bluuebunny/crossref_metadata_2025 huggingface dataset:
Bireyselleştirilmiş Bilgisayarlı Sınıflama Testi Kriterlerinin Test Etkililiği ve Ölçme Kesinliği Açısından Karşılaştırılması
Authors: Gündeğer Ceylan , Doğan Nuri
Published: June 2018

Bu çalışmada Bireyselleştirilmiş Bilgisayarlı
Sınıflama Testleri’nin (BBST) etkililiğinin sınıflama kriterlerine, madde seçme
ve yetenek kestirim yöntemlerine göre nasıl değiştiğinin belirlenmesi
amaçlanmıştır. Bu amaçla 3 Parametreli Lojistik Model temel alınmış; belirlenen
kesme noktası ve etrafında yüksek bilgi verecek şekilde 500 maddelik bir havuz
oluşturulmuş; birey yetenekleri (N(0,1)) 3000 kişi üzerinden türetilmiş ve
bireylerin madde cevap örüntüleri R yazılımda rasgele türetilmiştir. Sınıflama
kriterlerinden Ardışık Olasılık Oran Testi (AOOT), Genelleştirilmiş Olabilirlik
Oranı (GOO) ve Güven Aralığı (GA) yöntemleri; yetenek kestirim yöntemlerinden
Beklenen Sonsal Dağılım (BSD) ve Ağırlıklandırılmış Olabilirlik Kestirimi (AOK)
yöntemleri; madde seçme yöntemlerinden ise kesme noktasında (KN) ve kestirilen
yetenek (KY) temelinde Maksimum Fisher Bilgisi (MFB) ve Kullback-Leibler
Bilgisi (KLB) yöntemleri çaprazlanarak 48 koşul oluşturulmuştur. R yazılımında
yürütülen BBST simülasyonu sonunda, ortalama test uzunluğu (OTU), ortalama
sınıflama doğruluğu (OSD), bireylerin gerçek yetenek düzeyleri ile kestirilen
yetenek düzeyleri arasındaki korelasyon (r), yanlılık, RMSE ve ortalama mutlak
hata (OMH) değerlerinin 25 tekrara ait ortalamaları hesaplanmıştır. Araştırma
sonuçlarına göre test etkililiği bakımından GOO ve GA yöntemlerinin; ölçme
kesinliği bakımından ise AOOT’nin daha iyi performans gösterdiği; sınıflama
kriterlerinin farksızlık bölgesi genişledikçe veya hata düzeyi değeri
küçüldükçe test etkililiğinin arttığı; sınıflama kriterlerinin tümünün her
koşulda oldukça yüksek düzeyde sınıflama doğruluğuna sahip olduğu
belirlenmiştir. Bireylerin gerçek yetenek düzeyleri ile kestirilen yetenek
düzeyleri arasındaki korelasyon bakımından BSD ve AOK yetenek kestirim
yöntemlerinin her ikisinin de başarılı kestirimlerde bulundukları ancak ölçme
kesinliği bakımından BSD’nin daha iyi performans sergilediği; madde seçme
yöntemlerinin ise tümünün birbirine benzer çalıştığı ancak MFB-KY’nin tüm
bağımlı değişkenler açısından tüm koşullarda daha iyi performans gösterdiği
görülmüştür.
Evaluation of the Breakdown Pressure to Initiate Hydraulic Fractures of Tight Sandstone and Shale Formations
Authors: Farid Ibrahim Ahmed , Nasr-El-Din Hisham
Published: June 2018

Hydraulic Fracturing has been used successfully in the oil and gas industry to enhance oil and gas production. Recent years have seen the great development of tight gas, coalbed methane, and shale gas. Different fluids were used as fracturing fluids in shale and sandstone formations, including the use of CO2, N2 and CO2 foam, slick water, crosslinked solutions, and oil-based fracturing fluids. The objective of this study is to develop an experimental setup to measure the breakdown pressure to initiate the fractures in shale and tight sandstone cores.

This study investigated the effect of injection flow rate, temperature, fluid viscosity, and fluid type on the breakdown pressure of different rock cores. 5 wt% KCl brine, slick water with a friction reducer, linear gel systems were used as a fracturing fluid. Kentucky, Scioto, Bandera, and Berea sandstone cores were used. Also, Mancos, Marcellus, and Barnett shale cores were used in this study. Finally, the behavior of the breakdown pressure was examined as a function of the back pressure (0, 100, 300 psi).

The preliminary results show that the breakdown pressure increased as the injection flow rate increased. Where the breakdown pressure increased from 438 to 1,000 psi as the flow rate increased from 5 to 10 cm3/min in case of 5 wt% KCl with Kentucky sandstone cores. The breakdown pressure increased in Marcellus shale to 1,800 psi in case of 5 wt% KCl at 5 cm3/min. As the fluid viscosity increased the breakdown pressure increased, it increased to 1,115 psi in case of 2 gptg friction reducer (5 cp) comparing to 5 wt% KCl (1.1 cp) case at 5 cm3/min. A straight line relationship was found between the breakdown pressure and the logarithmic scale of the fluid viscosity.

This study will give recommendations for the fluid viscosity, type, and the injection flow rate that will improve the efficiency of the hydraulic fracturing operation.
IMPROVEMENT OF ORGANIZATION OF TUBERCULOSIS DETECTION IN THE PRACTICE OF A DISTRICT PRACTITIONER
Authors: Borodulina E. V.
Published: June 2018

.
A New Quantum Encryption Scheme
Authors: Plesa Mihail-Iulian , Mihai Togan
Published: June 2018

The model of quantum computation has advanced very quickly in the last years. This model brings with it an efficient algorithm for factoring, namely the Shor algorithm. This means that the public key infrastructure will soon be obsolete. In this paper we propose a new quantum cryptographic scheme which aims to replace the RSA algorithm from current public key infrastructures. We analyze the security of our scheme and also, we describe the implementation of the scheme using IBM Q SDK, qiskit. We run a number of experiments in order to build a proof of concept application that uses the proposed scheme.
ORTAK HAYATA SON VERİLMESİ SONRASI ORTAK VELÂYET HUSUSUNDA YASAL DÜZENLEME GEREĞİ
Authors: APAYDIN Eylem
Published: June 2018

Türk
hukukunda, boşanma sonrası, anne babanın velayet hakkını birlikte kullanmasının
mümkün olup olmadığı son yıllarda yoğun olarak tartışılmıştır.     Doktrinde
baskın görüşe göre konuyu düzenleyen Türk Medeni Kanun hükümleri boşanma
sonrasında, eşlerden yalnızca birinin velâyet hakkına sahip olacağını öngörmüştür.
Yargıtay yerleşmiş istikrarlı kararları ile ortak velayetin Türk hukukunda
mümkün olmadığına ve hatta ortak velayetin kamu düzene aykırı olduğuna
hükmetmiştir. Ancak Yargıtay 2. Hukuk Dairesi’nin 2016/15771E. 2017/1737K.
sayılı kararında ortak velâyet düzenlenmesinin, Türk kamu
düzenine açıkça aykırı olmadığı ve Türk toplumunun temel yapısı ve temel
çıkarlarını ihlal etmediği yönünde karar vermiştir. Bu karardan sonra Türk
mahkemeleri boşanma sonrasında eşlerin velayeti birlikte kullanabileceklerine
dair kararlar vermiştir.

Bu
çalışmada, Türk Medeni Kanununun ortak hayata son verilmesi sonrası ortak
velâyet kavramına yaklaşımı, öğretideki ve yargı kararlarındaki bakış dikkate
alınarak değerlendirilecektir. Bu noktada, Türkiye’nin taraf olduğu
uluslararası antlaşmalar, uluslararası kuruluşların ve mahkemelerin kararları
da göz önünde tutulacaktır. Son olarak, ortak hayata son verilmesi sonrası
ortak velâyetin bir kurum olarak kanunla düzenlemesi gerektiği görüşünün
savunulmasını takiben bu kanunda yer verilmesi gereken ilkelere değinilecektir.
Experimental investigation of the effect of temperature differentials on hydraulic performance and flow pattern of a sediment retention pond
Authors: Hendi Ehsan , Shamseldin Asaad Y. , Melville Bruce W. , Norris Stuart E.
Published: June 2018

Existing studies on sediment retention ponds (SRPs) have examined the effects of pond layout, inlet and outlet geometry and the installation of baffles on the performance of the SRPs. However, the effects of a temperature difference between the ambient water in the pond and the inflow are often neglected, and the buoyancy forces arising from these differences in temperature can potentially change the flow in the pond and hence its hydraulic performance. This study has experimentally evaluated the effect of these temperature differences on the flow field and residence time in a retention pond for a range of temperature differences. As expected a cold inflow sinks to the bottom of the pond while a hot inflow remains at the surface, but in both cases the inflow flows more rapidly towards the outlet than is the case for isothermal inflow. A counter-current was observed at the bottom or the surface of the pond for colder or hotter influents, respectively. These thermally induced flows significantly reduced the residence time of the pond, reducing the hydraulic performance of the pond and causing severe short-circuiting. The results have also shown that the temperature differences in the pond decrease with time, yet small temperature differences persist with the pond remaining thermally stratified.
State of the Art on Carbonic Anhydrase Modulators for Biomedical Purposes
Authors: Bozdag Murat , Altamimi Abdulmalik Saleh Alfawaz , Vullo Daniela , Supuran Claudiu T. , Carta Fabrizio
Published: June 2018

The current review is intended to highlight recent advances in the search of new
and effective modulators of the metalloenzymes Carbonic Anhydrases (CAs, EC 4.2.1.1) expressed
in humans (h). CAs reversibly catalyze the CO2 hydration reaction, which is of crucial
importance in the regulation of a plethora of fundamental processes at cellular level as well as
in complex organisms. The first section of this review will be dedicated to compounds acting
as activators of the hCAs (CAAs) and their promising effects on central nervous system affecting
pathologies mainly characterized from memory and learning impairments. The second
part will focus on the emerging chemical classes acting as hCA inhibitors (CAIs) and their
potential use for the treatment of diseases.
Sonocatalyzed Total Synthesis of N,N-diaryl-formamides Through Oxidation and Hydrolysis Reaction of gem-dichloroaziridines using DMSO/H2O
Authors: Rabiei Khadijeh , Naeimi Hossein
Published: June 2018

Background:.Aziridine compounds are among the most fascinating intermediates in organic synthesis,
acting as precursors of many complex molecules due to the strain incorporated in their skeletons and can
be opened in a stereo controlled manner with various nucleophiles, providing access to a wide range of important
nitrogen-containing products. Sonochemistry involves the use of ultrasound technique to promote organic
reactions. In recent years sonochemistry has been widely used in organic syntheses as it offers a versatile and
facile pathway for a bewildering range of organic reactions.

Materials and Method:

The synthesis of some Schiff bases was done in according the previously reported procedure
in literature. The synthesized Schiff bases in the presence of magnesium powder and CCl4 in anhydrous
tetrahydrofuran was converted to gem-dichloroaziridines at ultrasonic irradiation. Finally, the synthesized 2,2-
dichloro-1,3-bis(4-chlorophenyl) aziridine was treated with DMSO and H2O with ultrasonic irradiation to produce
the N-(4-chlorophenyl)-N-[4-(chlorophenyl)hydroxy-methyl] formamides.

Results:

Here, total synthesis of N-(α-hydroxybenzyl)-formamides through ultrasonic promoted oxidation and
hydrolysis reaction of gem-dichloroaziridine derivatives in the presence of dimethyl sulfoxide and water has
been investigated.

Conclusion:

In this study, ultrasonic promoted oxidation and hydrolysis of gem-dichloroaziridines toward N-
(α-hydroxybenzyl)-formamides in the presence of DMSO and H2O under neutral medium reaction conditions
has been reported. Excellent yields of products were obtained through this method. Other advantages of this
reaction are short reaction times, simplicity of the method and high purity of products.
Inflammatory Potential of Diet and the Risk of Prostate Cancer: A Casecontrol Study in the West of Iran
Authors: Bagheri Amir , Nachvak Seyed M. , Abdollahzad Hadi , Rezaei Mansour
Published: June 2018

Background:

Prostate cancer is one of the most common cancer in worldwide and inflammatory
reactions may be the major risk factors for it. Diet has a potential role in the running of inflammatory
reactions. Dietary Inflammatory Index (DII) is a tool that can assess the inflammatory potential
of a diet.

Objective:

Study of the effect of Dietary Inflammatory Index (DII) and body composition on the risk
of prostate cancer was the aim of this research.

Methods:

We assessed the ability of Dietary Inflammatory Index (DII) to predict prostate cancer in a
case-control study conducted in Kermanshah, Iran in 2016. The study included 50 cases with primary
prostate cancer and 150 healthy controls. Anthropometric indices were measured by Bioelectric Impedance
Analysis (BIA). The DII was computed based on the intake of 32 nutrients assessed using a
147-items food frequency questionnaire. The multivariate logistic regression was used to evaluate the
odds ratio, with DII expressed as a dichotomous variable.

Results:

There were no statistically significant differences in body composition between case and control
groups, but participants with DII > 0.80 had significant differences in BMI, LBM, SLM, MBF and TBW
versus participant with DII ≤ 0.80. Also, men with higher DII scores were at increased risk of prostate
cancer [OR: 1.77; 95% confidence interval 1.28-2.44] and categorical variable [OR DII>0.80 vs ≤ 0.80:
3.81; 95% confidence interval: 1.49-9.75].

Conclusion:

These findings suggest that a pro-inflammatory diet is a risk factor for prostate cancer
and also can have the impact on body composition.
Fungal Bioactive Compounds in Pharmaceutical Research and Development
Authors: Saxena Sanjai , Chhibber Manmohan , Singh Inder Pal
Published: June 2018

Background:

Exploration of antibiotics from microorganisms became widespread in the academia and the industry with the serendipitous discovery of Penicillin from Penicillium notatum by Sir Alexander Fleming. This embarked the golden era of antibiotics which lasted for over 60 years. However, the traditional phenotypic screening was replaced with more rational and smarter methods of exploration of bioactive compounds from fungi and microorganisms. Fungi have been responsible for providing a variety of bioactive compounds with diverse activities which have been developed into blockbuster drugs such as Cyclosporine, Caspofungin, Lovastatin and Fingolimod etc. It has been reported that ca. 40% of the 1453 New Chemical Entities (NCE’s) approved by USFDA are natural products, natural product inspired or mimics many of which have their origins from fungi. Hence fungal compounds are playing a very important role in drug discovery and development in the pharmaceutical industry.

Methods:

We undertook structured searches of bibliographic databases of peer-reviewed research literature which pertained to natural products, medicinal chemistry of natural products and drug discovery from fungi. With the strategic improvement in screening and identification methods, fungi are still a potential resource for novel chemistries. Thus the searches also comprised of bioactive agents from fungi isolated or derived from special ecological groups and lineages. To find different molecules derived or isolated from fungi under clinical studies, clinical trial data from the NIH as well as from pharmaceutical companies were also explored. This comprised of data wherein the pharmaceutical industries have acquired or licensed a fungal bioactive compound for clinical study or a trial.

Results:

Natural product chemistry and medicinal chemistry continue to play an important role in converting a bioactive compound into therapeutic moieties or pharmacophores for new drug development.

Conclusion:

Thus one can say fungal bioactive compounds are alive and well for development into new drugs as novel ecological groups of fungi as well as novel chemistries are being uncovered. This review further emphasizes the collaboration of fungal biologists with chemists, pharmacologists and biochemists towards the development of newer drugs for taking them into the drug development pipeline.
Development and Validation of a Specific RP-HPLC Method for Simultaneous Estimation of Anti-retroviral Drugs: Application to Nanoparticulate Formulation System
Authors: Varghese Nila Mary , Senthil Venkatachalam , Jose Sajan , Thomas Cinu , Harindran Jyoti
Published: June 2018

Objective:

A simple, accurate and economical reverse phase- high performance liquid chromatographic method has been developed for the simultaneous quantitative estimation of two anti-retro viral drugs, Etravirine and Elvitegravir in nanoparticulate formulations for the first time. This method is a novel analytical technique for the detection of the both the drugs concurrently, as there is no method available for their simultaneous quantification, to the best of our knowledge.

Methods:

Optimization and validation of the chromatographic conditions were completed according to the standard ICH guidelines. The separation was done on a C18 column (250 mm x 4.6mm, 5μm) using methanol and phosphate buffer of pH (5.6) as the mobile phase in the ratio 78:22 v/v at a flow rate of 1ml/min for a short run time of 13 min. The detection wavelength was 285nm and the column temperature was maintained at 32oC.

Results:

The developed method was linear over 10 to 160 μg/ml with a regression coefficient of 0.999 for each. The LOD values were 4.83 and 9.25 µg/ml while LOQ values were 14.63 and 28.01 µg/ml for etravirine and elvitegravir respectively. The recovery values obtained by etravirine and elvitegravir were between 97.6% and 100.8%.

Conclusion:

The method was specific, precise, fast and accurate with good inter and intra day precision. The method was also effectively employed for the characterization and simultaneous quantification of both drugs in nanoparticulate formulation.
Names of Blantyre, Carluke, and Carnwath, near Glasgow
Authors: Breeze Andrew
Published: June 2018

No abstract
Gaelic Names of Pibrochs: A Classification
Authors: Cannon Roderick D.
Published: June 2018

No abstract
Geikie’s A Blind Fiddler and Two Associated Traditions
Authors: Campbell Katherine
Published: June 2018

No abstract
Does Ethnology Have A Future?
Authors: Porter James
Published: June 2018

No abstract
Book Reviews
Authors: - -
Published: June 2018

No abstract
Bawdy New Year’s Rhyme from Gaelic Scotland
Authors: Black Ronald
Published: June 2018

No abstract
Richard Wagner’s Der fliegende Holländer – A Flying Hebridean in Disguise?
Authors: Ahlander Per G.L.
Published: June 2018

Several scholars have drawn attention both to the many Scottish references in Richard Wagner’s initial sketches of The Flying Dutchman and to the close links between the opera and the composer’s own disastrous Nordic sea journey, but discussions tend to centre on the opera’s libretto. What appear to be musical reminiscences of Hebridean songs in the opera’s core thematic material have not been alluded to since Marjory Kennedy-Fraser pointed them out at the beginning of the twentieth century. Having a long-standing interest in Wagner’s oeuvre, she associated various themes and tunes she had collected in the Outer Hebrides with the German composer, and among her extant field recordings – now at Edinburgh University Library – there are indeed snippets of music that closely resemble Wagnerian leitmotifs and airs, in particular Senta’s ballad in Der fliegende Holländer. Drawing on a paper Kennedy-Fraser read to the Musical Association in London in 1918, various scattered references, and letters from Sir Granville Bantock and John Lorne Campbell, my article discusses the potential links between Hebridean songs and, in particular, Senta’s ballad.
Learning and Remembering Gaelic Stories: Brian Stewart
Authors: Zall Carol
Published: June 2018

Questions about how Gaelic storytellers have learned, remembered and performed their tales are key to understanding the Gaelic narrative tradition. This article examines the experience of Brian Stewart, a Scottish Gaelic storyteller, and the techniques he reported using for learning, remembering and telling traditional Gaelic stories. Mr Stewart learned his stories – native heroic or international wonder tales – from his grandmother Susie Stewart and his uncle Alasdair Stewart (also known as ‘Alilidh Dall’). Strategies considered include taking an interest in stories; repeatedly listening to tales being told by a more experienced tradition bearer; practicing in front of, and being corrected by, another storyteller; consciously reviewing and rehearsing tales; visualizing stories; and retaining a faithful memory of formulaic language or runs. The difference between learning a story and learning a song is also discussed. It is suggested that studying these strategies can contribute to a better understanding of the Stewarts’ storytelling ethos.
Entre Planos Quinquenais: Presença de Empresas Chinesas na América do Sul
Authors: Wegner Rubia Cristina
Published: June 2018

O objetivo deste artigo é descrever e analisar o panorama do Investimento Direto Externo (IDE) de empresas chinesas na América do Sul nos últimos anos, tendo em vista os delineamentos apresentados no último plano quinquenal para o desenvolvimento de longo prazo da China. Iniciativas como o Plano “Made in China 2025”e “Um cinturão, uma rota” também fazem parte desse panorama. O estudo parte de uma revisão teórica sobre o IDE da China em países em desenvolvimento e passa a uma breve discussão sobre as perspectivas dos países sul-americanos nas estratégias das empresas multinacionais chinesas no âmbito da transição de desenvolvimento da economia chinesa. São apresentados dados de IDE a partir de diversas fontes, bem como dados sobre as empresas chinesas que têm investido nos países sul-americanos.
A avaliação do impacto da Companhia Integrada de Polícia de Proximidade (CIPP)
Authors: Vaz Bruno Ottoni Eloy , Caldas Emmanuel Emmanuel Antonio Rapizo Magalhães
Published: June 2018

Este trabalho apresenta uma avaliação de impacto da implementação da Companhia Integrada de Polícia de Proximidade (CIPP), projeto realizado pela Polícia Militar do Estado do Rio de Janeiro (PMERJ). Utilizando o método de controle sintético, e dados do Instituto de Segurança Pública do Rio de Janeiro (ISP), encontra-se que a CIPP implica em uma redução de crimes comparativamente ao grupo de controle. Porém, nota-se que a redução dos crimes decorrentes da implementação da CIPP não é estatisticamente diferente daquelaobservadaem áreas que ficaram fora do programa.
A Historical Study of the First 30 Years ofAccounting Horizons
Authors: Zeff Stephen A. , Dyckman Thomas R.
Published: June 2018

In this paper, we undertake a historical study of the first 30 years of the American Accounting Association's journal, Accounting Horizons. The journal was initially intended to bridge academe and practice. We review the founding of the journal and then trace the development of both the Commentaries and Main Articles sections. One of our principal findings is that there was a steep increase in the percentage of Main Articles using regression analysis-statistical tests during the 30 years, eventually exceeding that in The Accounting Review. Our analysis of the likely reasons for this trend leads us to conclude that foundational changes in the culture of the public accounting profession and in accounting academe had a profound impact on the content of Horizons during our period of study. We conclude with some suggestions for the journal moving forward.
Boardroom Backscratching and Audit Fees
Authors: Hanlon Dean , Khedmati Mehdi , Lim Edwin KiaYang
Published: June 2018

This study investigates the impact of backscratching between the CEO and directors on a firm's future performance, financial reporting quality, and audit fees. We find that the presence and extent of boardroom backscratching are associated with weaker future performance, poorer quality financial reporting, and higher audit fees. We attribute these findings to backscratching firms' increased business and information risks inducing auditors to exert greater effort and charge risk premiums in response to heightened audit engagement risks. We observe consistent results when extending our investigation to backscratching between the CEO and audit committee and between the CEO and the CFO, given that the audit committee and the CFO influence financial reporting quality. Finally, we provide evidence that backscratching firms display greater audit report lag and a higher likelihood of receiving a going concern audit opinion. Our study offers insights to regulators concerning policy development to strengthen board effectiveness and remuneration disclosures.
Are CFOs Effective Operators? An Empirical Analysis of CFO/COO Duality
Authors: Buchheit Steve , Reitenga Austin L. , Ruch George , Street Daniel A.
Published: June 2018

While the popular press has documented Chief Financial Officer (CFO) role expansion into traditional operations functions, recent research suggests that time spent on non-core CFO activities harms financial reporting quality. We examine the operational acumen of CFOs and potential negative reporting consequences stemming from one person simultaneously holding the role of CFO and Chief Operations Officer (COO) (CFO/COO duality). Empirically, CFO/COO duality occurs with increasing frequency during our sample period (2000–2016); duality is not uncommon (among firms with a COO, over 10 percent have a unified CFO/COO executive). We find no evidence that combining the CFO and COO positions adversely affects operations. Regarding financial reporting quality, we find some evidence that CFO/COO duality firms have relatively more volatile discretionary accruals; however, these accruals are also relatively more predictive of future cash flows. Collectively, our results suggest that unifying control of operations and reporting can be an effective corporate reconfiguration.
Business Strategy and the Cost of Equity Capital: An Evaluation of Pure versus Hybrid Business Strategies
Authors: Khedmati Mehdi , Lim Edwin KiaYang , Naiker Vic , Navissi Farshid
Published: June 2018

We examine the effect of pure (product differentiation or cost leadership) versus hybrid (a mix of product differentiation and cost leadership) business strategies on the cost of equity capital. Our results suggest that firms with a pure, relative to a hybrid, business strategy have a significantly lower cost of equity, and the cost of equity effect is equally driven by pure product differentiation and pure cost leadership strategies. We also find that firms following a pure business strategy are associated with lower systematic risk. Further, the lower cost of equity effect of a pure product differentiation strategy is more pronounced in high-technology industries and in regions with greater innovative capital. Our findings are robust to an array of robustness checks including change specification regressions and various methods for addressing endogeneity.

Data Availability: All data used in this study are publicly available from the sources identified in the paper.
Basal Insulin in Clinical Practice—Can Virtual Patient Simulation Improve Use in T2D?
Authors: LARKIN AMY , LACOUTURE MICHAEL , WARTERS MARTIN , LITTMAN GWEN S.
Published: June 2018

We sought to determine if online, virtual patient simulation (VPS)-based continuing medical education (CME) intervention could improve performance of primary care physicians (PCPs) and diabetologists/endocrinologists (D/Es) in evidence-based use of basal insulin for T2D. The intervention comprised two patients presenting in a VPS platform that allows learners to order lab tests, make diagnoses, and prescribe treatments in a manner matching the scope and depth of actual practice. Tailored clinical guidance (CG), based on current evidence and expert recommendation, was provided following each decision, followed by the opportunity to modify to their decisions. Decisions were collected post-CG and compared with each user’s baseline (pre-CG) decisions using a 2-tailed paired t-test to determine P values.

Significant improvements were observed after CG: Case 1 (n=417 PCPs; n=100 D/Es):Appropriate basal insulin initiation: 44% absolute improvement among PCPs (24% pre-CG vs. 68% post-CG; P<.001), 50% improvement among D/Es (30% pre-CG vs. 80% post-CG; P<.001) Order diabetes self-management education (DSME) in newly diagnosed patient: 19% absolute improvement among PCPs (50% pre-CG vs. 69% post-CG; P<.001), 14% improvement among D/Es (59% pre-CG vs. 73% post-CG; P=.017) Titration plan: 27% improvement among PCPs (28% pre-CG vs. 55% post-CG; P<.001), 26% absolute improvement among D/Es (29% pre-CG vs. 55% post-CG; P<.001).

Case 2 (n= 537 PCPs, n=132 D/Es): Selection of longer-acting basal insulin in T2D patient complaining of hypoglycemia: 34% absolute improvement among PCPs (31% pre-CG vs. 65% post-CG; P<.001), 39% improvement among D/Es (39% pre-CG vs. 75% post-CG; P<.001) Titration plan: 22% improvement among PCPs (29% pre-CG vs. 51% post-CG; P<.001), 21% absolute improvement among D/Es (34% pre-CG vs. 55% post-CG; P<.001) VPS that immerses and engages specialists in an authentic and practical learning experience can improve evidence-based clinical decisions related to use of basal insulin in T2D.

Disclosure

A. Larkin: None. M. LaCouture: None. M. Warters: None. G.S. Littman: None.
Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin (U-500R) Administered via Continuous Subcutaneous Insulin Infusion (CSII) vs. Subcutaneous Injection (SCI) in Adults with Type 2 Diabetes and High Insulin Requirements
Authors: MA XIAOSU , PRESCILLA RANDY P. , ZHANG SHUYU , LINNEBJERG HELLE , MORROW LINDA , JACKSON JEFFREY A. , JOHNSON JENNAL , LEISHMAN DEREK
Published: June 2018

There have been no euglycemic clamp studies on U-500R in obese patients with type 2 diabetes mellitus (T2DM) and high insulin requirements. This open-label, randomized, 2-way crossover, euglycemic clamp study (NCT02588950) evaluated PK/PD of U-500R administered by CSII (using an investigational Omnipod® U-500 Insulin Management System) compared to SCI (using a U-100 syringe), in adults with T2DM requiring >150 U/day of insulin. Subjects (N=11, mean BMI: 39.6 kg/m2, mean A1C: 10.2%) each received a 100 U dose via CSII [primed with a 12-hour (hour) U-500R basal infusion] and a single SCI, both followed by a 24 hour clamp. Serum insulin concentrations were corrected for endogenous insulin using C-peptide for both administration methods. Basal infusion values in CSII were adjusted with baseline and model corrections. Following SCI, using model corrected method, time of maximum observed drug concentration (tmax) was about 1.5 hour longer compared to CSII [LSmean ratio (90% CI): 1.46 (1.08, 1.97)]. There was no statistically significant difference between CSII and SCI in median tmax, areas under the curve [AUC(0-24), AUC(0-tlast)], and maximum concentration. There was no statistically significant difference between CSII and SCI in median time to maximum glucose infusion rate (GIR) [CSII: 7.2 hour; SCI: 8 hour], median time of 50% of maximum GIR before Rmax (tRmax50) [CSII: 2.85 hour; SCI: 3.59 hour], and median time to last GIR [CSII: 18.9 hour; SCI: 14.6 hour]. No severe hypoglycemia was reported. U-500R was well tolerated whether given by syringe or CSII. The PK/PD profiles and time action parameters were similar with both methods of administration.

Disclosure

X. Ma: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R.P. Prescilla: None. S. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. L. Morrow: Stock/Shareholder; Self; ProSciento. Employee; Spouse/Partner; Eli Lilly and Company. J.A. Jackson: Other Relationship; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Johnson: Employee; Self; Eli Lilly and Company. D. Leishman: Employee; Self; Eli Lilly and Company.
Efficacy and Safety of Biphasic Insulin Aspart Treatment in Hospitalized Patients with T2DM—A Real-World Study
Authors: ERUKULAPATI RAVI S. , YERRAMILLI APARNA , KANCHERLA VISALAKSHI , SREELALITHA GOPALA RAO S. , POOJARI ANITHA , KHAN FATHIMA Z. , CHAPPIDI KRISHNA REDDY
Published: June 2018

Aim: To evaluate the efficacy and safety of biphasic insulin aspart during first 2 to 8 days of hospital admission of patients with type 2 diabetes (T2DM) for non-glycemia related medical ailments.

Methods: An open-label, non-randomized, observational, single-center study in patients with T2DM aged between 18 and 70 years at a tertiary multispecialty hospital in India. T2DM patients with capillary blood glucose (BG) between 70 mg/dl to 400 mg/dl at admission, requiring subcutaneous biphasic insulin aspart were included in this study. Insulin dosage was individualized as per the clinician’s judgement considering the clinical status, HbA1c and other co-morbidities. The primary endpoint was mean capillary BG levels at fasting, prelunch, predinner and at midnight during day 2 to day 8 of hospital stay. Secondary endpoints were frequency and severity of hypoglycemic episodes. Appropriate statistics were applied at 2-tailed p ≤0.significance.

Results: Total 2T2DM patients were included in this study. Median age was 57 years, 66.3% male and 33.7% female. Mean duration of T2DM was 9.9 years, HbA1c 7.3%, BMI 25.9 kg/m2 and hospital stay 8.9 days. The mean (SD) BG at admission was 208.5 (82.9) mg/dL and after usage of Biphasic Insulin Aspart 188.2 (45.3) mg/dL. Mean capillary BG levels at fasting, prelunch, predinner, and at midnight were 166.9 (46.7) mg/dL, 201.0 (58.8) mg/dL, 203.9 (60.1) mg/dL, and 179.0 (48.7) mg/dL respectively. BG readings that met the target BG range (140-180 mg/dL) levels were 34.6%. During the study 5.9% of patient’s experienced hypoglycemic event of which 2% were severe requiring intravenous dextrose and 3.9% were mild. There was a significant difference in BG reduction correlating with BMI, HbA1c (p =0.05).

Conclusions: Treatment with biphasic insulin aspart is observed to be effective in achieving optimal BG levels, is well-tolerated with low hypoglycemic events in patients admitted in hospital for non-glycemia related medical ailments.

Disclosure

R.S. Erukulapati: None. A. Yerramilli: None. V. Kancherla: None. G.S. Sreelalitha: None. A. Poojari: None. F.Z. Khan: None. K. Chappidi: None.
Insulin Therapy in Type 3c Diabetes—More Common in Chronic Rather than Acute Pancreatitis
Authors: HINTON WILLIAM , FEHER MICHAEL , MUNRO NEIL M. , COYLE RACHEL M. , DE LUSIGNAN SIMON
Published: June 2018

Background and Aims: Prevalence of diabetes following pancreatic disease (type 3c diabetes/T3cDM) is estimated to affect 5-10% of people with diabetes in Western populations. However, misclassification of T3cDM is common. Consequently, there is little real-world data on prescribing of antihyperglycaemic medications in people with T3cDM. The aim of this study is to evaluate prescribing of antihyperglycaemic medications in people with T3cDM.

Methods: A cohort of adults with a diagnosis of pancreatitis preceding diabetes, i.e., probable T3cDM, were identified from primary care records in England, the Royal College of General Practitioners Research and Surveillance Centre database (N = 1,595,445). The cohort was divided into those with acute (AP) or chronic pancreatitis (CP). People who presented initially with AP and subsequently developed CP were categorised as the latter. We performed retrospective analyses to compare the proportions of antihyperglycaemic medications prescribed in these subgroups. Chi square (X2) tests were used to test for differences between proportions.

Results: Of the 45,615 people living with diabetes, we identified 725 (1.6%) with pancreatitis preceding their diagnosis (AP = 456; CP = 269). The majority of those affected were prescribed non-insulin therapies (74.8%). Metformin was the most commonly prescribed medication (56.4%), followed by sulfonylureas (28.3%), insulin (25.2%) and DPP-4 inhibitors (11.6%). People with AP were more likely to be prescribed metformin (63.2% vs. 45.0%; p<0.001) and DPP-4 inhibitors (13.6% vs. 8.2%, p=0.037) than those with CP, whilst people with CP were more likely to be prescribed insulin (34.9% vs. 19.5%; p<0.001). No differences in prescribing were found for other antihyperglycaemic medication classes.

Conclusion: The differences in prescribing in people with CP compared to AP suggests progressive pancreatic damage and loss of endocrine function, with more patients requiring insulin therapy.

Disclosure

W. Hinton: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk Limited. M. Feher: Advisory Panel; Self; Novo Nordisk Limited, Sanofi, AstraZeneca. N.M. Munro: None. R.M. Coyle: None. S. de Lusignan: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk Limited, AstraZeneca.
Mobile-Based Artificial Intelligence Significantly Improves Type 1 Diabetes Management
Authors: DOUPIS JOHN , PAPANDREOPOULOU VASILIKI , GLYKOFRIDI SPYRIDOULA , ANDRIANESIS VASILEIOS
Published: June 2018

Background: Type 1 diabetes involves a multiple decision making process on a daily basis.Mobile technology has been widely spread not only as a mean of communication, but also as multi-usage tool involving a large variety of applications, making everyday life more convenient. “D-Partner” (Diabetes Innovations Ltd) is a mobile based application that serves as a self-management tool for type 1 diabetes, including a bolus wizard (with food database),a basal insulin titration manager, as well as, a large number of automated notifications, warnings or reward messages, according to the data imported by the patient. In addition,“D-Partner” serves as a telemedicine tool, as information of meals, insulin dosage, measurements of glucose, blood pressure, body weight, and lab values, may be monitored by the physician through an on-line, web-based platform.

Aim: To investigate the efficacy of "D-Partner" mobile application, in glucose management, in patients with type 1 diabetes.

Methods: 24 patients with type 1 diabetes (14 male, 10 female), with diabetes duration of 14,2±8,8 years, mean age of 37.4±11,7 years and HBA1c >7%, on basal bolus insulin therapy, were randomized to receive either standard care, or standard care plus the ‘D-Partner” application usage. HBA1c, somatometric data, blood pressure, heart rate and hypoglycemia frequency data, were obtained at baseline and 3 months after the intervention.

Results: The intervention group presented a significantly improved glucose control as recorded by HBA1c reduction, compared to the control group (p=0.01). Additionally, hypoglycemia incidence was significantly lower in the intervention group (p=0.04). There were no significant changes in somatometric data blood pressure, and heart rate, among the 2 groups.

Concusion: D-partner, is a mobile based self-management application, that may contribute to a better management of type 1 diabetes, potentially improving the life quality of the patient.

Disclosure

J. Doupis: Consultant; Self; Novo Nordisk Inc., Eli Lilly and Company, Sanofi, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.. V. Papandreopoulou: None. S. Glykofridi: None. V. Andrianesis: None.
ITCA 650 Provides Consistent Efficacy in T2D Irrespective of Baseline Characteristics—Results of a Pooled Subgroup Analysis
Authors: PRABHAKAR PRAKASH , KJEMS LISE L. , HUANG HOLLY , SCHWARTZ BRIAN , BARON MICHELLE A.
Published: June 2018

ITCA 650 consists of a small titanium osmotic mini—pump that is subdermally placed in the abdominal wall during a brief in-office procedure. As an investigational product for the treatment of type 2 diabetes (T2D), ITCA 650 provides a continuous subcutaneous infusion of exenatide over 3 or 6 months. Pooled 39-week data from two double-blind, randomized, Phase 3 studies were used to evaluate the efficacy of ITCA 650 20/60 mcg/d in patients with T2D inadequately controlled by oral antidiabetic drugs (OADs). Results in the overall population (N=683) and in subgroups according to age, gender, BMI, ethnicity, time since diagnosis, baseline HbA1c, GI adverse events, presence of anti-drug antibodies, and renal function are reported. As shown in the Figure, the overall mean (standard deviation [SD]) reduction in HbA1c (%) was 1.5% (1.2) with clinically meaningful reductions in HbA1c consistently observed irrespective of age, gender, BMI, ethnicity, time from T2D diagnosis, eGFR and background OADs (data not shown). Patients with a higher baseline HbA1c had a greater response. Mean weight loss was 3.4 kg (SD 4.7), and 40.7% (95% CI 0.36-0.46) of patients achieved a composite endpoint of HbA1c/weight reduction of >0.5%/≥2 kg. Similar changes were likewise seen consistently across subgroups. ITCA 650 demonstrated consistent efficacy across a wide spectrum of patients with T2D.

Disclosure

P. Prabhakar: None. L.L. Kjems: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. H. Huang: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..
Effect of Single Dose of Insulin Glargine/Lixisenatide Fixed-Ratio Combination (IGlarLixi) on Postprandial Glucodynamic Response in Japanese Patients with Type 2 Diabetes Mellitus
Authors: INOUE MEGUMI , LORENZ MARTIN , MUTO HIDEYA , HASHIMOTO YASUHIRO
Published: June 2018

Fixed ratio combination of insulin glargine/lixisenatide (iGlarLixi) is expected to bring benefits such as better efficacy, mitigating barriers to their individual use, and convenient single daily injection. Based on the study results which demonstrated the efficacy and safety of iGlarLixi, approvals from FDA and EMA were obtained. Currently, specific clinical development of iGlarLixi in Japan is ongoing. A randomized, open-label, placebo-controlled, 4-sequence, 4-period, 4-treatment crossover study to investigate the postprandial glucodynamic response to single subcutaneously (SC) dose of iGlarLixi in Japanese T2DM patients was conducted. This study primary aimed at investigating the PD of lixisenatide at doses up to 10 μg in the combination with insulin glargine as compared to placebo and low-dose insulin glargine alone in Japanese T2DM patients. Twenty patients were assigned to one of the four sequences of treatments, all of which included iGlarLixi (5 U/5 μg and 10 U/10 μg), 5 U insulin glargine and placebo. The parameter PPG-AUC0-2h was evaluated as primary endpoint. The LS mean differences of PPG-AUC0-2h between iGlarLixi (5 U/5 μg) and placebo, iGlarLixi (10 U/10 μg) and placebo, iGlarLixi (10 U/10 μg) and iGlarLixi (5 U/5 μg), and iGlarLixi (5 U/5 μg) and 5U insulin glargine were -7.48 (p < 0.0001), -10.75 (p < 0.0001), -3.28 (p < 0.0001), and -7.30 (p < 0.0001), respectively. These results demonstrated the 2 doses of iGlarLixi significantly decreased PPG in a dose-dependent manner following a standardized breakfast when compared to placebo. And by combining the complementary therapeutic benefits of insulin glargine predominantly on FPG and the effect of lixisenatide on PPG, the combination product can affect both components of hyperglycemia as a therapeutic principle. No SAEs were reported and no patients discontinued the study. Single SC doses of iGlarLixi were safe and well tolerated.

Disclosure

M. Inoue: None. M. Lorenz: None. H. Muto: Employee; Self; Sanofi K.K. Y. Hashimoto: Employee; Self; Sanofi K.K..
In Vitro Studies to Evaluate the Receptor Kinetics of Efpeglenatide vs. Other Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists
Authors: CHOI IN YOUNG , MOON MI JIN , TRAUTMANN MICHAEL E. , HOMPESCH MARCUS , SORLI CHRISTOPHER H.
Published: June 2018

Efpeglenatide (efpeg) is a long-acting GLP-1 R agonist in development for the treatment of T2D. Efpeg’s effects on the GLP-1 R suggest that it is a superagonist: a ligand that leads to greater maximal signaling and stimulation compared with its endogenous ligand. In vitro studies evaluated the superagonistic effects of efpeg and compared them to the effects of liraglutide (lira) and dulaglutide (dula) on GLP-1 R-binding kinetics and internalization, and cell signaling/desensitization. Efpeg had a higher dissociation constant vs. lira or dula (360.7 vs. 58.7 and 39.4 nmol/L, respectively) indicating a lower binding affinity for GLP-1 R (∼6.1 fold vs. lira, ∼9.2 vs. dula) and faster dissociation vs. lira (∼3.6 fold; p<0.001) or dula (∼2.9 fold; p<0.001). At 100nM, efpeg led to less receptor internalization vs. lira or dula (% of initial internalized receptor: 140% vs. 1191% and 714%, respectively; p<0.001 each) and lower proportions of receptor lost from the cell surface (32% vs. 74% and 69%; p<0.001). After pretreatment (4 or 24 h), efpeg led to significantly greater accumulation of cAMP and insulinotropic activity vs. lira or dula (Figure). The superagonistic effect of efpeg on GLP-1 R may be due to its specific binding characteristics, allowing more cell-surface receptor availability for intracellular signaling. The clinical relevance of these findings should be assessed further.

Disclosure

I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M. Moon: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. M. Hompesch: Other Relationship; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.
Bone Protective Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in an Animal Model
Authors: LEE SANGDON , KIM YU-YON , LEE JONG SUK , LEE SANG HYUN , KIM YOUNG HOON , CHOI IN YOUNG , KIM SUN JIN
Published: June 2018

Severe weight loss is often associated with reduction of bone mineral density (BMD) and an imbalance between bone formation and reabsorption in obese people. As a consequence, there can be an increased risk of bone fractures with body weight loss. Several studies have proposed that the gut hormones, GIP and GLP-1, might be modulators of bone growth and remodeling. HM15211 is a novel long-acting GLP-1/GIP/Glucagon agonist that is being developed for the treatment of obesity. In this study, we investigated whether treatment with HM15211 prevents bone loss under a severe weight loss condition, and the underlying mechanism of action. First, the bone protective effect of HM15211 was evaluated using diet induced obesity ovariectomized osteoporosis rat model. After 4 weeks subcutaneous treatment of HM15211 (120 µg/kg/Q3D), lower levels of serum decarboxylated osteocalcin (42.2 ng/mL) and higher serum P1NP (procollagen type I pro-peptide, 53.2 ng/mL) were observed compared with those of vehicle- (156.4 ng/mL for osteocalcin, 28.6 ng/mL for PINP) and liraglutide-treated groups (94 µg/kg/BID, 120.6 ng/mL for osteocalcin, 29.4 ng/mL for PINP). Furthermore, HM15211 showed comparable BMD of femur bones and lumbar spine with vehicle group while weight loss was greater (-26.0% vs. vehicle) compared to liraglutide (-11.5% vs. vehicle). These results suggest that treatment with HM15211 effectively prevents bone loss even after potent body weight loss in high fat dieted ovariectomized obese rats. Second, to elucidate the underlying molecular mechanism, related marker gene expression was investigated using the SaOS2 cell, human osteogenic cell. In line with the bone protective effect in vivo, HM15211 led to significant increases in type 1 collagen-α1, -α2, and carboxylated osteocalcin expression, which were blunted by inhibition of GIPR-mediated signaling.

In conclusion, these results suggest that HM15211 might provide potent weight loss without the otherwise inevitable bone loss.

Disclosure

S. Lee: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None. J. Lee: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. Y. Kim: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical.