bluuebunny/crossref_metadata_2025 huggingface dataset:
Pseudotumoral Actinomycosis Mimicking Malignant Colic Disease: A Case Report and Literature Review
Authors: Jabi Rachid , Ramdani Hanae , Elmir Siham , Elmejjati Fouad , Serji Badr , El Harroudi Tijani , Bouziane Mohammed
Published: October 2019

Abdominal actinomycosis is a rare, chronic, and often unrecognized suppurative disease. It is caused by an anaerobic gram-positive bacterium, most commonly Actinomyces israeli. Colonic actinomycosis is rarely reported and may be responsible for a pseudotumoral syndrome leading, in the suspicion of malignancy, to a large and mutilating excisional surgery. It is usually the histopathological examination of the surgical specimens that accurately corrects the diagnosis. Here, we report a rare case of a colic actinomycotic involvement taking a pseudotumoral form. The diagnosis was made based on the pathological examination of the surgical piece. Intravenous and then adjuvant oral penicillin G treatment has allowed a favorable clinical evolution. This observation illustrates the preoperative diagnostic difficulties of this rare disease.
The Two Faces of First-Rank Symptoms
Authors: Picardi Angelo
Published: October 2019

Recently, there has been renewed interest in Schneider’s first-rank symptoms (FRS) of schizophrenia, thanks in part to a meta-analysis of their diagnostic accuracy, which deserves much credit for its methodological rigor. Conceptualising FRS as a diagnostic test whose performance can be measured in terms of sensitivity and specificity involves some issues that require reflection. First, the full adequacy of sensitivity as a measure of diagnostic accuracy for FRS might be questioned. However, it is conceptually acceptable, though FRS are at a disadvantage as compared with many other psychiatric “diagnostic tests” that should have perfect sensitivity under ideal conditions. Also, from a psychopathological perspective it may well be argued that FRS cannot be conceptualised as a simple, inexpensive diagnostic test suitable for screening purposes; however, the history of the concept reveals some reasons why it may be legitimate to view them this way. While no other relevant study has appeared after the publication of the meta-analysis, data on a further 166 patients from a study that could not be included due to incompletely reported data were located. This brought the total to 4,236 patients from 17 studies on the ability of FRS to differentiate schizophrenia from other psychoses. The resulting summary estimates of sensitivity, specificity and positive and negative likelihood ratios are 60.2%, 75.9%, 2.50, and 0.52, respectively. FRS have a kind of double nature, as they can be legitimately considered as belonging to both a sophisticated framework grounded in phenomenological psychopathology and an eminently pragmatic framework grounded in clinical epidemiology. When FRS are conceptualised as simple clinical indicators that require low levels of inference, the available estimates of their diagnostic accuracy are a fairly valid appraisal of their performance and usefulness, and suggest that FRS have some value in differential diagnosis. However, when FRS are conceptualised as profoundly anomalous experiences that can be properly identified and evaluated only by using a phenomenological approach, these estimates can hardly be seen as a valid evaluation of their diagnostic significance. Phenomenologically informed studies are needed to address this research gap.
Exercise Pressor Reflex Contributes to the Cardiovascular Abnormalities Characterizing
Authors: Sidhu Simranjit K. , Weavil Joshua C. , Rossman Matthew J. , Jessop Jacob E. , Bledsoe Amber D. , Buys Michael J. , Supiano Mark S. , Richardson Russell S. , Amann Markus
Published: October 2019

We investigated the impact of hypertension on circulatory responses to exercise and the role of the exercise pressor reflex in determining the cardiovascular abnormalities characterizing patients with hypertension. After a 7-day drug washout, 8 hypertensive (mean arterial pressure [MAP] 130±4 mm Hg; 65±3 years) and 8 normotensive (MAP 117±2 mm Hg; 65±2 years) individuals performed single-leg knee-extensor exercise (7 W, 15 W, 50%, 80%-W
peak
) under control conditions and with lumbar intrathecal fentanyl impairing feedback from µ-opioid receptor-sensitive leg muscle afferents. Femoral artery blood flow (Q
L
), MAP (femoral artery), leg vascular conductance, and changes in cardiac output were continuously measured. While the increase in MAP from rest to control exercise was significantly greater in hypertension compared with normotension, the exercise-induced increase in cardiac output was comparable between groups, and Q
L
and leg vascular conductance responses were ≈18% and ≈32% lower in the hypertensive patients (
P
<0.05). The blockade-induced decreases in MAP were significantly larger during exercise in hypertensive (≈11 mm Hg) compared with normotensive (≈6 mm Hg). Afferent blockade attenuated the central hemodynamic response to exercise similarly in both groups resulting in a ≈15% lower cardiac output at each workload. With no effect in normotensive, afferent blockade significantly raised the peripheral hemodynamic response to exercise in hypertensive, resulting in ≈14% and ≈23% higher Q
L
and leg vascular conductance during exercise. Finally, Q
L
and MAP during fentanyl-exercise in hypertensive were comparable to that of normotensive under control conditions (
P
>0.2). These findings suggest that exercise pressor reflex abnormalities largely account for the exaggerated MAP response and the impaired peripheral hemodynamics during exercise in hypertension.
Headache Outcomes After Treatment of Unruptured Intracranial Aneurysm
Authors: Dandurand Charlotte , Parhar Harman S. , Naji Faysal , Prakash Swetha , Redekop Gary , Haw Charles S. , Prisman Eitan , Gooderham Peter A.
Published: October 2019

Background and Purpose—

While unruptured intracranial aneurysms may be discovered incidentally in the workup of chronic headache, it remains unclear whether their treatment ultimately impacts headache severity. We aim to conduct a systematic review and meta-analysis assessing headache severity after treatment of unruptured intracranial aneurysm.

Methods—

MEDLINE and EMBASE were systematically reviewed.

Results—

Data from 7 studies met inclusion criteria (309 nonduplicated patients). The standard mean difference in pre- and post-intervention headache severity was estimated at −0.448 (95% CI, −0.566 to −0.329) under a random effects model. No significant heterogeneity was noted nor was any significant publication bias demonstrated.

Conclusions—

This is the first systematic review assessing postoperative headache severity following treatment of unruptured intracranial aneurysm. While a significant reduction in headache severity was observed, further investigation into this phenomenon is recommended before it influences clinical practice. Future study should stratify headache outcomes by aneurysm size, location, and treatment modality.
ELEKTRONİK TİCARETİN KULLANIMINDA KRİTİK BAŞARI FAKTÖRLERİNİN ETKİSİ VE TÜRKİYE’DE FAALİYET GÖSTEREN ELEKTRONİK TİCARET İŞLETMELERİNDE BİR ARAŞTIRMA
Authors: ZENGİN Nevzat
Published: October 2019

Bu çalışma, elektronik ticaretin kullanımında kritik başarı faktörlerinin etkisin anlamak amacına hizmet etmektedir. Araştırmanın modeli, niceliksel araştırma türünde olup tarama modellerinden genel tarama modelidir. Anket araştırması kısmında ise kolayda örnekleme yöntemi ile Türkiye’nin farklı yerlerinde elektronik ticaret faaliyetleri yürüten firmaların karar vericileri -yöneticileri, firma sahipleri ya da ortakları- ile görüşülmüştür. Araştırmaya toplam 371 kişi katılmış ve kendilerine 45 soru yöneltilmiştir. Yöneltilen sorular elektronik ticaret performanslarını ölçmeye yöneliktir ve firmaların bulunduğu yer, e-ticaret yapma süreleri, hukuki altyapıları gibi çok fazla değişkenin incelenmesine çalışılmıştır. Sonuçlar, SPSS 21 istatistik programı yardımı ile analiz edilmiştir. Araştırmanın analizinde, geçerlilik ve güvenilirlik analizleri, faktör analizleri, ölçek puanlarının betimleyici istatistikleri, karşılaştırma analizleri ile beraber elektronik ticarette kritik başarı faktörlerinin etkisi değerlendirilmeye çalışılmıştır. Çalışmanın sonucunda; elektronik ticareti etkileyen kritik başarı faktörleri bulguları ortaya çıkmıştır. Bu faktörler ise sırasıyla, Sitenin etkinliği ve erişilebilirliği, İşletmeye ve siteye yönelik marka değeri, Müşteriye yönelik sosyal fayda, İşletme içi ve devlet odaklı yönetimsel etkenler olmak üzere 4 kritik başarı faktörü bulunmuştur.
GENDER INEQUALITY IN LABOR FORCE PARTICIPATION IN TURKEY: CLOSING THE GENDER GAP?
Authors: İNCE YENİLMEZ Meltem
Published: October 2019

The roles and status of women have been discovered to be lagging behind in developing countries, especially when it comes to distribution of resources. Why? You may ask. The answer is not far-fetched. The cultural and demographic values developed overtime, as well as the practice of having a social system that is run by males rather than females, are a few reasons for this. Owing to the fact that the existing socio-cultural environment goes a long way to determine how things are accorded to both genders both in the home front, as well as in the labor market, it is not surprising to find women in Turkey lagging behind in many aspects. The purpose of this study is to observe and understand the inherent relationship between female unemployment and economic inequality with regards to the social and demographic norms surrounding the female gender in Turkey. In addition, reducing informal employment, promoting high quality and productive jobs are crucial for addressing the problems of female unemployment.
Iodosphaeria honghense sp. nov. (Iodosphaeriaceae, Xylariales) from Yunnan Province, China

Authors: MARASINGHE DIANA S. , SAMARAKOON MILAN C. , HONGSANAN SINANG , BOONMEE SARANYAPHAT , MCKENZIE ERIC H. C.
Published: October 2019

Iodosphaeria honghense sp. nov., collected from dead twigs of an unknown host in Honghe, Yunnan Province, China, is introduced based on morphological characteristics and phylogenetic analyses. Iodosphaeria honghense is distinct from other similar taxa in having cylindrical to allantoid, guttulate ascospores without a mucilaginous sheath. Maximum likelihood and Bayesian analyses based on combined LSU, ITS and RPB2 data matrix indicate that I. honghense forms a distinct lineage within the Iodosphaeriaceae. This study provides a detailed description and illustrations with morphological comparisons, and includes a key to accepted Iodosphaeria species.
New combinations and a new name for including Nemum species in Bulbostylis (Abildgaardieae: Cyperaceae)
Authors: LARRIDON ISABEL , GOETGHEBEUR PAUL , ROALSON ERIC H.
Published: October 2019

N/A
A new species and new record of the genus Discoelius Latreille, 1809 (Hymenoptera: Vespidae: Eumeninae) from China
Authors: WANG HUA-CHUAN , CHEN BIN , LI TING-JING
Published: October 2019

Discoelius brevilamellatus Wang, Chen & Li, sp. nov. is described and illustrated from Tibet, China, and Discoelius turneri (Meade-Waldo, 1910) is newly recorded from China.
Lost in Informational Paradise: Cognitive Arrest to Epistemic Inertia in Problem Solving
Authors: Kim Jeong-Nam , Grunig James E.
Published: October 2019

We conceptualize two cognitive modi operandi by which lay individuals (cf. experts) solve everyday life problems: cognitive retrogression and cognitive progression. The key demarcation between these two strategies is when a conclusion is finalized and how one’s cognitive and communicative efforts are expended in a problematic situation. Using these two concepts of cognitive strategies in problem solving, we explicate the emerging processes of cognitive arrest and epistemic inertia in the digital age and changing information environment. We apply the cognitive and communicative account to an exemplary case of cognitive arrest among lay publics: that of conspiracism and close-mindedness.
Social and Economic Impact Analysis of Vadinar Refinery of Essar Oil: The Case of a Mega Refinery
Authors: Chaudhuri Sumana , Ray Shovan
Published: October 2019

The article is a case study on Essar Oil’s Vadinar Refinery in Gujarat. In the wake of the decision to divest the stake to Rosneft group of Russia, the Ruia’s-led Essar Group were interested to present a portrayal of the financial profitability and socio-economic importance of their refinery project at Vadinar. The project was assigned to the authors towards evaluation. The analysis assumes significance as refinery is a strategic sector, and there lies immense potential for Indian refiners to attain sustainable competitive advantage through economies of scale and adoption of most advanced technologies to process sour crude of the highest complexity, thus, producing the cleanest fuels in multiple distillates. Using a social cost–benefit approach, the article evaluates the financial viability and socio-economic contribution of the refinery at Vadinar at the local and regional level, focusing on multiplier effect of income, tax and savings generated, including other externalities. The present findings would assist in policy implications for the strategic investment in refinery operations as well as building a template for future researchers interested to explore the economic aspect of oil refineries from welfare perspective.

JEL: B41, D60, D61, D62, H23, H43, L71, O22, Q43
Assessing Organizational Information Visibility: Development and Validation of the Information Visibility Scale
Authors: ter Hoeven Claartje L. , Stohl Cynthia , Leonardi Paul , Stohl Michael
Published: October 2019

A common observation in the digital age is that new technologies are making people’s behaviors, decisions, and preferences more visible. For scholars who study organizations and their effects upon society, increased information visibility raises the hope that organizations might become more transparent. Typically, we assume that increased information visibility will translate into high levels of organizational transparency, but we lack empirical evidence to support this assumption. Our ability to gather data on this important topic is limited because there have been few reliable ways to assess organizational information visibility. To remedy this problem, we develop and validate the Information Visibility Scale to measure the core aspects of information visibility. We then employ the scale to test the relationship between information visibility and transparency. We discuss the theoretical and practical implications of the scale and consider the limitations and further research possibilities that the scale construction and validation suggest.
Relationship Quality in the Context of Cyber Dating Abuse: The Role of Attachment
Authors: Lancaster Morgan , Seibert Gregory S. , Cooper Ashley N. , May Ross W. , Fincham Frank
Published: October 2019

Cyber dating abuse can lead to negative outcomes for the message receiver and for the relationship. Extending previous research examining problematic technology-based behavior and attachment security, this study examined whether insecure attachment moderates the relationship between cyber dating abuse and relationship quality in emerging adults (N = 177). Through survey methodology, findings detail an interaction between cyber dating abuse and attachment avoidance pertaining to positive, but not negative, relationship quality. Victims of cyber dating abuse who were high in attachment avoidance reported significantly lower positive relationship quality compared to those who are not victims of cyber dating abuse. The present study contributes to a limited body of cyber abuse research within intimate relationships providing a nuanced understanding of the differentiation between positive and negative elements of relationship quality. Implications suggest clinicians should incorporate psychoeducation about the impact of cyber dating abuse to help couples interrupt and improve negative communication through technology.
Relationships between negative exchanges and depressive symptoms in older couples: The moderating roles of care and gender
Authors: Kwak Minyoung , Ingersoll-Dayton Berit
Published: October 2019

Marital relationships have a significant impact on older adults’ well-being. However, when contending with spousal illness or disability, negative exchanges may be particularly detrimental. This study examines the extent to which negative spousal exchanges have more impact on caregiving versus non-caregiving couples. Using dyadic analyses, this investigation compares three different groups consisting of (a) couples who did not provide or receive care, (b) couples in which husbands received care from their wives, and (c) couples in which wives received care from their husbands. We tested for gender differences in the effect of negative exchanges on depressive symptoms among caregivers and care recipients. Based on the 2012 and 2014 Health and Retirement Study, the sample consisted of 3,530 couples in which at least one of the spouses was aged 51 or over. Structural equation modeling was used to test the moderating effects of care and gender. Sociodemographic characteristics were included as control variables. Results indicated that there were significant differences in the magnitude of the path between negative exchanges and depressive symptoms across the subgroups. Among husbands, there was a stronger relationship between negative exchanges and depressive symptoms for care-receiving husbands than for caregiving husbands or husbands in non-caregiving relationships. Among wives, however, there was no significant difference in the path from negative exchanges with spouses to depressive symptoms across care status. We also found gender differences in the effect of negative exchanges on depressive symptoms among caregivers, but not among care recipients. Findings suggest that care status and gender of caregivers and care recipients have significant effects on the association between negative interactions within couples and mental health outcomes.
The Influence of Sexual Assault Resistance on Reporting Tendencies and Law Enforcement Response: Findings From the National Crime Victimization Survey
Authors: Pinciotti Caitlin M. , Seligowski Antonia V.
Published: October 2019

Despite its prevalence, sexual assault remains a vastly underreported crime. Previous research suggests that engagement in certain types of resistance during an assault affects the way in which both victims and others perceive the attack; such perceptions influence victims’ likelihood of reporting the assault to law enforcement as well as the criminal justice system response to reported allegations. Using a fight/flight/freeze theoretical framework, the current study sought to examine how forceful, nonforceful, and freeze responding influenced victim reporting and the extent to which reported assaults were pursued and investigated by law enforcement. Using data from the National Crime Victimization Survey between 2010 and 2016, logistic regression analysis indicated that victims are significantly less likely to report to law enforcement if they froze during the attack. Interestingly, although engagement in forceful resistance increases victims’ likelihood of reporting to law enforcement, it has no bearing on law enforcement response beyond the effect of physical injury. Rather, physical injury (e.g., bruises, cuts, broken bones) is the only predictor of law enforcement response to sexual assault allegations. Findings suggest that whereas fight and freeze responses to sexual victimization influence victims’ willingness to report to law enforcement, resistance is not uniquely predictive of law enforcement response once physical injury is considered.
Intimate Partner Violence and Illicit Substance Use Among Sexual and Gender Minority Youth: The Protective Role of Cognitive Reappraisal
Authors: Scheer Jillian R. , Mereish Ethan H.
Published: October 2019

Sexual and gender minority youth (SGMY) disproportionately experience intimate partner violence (IPV) and report illicit substance use compared with cisgender heterosexual youth. Cognitive reappraisal strategies have been shown to decrease trauma-exposed individuals’ likelihood of engaging in substance use. However, virtually no research has examined the relationship between various forms of IPV, including identity abuse, and illicit substance use, as well as the protective role of cognitive reappraisal among IPV-exposed SGMY. The current study addressed these limitations and examined cognitive reappraisal as a moderator of the associations between various IPV forms and illicit substance use among 149 SGMY (ages 18-25; 28.9% bisexual, 42.3% transgender or gender nonbinary, 45.0% racial and ethnic minority) between 2016 and 2017. Results indicated that many SGMY used cocaine in the past 6 months (24.8%), followed by hallucinogens (24.8%), stimulants (22.8%), and heroin (20.8%). More than half (62.4%) of SGMY experienced psychological abuse, 44.3% physical abuse, and 43.6% identity abuse in the past year. Cognitive reappraisal buffered the associations between two forms of IPV, identity abuse and physical abuse, and illicit substance use among SGMY, underscoring its importance for clinical intervention. Specifically, past year identity abuse and physical abuse were associated with greater illicit substance use only for SGMY with lower cognitive reappraisal, not for youth with higher cognitive reappraisal. This study adds to the burgeoning literature on identity, physical, and psychological forms of IPV and illicit substance use among SGMY. Our findings provide evidence that cognitive reappraisal strategies buffer the effect of identity abuse and physical abuse on illicit drug use among SGMY. These findings shed light on new avenues for clinical intervention that may help to reduce the prevalence of illicit substance use among IPV-exposed SGMY.
A Parent-Implemented Playdate Intervention for Young Children With Autism and Their Peers
Authors: Raulston Tracy J. , Hansen Sarah G. , Frantz Rebecca , Machalicek Wendy , Bhana Naima
Published: October 2019

Children with autism spectrum disorder (ASD) present with social skills difficulties, which can create barriers for them to develop friendships with their peers. Playdates are a common way that young children practice play and friendship skills in home and community environments. Few studies have trained parents to embed social skills instruction into playdates for children with ASD, and such studies have been comprised of children with mild to moderate needs. In the current study, we employed a concurrent single-case multiple probe across three parent–child–peer triads design to evaluate the effects of training and coaching in a parent-implemented playdate intervention on parental strategy use and cascading effects on child–peer social interactions during playdates. Parents also rated the social validity of the intervention. Results indicated that two of the three parents reached criterion on the strategies quickly, and the third triad required a procedural modification. Challenging behavior appeared to be a barrier to implementation. Implications and future directions are discussed.
Canal occlusion in cemented primary total hip replacement: autologous compacted bone block compared to a commercially available gelatine plug
Authors: Agrawal Pranshu , Chacko Vinay J , Divecha Hiren , Board Tim N
Published: October 2019

Aims:

To evaluate the stability of 2 canal occlusion systems; an autologous, compacted bone block and the biodegradable C-plug. We also sought to investigate any relationship between stability of the systems and the quality of cementation. A retrospective radiographic comparative review was conducted.

Methods:

A total of 203 consecutive patients were analysed, 89 received an autologous bone block and 114 had C-plugs. There was no significant differences between the groups in terms of age, sex and primary diagnosis. The mean cement tail length in the bone block group (6.42 mm; range 0–31) was significantly shorter than in the C-plug group (17.11 mm; range 0–65.7).

Results:

The proportion of patients with good quality of cementation (Barrack grade A) was significantly higher in the bone block group (80.6%) as compared to the C-plug group (56%) ( p < 0.001). There was a negative correlation between the length of the cement tail and the Barrack grade, indicating that a short cement tail is associated with better quality cementation.

Conclusions:

We have shown that improved cement penetration and shorter cement tails can be achieved with the cheapest of all options for canal occlusion, an autologous compacted bone block and hence recommend this technique.
A Study of Digitally Enhanced People–Space Interaction: A Place-Centric Perspective
Authors: Wang Weijia
Published: October 2019

With the rapid development of information and communication technology, physical space has been increasingly enhanced by digital technology. The way people and space interact is significantly changed. In particular, an increased interest in the notion of place has emerged in examining smart city development, digital engagement, and people–technology relationships in hybrid physical–digital space. In this article, a place-centric perspective is employed to investigate digitally enhanced people–space interactions. Based on a multimethod research design that combines physical survey, field observation, and interview, this research employs a case study of a shopping mall to examine people’s everyday practices of digitally enabled placemaking. It is found that a range of digital interfaces functions as a system at various proxemic scales in hybrid space, which open up new spatialities by mediating trans-scale placemaking practices. Type-forms of digitally enabled people–space interactions are also summarized. The paper concludes that digitally enabled placemaking in this particular case is constituted within a closed mechanism. Future research directions are also raised at the end.
Envy: An Adversarial Review and Comparison of Two Competing Views
Authors: Crusius Jan , Gonzalez Manuel F. , Lange Jens , Cohen-Charash Yochi
Published: October 2019

The nature of envy has recently been the subject of a heated debate. Some researchers see envy as a complex, yet unitary construct that despite being hostile in nature can lead to both hostile and nonhostile reactions. Others offer a dual approach to envy, in which envy’s outcomes reflect two types of envy: benign envy, involving upward motivation, and malicious envy, involving hostility against superior others. We compare these competing conceptualizations of envy in an adversarial (yet collaborative) review. Our goal is to aid the consumers of envy research in navigating the intricacies of this debate. We identify agreements and disagreements and describe implications for theory, methodology, and measurement, as well as challenges and opportunities for future work.
Splicing Control in Normal and Aberrant Erythropoiesis
Authors: Obeng Esther
Published: October 2019

Alternative splicing is employed by all eukaryotic cells to increase proteome diversity and to regulate gene expression. RNA sequencing analysis of purified populations of erythroblasts at different stages of maturation has led to the identification of a dynamic alternative splicing program that directly modulates the protein isoform expression of cytoskeletal proteins and genes involved in RNA processing, heme biosynthesis, and iron transport. Regulated interactions of multiple RNA-binding proteins and cis-regulatory sequences located within exons or their flanking introns promote or inhibit functional spliceosome assembly at splice junctions, leading to altered exon inclusion or intron retention. Exon skipping regulates tissue and stage specific isoform expression of red cell membrane cytoskeletal proteins including EPB41, ankyrin, and band 3. Intron retention can lead to a frame shift during translation and introduction of a premature termination codon (PTC), that marks the transcript for degradation via the nonsense mediated decay pathway (NMD) upon export from the nucleus into the cytoplasm. Intron retention leading to posttranscriptional regulation of gene expression during terminal erythroid maturation has been identified in genes involved in RNA processing and iron transport including SF3B1, SNRNP70, SLC25A37 and SLC25A28. Mutations that alter mRNA splice sites or introduce PTCs lead to a variety of congenital anemias including beta thalassemia, hereditary pyropoikilocytosis, hereditary elliptocytosis, and hereditary spherocytosis. Aberrant mRNA splicing has subsequently been shown to lead to acquired anemias in subsets of patients with myelodysplastic syndromes (MDS). Somatic missense mutations in components of the spliceosome are the most common category of mutations in MDS. These point mutations lead to changes in the RNA binding specificity of the involved proteins and aberrant splicing of a subset of transcripts. Mutant SF3B1, the most commonly mutated splicing factor in MDS, has been shown to cause aberrant pre-mRNA splicing and an increase in transcripts predicted to undergo NMD due to use of upstream, cryptic 3' splice sites. Our group and others evaluating the strong genotype-phenotype association between SF3B1 point mutations and subtypes of MDS with ring sideroblasts have shown that the expression of the mitochondrial iron transporter, ABCB7, is decreased in samples from SF3B1-mutant MDS patients due to cryptic 3' splice site selection and introduction of a PTC between exons 8 and 9. The identification and functional validation of additional aberrantly spliced mutant-SF3B1 target genes is ongoing, with the goal of understanding how point mutations in a core component of the mRNA splicing machinery can lead to such specific effects on erythroid maturation.

Disclosures

No relevant conflicts of interest to declare.
Cost-Effectiveness Analyses of FDA-Approved Drugs for Cancer Indications, 2015-2017
Authors: Oren Ohad
Published: October 2019

Background:

In addition to a drug's anti-tumor efficacy and tissue toxicity, it is now apparent that affordability is a pivotal factor determining the net therapeutic value of an anti-cancer compound. Cost-Effectiveness Analyses (CEA) are therefore key to appreciating the overall balance between the clinical and economical repercussions of a pharmaceutical agent. We aimed to investigate the cost-effectiveness data of newly approved drugs in cancer care.

Methods:

The FDA website was reviewed for all drugs approved for any cancer indication between the years 2015-2017. A systematic search of Pubmed and Google Scholar was conducted for Cost-Effectiveness Analyses (CEA) of each of these medications. Average Wholesale Prices were collected from Uptodate.com.

Results:

30 drugs were approved for cancer indications in 2015-2017. Each of the approved drugs had an average of 1.27 CEA studies (range 0-6). 4 of the 38 (10.5%) available CEAs were done before approval of an index drug. 18 (60%) of the approved medications had an available published CEA at the time of our search (March, 2018). Partition survival modelling (31.5%) and Markov modelling (26.3%) were the most common methods of analysis. 47.3% (18/38) of the CEAs were thought to reflect a favorable ICER per the analysis's investigators. The nature of the malignancy (solid versus hematologic) did not distinguish between the mean number of a drug's CEAs (1.25; 1.2) but drugs for solid cancer indications were less likely to be associated with a favorable CE assessment compared with hematological cancers (47.8% versus 58.3%). "Expensive" drugs (defined as monthly cost greater than 8,618 dollars) had a lower mean number of CEA studies than "less expensive" drugs (1.09 versus 1.36) and were less likely to be associated with a favorable cost-effectiveness profile (27.2% versus 73.6%). 47.3% (18/38) of the economic evaluations were published as conference proceeding/abstract, 36.8% (14/38) were in the form of a full-text article, and the remainder as journal letters or conference posters (6/38; 15.7%).

Conclusion:

Insufficient data on the cost-effectiveness profile of novel anti-cancer medications jeopardises our ability to determine their real value. Although these drugs are being routinely used in a large-scale fashion, gaps persist as to their financial harm relative to the associated (potential) clinical benefit. Our study shows that recently-approved anti-cancer drugs have a very small number of CEAs to back their clinical-societal merit. Paradoxically, more costly drugs have fewer CEAs compared with cheaper drugs. Also of note, the majority of the analyses followed the approval of the drug, were published in a non full-text format, and were associated with non-sustainable ICER values. We argue that publication of rigorous, peer-reviewed CEAs should be a mandatory pre-approval step for academia/industry and serve as a pre-requisite to the routine distribution and usage of new cancer-directed medications.

Disclosures

No relevant conflicts of interest to declare.
The Appropriateness of Testing PF4/Heparin Antibody in Patients Suspected of Heparin-Induced Thrombocytopenia
Authors: Jindal Vishal , Singh Aditi , Siddiqui Ahmad Daniyal , Leb Laszlo
Published: October 2019

Heparin Induced thrombocytopenia (HIT) is an adverse reaction to the administration of heparin due to activation of platelet by the IgG antibody-PF4/heparin immune complex. Since the clinical outcome is uncertain as it could be associated with significant morbidity and sometimes death, an early diagnosis and appropriate treatment is necessary. The 4Ts pretest clinical scoring system and testing for all anti PF4/heparin antibody can markedly improve the diagnosis and prompt adequate treatment. Our study was undertaken to evaluate the appropriateness of ordering the PF4-ELISA test reviewing retrospectively the use of 4Ts scoring system in a tertiary institution. We examined a database of 118 patients who had the PF4-ELISA and we calculated retrospectively their 4Ts scores. A total of 107 patients were evaluated; 95 patients (88.79%) had negative PF4-ELISA assay and 12 patients tested positive (11.21%). Only one patient tested weakly positive in the low probability group (negative predictive value 98%). In the intermediate group, six patients were strongly positive (OD >1.0). In this latter group further confirmatory testing (SRA) could have been done. We also evaluated the setting where the tests were performed and found that the majority patients (63.55%) were tested in the ICU where thrombocytopenia is multifactorial. We conclude that the large majority of patients were not appropriately evaluated prior to testing which incurred unnecessary expense and patient distress. For the proper identification of patients suspected of HIT who should undergo PF4/heparin antibody testing, further education of the ordering physicians is recommended.

Disclosures

No relevant conflicts of interest to declare.
Mitochondria Clearance Mechanisms Via Interaction with Macrophages in Erythropoiesis
Authors: Yang Chong , Suda Toshio , Lin Xiaoxuan , Endo Mitsuhiro
Published: October 2019

Adult erythropoiesis involves a series of well-coordinated events resulting in the production of mature red blood cells. One of such events is the mitochondria clearance, which is known to occur cell-autonomously via autophagy-dependent mechanisms. Interestingly, we identified a sequential changes in the transcriptional pattern during terminal erythroid differentiation based on the expression of several macroautophagy (e.g. Atg3, Atg5, Atg7 and Atg10) and non-canonical mitophagy (e.g. Pink1, Park2, Bnip3l/Nix, P62 and Ulk1) genes. Hence we hypothesize that the progressive reduction in mitochondria during terminal erythroid differentiation is directed by distinct transcriptionally-regulated programs. Notably, we revealed a gradual reduction of the expression of lysosome related genes (e.g. Lamp1, CD63, and Atp6v) and lysosomal activities from early to late stages of terminal differentiation. On the other hand, P62-Pink1-Parkin mediated ubiquitin proteasome degradation of mitochondria proteins seems to be more prominent during late stage erythropoiesis. Hence our data suggest that mitochondria clearance is predominantly mediated by canonical autophagy during early stages of terminal differentiation, whereas non-canonical mitophagy pathway seem to play a more predominant role to regulate late stages erythroid maturation.

Next, we discovered mitochondria transfer activities from erythroblasts to their niche. In the context of erythropoiesis, macrophages are known to interact closely with erythroblasts to provide a specialized niche for erythroid precursors to proliferate, differentiate and enucleate. We showed defective erythropoiesis after macrophage depletion in the bone marrow. Subsequently, we identified a tendency for early erythroblasts to associate with macrophages and isolated those erythroblasts from mito-dendra2 mice with trackable mitochondria to establish a murine primary cell co-culture system. Then we report mitochondria transfer activities in the erythroid niche via different modes including direct uptake, micro-vesicle transfer and tunnelling nanotubes (TNT). Interestingly, interchangeable structures between micro-vesicles and TNTs have been observed, suggesting an interplay between cytoskeleton and membrane lipid molecules in the mitochondria transfer mechanisms. Furthermore, mitochondria transfer activities have also been observed in the co-culture of mito-dendra2 erythroid cells with a macrophage cell line, RAW cells, and are significantly enhanced by the activation of the RAW cells via Tfe3 activation.

In summary, our findings may provide insight into the mitochondria clearance machineries that mediates erythroid maturation to fulfil the clinical demand for large scale transfusable blood cell production in vitro.

Disclosures

No relevant conflicts of interest to declare.
The Incidence of Post-Thrombotic Syndrome after the Treatment of Upper Extremity Deep Vein Thrombosis with Oral Rivaroxaban
Authors: Lobastov Kirill , Barinov Victor , Schastlivtsev Iliya , Laberko Leonid , Rodoman Grigory , Zhuravlev Sergey , Boyarintsev Valeriy
Published: October 2019

Aim: To assess oral rivaroxaban's efficacy and safety in the treatment of upper extremity deep vein thrombosis (UEDVT).

Methods: This was a prospective observational study involving patients with their first UEDVT episodes confirmed by duplex ultrasound (DUS) without symptoms of pulmonary embolism (PE). All patients initially received low-molecular-weight heparin for 1 to 2 days and were then switched to oral rivaroxaban (15 mg bid) for three weeks and then to 20 mg qid for up to three months. Patients who had already undergone interventional UEDVT treatment were excluded. Patients were followed up with clinical examination and DUS for six months. The endpoints of the study were symptomatic PE, recurrent UEDVT, major, clinically relevant non-major and minor bleeding, recanalization of the affected veins, recognized as a blood flow with DUS, post-thrombotic syndrome (PTS) incidence of the affected limb assessed by modified Villata score by Czihal.

Results: A total of 30 patients (13 men and 17 women) aged 28-78 years (mean age 52.4 ± 17.3) were included in the study. Some (16.7%) of them had undergone physical exertion which triggered the UEDVT. In 13.3%, there was a pacemaker previously implanted through the affected limb. Also, patients had from 0 to 5 individual risk factors for venous thromboembolism (mean 1.9±1.6). The subclavian vein, predominantly on the right side (60%), was involved in the thrombotic process in all cases. The mean duration of symptoms before diagnosis was 1.8±1.7 days.

All 30 patients were followed for six months. There were no episodes of symptomatic PE and/or recurrent UEDVT during the period of anticoagulation (0-3 months) and after stop of treatment (3-6 months). No episodes of major bleeding were observed. Clinically relevant non-major bleeding occurred in 2 patients (6.7%: 95% confidence interval [CI]: 1.9-21.4%) caused by uterine bleeding and large skin hemorrhage. Minor bleeding was observed in two patients (6.7%: 95% CI: 1.9-21.4%) caused by nasal and gingival bleeding. Thus, cumulative bleeding incidence was 13.4% (95% CI: 5.4-29.8%). Recanalization of upper extremity deep veins was observed in all affected limbs at three months and persist up to six months. The signs of upper limbs PTS (≥5 modified Villalta score) were found in four patients (13.4 %; 95% CI: 5.4-29.8%), and the mean score was 2.1±1.9.

Conclusion: Treatment of UEDVT with oral rivaroxaban seems to be effective, safe, and associated with the low incidence of upper limb PTS.

Disclosures

Lobastov: Bayer: Honoraria, Speakers Bureau; Servier: Honoraria, Speakers Bureau. Barinov:Bayer: Honoraria, Speakers Bureau; Servier: Honoraria, Speakers Bureau. Schastlivtsev:Bayer: Honoraria, Speakers Bureau; Servier: Honoraria, Speakers Bureau.
Long-Term Results of Non- Fludarabine Versus Fludarabine-Based Conditioning Regimens in Severe Aplastic Anemia Patients
Authors: Aladag Elifcan , Demiroglu Haluk , Ciftciler Rafiye , Buyukasik Yahya , Sayinalp Nilgun , Aksu Salih , Haznedaroglu Ibrahim Celalettin , Ozcebe Osman , Chao Nelson J. , Goker Hakan
Published: October 2019

BACKGROUND AND OBJECTIVE: Allogenic hematopoietic cell transplantation (AHSCT) is the best therapeutic modality capable of correcting the hematologic manifestations of severe aplastic anemia (SAA), here in this study we have compared the results of well-tolerated fludarabine-based conditioning regimens for SAA patients who are heavily transfused undergoing AHSCT.

DESIGN AND SETTINGS: This is a retrospective study consist of 25 patients diagnosed with SAA who underwent AHSCT between February 2002 and March 2015 at the Bone Marrow Transplantation Unit of Hacettepe University. All patients gave written informed consent for the procedure.

PATIENTS AND METHODS: We analyzed the outcome of 25 SAA patients who had undergone AHSCT between 2002 and 2015. the median age at transplantation was 27(16-55) years. Patients received transplants from an HLA-identical sibling (n=24) and mismatched allogeneic related HSCT (n=1). Hematopoietic Stem Cells (HSC) were collected from the donors via apheresis. Eight patients underwent standard CY 50 mg/kg plus ATG-FreseniusR 5-10 mg/kg as conditioning fort he transplantation procedure and 13 patients conditioned with CY(50 mg/kg for 2 days) plus fludarabine 25 mg/m2 for 5 days and ATG-FreseniusR 5-10 mg/kg as AHSCT conditioning and received GvHD (Graft-vs-Host Disease) prophylaxis was standard CsA 3 mg/kg IV inf. plus Methotrexate(MTX) 10mg/m2 on day 1,and MTX 5 mg/m2 on days 3.,6. and 11.

RESULTS: The median follow-up period for all the survivors was 117 months [minimum 3 and maximum 159 months]. The 5-year overall survival (os) for patients who did or did not receive fludarabine-based preparative regimens for the allograft was 93%, and 87%, respectively. However, there were no statistically significant differences in os rates between these two groups (P=0,58). Median neutrophil engraftment time was 11 days and median platelet engraftment time was 13 days. Primary graft failure occurred in 1 patients (4%) who received fludarabine-based conditioning regimens.

CONCLUSION: Fludarabine-Based (Flu-CY-ATG) conditioning is a safe and viable option when compared to the standard CY-ATG conditioning in heavily-transfused SAA patients who undergo Allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Disclosures

No relevant conflicts of interest to declare.
Identification of a Whole Blood Signature for Venous Thromboembolism
Authors: Hogan Marie , Zhou Hua , Lhakhang Tenzin , Barrett Tessa Jo , O'Reilly Deirdre , Smilowitz Nathaniel , Heguy Adriana , Maldonado Thomas , Tsirigos Aristotelis , Berger Jeffrey
Published: October 2019

Venous thromboembolism (VTE), comprised of deep vein thrombosis and pulmonary embolism, is a common health problem both in the United States and worldwide, with significant associated morbidity and mortality. Despite multiple known genetic and situational risk factors, an estimated 30% of all events remain classified as idiopathic, demonstrating a significant knowledge gap in the pathophysiology VTE. While platelets are well established as an essential contributor to thrombus formation and there has been recent interest in the role of neutrophil extracellular traps, specific cell types and pathways involved in the pathogenesis of VTE remain uncertain. In this study, our primary aims were to define a unique transcriptional signature for VTE and to identify the types of cells and specific pathways involved in development of VTE.

Whole blood was collected in PAX gene tubes and RNA sequencing for coding mRNA was performed in an unbiased manner in 201 patients with prevalent VTE as well as 43 healthy controls. We used a bioinformatics approach to develop a unique signature for VTE by identifying differentially expressed genes, developing cell-type modules, and ascertaining pathways driving differentially expressed transcripts. We performed additional analyses on subgroups of patients with idiopathic VTE, patients with incident VTE, and VTE patients matched to healthy controls by age and sex. We went on to use machine learning methods to learn models that best differentiate VTE patients from healthy controls and validated it on a left out test set within our VTE population.

Genes specific to neutrophils, erythrocytes, and platelets, in that order, were most significantly upregulated in patients with VTE compared to healthy controls. Genes related to T-cells were downregulated. Pathway analysis revealed upregulated neutrophil activation and degranulation, erythrocyte differentiation and homeostasis, and platelet degranulation. A gene signature of 217 transcripts was outstanding at differentiating patients with VTE versus healthy controls (AUC 0.94). Following adjustment for age, sex, and race/ethnicity our genetic signature remained significantly robust at differentiating patients with VTE versus controls (AUC 0.83). Our expression signature remained stable across patients with idiopathic VTE (AUC 0.93), and in patients who went on to develop future VTE events (AUC 0.95).

In summary, we have demonstrated a whole blood transcriptional signature for prevalent and incident VTE. Genes related to neutrophils, erythrocytes, and platelets are upregulated in patients with VTE and genes related to T-cells were downregulated. These findings suggest an active role of cell types once thought to be passively entrapped within thrombus and provide new areas of study to establish the pathophysiology of VTE.

Disclosures

No relevant conflicts of interest to declare.