bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-Time Well Construction Process Inference through Probabilistic Data Fusion
Authors: Chambon Sylvain , Venkatakrishnan Sai , Hamzah Mohammad Khairi , Belaskie Jim , Yu Yingwei
Published: February 2018

Well construction process automation systems rely on the tracking of the state of the world (equipment, wellbore, process) with a high degree of confidence for safe and efficient operations. Robust state detection algorithms are paramount as they depend on uncertain models and data from imperfect sensors. The proposed solution outlined here is a practical implementation for well construction state inference, focused on bit-rock interaction.

Probabilistic mixture models are learned from input sensor data stream, e.g. surface torque and hook load, accounting for noise and suitable priors. These models are then used for online classification of observations related to the underlying state of operations (e.g. on bottom drilling vs off bottom rotating). Multiple classified observables from different types of measurements are subsequently fused into system states using a Bayesian network, giving a robust state detection under uncertainty. The method required drilling mechanics knowledge in the interpretation of the classification as well as the design of the Bayesian network model.

The algorithm was applied on real sensor data (hook load and surface torque), for the inference of elementary states of bit-rock interaction (no interaction, bit fully engaged with formation, in transition). The use of streaming input data to continuously learn the mixture model allows the tracking of levels. For instance, hook load is modeled as the mixture of several distributions evolving as the well progresses, correlated to the drill string being in slips, out of slips off bottom, or on bottom rotating. Observations inferred from the mixture models have various levels of confidence. The Bayesian network allows their fusion into a robust system state.

The presented Bayesian network backed by mixture model is a fast, adaptive and robust solution to detect system state from drilling time series data with complex temporally correlated patterns. By learning from data and using priors from domain experts, the inference algorithms operate without user tuned thresholds or parameters. The probabilistic Bayesian approach provides a framework for dealing with uncertainty in drilling systems and can be extended in the future with additional observations drawn from new measurements.
Real-Time Downhole Data Resolves Lithology Related Drilling Behavior
Authors: Viens Christopher , Clark Tyler , Lightfoot Jonathan , Mercado Carlos
Published: February 2018

Utilizing azimuthal gamma imaging, continuous inclination, and downhole bending moment measurements to understand thinly layered shale lithology while maintaining the wellbore within the target formation has led to improvements in placement and drilling time reduction. A close examination of this approach in six wells in the Midland Basin demonstrates that utilizing a stabilized bottom-hole assembly (BHA) while drilling horizontally can result in a ‘locked-in’ phenomenon from contrasting hardness of the layers immediately above and below the wellbore. With proper interpretation of real-time downhole measurements, drillers are able to keep the well path in the target zone with minimal slide drilling. The ‘locked-in’ phenomenon was used most effectively in the Wolfcamp A formation where the thin beds are homogenous and laterally continuous. The phenomenon could not be leveraged as effectively in the Wolfcamp B, whose geology is a product of higher energy deposition when compared to the Wolfcamp A.
Offshore Well Intersection and Casing Pull Through to Deliver Pipeline Segment
Authors: Leonard B. A. , Pfeifer D. W. , Katuaga G. , Clark P. J. , Armistead G. T.
Published: February 2018

Due to technical and logistical challenges, an inovative solution was required to connect two offshore platforms in shallow water to allow gas transit as part of a pipeline network. A primary obstacle to conventional pipeline installation at this location was the presence of a large subsea canyon. As a result, the project team decided to utilize jack-up drilling rigs to drill a conduit and then install casing as a pipeline segment.

The project utilized some unusual drilling technologies and unique techniques to deliver the final gas conduit. These included a robust program design for a remote location, large diameter hole opening in horizontal wells, active magnetic ranging to affect wellbore intersection at very low incident angle, and synchronizing two rigs' activities as they latched drill pipe and then pulled casing as a single string. Execution was ultimately successful due to the extensive planning work and diligence of the operations teams, and a number of interesting observations and lessons were captured in the process.
A Cyber-Physical Approach to Early Kick Detection
Authors: Andia P. , Israel R. R.
Published: February 2018

This paper describes a novel approach to early kick detection. A cyber-physical approach is utilized to improve the speed and consistency at which a kick can be identified during drilling operations, thus automating the kick detection process. The proposed methodology combines physics-based modelling with Bayesian mathematics for detecting subtle changes in noisy and uncertain measurements. For early kick detection purposes, the physics model is that of a lumped parameter model that describes the fluid flow in a well and the noisy and uncertain measurements are the data streams from rig sensors available during well construction operations, which are used to fit/correct the results of the model via an extended Kalman filter approach.

A tool was built that is able to consume real-time and archived data, solve the lumped parameter model and Kalman filter implementation, and output the computed results for real-time viewing purposes. Historical datasets were used to demonstrate that the tool is able to detect kicks earlier than conventional methods, while providing an acceptable low false alarm rate. A real-time trial was conducted within a real-time monitoring center to evaluate the performance of the tool as an effective early kick detection technology via a set of key performance indicators and test the developed operational protocols and training materials with monitoring center personnel. The metrics put in place evaluated the tool in three categories: software robustness, data quality and early kick detection technical performance. A test plan was developed with test procedures and a workflow for utilizing the information given by the tool in the context of a real-time monitoring center. No kicks occurred during the construction of the well. However, certain operational events that resemble a kick demonstrated that the tool is able to identify them and trigger an alarm. The overall results of the real-time trial were favorable and potential enhancements to the tool were identified.
Probabilistic Real-Time Trajectory Control Considering Uncertainties of Drilling Parameters and Rock Properties
Authors: Liu Zhengchun , Samuel Robello
Published: February 2018

This work provides a probabilistic approach to proactively adjust drilling parameters (which can be uncertain) in real time to help ensure the actual drilling path overlaps the target drilling path to the maximum extent. The planned well path is initially adjusted by a probabilistic formation earth model (EM) for maximum production potential and then adjusted to help improve well path smoothness to allow the passage of tubular strings. Drilling parameters and EM data can be updated in real time during drilling operations.

Considering the uncertainty associated with petrophysical properties and drilling parameters, the overlap probability between actual and target well paths was computed for current and to-be-drilled locations. All position-related data were described as distributions. The mean value and standard deviation were computed in real time. Overlapping probability (between actual and target well paths) was used as feedback for drilling parameter adjustments.

This closed-loop feedback process enables proactive control of the actual well path. Here, it is illustrated using a horizontal well case study from a typical shale field. Based on log data, formation properties [Young's modulus, porosity (Φ), and total organic carbon (TOC)] are calculated using the real-time EM. At the current drill-bit location, those properties are described statistically as normal distributions rather than single values, as are the drilling parameters, including weight on bit (WOB), rotary speed (RPM), and flow rate (Q).

Statistical methods are applied to quantify the uncertainty of the predicted actual well path. All position-related data are described as distributions. The drilling path simulation indicates that the trajectory resulting from using this new control method provides better reservoir access and maintains dogleg severity (DLS) at an acceptable level.
Artificial Islands vs. Wellhead Towers: Search for Optimized Infrastructure for Shallow-Water Developments
Authors: Hess Joe , Franco Miguel , Gille Brian
Published: February 2018

This paper describes how a multidiscipline project team incorporated artificial islands with wellhead towers (WHTs) to develop an optimized drilling scenario reaching several hundred proposed drilling targets.

As part of an economic optimization plan for a field in shallow waters, a project was undertaken to explore a means of taking advantage of artificial islands to reduce field development time, costs, and potential risks. The team collaborated with multiple stakeholders to identify the fundamental objectives of the field development project. Advanced planning and visualization software made it possible to analyze various combinations of wellhead towers and artificial islands and their surface locations, with each combination representing a different drilling scenario. Each scenario was then evaluated based on four criteria: technical feasibility of well construction, total development cost, total time for development, and degree of potential risk.

This paper focuses on the methodology applied for this project, and results discussed are limited to two randomly selected scenarios and do not reflect the complete results of the numerous scenarios evaluated in this study, nor do they reflect any decisions made as a result of this study.

The results of the analysis demonstrated that the level of feasibility and potential risk varied greatly depending on the scenario chosen, which led to a potential project cost difference of more than several hundred million USD. Collaborative planning among all stakeholders allowed the analysis of the various development scenarios to be completed on time and on budget with fundamental objectives met.
Manufacturing of CD19 Specific CAR T-Cells and Evaluation of their Functional Activity in Vitro
Authors: Petukhov A.V. , Markova V.A. , Motorin D.V. , Titov A.K. , Belozerova N.S. , Gershovich P.M. , Karabel'skii A.V. , Ivanov R.A. , Zaikova E.K. , Smirnov E.Yu. , Butylin P.A. , Zaritskii Andrei Yur'evich
Published: February 2018

Background. The most promising variant of adoptive immunotherapy of the B-line oncohematological diseases includes the use of cells with the chimeric antigen receptor (CAR T-cells), that showed extraordinary results in clinical studies. Aim. To manufacture CAR T-cells for the clinical use and to study their cytotoxicity in vitro. Methods. Human T-lymphocytes were transduced by the lentiviral vector containing anti-CD19-CAR, RIAD, and GFP genes. The T-cell transduction efficacy was assessed on the basis of GFP protein signal by flow cytometry. Propidium iodide was used to analyse the cell viability. Cytotoxic activity of the manufactured CAR T-cells was studied in the presence of the target cells being directly co-cultivated. Analysis of the number and viability of CAR T-cells and cytokine expression was performed by flow cytometry. Results. The viability of the transduced T-cells and GFP expression reached 91.87 % and 50.87 % respectively. When cultured in the presence of IL-2 and recombinant CD19 (the target antigen), the amount of CAR-T after 120 h of the process was 1.4 times larger compared with the period of 48 h. In the cytotoxic test of co-cultivation CART with the K562-CD19+ cells the percentage of CAR-T increased to 57 % and 84.5 % after 48 h and 120 h of exposure respectively. When cultured with the K562 cells (test line not expressing CD19) the number of CAR T-cells decreased to 36.2 % within 48 h while the number of K562 cells increased to 58.3 %. The viability of target cells in the experimental and control groups was 3.5 % and 36.74 % respectively. Comparison of IL-6 level in the control and experimental groups revealed that the differences are insignificant, as opposed to the level of other cytokines (IFN-y, IL-2, TNF) which proved to be different in both groups. Conclusion. The present work resulted in the production of anti-CD19 CAR T-cells with adequate viability. The in vitro model demonstrated their cytotoxicity. Manufacturing of CAR T-cells for clinical use is the first step of the development of adoptive immunotherapy in the Russian Federation.
Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia
Authors: Okhmat Vladimir Aleksandrovich , Klyasova G.A. , Parovichnikova E.N. , Troitskaya V.V. , Gribanova E.O. , Savchenko V.G.
Published: February 2018

Aim. To estimate the efficacy of antibiotic treatment of febrile neutropenia in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Materials & Methods. The prospective study (2013 to 2015) included 66 AML and 44 ALL patients receiving 480 chemotherapy cycles within the period of 6 months. Results. Febrile neutropenia was registered during 242 (50 %) chemotherapy cycles occurring more frequently in AML than in ALL patients (93 % vs. 18 %, p < 0.0001). In AML patients infections were more common during induction and consolidation (98 and 89 %) phases compared to ALL patients who most commonly had infection during induction phase (55 %). Compared to ALL patients, AML patients had lower recovery rates after first-line antibiotic monotherapy (24 % vs. 57 %, p < 0.0001), compared to combination therapy (37 % vs. 18 %, p = 0.01). The use of beta-lactam antibiotics in ALL patients was associated with lower recovery rates during the induction phase compared to consolidation phase (47 % vs. 72 %, p = 0.0004). In cases of granulocytopaenia longer that 14 days the clinical recovery rate with administration of the first-line antibiotics and carbapenems accounted for 23-24 % compared to 47 % with other antimicrobials, more commonly with antifungal (21 %) administration. In patients with fever of unknown origin the monotherapy with first-line antibiotics proved to be successful (45 %). In patients with clinically and microbiologically defined infections the best results were achieved by the combined treatment with the beta-lactam antibiotics and other drugs (43 %). Conclusion. Antibiotic escalation has proved to be the optimal strategy in treatment of ALL patients and in cases of fever of unknown origin. The efficacy of the beta-lactam antibiotic monotherapy was lower in AML patients during the induction phase as well as in cases of continuous neutropenia (> 14 days) and clinically and microbiologically diagnosed infections. The adding of other antimicrobial administration resulted in the recovery in 37-48 % of cases.
Clinical Significance of the PRAME Gene Expression in Oncohematological Diseases
Authors: Misyurin V.A.
Published: February 2018

Although the PRAME activity was first discovered in solid tumors, this gene is very frequently expressed in oncohematological diseases. PRAME can be regarded as a reliable biomarker of tumor cells. Determination of PRAME transcripts is used in residual disease monitoring and molecular relapse diagnostics. Experimentation with PRAME expressing lines of leukemia cells yielded controversial results. Therefore, it is hardly possible to estimate the prognostic value of PRAME activity in oncohematological diseases. In chronic myeloproliferative disease and chronic myeloid leukemia, however, PRAME activity proves to be a predictor of negative prognosis, and on the contrary, it can be regarded as a positive prognostic factor in acute myeloid or lymphoid leukemia. Despite many clinical studies prognostic value of PRAME expression in some diseases requires further investigation. The present literature review contains the data concerning PRAME expression in oncohematological diseases.
Current Opportunities for Treatment Optimization of Mycosis Fungoides and Sezary Syndrome
Authors: Chernova Natal'ya Gennad'evna , Kolomeitsev O.A.
Published: February 2018

Aim. To estimate vorinostat efficacy in patients with relapsed/refractory mycosis fungoides and Sezary syndrome. Materials & Methods. The total of 21 patients with refractory and progressive mycosis fungoides and Sezary syndrome receiving vorinostat 400 mg once daily were followed up from 2014 to 2017. The median age was 62 years (range 3479). The male to female ratio was 10/11. The median number of various regimens of pre-study systemic treatment was 4 (range 1-7). Progressive disease were observed in 85,7 % of patients before administration of vorinostat and after mono-and polychemotherapy. Results. The study group included 15 patients with mycosis fungoides and 6 patients with Sezary syndrome. Early stages of primary cutaneous T-cell lymphoma were diagnosed in 4 patients, the advanced stages in 17 patients. Seventeen patients received vorinostat treatment in monoregime; 4 patients were administered with vorinostat in combination with methotrexate or а-interferon. The median duration of vorinostat therapy was 6 months (range 1-38). Stabilization of the disease was observed in 47.6 % of cases, response to treatment in 38.1 % of cases (with 5 cases of complete response and 3 cases of partial response), and 14.3 % of patients had progression of the disease. The decrease of skin itching was reported in 38.1 % of patients; skin itching completely resolved in 28.6 % of cases. The adverse events required the vorinostat dose adjustment in 3 cases and treatment discontinuation in 3 cases. The total of 9 patients continue to receive vorinostat. Conclusion. Vorinostat treatment was shown to be effective in patients with refractory and advanced mycosis fungoides and Sezary syndrome not responding to various types of external, mono- and polychemotherapy. The therapy with vorinostat was associated with higher life expectancy and improved quality of life.
Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression
Authors: Mamaev Nikolai Nikolaevich , Gudozhnikova Ya.V. , Gindina T.L. , Barkhatov I.M. , Shakirova A.L. , Katerina V.A. , Gubina M.V. , Nikolaeva E.S. , Semenova E.V. , Paina O.V. , Darskaya E.I. , Pirogova O.V. , Porunova V.V. , Moiseev I.S. , Mikhailova I.A. , Ayubova B.I. , Kravtsova V.M. , Bondarenko S.N. , Zubarovskaya L.S. , Afanas'ev B.V.
Published: February 2018

Aim. To estimate the efficacy of chemotherapy in acute leukemia patients resistant to previous standard treatment according to the series measurement of WT1 expression. Materials & Methods. The series measurement of WT1 expression formed the basis of the efficacy estimation of induction chemotherapy in 31 patients (15 men and 16 women aged from 3 months to 68 years; the median age was 28 years) with prognostically unfavourable variants of acute myeloid (AML) and lymphoblastic leukemia (ALL) (23 AML and 8 ALL patients). The WT1 gene expression was measured at baseline and 2-3 weeks after the treatment by the quantitative real-time PCR. The threshold level for detection was 250 copies of WT1/104 copies of ABL. The cytogenetic profile of leukemia cells was assessed by standard cytogenetics and FISH. Results. The baseline expression level of WT1 varied from 305 to 58,569 copies/104 copies of ABL. The expected reduction of WT1 expression after the first induction chemotherapy treatment was reported in 22/23 (96 %) AML patients and in 6/8 (75 %) ALL patients. According to our results WT1 expression reached the threshold in 13/31 (42 %) patients, including 9 AML patients and 4 ALL patients. After 11/31 (35 %) patients received the second course of treatment, WT1 expression level became normal in 8 cases (5 ALL and 3 AML patients). Despite high dose chemotherapy, HSCT and such agents as blinatumomab and gemtuzumab, an unfavourable outcome was observed in 18/31 (58 %) patients including 6 patients with complex karyotype (CK+) and 2 patients with monosomal karyotype (MK+). Once the MK+ and CK+ combination was observed, in another case the MK+ was combined with the prognostically unfavourable inv(3)(q21q26) inversion. Conclusion. Our results show that the molecular monitoring should be included as part of treatment of the prognostically unfavourable acute leukemia. The WT1 gene was shown to be the most appropriate marker. WT1 expression was shown to correlate with the common fusion genes allowing to estimate the blast cell count at the molecular level.
Estrogenic activity, selected plasticizers and potential health risks associated with bottled water in South Africa
Authors: Aneck-Hahn Natalie H. , Van Zijl Magdalena C. , Swart Pieter , Truebody Barry , Genthe Bettina , Charmier Jessica , Jager Christiaan De
Published: February 2018

Potential endocrine disrupting chemicals (EDCs) are present in bottled water from various countries. In South Africa (SA), increased bottled water consumption and concomitant increases in plastic packaging create important consequences for public health. This study aimed to screen SA bottled water for estrogenic activity, selected target chemicals and assessing potential health risks. Ten bottled water brands were exposed to 20 °C and 40 °C over 10 days. Estrogenic activity was assessed using the recombinant yeast estrogen screen (YES) and the T47D-KBluc reporter gene assay. Solid phase extracts of samples were analyzed for bis(2-ethylhexyl) adipate (DEHA), selected phthalates, bisphenol-A (BPA), 4-nonylphenol (4-NP), 17β-estradiol (E2), estrone (E1), and ethynylestradiol (EE2) using gas chromatography–mass spectrophotometry. Using a scenario-based health risk assessment, human health risks associated with bottled water consumption were evaluated. Estrogenic activity was detected at 20 °C (n = 2) and at 40 °C (n = 8). Estradiol equivalent (EEq) values ranged from 0.001 to 0.003 ng/L. BPA concentrations ranged from 0.9 ng/L to 10.06 ng/L. Although EEqs and BPA concentrations were higher in bottled water stored at 40 °C compared to 20 °C, samples posed an acceptable risk for a lifetime of exposure. Irrespective of temperature, bottled water from SA contained chemicals with acceptable health risks.
Relevance of n-butanol as a reference gas for odorants and complex odors
Authors: Feilberg Anders , Hansen Michael J. , Pontoppidan Ole , Oxbøl Arne , Jonassen Kristoffer
Published: February 2018

Odor analysis by olfactometry relies on the use of n-butanol as a reference compound for standardizing the selection of human panelists. This requires that human sensitivity towards n-butanol is correlated to sensitivity towards other odorants as well as complex odor mixtures. However, there is limited evidence in the literature of such correlations. In this work, datasets from three odor laboratories were investigated in order to clarify this. All panels routinely analyzed n-butanol and H2S samples. Two of the laboratories analyzed samples from pig production or industry, whereas one laboratory determined odor threshold values for typical pig production odorants. Non-significant correlations were observed in most cases and odor threshold values for structurally related compounds were not well correlated. The work presented strongly indicates that the sensitivity of odor panelists towards n-butanol is not well transferred to other odorants or odor samples. Furthermore, minimization of variance by using n-butanol is not transferable to other odorants or environmental samples. Thus, the harmonization of human panelists for odor analysis based on n-butanol does not appear to result in harmonization with respect to other odorants or odor samples.
Fluorescent Imaging of Amyloid-β Deposits in Brain: An Overview of Probe Development and a Highlight of the Applications for In Vivo Imaging
Authors: Fu Hualong , Cui Mengchao
Published: February 2018

The β-amyloid (Aβ) plaques presented within the brain parenchyma have been
widely proved to be one of the hallmarks of Alzheimer’s disease (AD). According to the amyloid
cascade hypothesis, the accumulation of Aβ plaques in the brain is intrinsic and fundamental
for disease onset, and much research about the early diagnosis of AD is based on this.
A recent development in Aβ detection has focused on the mapping of the molecule events in
the brain using an exquisite, noninvasive, and inexpensive optical imaging technique, which
has stimulated the rapid development of Aβ-specific fluorescent probes. Among them, nearinfrared
(NIR) fluorophores have gained adequate attention due to the weak light attenuation
in tissues and avoidance from auto-fluorescence of biological matter. In this review, we
showcase the current developments of fluorescent probes that are subject to in vitro or in vivo
detection of Aβ plaques in the brain, and give an emphasis on the probes used for in vivo twophoton
microscopy and NIR imaging by highlighting their biological and photochemical
properties.
Natural Terpenoids Against Female Breast Cancer: A 5-year Recent Research
Authors: Ateba Sylvin Benjamin , Mvondo Marie Alfrede , Ngeu Sadrine Tchoukouegno , Tchoumtchoua Job , Awounfack Charline Florence , Njamen Dieudonne , Krenn Liselotte
Published: February 2018

Background:

The approval of Taxol® in 1993 marked the great entrance of terpenoids
in the anti-cancer area and this drug is still highly important in the treatment of refractory
ovarian, breast and other cancers. Over decades, other prominent natural terpenoids
have become indispensable for the modern pharmacotherapy of breast cancer. However,
given the rapid evolution of drug resistance, effective treatments for advanced breast cancers
requiring cytotoxic chemotherapy represent a major unmet clinical need. Therefore, innovative
agents effective in long-term chemotherapy are urgently needed.

Objective:

This review examines recent advances/research about natural terpenoids, and
their mechanisms against female breast cancer over the period covering January 1st, 2012 to
December 31st, 2016.

Results:

Carcinogenesis constitutes a multistep process wherein each stage is characterized
by distinct phenotypic changes. Numerous chemicals recorded in this review have been
shown to significantly inhibit proliferation, migration, apoptosis resistance, tumor angiogenesis
or metastasis in different breast cancer cells/tumours in vitro and in vivo. Targeting
simultaneously several or all these aspects/steps of cancer progression could be an advantage.
In line with this, phytochemicals such as thymoquinone (8), costunolide (46),
tanshinone IIA (132), triptolide (136), cucurbitacin B (179), celastrol (226) and lycopene
(238) had caught our attention.

Conclusion:

These compounds appear to be promising to overcome breast cancer treatment
failure. However, despite the interesting activities, additional preclinical investigations are
needed in further breast cancer cell/tumor models in vitro and in vivo.
Electrochemistry of Alzheimer Disease Amyloid Beta Peptides
Authors: Chiorcea-Paquim Ana-Maria , Enache Teodor Adrian , Oliveira-Brett Ana Maria
Published: February 2018

Alzheimer’s disease (AD) is a widespread form of dementia that is estimated to
affect 44.4 million people worldwide. AD pathology is closely related to the accumulation of
amyloid beta (Aβ) peptides in fibrils and plagues, the small oligomeric intermediate species
formed during the Aβ peptides aggregation presenting the highest neurotoxicity.

This review discusses the recent advances on the Aβ peptides electrochemical
characterization. The Aβ peptides oxidation at a glassy carbon electrode occurs in one or two
steps, depending on the amino acid sequence, length and content. The first electron transfer
reaction corresponds to the tyrosine Tyr10 amino acid residue oxidation, and the second to all
three histidine (His6, His13 and His14) and one methionine (Met35) amino acid residues. The
Aβ peptides aggregation and amyloid fibril formation are electrochemically detected via the
electroactive amino acids oxidation peak currents decrease that occurs in a time dependent
manner. The Aβ peptides redox behaviour is correlated with changes in the adsorption
morphology from initially random coiled structures, corresponding to the Aβ peptide
monomers in random coil or in α-helix conformations, to aggregates, protofibrils and two
types of fibrils, corresponding to the Aβ peptides in a β-sheet configuration, observed by
atomic force microscopy. Electrochemical studies of Aβ peptides aggregation, mediated by
the interaction with metal ions, particularly zinc, copper and iron, and different methodologies
concerning the detection of Aβ peptide biomarkers of AD in biological fluids, using
electrochemical biosensors, are also discussed.
Immunomodulatory Effects of Flavonoids in the Prophylaxis and Treatment of Inflammatory Bowel Diseases: A Comprehensive Review
Authors: Ribeiro Daniela , Proenca Carina , Rocha Silvia , Lima Jose L.F.C. , Carvalho Felix , Fernandes Eduarda , Freitas Marisa
Published: February 2018

Inflammatory Bowel Diseases (IBD) comprised of two disorders of idiopathic
chronic intestinal inflammation that affect about three million people worldwide: Crohn’s disease
and ulcerative colitis. Nowadays, the first-line of treatment for patients with mild to
moderate symptoms of IBD is comprised of corticosteroids, immunosuppressants, antibiotics,
and biological agents. Unfortunately, none of these drugs are curative, and their long-term use
may cause severe side effects and complications. Almost 40% of IBD patients use alternative
therapies to complement the conventional one, and flavonoids are gaining attention for this
purpose. The biological properties of flavonoids are well documented and their antioxidant
and anti-inflammatory activities have been arousing attention in the scientific community.
Flavonoids are the most widely distributed polyphenols in plants and fruits, making part of
the human diet. Taking into account that all ingested flavonoids are expected to exert biological
actions at the gastrointestinal level, research on the modulatory effect of these compounds
in IBD is of paramount importance. This review intends to summarize, in an integrated and
comprehensive form, the effect of flavonoids, both in vitro and in vivo, in the different phases
of the characteristic IBD inflammatory network.
Vitamin D Receptor: A Novel Therapeutic Target for Kidney Diseases
Authors: Yang Shikun , Li Aimei , Wang JianWen , Liu Jun , Han Yachun , Zhang Wei , Li Yan Chun , Zhang Hao
Published: February 2018

Background:

Kidney disease is a serious problem that adversely affects human
health, but critical knowledge is lacking on how to effectively treat established chronic kidney
disease. Mounting evidence from animal and clinical studies has suggested that Vitamin D Receptor
(VDR) activation has beneficial effects on various renal diseases.

Methods:

A structured search of published research literature regarding VDR structure and
function, VDR in various renal diseases (e.g., IgA nephropathy, idiopathic nephrotic syndrome,
renal cell carcinoma, diabetic nephropathy, lupus nephritis) and therapies targeting VDR was
performed for several databases.

Result:

Included in this study are the results from 177 published research articles. Evidence
from these papers indicates that VDR activation is involved in the protection against renal injury
in kidney diseases by a variety of mechanisms, including suppression of RAS activation,
anti-inflammation, inhibiting renal fibrogenesis, restoring mitochondrial function, suppression
of autoimmunity and renal cell apoptosis.

Conclusion:

VDR offers an attractive druggable target for renal diseases. Increasing our understanding
of VDR in the kidney is a fertile area of research and may provide effective weapons
in the fight against kidney diseases.
Current Trends and Future Directions of Fluoroquinolones
Authors: Mohammed Hamada H.H. , Abuo-Rahma Gamal El-Din A.A. , Abbas Samar H. , Abdelhafez El-Shimaa M.N.
Published: February 2018

Fluoroquinolones represent an interesting synthetic class of antimicrobial agents with broad spectrum and potent activity. Since the discovery of nalidixic acid, the prototype of quinolones, several structural modifications to the quinolone nucleus have been carried out for improvement of potency, spectrum of activity, and to understand their structure activity relationship (SAR). The C-7 substituent was reported to have a major impact on the activity. Accordingly, Substitution at C-7 or its N-4-piperazinyl moiety was found to affect potency, bioavailability, and physicochemical properties. Also, it can increase the affinity towards mammalian topoisomerases that may shift quinolones from antibacterial to anticancer candidates. Moreover, the presence of DNA topoisomerases in both eukaryotic and prokaryotic cells makes them excellent targets for chemotherapeutic intervention in antibacterial and anticancer therapies. Based on this concept, several fluoroquionolones derivatives have been synthesized and biologically evaluated as antibacterial, antituberculosis, antiproliferative, antiviral and antifungal agents. This review is an attempt to focus on the therapeutic prospects of fluoroquinolones with an updated account on their atypical applications such as antitubercular and anticancer activities.
Herbal Compounds with Special Reference to Gastrodin as Potential Therapeutic Agents for Microglia Mediated Neuroinflammation
Authors: Li Juan-Juan , Liu Shun-Jin , Liu Xiao-Yu , Ling Eng-Ang
Published: February 2018

Background:

Activated microglia play a pivotal role neurodegenerative diseases by producing
a variety of proinflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-
1beta (IL-1β) and nitric oxide (NO) that are toxic to neurons and oligodendrocytes.

Methods:

In view of the above, suppression of microglia mediated neuroinflammation is deemed a
therapeutic strategy for neurodegenerative diseases. Several potential Chinese herbal extracts have been
reported to exert neuroprotective effects against neurodegenerative diseases targeting specifically at the
activated microglia. In this connection, the phenolic glucoside gastrodin, a main constituent of the Chinese
herbal medicine Gastrodia rhizoma, produced widely in the local community exhibits potential
neuroprotective effects through suppression of neurotoxic proinflammatory mediators.

Results:

Here, we first review the roles of activated microglia in different brain diseases. The effects of
gastrodin on activated microglia are then considered. We have identified gastrodin as a putative therapeutic
agent as it has been found to suppress microglial activation thus ameliorating neuroinflammation.
More importantly, gastrodin downregulates the expression of renin angiotensin system (RAS) and production
of proinflammatory mediators. Remarkably, gastrodin promotes Sirtuin 3 (Sirt3) up-regulation
and nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX-2) down-regulation after ischemichypoxia
in activated microglia mediated by AT1 or AT2 receptors which are angiotensin II receptors subtypes,
indicating a possible molecular link between RAS and Sirt3 survival genes.

Conclusion:

This review summarizes the beneficial effects of gastrodin acting on activated microglia
along with other herbal compounds. Its efficacy in neuroprotection is consistent with some common
herbal products in China.
Antioxidant and Prebiotic Properties of γ- Radiation Processed Alginate
Authors: Anant Bhoir Shraddha , Pritamdas Chawla Surinder
Published: February 2018

Background:

Recently, many carbohydrates and their derivatives are being investigated for
bioactivity. In the present study, we aimed at developing a novel antioxidant and prebiotic component
by radiation processing of sodium alginate.

Method: Gamma irradiated (0.5 to 40 kGy) aqueous solution of sodium alginate was characterised by
UV-visible, fluorescence, Fourier transform infrared (FT-IR) spectroscopy and thin layer chromatography
(TLC) analysis. Antioxidant potential of processed alginate was determined using different in vitro
assays and prebiotic activity was evaluated by co-culturing of E. coli and Lactobacillus plantarum.

Observation: Approximately, 50% of superoxide radicals and 75% of 1,1-diphenyl-2-picrylhydrazyl
(DPPH) radicals were scavenged by oligomers at concentrations of 1 mg/ml and 5 mg/ml, respectively.
The ability to chelate iron and to inhibit the oxidation of β-carotene was not affected. Radiation processing
improved the prebiotic activities as seen by enhanced cell number of L. plantarum by one log and
reduction in E. coli count. The efficiency in reducing E. coli depended directly on the absorbed dose.

Conclusion:

Results suggest that radiation processing of alginate is a practical method for improving its
antioxidant and prebiotic activity and thus improving the applicability of alginate in nutraceutical industries.
Preserving the Characteristics of Urban Heritage: An insight into the concept of Malaysian Royal Towns
Authors: Samsudin Noor Aimran , Rosley Muhamad Solehin Fitry , Raja Shahminan Raja Nafida , Mohamad Sapura
Published: February 2018

Royal towns in Malaysia are the finest examples of traditional Malay towns, which are strongly associated with the long history of Malay Sultanates in Malaysia. This study aims to identify the significant characteristics that perhaps homogenously shared by the Malaysian Royal Towns to be inferred as the symbol and identity of the place. The study begins with thorough literature reviews of historical Malay manuscripts for some insights into how the traditional Malay towns were during the early 14th to the 19th century. From this, the study managed to identify three prominent characteristics that shaped the whole physical images of Malaysian Royal Towns. These characteristics are known as the king’s palace, traditional Malay settlements known as kampongs and lastly, traditional Malay fortification system. Nevertheless, these characteristics are being threatened due to improper planning and modernisation of the Royal Towns. A conventional conservation approach, however, seems insufficient to address the whole idea of a Malaysian Royal Town. These identified characteristics, in this case, are interrelated and thus required in-depth study of each Royal Town to investigate the traditional knowledge lies within the culture and a new comprehensive in-depth method of conservation and preservation in order to sustain the image of the place as a cradle of the Malay civilisation.
Protocol for a Systematic Review of Gamified Attention Bias Interventions for Psychiatric Disorders (Preprint)
Authors: Melvyn Zhang , Ying Jiangbo , Ho Roger CM
Published: February 2018

UNSTRUCTURED

Background
Attention biases are subconscious processes that tend to result in individuals having increased attention for threatening or stimuli with high salience. These biases have been posited to be involved in the psychopathologies of several psychiatric disorders. Technological advances have transformed how such interventions are being delivered. Gamification technologies are increasingly being used for bias modification, as it could help increase motivation to train and make these tasks more engaging. While there are published research on gamification and attention bias, there remains several gaps in knowledge.

Objectives
The primary objective of the review is thus to identify attention bias modification games that have been published in the literature and to synthesise the current evidence for such interventions and to identify, if possible, the rationale for gamification. The secondary objective is to determine if gamified attention or cognitive bias modification influences secondary outcomes measures, as such anxiety levels or severity of depressive symptoms.

Methods
To achieve the objective of this review, a systematic review will be undertaken. For the studies that are identified, they will be reviewed by independent assessors and screened against our predefined inclusion and exclusion criteria. The Cochrane risk of bias tool will be used for assessment of the risk of biases in randomised trials that have been identified. The evidence will be synthesized by means of a qualitative synthesis.

Results
We expect that the review will be completed 12 months from the publication of this protocol.

Conclusions
This review is pertinent as it helps to provide an overview of the evidence base for gamified attention bias interventions. The findings from the current review will help in the future conceptualisation of gamified attention bias interventions.
The untapped potential of the gaming community: A narrative review. (Preprint)
Authors: Goodman William , McFerran Ethna , Purves Richard , Redpath Ian , Beeken Rebecca J
Published: February 2018

UNSTRUCTURED

Video gamers are a population at heightened risk of developing obesity due to the sedentary nature of gaming, increased energy intake and the disruption caused to their sleep. This increases their risk of developing a number of non-communicable diseases. To date, research seeking to improve health behaviours has focussed on developing novel video games to promote behaviour change. Although positive results have emerged from this research, the success has been limited due to the lack of transferability to more mainstream games and the focus on children and adolescents. However, the gaming community has a number of unique aspects which, in comparison to the development of new video games, have received less attention. Research has found that advertising can have implicit effects on individual’s memories which could influence their later decisions. Yet the effect of the exponential growth of in-game advertisements, and brand sponsorship of gaming events and professional gamers, has not been explored in the gaming community. Nor has the possibility of using advertising techniques to encourage positive health behaviours within games or at these events. Research suggests that virtual communities can be effective at disseminating health information, but the efficacy of this needs to be explored utilising known community influencers within the gaming community. The purpose of this paper is to highlight these under-researched areas that have the potential to encourage positive health behaviour among this community.
Blockchain Technology for Detecting Falsified and Substandard Drugs in Distribution: Pharmaceutical Supply Chain Intervention (Preprint)
Authors: Sylim Patrick , Liu Fang , Marcelo Alvin , Fontelo Paul
Published: February 2018

BACKGROUND

Drug counterfeiting is a global problem with significant risks to consumers and the general public. In the Philippines, 30% of inspected drug stores in 2003 were found with substandard/spurious/falsely-labeled/falsified/counterfeit drugs. The economic burden on the population drug expenditures and on governments is high. The Philippine Food and Drug Administration (FDA) encourages the public to check the certificates of product registration and report any instances of counterfeiting. The National Police of Philippines responds to such reports through a special task force. However, no literature on its impact on the distribution of such drugs were found. Blockchain technology is a cryptographic ledger that is allegedly immutable through repeated sequential hashing and fault-tolerant through a consensus algorithm. This project will develop and test a pharmacosurveillance blockchain system that will support information sharing along the official drug distribution network.

OBJECTIVE

This study aims to develop a pharmacosurveillance blockchain system and test its functions in a simulated network.

METHODS

We are developing a Distributed Application (DApp) that will run on smart contracts, employing Swarm as the Distributed File System (DFS). Two instances will be developed: one for Ethereum and another for Hyperledger Fabric. The proof-of-work (PoW) consensus algorithm of Ethereum will be modified into a delegated proof-of-stake (DPoS) or practical Byzantine fault tolerance (PBFT) consensus algorithm as it is scalable and fits the drug supply chain environment. The system will adopt the GS1 pedigree standard and will satisfy the data points in the data standardization guidelines from the US FDA. Simulations will use the following 5 nodes: for FDA, manufacturer, wholesaler, retailer, and the consumer portal.

RESULTS

Development is underway. The design of the system will place FDA in a supervisory data verification role, with each pedigree type–specific data source serving a primary data verification role. The supply chain process will be initiated by the manufacturer, with recursive verification for every transaction. It will allow consumers to scan a code printed on the receipt of their purchases to review the drug distribution history.

CONCLUSIONS

Development and testing will be conducted in a simulated network, and thus, results may differ from actual practice. The project being proposed is disruptive; once tested, the team intends to engage the Philippine FDA to discuss implementation plans and formulate policies to facilitate adoption and sustainability.

REGISTERED REPORT IDENTIFIER

RR1-10.2196/10163
Trends in transfusion rates after the FOCUS trial
Authors: Howard David H , Roback John D , Murphy David J
Published: February 2018

Aim:
We estimate the impact of the FOCUS trial, which concluded that hip surgery patients with hemoglobin values above 8 g/dl do not benefit from routine transfusions, on transfusion rates.
Methods:
We evaluated trends in transfusion rates using inpatient discharge data from four states.
Results:
The transfusion rate was 5.2 percentage points lower in the fourth quarter of 2013 than it would have been had pre-FOCUS trends continued. Transfusion rates declined more in hospitals with a low end-of-life treatment intensity index, a general measure of treatment intensity.
Conclusion:
The FOCUS trial affected practice, but there are additional opportunities to reduce the use of transfusions.
Drowning the Greek economy: Injurious speech and sovereign debt
Authors: Donnelly Faye , Vlcek William
Published: February 2018

Drawing on Judith Butler's concept of injurious speech, this article conceptualises the ‘Grexit’ crisis as a series of performances. More specifically, we investigate how the Greek government framed the bailout plans tabled by the Troika as a form of torture. By adopting phrases such as ‘fiscal water-boarding’, ‘asphyxiation’, and ‘suicide’, the Syriza government sought to narrate the harm inflicted on Greece by its creditors. Paying attention to this language is important as it casts new light on how Greek sovereign debt has been framed, negotiated, and contested. In many ways, the overarching objective of this article is to tell a different story that takes discursive transitivity and restaging into account. By shifting the emphasis onto injurious speech, the article also brings the unintended effects of this language into focus. Despite the recurrent accusations made by Syriza as it attempted to resolve the Greek sovereign debt crisis, this article questions whether their bargaining strategy ‘misfired’. On closer consideration, we find that the injurious speech acts performed by the Syriza government compromised their ability to negotiate a third bailout deal in 2015. The observations remind us that words can wound in ambivalent ways.