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Authors: Syed Asif Hassan, Tabrej Khan

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Tuberculosis (TB) caused by bacillus Mycobacterium tuberculosis (Mtb) continues to take a disturbing toll on human life and healthcare facility worldwide. The global burden of TB remains enormous. The alarming rise of multi-drug resistant strains of Mycobacterium tuberculosis calls for an increase in research efforts towards the development of new target specific therapeutics against diverse strains of M. tuberculosis. Therefore, the discovery of new molecular scaffolds targeting new drug sites should be a priority for a workable plan for fighting resistance in Mycobacterium tuberculosis (Mtb). Mtb non-acylated lipoprotein LprG (Rv1411c) has a Toll-like receptor 2 (TLR2) agonist actions that depend on its association with triacylated glycolipids binding specifically with the hydrophobic pocket of Mtb LprG lipoprotein. The detection of a glycolipid carrier function has important implications for the role of LprG in Mycobacterial physiology and virulence. Therefore, considering the pivotal role of glycolipids in mycobacterial physiology and host-pathogen interactions, designing competitive antagonist (chemotherapeutics) ligands that competitively bind to glycolipid binding domain in LprG lipoprotein, will lead to inhibition of tuberculosis infection in humans. In this study, a unified approach involving ligand-based virtual screening protocol USRCAT (Ultra Shape Recognition) software and molecular docking studies using Auto Dock Vina 1.1.2 using the X-ray crystal structure of Mtb LprG protein was implemented. The docking results were further confirmed by DSX (DrugScore eXtented), a robust program to evaluate the binding energy of ligands bound to the Ligand binding domain of the Mtb LprG lipoprotein. The ligand, which has the higher hypothetical affinity, also has greater negative value. Based on the USRCAT, Lipinski’s values and molecular docking results, [(2R)-2,3-di(hexadecanoyl oxy)propyl][(2S,3S,5S,6R)-3,4,5-trihydroxy-2,6-bis[[(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6 (hydroxymethyl)tetrahydropyran-2-yl]oxy]cyclohexyl] phosphate (XPX) was confirmed as a promising drug-like lead compound (antagonist) binding specifically to the hydrophobic domain of LprG protein with affinity greater than that of PIM2 (agonist of LprG protein) with a free binding energy of -9.98e+006 Kcal/mol and binding affinity of -132 Kcal/mol, respectively. A further, in vitro assay of this compound is required to establish its potency in inhibiting molecular evasion mechanism of MTB within the infected host macrophages. These results will certainly be helpful in future anti-TB drug discovery efforts against Multidrug-Resistance Tuberculosis (MDR-TB).

Keywords: antagonist, agonist, binding affinity, chemotherapeutics, drug-like, multi drug resistance tuberculosis (MDR-TB), RV1411c protein, toll-like receptor (TLR2)

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Authors: Asghar Arif

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Lung cancer has been recognized as one of the greatest common cancers, causing the annual mortality rate of about 1.2 million people in the world. Lung cancer is the most prevalent cancer in men and the third-most common cancer among women (after breast and digestive cancers).Recent evidences have shown the inflammatory process as one of the potential factors of cancer. Tuberculosis (TB), pneumonia, and chronic bronchitis are among the most important inflammation-inducing factors in the lungs, among which TB has a more profound role in the emergence of cancer.TB is one of the important mortality factors throughout the world, and 205,000 death cases are reported annually due to this disease. Chronic inflammation and fibrosis due to TB can induce genetic mutation and alternations. Parenchyma tissue of lung is involved in both diseases of TB and lung cancer, and continuous cough in lung cancer, morphological vascular variations, lymphocytosis processes, and generation of immune system mediators such as interleukins, are all among the factors leading to the hypothesis regarding the role of TB in lung cancer Some reports have shown that the induction of necrosis and apoptosis or TB reactivation, especially in patients with immune-deficiency, may result in increasing IL-17 and TNF_α, which will either decrease P53 activity or increase the expression of Bcl-2, decrease Bax-T, and cause the inhibition of caspase-3 expression due to decreasing the expression of mitochondria cytochrome oxidase. It has been also indicated that following the injection of BCG vaccine, the host immune system will be reinforced, and in particular, the rates of gamma interferon, nitric oxide, and interleukin-2 are increased. Therefore, CD4 + lymphocyte function will be improved, and the person will be immune against cancer.Numerous prospective studies have so far been conducted on the role of TB in lung cancer, and it seems that this disease is effective in that particular cancer.One of the main challenges of lung cancer is its correct and timely diagnosis. Unfortunately, clinical symptoms (such as continuous cough, hemoptysis, weight loss, fever, chest pain, dyspnea, and loss of appetite) and radiological images are similar in TB and lung cancer. Therefore, anti-TB drugs are routinely prescribed for the patients in the countries with high prevalence of TB, like Pakistan. Regarding the similarity in clinical symptoms and radiological findings of lung cancer, proper diagnosis is necessary for TB and respiratory infections due to nontuberculousmycobacteria (NTM). Some of the drug resistive TB cases are, in fact, lung cancer or NTM lung infections. Acid-fast staining and histological study of phlegm and bronchial washing, culturing and polymerase chain reaction TB are among the most important solutions for differential diagnosis of these diseases. Briefly, it is assumed that TB is one of the risk factors for cancer. Numerous studies have been conducted in this regard throughout the world, and it has been observed that there is a significant relationship between previous TB infection and lung cancer. However, to prove this hypothesis, further and more extensive studies are required. In addition, as the clinical symptoms and radiological findings of TB, lung cancer, and non-TB mycobacteria lung infections are similar, they can be misdiagnosed as TB.

Keywords: TB and lung cancer, TB people, TB servivers, TB and HIV aids

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Authors: Carolina N. França, Jônatas B. do Amaral, Maria C.O. Izar, Ighor L. Teixeira, Francisco A. Fonseca

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Introduction: Atherosclerosis is a progressive disease, characterized by lipid and fibrotic element deposition in large-caliber arteries. Conditions related to the development of atherosclerosis, as dyslipidemia, hypertension, diabetes, and smoking are associated with endothelial dysfunction. There is a frequent recurrence of cardiovascular outcomes after acute myocardial infarction and, at this sense, cycles of mobilization of monocyte subtypes (classical, intermediate and nonclassical) secondary to myocardial infarction may determine the colonization of atherosclerotic plaques in different stages of the development, contributing to early recurrence of ischemic events. The recruitment of different monocyte subsets during inflammatory process requires the expression of chemokine receptors CCR2, CCR5, and CX3CR1, to promote the migration of monocytes to the inflammatory site. The aim of this study was to evaluate the effect of lipid-lowering treatment by six months in the monocyte phenotype and chemokine receptor levels of patients after Acute Myocardial Infarction (AMI). Methods: This is a PROBE (prospective, randomized, open-label trial with blinded endpoints) study (ClinicalTrials.gov Identifier: NCT02428374). Adult patients (n=147) of both genders, ageing 18-75 years, were randomized in a 2x2 factorial design for treatment with rosuvastatin 20 mg/day or simvastatin 40 mg/day plus ezetimibe 10 mg/day as well as ticagrelor 90 mg 2x/day and clopidogrel 75 mg, in addition to conventional AMI therapy. Blood samples were collected at baseline, after one month and six months of treatment. Monocyte subtypes (classical - inflammatory, intermediate - phagocytic and nonclassical – anti-inflammatory) were identified, quantified and characterized by flow cytometry, as well as the expressions of the chemokine receptors (CCR2, CCR5 and CX3CR1) were also evaluated in the mononuclear cells. Results: After six months of treatment, there was an increase in the percentage of classical monocytes and reduction in the nonclassical monocytes (p=0.038 and p < 0.0001 Friedman Test), without differences for intermediate monocytes. Besides, classical monocytes had higher expressions of CCR5 and CX3CR1 after treatment, without differences related to CCR2 (p < 0.0001 for CCR5 and CX3CR1; p=0.175 for CCR2). Intermediate monocytes had higher expressions of CCR5 and CX3CR1 and lower expression of CCR2 (p = 0.003; p < 0.0001 and p = 0.011, respectively). Nonclassical monocytes had lower expressions of CCR2 and CCR5, without differences for CX3CR1 (p < 0.0001; p = 0.009 and p = 0.138, respectively). There were no differences after the comparison between the four treatment arms. Conclusion: The data suggest a time-dependent modulation of classical and nonclassical monocytes and chemokine receptor levels. The higher percentage of classical monocytes (inflammatory cells) suggest a residual inflammatory risk, even under preconized treatments to AMI. Indeed, these changes do not seem to be affected by choice of the lipid-lowering strategy.

Keywords: acute myocardial infarction, chemokine receptors, lipid-lowering treatment, monocyte subtypes

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Authors: Atin Adhikari, Sushma Kurella, Pratik Banerjee, Nabanita Mukherjee, Yamini M. Chandana Gollapudi, Bushra Shah

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Different sharp instruments, drilling machines, and high speed rotary instruments are routinely used in dental clinics during dental cleaning. Therefore, these cleaning procedures release a lot of oral microorganisms including bacteria in clinic air and may cause significant occupational bioaerosol exposure risks for dentists, dental hygienists, patients, and dental clinic employees. Two major goals of this study were to quantify volumetric airborne concentrations of bacteria and to assess overall microbial activity in this type of occupational environment. The study was conducted in several dental clinics of southern Georgia and 15 dental cleaning procedures were targeted for sampling of airborne bacteria and testing of overall microbial activity in settled dusts over clinic floors. For air sampling, a Biostage viable cascade impactor was utilized, which comprises an inlet cone, precision-drilled 400-hole impactor stage, and a base that holds an agar plate (Tryptic soy agar). A high-flow Quick-Take-30 pump connected to this impactor pulls microorganisms in air at 28.3 L/min flow rate through the holes (jets) where they are collected on the agar surface for approx. five minutes. After sampling, agar plates containing the samples were placed in an ice chest with blue ice and plates were incubated at 30±2°C for 24 to 72 h. Colonies were counted and converted to airborne concentrations (CFU/m3) followed by positive hole corrections. Most abundant bacterial colonies (selected by visual screening) were identified by PCR amplicon sequencing of 16S rRNA genes. For understanding overall microbial activity in clinic floors and estimating a general cleanliness of the clinic surfaces during or after dental cleaning procedures, ATP levels were determined in swabbed dust samples collected from 10 cm2 floor surfaces. Concentration of ATP may indicate both the cell viability and the metabolic status of settled microorganisms in this situation. An ATP measuring kit was used, which utilized standard luciferin-luciferase fluorescence reaction and a luminometer, which quantified ATP levels as relative light units (RLU). Three air and dust samples were collected during each cleaning procedure (at the beginning, during cleaning, and immediately after the procedure was completed (n = 45). Concentrations at the beginning, during, and after dental cleaning procedures were 671±525, 917±1203, and 899±823 CFU/m3, respectively for airborne bacteria and 91±101, 243±129, and 139±77 RLU/sample, respectively for ATP levels. The concentrations of bacteria were significantly higher than typical indoor residential environments. Although an increasing trend for airborne bacteria was observed during cleaning, the data collected at three different time points were not significantly different (ANOVA: p = 0.38) probably due to high standard deviations of data. The ATP levels, however, demonstrated a significant difference (ANOVA: p <0.05) in this scenario indicating significant change in microbial activity on floor surfaces during dental cleaning. The most common bacterial genera identified were: Neisseria sp., Streptococcus sp., Chryseobacterium sp., Paenisporosarcina sp., and Vibrio sp. in terms of frequencies of occurrences, respectively. The study concluded that bacterial exposure in dental clinics could be a notable occupational biohazard, and appropriate respiratory protections for the employees are urgently needed.

Keywords: bioaerosols, hospital hygiene, indoor air quality, occupational biohazards

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Authors: G. C. Santini, C. Potrich, L. Lunelli, L. Vanzetti, S. Marasso, M. Cocuzza, C. Pederzolli

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The relevance of circulating miRNAs as non-invasive biomarkers for several pathologies is nowadays undoubtedly clear, as they have been found to have both diagnostic and prognostic value able to add fundamental information to patients’ clinical picture. The availability of these data, however, relies on a time-consuming process spanning from the sample collection and processing to the data analysis. In light of this, strategies which are able to ease this procedure are in high demand and considerable effort have been made in developing Lab-on-a-chip (LOC) devices able to speed up and standardise the bench work. In this context, a very promising polydimethylsiloxane (PDMS)-based microdevice which integrates the processing of the biological sample, i.e. purification of extracellular miRNAs, and reverse transcription was previously developed in our lab. In this study, we aimed at the improvement of the miRNA extraction performances of this micro device by increasing the ability of its surface to absorb extracellular miRNAs from biological samples. For this purpose, we focused on the modulation of two properties of the material: roughness and charge. PDMS surface roughness was modulated by casting with several templates (terminated with silicon oxide coated by a thin anti-adhesion aluminum layer), followed by a panel of curing conditions. Atomic force microscopy (AFM) was employed to estimate changes at the nanometric scale. To introduce modifications in surface charge we functionalized PDMS with different mixes of positively charged 3-aminopropyltrimethoxysilanes (APTMS) and neutral poly(ethylene glycol) silane (PEG). The surface chemical composition was characterized by X-ray photoelectron spectroscopy (XPS) and the number of exposed primary amines was quantified with the reagent sulfosuccinimidyl-4-o-(4,4-dimethoxytrityl) butyrate (s-SDTB). As our final end point, the adsorption rate of all these different conditions was assessed by fluorescence microscopy by incubating a synthetic fluorescently-labeled miRNA. Our preliminary analysis identified casting on thermally grown silicon oxide, followed by a curing step at 85°C for 1 hour, as the most efficient technique to obtain a PDMS surface roughness in the nanometric scaleable to trap miRNA. In addition, functionalisation with 0.1% APTMS and 0.9% PEG was found to be a necessary step to significantly increase the amount of microRNA adsorbed on the surface, therefore, available for further steps as on-chip reverse transcription. These findings show a substantial improvement in the extraction efficiency of our PDMS microdevice, ultimately leading to an important step forward in the development of an innovative, easy-to-use and integrated system for the direct purification of less abundant circulating microRNAs.

Keywords: circulating miRNAs, diagnostics, Lab-on-a-chip, polydimethylsiloxane (PDMS)

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Authors: Jacqueline Eleonora Ek, Michael Spiteri, Chris Giordimaina, Pierre Agius

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Background: Malta is known for being a key player as a frontline country with regard to irregular immigration from Africa to Europe. Every year the island experiences an influx of migrants as boat movement across the Mediterranean continues to be a humanitarian challenge. Irregular immigration and applying for asylum is both a lengthy and mentally demanding process. Those doing so are often faced with multiple challenges, which can adversely affect their mental health. Between January and August 2020, Malta disembarked 2 162 people rescued at sea, 463 of them between July & August. Given the small size of the Maltese islands, this regulation places a disproportionately large burden on the country, creating a backlog in the processing of asylum applications resulting in increased time periods of detention. These delays reverberate throughout multiple management pathways resulting in prolonged periods of detention and challenging access to health services. Objectives: To better understand the spatial dimensions of this humanitarian crisis, this study aims to assess disparities in the acute medical management of migrants presenting to the emergency department (ED) with acute mental health presentations as compared to that of local and non-local residents. Method: In this retrospective study, 17795 consecutive ED attendances were reviewed to look for acute mental health presentations. These were further evaluated to assess discrepancies in transportation routes to hospital, nature of presenting complaint, effects of language barriers, use of CT brain, treatment given at ED, availability of psychiatric reviews, and final admission/discharge plans. Results: Of the ED attendances, 92.3% were local residents, and 7.7% were non-locals. Of the non-locals, 13.8% were migrants, and 86.2% were other-non-locals. Acute mental health presentations were seen in 1% of local residents; this increased to 20.6% in migrants. 56.4% of migrants attended with deliberate self-harm; this was lower in local residents, 28.9%. Contrastingly, in local residents, the most common presenting complaint was suicidal thought/ low mood 37.3%, the incidence was similar in migrants at 33.3%. The main differences included 12.8% of migrants presenting with refused oral intake while only 0.6% of local residents presented with the same complaints. 7.7% of migrants presented with a reduced level of consciousness, no local residents presented with this same issue. Physicians documented a language barrier in 74.4% of migrants. 25.6% were noted to be completely uncommunicative. Further investigations included the use of a CT scan in 12% of local residents and in 35.9% of migrants. The most common treatment administered to migrants was supportive fluids 15.4%, the most common in local residents was benzodiazepines 15.1%. Voluntary psychiatric admissions were seen in 33.3% of migrants and 24.7% of locals. Involuntary admissions were seen in 23% of migrants and 13.3% of locals. Conclusion: Results showed multiple disparities in health management. A meeting was held between entities responsible for migrant health in Malta, including the emergency department, primary health care, migrant detention services, and Malta Red Cross. Currently, national quality-improvement initiatives are underway to form new pathways to improve patient-centered care. These include an interpreter unit, centralized handover sheets, and a dedicated migrant health service.

Keywords: emergency department, communication, health, migration

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Authors: Aberdam Edith, Sangari Linda, Petit Isabelle, Aberdam Daniel

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Background and Rationale: Transparent avascularised cornea is essential for normal vision and depends on limbal stem cells (LSC) that reside between the cornea and the conjunctiva. Ocular burns or injuries may destroy the limbus, causing limbal stem cell deficiency (LSCD). The cornea becomes vascularised by invaded conjunctival cells, the stroma is scarring, resulting in corneal opacity and loss of vision. Grafted autologous limbus or cultivated autologous LCS can restore the vision, unless the two eyes are affected. Alternative cellular sources have been tested in the last decades, including oral mucosa or hair follicle epithelial cells. However, only partial success has been achieved by the use of these cells since they were not able to uniformly commit into corneal epithelial cells. Human pluripotent stem cells (iPSC) display both unlimited growth capacity and ability to differentiate into any cell type. Our goal was to design a standardized and reproducible protocol to produce transplantable autologous LSC from patients through cell reprogramming technology. Methodology: First, keratinocyte primary culture was established from a small number of plucked hair follicles of healthy donors. The resulting epithelial cells were reprogrammed into induced pluripotent stem cells (iPSCs) and further differentiate into corneal epithelial cells (CEC), according to a robust protocol that recapitulates the main step of corneal embryonic development. qRT-PCR analysis and immunofluorescent staining during the course of differentiation confirm the expression of stage specific markers of corneal embryonic lineage. First appear ectodermal progenitor-specific cytokeratins K8/K18, followed at day 7 by limbal-specific PAX6, TP63 and cytokeratins K5/K14. At day 15, K3/K12+-corneal cells are present. To amplify the iPSC-derived LSC (named COiPSC), intact small epithelial colonies were detached and cultivated in limbal cell-specific medium. In that culture conditions, the COiPSC can be frozen and thaw at any passage, while retaining their corneal characteristics for at least eight passages. To evaluate the potential of COiPSC as an alternative ocular toxicity model, COiPSC were treated at passage P0 to P4 with increasing amounts of SDS and Benzalkonium. Cell proliferation and apoptosis of treated cells was compared to LSC and the SV40-immortalized human corneal epithelial cell line (HCE) routinely used by cosmetological industrials. Of note, HCE are more resistant to toxicity than LSC. At P0, COiPSC were systematically more resistant to chemical toxicity than LSC and even to HCE. Remarkably, this behavior changed with passage since COiPSC at P2 became identical to LSC and thus closer to physiology than HCE. Comparative transcriptome analysis confirmed that COiPSC from P2 are similar to a mixture of LSC and CEC. Finally, by organotypic reconstitution assay, we demonstrated the ability of COiPSC to produce a 3D corneal epithelium on a stromal equivalent made of keratocytes. Conclusion: COiPSC could become valuable for two main applications: (1) an alternative robust tool to perform, in a reproducible and physiological manner, toxicity assays for cosmetic products and pharmacological tests of drugs. (2). COiPSC could become an alternative autologous source for cornea transplantation for LSCD.

Keywords: Limbal stem cell deficiency, iPSC, cornea, limbal stem cells

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Authors: P.P. Rupasinghe, A.H. Farid

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The Aleutian mink disease virus (AMDV, Carnivore amdoparvovirus 1) causes persistent infection, plasmacytosis, and formation and deposition of immune complexes in various organs in adult mink, leading to glomerulonephritis, arteritis and sometimes death. The disease has no cure nor an effective vaccine, and identification and culling of mink positive for anti-AMDV antibodies have not been successful in controlling the infection in many countries. The failure to eradicate the virus from infected farms may be caused by keeping false-negative individuals on the farm, virus transmission from wild animals, or neighboring farms. The identification of sources of infection, which can be performed by comparing viral sequences, is important in the success of viral eradication programs. High mutation rates could cause inaccuracies when viral sequences are used to trace back an infection to its origin. There is no published information on the mutation rate of AMDV either in vivo or in vitro. The in vivo estimation is the most accurate method, but it is difficult to perform because of the inherent technical complexities, namely infecting live animals, the unknown numbers of viral generations (i.e., infection cycles), the removal of deleterious mutations over time and genetic drift. The objective of this study was to determine the mutation rate of AMDV on which no information was available. A homogenate was prepared from the spleen of one naturally infected American mink (Neovison vison) from Nova Scotia, Canada (parental template). The near full-length genome of this isolate (91.6%, 4,143 bp) was bidirectionally sequenced. A group of black mink was inoculated with this homogenate (descendant mink). Spleen sampled were collected from 10 descendant mink after 16 weeks post-inoculation (wpi) and from anther 10 mink after 176 wpi, and their near-full length genomes were bi-directionally sequenced. Sequences of these mink were compared with each other and with the sequence of the parental template. The number of nucleotide substitutions at 176 wpi was 3.1 times greater than that at 16 wpi (113 vs 36) whereas the estimates of mutation rate at 176 wpi was 3.1 times lower than that at 176 wpi (2.85×10-3 vs 9.13×10-4 substitutions/ site/ year), showing a decreasing trend in the mutation rate per unit of time. Although there is no report on in vivo estimate of the mutation rate of DNA viruses in animals using the same method which was used in the current study, these estimates are at the higher range of reported values for DNA viruses determined by various techniques. These high estimates are logical based on the wide range of diversity and pathogenicity of AMDV isolates. The results suggest that increases in the number of nucleotide substitutions over time and subsequent divergence make it difficult to accurately trace back AMDV isolates to their origin when several years elapsed between the two samplings.

Keywords: Aleutian mink disease virus, American mink, mutation rate, nucleotide substitution

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Authors: Dina Farran, Mark Ashworth, Fiona Gaughran

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Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is associated with an increased risk of stroke, contributing to heart failure and death. In this project, we aim to improve patient safety by screening for stroke risk among people with AF and co-morbid mental illness. To do so, we started by conducting a systematic review and meta-analysis on prevalence, management, and outcomes of AF in people with Serious Mental Illness (SMI) versus the general population. We then evaluated oral anticoagulation (OAC) prescription trends in people with AF and co-morbid SMI in King’s College Hospital. We also evaluated the association between mental illness severity and OAC prescription in eligible patients in South London and Maudsley (SLaM) NHS Foundation Trust. Next, we implemented an electronic clinical decision support system (eCDSS) consisting of a visual prompt on patient electronic Personal Health Records to screen for AF-related stroke risk in three Mental Health of Older Adults wards at SLaM. Finally, we assessed the feasibility and acceptability of the eCDSS by qualitatively investigating clinicians’ perspectives of the potential usefulness of the eCDSS (pre-intervention) and their experiences and their views regarding its impact on clinicians and patients (post-intervention). The systematic review showed that people with SMI had low reported rates of AF. AF patients with SMI were less likely to receive OAC than the general population. When receiving warfarin, people with SMI, particularly bipolar disorder, experienced poor anticoagulation control compared to the general population. Meta-analysis showed that SMI was not significantly associated with an increased risk of stroke or major bleeding when adjusting for underlying risk factors. The main findings of the first observational study were that among AF patients having a high stroke risk, those with co-morbid SMI were less likely than non-SMI to be prescribed any OAC, particularly warfarin. After 2019, there was no significant difference between the two groups. In the second observational study, patients with AF and co-morbid SMI were less likely to be prescribed any OAC compared to those with dementia, substance use disorders, or common mental disorders, adjusting for age, sex, stroke, and bleeding risk scores. Among AF patients with co-morbid SMI, warfarin was less likely to be prescribed to those having alcohol or substance dependency, serious self-injury, hallucinations or delusions, and activities of daily living impairment. In the intervention, clinicians were asked to confirm the presence of AF, clinically assess stroke and bleeding risks, record risk scores in clinical notes, and refer patients at high risk of stroke to OAC clinics. Clinicians reported many potential benefits for the eCDSS, including improving clinical effectiveness, better identification of patients at risk, safer and more comprehensive care, consistency in decision making and saving time. Identified potential risks included rigidity in decision-making, overreliance, reduced critical thinking, false positive recommendations, annoyance, and increased workload. This study presents a unique opportunity to quantify AF patients with mental illness who are at high risk of severe outcomes using electronic health records. This has the potential to improve health outcomes and, therefore patients' quality of life.

Keywords: atrial fibrillation, stroke, mental health conditions, electronic clinical decision support systems

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Authors: Okunola Oluseye Ademola

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The study investigated various socio-cultural factors influencing adherence to antiretroviral drugs among people living with HIV in a University Teaching Hospital in South-western Nigeria. The objectives are to examine the perception of people living with HIV/AIDS (PLWHA) of antiretroviral therapy (ART) in Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, investigate the influence of socio-cultural factors on adherence of PLWHA to treatment regimen in the study area and assess the prevalence of adherence to ART among PLWHA in the study area. It was a cross-sectional where both qualitative and quantitative research methods were adopted. The participants were HIV diagnosed patients attending clinic at the Obafemi Awolowo University Teaching Hospitals Complex in Ile-Ife between the ages of 18 and 60 years. Also three healthcare delivery personnel working in the clinic were interviewed. Out of the 3007 patients receiving treatment, using Fischer’s formula of sampling technique, 336 patients living with HIV/AIDS were selected for the study. These participants had been on antiretroviral drugs for more than six months prior to the study and were selected using simple random sampling technique. Two focus group discussion sessions comprising of 10 male and 10 female living with HIV and currently on ART were conducted. These groups were purposively selected based on their being on ART for more than one year. Also in-depth interviews were conducted among three purposively selected healthcare givers (an experienced nurse, a doctor and a pharmacist) who are working in this clinic. All the participants were interviewed at the clinic on the various clinic days. Data were collected using a structured questionnaire, an interview guide and tape-recorder. The quantitative data were analysed using descriptive and inferential statistics. Content analysis was employed to analyse responses from IDI and FGD sessions. The findings from the study revealed a very positive perception to ART among PLWHA which was about 86.3% while the level of adherence to ART was 89.0% among the respondents. There was a very strong relationship between social and family supports and the degree of adherence to ART in the PLWHA. Nutrition, polygamy, difficulty in financing transportation fare to the clinic, unemployment, drug hawkers, religion, excuse duty from work and waking up very early were highlighted as socio-cultural barriers to adherence to ART. Fear of death, strong family support, religion belief, not seeking alternative treatment, absence of rituals and perceived improved health status were identified as very strong facilitators to adherence. The study concluded that to achieve a very optimal outcome in the management of HIV among PLWHA, various social and cultural contexts should be taken into consideration as this study was able to ascertain the influence of various socio-cultural factors militating and facilitating adherence to ART.

Keywords: ART, HIV, PLWHA, socio-cultural

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Authors: Adae Amoako, Daniel Montero, Peter Murray, George Pujalte

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We present a case of a 42-year-old, right-handed Caucasian male who presented to a medical orthopedics clinic with left wrist pain. The patient indicated that the pain started two months prior to the visit. He could only remember helping a friend move furniture prior to the onset of pain. Examination of the left wrist showed limited extension compared to the right. There was clicking with flexion and extension of the wrist on the dorsal aspect. Mild tenderness was noticed over the distal radioulnar joint. There was ulnar and radial deviation on provocation. Initial 4-view x-rays of the left wrist showed mild radiocarpal and scapho-trapezium-trapezoid (ST-T) osteoarthritis, with subchondral cysts seen in the lunate and scaphoid, with no obvious fractures. The patient was initially put in a wrist brace and diclofenac topical gel was prescribed for pain control, as a patient could not take non-steroidal anti-inflammatory drugs (NSAIDs) due to gastritis. Despite diclofenac topical gel use and bracing, symptoms remained, and a steroid injection with 1 mL of lidocaine with 10 mg of triamcinolone acetonide was performed under fluoroscopy. He obtained some relief but after 3 months, the injection had to be repeated. On 2-month follow up after the initial evaluation, symptoms persisted. Magnetic resonance imaging (MRI) was obtained which showed an abnormal T1 hypodense signal involving the proximal pole of the scaphoid and articular collapse proximally of the scaphoid, with marked irregularity of the overlying cartilage, suggesting a remote injury, findings consistent with avascular necrosis of the proximal pole of the scaphoid. A month after that, the patient had the left proximal pole of the scaphoid debrided and an intercompartmental supraretinacular artery vascularized. Pedicle bone graft reconstruction of the proximal pole of the left scaphoid was done. A non-vascularized autograft from the left radius was also applied. He was put in a thumb spica cast with the interphalangeal joint free for 6 weeks. On 6-week follow-up after surgery, the patient was healing well and could make a composite fist with his left hand. The diagnosis of Preiser’s disease is primarily based on radiological findings. Due to the fact that necrosis happens over a period of time, most AVNs are diagnosed at the late stages of the disease. There appear to be no specific guidelines on the management AVN of the scaphoid. In the past, immobilization and arthroscopic debridement had been used. Radial osteotomy has also been tried. Vascularized bone grafts have also been used to treat Preiser’s disease. In our patient, we used three of these treatment modalities, starting with conservative management with topical NSAIDS and immobilization, then debridement with vascularized bone grafts.

Keywords: wrist pain, avascular necrosis of the scaphoid, Preiser’s disease, vascularized bone grafts

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Authors: A. Bhatt, C. Bassi, H. Farragher, J. Musk

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Background: All medicines placed on the EU market are legally required to be accompanied by labeling and package leaflet, which provide comprehensive information, enabling its safe and appropriate use. Mock-ups with results of assessments using a target patient group must be submitted for a marketing authorisation application. Consumers need confidence in non-prescription, OTC medicines in order to manage their minor ailments and umbrella brands assist purchasing decisions by assisting easy identification within a particular therapeutic area. A number of regulatory agencies have risk management tools and guidelines to assist in developing umbrella brands for OTC medicines, however assessment and decision making is subjective and inconsistent. This study presents an evaluation in the UK following the US FDA warning concerning methaemoglobinaemia following 21 reported cases (11 children under 2 years) caused by OTC oral analgesics containing benzocaine. METHODS: A standard face to face, 25 structured task based user interview testing methodology using a standard questionnaire and rating scale in consumers aged 15-91 years, was conducted independently between June and October 2015 in their homes. Whether individuals could discriminate between the labelling, safety information and warnings on cartons and PILs between 3 different OTC medicines packs with the same umbrella name was evaluated. Each pack was presented with differing information hierarchy using, different coloured cartons, containing the 3 different active ingredients, benzocaine (oromucosal spray) and two lozenges containing 2, 4, dichlorobenzyl alcohol, amylmetacresol and hexylresorcinol respectively (for the symptomatic relief of sore throat pain). The test was designed to determine whether warnings on the carton and leaflet were prominent, accessible to alert users that one product contained benzocaine, risk of methaemoglobinaemia, and refer to the leaflet for the signs of the condition and what to do should this occur. Results: Two consumers did not locate the warnings on the side of the pack, eventually found them on the back and two suggestions to further improve accessibility of the methaemoglobinaemia warning. Using a gold pack design for the oromucosal spray, all consumers could differentiate between the 3 drugs, minimum age particulars, pharmaceutical form and the risk factor methaemoglobinaemia. The warnings for benzocaine were deemed to be clear or very clear; appearance of the 3 packs were either very well differentiated or quite well differentiated. The PIL test passed on all criteria. All consumers could use the product correctly, identify risk factors ensuring the critical information necessary for the safe use was legible and easily accessible so that confusion and errors were minimised. Conclusion: Patients with known methaemoglobinaemia are likely to be vigilant in checking for benzocaine containing products, despite similar umbrella brand names across a range of active ingredients. Despite these findings, the package design and spray format were not deemed to be sufficient to mitigate potential safety risks associated with differences in target populations and contraindications when submitted to the Regulatory Agency. Although risk management tools are increasingly being used by agencies to assist in providing objective assurance of package safety, further transparency, reduction in subjectivity and proportionate risk should be demonstrated.

Keywords: labelling, OTC, risk, user testing

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Authors: Nigar Kantarci Carsibasi

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Coarse-grained elastic network models, namely Gaussian network model (GNM) and Anisotropic network model (ANM), are utilized in order to investigate the fluctuation dynamics of Murine Double Minute 2 (MDM2), which is the native inhibitor of p53. Conformational dynamics of MDM2 are elucidated in unbound, p53 bound, and non-peptide small molecule inhibitor bound forms. With this, it is aimed to gain insights about the alterations brought to global dynamics of MDM2 by native peptide inhibitor p53, and two small molecule inhibitors (HDM201 and NVP-CGM097) that are undergoing clinical stages in cancer studies. MDM2 undergoes significant conformational changes upon inhibitor binding, carrying pieces of evidence of induced-fit mechanism. Small molecule inhibitors examined in this work exhibit similar fluctuation dynamics and characteristic mode shapes with p53 when complexed with MDM2, which would shed light on the design of novel small molecule inhibitors for cancer therapy. The results showed that residues Phe 19, Trp 23, Leu 26 reside in the minima of slowest modes of p53, pointing to the accepted three-finger binding model. Pro 27 displays the most significant hinge present in p53 and comes out to be another functionally important residue. Three distinct regions are identified in MDM2, for which significant conformational changes are observed upon binding. Regions I (residues 50-77) and III (residues 90-105) correspond to the binding interface of MDM2, including (α2, L2, and α4), which are stabilized during complex formation. Region II (residues 77-90) exhibits a large amplitude motion, being highly flexible, both in the absence and presence of p53 or other inhibitors. MDM2 exhibits a scattered profile in the fastest modes of motion, while binding of p53 and inhibitors puts restraints on MDM2 domains, clearly distinguishing the kinetically hot regions. Mode shape analysis revealed that the α4 domain controls the size of the cleft by keeping the cleft narrow in unbound MDM2; and open in the bound states for proper penetration and binding of p53 and inhibitors, which points to the induced-fit mechanism of p53 binding. P53 interacts with α2 and α4 in a synchronized manner. Collective modes are shifted upon inhibitor binding, i.e., second mode characteristic motion in MDM2-p53 complex is observed in the first mode of apo MDM2; however, apo and bound MDM2 exhibits similar features in the softest modes pointing to pre-existing modes facilitating the ligand binding. Although much higher amplitude motions are attained in the presence of non-peptide small molecule inhibitor molecules as compared to p53, they demonstrate close similarity. Hence, NVP-CGM097 and HDM201 succeed in mimicking the p53 behavior well. Elucidating how drug candidates alter the MDM2 global and conformational dynamics would shed light on the rational design of novel anticancer drugs.

Keywords: cancer, drug design, elastic network model, MDM2

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Authors: N. Reza Pour, S. Chuah, T. Vo

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Background: Vertebral artery dissection (VAD) is a rare complication of pregnancy. It can occur spontaneously or following a traumatic event. The pathogenesis is unclear. Predisposing factors include chronic hypertension, Marfan’s syndrome, fibromuscular dysplasia, vasculitis and cystic medial necrosis. Physiological changes of pregnancy have also been proposed as potential mechanisms of injury to the vessel wall. The clinical presentation varies and it can present as a headache, neck pain, diplopia, transient ischaemic attack, or an ischemic stroke. Isolated cases of VAD in pregnancy and puerperium have been reported in the literature. One case was found to have posterior circulation stroke as a result of bilateral VAD and labour was induced at 37 weeks gestation for preeclampsia. Another patient at 38 weeks with severe neck pain that persisted after induction for elevated blood pressure and arteriography showed right VAD postpartum. A single case of lethal VAD in pregnancy with subsequent massive subarachnoid haemorrhage has been reported which was confirmed by the autopsy. Case Presentation: We report two cases of vertebral artery dissection in pregnancy. The first patient was a 32-year-old primigravida presented at the 38th week of pregnancy with the onset of early labour and blood pressure (BP) of 130/70 on arrival. After 2 hours, the patient developed a severe headache with blurry vision and BP was 238/120. Despite treatment with an intravenous antihypertensive, she had eclamptic fit. Magnesium solfate was started and Emergency Caesarean Section was performed under the general anaesthesia. On the second day after the operation, she developed left-sided neck pain. Magnetic Resonance Imaging (MRI) angiography confirmed a short segment left vertebral artery dissection at the level of C3. The patient was treated with aspirin and remained stable without any neurological deficit. The second patient was a 33-year-old primigavida who was admitted to the hospital at 36 weeks gestation with BP of 155/105, constant headache and visual disturbances. She was medicated with an oral antihypertensive agent. On day 4, she complained of right-sided neck pain. MRI angiogram revealed a short segment dissection of the right vertebral artery at the C2-3 level. Pregnancy was terminated on the same day with emergency Caesarean Section and anticoagulation was started subsequently. Post-operative recovery was complicated by rectus sheath haematoma requiring evacuation. She was discharged home on Aspirin without any neurological sequelae. Conclusion: Because of collateral circulation, unilateral vertebral artery dissections may go unrecognized and may be more common than suspected. The outcome for most patients is benign, reflecting the adequacy of the collateral circulation in young patients. Spontaneous VAD is usually treated with anticoagulation or antiplatelet therapy for a minimum of 3-6 months to prevent future ischaemic events, allowing the dissection to heal on its own. We had two cases of VAD in the context of hypertensive disorders of pregnancy with an acceptable outcome. A high level of vigilance is required particularly with preeclamptic patients presenting with head/neck pain to allow an early diagnosis. This is as we hypothesize, early and aggressive management of vertebral artery dissection may potentially prevent further complications.

Keywords: eclampsia, preeclampsia, pregnancy, Vertebral Artery Dissection

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Authors: Sakshi Piplani, Ajit Kumar

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Valproic acid (VPA) is the first synthetic therapeutic agent used to treat epileptic disorders, which account for affecting nearly 1% world population. Teratogenicity caused by VPA has prompted the search for next generation drug with better efficacy and lower side effects. Recent studies have posed HDAC8 as direct target of VPA that causes the teratogenic effect in foetus. We have employed molecular dynamics (MD) and docking simulations to understand the binding mode of VPA and their analogues onto HDAC8. A total of twenty 3D-structures of human HDAC8 isoforms were selected using BLAST-P search against PDB. Multiple sequence alignment was carried out using ClustalW and PDB-3F07 having least missing and mutated regions was selected for study. The missing residues of loop region were constructed using MODELLER and energy was minimized. A set of 216 structural analogues (>90% identity) of VPA were obtained from Pubchem and ZINC database and their energy was optimized with Chemsketch software using 3-D CHARMM-type force field. Four major neurotransmitters (GABAt, SSADH, α-KGDH, GAD) involved in anticonvulsant activity were docked with VPA and its analogues. Out of 216 analogues, 75 were selected on the basis of lower binding energy and inhibition constant as compared to VPA, thus predicted to have anti-convulsant activity. Selected hHDAC8 structure was then subjected to MD Simulation using licenced version YASARA with AMBER99SB force field. The structure was solvated in rectangular box of TIP3P. The simulation was carried out with periodic boundary conditions and electrostatic interactions and treated with Particle mesh Ewald algorithm. pH of system was set to 7.4, temperature 323K and pressure 1atm respectively. Simulation snapshots were stored every 25ps. The MD simulation was carried out for 20ns and pdb file of HDAC8 structure was saved every 2ns. The structures were analysed using castP and UCSF Chimera and most stabilized structure (20ns) was used for docking study. Molecular docking of 75 selected VPA-analogues with PDB-3F07 was performed using AUTODOCK4.2.6. Lamarckian Genetic Algorithm was used to generate conformations of docked ligand and structure. The docking study revealed that VPA and its analogues have more affinity towards ‘hydrophobic active site channel’, due to its hydrophobic properties and allows VPA and their analogues to take part in van der Waal interactions with TYR24, HIS42, VAL41, TYR20, SER138, TRP137 while TRP137 and SER138 showed hydrogen bonding interaction with VPA-analogues. 14 analogues showed better binding affinity than VPA. ADMET SAR server was used to predict the ADMET properties of selected VPA analogues for predicting their druggability. On the basis of ADMET screening, 09 molecules were selected and are being used for in-vivo evaluation using Danio rerio model.

Keywords: HDAC8, docking, molecular dynamics simulation, valproic acid

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Authors: Simona Dostalova, Pavel Kopel, Marketa Vaculovicova, Vojtech Adam, Rene Kizek

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Protein apoferritin seems to be a very promising structure for use as a nanocarrier. It is prepared from intracellular ferritin protein naturally found in most organisms. The role of ferritin proteins is to store and transport ferrous ions. Apoferritin is a hollow protein cage without ferrous ions that can be prepared from ferritin by reduction with thioglycolic acid or dithionite. The structure of apoferritin is composed of 24 protein subunits, creating a sphere with 12 nm in diameter. The inner cavity has a diameter of 8 nm. The drug encapsulation process is based on the response of apoferritin structure to the pH changes of surrounding solution. In low pH, apoferritin is disassembled into individual subunits and its structure is “opened”. It can then be mixed with any desired cytotoxic drug and after adjustment of pH back to neutral the subunits are reconnected again and the drug is encapsulated within the apoferritin particles. Excess drug molecules can be removed by dialysis. The receptors for apoferritin, SCARA5 and TfR1 can be found in the membrane of both healthy and cancer cells. To enhance the specific targeting of apoferritin nanocarrier, it is possible to modify its surface with targeting moieties, such as antibodies. To ensure sterically correct complex, we used a a peptide linker based on a protein G with N-terminus affinity towards Fc region of antibodies. To connect the peptide to the surface of apoferritin, the C-terminus of peptide was made of cysteine with affinity to gold. The surface of apoferritin with encapsulated doxorubicin (ApoDox) was coated either with gold nanoparticles (ApoDox-Nano) or gold (III) chloride hydrate reduced with sodium borohydride (ApoDox-HAu). The applied amount of gold in form of gold (III) chloride hydrate was 10 times higher than in the case of gold nanoparticles. However, after removal of the excess unbound ions by electrophoretic separation, the concentration of gold on the surface of apoferritin was only 6 times higher for ApoDox-HAu in comparison with ApoDox-Nano. Moreover, the reduction with sodium borohydride caused a loss of doxorubicin fluorescent properties (excitation maximum at 480 nm with emission maximum at 600 nm) and thus its biological activity. Fluorescent properties of ApoDox-Nano were similar to the unmodified ApoDox, therefore it was more suited for the intended use. To evaluate the specificity of apoferritin modified with antibodies, we used ELISA-like method with the surface of microtitration plate wells coated by the antigen (goat anti-human IgG antibodies). To these wells, we applied ApoDox without targeting antibodies and ApoDox-Nano modified with targeting antibodies (human IgG antibodies). The amount of unmodified ApoDox on antigen after incubation and subsequent rinsing with water was 5 times lower than in the case of ApoDox-Nano modified with targeting antibodies. The modification of non-gold ApoDox with antibodies caused no change in its targeting properties. It can therefore be concluded that the demonstrated procedure allows us to create nanocarrier with enhanced targeting properties, suitable for nanomedicine.

Keywords: apoferritin, doxorubicin, nanocarrier, targeting antibodies

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Authors: Olatokunbo Yakeem

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Human trafficking is a crime against gross violations of human rights. Trafficking in persons is a severe socio-economic dilemma that affects the national and international dimensions. Human trafficking or modern-day-slavery emanated from slavery, and it has been in existence before the 6ᵗʰ century. Today, no country is exempted from dehumanizing human beings, and as a result, it has been an international issue. The United Nations (UN) presented the International Protocol to fight human trafficking worldwide, which brought about the international definition of human trafficking. The protocol is to prevent, suppress, and punish trafficking in persons, especially women and children. The trafficking protocol has a link with transnational organised crime rather than migration. Over a hundred and fifty countries nationwide have enacted their criminal and panel code trafficking legislation from the UN trafficking protocol. Sex trafficking is the most common type of exploitation of women and children. Other forms of this crime involve exploiting vulnerable victims through forced labour, child involvement in warfare, domestic servitude, debt bondage, and organ removal for transplantation. Trafficking of women and children into sexual exploitation represents the highest form of human trafficking than other types of exploitation. Trafficking of women and children can either happen internally or across the border. It affects all kinds of people, regardless of their race, social class, culture, religion, and education levels. However, it is more of a gender-based issue against females. Furthermore, human trafficking can lead to life-threatening infections, mental disorders, lifetime trauma, and even the victim's death. The study's significance is to explore why the root causes of women and children trafficking in Nigeria are based around poverty, entrusting children in the hands of relatives and friends, corruption, globalization, weak legislation, and ignorance. The importance of this study is to establish how the national, regional, and international organisations are using the 3P’s Protection, Prevention, and Prosecution) to tackle human trafficking. The methodology approach for this study will be a qualitative paradigm. The rationale behind this selection is that the qualitative method will identify the phenomenon and interpret the findings comprehensively. The data collection will take the form of semi-structured in-depth interviews through telephone and email. The researcher will use a descriptive thematic analysis to analyse the data by using complete coding. In summary, this study aims to recommend to the Nigerian federal government to include human trafficking as a subject in their educational curriculum for early intervention to prevent children from been coerced by criminal gangs. And the research aims to find the root causes of women and children trafficking. Also, to look into the effectiveness of the strategies in place to eradicate human trafficking globally. In the same vein, the research objective is to investigate how the anti-trafficking bodies such as law enforcement and NGOs collaborate to tackle the upsurge in human trafficking.

Keywords: children, Nigeria, trafficking, women

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Authors: Ren-Jy Ben, Jo-Chi Jao, Chiu-Ya Liao, Ya-Ru Tsai, Lain-Chyr Hwang, Po-Chou Chen

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Cancer is still one of the serious diseases threatening the lives of human beings. How to have an early diagnosis and effective treatment for tumors is a very important issue. The animal carcinoma model can provide a simulation tool for the study of pathogenesis, biological characteristics and therapeutic effects. Recently, drug delivery systems have been rapidly developed to effectively improve the therapeutic effects. Liposome plays an increasingly important role in clinical diagnosis and therapy for delivering a pharmaceutic or contrast agent to the targeted sites. Liposome can be absorbed and excreted by the human body, and is well known that no harm to the human body. This study aimed to compare the therapeutic effects between encapsulated (doxorubicin liposomal, LipoDox) and un-encapsulated (doxorubicin, Dox) anti-tumor drugs using Magnetic Resonance Imaging (MRI). Twenty-four New Zealand rabbits implanted with VX2 carcinoma at left thigh were classified into three groups: control group (untreated), Dox-treated group and LipoDox-treated group, 8 rabbits for each group. MRI scans were performed three days after tumor implantation. A 1.5T GE Signa HDxt whole body MRI scanner with a high resolution knee coil was used in this study. After a 3-plane localizer scan was performed, Three-Dimensional (3D) Fast Spin Echo (FSE) T2-Weighted Images (T2WI) was used for tumor volumetric quantification. And Two-Dimensional (2D) spoiled gradient recalled echo (SPGR) dynamic Contrast-enhanced (DCE) MRI was used for tumor perfusion evaluation. DCE-MRI was designed to acquire four baseline images, followed by contrast agent Gd-DOTA injection through the ear vein of rabbits. Afterwards, a series of 32 images were acquired to observe the signals change over time in the tumor and muscle. The MRI scanning was scheduled on a weekly basis for a period of four weeks to observe the tumor progression longitudinally. The Dox and LipoDox treatments were prescribed 3 times in the first week immediately after VX2 tumor implantation. ImageJ was used to quantitate tumor volume and time course signal enhancement on DCE images. The changes of tumor size showed that the growth of VX2 tumors was effectively inhibited for both LipoDox-treated and Dox-treated groups. Furthermore, the tumor volume of LipoDox-treated group was significantly lower than that of Dox-treated group, which implies that LipoDox has better therapeutic effect than Dox. The signal intensity of LipoDox-treated group is significantly lower than that of the other two groups, which implies that targeted therapeutic drug remained in the tumor tissue. This study provides a radiation-free and non-invasive MRI method for therapeutic monitoring of targeted liposome on an animal tumor model.

Keywords: doxorubicin, dynamic contrast-enhanced MRI, lipodox, magnetic resonance imaging, VX2 tumor model

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Authors: Olga Smilevska Spasova, Katerina Boshkovska, Gorica Popova, Mirjana Popovska

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Introduction: Pneumonia is an infection of the pulmonary parenchyma. HPIV 3 is one of four viruses that is a member of the Paramyxoviridae family designated types 1-4 that have a nonsegmented, single-stranded RNA genome with a lipid-containing envelope. They are spread from the respiratory tract by aerosolized secretions or by direct contact with secretions. Type 3 is endemic and can cause serious illness in immunocompromised patients. Illness caused by parainfluenza occurs shortly after inoculation with the virus. The level of immunoglobulin A antibody in serum is the best predictor of susceptibility to infection. Streptococcus pneumonia or pneumococcus is a Gram-positive, spherical bacteria, usually found in pairs and it is a member of the genus Streptococcus. Streptococcus pneumonia resides asymptomatically in healthy carriers typically colonizing the respiratory tract, sinuses, and nasal cavity. In individuals with weaker immune systems like young infants, pneumococcal bacterium is the most common cause of community-acquired pneumonia in the world. Case Report: The aim is to present a case of lower respiratory tract infection in an infant caused by parainfluenza virus 3, S. pneumonia and undifferentiated gram-negative bacteria that was successfully treated. The infant is with a history of recurrent episodes of wheezing in the past 3mounts.Infant of 10months presents 2weeks before admittance with high fever, runny nose, and cough. The primary pediatrician prescribed oral cefpodoxime for 10days and inhaled salbutamol. Two days before admittance in hospital the infant with high fever, cough, and difficulty breathing. At admittance, infant is pale, anxious with rapid respirations, cough, wheezing and tachycardia. On auscultation: vesicular breathing sounds with high pitched wheezing and on the right coarse crackles. Investigations: Blood analysis: RBC: 4, 7 x1012L, WBC: 8,3x109L: Neut: 42.73% Lym: 41.57%, Hgb: 9.38 g/dl MCV: 62.7fl, MCH: 20.0pg MCHC: 31.8 g/dl RDW: 18.7% Plt-307.9 x109LCRP: 2,5mg/l, serum iron-7.92umol/l, O2sat-97% on blood gas analysis, puls-125/min.X-ray of chest with hyperinflationand right pericardial consolidation. Microbiological analysis of sputum sample is positive for undifferentiated gram-negative bacteria (colonizer)–resistant to cefotaxime, ampicillin, cefoxitin, sulfamet.+trimetoprim and sensitive to amikacin, gentamicin, and ciprofloxacin. Molecular multiplex RT-PCR for 19 viruses and multiplex PCR for 7 bacteria test for respiratory pathogens positive for Parainfluenza virus 3(Ct=22.73), Streptococcus pneumonia (Ct=26.75).IED: IgG-9.31g/l, IgA-0.351g/l, IgM-0.86g/l. Therapy: Treatment was started with inhaled salbutamol, intravenous antibiotic cefotaxime as well as systemic corticosteroids. On day 7 because of slow clinical resolution of chest auscultation findings and an etiologic clue with a positive sputum sample for resistant undifferentiated gram negative bacteria, a second intravenous antibiotic was administered amikacin. The infant is discharged on day 14 with resolution of clinical findings. Conclusion: Mixed co-infections with respiratory viruses and bacteria in immunocompromised infants are likely to lead to a more severe form of community acquired pneumonia that will need hospitalization.

Keywords: HPIV- 3, infant, pneumonia, S. pneumonia, x-ray chest

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Authors: Sebastian Del Corral Winder, Kiriana Sanchez, Mixalis Poulakis, Samantha Gray

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This paper seeks to explore White privilege and Whiteness. Being White in the U.S. is often perceived as the norm and it brings significant social, economic, educational, and health privileges that often are hidden in social interactions. One quality of Whiteness has been its invisibility given its intrinsic impact on the system, which becomes only visible when paying close attention to White identity and culture and during cross-cultural interactions. The cross-cultural interaction provides an emphasis on differences between the participants and people of color are often viewed as “the other.” These interactions may promote an increased opportunity for discrimination and negative stereotypes against a person of color. Given the recent increase of violence against culturally diverse groups, there has been an increased sense of otherness and division in the country. Furthermore, the accent prestige theory has found that individuals who speak English with a foreign accent are perceived as less educated, competent, friendly, and trustworthy by White individuals in the United States. Using the consensual qualitative research (CQR) methodology, this study explored the cross-cultural dyad from the White individual’s perspective focusing on the psychotherapeutic relationship. The participants were presented with an audio recording of a conversation between a psychotherapist with a Hispanic accent and a patient with an American English accent. Then, the participants completed an interview regarding their perceptions of race, culture, and cross-cultural interactions. The preliminary results suggested that the Hispanic accent alone was enough for the participants to assign stereotypical ethnic and cultural characteristics to the individual with the Hispanic accent. Given the quality of the responses, the authors completed a secondary analysis to explore Whiteness and White privilege in more depth. Participants were found to be on a continuum in their understanding and acknowledgment of systemic racism; while some participants listed examples of inequality, other participants noted: “all people are treated equally.” Most participants noted their feelings of discomfort in discussing topics of cultural diversity and systemic racism by fearing to “say the ‘wrong thing.” Most participants placed the responsibility of discussing cultural differences with the person of color, which has been observed to create further alienation and otherness for culturally diverse individuals. The results indicate the importance of examining racial and cultural biases from White individuals to promote an anti-racist stance. The results emphasize the need for greater systemic changes in education, policies, and individual awareness regarding cultural identity. The results suggest the importance for White individuals to take ownership of their own cultural biases in order to promote equity and engage in cultural humility in a multicultural world. Future research should continue exploring the role of White ethnic identity and education as they appear to moderate White individuals’ attitudes and beliefs regarding other races and cultures.

Keywords: culture, qualitative research, whiteness, white privilege

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Authors: Natalia V. Beloglazova, Pieterjan Lenain, Martin Hedstrom, Dietmar Knopp, Sarah De Saeger

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In recent years polycyclic aromatic hydrocarbons (PAHs), which represent a hazard to humans and entire ecosystem, have been receiving an increased interest due to their mutagenic, carcinogenic and endocrine disrupting properties. They are formed in all incomplete combustion processes of organic matter and, as a consequence, ubiquitous in the environment. Benzo(a)pyrene (BaP) is on the priority list published by the Environmental Agency (US EPA) as the first PAH to be identified as a carcinogen and has often been used as a marker for PAHs contamination in general. It can be found in different types of water samples, therefore, the European Commission set up a limit value of 10 ng L–1 (10 ppt) for BAP in water intended for human consumption. Generally, different chromatographic techniques are used for PAHs determination, but these assays require pre-concentration of analyte, create large amounts of solvent waste, and are relatively time consuming and difficult to perform on-site. An alternative robust, stand-alone, and preferably cheap solution is needed. For example, a sensing unit which can be submerged in a river to monitor and continuously sample BaP. An affinity sensor based on capacitive transduction was developed. Natural antibodies or their synthetic analogues can be used as ligands. Ideally the sensor should operate independently over a longer period of time, e.g. several weeks or months, therefore the use of molecularly imprinted polymers (MIPs) was discussed. MIPs are synthetic antibodies which are selective for a chosen target molecule. Their robustness allows application in environments for which biological recognition elements are unsuitable or denature. They can be reused multiple times, which is essential to meet the stand-alone requirement. BaP is a highly lipophilic compound and does not contain any functional groups in its structure, thus excluding non-covalent imprinting methods based on ionic interactions. Instead, the MIPs syntheses were based on non-covalent hydrophobic and π-π interactions. Different polymerization strategies were compared and the best results were demonstrated by the MIPs produced using electropolymerization. 4-vinylpyridin (VP) and divinylbenzene (DVB) were used as monomer and cross-linker in the polymerization reaction. The selectivity and recovery of the MIP were compared to a non-imprinted polymer (NIP). Electrodes were functionalized with natural receptor (monoclonal anti-BaP antibody) and with MIPs selective towards BaP. Different sets of electrodes were evaluated and their properties such as sensitivity, selectivity and linear range were determined and compared. It was found that both receptor can reach the cut-off level comparable to the established ML, and despite the fact that the antibody showed the better cross-reactivity and affinity, MIPs were more convenient receptor due to their ability to regenerate and stability in river till 7 days.

Keywords: antibody, benzo(a)pyrene, capacitive sensor, MIPs, river water

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Authors: Marielle Leijten, Catherine Meulemans, Sven De Maeyer, Luuk Van Waes

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For the diagnosis of Alzheimer's disease (AD), a large variety of neuropsychological tests are available. In some of these tests, linguistic processing - both oral and written - is an important factor. Language disturbances might serve as a strong indicator for an underlying neurodegenerative disorder like AD. However, the current diagnostic instruments for language assessment mainly focus on product measures, such as text length or number of errors, ignoring the importance of the process that leads to written or spoken language production. In this study, it is our aim to describe and test differences between cognitive and impaired elderly on the basis of a selection of writing process variables (inter- and intrapersonal characteristics). These process variables are mainly related to pause times, because the number, length, and location of pauses have proven to be an important indicator of the cognitive complexity of a process. Method: Participants that were enrolled in our research were chosen on the basis of a number of basic criteria necessary to collect reliable writing process data. Furthermore, we opted to match the thirteen cognitively impaired patients (8 MCI and 5 AD) with thirteen cognitively healthy elderly. At the start of the experiment, participants were each given a number of tests, such as the Mini-Mental State Examination test (MMSE), the Geriatric Depression Scale (GDS), the forward and backward digit span and the Edinburgh Handedness Inventory (EHI). Also, a questionnaire was used to collect socio-demographic information (age, gender, eduction) of the subjects as well as more details on their level of computer literacy. The tests and questionnaire were followed by two typing tasks and two picture description tasks. For the typing tasks participants had to copy (type) characters, words and sentences from a screen, whereas the picture description tasks each consisted of an image they had to describe in a few sentences. Both the typing and the picture description tasks were logged with Inputlog, a keystroke logging tool that allows us to log and time stamp keystroke activity to reconstruct and describe text production processes. The main rationale behind keystroke logging is that writing fluency and flow reveal traces of the underlying cognitive processes. This explains the analytical focus on pause (length, number, distribution, location, etc.) and revision (number, type, operation, embeddedness, location, etc.) characteristics. As in speech, pause times are seen as indexical of cognitive effort. Results. Preliminary analysis already showed some promising results concerning pause times before, within and after words. For all variables, mixed effects models were used that included participants as a random effect and MMSE scores, GDS scores and word categories (such as determiners and nouns) as a fixed effect. For pause times before and after words cognitively impaired patients paused longer than healthy elderly. These variables did not show an interaction effect between the group participants (cognitively impaired or healthy elderly) belonged to and word categories. However, pause times within words did show an interaction effect, which indicates pause times within certain word categories differ significantly between patients and healthy elderly.

Keywords: Alzheimer's disease, keystroke logging, matching, writing process

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Authors: Kyriaki Hatziagapiou, Konstantinos Bethanis, Olti Nikola, Elias Christoforides, Eleni Koniari, Eleni Kakouri, George Lambrou, Christina Kanaka-Gantenbein

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Glioblastoma multiforme (GBM) remains a serious health challenge, as current therapeutic modalities continue to yield unsatisfactory results, with the average survival rarely exceeding 1-2 years. Natural compounds still provide some of the most promising approaches for discovering new drugs. The non-psychotropic cannabidiol (CBD) deriving from Cannabis sativa L. provides such promise. CBD is endowed with anticancer, antioxidant, and genoprotective properties as established in vitro and in in vivo experiments. CBD’s selectivity towards cancer cells and its safe profile suggest its usage in cancer therapies. However, the bioavailability of oral CBD is low due to poor aqueous solubility, erratic gastrointestinal absorption, and significant first-pass metabolism, hampering its therapeutic potential and resulting in a variable pharmacokinetic profile. In this context, CBD can take great advantage of nanomedicine-based formulation strategies. Cyclodextrins (CDs) are cyclic oligosaccharides used in the pharmaceutical industry to incorporate apolar molecules inside their hydrophobic cavity, increasing their stability, water solubility, and bioavailability or decreasing their side effects. CBD-inclusion complexes with CDs could be a good strategy to improve its properties, like solubility and stability to harness its full therapeutic potential. The current research aims to study the potential cytotoxic effect of CBD and CBD-CDs complexes CBD-RMβCD (randomly methylated β-cyclodextrin) and CBD-HPβCD (hydroxypropyl-b-CD) on the A172 glioblastoma cell line. CBD is diluted in 10% DMSO, and CBD/CDs solutions are prepared by mixing solid CBD, solid CDs, and dH2O. For the biological assays, A172 cells are incubated at a range of concentrations of CBD, CBD-RMβCD and CBD-HPβCD, RMβCD, and HPβCD (0,03125-4 mg/ml) at 24, 48, and 72 hours. Analysis of cell viability after incubation with the compounds is performed with Alamar Blue viability assay. CBD’s dilution to DMSO 10% was inadequate, as crystals are observed; thus cytotoxicity experiments are not assessed. CBD’s solubility is enhanced in the presence of both CDs. CBD/CDs exert significant cytotoxicity in a dose and time-dependent manner (p < 0.005 for exposed cells to any concentration at 48, 72, and 96 hours versus cells not exposed); as their concentration and time of exposure increases, the reduction of resazurin to resofurin decreases, indicating a reduction in cell viability. The cytotoxic effect is more pronounced in cells exposed to CBD-HPβCD for all concentrations and time-points. RMβCD and HPβCD at the highest concentration of 4 mg/ml also exerted antitumor action per se since manifesting cell growth inhibition. The results of our study could afford the basis of research regarding the use of natural products and their inclusion complexes as anticancer agents and the shift to targeted therapy with higher efficacy and limited toxicity. Acknowledgments: The research is partly funded by ΙΚΥ (State Scholarships Foundation) – Post-doc Scholarships-Partnership Agreement 2014-2020.

Keywords: cannabidiol, cyclodextrins, glioblastoma, hydroxypropyl-b-Cyclodextrin, randomly-methylated-β-cyclodextrin

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Authors: Justine Salam

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As a federal state, Canada’s constitutional arrangements regarding the management of natural resources is unique because it gives complete ownership and control of natural resources to the provinces (subnational level). However, the province of Alberta—home to the third largest oil reserves in the world—lags behind comparable jurisdictions in levying royalties on oil corporations, especially oil sands royalties. While Albertans own the oil sands, scholars have argued that natural resource exploitation in Alberta benefits corporations and industry more than it does Albertans. This study provides a systematic understanding of the causal factors affecting royalties in Alberta to map dynamics of power and how they manifest themselves during policy-making. Mounting domestic and global public pressure led Alberta to review its oil sands royalties twice in less than a decade through public-commissioned Royalty Review Panels, first in 2007 and again in 2015. The Panels’ task was to research best practices and to provide policy recommendations to the Government through public consultations with Albertans, industry, non-governmental organizations, and First Nations peoples. Both times, the Panels recommended a relative increase to oil sands royalties. However, irrespective of the Reviews’ recommendations, neither the right-wing 2007 Progressive Conservative Party (PC) nor the left-wing 2015 New Democratic Party (NDP) government—both committed to increase oil sands royalties—increased royalty intake. Why did two consecutive political parties at opposite ends of the political spectrum fail to account for the recommendations put forward by the Panel? Through a qualitative case-study analysis, this study assesses domestic and global causal factors for Alberta’s inability to raise oil sands royalties significantly after the two Reviews through an institutions, interests, and ideas framework. Indeed, causal factors can be global (e.g. market and price fluctuation) or domestic (e.g. oil companies’ influence on the Alberta government). The institutions, interests, and ideas framework is at the intersection of public policy, comparative studies, and political economy literatures, and therefore draws multi-faceted insights into the analysis. To account for institutions, the study proposes to review international trade agreements documents such as the North American Free Trade Agreement (NAFTA) because they have embedded Alberta’s oil sands into American energy security policy and tied Canadian and Albertan oil policy in legal international nods. To account for interests, such as how the oil lobby or the environment lobby can penetrate governmental decision-making spheres, the study draws on the Oil Sands Oral History project, a database of interviews from government officials and oil industry leaders at a pivotal time in Alberta’s oil industry, 2011-2013. Finally, to account for ideas, such as how narratives of Canada as a global ‘energy superpower’ and the importance of ‘energy security’ have dominated and polarized public discourse, the study relies on content analysis of Alberta-based pro-industry newspapers to trace the prevalence of these narratives. By mapping systematically the nods and dynamics of power at play in Alberta, the study sheds light on the factors that influence royalty policy-making in one of the largest industries in Canada.

Keywords: Alberta Canada, natural resources governance, oil sands, political economy

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Authors: Angela O. Ugwu, Sunday Ocheni

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Background: Cancer-associated thrombosis (CAT) is a cause of morbidity and mortality among cancer patients. Several risk factors for developing venous thromboembolism (VTE) also coexist with cancer patients, such as chemotherapy and immobilization, thus contributing to the higher risk of VTE in cancer patients when compared to non-cancer patients. This study aimed to determine if there is any correlation between levels of some inflammatory cytokines/haematological parameters and Khorana scores of newly diagnosed chemotherapy naïve ambulatory cancer patients (CNACP). Methods: This was a cross-sectional analytical study carried out from June 2021 to May 2022. Eligible newly diagnosed cancer patients 18 years and above (case group) were enrolled consecutively from the adult Oncology Clinics of the University of Nigeria Teaching Hospital, Ituku/Ozalla (UNTH). The control group was blood donors at UNTH Ituku/Ozalla, Enugu blood bank, and healthy members of the Medical and Dental Consultants Association of Nigeria (MDCAN), UNTH Chapter. Blood samples collected from the participants were assayed for IL-6, TNF-Alpha, and haematological parameters such as haemoglobin, white blood cell count (WBC), and platelet count. Data were entered into an Excel worksheet and were then analyzed using Statistical Package for Social Sciences (SPSS) computer software version 21.0 for windows. A P value of < 0.05 was considered statistically significant. Results: A total of 200 participants (100 cases and 100 controls) were included in the study. The overall mean age of the participants was 47.42 ±15.1 (range 20-76). The sociodemographic characteristics of the two groups, including age, sex, educational level, body mass index (BMI), and occupation, were similar (P > 0.05). Following One Way ANOVA, there were significant differences between the mean levels of interleukin-6 (IL-6) (p = 0.036) and tumor necrotic factor-α (TNF-α) (p = 0.001) in the three Khorana score groups of the case group. Pearson’s correlation analysis showed a significant positive correlation between the Khorana scores and IL-6 (r=0.28, p = 0.031), TNF-α (r= 0.254, p= 0.011), and PLR (r= 0.240, p=0.016). The mean serum levels of IL-6 were significantly higher in CNACP than in the healthy controls [8.98 (8-12) pg/ml vs. 8.43 (2-10) pg/ml, P=0.0005]. There were also significant differences in the mean levels of the haemoglobin (Hb) level (P < 0.001)); white blood cell (WBC) count ((P < 0.001), and platelet (PL) count (P = 0.005) between the two groups of participants. Conclusion: There is a significant positive correlation between the serum levels of IL-6, TNF-α, and PLR and the Khorana scores of CNACP. The mean serum levels of IL-6, TNF-α, PLR, WBC, and PL count were significantly higher in CNACP than in the healthy controls. Ambulatory cancer patients with high-risk Khorana scores may benefit from anti-inflammatory drugs because of the positive correlation with inflammatory cytokines. Recommendations: Ambulatory cancer patients with 2 Khorana scores may benefit from thromboprophylaxis since they have higher Khorana scores. A multicenter study with a heterogeneous population and larger sample size is recommended in the future to further elucidate the relationship between IL-6, TNF-α, PLR, and the Khorana scores among cancer patients in the Nigerian population.

Keywords: thromboprophylaxis, cancer, Khorana scores, inflammatory cytokines, haematological parameters

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Authors: Mark Kennedy, E. Bantugon, Noruane A. Daileg

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Leaks arising from aircraft fuel tanks is a protracted problem for the aircraft manufacturers, operators, and maintenance crews. It principally arises from stress, structural defects, or degraded sealants as the aircraft age. It can be ignited by different sources, which can result in catastrophic flight and consequences, exhibiting a major drain both on time and budget. In order to mitigate and eliminate this kind of problem, the researcher produced an experimental sealant having a base material of natural tree resin, the Pili Tree Resin. Aside from producing an experimental sealant, the main objective of this research is to analyze its physical, chemical, mechanical, thermal, and rheological properties, which is beneficial and effective for specific aircraft parts, particularly the integral fuel tank. The experimental method of research was utilized in this study since it is a product invention. This study comprises two parts, specifically the Optimization Process and the Characterization Process. In the Optimization Process, the experimental sealant was subjected to the Flammability Test, an important test and consideration according to 14 Code of Federal Regulation Appendix N, Part 25 - Fuel Tank Flammability Exposure and Reliability Analysis, to get the most suitable formulation. Followed by the Characterization Process, where the formulated experimental sealant has undergone thirty-eight (38) different standard testing including Organoleptic, Instrumental Color Measurement Test, Smoothness of Appearance Test, Miscibility Test, Boiling Point Test, Flash Point Test, Curing Time, Adhesive Test, Toxicity Test, Shore A Hardness Test, Compressive Strength, Shear Strength, Static Bending Strength, Tensile Strength, Peel Strength Test, Knife Test, Adhesion by Tape Test, Leakage Test), Drip Test, Thermogravimetry-Differential Thermal Analysis (TG-DTA), Differential Scanning Calorimetry, Calorific Value, Viscosity Test, Creep Test, and Anti-Sag Resistance Test to determine and analyze the five (5) material properties of the sealant. The numerical values of the mentioned tests are determined using product application, testing, and calculation. These values are then used to calculate the efficiency of the experimental sealant. Accordingly, this efficiency is the means of comparison between the experimental and commercial sealant. Based on the results of the different standard testing conducted, the experimental sealant exceeded all the data results of the commercial sealant. This result shows that the physicochemical-mechanical, thermal, and rheological properties of the experimental sealant are far more effective as an aircraft integral fuel tank sealant alternative in comparison to the commercial sealant. Therefore, Pili Tree possesses a new role and function: a source of ingredients in sealant production.

Keywords: Aircraft Integral Fuel Tank, Physicochemi-mechanical, Pili Tree Resin, Properties, Rheological, Sealant, Thermal

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Authors: Giulia Bonaldo, Alberto Vaccheri, Ottavio D'Annibali, Domenico Motola

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The Human Papilloma Virus (HPV) was shown to be the cause of different types of carcinomas, first of all of the cervical intraepithelial neoplasia. Since the early 80s to today, thanks first to the preventive screening campaigns (pap-test) and following to the introduction of HPV vaccines on the market; the number of new cases of cervical cancer has decreased significantly. The HPV vaccines currently approved are three: Cervarix® (HPV2 - virus type: 16 and 18), Gardasil® (HPV4 - 6, 11, 16, 18) and Gardasil 9® (HPV9 - 6, 11, 16, 18, 31, 33, 45, 52, 58), which all protect against the two high-risk HPVs (6, 11) that are mainly involved in cervical cancers. Despite the remarkable effectiveness of these vaccines has been demonstrated, in the recent years, there have been many complaints about their risk-benefit profile due to Adverse Events Following Immunization (AEFI). The purpose of this study is to provide a support about the ongoing discussion on the safety profile of HPV vaccines based on real life data deriving from spontaneous reports of suspected AEFIs collected in the Vaccine Adverse Events Reporting System (VAERS). VAERS is a freely-available national vaccine safety surveillance database of AEFI, co-administered by the Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA). We collected all the reports between January 2007 to December 2017 related to the HPV vaccines with a brand name (HPV2, HPV4, HPV9) or without (HPVX). A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% confidence interval and p value ≤ 0.05 was performed. Over the 10-year period, 54889 reports of AEFI related to HPV vaccines reported in VAERS, corresponding to 224863 vaccine-event pairs, were retrieved. The highest number of reports was related to Gardasil (n = 42244), followed by Gardasil 9 (7212) and Cervarix (3904). The brand name of the HPV vaccine was not reported in 1529 cases. The two events more frequently reported and statistically significant for each vaccine were: dizziness (n = 5053) ROR = 1.28 (CI95% 1.24 – 1.31) and syncope (4808) ROR = 1.21 (1.17 – 1.25) for Gardasil. For Gardasil 9, injection site pain (305) ROR = 1.40 (1.25 – 1.57) and injection site erythema (297) ROR = 1.88 (1.67 – 2.10) and for Cervarix, headache (672) ROR = 1.14 (1.06 – 1.23) and loss of consciousness (528) ROR = 1.71 (1.57 – 1.87). In total, we collected 406 reports of death and 2461 cases of permanent disability in the ten-year period. The events consisting of incorrect vaccine storage or incorrect administration were not considered. The AEFI analysis showed that the most frequently reported events are non-serious and listed in the corresponding SmPCs. In addition to these, potential safety signals arose regarding less frequent and severe AEFIs that would deserve further investigation. This already happened with the referral of the European Medicines Agency (EMA) for the adverse events POTS (Postural Orthostatic Tachycardia Syndrome) and CRPS (Complex Regional Pain Syndrome) associated with anti-papillomavirus vaccines.

Keywords: adverse drug reactions, pharmacovigilance, safety, vaccines

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Authors: Priyanka Mokashi, Aparna Khanna, Nancy Pandita

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Diabetes mellitus is a chronic metabolic disorder which will be the 7th leading cause of death by 2030. The current line of treatment for the diabetes mellitus is oral antidiabetic drugs (biguanides, sulfonylureas, meglitinides, thiazolidinediones and alpha-glycosidase inhibitors) and insulin therapy depending upon the type 1 or type 2 diabetes mellitus. But, these treatments have their disadvantages, ranging from the developing of resistance to the drugs and adverse effects caused by them. Alternative to these synthetic agents, natural products provides a new insight for the development of more efficient and safe drugs due to their therapeutic values. Enicostema littorale blume (A. Raynal) is a traditional Indian plant belongs to the Gentianaceae family. It is widely distributed in Asia, Africa, and South America. There are few reports on Swrtiamarin, major component of this plant for its antidiabetic activity. However, the antidiabetic activity of flavonoids from E. littorale and their mechanism of action have not yet been elucidated. Flavonoids have a positive relationship with disease prevention and can act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, adipocytes, hepatocytes and skeletal myofibers. They may exert beneficial effects in diabetes by (i) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (ii) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells; (iii) increasing glucose uptake in hepatocytes, skeletal muscle and white adipose tissue (iv) reducing insulin resistance, inflammation and oxidative stress. Therefore, we have isolated four flavonoid rich fractions, Fraction A (FA), Fraction B (FB), Fraction C (FC), Fraction D (FD) from crude alcoholic hot (AH) extract from E. littorale, identified by LC/MS. Total eight flavonoids were identified on the basis of fragmentation pattern. Flavonoid FA showed the presence of swertisin, isovitexin, and saponarin; FB showed genkwanin, quercetin, isovitexin, FC showed apigenin, swertisin, quercetin, 5-O-glucosylswertisin and 5-O-glucosylisoswertisin whereas FD showed the presence of swertisin. Further, these fractions were assessed for their antidiabetic activity on stimulating glucose uptake in insulin-resistant HepG2 cell line model (IR/HepG2). The results showed that FD containing C-glycoside Swertisin has significantly increased the glucose uptake rate of IR/HepG2 cells at the concentration of 10 µg/ml as compared to positive control Metformin (0.5mM) which was determined by glucose oxidase- peroxidase method. It has been reported that enhancement of glucose uptake of cells occurs due the translocation of Glut4 vesicles to cell membrane through IR/IRS1/AKT pathway. Therefore, we have studied expressions of three genes IRS1, AKT and Glut4 by real-time PCR to evaluate whether they follow the same pathway or not. It was seen that the glucose uptake rate has increased in FD treated IR/HepG2 cells due to the activation of insulin receptor substrate-1 (IRS1) followed by protein kinase B (AKT) through phosphoinositide 3-kinase (PI3K) leading to translocation of Glut 4 vesicles to cell membrane, thereby enhancing glucose uptake and insulin sensitivity of insulin resistant HepG2 cells. Hence, the up-regulation indicated the mechanism of action through which FD (Swertisin) acts as antidiabetic candidate in the treatment of type 2 diabetes mellitus.

Keywords: E. littorale, glucose transporter, glucose uptake rate, insulin resistance

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Authors: Rodchares Hanrinth, Theerapong Srisil, Peeraya Sriphong, Pawich Paktipat

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The trigger tool is the low-cost, low-tech method to detect adverse events through clues called triggers. The Institute for Healthcare Improvement (IHI) has developed the Global Trigger Tool for measuring and preventing adverse events. However, this tool is not specific for detecting adverse drug events. The pharmacy-based trigger tool is needed to detect adverse drug events (ADEs). Group concept mapping is an effective method for conceptualizing various ideas from diverse stakeholders. This technique was used to identify a pharmacy-based trigger to detect adverse drug events (ADEs). The aim of this study was to involve the pharmacists in conceptualizing, developing, and prioritizing a feasible trigger tool to detect adverse drug events in a provincial hospital, the northeastern part of Thailand. The study was conducted during the 6-month period between April 1 and September 30, 2017. Study participants involved 20 pharmacists (17 hospital pharmacists and 3 pharmacy lecturers) engaging in three concept mapping workshops. In this meeting, the concept mapping technique created by Trochim, a highly constructed qualitative group technic for idea generating and sharing, was used to produce and construct participants' views on what triggers were potential to detect ADEs. During the workshops, participants (n = 20) were asked to individually rate the feasibility and potentiality of each trigger and to group them into relevant categories to enable multidimensional scaling and hierarchical cluster analysis. The outputs of analysis included the trigger list, cluster list, point map, point rating map, cluster map, and cluster rating map. The three workshops together resulted in 21 different triggers that were structured in a framework forming 5 clusters: drug allergy, drugs induced diseases, dosage adjustment in renal diseases, potassium concerning, and drug overdose. The first cluster is drug allergy such as the doctor’s orders for dexamethasone injection combined with chlorpheniramine injection. Later, the diagnosis of drug-induced hepatitis in a patient taking anti-tuberculosis drugs is one trigger in the ‘drugs induced diseases’ cluster. Then, for the third cluster, the doctor’s orders for enalapril combined with ibuprofen in a patient with chronic kidney disease is the example of a trigger. The doctor’s orders for digoxin in a patient with hypokalemia is a trigger in a cluster. Finally, the doctor’s orders for naloxone with narcotic overdose was classified as a trigger in a cluster. This study generated triggers that are similar to some of IHI Global trigger tool, especially in the medication module such as drug allergy and drug overdose. However, there are some specific aspects of this tool, including drug-induced diseases, dosage adjustment in renal diseases, and potassium concerning which do not contain in any trigger tools. The pharmacy-based trigger tool is suitable for pharmacists in hospitals to detect potential adverse drug events using clues of triggers.

Keywords: adverse drug events, concept mapping, hospital, pharmacy-based trigger tool

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Authors: Xuechun Kan, Dongdong Li, Fan Li, Peidang Liu

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Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with a poor prognosis, and radiotherapy is one of the main treatment methods. However, due to the obvious resistance of tumor cells to radiotherapy, high dose of ionizing radiation is required during radiotherapy, which causes serious damage to normal tissues near the tumor. Therefore, how to improve radiotherapy resistance and enhance the specific killing of tumor cells by radiation is a hot issue that needs to be solved in clinic. Recent studies have shown that silver-based nanoparticles have strong radiosensitization, and silver nanoclusters (AgNCs) also provide a broad prospect for tumor targeted radiosensitization therapy due to their ultra-small size, low toxicity or non-toxicity, self-fluorescence and strong photostability. Aptamer 5TR1 is a 25-base oligonucleotide aptamer that can specifically bind to mucin-1 highly expressed on the membrane surface of TNBC 4T1 cells, and can be used as a highly efficient tumor targeting molecule. In this study, AgNCs were synthesized by DNA template based on 5TR1 aptamer (NC-T5-5TR1), and its role as a targeted radiosensitizer in TNBC radiotherapy was investigated. The optimal DNA template was first screened by fluorescence emission spectroscopy, and NC-T5-5TR1 was prepared. NC-T5-5TR1 was characterized by transmission electron microscopy, ultraviolet-visible spectroscopy and dynamic light scattering. The inhibitory effect of NC-T5-5TR1 on cell activity was evaluated using the MTT method. Laser confocal microscopy was employed to observe NC-T5-5TR1 targeting 4T1 cells and verify its self-fluorescence characteristics. The uptake of NC-T5-5TR1 by 4T1 cells was observed by dark-field imaging, and the uptake peak was evaluated by inductively coupled plasma mass spectrometry. The radiation sensitization effect of NC-T5-5TR1 was evaluated through cell cloning and in vivo anti-tumor experiments. Annexin V-FITC/PI double staining flow cytometry was utilized to detect the impact of nanomaterials combined with radiotherapy on apoptosis. The results demonstrated that the particle size of NC-T5-5TR1 is about 2 nm, and the UV-visible absorption spectrum detection verifies the successful construction of NC-T5-5TR1, and it shows good dispersion. NC-T5-5TR1 significantly inhibited the activity of 4T1 cells and effectively targeted and fluoresced within 4T1 cells. The uptake of NC-T5-5TR1 reached its peak at 3 h in the tumor area. Compared with AgNCs without aptamer modification, NC-T5-5TR1 exhibited superior radiation sensitization, and combined radiotherapy significantly inhibited the activity of 4T1 cells and tumor growth in 4T1-bearing mice. The apoptosis level of NC-T5-5TR1 combined with radiation was significantly increased. These findings provide important theoretical and experimental support for NC-T5-5TR1 as a radiation sensitizer for TNBC.

Keywords: 5TR1 aptamer, silver nanoclusters, radio sensitization, triple-negative breast cancer

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