Gut-brain circuits for fat preference.

The perception of fat evokes strong appetitive and consummatory responses1. Here we show that fat stimuli can induce behavioural attraction even in the absence of a functional taste system2,3. We demonstrate that fat acts after ingestion via the gut-brain axis to drive preference for fat. Using single-cell data, we identified the vagal neurons responding to intestinal delivery of fat, and showed that genetic silencing of this gut-to-brain circuit abolished the development of fat preference. Next, we compared the gut-to-brain pathways driving preference for fat versus sugar4, and uncovered two parallel systems, one functioning as a general sensor of essential nutrients, responding to intestinal stimulation with sugar, fat and amino acids, whereas the other is activated only by fat stimuli. Finally, we engineered mice lacking candidate receptors to detect the presence of intestinal fat, and validated their role as the mediators of gut-to-brain fat-evoked responses. Together, these findings reveal distinct cells and receptors that use the gut-brain axis as a fundamental conduit for the development of fat preference.

The gut-brain axis mediates sugar preference.

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste1-3. Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut-brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut-brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, we show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.

Novel mediators of aneurysm progression in bicuspid aortic valve disease.

Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and distal (less dilated) regions of the ascending aorta from five patients with BAV. We identified 180 differentially expressed genes, 40 of which were validated by RT-qPCR. Most genes had roles in inflammation and endothelial cell function including cytokines and growth factors, cell surface receptors and the Activator Protein 1 (AP-1) transcription factor family (FOS, FOSB and JUN) which was chosen for further study. AP-1 was differentially expressed within paired BAV aneurysmal samples (n = 8) but not Marfan patients (n = 5). FOS protein was significantly enriched in BAV aortas compared to normal aortas but unexpectedly, ERK1/2 activity, an upstream regulator of FOS was reduced. ERK1/2 activity was restored when BAV smooth muscle cells were cultured in vitro. An mRNA-miRNA network within paired patient samples identified AP-1 as a central hub of miRNA regulation. FOS knockdown in BAV SMCs increased expression of miR-27a, a stretch responsive miRNA. AP-1 and miR-27a were also dysregulated in a mouse model of aortic constriction. In summary, this study identified a central role for AP-1 signaling in BAV aortic dilatation by using paired mRNA-miRNA patient sample. Upstream analysis of AP-1 regulation showed that the ERK1/2 signaling pathway is dysregulated and thus represents a novel chain of mediators of aortic dilatation in BAV which should be considered in future studies.

Role of WNT/ß-catenin signaling in rejuvenating myogenic differentiation of aged mesenchymal stem cells from cardiac patients.

Autologous stem cell therapy has not been as effective as forecasted from preclinical studies. Patient age was reported as an important contributing factor. The goal of this study was to uncover age-dependent mechanisms of stem cell dysfunction and to investigate possible means to restore the cellular function. Bone marrow mesenchymal stem cells (MSCs) were isolated from cardiovascular patients. Cell proliferation and number of colonies were inversely correlated with patient age. Myogenic differentiation of MSCs in culture was induced with 5-azacytidine. Differentiation correlated with age, with less differentiation in MSCs from aged patients. We performed real-time PCR to identify genes in the WNT/ß-catenin signaling network and found that transcript levels of CTNNB1, LEF1, FZD8, WNT3A, and SFRP4 were negatively correlated with age, whereas FOSL1, LRP6, and FZD6 were positively correlated with age. Protein evaluation showed that ß-catenin nuclear translocation correlated with age and was lower in aged MSCs. Aged MSCs treated with lithium chloride-to increase the bioavailability of ß-catenin-recovered their capacity for myogenic differentiation through myocyte enhancer factor 2C but not with the knockdown of ß-catenin using small-interfering RNA. This study may be the first to relate reduced nuclear ß-catenin bioavailability in MSCs from aged patients. Most important, this abnormality was potentially recoverable, providing a target for improving the function of bone marrow stem cells and their clinical utility in aged patients.

Sparing the Prod: Providing an Alternative to Endomyocardial Biopsies With Noninvasive Surveillance After Heart Transplantation During COVID-19.

Background: The COVID-19 pandemic has reduced access to endomyocardial biopsy (EMB) rejection surveillance in heart transplant (HT) recipients. This study is the first in Canada to assess the role for noninvasive rejection surveillance in personalizing titration of immunosuppression and patient satisfaction post-HT. Methods: In this mixed-methods prospective cohort study, adult HT recipients more than 6 months from HT had their routine EMBs replaced by noninvasive rejection surveillance with gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) testing. Demographics, outcomes of noninvasive surveillance score, hospital admissions, patient satisfaction, and health status on the medical outcomes study 12-item short-form health survey (SF-12) were collected and analyzed, using t tests and χ2 tests. Thematic qualitative analysis was performed for open-ended responses. Results: Among 90 patients, 31 (33%) were enrolled. A total of 36 combined GEP/dd-cfDNA tests were performed; 22 (61%) had negative results for both, 10 (27%) had positive GEP/negative dd-cfDNA results, 4 (11%) had negative GEP/positive dd-cfDNA results, and 0 were positive on both. All patients with a positive dd-cfDNA result (range: 0.19%-0.81%) underwent EMB with no significant cellular or antibody-mediated rejection. A total of 15 cases (42%) had immunosuppression reduction, and this increased to 55% in patients with negative concordant testing. Overall, patients' reported satisfaction was 90%, and on thematic analysis they were more satisfied, with less anxiety, during the noninvasive testing experience. Conclusions: Noninvasive rejection surveillance was associated with the ability to lower immunosuppression, increase satisfaction, and reduce anxiety in HT recipients, minimizing exposure for patients and providers during a global pandemic.

Contexte: La pandémie de COVID-19 a réduit l'accès à la biopsie endomyocardique pour surveiller le risque de rejet après une greffe du cœur. Cette étude est la première à être menée au Canada pour évaluer le rôle de la surveillance non invasive du risque de rejet en personnalisant le titrage de l'immunosuppression et la satisfaction du patient après la greffe cardiaque. Méthodologie: Dans le cadre de cette étude de cohorte prospective à méthodes mixtes, des adultes ayant reçu une greffe cardiaque depuis plus de six mois ont vu leurs biopsies endomyocardiques régulières remplacées par une surveillance non invasive du risque de rejet qui consiste à établir le profil de l'expression génique et à analyser l'ADN acellulaire dérivé du donneur. Les données démographiques, les résultats du score de surveillance non invasive, les admissions à l'hôpital, la satisfaction des patients et l'état de santé tirés du questionnaire SF-12 (questionnaire abrégé sur la santé comprenant 12 items) de l'étude sur les issues médicales ont été colligés et analysés au moyen des tests T et des tests χ2. Les réponses ouvertes ont fait l'objet d'une analyse qualitative thématique. Résultats: Parmi 90 patients, 31 (33 %) ont été recrutés. Au total, 36 tests combinés de profilages de l'expression génique et d'ADN acellulaire dérivé du donneur ont été réalisés; les résultats ont été négatifs pour les deux tests dans 22 cas (61 %), positifs pour le profilage de l'expression génique et négatifs pour l'ADN acellulaire dans 10 cas (27 %), négatifs pour le profilage de l'expression génique et positifs pour l'ADN acellulaire dans quatre cas (11 %) et aucun cas n'a donné de résultats positifs pour les deux types de tests. Tous les patients qui ont donné des résultats positifs à l'analyse de l'ADN acellulaire dérivé du donneur (fourchette : 0,19 % à 0,81 %) ont subi une biopsie endomyocardique n'ayant révélé aucun rejet cellulaire ou à médiation par anticorps important. Au total, 15 cas (42 %) affichaient une immunosuppression réduite, proportion qui a grimpé à 55 % chez les patients dont les tests de concordance ont donné des résultats négatifs. Dans l'ensemble, le niveau de satisfaction rapporté par les patients était de 90 % et, à l'analyse thématique, ils étaient plus satisfaits et moins anxieux pendant les tests non invasifs. Conclusions: La surveillance non invasive du risque de rejet a été associée à la capacité de diminuer l'immunosuppression, d'augmenter la satisfaction et de réduire l'anxiété chez les patients qui ont reçu une greffe cardiaque, en plus de réduire l'exposition des patients et du personnel médical dans le contexte d'une pandémie.

Acupuncture for de Quervain's tenosynovitis: A randomized controlled trial.

BACKGROUND: Acupuncture has been an alternative approach for de Quervain's tenosynovitis (DQt), but trial evidence is still lacking. PURPOSE: This study aimed to assess the efficacy of acupuncture in patients with DQt. STUDY DESIGN: A randomized controlled trial. METHODS: A total of 68 subjects with DQt were recruited from outpatients of Department of Orthopaedics and Traumatology, and Chinese medicine clinics, The University of Hong Kong, and were randomized into the acupuncture group (n = 34) and the waitlist group (n = 34). Subjects in the acupuncture group received 5 acupuncture sessions over 2 weeks, followed by a 10-week follow-up. The waitlist control group received assessments only in the first 6 weeks of the waiting period and received the same acupuncture treatment and follow-up as the treatment group in the next 12 weeks. The primary outcome was the general pain intensity using the Visual Analogue Scale (VAS) at the end of treatment (week 2). Secondary outcomes were grip and pinch strengths of affected hands, the quick Disabilities of the Arm, Shoulder and Hand Score (Q-DASH), and the World Health Organization Quality of Life-brief Questionnaire (WHOQOL-BREF) at weeks 2 and 6. RESULTS: From baseline to 2 weeks, the mean VAS score decreased by 19.5 points in the acupuncture group and by 3.4 points in the waitlist group. The difference for acupuncture vs waitlist control was -16.2 points (95% CI, -26.7 to -5.6, p = 0.003). Acupuncture effects sustained for 10 weeks (mean difference compared with baseline, -30.6; 95% CI, -39.6 to -21.7). Secondary outcomes showed that acupuncture reduced pain intensity, improved grip and pinch strength of affected hands, and Q-DASH scores, but not the scores of WHOQOL-BREF in patients. No serious adverse event occurred during the study period. CONCLUSIONS: Our findings support that 2-week of acupuncture is safe and effective in the reduction of pain intensity, and improvement of strengths and disabilities of hand in DQt patients. Acupuncture also has long-term effects on DQt. TRIAL REGISTRATION: This study was registered at clinicaltrials.gov (NCT03472443).

Remote Mobile Outpatient Monitoring in Transplant (Reboot) 2.0: Protocol for a Randomized Controlled Trial.

BACKGROUND: The number of solid organ transplants in Canada has increased 33% over the past decade. Hospital readmissions are common within the first year after transplant and are linked to increased morbidity and mortality. Nearly half of these admissions to the hospital appear to be preventable. Mobile health (mHealth) technologies hold promise to reduce admission to the hospital and improve patient outcomes, as they allow real-time monitoring and timely clinical intervention. OBJECTIVE: This study aims to determine whether an innovative mHealth intervention can reduce hospital readmission and unscheduled visits to the emergency department or transplant clinic. Our second objective is to assess the use of clinical and continuous ambulatory physiologic data to develop machine learning algorithms to predict the risk of infection, organ rejection, and early mortality in adult heart, kidney, and liver transplant recipients. METHODS: Remote Mobile Outpatient Monitoring in Transplant (Reboot) 2.0 is a two-phased single-center study to be conducted at the University Health Network in Toronto, Canada. Phase one will consist of a 1-year concealed randomized controlled trial of 400 adult heart, kidney, and liver transplant recipients. Participants will be randomized to receive either personalized communication using an mHealth app in addition to standard of care phone communication (intervention group) or standard of care communication only (control group). In phase two, the prior collected data set will be used to develop machine learning algorithms to identify early markers of rejection, infection, and graft dysfunction posttransplantation. The primary outcome will be a composite of any unscheduled hospital admission, visits to the emergency department or transplant clinic, following discharge from the index admission. Secondary outcomes will include patient-reported outcomes using validated self-administered questionnaires, 1-year graft survival rate, 1-year patient survival rate, and the number of standard of care phone voice messages. RESULTS: At the time of this paper's completion, no results are available. CONCLUSIONS: Building from previous work, this project will aim to leverage an innovative mHealth app to improve outcomes and reduce hospital readmission in adult solid organ transplant recipients. Additionally, the development of machine learning algorithms to better predict adverse health outcomes will allow for personalized medicine to tailor clinician-patient interactions and mitigate the health care burden of a growing patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04721288; https://www.clinicaltrials.gov/ct2/show/NCT04721288. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/26816.

Anaphylaxis: assessing patients with allergies.

Adam's assessment identified the presence of the most severe symptoms of anaphylaxis, respiratory difficulty and shock. The actions of the ambulance crew ensured that on arrival at the ED, Adam's condition was improving. However, it was found that despite the interventions already undertaken, Adam was suffering significant respiratory difficulty due to the cascade of events that occur in anaphylaxis. Adam was seen on arrival and the ALSG's (2005) assessment method proved to be the most effective to ensure that Adam was assessed and treated rapidly. The most beneficial aspect of this assignment is that the author can return to practice with this knowledge and will be more confident when faced with other patients with anaphylaxis. Understanding the underlying processes and symptoms has decreased the fear of 'not knowing' and will aid accurate assessment. It will also provide a good basis for educating parents of affected children and members of nursing teams.

Progressive Aortic Dilation Is Regulated by miR-17-Associated miRNAs.

BACKGROUND: Patients with a bicuspid aortic valve (BAV) are at increased risk for progressive aortic dilation associated with extracellular matrix (ECM) degradation by matrix metalloproteinases (MMP). However, the mechanisms responsible for initiating this process are unknown. In the heart, MMP activity is regulated by micro-ribonucleic acid-17 (miR-17)-related downregulation of tissue inhibitors of metalloproteinases (TIMP); a similar process may exist in the aorta. OBJECTIVES: This study sought to ascertain whether aortic matrix degradation in BAV patients progresses by miR-17-related miRNA regulation of TIMP-MMP. METHODS: To eliminate confounding patient-related factors, severely dilated and less dilated aortic tissue samples were collected from 12 BAV patients. Gene and protein expression levels were evaluated in paired tissue samples from the same patient and were compared to aortic samples from 16 patients with aortas that appeared to be normal. RESULTS: Gene expression analyses confirmed increased expression of miR-17-related miRNAs in less dilated compared with severely dilated tissue from the same patient or normal aortic sample. TIMP-1, -2, and -3 were significantly decreased, and MMP2 activity was significantly increased in less dilated samples, suggesting that this normal-looking tissue was in the early stages of ECM degradation. Smooth muscle cells isolated from normal or BAV aortas transfected with an miR-17 mimic had decreased TIMP-1 and -2 expression and increased MMP2 activity, whereas the opposite effects were seen with an miR-17 inhibitor, suggesting that miR-17 may control the TIMP-MMP balance in these tissues. Luciferase reporter assays demonstrated that miR-17 regulated TIMP-1 and -2 expression. CONCLUSIONS: Our in vitro and in vivo studies taken together confirm that miR-17 directly regulates TIMP-1 and -2. Less dilated aortic BAV tissue may be in the initial stages of dilation under the control of miR-17-related miRNAs. New therapies that inhibit these miRNAs may prevent aortic dilation.

The IMPACT-CABG trial: A multicenter, randomized clinical trial of CD133+ stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy.

OBJECTIVES: The IMPACT-CABG trial is the first North American multicenter phase II randomized study of intramyocardial delivery of autologous CD133+ stem cells in patients with chronic ischemic cardiomyopathy undergoing coronary artery bypass grafting. The primary objective was to demonstrate safety, including freedom from major adverse cardiac events. The secondary objective was to evaluate feasibility of same-day autologous cell preparation. Although the trial was not powered to evaluate LV function, exploratory data were collected. METHODS: After 7 open-label patients who received cells, patients randomly received stem cells or placebo (N = 40 total, 20 per center). After completion of coronary anastomoses, up to 10 million CD133+, CD34+, CD45+ triple-positive cells or placebo were injected into the infarct and border zones. Patients were followed up clinically and underwent magnetic resonance imaging preoperatively and after 6 months. RESULTS: There were no procedural complications from bone marrow isolation and cell injection, no in-hospital mortality, and no protocol-related complications. Four patients had transient renal insufficiency, with 1 death during 6-month follow-up. Magnetic resonance imaging revealed that left ventricular volumes and ejection fractions improved in all patients (no difference between groups). CONCLUSIONS: The trial successfully met both primary and secondary objectives, demonstrating that same-day isolation and autologous CD133+ cell delivery with coronary artery bypass grafting is safe and feasible. The positive findings support a larger randomized, multicenter trial, with higher numbers of transplanted cells to demonstrate beneficial effects. The upcoming IMPACT-CABG II trial will evaluate higher cell doses and pharmacologic enhancement to determine whether these cells improve perfusion and myocardial function.

Autologous cell transplantation and a discussion of the implications for nursing practice.

Heart failure is a progressive disorder. An estimated 400,000 Canadians are diagnosed annually with heart failure, and a quarter experience severe heart failure that is unresponsive to medical therapy. Autologous cell transplantation (ACT) has been proposed as a new approach for cardiac repair, and holds enormous potential for the regeneration of injured myocardium cells. This paper explores the nursing implications of ACT. Specifically, the need for ongoing education, the delivery of psychosocial counseling interventions, and ongoing health assessments of the individual will be addressed.

Microplegia during coronary artery bypass grafting was associated with less low cardiac output syndrome: a propensity-matched comparison.

BACKGROUND: Microplegia delivers blood and additives for cardioplegia with minimal crystalloid. We retrospectively compared microplegia with standard 8:1 blood cardioplegia with a propensity-matched analysis in patients undergoing isolated coronary artery bypass graft (CABG) surgery. METHODS: Prospectively collected data for 2,630 consecutive patients who underwent isolated CABG surgery (2004 to 2006) with the exclusive use of microplegia was compared with an equivalent 3-year cohort (1998 to 2000) of 5,058 consecutive isolated CABG patients with the exclusive use of 8:1 diluted blood cardioplegia. Propensity score matching identified 1,980 matched pairs (in each group) for analysis. RESULTS: In the matched groups, the hospital mortality was identical (1.2%). The prevalence of low cardiac output syndrome was significantly (p< 0.001) lower in the later period when microplegia was employed (2.7%) compared with the standard cardioplegia group (5.0%). Although these results may also reflect improvements in care with time, a multivariable logistic regression analysis of the entire cohort (not matched) also demonstrated a twofold independent reduction in low cardiac output syndrome in microplegia patients (odds ratio, 1.9; 95% confidence interval 1.4 to 2.5). CONCLUSIONS: Compared with 8:1 blood cardioplegia, microplegia during isolated CABG surgery was associated with a lower incidence of postoperative low cardiac output syndrome. Microplegia may reduce postoperative cardiac edema, increase buffering, and permit more rapid recovery of ventricular function. Randomized trials are required to determine whether the relationship between microplegia and reduced low output syndrome is causal or is merely an association.

A multicenter prospective randomized trial of a second-generation anastomotic device in coronary artery bypass surgery.

OBJECTIVE: Our objective was to perform a prospective randomized trial to evaluate the clinical and angiographic outcomes of a second-generation anastomotic device used for saphenous vein grafts. METHODS: Patients undergoing nonemergency isolated coronary artery bypass grafting at 3 centers from August 2003 to December 2004 with at least 2 saphenous vein grafts were included. The proximal anastomoses were randomized, within each patient, to be constructed by the connector or by suture. One-year graft patency was evaluated by coronary angiography, magnetic resonance imaging, or computed tomography and analyzed on an intent-to-treat basis. RESULTS: A total of 151 patients (65 +/- 9 years, 87% male) who met inclusion/exclusion criteria were enrolled in the study and were analyzed. A total of 489 grafts were constructed (3.2 +/- 0.5 grafts per patient), including 327 vein grafts randomized to the connector (n = 162) or suture (n = 165). In 162 connector grafts, 151 devices were successfully implanted. Technical issues required explantation of 11 devices intraoperatively. Patency was evaluated in 120 (81%) patients with 260 study grafts. Seventy-four patients with 161 grafts were evaluated by coronary angiography, 31 patients with 69 grafts by magnetic resonance imaging, and 15 patients with 30 grafts by computed tomography. The 1-year patency rate for study grafts constructed with the anastomotic connector was 92.2% (118/128) and for hand-sutured grafts, 91.7% (121/132). CONCLUSIONS: This prospective multicenter randomized controlled trial demonstrated good in-hospital and late clinical outcomes and excellent 1-year patency for vein grafts anastomosed both by the St Jude Medical second-generation aortic connector system and by hand. The patency of the connector grafts did not differ from that of the hand-sutured grafts.