36 is not suited as a pre- to postprogram assessment tool for CR and PR. More studies, however, need to be conducted particularly in CR with regard to the responsiveness of the SF-36.

Depressive and stress symptoms in insomnia patients predict group cognitive-behavioral therapy for insomnia long-term effectiveness: A data-driven analysis.

BACKGROUND: Insomnia Disorder is characterized by high degree of phenotypic heterogeneity, that might influence treatment response. METHODS: 123 of 294 insomnia patients initially recruited (66.7% females, age=40.59±11.89) were assessed before and after group Cognitive-Behavioral Therapy for Insomnia (CBT-I), as well as at follow-up (7.8±1.6 years after the end-of-treatment). By use of latent class analysis (LCA) we identified insomnia subtypes according with baseline scores of insomnia severity and features, anxiety, depression, stress and sleepiness symptoms, circadian rhythm, and treatment effectiveness (Delta score of Insomnia Severity Index-ISI between baseline and end-of-treatment). RESULTS: By LCA we revealed three classes: "PURE INSOMNIA", "INSOMNIA+ANXIETY+DEPRESSION+STRESS", and "INSOMNIA+ANXIETY". The improvements in insomnia severity was maintained up to 10 years after the end-of-treatment, but with differences between classes (p<0.05). Class "INSOMNIA+ANXIETY+DEPRESSION+STRESS" showed at the end-of-treatment the largest percentage of responders (63.5% = Insomnia Severity Index decrease ≥8). However, at follow up the effect was less and 48.1% had a moderate or severe insomnia (Insomnia Severity Index >14). LIMITATIONS: The lack of a control group and the absence of a complete clinical assessment at the follow-up limit the interpretability of our results. CONCLUSIONS: Our data driven analysis suggest insomnia heterogeneity can be categorized into sub-classes by depression, anxiety, and stress symptoms. In addition, insomnia patients with stress and depression symptoms maintained highest percentage of clinical depression at the end-of-treatment and insomnia at follow-up, in comparison with others classes. Stress and depression symptoms should be considered risk factors that play an important role in the long-term outcome of CBT-I.

Decoding Causal Links Between Sleep Apnea and Alzheimer's Disease.

Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are two common chronic diseases with a well-documented association. Whether the association is causal has been highlighted by recent evidence reporting a neurobiological link between these disorders. This narrative review discusses the brain regions and networks involved in OSA as potential vulnerable areas for the development of AD neuropathology with a particular focus on gender-related implications. Using a neuroimaging perspective supported by neuropathological investigations, we provide a new model of neurodegeneration common to OSA and AD, that we have called OSA-AD neurodegeneration in order to decode the causal links between these two chronic conditions.

Risk factors of sleep-disordered breathing in haemodialysis patients.

BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with kidney disease; but often underdiagnosed as it is infrequently assessed in clinical practice. The objective of this study was to assess the risk factors of SDB in haemodialysis patients, and to identify useful assessment tools to detect SDB in this population. METHODS: We used nocturnal oximetry, Epworth Sleepiness Scale (ESS) and STOPBANG questionnaire to screen for SDB in haemodialysis patients. Presence of SDB was defined by Oxygen desaturation index (ODI≥5/h), and further confirmed by apnoea-hypopnea index (AHI) from an in-laboratory polysomnography. Blood samples were collected prior to commencing a haemodialysis treatment. RESULTS: SDB was detected in 70% of participants (N = 107, mean age 67 years). STOPBANG revealed that 89% of participants were at risk of SDB; however, only 17% reported daytime sleepiness on the ESS. Of the participants who underwent polysomnography (n = 36), obstructive sleep apnoea was identified in 86%, and median AHI was 34.5/h. Oximetry and AHI results were positively correlated (r = 0.62, P = 0.0001), as were oximetry and STOPBANG (r = 0.48; P<0.0001), but not ESS (r = 0.19; P = 0.08). Multivariate analysis showed that neck circumference (OR: 1.20; 95% CI: 1.07-1.34; P = 0.02) and haemoglobin (OR: 0.93; 95% CI: 0.88-0.97; P = 0.003) were independently associated with the presence of SDB. CONCLUSION: Dialysis patients with a large neck circumference and anaemia are at risk of SDB; using nocturnal oximetry is practical and reliable to screen for SDB and should be considered in routine management of dialysis patients, particularly for those who demonstrate risk factors.

A Comparative Effectiveness Review: RESPONSIVENESS OF PATIENT OUTCOME MEASURES IN CARDIAC AND PULMONARY REHABILITATION.

BACKGROUND: Cardiac and pulmonary rehabilitation have been shown to reduce the symptoms of disease, as well as reducing health care utilization. To ensure the continuation of these programs, patient outcome measures (POMs) are essential to map treatment effectiveness. This review is a comparative effectiveness literature review of studies with a pre- to post-POM assessment of responsiveness (ie, change in health status over time). METHODS: A quality review of the literature included not only randomized controlled trials but also parallel studies, as well as all observational and retrospective trials. This review included a list of articles and their characteristics; a quality assessment of the literature and a list of POMs utilized in this setting were assessed for responsiveness. RESULTS: There was inconsistency in the literature with the measurement of responsiveness or effect size. The most commonly used POM was the SF-36; however, it was found to be less responsive to change in health status pre- to post-rehabilitation, particularly in the mental domain of this instrument. The most responsive POM in this setting was the Global Mood Scale. CONCLUSION: The surveyed literature found no "gold standard" POM for either cardiac rehabilitation or pulmonary rehabilitation but there was some preference for the disease-specific POMs; however, some of these instruments lose their discriminatory power at the end of the rehabilitation period. This literature review found that a Likert scale is more responsive than a dichotomous scale and that a simple questionnaire is more responsive in a pre- to post-setting than a complex questionnaire.

Cardiac cell-integrated microneedle patch for treating myocardial infarction.

We engineered a microneedle patch integrated with cardiac stromal cells (MN-CSCs) for therapeutic heart regeneration after acute myocardial infarction (MI). To perform cell-based heart regeneration, cells are currently delivered to the heart via direct muscle injection, intravascular infusion, or transplantation of epicardial patches. The first two approaches suffer from poor cell retention, while epicardial patches integrate slowly with host myocardium. Here, we used polymeric MNs to create "channels" between host myocardium and therapeutic CSCs. These channels allow regenerative factors secreted by CSCs to be released into the injured myocardium to promote heart repair. In the rat MI model study, the application of the MN-CSC patch effectively augmented cardiac functions and enhanced angiomyogenesis. In the porcine MI model study, MN-CSC patch application was nontoxic and resulted in cardiac function protection. The MN system represents an innovative approach delivering therapeutic cells for heart regeneration.

Examining the efficacy of a multicomponent m-Health physical activity, diet and sleep intervention for weight loss in overweight and obese adults: randomised controlled trial protocol.

INTRODUCTION: Traditional behavioural weight loss trials targeting improvements in physical activity and diet are modestly effective. It has been suggested that sleep may have a role in weight loss and maintenance. Improving sleep health in combination with physical activity and dietary behaviours may be one strategy to enhance traditional behavioural weight loss trials. Yet the efficacy of a weight loss intervention concurrently targeting improvements in physical activity, dietary and sleep behaviours remains to be tested. METHODS AND ANALYSIS: The primary aim of this three-arm randomised controlled trial is to examine the efficacy of a multicomponent m-Health behaviour change weight loss intervention relative to a waitlist control group. The secondary aims are to compare the relative efficacy of a physical activity, dietary behaviour and sleep intervention (enhanced intervention), compared with a physical activity and dietary behaviour only intervention (traditional intervention), on the primary outcome of weight loss and secondary outcomes of waist circumference, glycated haemoglobin, physical activity, diet quality and intake, sleep health, eating behaviours, depression, anxiety and stress and quality of life. Assessments will be conducted at baseline, 6 months (primary endpoint) and 12 months (follow-up). The multicomponent m-Health intervention will be delivered using a smartphone/tablet 'app', supplemented with email and SMS and individualised in-person dietary counselling. Participants will receive a Fitbit, body weight scales to facilitate self-monitoring, and use the app to access educational material, set goals, self-monitor and receive feedback about behaviours. Generalised linear models using an analysis of covariance (baseline adjusted) approach will be used to identify between-group differences in primary and secondary outcomes, following an intention-to-treat principle. ETHICS AND DISSEMINATION: The Human Research Ethics Committee of The University of Newcastle Australia provided approval: H-2017-0039. Findings will be disseminated via publication in peer-reviewed journals, conference presentations, community presentations and student theses. TRIAL REGISTRATION NUMBER: ACTRN12617000735358; UTN1111-1219-2050.

Cardiac Stem Cell Patch Integrated with Microengineered Blood Vessels Promotes Cardiomyocyte Proliferation and Neovascularization after Acute Myocardial Infarction.

Cardiac stem cell (CSC) therapy has shown preclinical and clinical evidence for ischemic heart repair but is limited by low cellular engraftment and survival after transplantation. Previous versions of the cardiac patch strategy improve stem cell engraftment and encourage repair of cardiac tissue. However, cardiac patches that can enhance cardiomyogenesis and angiogenesis at the injured site remain elusive. Therapies that target cardiomyocyte proliferation and new blood vessel formation hold great potential for the protection against acute myocardial infarction (MI). Here, we report a new strategy for creating a vascularized cardiac patch in a facile and modular fashion by leveraging microfluidic hydrodynamic focusing to construct the biomimetic microvessels (BMVs) that include human umbilical vein endothelial cells (HUVECs) lining the luminal surface and then encapsulating the BMVs in a fibrin gel spiked with human CSCs. We show that the endothelialized BMVs mimicked the natural architecture and function of capillaries and that the resultant vascularized cardiac patch (BMV-CSC patch) exhibited equivalent release of paracrine factors compared to those of coculture of genuine human CSCs and HUVECs after 7 days of in vitro culture. In a rat model of acute MI, the BMV-CSC patch therapy induced profound mitotic activities of cardiomyocytes in the peri-infarct region 4 weeks post-treatment. A significant increase in myocardial capillary density was noted in the infarcted hearts that received BMV-CSC patch treatment compared to the infarcted hearts treated with conventional CSC patches. The striking therapeutic benefits and the fast and facile fabrication of the BMV-CSC patch make it promising for practical applications. Our findings suggest that the BMV-CSC patch strategy may open up new possibilities for the treatment of ischemic heart injury.

Targeted repair of heart injury by stem cells fused with platelet nanovesicles.

Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types.

Long-term clinical effect of group cognitive behavioral therapy for insomnia: a case series study.

OBJECTIVE: Cognitive-behavioral therapy for insomnia (CBT-I) is recognized as the first-choice intervention for insomnia. One of the best-known advantages of CBT-I in comparison with pharmacotherapy is its long-term effect. However, only few studies have assessed its benefits with follow-up periods of longer than three years. In this clinical case series study we aimed to describe the long-term effects of group CBT-I after a mean 7.8 ± 1.6 years of follow-up (range 4-10 years). METHODS: A total of 292 insomnia disorder (ID) patients were consecutively enrolled at the Sleep Disorders Center of San Raffaele Hospital, Milan; 123 patients (82 (66.7%) females and 41 (33.3%) males, mean age 40.59 ± 11.89 years) completed the follow-up evaluation within a range of 4-10 years. RESULTS: In the 258 patients who completed the treatment, insomnia severity index (ISI) total score improved significantly as well as all variables of the sleep diaries. Using ISI as the primary outcome, we demonstrated that the effect of CBT-I is maintained up to 10 years after the end of treatment. Furthermore, we found that patients that used only CBT-I techniques to deal with relapses were the ones with better outcomes, in particular compared to the patients that re-used medications. CONCLUSION: To the best of our knowledge this is the longest follow-up evaluation in the literature, both for group and individual CBT-I. These findings have an important clinical implication both suggesting and confirming that CBT-I can be considered the treatment of choice for insomnia.

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide.

Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart. Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker. Ex vivo targeting was analyzed by incubating organ sections with the CHP exosomes and analyzing with fluorescence microscopy. In vitro assays were performed on neonatal rat cardiomyocytes and H9C2 cells. For the animal study, we utilized an ischemia/reperfusion rat model. Animals were treated with either saline, scramble peptide exosomes, or CHP exosomes 24 h after surgery. Echocardiography was performed 4 h after surgery and 21 d after surgery. At 21 d, animals were sacrificed, and organs were collected for analysis. Results: By conjugating the exosomes with CHP, we demonstrate increased retention of the exosomes within heart sections ex vivo and in vitro with neonatal rat cardiomyocytes. In vitro studies showed improved viability, reduced apoptosis and increased exosome uptake when using CHP-XOs. Using an animal model of ischemia/reperfusion injury, we measured the heart function, infarct size, cellular proliferation, and angiogenesis, with improved outcomes with the CHP exosomes. Conclusions: Our results demonstrate a novel method for increasing delivery of for treatment of myocardial infarction. By targeting exosomes to the infarcted heart, there was a significant improvement in outcomes with reduced fibrosis and scar size, and increased cellular proliferation and angiogenesis.

REM Sleep Behavior Disorder and Alzheimer's Disease: Definitely No Relationship?

Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson's disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease's (AD). Although AD is reported as a possible development in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations.

The Impact of a Weight Loss Intervention on Diet Quality and Eating Behaviours in People with Obesity and COPD.

There is a paucity of evidence to guide clinicians about appropriate management strategies for people with obesity and Chronic Obstructive Pulmonary Disease (COPD). We have recently published results from the first weight loss intervention in adults (>18 years) with obesity (body mass index; BMI ≥ 30 kg/m²) and COPD, using a low-calorie diet coupled with a partial meal replacement plan and resistance exercise training, which resulted in a 6.4% reduction in weight while maintaining skeletal muscle mass and improving health status. This sub-study aims to evaluate the intervention by (a) examining changes in dietary intake and nutritional biomarkers and (b) examining predictors of weight loss. Dietary intake was evaluated using four-day food diaries, and analysis of plasma fatty acids and plasma carotenoids as biomarkers of dietary fat intake and fruit and vegetable intake, respectively. Twenty-eight obese COPD subjects (n = 17 males, n = 11 females) with a mean (standard deviation; SD) age of 67.6 (6.3) years completed the 12-week weight loss intervention. Pre-intervention, mean (SD) BMI was 36.3 (4.6) kg/m². Micronutrient intake improved from pre- to post-intervention, with the percentage of subjects meeting the Nutrient Reference Values increased for all micronutrients. Post-intervention, significant decreases in total (p = 0.009) and saturated fat intake (p = 0.037), and corresponding decreases in total (p = 0.007) and saturated plasma fatty acids (p = 0.003) were observed. There was a trend towards higher total carotenoids post-intervention (p = 0.078). Older age (p = 0.025), higher pre-intervention uncontrolled eating (p < 0.001) and plasma carotenoids (p = 0.009) predicted weight loss. This demonstrates the efficacy of a weight loss intervention in improving diet quality of obese COPD adults.

Intracoronary allogeneic cardiosphere-derived stem cells are safe for use in dogs with dilated cardiomyopathy.

Cardiosphere-derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non-ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c-kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells.

Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome.

Stem cell therapy represents a promising strategy in regenerative medicine. However, cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries immunogenicity and/or tumourigenicity risks. Mounting lines of evidence indicate that stem cells exert their beneficial effects mainly through secretion (of regenerative factors) and membrane-based cell-cell interaction with the injured cells. Here, we fabricate a synthetic cell-mimicking microparticle (CMMP) that recapitulates stem cell functions in tissue repair. CMMPs carry similar secreted proteins and membranes as genuine cardiac stem cells do. In a mouse model of myocardial infarction, injection of CMMPs leads to the preservation of viable myocardium and augmentation of cardiac functions similar to cardiac stem cell therapy. CMMPs (derived from human cells) do not stimulate T-cell infiltration in immuno-competent mice. In conclusion, CMMPs act as 'synthetic stem cells' which mimic the paracrine and biointerfacing activities of natural stem cells in therapeutic cardiac regeneration.

Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): study protocol for a randomised controlled trial.

BACKGROUND: Delirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium. METHODS: This trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72 h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4 mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14 days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep. DISCUSSION: Delirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471 . Registered on 20 December 2015.

A Regenerative Cardiac Patch Formed by Spray Painting of Biomaterials onto the Heart.

Layering a regenerative polymer scaffold on the surface of the heart, termed as a cardiac patch, has been proven to be effective in preserving cardiac function after myocardial infarction (MI). However, the placement of such a patch on the heart usually needs open-chest surgery, which is traumatic, therefore prevents the translation of this strategy into the clinic. We sought to device a way to apply a cardiac patch by spray painting in situ polymerizable biomaterials onto the heart with a minimally invasive procedure. To prove the concept, we used platelet fibrin gel as the "paint" material in a mouse model of MI. The use of the spraying system allowed for placement of a uniform cardiac patch on the heart in a mini-invasive manner without the need for sutures or glue. The spray treatment promoted cardiac repair and attenuated cardiac dysfunction after MI.