Foundation Center Research Articles

A4 A FRAMEWORK TO STUDY INFLAMMATORY BOWEL DISEASE AMONG INDIGENOUS PEOPLES AND PRELIMINARY RESULTS FROM SASKATCHEWAN, CANADA

Abstract Background Inflammatory Bowel Disease (IBD) is a chronic condition with significant life-threatening disease-related complications and reductions in quality of life if left untreated. Despite available research about IBD in the general population, there is limited-to-no evidence about IBD among Indigenous peoples in Canada and around the world. Aims We aimed to define a collaborative framework, estimate the prevalence and incidence rates of IBD among First Nations in Saskatchewan, Canada, and explore perceptions of IBD among Indigenous peoples in the province. Methods This study began when Indigenous patients shared their health experiences with IBD with research team members. An interdisciplinary research team was formed including Indigenous patient and family advocates (IPFAs, Indigenous patients living with IBD and parents of an Indigenous person with IBD), an IBD gastroenterologist, knowledge users, and Indigenous and non-Indigenous researchers. Our research team committed to raise awareness of IBD among Indigenous peoples within Indigenous communities and among health care providers and to advocate for better healthcare and well-being by providing evidence of IBD among Indigenous peoples living with IBD in Saskatchewan. We defined a mixed methodology. The first phase of the study used Saskatchewan administrative health data to estimate the prevalence and incidence rates with 95% confidence intervals (95%CI) of IBD among First Nations. The second phase of the study will use a photovoice methodology to gather “the voices” of Indigenous peoples with IBD, encouraging self-interpretation of pictures, engaging their communities, and empowering them with the study findings. Results The IPFAs play a critical role in the project by sharing their experiences and defining the directions of the project, as well as defining our research framework (Figure 1). Preliminary results show that the prevalence of IBD among First Nations in Saskatchewan increased from 66 (95%CI 65–68) per 100,000 population in 1999 to 148 (95%CI 145–151) per 100,000 people in 2015. In contrast, the incidence rates appear to be stable over time, 11/100,000 (95%CI 4–24) in 1999 and 11/100,000 (95%CI 5–20) in 2015. We started recruiting participants for the photovoice study in September 2019. Conclusions This ground-breaking patient-driven study is the first stage to improve health among Indigenous peoples living with IBD in Saskatchewan. This project will generate community-engaged knowledge and expertise to inform the development of an Indigenous IBD framework that could promote better and knowledge-based healthcare for Indigenous peoples with IBD in Canada and worldwide. Funding Agencies CIHRSaskatchewan Health Research Foundation (SHRF) and Saskatchewan Centre for Patient-Oriented Research (SCPOR)

Informal education of specialists working with at-risk teenagers at the facility of the “Compass” day center of the Kharkiv charity foundation “Blago”

This article reveals the problem of continuous training of specialists for work with children at risk, a growing number of which in Ukraine is caused, in particular, by the increase in social risks, caused by the socio-economic instability, uncontrolled population movements in the absence of effective mechanisms for regulation of migration processes in the interests of national development, a high level of external labor migration of the adult population, reduced educational potential of the family and other social institutions; publishes, develops, and implements at the facility of the day center Compass Kharkiv Charitable Foundation Blago the system of organizational-methodical and resource support for the training of specialists to provide quality and timely services to adolescent drug users.This article aims to show the effectiveness of the use of modern forms of training specialists in juvenile probation, juvenile prevention, school police officers, teachers and specialists of social-pedagogical service of educational institutions on the example of preparation of specialists to work with at-risk adolescents at the day center Compass Kharkiv Charitable Foundation Blago. Regarding professional development, the team of authors does not have in mind the legal term, but the general increase of the level of knowledge and skills in working with adolescents at risk by professionals, engaged in educational, preventive activities or carrying out social support of adolescents in difficult life circumstances. The creation of such a flexible and sustainable lifelong education, providing advanced training not only to specialists, but also to adolescents and not fully engaged employment groups (unemployed, elderly, students), prepares them for the development and implementation of new social and educational projects, aimed at training juveniles to life in the context of globalization and increasing migration, providing them with samples of the peaceful, orderly behavior, safe for the society.The proposed study can address issues, reduce the effects of labor migration of Ukraine's population in the aspect of reducing the level of social orphanhood, compensation of the pedagogical influence, lacked by children at risk, left without proper parental supervision, it is often the result of the distribution of the phenomenon of labor migration. The development of theoretical aspects of this form of enhancing the pedagogical potential of specialists will facilitate the empowerment of law enforcement and social professionals, probation services, social and psychological services of educational institutions to develop adolescent skills of safe behavior to maintain their sexual and reproductive health. In the future, this will influence the formation of a motivation for adolescents to further their professional development, their self-realization in Ukraine and, as a consequence, the state of the national labor market, while preserving the potential of skilled workers

Raising environmental awareness as a meaningful factor of integrated waste management in Moscow

The article is aimed at evaluating the prospects of promoting environmental awareness among the population in Moscow. To meet the goal, the author analyzed foreign studies on environmental awareness- building. The following methods were used during the research: the investigation of the legal and regulatory framework, analysis of surveys performed by the Public Opinion Foundation (FOM) and Levada Analytical Center, content analysis of the Moscow media sources with the use of the Public.ru database, and exploration of TV programs on Moscow 24 channel. The research indicated the key problem that is a low engagement of the population into the practice of separate waste collection. It undermines the process of integrated waste management in Moscow. The author uses a public-opinion survey to identify the reasons for such low engagement of the population. Those reasons include the lack of time for sorting, the lack of space in an apartment for arranging waste sorting, the lack of trust in a newly established infrastructure. The conclusion is that it is necessary to not only conduct awareness-raising campaigns but to educate the population as well. It is reasonable to arrange lessons on environmental protection to foster environmental awareness in children. When conducting awareness-raising campaigns, it is important to focus on increasing public confidence in the established infrastructure. For example, it makes sense to share information about transporting garbage from containers to sorting stations, and demonstrate how the sorting stations operate.

Impact of the immunohistochemical panel onpatients with breast cancer diagnosis cared for ina referral hospital in the state of Amazonas

Objective: To demonstrate the time between the diagnosis of the disease, the result of the immunohistochemical panel and the beginning of specialized treatment in patients diagnosed with breast cancer seen at the Foundation Center of Oncology of the State of Amazonas, from June to November 2018 and in the same period of 2019. Methods: The study was part retrospective, based on data from medical records, and part prospective, based on data from patients, and we evaluated the time between diagnosis from the immunohistochemical panel and the beginning of specialized treatment in breast cancer patients. Results: 170 patients diagnosed with breast cancer were included, 71 from June to November 2018 and 99 breast cancer patients seen from June to November 2019. The median time between diagnosis and immunohistochemistry results of all patients was 36 days, and comparing the two groups of patients, it was observed that for half of the 2018 patients, the time was less than 105 days, while for half of the 2019 patients, it was less than 27 days. If the times between the result of the immunohistochemical panel and the start of personalized treatment in both groups were compared, it was seen that the median time until the start of treatment was longer for patients in 2018, 94.5 days versus 79 days for patients in 2019. Conclusion: There was a decrease in the time between the diagnosis and the result of the molecular panel in 2019 compared to 2018. Achieving this result more quickly provided the choice of personalized treatment for each patient, having an important impact on survival in that population.

Fast-track hip and knee arthroplasty in older adults-a prospective cohort of 1,427 procedures in patients ≥85years.

fast-track protocols in total hip and knee arthroplasty (THA/TKA) have improved postoperative recovery and reduced postoperative morbidity. Additionally, increasing life expectancy and improved surgical techniques have led to an increasing number of older adult patients undergoing THA/TKA. However, no large detailed studies on fast-track THA/TKA in older adults are available. Consequently, we aimed to describe the length of stay (LOS) and postoperative morbidity in a large cohort of patients ≥85years within a continuous multicentre fast-track collaboration. we used a prospective observational cohort design with unselected consecutive data between 2010 and 2017 on primary elective THA and TKA patients ≥85years. Data were obtained from nine centres reporting to the Lundbeck Foundation Centre for Fast-track Hip and Knee Replacement database and the Danish National Patient Registry on LOS, readmissions and mortality. Causes of morbidity were determined by review of health records. we included 1,427 (3.9% of all THA/TKA) procedures with 62.3% THA. Median age was 87 (IQR: 85-88) years with 71% women. LOS decreased from median 4 (3-6) days in 2010 to 2 (2-3) days in 2017. The proportion with LOS > 4days decreased from 32 to 18%. Readmission and mortality rate remained at about 11.7 and 0.9% after 30 days and 16.0 and 1.5% after 90days, respectively. this detailed large multicentre fast-track THA/TKA study in patients ≥85years found major reductions in LOS without increase in readmission or mortality rates. The unchanged readmission rate poses an area for further improvements.

The people behind the papers - Madeleine Linneberg-Agerholm, Yan Fung Wong and Josh Brickman.

Our understanding of lineage decisions in early human development has been greatly aided by embryonic stem cell lines, which avoid many of the practical and ethical difficulties of in vivo material. A new paper in Development exploits naïve human embryonic stem cells to generate in vitro models for the extra-embryonic endoderm. We caught up with first authors Madeleine Linneberg-Agerholm and Yan Fung Wong, and their supervisor Josh Brickman, Professor of Stem Cell and Developmental Biology at the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) in Copenhagen, to hear more about the work.

Contrast Media Research 2019 “Ettore Majorana” Foundation and International Centre for Scientific Culture, Erice, Sicily, Italy, November 10–15, 2019 Conveners: Carlo C. Quattrocchi, MD, PhD and Silvio Aime, PhD

Contrast Media Research 2019 “Ettore Majorana” Foundation and International Centre for Scientific Culture, Erice, Sicily, Italy, November 10–15, 2019 Conveners: Carlo C. Quattrocchi, MD, PhD and Silvio Aime, PhD

Outcomes of stereotactic radiosurgery for pilocytic astrocytoma: an international multiinstitutional study.

The current standard initial therapy for pilocytic astrocytoma is maximal safe resection. Radiation therapy is considered for residual, recurrent, or unresectable pilocytic astrocytomas. However, the optimal radiation strategy has not yet been established. Here, the authors describe the outcomes of stereotactic radiosurgery (SRS) for pilocytic astrocytoma in a large multiinstitutional cohort. An institutional review board-approved multiinstitutional database of patients treated with Gamma Knife radiosurgery (GKRS) between 1990 and 2016 was queried. Data were gathered from 9 participating International Radiosurgery Research Foundation (IRRF) centers. Patients with a histological diagnosis of pilocytic astrocytoma treated using a single session of GKRS and with at least 6 months of follow-up were included in the analysis. A total of 141 patients were analyzed in the study. The median patient age was 14 years (range 2-84 years) at the time of GKRS. The median follow-up was 67.3 months. Thirty-nine percent of patients underwent SRS as the initial therapy, whereas 61% underwent SRS as salvage treatment. The median tumor volume was 3.45 cm3. The tumor location was the brainstem in 30% of cases, with a nonbrainstem location in the remainder. Five- and 10-year overall survival rates at the last follow-up were 95.7% and 92.5%, respectively. Five- and 10-year progression-free survival (PFS) rates were 74.0% and 69.7%, respectively. On univariate analysis, an age < 18 years, tumor volumes < 4.5 cm3, and no prior radiotherapy or chemotherapy were identified as positive prognostic factors for improved PFS. On multivariate analysis, only prior radiotherapy was significant for worse PFS. This represents the largest study of single-session GKRS for pilocytic astrocytoma to date. Favorable long-term PFS and overall survival were observed with GKRS. Further prospective studies should be performed to evaluate appropriate radiosurgery dosing, timing, and sequencing of treatment along with their impact on toxicity and the quality of life of patients with pilocytic astrocytoma.

Gender Differences in the Clinical Presentation of Cluster Headache: A Role for Sexual Hormones?

Introduction: Cluster Headache (CH) is a well-characterized primary headache that mostly affects men, although a progressive decrease in the male-to-female ratio has occurred over time. Available, but partly discordant, data on gender-related differences in CH suggest a more marked overlapping with migraine features in female subjects. The aim of this study is to carefully evaluate the female/male distribution of the typical migraine-associated symptoms and of other features of the disease in a large and well-characterized clinical population of CH subjects.Materials and Methods: We enrolled consecutive CH patients regularly followed at the tertiary Headache Science Center of the IRCCS Mondino Foundation of Pavia (Italy) who attended the Center for a CH bout between September 2016 and October 2018. The subjects were requested to fill in a semi-structured questionnaire focused on the presence of migraine-associated symptoms, familiarity for migraine and, for women, the relationship of CH onset with the reproductive events of their life. These data were compared and integrated with those recorded over time in our clinical database, including demographics and clinical characteristics. The primary outcome was the gender distribution of subjects who satisfied ICHD-III criterion D for migraine-associated symptoms. The secondary outcomes were represented by the gender distribution of individual migraine-associated symptoms and of other disease features included in the questionnaire and/or in the clinical database.Results: Data from 163 males (mean age 41.46 ± 10.37) and 87 females suffering of CH (mean age 42.24 ± 11.95) were analyzed. We did not find a different distribution between sexes as regards the primary outcome measure (F 73.6%, M 65.6%, p = 0.200). However, when we analyzed the occurrence of individual symptoms, nausea and osmophobia were reported more frequently by women (p = 0.048, p = 0.037, respectively). Ptosis and nasal congestion were predominant in females (p = 0.017 and p = 0.01, respectively), while enlarged temporal artery was more frequently reported by men (p = 0.001). Distribution of pain across the head tended to be larger in women, extending more frequently to the zygomatic (p = 0.050), parietal (p = 0.049), and frontal (p = 0.037) regions. Women had a longer mean attack duration (p = 0.004) than men. In CH women the onset of disease often corresponded with moments of important changes in the levels of sexual hormones (menarche, post-partum, menopause). Concomitant thyroid diseases and psychiatric disorders were observed more frequently in women than in men, while snoring and smoking habit was reported by a higher percentage of men than women.Conclusion: We confirmed the presence of distinct gender-related differences in CH and added some novel information that lends credibility to the hypothesis of a closer phenotypical similarity between CH and migraine in the female sex. These observations are relevant for advancing our knowledge on CH pathophysiology, as well as for a more refined diagnostic framing and improved management of the disease.

The Influence of Prolonged Strength Training Upon Muscle and Fat in Healthy and Chronically Diseased Elderly Close to Retirement Age

Background: Physical and cognitive function declines with age, accelerating after the age of 60. Strength training over a few months improves physical function, but less is known about how long-term strength training affects physical and cognitive function. Therefore, we aimed to investigate the effect of 1 year strength training of two different intensities upon muscle mass, function, and cognition in retirement-age individuals. Methods: In this randomized controlled trial (clinicaltrials.gov: NCT02123641), participants were allocated to either a) supervised, heavy resistance training (HRT, n=149, 3/wk), b) moderate intensity resistance training (MIT, n=154, 3/wk) or c) non-exercise activities (CON, n=148). 451 participants were randomized (62-70 yrs, women 61%, ≈80% with a chronic medical disease) and 419 were included in the intention-to-treat analysis (n=143, 144 and 132; HRT, MIT and CON). Changes in muscle power (primary outcome), strength and size, physical function, body composition, hippocampus volume and physical/mental well-being were analysed. Findings: Of the participants (HRT+MIT), 83% completed training at least 2/wk. Leg extensor power was unchanged in all groups, but strength training had positive effects on isometric knee extensor strength and muscle mass, whereas an increased cross-sectional area of vastus lateralis muscle, a decreased whole-body fat percentage and visceral fat content occurred in HRT only. Further, chair-stand performance and 400 m walking time improved in all groups. Hippocampus volume decreased in all groups over time with no influence of strength training, whereas mental health (SF-36) improved more in HRT than MIT. Interpretation:Together, the results indicate that long-term supervised strength training in both healthy and chronically diseased elderly individuals can be implemented with good compliance and induces consistent changes in physiological parameters of muscle and fat. Trial Registration: Clinicaltrials.gov (NCT02123641). Funding Statement: Nordea Foundation (Centre for Healthy Ageing grant). Declaration of Interests: Dr. Gylling reports grants from Nordea Foundation (Centre for Healthy Ageing grant), during the conduct of the study. All other authors declare no conflicts of interest. Ethics Approval Statement: All participants signed an informed consent before participating in the study. The study was approved by the regional ethical committee (Capital Region, Copenhagen, Denmark, No. H-3-2014-017), and complied with the declaration of Helsinki, and the study was approved by the Danish Data Protection Agency.

Venous Thromboembolism despite Ongoing Prophylaxis after Fast-Track Hip and Knee Arthroplasty: A Prospective Multicenter Study of 34,397 Procedures.

Venous thromboembolism (VTE) is a serious complication to total hip and knee arthroplasty (THA/TKA). However, recent publications found low 90-day incidences of VTE with in-hospital only thromboprophylaxis after fast-track THA and TKA, but with a subgroup with VTE despite thromboprophylaxis. We aimed to investigate in detail the incidence and risk for VTE despite ongoing thromboprophylaxis after fast-track THA and TKA. This is a prospective unselected multicenter cohort from January 2010 to August 2017. Data on preoperative characteristics were entered into the Lundbeck Foundation Centre for Fast-track Hip and Knee Replacement database (www.FTHK.dk). Length of stay (LOS) and complete 90-day follow-up was obtained from the Danish National Patient Registry and review of medical records. Patients with preoperative use of potent anticoagulants were excluded. Of 34,397 procedures, 32 (0.09%, 22.4% of all VTE) had VTE after median 2 (interquartile range: 2-4) days despite ongoing thromboprophylaxis. Twenty-nine (2.1% of LOS > 5 days) occurred with LOS > 5 days and 3 during primary admission with LOS ≤ 5 days. Note that 78% of VTEs despite ongoing thromboprophylaxis occurred without any identifiable pre-VTE complication. Risk factors were age from 81 to 85 years (odds ratio [OR] 6.3 [95% confidence interval: 1.8-22.4], p = 0.005), body mass index (BMI) < 18.5 (OR 11.1 [1.1-109.2], p = 0.040), BMI 35 to 40 (OR 5.1 [1.0-26.2], p = 0.050), and BMI ≥ 40 (OR 21.8 [4.6-103.6], p < 0.001). VTE after fast-track THA/TKA occurred after median 2 days in 0.09% (22% of all VTE) despite ongoing thromboprophylaxis. Further investigation of this "high-risk" population might help to improve the optimal choice for patient-specific thromboprophylaxis to further reduce incidence of postoperative VTE.

Whole-cell patch clamp for monitoring low--energy focused ultrasound (LEFUS)-induced electrical activity in individual neurons

The objective of this project was to integrate a LEFUS-system to a patch-clamp platform for exploration of LEFUS-modulated and/or -stimulated electrophysiological responses from individual cultured neurons. Mouse primary neurons and human neural progenitor cells were cultured and plated onto 35-mm diameter Petri dishes. A whole-cell patch-clamp setup in current-clamp mode was used to record electrophysiological activity generated by the neurons. The LEFUS system consisted of a 2.2-MHz planar transducer (diameter: 10-mm), administering 0.5–10 ms pulses at pressures of 6–50 kPa. Neuromodulation studies consisted in measuring changes in the activation threshold to electrical stimulation (current density required to trigger an action potential: AP) in LEFUS-treated neurons. Neurostimulation experiments consisted in measuring electrophysiological responses to LEFUS exposures in the form of triggered APs or electrical discharges from the patched neuron. Neuromodulation results showed that the activation threshold required for triggering APs could be either elevated or lowered by approximately 25% following LEFUS treatment. In neurostimulation experiments, LEFUS pressures of 25 kPa and pulse durations of 10 ms were sufficient for either disturbing the membrane potential of the cell and, occasionally, depolarizing the neuron by approximately 70 mV. [This project was supported by the French National Research Agency (ANR-16-TERC-0017), LabEx DevWeCan, and Focused Ultrasound Foundation (Centers of Excellence).]

2379Endothelial cell derived extracellular vesicles mediate immune cell deployment from the spleen and transcriptional programming following acute myocardial infarction

Abstract Background Acute myocardial infarction (AMI) induces transcriptional activation of monocyte en route to the injured myocardium, possibly through interactions involving plasma liberated extracellular vesicles (EVs), which are enriched for proteins and microRNAs (miRNAs) post-AMI. Neutrophils are the first immune cells to arrive at sites of injury and mediate further damage to the ischaemic myocardium. Here, we describe neutrophil-deployment from the spleen in AMI and by endothelial cell (EC) derived-EVs. Methods Patients presenting AMI provided informed consent as part of the Oxford Acute Myocardial Infarction Study (OxAMI). Plasma EV were isolated by differential ultra-centrifugation (120,000g, 2 hours) followed by washing and characterised for: morphology using transmission electron microscopy (TEM), size and concentration profiling by Nanoparticle Tracking Analysis, EV markers (TSG101, ALIX, CD9, HSP70) by western blot, and miRNAs by RT-qPCR. Mouse and human EC were used in vitro to derive EC-EV under control conditions or after inflammatory stimulation with tumour necrosis factor-alpha (TNF-α) (10ng/mL) and from CRISPR-edited miRNA-126 knock-out ECs. EC-EVs were tail vein injected into wild-type mice or exposed to primary human peripheral blood neutrophils in vitro. Results Patients presenting with AMI (N=15) have significantly more plasma EV at time of injury vs a 6-month follow-up measurement (2.2-fold more, P=0.008). Plasma EVs at the time of AMI presentation correlate significantly with the extent of ischaemic injury (R=0.046, P=0.006) and plasma neutrophils (R=0.37, P=0.017). Experimental AMI in wild-type mice induced a significant increase in peripheral blood neutrophils and a simultaneous reduction in splenic-neutrophils, suggesting splenic-neutrophil deployment (P=0.004). Human plasma EV are enriched for vascular cell adhesion molecule-1 (VCAM-1) and EC-associated miR-126 post-AMI (Akbar et al 2017). miRNA-126-mRNA targets are significantly over represented when compared to neutrophil Gene Ontology terms for: degranulation (P&lt;0.001), activation (P&lt;0.001), chemotaxis (P=0.008) and migration (P=0.008). Human and mouse EC release more EV after inflammatory stimulation and show enrichment for miRNA-126. CRISPR-edited miRNA-126 deficient human EC express more VCAM-1 (P&lt;0.001) and release more EC-EVs (P&lt;0.001). EC-EV exposure to primary human neutrophils alters inflammatory gene expression (IL-6 (P&lt;0.05), CCL7 (P&lt;0.001) and CCL18 (P&lt;0.001)). EC-EV tail vein injected into wild-type mice mobilise splenic-neutrophils to peripheral blood (P&lt;0.001). Conclusions Neutrophil deployment from the spleen is a novel finding in acute injury and interactions with EC-EV may mediate their splenic liberation and transcriptional programming following AMI, en route to the injured myocardium. The splenic neutrophil reserve may be a novel therapeutic target in AMI to modulate the inflammatory response before recruitment of cells to sites of injury. Acknowledgement/Funding British Heart Foundation Project Grant and Centre for Research Excellence Awards (RE/13/1/30181), Nuffield Benefaction for Medicine and ISSF

Microelectrode arrays (MEA) for measuring spatio-temporal neural activity generated by low-energy focused ultrasound (LEFUS) in ex vivo brain slices

The objective of this project was to study the electrical activities elicited by Low-Energy Focused Ultrasound (LEFUS) neurostimulation in ex vivo mouse hippocampal brain slices using a MicroElectrode Array (MEA) system. A mixed LEFUS/MEA platform was developed for spatial-temporal recording of neural responses induced by LEFUS exposures in ex-vivo hippocampal brain slices from a mouse model. Hippocampal slices were maintained functional in the 60 electrode MEA chip by perfusion with artificial cerebrospinal fluid. The LEFUS system consisted of a 1.78-MHz focused transducer (diameter: 15 mm, radius of curvature: 15 mm). LEFUS pulses (1.1 MPa, 284–568 cycles) were applied on slices at pulse repetition frequencies in the range of 0.2–1 Hz. Recorded signals resulting from LEFUS stimulation were characterized by negative deflections corresponding to LEFUS artifacts, followed by positive deflections corresponding to electrophysiological responses several milliseconds afterwards. This setup thus allows for the recording and differentiation of fiber volleys (latency ≈ 1–5 ms) and post-synaptic potentials (amplitude ≈ 100–800 μV) as a result of LEFUS stimulation. Such responses were observed in several electrodes across the MEA matrix while exhibiting a progressive drop in amplitude after every applied pulse (Long-term depression). [This project was supported by the French National Research Agency (ANR-16-TERC-0017) the LabEx DevWeCan, and the Focused Ultrasound Foundation (Centers of Excellence).]The objective of this project was to study the electrical activities elicited by Low-Energy Focused Ultrasound (LEFUS) neurostimulation in ex vivo mouse hippocampal brain slices using a MicroElectrode Array (MEA) system. A mixed LEFUS/MEA platform was developed for spatial-temporal recording of neural responses induced by LEFUS exposures in ex-vivo hippocampal brain slices from a mouse model. Hippocampal slices were maintained functional in the 60 electrode MEA chip by perfusion with artificial cerebrospinal fluid. The LEFUS system consisted of a 1.78-MHz focused transducer (diameter: 15 mm, radius of curvature: 15 mm). LEFUS pulses (1.1 MPa, 284–568 cycles) were applied on slices at pulse repetition frequencies in the range of 0.2–1 Hz. Recorded signals resulting from LEFUS stimulation were characterized by negative deflections corresponding to LEFUS artifacts, followed by positive deflections corresponding to electrophysiological responses several milliseconds afterwards. This setup thus allows for the ...

P4436Impaired myocardial healing in patients with diabetes after ST-Elevation Myocardial Infarction

Abstract Background Diabetes mellitus (DM) significantly increases mortality following myocardial infarction (MI). The underlying mechanism explaining this adverse prognosis is not completely understood. Purpose This study sought to investigate the characteristics of myocardial healing after MI in DM patients. Methods 62 recruited ST-elevation myocardial infarction (STEMI) patients (21 with DM and 41 controls) underwent acute (1–3 days post-STEMI) and 6 months (6M) follow-up cardiac magnetic resonance scans (CMR). Control cases were matched for the peak troponin levels and area at risk on the acute CMR scans. Blood samples were obtained 6, 24, 48 hours and 6 months after STEMI. Results Despite similar severity of the initial ischaemic injury, DM patients had lower myocardial salvage index (MSI) and as a result larger final infarct size at 6 months. Further segment-based analysis of the acute CMR scans showed significantly prolonged T1-mapping values in all segments including non-ischaemic myocardium in DM patients and poorer recovery of the late gadolinium enhancement (LGE) of the infarcted segments in that group. Additionally, DM patients had higher monocyte counts 24 hours post-MI (1.2±0.4x109/μl DM vs 0.88±0.3 x109/μl control, p=0.001). We found that HbA1C correlated with monocyte count measured 24 hours after STEMI (r=0.577, p=0.006, n=21). HbA1C also predicted myocardial salvage index (MSI) at 6M post STEMI in the DM patients (r=0.891, p=0.017, n=13). Conclusions DM patients presenting with STEMI have increased peripheral blood monocytosis and larger final infarct size compared with STEMI patients without DM. Poorly controlled DM predisposes to adverse cardiac remodelling after STEMI. Acknowledgement/Funding OHSRC Research Grant, National Institute for Health Research (NIHR), British Heart Foundation Centre of Excellence Oxford

P1936Selective inhibition of the Mek1/2-Erk1/2 signalling pathway induces the differentiation of human cardiac pericyte-like cells into contractile vascular smooth muscle cells

Abstract Background Arteriogenesis is key for tissue repair but whether myocardial stromal cells contribute to this phenomenon remains unknown. Purpose Investigate if cardiac pericytes are a druggable target for therapeutic arteriogenesis. Methods and results The localization of pericyte-like cells (PCs) was assessed in the human and murine heart by immunohistochemistry of typical antigenic markers. CD34+ PCs co-expressing NG2 and PDGFRβ but not endothelial cell (EC) or vascular smooth muscle cell (VSMC) antigens were identified in peri-arterial position in normal hearts. Interestingly, we also found rare PCs co-expressing αSMA in the peri-infarct myocardium, suggesting these cells could represent a transitory phenotype between PCs and VSMCs. Next, we isolated human cardiac PCs by immunosorting for CD31 and CD34 and established the purity of the isolated CD34+CD31- fraction by flow cytometry. Following culture expansion, cardiac PCs maintain the typical antigenic profile except for CD34. Moreover, we confirmed the PCs' ability to promote angiogenesis in-vitro. The withdrawal of EGF and bFGF from the culture media for 10 days induced the differentiation of PCs into mature VSMCs, as documented by a massive upregulation of contractile genes MYH11, CNN1 and ACTA2 (200-, 35- and 15-folds increase versus naïve PCs, p&lt;0.01), which was followed by the induction of SM-MHC, Smoothelin B, αSMA, Calponin and SM22α proteins (p&lt;0.05 versus PCs). In addition, PC-derived cells lost migratory capacity, secreted elastin, and responded to endothelin-1 in a contraction assay, thus phenocopying the behaviour of control coronary artery-derived VSMCs. We excluded contamination of the PC preparation by verifying similar phenomena occur in PCs expanded from single cell clonogeneic assays. Moreover, the process is partially reversible, with PC-derived VSMCs being able to reacquire some intermediate markers following EGF/bFGF re-challenge. ECs secrete EGF and bFGF, with this GF signalling being enhanced by hypoxia, suggesting ECs may control the PC phenotype in a paracrine fashion. Mechanistic studies revealed the Mek1/2-Erk1/2-Elk1 signalling is accountable for the transcriptional repression of VSMC genes in PCs. Accordingly, a selective Mek1/2 inhibitor (PD0325901) was able to switch the definitive VSMC phenotype of PCs maintained in full media. The drug prevented the phosphorylation of Erk1/2 and its downstream target Elk1. This likely relieves the complex SRF/MyocD and abolishes the transcriptional repression at the gene promoter. Conclusions Cardiac PCs have a VSMC potential which is under the inhibitory control of the Mek1/2-Erk1/2-Elk1 signalling. Mek1/2 inhibitors showed promises for the treatment of melanoma and solid tumours. A novel application of this class of compounds to improve arteriogenesis in myocardial ischemia is fascinating. The caveat about their potential cardiotoxicity could be less relevant with short duration treatments of myocardial ischemia. Acknowledgement/Funding British Heart Foundation Centre for Regenerative Medicine Award (II) - “Centre for Vascular Regeneration” (RM/17/3/33381)

Incidence of Residual Neuromuscular Blocking in Oncological Patients in the Anesthetic Rescue Room: Importance of Objective Monitoring in the Foundation Center of Control of Oncology of the State of Amazonas - Fcecon

Incidence of Residual Neuromuscular Blocking in Oncological Patients in the Anesthetic Rescue Room: Importance of Objective Monitoring in the Foundation Center of Control of Oncology of the State of Amazonas - Fcecon

Burden of non-communicable diseases in sub-Saharan Africa, 1990–2017: results from the Global Burden of Disease Study 2017

Although the burden of disease in sub-Saharan Africa continues to be dominated by infectious diseases, countries in this region are undergoing a demographic transition leading to increasing prevalence of non-communicable diseases (NCDs). To inform health system responses to these changing patterns of disease, we aimed to assess changes in the burden of NCDs in sub-Saharan Africa from 1990 to 2017. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to analyse the burden of NCDs in sub-Saharan Africa in terms of disability-adjusted life-years (DALYs)-with crude counts as well as all-age and age-standardised rates per 100 000 population-with 95% uncertainty intervals (UIs). We examined changes in burden between 1990 and 2017, and differences across age, sex, and regions. We also compared the observed NCD burden across countries with the expected values based on a country's Socio-demographic Index. All-age total DALYs due to NCDs increased by 67·0% between 1990 (90·6 million [95% UI 81·0-101·9]) and 2017 (151·3 million [133·4-171·8]), reflecting an increase in the proportion of total DALYs attributable to NCDs (from 18·6% [95% UI 17·1-20·4] to 29·8% [27·6-32·0] of the total burden). Although most of this increase can be explained by population growth and ageing, the age-standardised DALY rate (per 100 000 population) due to NCDs in 2017 (21 757·7 DALYs [95% UI 19 377·1-24 380·7]) was almost equivalent to that of communicable, maternal, neonatal, and nutritional diseases (26 491·6 DALYs [25 165·2-28 129·8]). Cardiovascular diseases were the second leading cause of NCD burden in 2017, resulting in 22·9 million (21·5-24·3) DALYs (15·1% of the total NCD burden), after the group of disorders categorised as other NCDs (28·8 million [25·1-33·0] DALYs, 19·1%). These categories were followed by neoplasms, mental disorders, and digestive diseases. Although crude DALY rates for all NCDs have decreased slightly across sub-Saharan Africa, age-standardised rates are on the rise in some countries (particularly those in southern sub-Saharan Africa) and for some NCDs (such as diabetes and some cancers, including breast and prostate cancer). NCDs in sub-Saharan Africa are posing an increasing challenge for health systems, which have to date largely focused on tackling infectious diseases and maternal, neonatal, and child deaths. To effectively address these changing needs, countries in sub-Saharan Africa require detailed epidemiological data on NCDs. Bill & Melinda Gates Foundation, National Health and Medical Research Centre (Australia).

Effectiveness of Motivational Therapy on Enhancing Self-esteem, to maintain Absti-nence among Alcohol Dependent Patients in Sri Sai Foundation psychiatric hospital, Tamaka, Kolar.

Background:Motivational therapy is very important among alcohol dependent patients to increase the self-esteem to bring the changes in the level of confidence, positive health, problem solving abilities, maintaining abstinence from the alcohol.1 Hence the researcher felt the need to improve the self-esteem level of alcohol dependent patients to maintain abstinence from alcohol in selected de-addiction centres, kolar. Objective: To find out the effectiveness of motivational therapy on enhancing self-esteem to maintain absti-nence among alcohol dependent patients. Materials and Methods: An evaluative approach with Pre experimental one group pre-test, post-test design was adopted. Rosenberg self-esteem scale was used to collect the data. The main study was conducted at Sri Sai Foundation and Life Care Centre Kolar with the sample size of 80 alcohol dependent patients, by using Non- probability, convenient sampling technique and the collected data were analyzed and interpreted by using de-scriptive and inferential statistics. Results: The findings of the study revealed that 100% (80) of alcohol dependent patients had low self-esteem level before Motivational therapy. Whereas after Motivational therapy 100% (80) of the alcohol dependent pa-tients had reached to normal self-esteem level. Further study revealed that after Motivational therapy mean scores of self-esteem level i.e 18.75 with SD of 2.14 was higher than before Motivational therapy mean score i.e 9.51with SD of 1.58 .The obtained t value 32.2 was greater than the table value (1.960) at 0.05 level of signifi-cance which indicates that Motivational therapy was effective on enhancing self-esteem levels of alcohol de-pendent patients. Conclusion: The self-esteem level of alcohol dependent patients was low before Motivational therapy whereas after Motivational therapy all the patients had reached to normal self-esteem level. Hence Motivational therapy is effective in improving self-esteem level of alcohol dependent patients. Key words- Effectiveness, Motivational therapy, Self-esteem, Abstinence, Alcohol Dependent patients

Primary immunodeficiencies in Central and Eastern Europe\u2014the power of networking Report on the activity of the Jeffrey Modell Foundation Centers Network in Central and Eastern Europe

Jeffrey Modell Foundation centers’ network activities in Central and Eastern Europe (JMF CEE) have contributed to the development of care for patients with primary immunodeficiencies. On the data continuously collected from individual centers in participating countries since 2011, we demonstrate a steady improvement in a number of aspects concerning complex care for patients with primary immunodeficiencies. The presented data show an improvement of awareness about these rare diseases across the whole Central and Eastern European region, an increase in newly diagnosed patients as well as genetically confirmed cases, earlier establishment of diagnosis, and improved access to clinical treatment. We also present an active patient involvement that is reflected in the expansion of patient organization centers and their activities. The cooperation within the JMF CEE network has also contributed to greater international exposure of participating centers and further to the gradual development of research activities in the rapidly evolving field of primary immunodeficiencies. The improvement of all important aspects of the complex field of primary immunodeficiencies within the JMF CEE network documents the strength and advantages of the joint and coordinated networking.