Local Research Ethics Committee Research Articles

Improving patient safety by enhancing raising concerns at medical school: a curriculum review

Raising concerns (RC) as a tool for improving patient safety has been researched among qualified doctors, but while medical students frequently encounter unprofessional behaviours, little is known about the barriers to, and the culture of, RC among medical undergraduates, which this study was first to address. This work was led by a final-year medical student in conjunction with the faculty. A university student–staff collaboration faculty development grant funded the work. Ethics was obtained through the local research ethics committee (REC). …

Research Ethics Committees' Oversight of Biomedical Research in South Africa: A Thematic Analysis of Ethical Issues Raised During Ethics Review of Non-Expedited Protocols.

In South Africa, biomedical research cannot commence until it has been reviewed and approved by a local research ethics committee (REC). There remains a dearth of empirical data on the nature and frequency of ethical issues raised by such committees. This study sought to identify ethical concerns typically raised by two South African RECs. Meeting minutes for 180 protocols reviewed between 2009 and 2014 were coded and analyzed using a preexisting framework. Results showed that the most frequent queries involved informed consent, respect for participants, and scientific validity. Interestingly, administrative issues (non-ethical) such as missing researchers' CVs and financial contracts emerged more frequently than ethical questions such as favorable risk/benefit ratio and fair participant selection. Although not generalizable to all RECs, our data provide insights into two South African RECs' review concerns. More education and awareness of the actual ethical issues typically raised by such committees might help improve review outcomes and relationships between researchers and RECs.

Macrophage Migration Inhibitory Factor in the Early Diagnosis of Endometriosis and Relationship to the Stage of the Disease

Background: Endometriosis is a chronic disease affecting women of reproductive age. Adolescent onset of symptoms is common. Macrophage migration inhibitory factor (MIF) is one of non-invasive blood biomarker that was found in endometriosis. Aim of the work: to evaluate the value of macrophage MIF in peripheral blood of women with and without endometriosis as a non-invasive early diagnostic method and correlate its level to the stage of the disease. Patient and methods: This observational case-control study was conducted in El-Hussein Hospital, Al-Azhar University, Cairo and private clinics. The study was approved by the local research ethics committee. During the period from May 2016 till July 2018. Results: Both groups were comparable as regard the incidence of infertility and the presence of chronic pelvic pain. The infertility was equal in both groups; it affected 96% of patients and control groups. The chronic pelvic pain was symmetrically present in both groups; it affected 70% of endometriosis and the control group. The level of MIF was 10.03±1.78 pg/ml in patients with endometriosis and 4.82±1.78 pg/ml in control group with significant P value (P <0.001). In our study, the level of MIF differed according to the stage of endometriosis, in stage I, it was 8.6±0.2 pg/ml, in stage II, it was 10.1±0.1 pg/ml, in stage III, it was 11.3±0.2 pg/ml and in stage IV, it was 14+0.0 pg/ml. Conclusion: MIF factor is a promising marker not only for noninvasive diagnosis of endometriosis but as a target for therapy also

Macrophage Migration Inhibitory Factor in the Early Diagnosis of Endometriosis and Relationship to the Stage of the Disease

Background: Endometriosis is a chronic disease affecting women of reproductive age. Adolescent onset of symptoms is common. Macrophage migration inhibitory factor (MIF) is one of non-invasive blood biomarker that was found in endometriosis. Aim of the work: to evaluate the value of macrophage MIF in peripheral blood of women with and without endometriosis as a non-invasive early diagnostic method and correlate its level to the stage of the disease. Patient and methods: This observational case-control study was conducted in El-Hussein Hospital, Al-Azhar University, Cairo and private clinics. The study was approved by the local research ethics committee. During the period from May 2016 till July 2018. Results: Both groups were comparable as regard the incidence of infertility and the presence of chronic pelvic pain. The infertility was equal in both groups; it affected 96% of patients and control groups. The chronic pelvic pain was symmetrically present in both groups; it affected 70% of endometriosis and the control group. The level of MIF was 10.03±1.78 pg/ml in patients with endometriosis and 4.82±1.78 pg/ml in control group with significant P value (P <0.001). In our study, the level of MIF differed according to the stage of endometriosis, in stage I, it was 8.6±0.2 pg/ml, in stage II, it was 10.1±0.1 pg/ml, in stage III, it was 11.3±0.2 pg/ml and in stage IV, it was 14+0.0 pg/ml. Conclusion: MIF factor is a promising marker not only for noninvasive diagnosis of endometriosis but as a target for therapy also

Extended vs Limited Pelvic Lymph Node Dissection During Radical Prostatectomy for Intermediate- and High-Risk Prostate Cancer: Early Oncological Outcomes from a Randomized Phase 3 Trial

Background: The role of extended pelvic lymph node dissection (EPLND) in the surgical management of prostate cancer (PCa) patients remains controversial, mainly because of lack of randomized controlled trials (RCT). Methods: In this randomized controlled phase 3 study, men with newly diagnosed clinically localized intermediate- or high-risk PCa who had chosen surgery as their treatment approach were enrolled from Sao Paulo State Cancer Institute, Brazil. Participants were randomly assigned (1:1) to have either extended (EPLND) or limited pelvic lymph node dissection (LPLND) at radical prostatectomy (RP). LPLND included the obturator chain bilaterally, whereas EPLND involved included obturator, external-, internal-, common-iliac and pre-sacral chains bilaterally. The primary endpoint was biochemical recurrence-free survival (BRFS) and the secondary outcomes were metastasis-free survival (MFS), cancer-specific survival (CSS) and histopathologic findings. This trial was registered with ClinicalTrials.gov, number NCT01812902. Findings: Between May 2012 and December 2016, 300 men were enrolled, of which 150 were randomly assigned to EPLND and 150 to LPLND. Median follow-up was 54.3 months. EPLND detected 4.9 times more lymph node metastases (16.8% [n=25] in the EPLND group vs. 3.4% [n=5] in the LPLND group, p<0.001). The median BRFS was 61.4 months in the LPLND group and not reached in the EPLND group (HR 0.91; 95% CI 0.63-1.32; p=0.623). The median metastasis-free survival was not reached in both groups (HR 0.57; 95% CI 0.17-1.8; p=0.345). CSS data were not available because no patient died from prostate cancer prior to the cutoff date. In exploratory subgroup analysis, patients with preoperative biopsy International Society of Urological Pathology (ISUP) grades 3-5 who were allocated to EPLND had improved BRFS (HR 0.33, 95% CI 0.14-0.74, interaction p<0.001). Interpretation: EPLND is not associated with an improvement in biochemical recurrence among men undergoing RP for intermediate- and high-risk localized PCa. Subgroup analyses suggest that preoperative ISUP 3, 4 or 5 biopsy is associated with an improvement in BRFS for patients undergoing EPLND. Trial Registration Number: This trial was registered with ClinicalTrials.gov, number NCT01812902. Funding: Foundation for Research Support of the State of Sao Paulo (FAPESP). Declaration of Interest: Lestingi, Coelho, Pontes, Faraj, Mitre, Cordeiro, Srougi, Nahas: none. Guglielmetti: Personal fees from Janssen; outside the submitted work. Trinh: Personal fees from Astellas, Bayer, InsighTec and Janssen. Grants from Intuitive Surgical; outside the submitted work. Bastos: Grants from Janssen and Astellas; outside the submitted work. Sarkis: Personal fees from Ferring and from MSD - Merck Sharp and Dohme; outside the submitted work. Ethical Approval: All patients participating in the study will sign the ICF and study was approved by the local Research Ethics Committee.

Ex Vivo Co-Culture of AML Blasts and Bone Marrow Mesenchymal Stromal Cells to Accurately Predict the Clinical Efficacy of Cytarabine-Daunorubicin Treatment

Introduction- The mainstream therapy for AML is cytarabine (AraC) and anthracycline-based intensive chemotherapy. Between 10-40% of patients however have a refractory disease. It is becoming increasingly accepted that the risk for refractory disease could be reduced by finding better ways of selecting the induction therapy. While multiple in vitro and in vivo experimental models exist for pre-clinical drug efficacy testing, they are either labour intensive, too time consuming or generate variable results, making them unsuitable for clinical application. Furthermore, very few, if any of these methods have been shown to replicate the clinical response of patients. The aim of this study was to develop a functional drug testing system that can rapidly and faithfully predict the clinical response of the patient and therefore be utilized to help the identification of patients suitable for AraC+daunorubicin (DnR) therapy.Methods- Primary samples were obtained through Blood Cancer Biobank Ireland. All patients were consented and the research project was approved by the local Research Ethics Committee of NUI, Galway. Mononuclear AML blasts were isolated from bone marrow (BM) aspirates of newly diagnosed patients by ficoll-paque gradient separation. HS-5 human bone marrow mesenchymal stromal cells (BMSC), healthy donor (HD)-derived BMSCs immortalised with hTERT (iMSC) and primary BMSCs (non-immortalised, pBMSC) from HDs and AML patients were used as feeder layers. Cytokine and chemokine secretion by BMSCs was determined using antibody arrays (R&D systems). Extracellular matrix (ECM) scaffold formation was determined by immunocytochemical detection of collagen I, III, IV, V, VI, laminin and fibronectin. AML blasts were cultured in direct contact on established BMSC feeder layer. BMSCs were identifiable by either GFP expression or green cell tracker labelling (CFSE) and the percentage of dying AML cells (negative for GFP/CFSE and positive for the viability dye, ToPro-3) was determined with FACS.Results- In order to choose the most suitable BMSC feeder layer, three main characteristics were studied: cytokine/chemokine secretion, formation of ECM-BMSC proteocellular scaffold and ability to support ex vivo AML blast survival were determined. HS-5 cells, iMSCs and primary, HD pBMSC secreted 66, 59 and 51 paracrine factors, respectively including angiopoietin 1, fibroblast growth factor, interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte colony stimulating factor (G-CSF), C-X-C motif chemokine 12 (CXCL12), CXCL10 and vascular endothelial growth factor. 51% of cytokines/chemokines were common between iMSCs and HD pBMSC, while the HS-5 secretome shared 43% commonality with HD pBMSC. iMSCs also showed an equal ability to establish an ECM-BMSC scaffold with HD pBMSC and they had a superior ability to support the ex vivo survival of AML blasts over HS-5 cells.To determine how closely iMSCs can replicate the effects of BMSCs of AML patients, AML blasts were cultured on matching BMSCs (BMSCs isolated from the same patient). When these AML-BMSC co-cultures were exposed to the BH3 mimetics ABT-199 and ABT-737 or AraC+DnR, iMSCs closely replicated the protective effect of the patients' own BMSCs.Using this optimized ex vivo co-culture model, we tested 16 AML patient samples by exposing iMSC-AML blast co-cultures to a clinically-relevant dosage of AraC+DnR. To quantify drug efficacy, the area under the curve (AUC) for each treatment timepoint (24 h and 48 h) was calculated. By applying a cut-off value of 35% efficacy, we found that the ex vivo test could predict the clinical response of the patient in 81.2% of cases (p-value= 0.002, Figure).Conclusions- The developed drug efficacy test can recapitulate the key features of the BM microenvironment and could predict the clinical response of patients with high accuracy. The advantages of this model over more complex pre-clinical AML models is its suitability to be developed into a laboratory diagnostic tool which could greatly advance the clinical decision on treatment choice. [Display omitted] DisclosuresQuinn:Janssen: Honoraria.

Genetic Predisposition to Prenatal Methylmercury Toxicity and Child Cognitive Development at Age 8 Years

Background: The association of childhood cognitive function and prenatal exposure to methylmercury was previously found to be modified by genetic variation. We further explored the potential genetic predisposition in an extended study of children from the Avon Longitudinal Study of Parents and Children (Bristol, UK) (ALSPAC). Methods: A subgroup (n = 1 127 from the pilot study and 1 045 from the present study) of the ALSPAC cohort was identified based on the availability of the mercury (Hg) concentration of umbilical cord tissue as a measure of prenatal methylmercury exposure, data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as scores on the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) at age 8 years. Multivariable regression models were used to assess the associations between methylmercury exposure and IQ as a cognitive development measure and to determine possible gene-environment interactions. Inclusion of covariate variables reduced the total sample size from 2 172 to 1 723 complete cases; inverse probability weighting was applied in final models. Findings: At the low exposure level in this population, the log10-transformed mercury concentration was positively associated with IQ, but adjustment for nutritional and sociodemographic cofactors attenuated this association. Inclusion of selenium and vitamin D measured in pregnancy blood samples did not affect these findings. Enhanced interaction with methylmercury neurotoxicity was replicated in the new study for the minor allele of rs1042838 (progesterone receptor) (Beta; 95% Confidence Interval) = (-11.8; -23.0 to -0.7) (P-for-interaction = 0.004) and less clearly for rs662 (paraoxonase 1) (-3.6; -11.5 to 4.2) (P = 0.115). In the joint sample, new potential interacting SNPs were discovered in relation to superoxide dismutase 2, ATP binding cassette subfamily A member 1 and metallothionein 1M genes. Interpretation: Low-level prenatal exposure to methylmercury was weakly, though positively, associated with child cognitive development 8 years later. However, for PGR rs1042838, the presence of the minor allele revealed a clear negative association of mercury exposure with IQ. These findings emphasize that understanding of methylmercury neurotoxicity can be enhanced by integrating genetic data into the analysis. Funding Statement: Spanish Institute of Health Carlos III. Declaration of Interests: The authors have no conflicts of interest to declare. All the authors have no financial relationships relevant to this article to disclose. Ethics Approval Statement: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.

Protocol for the Lactoferrin Infant Feeding Trial (LIFT): a randomised trial of adding lactoferrin to the feeds of very-low birthweight babies prior to hospital discharge

IntroductionVery-low birthweight (VLBW, <1500 g) infants comprise about 1%–1.4% of all births in high-income countries. Every year, about 3000 VLBW babies in Australia and New Zealand receive intensive care. Many...

Doppler-Based Renal Venous Stasis Index as a New Prognostic Marker in Right Heart Failure

Background: Persistent congestion with deteriorating renal function is an important cause of adverse outcomes in heart failure. Renal Doppler ultrasonography has been proposed to assess renal congestion but is not fully characterized, and current approaches do not reflect the full continuum of renal congestion. We aimed to characterize new approaches to evaluate renal congestion using Doppler ultrasonography. Methods: We enrolled 205 patients with suspected or pre-diagnosed pulmonary hypertension (PH) undergoing right heart catheterization. PH is the most common precursor to right ventricular failure, and thus represents an ideal scenario to study congestion. Patients underwent renal Doppler ultrasonography and assessment of invasive cardiopulmonary haemodynamics, echocardiography, renal function, intra-abdominal pressure, and hormonal and hydration status. Four renal venous flow patterns (RVFPs) and a novel renal venous stasis index (RVSI) were defined. The rate of PH-related morbidity and all-cause mortality (composite endpoint) was evaluated for 1 year post-discharge. Associations with outcome were assessed using Cox proportional hazard models. Prognostic utility of RVSI and RVFP was compared using receiver operating characteristic (ROC) curves. Findings: RVSI increased across the RVFPs (p<0*0001), and was significantly associated with right heart and renal function, intra-abdominal pressure, and hormonal and hydration status. During follow-up, the morbidity/mortality endpoint occurred in 91 patients and was independently predicted by RVSI (RVSI in 3rd tertile vs RVSI=0: hazard ratio 4*72 [95% confidence interval 2*10-10*59; p<0*0001]). ROC curves suggested superiority of RVSI to RVFPs in predicting outcome (area under curve: 0*789 and 0*761, respectively). Interpretation: We describe four RVFPs, and we propose RVSI as a conceptually new, non-invasive, objective, and reproducible Doppler index of renal congestion. RVSI might provide additional information to stratify vulnerable patients with right heart failure. Clinical Trial Number: The study is registered at www.ClinicalTrials.gov (NCT03039959). Funding: This study was funded by the German Research Foundation (DFG) SFB1213, projects B08 and B07. Declaration of Interests: Dr. Seeger disclosed personal fees for consulting from Bayer Pharma AG, from Liquidia Technologies, Inc, and from United Therapeutics Corporation outside the submitted work. Dr. Gall discloses personal fees and non-financial support from Actelion, AstraZeneca, Bayer, BMS, GlaxoSmithKline, Janssen Cilag, Lilly, MSD, Novartis, Pfizer, and United Therapeutics/OMT outside the submitted work. Dr. Gofrani discloses grants from German Research Foundation (DFG) during the conduct of the study, and personal fees from Actelion, Bayer, GSK, Novartis, Pfizer, Bellerophon Pulse Technologies, and MSD Merck Sharpe & Dohme outside the submitted work. None of the other authors declare any competing interests. Ethical Approval Statement: The study was approved by the local Human Research Ethics Committee (AZ 237/16) and complied with the Declaration of Helsinki. All participants gave signed informed consent and were included in the Giessen PH registry.

Meta-Analysis of Maternal Prenatal Smoking GFI1-Locus and Cardio-Metabolic Phenotypes in Adults

Background: DNA methylation at GFI1-locus has been repeatedly associated with exposure to smoking from foetal period onwards. We explored whether DNA methylation maybe a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n=18212). DNA methylation at GFI1-locus was measured in whole-blood. Multivariable regression analyses were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Hypomethylation at four out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Cg14179389 hypomethylation, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, hypomethylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10 - 7 < P < 0·01). Similarly, hypo-methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10 - 8 < P < 0·001). Hypomethylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. This introduces a molecular mechanism and biomarker of smoking exposure. Funding: Not applicable Declaration of interests: The authors declare no competing interests. Ethical Approval Statement: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.

'Bioethical Realism': A Framework for Implementing Universal Research Ethics.

Implementation of existing ethical guidelines for international collaborative medical and health research is still largely controversial in sub-Saharan Africa for two major reasons: One, they are seen as foreign and allegedly inconsistent with what has been described as an 'African worldview', hence, demand for their strict implementations reeks of 'bioethical imperialism'. Two, they have other discernible inadequacies - lack of sufficient detail, apparent as well as real ambiguities, vagueness and contradictions. Similar charges exist(ed) in other non-Western societies. Consequently, these guidelines have been correctly judged as an inadequate response to the complex and ever shifting dilemmas met by researchers and research regulators in the field. This paper proposes a framework for effective implementation of existing guidelines without much worry about bioethical imperialism and other inadequacies. This framework is proposed using an analogy of Legal Realism, specifically its key assertions on how, in reality, judicial systems operate using general legal rules to settle specific cases. Legal realists assert that in judicial decision-making, general legal rules do not totally dictate court decisions in specific cases. This analogy is used to coin a new term, 'Bioethical Realism.' The framework suggests that local Research Ethics Committees ought to be construed as analogues of judicial courts with the resulting implications. Consequently, just like legal rules are general rules that do not always dictate court decisions, similarly international bioethical guidelines are general ethical rules that should not always dictate local RECs' decisions and such decisions (ought to) enjoy considerable immunity from outsiders.

Development and implementation of participant safety plans for international research with stigmatised populations

People who inject drugs with high-risk sharing practices have high rates of HIV transmission and face barriers to HIV care. Interventions to overcome these barriers are needed; however, stigmatisation of drug use and HIV infection leads to safety concerns during the planning and conduct of research on such interventions. In preparing to address concerns about safety and wellbeing of participants in an international research study, HIV Prevention Trials Network 074, we developed participant safety plans (PSPs) at each site to supplement local research ethics committee oversight, community engagement, and usual clinical trial procedures. The PSPs were informed by systematic local legal and policy assessments, and interviews with key stakeholders. After PSP refinement and implementation, we assessed social impacts at each study visit to ensure continued safety. Throughout the study, five participants reported a negative social impact, with three resulting from study participation. Future research with stigmatised populations should consider using and assessing this approach to enhance safety and welfare.

Neuraxial Labour Analgesia is Associated with a Reduced Risk of Postpartum Depressive Symptoms: A Multicentre, Prospective Cohort Study

Background: Neuraxial labour analgesia is associated with reduced postpartum depression but evidence is conflicting. Here we set out to investigate whether neuraxial labour analgesia was associated with a decreased risk of postpartum depressive symptoms (PDS). Methods: In this multicentre, prospective, observational cohort study, 577 nulliparous women with cephalic term singleton pregnancy who planned vaginal delivery self-selected neuraxial analgesia or no analgesia. Perinatal depressive symptoms were screened with the Chinese version Edinburgh Postnatal Depression Scale (EPDS). An EPDS score of ≥10 was used as the threshold of prenatal and postpartum depressive symptoms. The primary outcome was the development of 6-week PDS. Logistic regression models were established to assess the association between the use of labour analgesia and the risk of PDS development. Findings: Of enrolled parturients, 14.6% (84/577) had prenatal depressive symptoms and 17.3% (100/577) developed PDS. The prevalence of PDS was lower in parturients who received neuraxial analgesia than in those who did not (14.9% [62/417] vs. 23.8% [38/160], p=0.012 in all parturients; 10.4% [37/356] vs. 18.2% [25/137], p=0.020 in those without prenatal depressive symptoms). After adjusted with confounding factors, the use of neuraxial analgesia was associated with decreased odds of PDS (odds ratio [OR] 0.55, 95% CI 0.34-0.91, p=0.019 in all parturients; OR 0.50, 95% CI 0.28-0.90, p=0.022 in those without prenatal depressive symptoms). Interpretation: In nulliparae with cephalic term singleton pregnancy and planned vaginal delivery, neuraxial analgesia during labour was associated with a decreased risk of PDS development. Clinical Trial Number: This trial was registered with www.clinicaltrials.gov(NCT02823418). Funding Statement: This study was funded by Capital Characteristic Clinic Project (Z151100004015160), Beijing, China. Declaration of Interests: DM is supported by grants from the British Oxygen Chair, and British Journal of Anaesthesia Fellowship, London, UK. The other authors declare no competing interests. Part of the work was presented as an e-poster at the Euroanaesthesia 2018 Annual Meeting, Copenhagen, Denmark (June 2-4, 2018). Ethics Approval Statement: The study protocol was approved by the local Clinical Research Ethics Committees in Peking University First Hospital (2014[714]).

A case of streptococcus necrotizing fasciitis secondary to acute tonsillitis and review of literatures

Necrotizing fasciitis, officially named by Wilson in 1952, was a rare potentially life-threatening necrotizing soft tissue infections disease. The main lesions showed subcutaneous fat and fascia layer in progressive necrosis, generally not involving muscles. It was characterized by acute onset, rapid progress, and dangerous condition, often accompanied by systemic toxin shock, which was a relatively rare clinical acute critical disease with high mortality rate. Necrotizing fasciitis is a rare but clinical critical disease. The overall incidence of necrotizing fasciitis is approximately 0.04 cases per 1000 persons in the United States, the 30-day mortality is 27%, and necrotizing fasciitis–related mortality in Asian region is about 28%. Streptococcus pyogenes (group A streptococcus) are human-specific pathogens that can cause upper respiratory tract infection such as tonsillitis, associated with post-infection diseases such as rheumatic fever, and also can induce severe invasive diseases such as necrotizing fasciitis and streptococcus toxin shock syndrome. This article reports a case of streptococcus necrotizing fasciitis secondary to suppurative tonsillitis, which was seldom reported before and our successful management with delayed debridement. This study was anonymous and was approved by the local Research Ethics Committee. Informed consent was obtained from the patient.

Experience in the global forum of bioethics in research. Challenges for the ethical review in Chile

The Global Forum on Bioethics in Research annually convenes a number of researchers, bioethicists and stakeholders with a shared interest in the ethics of conducting research in low and middle-income countries (LMIC). It provides a useful platform to discuss ethical issues that affect research practice in different scenarios, promoting ethically conducted research, global development for health research ethics and partnerships between the global north and south. As participant of the last three meetings, in this article the author analyzes the main ethical issues that were discussed in this forum, namely "Emerging epidemic infections and experimental medical treatments" (Annecy, France, 2015); "Ethics of research in pregnancy" (Buenos Aires, Argentina, 2016), and "The ethics of alternative clinical trial designs and methods in LMIC research" (Bangkok, Thailand, 2017). Local research ethics committees are not well prepared to face the new ethical challenges associated with research conducted in emergency situations or in pregnant women, or to evaluate new methods, such as alternative clinical trial designs (cluster randomized trials, adaptive platforms, or controlled human infection models, among others). According to this scenario, research ethics committees should be trained to carefully assess the risks and benefits of approving this type of research. In this context, it is necessary to harmonize local regulations with the new international standards in research ethics.

Central interaction between the apelinergic and vasopressinergic systems in the regulation of the hemodynamics parameters in rats maintained on high fat diet

IntroductionIt seems that changes in expression of APJ apelin and vasopressin V1a and V1b receptors may significantly affect action and interactions of these two peptides, can play important role in cardiovascular regulation in different pathophysiological states such obesity. Apelin (APLN) is one of adipokines; its dysregulation has been implicated in obesity and type II diabetes. APLN its receptor APJ are co‐localized with vasopressin (AVP) in paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. It has been suggested that the apelinergic system may play an important role in the regulation of the vasopressinergic neurons activity. Thus, changes in expression of APJ and V1a and V1b receptors may significantly affect action and interactions of these two peptides, and contribute to cardiovascular dysregulation in different pathological states.PurposeThe aim of this project is to test the hypothesis the central dysregulation of APJ and V1a and V1b receptors may affect the apelin‐vasopressin interaction and contribute to changes in the hemodynamic parameters in obesity.MethodsSprague‐Dawley rats were on maintained on high fat diet (HFD) or a normal fat diet (NFD). Animals in experimental groups had intracerebroventricular (ICV) cannula implants for delivery of tested substances and abdominal aorta catheters for measuring mean arterial blood pressure (MABP) and heart rate (HR). Group I rats had ICV infusion of saline (NaCl) or/and V1a receptor antagonist (V1aRANT) or/and apelin‐13 (APLN‐13). Group II rats had ICV infusion of NaCl or/and APJ antagonist (F13A) or/and AVP. Brain tissue was collected from additional groups, for the analyses of mRNA expression and protein level of APJ, V1a, and V1b receptors. Consent was obtained from The Local Animal Research Ethics Committee (37/2015).ResultsInfusion of V1aRANT resulted in a significant decrease in MABP in both NFD and HFD; the decrease was greater in HFD. Infusion of APLN‐13 alone resulted in increased MABP only in NFD rats; this effect was absent when infusion of APLN‐13 was preceded by infusion of V1aRANT. Infusion of APLN‐13 preceded by infusion of V1aRANT resulted in decreased HR only in HFD rats. ICV infusion of F13A resulted in a significant decrease in MABP in both NFD and HFD rats; this decrease was greater in NFD rats. Infusion of AVP resulted in an increase in both MABP and HR only in HFD rats. There was no difference in hypothalamic mRNA expression of APJ and V1b receptors between the NFD and HFD rats. Expression of V1a receptor was significantly lower in HFD rats compared to NFD rats. The protein levels of APJ, V1a, and V1b receptors in the hypothalamus were significantly higher in HFD rats compared to NFD rats.ConclusionThese results provide evidence for the involvement of receptor V1a receptor in the regulation of blood pressure by centrally acting apelin. Furthermore, our studies suggest that the interaction of the apelinergic and vasopressinergic system may play an important role in central regulation of cardiovascular system.Support or Funding InformationFunding: Preludium; National Science Centre (UMO‐2016/21/N/NZ4/03758D).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P6-08-25: Outcome of breast cancer patients treated in the private health care in Brazil

Abstract Background Developing countries like Brazil often present a dichotomous health care system, where patients may be treated in either public or private institutions that differ substantially in terms of level of access to diagnostic and therapeutics procedures. Herein, we present the first report of a comprehensive study to assess real-world data in breast cancer patients treated in the private health care in Brazil. Methods This is a prospective study of breast cancer patients treated in a private health care institution, comprising six unities in Rio de Janeiro and surroundings. Eligible patients were at least 18 years old and had a histology-proven diagnosis of breast cancer between July 2012 and November 2016. For this analysis, only female patients with an invasive component were included. Patients with prior malignancies and those who initiated therapy in other institutions were excluded. Patients or relatives were contacted by telephone to ensure that all information was annotated. Data quality was certified by regular monitoring. This study was approved by the local Research Ethics Committee. Results One thousand three hundred and ninety patients were enrolled. One hundred sixty were excluded in this analysis, 11 due to male gender and 151 with exclusively in situ carcinoma. The report comprises 1230 female patients, predominantly diagnosed in early (79.0% stages I-II) or locally advanced (16.1% stage III) stages. One thousand thirty-three (84.0%) patients had hormone receptor (HR)-positive tumors, and 185 (15.0%) were HER2 positive. One hundred twenty-six (10.2%) cases were triple negative. The primary tumor was resected in 89.0% of times, most often through breast-conserving surgery (55.1%). Axillary lymph nodes were assessed in 83.4% of cases, and 32.0% required complete axillary dissection. Chemotherapy was used in 61.3% of cases, and radiation therapy in 59.6%. Patients with locally advanced disease received more aggressive therapy than patients with early stage (higher rates of mastectomy, axillary dissection and chemotherapy use). After a median follow up of 22.5 months (95% CI, 21.09-23.90), 54 (4.4%) deaths were reported. The estimated 2-year overall survival (OS) was 95.3%. 2-year OS was significantly longer among patients with stages I-II (97.9% and 97.5%, respectively) than in stages III and IV (89.4% and 69.5%, respectively) (p&amp;lt;0.01). HER2/HR status (p&amp;lt;0.01) and tumor grade (p=0.05) were also correlated to OS in the overall cohort, however triple-negative cases were only prognostic in stage III. Age (p=0.10), menopausal status (p=0.74), and histological subtype (p=0.55) were not correlated to OS. Conclusion To our knowledge, this is the most comprehensive and best-annotated study in breast cancer patients treated in the private health care in Brazil. More oncological interventions were used in advanced stages, reflecting international recommendations, but also a need to pursue early diagnoses, where outcome is optimal despite less aggressive therapy. Outcomes are favorably similar to the current literature from developed countries in all stages. The data provided helps comprehending the current scenario of breast cancer presentation and treatment in Brazil, and may serve as a foundation to guide resource allocation in the years to come. Citation Format: Boukai A, Gonçalves AC, Andrade PM, Carvalho N, Almeida T, Lemos F, Padoan M, Teich NS, Araujo LH. Outcome of breast cancer patients treated in the private health care in Brazil [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-08-25.

Cerebral Cortical Abnormalities and Classification for Schizophrenia Via High-Resolution Magnetic Resonance Imaging

Background: Evidence from neuroimaging has implicated abnormal cerebral cortical patterns in schizophrenia. Application of machine learning techniques is required for identifying a structural signature at the individual level reflecting neurobiological substrates of schizophrenia. Methods: 52 Patients and 66 healthy controls were recruited within the same period. Multivariate computation was used to examine the abnormalities of cortical features in schizophrenia. Features were selected by least absolute shrinkage and the selection operator (LASSO) method. The diagnostic capacity of multi-dimensional cortical neuroanatomical pattern-based classification was evaluated based on diagnostic tests. Findings: The features of mean curvature (left insula and left inferior frontal gyrus), cortical thickness (left fusiform gyrus), and metric distortion (left cuneus and right superior temporal gyrus) revealed both group differences and diagnostic capacity. Area under the receiver operating characteristic curve was 0.88, and the sensitivity, specificity, and accuracy were 94%, 82%, and 88% respectively. There was a positive association between the index score derived from multi-dimensional patterns and symptom severity (r = 0.40, P< 0.01) for patients. Our findings demonstrated a view of cortical differences with the capacity to discriminate patients with schizophrenia. Structural neuroimaging-based signatures hold potential promise of paving the road for clinical utility in schizophrenia. Interpretation: Our findings demonstrate a view of cortical differences with capacity to discriminate patients with schizophrenia. Structural neuroimaging-based signatures hold potential promise of paving the road for clinical utility in schizophrenia. Funding Statement:This study was supported by the National Basic Research Program of China under Grant Nos. 2014CB543203 and 2015CB856403, the National Natural Science Foundation of China under Grant Nos. 81471811, 81471738 and 61401346, the Fundamental Research Funds for the Central Universities (Dr Qin) and grants 81571651 from the National Natural Science Foundation of China and 2017ZDXM-SF-048 from the Key Research and Development Program of Shaanxi Province (Dr Yin). Declaration of Interest: No disclosure was reported. Ethics Approval Statement: This study was approved by the local Research Ethics Committee (Xijing Hospital, Fourth Military Medical University). All participants gave written informed consent after a complete description of this study

Experiences of a patient-initiated self-monitoring service in inflammatory arthritis: A qualitative exploration.

The aim of the present study was to explore patients' experience of a patient-initiated self-monitoring service for people with rheumatoid or psoriatic arthritis who are on methotrexate. The study took the form of qualitative semi-structured interviews, embedded within a randomized controlled trial. Twelve participants who were randomly assigned to the intervention arm were interviewed. Interviews digitally, transcribed verbatim and analysed using inductive thematic analysis. The study received full National Health Service ethics approval from Camden and Islington Community Local Research Ethics Committee (Ref. 09/H0722/91). Analysis revealed five key themes. Participants described usual care as burdensome and an inefficient use of time, particularly those in employment. Being able to self-monitor and initiate their own care increased patients' knowledge about their illness and its treatment, and enabled them to gain a sense of control and ownership over their arthritis. They appreciated the personalized nature of the new service, which allowed them to be seen at a time and by a method more appropriate to their needs. There were, however, some concerns about fidelity to the service protocol, confusion about the lack of consistency between symptoms and laboratory results, and anxiety about self-monitoring. Overall, participants were positive about the new service, in comparison with usual care, valuing its tailored approach and empowering effects. Further work is needed to ensure adherence to the service protocol and address anxieties around self-monitoring prior to any widespread implementation of the service.

Brain Gliomas: Multicenter Standardized Assessment of Dynamic Contrast-enhanced and Dynamic Susceptibility Contrast MR Images.

Purpose To evaluate the feasibility of a standardized protocol for acquisition and analysis of dynamic contrast material-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance (MR) imaging in a multicenter clinical setting and to verify its accuracy in predicting glioma grade according to the new World Health Organization 2016 classification. Materials and Methods The local research ethics committees of all centers approved the study, and informed consent was obtained from patients. One hundred patients with glioma were prospectively examined at 3.0 T in seven centers that performed the same preoperative MR imaging protocol, including DCE and DSC sequences. Two independent readers identified the perfusion hotspots on maps of volume transfer constant (Ktrans), plasma (vp) and extravascular-extracellular space (ve) volumes, initial area under the concentration curve, and relative cerebral blood volume (rCBV). Differences in parameters between grades and molecular subtypes were assessed by using Kruskal-Wallis and Mann-Whitney U tests. Diagnostic accuracy was evaluated by using receiver operating characteristic curve analysis. Results The whole protocol was tolerated in all patients. Perfusion maps were successfully obtained in 94 patients. An excellent interreader reproducibility of DSC- and DCE-derived measures was found. Among DCE-derived parameters, vp and ve had the highest accuracy (are under the receiver operating characteristic curve [Az] = 0.847 and 0.853) for glioma grading. DSC-derived rCBV had the highest accuracy (Az = 0.894), but the difference was not statistically significant (P > .05). Among lower-grade gliomas, a moderate increase in both vp and rCBV was evident in isocitrate dehydrogenase wild-type tumors, although this was not significant (P > .05). Conclusion A standardized multicenter acquisition and analysis protocol of DCE and DSC MR imaging is feasible and highly reproducible. Both techniques showed a comparable, high diagnostic accuracy for grading gliomas. © RSNA, 2018 Online supplemental material is available for this article.