bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of a 25% Inferior Vena Cava Collapsibility in Detecting Fluid Responsiveness When Assessed by Novice Versus Expert Physician Sonologists
Authors: Corl Keith A. , Azab Nader , Nayeemuddin Mohammed , Schick Alexandra , Lopardo Thomas , Zeba Fatima , Phillips Gary , Baird Grayson , Merchant Roland C. , Levy Mitchell M. , Blaivas Michael , Abbasi Adeel
Published: October 2019

Objectives:

Inferior vena cava collapsibility (cIVC) measured by point-of-care ultrasound (POCUS) has been proposed as a noninvasive means of assessing fluid responsiveness. We aimed to prospectively evaluate the performance of a 25% cIVC cutoff value to detect fluid responsiveness among spontaneously breathing intensive care unit (ICU) patients when assessed with POCUS by novice versus expert physician sonologists.

Methods:

Prospective observational study of spontaneously breathing ICU patients. Fluid responsiveness was defined as a >10% increase in cardiac index following a 500 mL fluid bolus, measured by bioreactance. Novice sonologist measured cIVC with POCUS. Their measurements were later compared to an expert physician sonologist who independently reviewed the POCUS images and assessed cIVCs.

Results:

Of the 85 participants, 44 (52%) were fluid responders. A 25% cIVC cutoff value performed better when assessed by expert sonologists than novice physician sonologists (receiver–operator characteristic curve, ROC = 0.82 [0.74-0.88] vs ROC = 0.69 [0.60-0.77]).

Conclusions:

A 25% cIVC cutoff value measured by POCUS detects fluid responsiveness. However, the experience of the physician sonologist affects test performance and should be considered when interpreting and clinically using cIVC to direct intravenous fluid resuscitation.
Dementia and patient safety: A Gewirthian analysis
Authors: Ó Néill Clayton
Published: October 2019

This article deals with the relationship between dementia and patient safety and proposes that measures to promote patient safety should be situated within a rights-based framework. This article calls for the current perspectives on patient safety to be broadened to further encompass patient safety procedures that encompass a holistic and individualistic view of the patient. Alan Gewirth’s Principle of Generic Consistency, as an underpinning moral principle, is applied in order to assess the appropriateness of current law, policy and practice. The article promotes the adoption of this principle as a moral justification for decisions that are taken in respect of patients with dementia and that are purported to protect their safety. It is argued that greater consideration needs to be given to ensuring that patient safety protocols are based upon a principled and empowering stance that does not impede the patient’s realisation of self-fulfilment. This process will be facilitated by adopting rights-based patient safety measures that promotes empowerment. Through the narrative of a fictional patient, Molly, the article presents a novel way of conceptualising patients with dementia, involving the movement from presenting the patient in terms of a linear, declining progression towards a conceptualisation of the patient as a persisting self.
Effect of Aid for Trade Unpredictability on Trade Policy in Recipient-Countries
Authors: Gnangnon Sèna Kimm
Published: October 2019

This article examines the effect of the unpredictability of Aid for Trade (AfT) flows on trade policy in 124 recipient-countries, of which 42 are least developed countries (LDCs), over the period 2002–2016. The analysis shows that while AfT flows exert a positive effect on trade policy liberalisation, AfT unpredictability induces the adoption of restrictive trade policies. These results apply to LDCs and other countries, although the magnitude of the negative effect of AfT unpredictability on trade policy liberalisation is higher for LDCs than for other countries. Furthermore, AfT unpredictability reduces the positive trade policy liberalisation effect of AfT flows.

JEL: F13, F14, F35
Etiology of Cleft Lip Lower Lip Deformity: Use of an Objective Analysis to Measure Severity
Authors: Langeveld Mirte , Bruun Richard A. , Koudstaal Maarten J. , Padwa Bonnie L.
Published: October 2019

Objective:

Measure lower lip thickness and eversion in patients with cleft lip and palate (CLP) and maxillary hypoplasia. The specific aims were to (1) compare lower lip thickness/eversion in patients with CLP to noncleft controls with maxillary hypoplasia, (2) determine differences between patients with unilateral CLP (UCLP) and bilateral CLP (BCLP), and (3) document changes in the lower lip that occur with Le Fort I advancement.

Design:

Retrospective case–control study.

Setting:

Tertiary care center.

Patients/Participants:

Patients with available pre- and postoperative CT scans and 2D lateral photographs who had a Le Fort I advancement between 2009 and 2017. There were 32 patients with CLP (17 females; mean age 17.7 ± 1.9 years) and 33 noncleft controls (21 females; mean age 18.8 ± 2.6 years).

Main Outcome Measures:

Lower lip thickness and eversion.

Results:

Patients with CLP and maxillary hypoplasia have a significantly thicker lower lip ( P = .019) and outward rotation of the vermilion border ( P = .003) compared to noncleft controls. The lower lip was significantly thicker in patients with BCLP than in those with UCLP ( P = .035). Lower lip thickness and rotation did not change after maxillary advancement.

Conclusions:

Patients with CLP and maxillary hypoplasia have a thicker and more everted lower lip than noncleft controls. Patients with BCLP have a significantly thicker lower lip than those with UCLP. Strain of the lower lip musculature appears to be an important contributor to the development of the cleft lip lower lip deformity.
Poorly Cohesive (Signet Ring Cell) Carcinoma of the Ampulla of Vater
Authors: Tuncel Deniz , Basturk Olca , Bradley Kyle T. , Kim Grace E. , Xue Yue , Reid Michelle D. , Balci Serdar , Erbarut Ipek , Adsay Volkan
Published: October 2019

In the ampulla of Vater, carcinomas with “diffuse-infiltrative”/“signet ring cell” morphology, designated as “poorly cohesive carcinoma” (PCC) in the WHO classification, are very rare and poorly characterized. Nine cases with a classical PCC morphology constituting >50% of the tumor were identified. Mean age was 64.8 years (vs 64.6 in ampullary carcinomas [ACs]) and 6 were males, 3 females. The mean invasive tumor size was 2.5 cm (vs 1.9 in ACs). Other morphologic patterns displayed included cord-like infiltration (n=2), plasmacytoid cells (n=2), and microglandular component (n=4), including goblet cell adenocarcinoma-like foci. None of the cases were associated with dysplasia. By immunohistochemistry, the carcinomas did not show intestinal differentiation (CDX2 0/9, CK20 1/9, MUC2 3/9), MUC1 was positive in 4/9, MUC5AC was positive in 7/8. E-cadherin loss was noted in 4/9. All cases were advanced stage (6/9-pT3, 3/9-pT4) (vs 43% in ACs). Lymph node metastases were identified in 44% (vs 45% in AC). Six patients (67%) died of disease at a median of 25 months, 3 were alive at 13, 15, and 60 months. Overall median survival was significantly worse than that of intestinal-type ACs (26 vs 122 months, P = .006) and trended toward worse than pancreatobiliary type (26 vs 42 months, P = .1). In conclusion, PCCs constitute 2.45% of all ACs. These present as advanced tumors and express upper-gastrointestinal immunoprofile with frequent MUC5AC labeling, which may be helpful in identifying subtle infiltration in the surface mucosa since MUC5AC is not expressed in the ampullary mucosa. Patients have poor prognosis.
A Mixed Methods Study of Change Processes Enabling Effective Transition to Team-Based Care
Authors: Kyle Michael Anne , Aveling Emma-Louise , Singer Sara
Published: October 2019

Team-based care is considered central to achieving value in primary care, yet results of large-scale primary care transformation initiatives have been mixed. We explore how underlying change processes influence the effectiveness of transition to team-based care. We studied 12 academically affiliated primary care practices participating in a learning collaborative, using longitudinal staff survey data to measure progress toward team-based care and qualitative interviews with practice staff to understand practice transformation. Transformation efforts focused on team formation and capacity building for quality improvement. Using thematic analysis, we explored types of change processes undertaken and the relationship between change processes and effective team-based care. We identified three prototypical approaches to change: pursuing functional and cultural change processes, functional only, and cultural only. Practice sites prioritizing both change processes formed the most effective teams: simultaneous functional and cultural change spurred a mutually reinforcing virtuous cycle. We describe implications for research, practice, and policy.
Parenting Interventions for Mothers With Problematic Substance Use: A Systematic Review of Research and Community Practice
Authors: Milligan Karen , Meixner Tamara , Tremblay Monique , Tarasoff Lesley A. , Usher Amelia , Smith Ainsley , Niccols Alison , Urbanoski Karen A.
Published: October 2019

Women with problematic substance use are frequently referred to interventions to promote positive parenting. Parenting interventions that attend to the unique risks faced by this population may enhance engagement and outcomes. While reviews of extant parenting interventions in the research literature have been undertaken, no studies have examined parenting interventions being implemented in community practice and the extent to which these are informed by current research. We systematically compared parenting interventions offered in 12 maternal substance use treatment programs in one Canadian province with those described in the research literature ( K = 21). Few parenting interventions were replicated, either within or across the two samples. However, parenting interventions within both samples were largely similar in their objectives. Across both research and community samples, approximately half of the interventions were developed or adapted for a problematic substance use population. Parenting knowledge, psychosocial risk, and maternal emotional regulation were most commonly addressed. Risks pertaining to the impact of drug craving and substance-related changes in neurobiology associted with parenting were less commonly addressed. Findings highlight current strengths and limitations of parenting interventions within research and community settings, with recommendations offered for future research and knowledge translation.
Examination of nursing drug administration practices via central venous catheter: An observational study
Authors: Gürol Arslan Gülşah , Özden Dilek , Alan Nurten , Yilmaz İlkin , Ayik Cahide , Göktuna Gizem
Published: October 2019

Aim:

To determine the compliance with nursing drug administration procedure steps associated with access to the central venous catheter for bolus infusion in intensive care units.

Methods:

This observational study was conducted with 30 nurses working in an intensive care unit of a university hospital. The drug administrations practiced by nurses via central venous catheter were monitored simultaneously at 12:00 a.m., 02:00 p.m., and 06:00 p.m. by two observers. The data were collected using a data collection form and central venous catheter drug administration procedure steps.

Results:

A total of 90 different drug administrations were observed in three different treatment hours from 30 nurses. The interobserver conformity was found to be moderate in two steps (kappa = 0.520–0.627, P = 0.01) and perfect in all other steps (kappa = 0.821–1.000, P = 0.000). According to the drug administration procedure steps via a central venous catheter, all nurses applied the following steps correctly during all treatment hours: drug card control, preparation of treatment materials, checking the patient’s identity, and steps of drug treatment administration. The following tasks were frequently performed incorrectly or not at all: hand hygiene (before treatment 87.8%; after treatment 82.2%), scrubbing the three-way stopcock entrance with an alcohol swab (55.6%), waiting for the alcohol to dry (81.1%), and flushing the lumen with a compatible fluid (before treatment 84.4%: after treatment 75.6%).

Conclusion:

Observation of drug administration procedure steps via central venous catheter according to the treatment hours showed that the nurses performed many incomplete or inaccurate drug administration procedure steps and the mistakes increased toward the evening hours.
Modeling and experimental study of power losses in a rolling bearing
Authors: Giannetti Guglielmo , Meli Enrico , Rindi Andrea , Ridolfi Alessandro , Shi Zhiyong , Tangredi Anna , Facchini Bruno , Fondelli Tommaso , Massini Daniele
Published: October 2019

Due to the growing demand for very high performance in aeronautical mechanisms and systems, particular attention must be paid on the bearing modeling and design. In this framework, a fundamental role is played by high peripheral speed and very low power losses. Looking toward this direction, this paper presents an improved model of rolling bearings able to describe the system dynamic behavior and the important effect of different kinds of power losses (friction losses, fluid dynamic losses, etc.). The proposed model is characterized by a high numerical efficiency and allows the investigation of the rolling bearing behavior both under transient and steady conditions. A comparison between the experimental and simulated results is also presented in this paper. The analysis of the results is encouraging and shows a good agreement between experiments and model simulations.
The long-term outcomes of CIS patients in the Barcelona inception cohort: Looking back to recognize aggressive MS
Authors: Tintore Mar , Arrambide Georgina , Otero-Romero Susana , Carbonell-Mirabent Pere , Río Jordi , Tur Carmen , Comabella Manuel , Nos Carlos , Arévalo María Jesús , Anglada Elisenda , Menendez Rebeca , Midaglia Luciana , Galán Ingrid , Vidal-Jordana Angela , Castilló Joaquin , Mulero Patricia , Zabalza Ana , Rodríguez-Acevedo Breogan , Rodriguez Marta , Espejo Carmen , Sequeira Joao , Mitjana Raquel , de Barros Andrea , Pareto Deborah , Auger Cristina , Pérez-Hoyos Santiago , Sastre-Garriga Jaume , Rovira Alex , Montalban Xavier
Published: October 2019

Objective:

To explore the long-term outcomes of patients with clinically isolated syndromes from the Barcelona cohort.

Methods:

We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years).

Results:

In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irreversible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast-enhancing lesions (CEL) was 71 (28–95) versus 7 (1–19) and 3 (1–24) versus 0 (0–1), respectively. The cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL.

Conclusion:

Although MS natural history is changing, a high lesion load at onset is helpful to identify patients at risk of presenting an aggressive MS.
The importance and potential of community partnerships in urban schools in an era of high-stakes accountability
Authors: Cummings Marlon I. , Olson Jennifer D.
Published: October 2019

In today’s era of increased accountability and standards-based reforms within the United States educational system, Community Partner Organizations (CPOs) can offer essential support to teachers, schools, and districts. CPOs have the potential to have a positive impact in urban schools in particular, where high-stakes testing and accountability policies are often more demanding and the threat of school closure or turnaround is the everyday reality for teachers who are under enormous pressure to improve student outcomes. Collaborative social relationships between schools and community organizations can facilitate school improvement, combat social and economic barriers, and meet the increasing demands of local, state, and federal accountability policies.
A systematic review and thematic synthesis exploring how a previous experience of physical activity influences engagement with cardiac rehabilitation
Authors: McHale Sheona , Astin Felicity , Neubeck Lis , Dawkes Susan , Hanson Coral L
Published: October 2019

Background:

Exercise-based cardiac rehabilitation is recognised internationally as an effective therapy to improve quality of life and reduce the risk of hospital readmission for individuals diagnosed with acute coronary syndrome. Despite this, half of eligible individuals choose not to engage and the main reason is lack of interest. Furthermore, prior to attending, 40% of eligible individuals report meeting physical activity guidelines. It is unclear whether this influences decisions about engagement.

Aims:

The aim of this review is to examine systematically qualitative evidence describing patients’ perceptions and experiences, and synthesise what is known about how a previous experience of physical activity in adults diagnosed with acute coronary syndrome influences engagement with physical activity during cardiac rehabilitation.

Methods:

A systematic review and thematic synthesis was conducted of primary qualitative studies to examine peer-reviewed literature published between1990 and 2017, accessed from database searches of MEDLINE, CINHAL, PsycINFO and Embase.

Results:

The initial search produced 486 studies, and of these 12 relevant studies were included in this review. Studies included 388 participants from six countries. For previously active individuals, communication factors, self-perceptions of an exercise identity and experience of cardiac rehabilitation influence engagement in physical activity during cardiac rehabilitation.

Conclusion:

In adults diagnosed with acute coronary syndrome, communication post event and during cardiac rehabilitation is a source of self-appraisal and creates expectations of cardiac rehabilitation. In addition, perceptions of an exercise identity and experience of exercise-based cardiac rehabilitation influence decisions about engagement. To improve uptake and adherence, health professionals should consider previous physical activity levels and tailor information to optimise physical activity post event.
Flame-retardant cotton fabrics modified with phosphoramidate derivative via electron beam irradiation process
Authors: Liu Ying , Zhou Li , Ding Fang , Li Shanshan , Li Rong , Li Zhiguang , Huang Dan , Ren Xuehong
Published: October 2019

In this study, a novel flame-retardant diethyl methacryloylphosphoramidate containing phosphorus and nitrogen was synthesized and characterized by Fourier transform infrared and nuclear magnetic resonance. The synthesized compound was grafted onto cotton fabrics using electron beam irradiation and pad dry cure processes. Scanning electron microscope and X-ray photoelectron spectroscopy were used to characterize the surfaces of the modified cotton fabrics to confirm that diethyl methacryloylphosphoramidate was grafted on cotton fabrics successfully. Both electron beam–cotton and pad dry cure–cotton exhibited efficient flame retardancy which was proved by limiting oxygen index and vertical flammability test. Thermogravimetric analysis results showed that both electron beam-cotton and pad dry cure–cotton degraded at lower temperature and produced higher yields at 600℃. The tensile loss of electron beam–cotton was lower than that of pad dry cure–cotton, and within the acceptable range in flame retardant finishing.
The reification of structural violence in video games
Authors: Denham Jack , Hirschler Steven , Spokes Matthew
Published: October 2019

The Grand Theft Auto franchise features prominently within existing research exploring graphic, virtual, lawless, and damagingly realistic interpersonal violence within video games. Following a review of this literature, we empirically interrogate notions of the ‘realistic’ and the ‘violent’ during gameplay, finding that the undertones of systemic, structural, capitalistic violence are experienced by players as providing the gritty sense of the ‘real’ that the game has been criticised for. Using Galtung’s concept of ‘structural violence’ and Žižek’s notion of the ‘real’, we unpack structural violence as the forerunning violent experience in the open world game. Due to the hidden and subdued nature of this violence, often taken for granted and experienced passively, we argue that it is the most impactful player experience that simultaneously makes the game playable and contextualises violent game activities. For cultural criminology, our data suggest that embedded and discrete forms of violence should be the leading edge of concern when studying the digital economy and playable forms of social harm.
Abjection, Derision and Power: Writing in the Voice of the Victim in Three French Post-War Texts
Authors: Atack Margaret
Published: October 2019

Alongside the well-known narratives of the mode rétro, which returned in the 1970s to the years of war and Occupation in France, there were texts that challenged simplistic notions of guilt and innocence through a virtuoso deployment of sarcasm and derision. Romain Gary’s La Danse de Gengis Cohn (1967), Albert Cohen’s Ô vous frères humains (1972) and Serge Gainsbourg’s album Rock Around the Bunker (1975) are all confronting the cruelty and abjection of a murderous anti-Semitism in intimate and disturbing ways. These are very different texts – a novel, an autofictional essay and an LP – but each one gives a powerful voice to the victim in these complex stories of hatred and fear. Derision enacts an aggressive dismantling of the stereotypes and tropes of the abject Other, exposing the vacuity of established pieties, the contradictions and hypocrisies at the heart of a rhetoric of superiority. Briefly situated in relation to earlier (Camus, Céline, Sartre) and later (Littell) narratives of derision relating to war and occupation centred on the perpetrator, a detailed critical and narrative analysis draws on Julia Kristeva’s analysis of abjection in order to identify what is at stake in these elaborate, stylised and unsettling texts where it is the abjected victim who is the subject of their own story.
Protocol for the Study of Heart and Renal Protection-Extended Review: Additional 5-Year Follow-up of the Australian, New Zealand, and Malaysian SHARP Cohort
Authors: Sukkar Louisa , Talbot Ben , Jun Min , Dempsey Erika , Walker Robert , Hooi Lai , Cass Alan , Jardine Meg , Gallagher Martin
Published: October 2019

Background:

There are limited studies on the effects of statins on outcomes in the moderate chronic kidney disease (CKD) population and their trajectory to end-stage kidney disease.

Objective:

To examine the long-term effects of lipid-lowering therapy on all-cause mortality, cardiovascular morbidity, CKD progression, and socioeconomic well-being in Australian, New Zealand, and Malaysian SHARP (Study of Heart and Renal Protection) trial participants—a randomized controlled trial of a combination of simvastatin and ezetimibe, compared with placebo, for the reduction of cardiovascular events in moderate to severe CKD.

Design:

Protocol for an extended prospective observational follow-up.

Setting:

Australian, New Zealand, and Malaysian participating centers in patients with advanced CKD.

Patients:

All SHARP trial participants alive at the final study visit.

Measurements:

Primary outcomes were measured by participant self-report and verified by hospital administrative data. In addition, secondary outcomes were measured using a validated study questionnaire of health-related quality of life, a 56-item economic survey.

Methods:

Participants were followed up with alternating face-to-face visits and telephone calls on a 6-monthly basis until 5 years following their final SHARP Study visit. In addition, there were 6-monthly follow-up telephone calls in between these visits. Data linkage to health registries in Australia, New Zealand, and Malaysia was also performed.

Results:

The SHARP-Extended Review (SHARP-ER) cohort comprised 1136 SHARP participants with a median of 4.6 years of follow-up. Compared with all SHARP participants who originally participated in the Australian, New Zealand, and Malaysian regions, the SHARP-ER participants were younger (57.2 [48.3-66.4] vs 60.5 [50.3-70.7] years) with a lower proportion of men (61.5% vs 62.8%). There were a lower proportion of participants with hypertension (83.7% vs 85.0%) and diabetes (20.0% vs 23.5%).

Limitations:

As a long-term follow-up study, the surviving cohort of SHARP-ER is a selected group of the original study participants, which may limit the generalizability of the findings.

Conclusion:

The SHARP-ER study will contribute important evidence on the long-term outcomes of cholesterol-lowering therapy in patients with advanced CKD with a total of 10 years of follow-up. Novel analyses of the socioeconomic impact of CKD over time will guide resource allocation.

Trial Registration:

The SHARP trial was registered at ClinicalTrials.gov NCT00125593 and ISRCTN 54137607.
Are Achievement Gaps Related to Discipline Gaps? Evidence From National Data
Authors: Pearman Francis A. , Curran F. Chris , Fisher Benjamin , Gardella Joseph
Published: October 2019

There is growing interest in the relation between the racial achievement gap and the racial discipline gap. However, few studies have examined this relation at the national level. This study combines data from the Stanford Education Data Archive and the Civil Rights Data Collection and employs a district fixed effects analysis to examine whether and the extent to which racial discipline gaps are related to racial achievement gaps in Grades 3 through 8 in districts across the United States. In bivariate models, we find evidence that districts with larger racial discipline gaps have larger racial achievement gaps (and vice versa). Though other district-level differences account for the positive association between the Hispanic-White discipline gap and the Hispanic-White achievement gap, we find robust evidence that the positive association between the Black-White discipline gap and the Black-White achievement gap persists after controlling for a multitude of confounding factors. We also find evidence that the mechanisms connecting achievement to disciplinary outcomes are more salient for Black than White students.
Enhancing a Wnt-Telomere Feedback Loop Restores Intestinal Stem Cell Function in Dyskeratosis Congenita
Authors: Lengner Christopher
Published: October 2019

Patients with dyskeratosis congenita (DC) suffer from stem cell failure in numerous organs, including the skin, intestine, blood, lung, and liver, due to hypomorphic loss-of-function mutations in proteins that promote telomere elongation or capping. Few therapeutic options exist for this disorder, and while patients are treated with bone marrow transplantation to restore hematopoietic function, this does not address the multi-organ failure, and in some cases can exacerbate it. We generated isogenic DC patient and disease allele-corrected induced pluripotent stem (iPS) cell lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene correction to model the stem cell failure characteristic of DC in multiple organ systems through the directed differentiation. We focused first on the intestinal epithelium, as GI manifestations of DC (enteropathy/enterocolitis ) are often the first and most severe symptoms in pediatric patients. We demonstrate that DC tissue has suboptimal Wnt pathway activity causing intestinal stem cell failure and that enhanced expression of the telomere-capping protein TRF2, a Wnt target gene, can alleviate DC phenotypes. Treatment with the clinically relevant Wnt agonists LiCl or CHIR99021 restored TRF2 expression and reversed gastrointestinal DC phenotypes, including organoid formation in vitro, and maturation of intestinal tissue and xenografted organoids in vivo. These findings establish the existence of a feed-forward loop between telomerase/telomere capping and the canonical Wnt pathway which is broken in DC, but can be restored by promoting capping and/or Wnt pathway agonists. Moving forward, we have begun to extend these investigations into the lung and liver, where fibrosis and organ failure are major clinical concerns in DC. Thus, the isogenic DC iPS cell model provides a framework for therapeutic discovery and identifies Wnt modulation as a potential strategy for treatment of DC patients.

Disclosures

No relevant conflicts of interest to declare.
High Neuropilin-1 Expression in Acute Myeloid Leukemia Is Mainly Associated with Monocytic Subtypes and Extramedullary Invasion
Authors: ElNahass Yasser H , Samra Mohamed Abdel Mooti , Fahmy Omar A , Elrefaey Fatma A , Eltokhy Soad , Mahmoud Hossam K
Published: October 2019

Introduction: Neuropilins are single-pass transmembrane glycoproteins acting as receptors for the vascular endothelial growth factor (VEGF) family that mediates angiogenesis and vascular development. In Acute Myeloid leukemia (AML), Neuropilin-1 high expression was found to contribute in disease evolution.

Aim of Work: To evaluate Neuropilin-1 (NRP-1) expression in AML patients especially monocytic subtypes and assess its role in disease progression and extramedullary invasion (EMI).

Patients and Methods: We measured NRP-1 expression level in 50 denovo AML patients who presented to the National Cancer institute, Cairo university. Expression was assessed by Real time quantitative PCR (RQ-PCR) using normalized copy number equation (2 -ΔΔ CT) in relation to normal healthy controls. AML patients were characterized according to their Bone marrow and peripheral blood morphology, karyotype, immunophenotyping and FLT3 internal tandem duplication (FLT3-ITD) by polymerase chain reaction (PCR). Patients were classified into 2 groups according to median NRP-1 expression into low ≤60 and high >60-fold expression.

Results: 33 males (66%) and 17 females (34%) with a median age of 34 years (18-73) were included. Cytogenetic risk categories were low in 12 (24%), intermediate in 34 (68%) and high in 4 (8%) patients. No correlation was found between high NRP-1 and cytogenetic risk classes or FLT3-ITD.

Out of 26 patients showing high NRP-1 expression; 19 (73%) were <40 years vs. 7(27%) >40 years (p=0.049) and 24 (92%) showed BM blasts >50% vs. 2 (8%) with < 50% BM blasts (p<0.001). A positive correlation was found between NRP-1 Fold -change and BM blasts (r=0.653, p=0.004). Out of 19 monocytic FAB subtypes (M4, M5), high NRP-1 expression was expressed in 16 (84%) vs. 10/31 (32%) patients presenting with other FAB subtypes (p=0.042). Out of 26 patients showing high NRP-1 expression, extramedullary invasion (EMI) was found in 23/26 (88%) vs. 3/26 (12%) patients only with no EMI (p=0.001).

Conclusion: Neuropilin-1 is useful as a prognostic marker of extramedullary invasion for AML patients especially in monocytic subtypes . Its role in disease progression and severity is still to be evaluated in our patients.

Key Words: Neuropilin-1, AML, extramedullary invasion

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Adverse Reactions of Gemcitabine Combined with Cyclophosphamide, Vinblastine and Prednisone Hydrogenation Regiments in Relapse and/or Refractory Non-Hodgkin's Lymphoma
Authors: Wang Baiyan , Liu Jie , Chen Yin-Xia , Cao Xing-Mei , Zhao Wan-Hong , Wang Jian-Li , Ma Xiao-Rong , Yang Yun , Zhang Peng-Yu , Wang Fang-Xia , Gu Liu-Fang , Lei Bo , Wang Jin , Bai Ju , Zhang Yi-Lin , Xu Yan , He Ai-Li , Zhang Wang-Gang
Published: October 2019

Objective: To explore the clinical efficacy and adverse reactions of gemcitabine combined with cyclophosphamide, vinblastine and prednisolone (GCVP regiments) in the treatment of relapse and/or refractory non-hodgkin's lymphoma (NHL) in adults patients. Methods: 27 relapse and/or refractory non-hodgkin's lymphoma adult patients (Median:58 years old; range:47-72 years old) were diagnosed and previously treated with regimens such as R-CHOP(E), CHOP(E), MAED (Mitoxantrone, Cytarabine, Etoposide, Dexamethasone), FCM (Fludarabine, Cyclophosphamide, Mitoxantrone) based chemotherapy. There were 19 cases of diffuse large B cell lymphoma, 6 cases of follicular lymphoma, 1 case of NK/T cell type and 1 case of T cell NHL respectively. The GCVP chemotherapy (1000mg/m2 of gemcitabine, 750mg/m2 of cyclophosphamide, 25mg/m2 of vinblastine, intravenous drip on day 1 and day 8, prednisolone 50mg by intravenous drip on day 1 to day 5) were applied to these patients, safety and efficacy analyses were evaluated after two cycles. All patients provided written informed consent. Results: Among all the 27 patients who received GCVP chemotherapy, 3 patients achieved complete remission (CR) (11.11%), 15 patients achieved partial remission (PR) (55.56%), 9 patients with stable disease (SD) (33.33%), the overall response rate (ORR, CR+PR) was 66.67%. Patient's follow-up was continued after treatment, and the median duration of progression-free survival was 60 days. The main adverse events were bone marrow suppression, others were mild to moderate gastrointestinal reactions, a few had mild liver function damage, and it was reversible through hepatoprotection therapy. The most common grade ≥3 adverse events were leukopenia (33.33%, 9/27 cases), thrombocytopenia (40.74%, 11/27 cases), while anemia and gastrointestinal reaction were 11.11% (3/27 cases) and 3.70% (1/27 cases) respectively, no treatment-related death occurred. Discussion and conclusion: The overall outcomes for patients with lymphoma was improved, but there still part of NHL patients suffered form relapse or primary drug resistance, and the prognosis of these patients was poor. Gemcitabine combined with cyclophosphamide, vinblastine and hydrogenated prednisone has a good short-term efficacy in the treatment of relapse and/or refractory NHL. The main adverse reactions were hematologic toxicity and gastrointestinal reaction, mild liver function damage, and no treatment-related death was observed.

Disclosures

No relevant conflicts of interest to declare.
The Impact on Survival of EBV Positive Diffuse Large B- Cell Lymphoma, Not Otherwise Specified in Young Adults
Authors: Beltrán Brady E. , Castro Denisse A. , Vega Julio , Malaga Jose Manuel , Postigo Mauricio , Gallo Ali , Sotomayor Eduardo , Castillo Jorge J.
Published: October 2019

Introduction: Epstein Barr virus-positive (EBV+) diffuse large B- cell lymphoma (DLBCL), not otherwise specified (NOS) is a new entity recognized by the WHO 2016. This entity was widely studied in older age patients, but in recent years there are few reports that show that EBV positive DLBCL, NOS can affect younger adults and there is a lack of evidence in this age group. The aim of this study is to evaluate the impact on survival in EBV+ DLBCL, NOS in young adults.

Methods: The study was retrospective, reviewing clinical records of patients treated at Rebagliati Martins Hospital between years 2002 - 2013. Patients of both sexes ≥ 18 years old, but ≤ 50 years old, with the diagnosis of EBV+DLBCL, NOS were included. IRB approval was obtained prior to research. Pathological samples were reviewed by hematopathologists at our institution to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. Overall survival (OS) was determinate according to the Kaplan -Meier method, the comparison of the survival curves were made with the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratios (HR) for OS.

Results: A total of 57 patients with a diagnosis of EBV+DLBCL, NOS were included in this analysis. The median age at diagnosis was 43 years (range 25-50 years), 61 % of patients were older than 40 years old and there was a slight female predominance (51%). Clinically, 55% presented ECOG >1, 57% had B symptoms, 68% had an extranodal disease as a primary tumor, 50% had stage III/IV and 26% had ≥ 1 extranodal site involved. EBV positivity was present in 16% of patients (9 patients). PDL-1 expression was present in 12% of patients. 92% received first-line treatment, but 7% of patients did not for progressive disease and death at diagnosis. During the treatment, 92% of patients received R-CHOP and 8% received other regimens. The overall response rate was 71%; 63% had a complete response and 7% had a partial response. The 5-year OS rate was 59%. In the univariate analysis, EBV positivity (<0.001) and ≥ 1 extranodal site involved (p=0.011) were associated with a poor prognosis. In the multivariate analysis, patients with EBV positive had a worse outcome (HR 7.8, 95% 2.2-25.9.2; p=0.001).

Conclusions: The prevalence of EBV in young adults with DLBCL is high compared with other series and there is an adverse impact on overall survival in this group of patients.

Figure. Figure.

Disclosures

Castillo: Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Millennium: Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.
BCOR Regulates Cell Fate Transition, Myeloid Differentiation and Leukaemogenesis
Authors: Kats Lev M , Kelly Madison J , Gregory Gareth , Johnstone Ricky W , Vervoort Stephin J
Published: October 2019

Stem cell self-renewal and lineage specification are highly dynamic and tightly controlled processes that are essential for normal haematopoiesis and are dysregulated in cancer. The X-linked BCL6 Corepressor (BCOR) gene encodes a protein that is widely expressed across adult human tissues and is a component of a non-canonical Polycomb repressive complex 1 (PRC1). The BCOR gene is recurrently mutated in various malignant and non-malignant blood disorders, and we and others have recently provided experimental evidence that BCOR has cell-context dependent functions in regulating the proliferation, differentiation and survival of haematopoietic cells. To comprehensively examine the role of BCOR in haematopoiesis in vivo we used a conditional mouse model that mimics the truncating mutations observed in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Using stem and progenitor populations isolated ex vivo we comprehensively analysed the role of BCOR in regulating gene expression, modifying chromatin and altering genome architecture. We demonstrate that BCOR has a pivotal role in down-regulating haematopoietic stem cell (HSC) associated transcriptional networks during the transition from multi-potent stem cells to lineage-committed myeloid progenitors. Inactivation of Bcor in HSCs results in expansion of myeloid progenitors and co-operates with oncogenic KrasG12D in the initiation of an aggressive and fully transplantable acute leukaemia. Mechanistically, Bcor regulates a subset of PRC1-target genes including key HSC super-enhancer-linked transcription factors that are normally down-regulated during myeloid differentiation. We used CRISPR/Cas9 to explore the function of Bcor target genes and identified those that are necessary for the proliferation of Bcor mutant leukaemic cells. This study provides a comprehensive mechanistic understanding of how BCOR regulates cell fate decisions and contributes to the development of leukaemia.

Disclosures

No relevant conflicts of interest to declare.
Composition of Classical Hodgkin Lymphoma Microenvironment Is Associated with Clinical Outcome
Authors: Novosad Olga , Skrypets Tetiana , Svergun Nataliia , Skachkova Oksana , Gorbach Oleksandr , Khranovska Nataliia , Krotevych Mykhailo , Skoroda Larisa , Koshubarova Maryna , Novikov Dmitry , Kriachok Iryna
Published: October 2019

Background.

Classical Hodgkin's lymphoma (cHL) is characterized by only few malignant cells and an abundance of inflammatory cells.cHL infiltrating cells produce cytokines and growth factors that provide essential stimulatory signals for survival and proliferation of Hodgkin and Reed-Sternberg (HRS) cells. Moreover, clinical behaviour of cHL may be directly regulated by the cross-talk between HRS cells and other cells in their microenvironment. The aim of our study was to estimate the role of microenvironmental composition in clinical outcome of cHL.

Methods.79 patients (pts) with cHL were included in this study (median age: 41, range: 18-65 years; males: 26, females: 53).Patients were treated with ABVD or BEACOPP (14/esc) and radiation therapy. CR/PR was achieved in 86.1% of patients. 13.9% of pts had relapse or disease progression during the therapy.

Using IHC and qPCR techniques, we analyzed lymph-node biopsy obtained from patients during diagnostic to determine cellular and cytokine signature (CD3, CD19, CD11b, PD-L1, PD-L2, IDO, TGF-β, IL-13) that correlates with cHL treatment outcome.

Results. Expression level of tested markers was heterogeneous across the samples and did not correlate with histological variant or stage of cHL. For most of cytokines as well as immunomodulatory molecules we did not notice significant independent effect on cHL clinical outcome, except IL-13, which appeared to be a strong and independent marker of cHL prognosis. High expression of IL-13 was associated with lower EFS and OS rates comparing to IL-13 low/negative group (p<0.05).

We found that the presence of myeloid CD11b+ cells in cHL microenvironment correlates significantly with shortened EFS rate (p<0.05). Multivariate analysis has shown that the negative impact of presence of myeloid cells increases gradually when combined with elevated expression of one or more following markers - PD-L1, IDO or TGF-β (p<0.05). At the same time, we did not find any significant associations between cHL outcome and B- or T-cells populations

Conclusion.In summary, our study showed the presence of CD11b+ myeloid cells together with increased expression of checkpoints molecules and cytokines (PDL1, IDO, TGF-β and IL-13)in diagnostic lymph-node samples is associated with cHL clinical outcome.

Disclosures

No relevant conflicts of interest to declare.
"Ultrasensitive Reactive C-Protein As an Affordable Biomarker of Quantitative Expression of the BCR-ABL Transcript in Chronic Myeloid Leukemia. an Exploratory Study."
Authors: Villela Luis , Otañez Arce Melani , Best Carlos , Guzman Alicia , Estrada Elva Gabriela , Rivera Mendoza Laura , Lopez Hernandez Juan Carlos , Robles Arianna , Gomez-Almaguer David
Published: October 2019

INTRODUCTION

Real-time PCR (PCRq) quantification of the BCR-ABL transcript is the most reliable response marker in Chronic Myeloid Leukemia (CML), its levels have proven prognostic implications. However, in some centers it is still a difficult diagnostic tool to access. The ultrasensitive C reactive protein (pcrU) is an exquisite marker of inflammation and contextually the increased activity of the BCR-ABL transcript is associated with an inflammatory state mediated among others by IL-6. Here we explore the association between the molecular response (RM) induced with Imatinib mesylate and the serum levels of pcrU as a possible biomarker of leukemic activity.

OBJECTIVE

To explore the association between the quantitative expression of the BCR-ABL transcript and the serum levels of pcrU by turbidimetry.

PATIENTS AND METHODS

15 patients with CML were studied, in 14 of them the BCR-ABL transcript was determined after 1 year of treatment by PCRq together with the serum levels of pcrU, any inflammatory state present during the sampling was ruled out. As a control 1 patient was studied at diagnosis as described.

RESULTS

There is a significant concordance between molecular status and serum levels of pcrU in 13 of the 15 patients studied (87% true negatives and 13% false positives). Table 1. When the diagnostic test was performed to evaluate pcrU as a possible MRI biomarker, we observed that it presents a sensitivity of 100%, specificity 84.6% (in an area under the curve of 93%), Positive Predictive Value (PPV) 50% and Negative Predictive Value (NPV) 100%. The probability index (+) = 6.5 (IC95%: 1.8 to 23.2), while the probability index (-) = 0.

DISCUSSION

The inflammation promoted by the tumor and the escape of the immunologically mediated tumor destruction, have been recognized as the hallmark of cancer and the myeloid cells are key players in this process. Therefore, the detection of an ultrasensitive biomarker of inflammation theoretically has the potential to detect leukemic activity. In this exploratory study a remarkable association was found between the molecular status and the levels of pcrU, making an extension of this study a goal to be pursued.

Disclosures

Best: Novartis: Consultancy; AbbVie: Consultancy. Gomez-Almaguer:AbbVie: Consultancy; Novartis: Consultancy.
Novel Thyrointegrin αvβ3 Antagonist for the Treatment of Acute Myeloid Leukemia
Authors: Mousa Shaker A , Sudha Thangirala Institute , Godugu Kavitha , Rajabi Mehdi , Tipu Nazeer , Davis Paul J
Published: October 2019

Acute myeloid leukemia accounts for up to one-third of the more than 60,000 leukemias diagnosed annually in the U.S. Primary AML cells express membrane αvβ3 integrin, which is associated with adverse prognosis and resistance to chemotherapies used in AML. A macromolecule Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) acts with high affinity (Ki 3.1 nM) and specificity for the thyrointegrin αvβ3 receptors, without nuclear translocation and has demonstrated effective suppression of cancer cell proliferation, NF-kB expression and invasion in leukemic cells.

We evaluated P-bi-TAT in two different AML models against two forms of acute leukemia (monocytic and myelocytic) that are largely resistant to existing therapy, by grafting human leukemia cells in immunocompromised male and female mice. IVIS imaging scans revealed that leukemic colonies were extensively established in bone marrow throughout the control (untreated) grafted animals, as well in liver, lung and kidney. Smears of bone marrow aspirates from untreated animals were found to contain multinucleate myeloblast and monoblast leukemic cells, and peripheral blood smears contained blast cells, multinucleated megakaryocytes, giant platelets and platelet aggregates, which are hallmarks of acute leukemia. IVIS imaging scans revealed 95% reduction in bone marrow colonies and resolution of liver, kidney and lung colonies in animals treated with P-bi-TAT at daily doses ranging from 1-10 mg/kg, subcutaneously for 2-3 weeks. Peripheral blood smears from treated animals were normal. Normal myeloblasts, which are the source of functional white blood cells, were found in the marrow smears, but leukemic cells were not detected in P-bi-TAT treated animals. Thus, against two forms of leukemia models, P-bi-TAT was extraordinarily effective, with the potential in treating most AML sub-types because αvβ3 receptors are expressed in the majority of AML. Among genes targeted by multiple laboratories for pharmacological downregulation of expression in AML are BCL2, VEGF, AKT1, KIT, IDH2, CDK4/6, TIMP1, VEGF, EGFR, and PD-L1. In that regard, P-bi-TAT has been shown in various tumor cell models to downregulate transcription of each of the genes listed, which are relevant to AML disease progression. Additionally, the pro-apoptotic P53 gene transcription is enhanced by P-bi-TAT.

In conclusion, P-bi-TAT is a promising lead clinical candidate that warrants clinical trials in AML patients.

Disclosures

Mousa: NanoPharmaceuticals LLC: Equity Ownership, Patents & Royalties. Davis:NanoPharmaceuticals LLC: Employment, Equity Ownership.