Search results for: adjunctive therapy

Authors: George Zhou, Yunchan Chen, Candace Chien

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Kidney replacement therapy is the current standard of care for end-stage renal diseases. In-center or home hemodialysis remains an integral component of the therapeutic regimen. Arteriovenous fistulas (AVF) make up the vascular circuit through which blood is filtered and returned. Naturally, AVF patency determines whether adequate clearance and filtration can be achieved and directly influences clinical outcomes. Our aim was to build a deep learning model for automated AVF stenosis screening based on the sound of blood flow through the AVF. A total of 311 patients with AVF were enrolled in this study. Blood flow sounds were collected using a digital stethoscope. For each patient, blood flow sounds were collected at 6 different locations along the patient’s AVF. The 6 locations are artery, anastomosis, distal vein, middle vein, proximal vein, and venous arch. A total of 1866 sounds were collected. The blood flow sounds are labeled as “patent” (normal) or “stenotic” (abnormal). The labels are validated from concurrent ultrasound. Our dataset included 1527 “patent” and 339 “stenotic” sounds. We show that blood flow sounds vary significantly along the AVF. For example, the blood flow sound is loudest at the anastomosis site and softest at the cephalic arch. Contextualizing the sound with location metadata significantly improves classification performance. How to encode and incorporate categorical metadata is an active area of research1. Herein, we study ordinal (i.e., integer) encoding schemes. The numerical representation is concatenated to the flattened feature vector. We train a vision transformer (ViT) on spectrogram image representations of the sound and demonstrate that using scalar multiples of our integer encodings improves classification performance. Models are evaluated using a 10-fold cross-validation procedure. The baseline performance of our ViT without any location metadata achieves an AuROC and AuPRC of 0.68 ± 0.05 and 0.28 ± 0.09, respectively. Using the following encodings of Artery:0; Arch: 1; Proximal: 2; Middle: 3; Distal 4: Anastomosis: 5, the ViT achieves an AuROC and AuPRC of 0.69 ± 0.06 and 0.30 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 10; Proximal: 20; Middle: 30; Distal 40: Anastomosis: 50, the ViT achieves an AuROC and AuPRC of 0.74 ± 0.06 and 0.38 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 100; Proximal: 200; Middle: 300; Distal 400: Anastomosis: 500, the ViT achieves an AuROC and AuPRC of 0.78 ± 0.06 and 0.43 ± 0.11. respectively. Interestingly, we see that using increasing scalar multiples of our integer encoding scheme (i.e., encoding “venous arch” as 1,10,100) results in progressively improved performance. In theory, the integer values do not matter since we are optimizing the same loss function; the model can learn to increase or decrease the weights associated with location encodings and converge on the same solution. However, in the setting of limited data and computation resources, increasing the importance at initialization either leads to faster convergence or helps the model escape a local minimum.

Keywords: arteriovenous fistula, blood flow sounds, metadata encoding, deep learning

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Authors: Isaac Martin, Abigail Lark, Sandra Morales, Eric W. Alton, Jane C. Davies

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Objectives: The cystic fibrosis (CF) lung is a unique microbiological niche, wherein harmful bacteria persist for many years despite antibiotic therapy. Pseudomonas aeruginosa (Pa), the major culprit leading to lung decline and increased mortality, thrives in the lungs of patients with CF due to several factors that have been linked with poor antibiotic performance. Our group is investigating alternative therapies including bacteriophage cocktails with which we have previously demonstrated efficacy against planktonic organisms. In this study, we explored the effects of a 4-phage cocktail on Pa grown in two different conditions, intended to mirror the CF lung: a) alongside standard antibiotic treatment in pre-formed biofilms (structures formed by Pa-secreted exopolysaccharides which provide both physical and cell division barriers to antimicrobials and host defenses and b) in an acidic environment postulated to be present in the CF airway due both to the primary defect in bicarbonate secretion and secondary effects of inflammation. Methods: 16 Pa strains from CF patients at the Royal Brompton Hospital were selected based on sensitivity to a) ceftazidime/ tobramycin and b) the phage cocktail in a conventional plaque assay. To assess efficacy of phage in biofilms, 96 well plates with Pa (5x10⁷ CFU/ ml) were incubated in static conditions, allowing adherent bacterial colonies to form for 24 hr. Ceftazidime and tobramycin (both at 2 × MIC) were added, +/- bacteriophage (4x10⁸ PFU/mL) for a further 24 hr. Cell viability and biomass were estimated using fluorescent resazurin and crystal violet assays, respectively. To evaluate the effect of pH, strains were grown planktonically in shaking 96 well plates at pH 6.0, 6.6, 7.0 and 7.5 with tobramycin or phage, at varying concentrations. Cell viability was quantified by fluorescent resazurin assay. Results: For the biofilm assay, treatment groups were compared with untreated controls and expressed as percent reduction in cell viability and biomass. Addition of the 4-phage cocktail resulted in a 1.3-fold reduction in cell viability and 1.7-fold reduction in biomass (p < 0.001) when compared to standard antibiotic treatment alone. Notably, there was a 50 ± 15% reduction in cell viability and 60 ± 12% reduction in biomass (95% CI) for the 4 biofilms demonstrating the most resistance to antibiotic treatment. 83% of strains tested (n=6) showed decreased bacterial killing by tobramycin at acidic pHs (p < 0.01). However, 25% of strains (n=12) showed improved phage killing at acidic pHs (p < 0.05), with none showing the pattern of reduced efficacy at acidic pH demonstrated by tobramycin. Conclusion: The 4-phage anti-Pa cocktail tested against Pa performs well in pre-formed biofilms and in acidic environments; two conditions intended to mimic the CF lung. To our knowledge, these are the first data looking at the effects of subtle pH changes on phage-mediated bacterial killing in the context of Pa infection. These findings contribute to a growing body of evidence supporting the use of nebulised lytic bacteriophage as a treatment in the context of lung infection.

Keywords: biofilm, cystic fibrosis, pH, Pseudomonas aeruginosa, lytic bacteriophage

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Authors: Lijuan Li

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Nitric oxide (NO) has become a fascinating entity in biological chemistry over the past few years. It is a gaseous lipophilic radical molecule that plays important roles in several physiological and pathophysiological processes in mammals, including activating the immune response, serving as a neurotransmitter, regulating the cardiovascular system, and acting as an endothelium-derived relaxing factor. NO functions in eukaryotes both as a signal molecule at nanomolar concentrations and as a cytotoxic agent at micromolar concentrations. The latter arises from the ability of NO to react readily with a variety of cellular targets leading to thiol S-nitrosation, amino acid N-nitrosation, and nitrosative DNA damage. Nitric oxide can readily bind to metals to give metal-nitrosyl (M-NO) complexes. Some of these species are known to play roles in biological NO storage and transport. These complexes have different biological, photochemical, or spectroscopic properties due to distinctive structural features. These recent discoveries have spawned a great interest in the development of transition metal complexes containing NO, particularly its iron complexes that are central to the role of nitric oxide in the body. Spectroscopic evidence would appear to implicate species of “Fe(NO)2+” type in a variety of processes ranging from polymerization, carcinogenesis, to nitric oxide stores. Our research focuses on isolation and structural studies of non-heme iron nitrosyls that mimic biologically active compounds and can potentially be used for anticancer drug therapy. We have shown that reactions between Fe(NO)2(CO)2 and a series of imidazoles generated new non-heme iron nitrosyls of the form Fe(NO)2(L)2 [L = imidazole, 1-methylimidazole, 4-methylimidazole, benzimidazole, 5,6-dimethylbenzimidazole, and L-histidine] and a tetrameric cluster of [Fe(NO)2(L)]4 (L=Im, 4-MeIm, BzIm, and Me2BzIm), resulted from the interactions of Fe(NO)2 with a series of substituted imidazoles was prepared. Recently, a series of sulfur bridged iron di nitrosyl complexes with the general formula of [Fe(µ-RS)(NO)2]2 (R = n-Pr, t-Bu, 6-methyl-2-pyridyl, and 4,6-dimethyl-2-pyrimidyl), were synthesized by the reaction of Fe(NO)2(CO)2 with thiols or thiolates. Their structures and properties were studied by IR, UV-vis, 1H-NMR, EPR, electrochemistry, X-ray diffraction analysis and DFT calculations. IR spectra of these complexes display one weak and two strong NO stretching frequencies (νNO) in solution, but only two strong νNO in solid. DFT calculations suggest that two spatial isomers of these complexes bear 3 Kcal energy difference in solution. The paramagnetic complexes [Fe2(µ-RS)2(NO)4]-, have also been investigated by EPR spectroscopy. Interestingly, the EPR spectra of complexes exhibit an isotropic signal of g = 1.998 - 2.004 without hyperfine splitting. The observations are consistent with the results of calculations, which reveal that the unpaired electron dominantly delocalize over the two sulfur and two iron atoms. The difference of the g values between the reduced form of iron-sulfur clusters and the typical monomeric di nitrosyl iron complexes is explained, for the first time, by of the difference in unpaired electron distributions between the two types of complexes, which provides the theoretical basis for the use of g value as a spectroscopic tool to differentiate these biologically active complexes.

Keywords: di nitrosyl iron complex, metal nitrosyl, non-heme iron, nitric oxide

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Authors: K. Yu Vlasova, M. A. Abakumov, H. Wishwarsao, M. Sokolsky, N. V. Nukolova, A. G. Majouga, Y. I. Golovin, N. L. Klyachko, A. V. Kabanov

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Introduction:Nowadays pharmaceutical medicine is aimed to create systems for combined therapy, diagnostic, drug delivery and controlled release of active molecules to target cells. Magnetic nanoparticles (MNPs) are used to achieve this aim. MNPs can be applied in molecular diagnostics, magnetic resonance imaging (T1/T2 contrast agents), drug delivery, hyperthermia and could improve therapeutic effect of drugs. The most common drug containers, containing MNPs, are liposomes, micelles and polymeric molecules bonded to the MNPs surface. Usually superparamagnetic nanoparticles are used (the general diameter is about 5-6 nm) and all effects of high frequency magnetic field (MF) application are based on Neel relaxation resulting in heating of surrounded media. In this work we try to develop a new method to improve drug release from MNPs under super low frequency MF. We suppose that under low frequency MF exposures the Brown’s relaxation dominates and MNPs rotation could occur leading to conformation changes and release of bioactive molecules immobilized on MNPs surface.The aim of this work was to synthesize different systems with active drug (biopolymers coated MNPs nanoclusters with immobilized enzymes and doxorubicin (Dox) loaded magnetic liposomes/micelles) and investigate the effect of super low frequency MF on these drug containers. Methods: We have synthesized MNPs of magnetite with magnetic core diameter 7-12 nm . The MNPs were coated with block-copolymer of polylysine and polyethylene glycol. Superoxide dismutase 1 (SOD1) was electrostatically adsorbed on the surface of the clusters. Liposomes were prepared as follow: MNPs, phosphatidylcholine and cholesterol were dispersed in chloroform, dried to get film and then dispersed in distillated water, sonicated. Dox was added to the solution, pH was adjusted to 7.4 and excess of drug was removed by centrifugation through 3 kDa filters. Results: Polylysine coated MNPs formed nanosized clusters (as observed by TEM) with intensity average diameter of 112±5 nm and zeta potential 12±3 mV. After low frequency AC MF exposure we observed change of immobilized enzyme activity and hydrodynamic size of clusters. We suppose that the biomolecules (enzymes) are released from the MNPs surface followed with additional aggregation of complexes at the MF in medium. Centrifugation of the nanosuspension after AC MF exposures resulted in increase of positive charge of clusters and change in enzyme concentration in comparison with control sample without MF, thus confirming desorption of negatively charged enzyme from the positively charged surface of MNPs. Dox loaded magnetic liposomes had average diameter of 160±8 nm and polydispersity index (PDI) 0.25±0.07. Liposomes were stable in DW and PBS at pH=7.4 at 370C during a week. After MF application (10 min of exposure, 50 Hz, 230 mT) diameter of liposomes raised to 190±10 nm and PDI was 0.38±0.05. We explain this by destroying and/or reorganization of lipid bilayer, that leads to changes in release of drug in comparison with control without MF exposure. Conclusion: A new application of low frequency AC MF for drug delivery and controlled drug release was shown. Investigation was supported by RSF-14-13-00731 grant, K1-2014-022 grant.

Keywords: magnetic nanoparticles, low frequency magnetic field, drug delivery, controlled drug release

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Authors: Heba M. Saad Eldien, Ola Abdel-Tawab Hussein, Ahmed Yassein Nassar

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Background: Indomethacin is a non-steroidal anti inflammatory drug. Indomethacin induces an injury to gastrointestinal mucosa in experimental animals and humans and their use is associated with a significant risk of hemorrhage, erosions and perforation of both gastric and intestinal ulcers. The anti-inflammatory action of copper complexes is an important activity of their anti-ulcer effect achieved by their intermediary role as a transport form of copper that allow activation of the several copper-dependent enzymes. Therefore, several copper complexes were synthesized and investigated as promising alternative anti-ulcer therapy. Aim of the work: The purpose of this study was to evaluate a copper chelating complex consisting of egg albumin and copper as one of the copper peptides that can be used as anti-inflammatory agent and effective in ameliorates the hazards of the indomethacin on the histological structure of the fundus of the stomach that could be added to raise the efficacy of the currently used simple and cheap gastric anti-inflammatory drug mucogel. Material &methods: This study was carried out on 40 adult male albino rats,divided equally into 4 groups;Group I(control group) received distilled water,Group II(indomethacin treated group) received (25 mg/kg body weight, oral intubation) once, Group III (mucogel treated group)2 mL/rat once daily, oral incubation, Group IV(copper complex group) 1 mL /rat of 30 gm of copper albumin complex was mixed uniformly with mucogel to 100 mL. Treatment has been started six hour after Induction of Ulcers and continued till the 3rd day. The animals sacrificed and was processed for light, transmission electron microscopy(TEM) and immunostaining for inducible nitric oxide synthase(iNOS). Results: Fundic mucosa of group II, showed exfoliation of epithelial cells lining the gland, discontinuity of surface epithelial cells (ulcer formation), vacuolation and detachment of cells, eosinophilic infiltration and congestion of blood vessels in the lamina propria and submucosa. There was thickening and disarrangement of mucosa, weak positive reaction for PAS and marked increase in the collagen fibers lamina propria and the submucosa of the fundus. TEM revealed degeneration of cheif and parietal cells.Marked increase positive reactive of iNOS in all cells of the fundic gland. Group III showed reconstruction of gastric gland with cystic dilatation and vacuolation, moderate decrease of collagen fibers, reduced the intensity of iNOS while in Group IV healthy mucosa with normal surface lining epithelium and fundic glands, strong positive reaction for PAS, marked decrease of collagen fibers and positive reaction for iNOS. TEM revealed regeneration of cheif and parietal cells. Conclusion: Co treatment of copper-albumin complex seems to be useful for gastric ulcer treatment and ameliorates most of hazards of indomethacin.

Keywords: copper complex, gastric ulcer, indomethacin, rat

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Authors: Seyed Reza Aghili, Tahereh Shokohi, Shirin Sadat Hashemi Fesharaki, Mohammad Ali Boroumand, Bahar Salmanian

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Introduction: Intravenous catheter-associated fungal infection as nosocomial infection continue to be a deep problem among hospitalized patients, decreasing quality of life and adding healthcare costs. The capacity of catheters in the spread of candidemia in heart failure patients is obvious. The aim of this study was to evaluate the prevalence and genetic identification of Candida species in heart disorder patients. Material and Methods: This study was conducted in Tehran Hospital of Cardiology Center (Tehran, Iran, 2014) during 1.5 years on the patients hospitalized for at least 7 days and who had central or peripheral vein catheter. Culture of catheters, blood and skin of the location of catheter insertion were applied for detecting Candida colonies in 223 patients. Identification of Candida species was made on the basis of a combination of various phenotypic methods and confirmed by sequencing the ITS1-5.8S-ITS2 region amplified from the genomic DNA using PCR and the NCBI BLAST. Results: Of the 223 patients samples tested, we identified totally 15 Candida isolates obtained from 9 (4.04%) catheter cultures, 3 (1.35%) blood cultures and 2 (0.90%) skin cultures of the catheter insertion areas. On the base of ITS region sequencing, out of nine Candida isolates from catheter, 5(55.6%) C. albicans, 2(22.2%) C. glabrata, 1(11.1%) C. membranifiaciens and 1 (11.1%) C. tropicalis were identified. Among three Candida isolates from blood culture, C. tropicalis, C. carpophila and C. membranifiaciens were identified. Non-candida yeast isolated from one blood culture was Cryptococcus albidus. One case of C. glabrata and one case of Candida albicans were isolated from skin culture of the catheter insertion areas in patients with positive catheter culture. In these patients, ITS region of rDNA sequence showed a similarity between Candida isolated from the skin and catheter. However, the blood samples of these patients were negative for fungal growth. We report two cases of catheter-related candidemia caused by C. membranifiaciens and C. tropicalis on the base of genetic similarity of species isolated from blood and catheter which were treated successfully with intravenous fluconazole and catheter removal. In phenotypic identification methods, we could only identify C. albicans and C. tropicalis and other yeast isolates were diagnosed as Candida sp. Discussion: Although more than 200 species of Candida have been identified, only a few cause diseases in humans. There is some evidence that non-albicans infections are increasing. Many risk factors, including prior antibiotic therapy, use of a central venous catheter, surgery, and parenteral nutrition are considered to be associated with candidemia in hospitalized heart failure patients. Identifying the route of infection in candidemia is difficult. Non-albicans candida as the cause of candidemia is increasing dramatically. By using conventional method, many non-albicans isolates remain unidentified. So, using more sensitive and specific molecular genetic sequencing to clarify the aspects of epidemiology of the unknown candida species infections is essential. The positive blood and catheter cultures for candida isolates and high percentage of similarity of their ITS region of rDNA sequence in these two patients confirmed the diagnosis of intravenous catheter-associated candidemia.

Keywords: catheter-associated infections, heart failure patient, molecular genetic sequencing, ITS region of rDNA, Candidemia

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Authors: Sandy Elsayed, Aya Mohamed, Noha Nassar

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Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behavior. Multiple studies suggest that oxidative stress and neuroinflammation are key factors in the etiology of ASD and often associated with worsening of ASD-related behaviors. Nuclear factor erythroid 2-related factor 2 (NRF-2) is a transcription factor that promotes expression of antioxidant response element genes in oxidative stress. In ASD subjects, decreased expression of NRF-2 in frontal cortex shifted the redox homeostasis towards oxidative stress, and resulted in inflammation evidenced by elevation of nuclear factor kappa B (NF-κB) transcriptional activity. Dimethyl fumarate (DMF) is a NRF-2 activator that is used in the treatment of psoriasis and multiple sclerosis. It participates in the transcriptional control of inflammatory factors via inhibition of NF-κB and its downstream targets. This study aimed to investigate the role of DMF in alleviating the cognitive impairments and behavior deficits associated with ASD through mitigation of oxidative stress and inflammation in prenatal valproic acid (VPA) rat model of autism. Methods: Pregnant female Wistar rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like-behavioral and neurobiological alterations in their offspring. Chronic oral gavage of DMF (150mg/kg/day) started from postnatal day (PND) 24 till PND62 (39 days). Prenatal VPA exposure elicited autistic behaviors including decreased social interaction and stereotyped behavior. Social interaction was evaluated using three-chamber sociability test and calculation of sociability index (SI), while stereotyped repetitive behavior and anxiety associated with ASD were assessed using marble burying test (MBT). Biochemical analyses were done on prefrontal cortex homogenates including NRF-2, and NF-κB expression. Moreover, inducible nitric oxide synthase (iNOS) gene expression and tumor necrosis factor (TNF-) protein expression were evaluated as markers of inflammation. Results: Prenatal VPA elicited decreased social interaction shown by decreased SI compared to control group (p < 0.001) and DMF enhanced SI (p < 0.05). In MBT, prenatal injection of VPA manifested stereotyped behavior and enhanced number of buried marbles compared to control (p < 0.05) and DMF reduced the anxiety-related behavior in rats exhibiting ASD-like behaviors (p < 0.05). In prefrontal cortex, NRF-2 expression was downregulated in prenatal VPA model (p < 0.0001) and DMF reversed this effect (p < 0.0001). The inflammatory transcription factor NF-κB was elevated in prenatal VPA model (p < 0.0001) and reduced (p < 0.0001) upon NRF-2 activation by DMF. Prenatal VPA expressed higher levels of proinflammatory cytokine TNF- compared to control group (p < 0.0001) and DMF reduced it (p < 0.0001). Finally, the gene expression of iNOS was downregulated upon NRF-2 activation by DMF (p < 0.01). Conclusion: This study proposes that DMF is a potential agent that can be used to ameliorate autistic-like-changes through NRF-2 activation along with NF-κB downregulation and therefore, it is a promising novel therapy for ASD.

Keywords: autism spectrum disorders, dimethyl fumarate, neuroinflammation, NRF-2

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Authors: Rishana Bilimoria, Selina Tang, Sajni Shah, Marianne Henien, Christopher Sproat

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Temporomandibular disorders (TMD) may affect up to a third of the general population, and there is evidence demonstrating the majority of Myofascial TMD cases improve after education and conservative measures. In 2015 our department implemented a modified care pathway for myofascial TMD patients in an attempt to improve the patient journey. This involved the use of an interactive group therapy approach to deliver education, reinforce conservative measures and promote self-management. Patient reported experience measures from the new group clinic revealed 71% patient satisfaction. This service is efficient in improving aspects of health status while reducing health-care costs and redistributing clinical time. Since its’ establishment, 52 hours of clinical time, resources and funding have been redirected effectively. This Quality Improvement Project was initiated because it was felt that this new service was being underutilised by our surgical teams. The ‘Plan-Do-Study-Act cycle’ (PDSA) framework was employed to analyse utilisation of the service: The ‘plan’ stage involved outlining our aims: to raise awareness amongst clinicians of the unified care pathway and to increase referral to this clinic. The ‘do’ stage involved collecting data from a sample of 96 patients over 4 month period to ascertain the proportion of Myofascial TMD patients who were correctly referred to the designated clinic. ‘Suitable’ patients who weren’t referred were identified. The ‘Study’ phase involved analysis of results, which revealed that 77% of suitable patients weren’t referred to the designated clinic. They were reviewed on other clinics, which are often overbooked, or managed by junior staff members. This correlated with our original prediction. Barriers to referral included: lack of awareness of the clinic, individual consultant treatment preferences and patient, reluctance to be referred to a ‘group’ clinic. The ‘Act’ stage involved presenting our findings to the team at a clinical governance meeting. This included demonstration of the clinical effectiveness of the care-pathway and explaining the referral route and criteria. In light of the evaluation results, it was decided to keep the group clinic and maximize utilisation. The second cycle of data collection following these changes revealed that of 66 Myofascial TMD patients over a 4 month period, only 9% of suitable patients were not seen via the designated pathway; therefore this QIP was successful in meeting the set objectives. Overall, employing the PDSA cycle in this QIP resulted in appropriate utilisation of the modified care pathway for patients with myofascial TMD in Guy’s Oral Surgery Department. In turn, this leads to high patient satisfaction with the service and effectively redirected 52 hours of clinical time. It permitted adoption of a collaborative working style with oral surgery colleagues to investigate problems, identify solutions, and collectively raise standards of clinical care to ensure we adopt a unified care pathway in secondary care management of Myofascial TMD patients.

Keywords: myofascial, quality Improvement, PDSA, TMD

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Authors: Julia Wimmers Klick

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Interprofessional Education (IPE) is widely recognized as a valuable approach in healthcare education, despite the challenges it presents. This study explores IP surface anatomy lab sessions, with a focus on fostering trust and collaboration among healthcare students. The research is conducted within the context of rural healthcare settings in British Columbia (BC), where a medical school and a physical therapy (PT) program operate under the Faculty of Medicine at the University of British Columbia (UBC). While IPE sessions addressing soft skills have been implemented, the integration of hard skills, such as Anatomy, remains limited. To address this gap, a pilot feasibility study was conducted with a positive outcome, a follow-up study involved these IPE sessions aimed at exploring the influence of bonding and trust between medical and PT students. Data were collected through focus groups comprising participating students and faculty members, and a structured SWOC (Strengths, Weaknesses, Opportunities, and Challenges) analysis was conducted. The IPE sessions, 3 in total, consisted of a 2.5-hour lab on surface anatomy, where PT students took on the teaching role, and medical students were newly exposed to surface anatomy. The focus of the study was on the relationship-building process and trust development between the two student groups, rather than assessing the acquisition of surface anatomy skills. Results indicated that the surface anatomy lab served as a suitable tool for the application and learning of soft skills. Faculty members observed positive outcomes, including productive interaction between students, reversed hierarchy with PT students teaching medical students, practicing active listening skills, and using a mutual language of anatomy. Notably, there was no grade assessment or external pressure to perform. The students also reported an overall positive experience; however, the specific impact on the development of soft skill competencies could not be definitively determined. Participants expressed a sense of feeling respected, welcomed, and included, all of which contributed to feeling safe. Within the small group environment, students experienced becoming a part of a community of healthcare providers that bonded over a shared interest in health professions education. They enjoyed sharing diverse experiences related to learning across their varied contexts, without fear of judgment and reprisal that were often intimidating in single professional contexts. During a joint Christmas party for both cohorts, faculty members observed students mingling, laughing, and forming bonds. This emphasized the importance of early bonding and trust development among healthcare colleagues, particularly in rural settings. In conclusion, the findings emphasize the potential of IPE sessions to enhance trust and collaboration among healthcare students, with implications for their future professional lives in rural settings. Early bonding and trust development are crucial in rural settings, where healthcare professionals often rely on each other. Future research should continue to explore the impact of content-concentrated IPE on the development of soft skill competencies.

Keywords: interprofessional education, rural healthcare settings, trust, surface anatomy

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Authors: Abdou Elhendy

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Numerous study have shown the efficacy of the percutaneous intervention (PCI) and coronary stenting in improving left ventricular function and relieving exertional angina. Furthermore, PCI remains the main line of therapy in acute myocardial infarction. Improvement of procedural techniques and new devices have resulted in an increased number of PCI in those with difficult and extensive lesions, multivessel disease as well as total occlusion. Immediate and late outcome may be compromised by acute thrombosis or the development of fibro-intimal hyperplasia. In addition, progression of coronary artery disease proximal or distal to the stent as well as in non-stented arteries is not uncommon. As a result, complications can occur, such as acute myocardial infarction, worsened heart failure or recurrence of angina. In a stent, restenosis can occur without symptoms or with atypical complaints rendering the clinical diagnosis difficult. Routine invasive angiography is not appropriate as a follow up tool due to associated risk and cost and the limited functional assessment. Exercise and pharmacologic stress testing are increasingly used to evaluate the myocardial function, perfusion and adequacy of revascularization. Information obtained by these techniques provide important clues regarding presence and severity of compromise in myocardial blood flow. Stress echocardiography can be performed in conjunction with exercise or dobutamine infusion. The diagnostic accuracy has been moderate, but the results provide excellent prognostic stratification. Adding myocardial contrast agents can improve imaging quality and allows assessment of both function and perfusion. Stress radionuclide myocardial perfusion imaging is an alternative to evaluate these patients. The extent and severity of wall motion and perfusion abnormalities observed during exercise or pharmacologic stress are predictors of survival and risk of cardiac events. According to current guidelines, stress echocardiography and radionuclide imaging are considered to have appropriate indication among patients after PCI who have cardiac symptoms and those who underwent incomplete revascularization. Stress testing is not recommended in asymptomatic patients, particularly early after revascularization, Coronary CT angiography is increasingly used and provides high sensitive for the diagnosis of coronary artery stenosis. Average sensitivity and specificity for the diagnosis of in stent stenosis in pooled data are 79% and 81%, respectively. Limitations include blooming artifacts and low feasibility in patients with small stents or thick struts. Anatomical and functional cardiac imaging modalities are corner stone for the assessment of patients after PCI and provide salient diagnostic and prognostic information. Current imaging techniques cans serve as gate keeper for coronary angiography, thus limiting the risk of invasive procedures to those who are likely to benefit from subsequent revascularization. The determination of which modality to apply requires careful identification of merits and limitation of each technique as well as the unique characteristic of each individual patient.

Keywords: coronary artery disease, stress testing, cardiac imaging, restenosis

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Authors: Brian Bacia, Esther Githaiga, Teresia Kabucho, Paul Moses Ndegwa, Lucy Gichohi

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Purpose: The aim of the study is to ensure an appropriate mix of evidence-based prevention strategies geared towards the reduction of new HIV infections and the incidence of Sexually transmitted Illnesses Background: In Nakuru County, more than 90% of all HIV-infected patients are adults and on a single-dose medication-one pill that contains a combination of several different HIV drugs. Nakuru town has been identified as the hardest hit by HIV/Aids in the County according to the latest statistics from the County Aids and STI group, with a prevalence rate of 5.7 percent attributed to the high population and an active urban center. Method: 2 key studies were carried out to provide evidence for the effectiveness of antiretroviral therapy (ART) when used optimally on preventing sexual transmission of HIV. Discussions based on an examination, assessments of successes in planning, program implementation, and ultimate impact of prevention and treatment were undertaken involving health managers, health workers, community health workers, and people living with HIV/AIDS between February -August 2021. Questionnaires were carried out by a trained duo on ethical procedures at 15 HIV treatment clinics targeting patients on ARVs and caregivers on ARV prevention and treatment of pediatric HIV infection. Findings: Levels of AIDS awareness are extremely high. Advances in HIV treatment have led to an enhanced understanding of the virus, improved care of patients, and control of the spread of drug-resistant HIV. There has been a tremendous increase in the number of people living with HIV having access to life-long antiretroviral drugs (ARV), mostly on generic medicines. Healthcare facilities providing treatment are stressed challenging the administration of the drugs, which require a clinical setting. Women find it difficult to take a daily pill which reduces the effectiveness of the medicine. ART adherence can be strengthened largely through the use of innovative digital technology. The case management approach is useful in resource-limited settings. The county has made tremendous progress in mother-to-child transmission reduction through enhanced early antenatal care (ANC) attendance and mapping of pregnant women Recommendations: Treatment reduces the risk of transmission to the child during pregnancy, labor, and delivery. Promote research of medicines through patients and community engagement. Reduce the risk of transmission through breastfeeding. Enhance testing strategies and strengthen health systems for sustainable HIV service delivery. Need exists for improved antenatal care and delivery by skilled birth attendants. Develop a comprehensive maternal reproductive health policy covering equitability, efficient and effective delivery of services. Put in place referral systems.

Keywords: evidence-based prevention strategies, service delivery, human management, integrated approach

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Authors: G. Cunningham, E. Cantor, X. Wu, F. Shen, G. Jiang, S. Philips, C. Bales, Y. Xiao, T. R. Cummins, J. C. Fehrenbacher, B. P. Schneider

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Background: Taxane-induced peripheral neuropathy (TIPN) is the most devastating survivorship issue for patients receiving therapy. Dose reductions due to TIPN in the curative setting lead to inferior outcomes for African American patients, as prior research has shown that this group is more susceptible to developing severe neuropathy. The mechanistic underpinnings of TIPN, however, have not been entirely elucidated. While it would be appealing to use primary tissue to study the development of TIPN, procuring nerves from patients is not realistically feasible, as nerve biopsies are painful and may result in permanent damage. Therefore, our laboratory has investigated paclitaxel-induced neuronal morphological and molecular changes using an ex vivo model of human-induced pluripotent stem cell (iPSC)-derived neurons. Methods: iPSCs are undifferentiated and endlessly dividing cells that can be generated from a patient’s somatic cells, such as peripheral blood mononuclear cells (PBMCs). We successfully reprogrammed PBMCs into iPSCs using the Erythroid Progenitor Reprograming Kit (STEMCell Technologiesᵀᴹ); pluripotency was verified by flow cytometry analysis. iPSCs were then induced into neurons using a differentiation protocol that bypasses the neural progenitor stage and uses selected small-molecule modulators of key signaling pathways (SMAD, Notch, FGFR1 inhibition, and Wnt activation). Results: Flow cytometry analysis revealed expression of core pluripotency transcription factors Nanog, Oct3/4 and Sox2 in iPSCs overlaps with commercially purchased pluripotent cell line UCSD064i-20-2. Trilineage differentiation of iPSCs was confirmed with immunofluorescent imaging with germ-layer-specific markers; Sox17 and ExoA2 for ectoderm, Nestin, and Pax6 for mesoderm, and Ncam and Brachyury for endoderm. Sensory neuron markers, β-III tubulin, and Peripherin were applied to stain the cells for the maturity of iPSC-derived neurons. Patch-clamp electrophysiology and calcitonin gene-related peptide (CGRP) release data supported the functionality of the induced neurons and provided insight into the timing for which downstream assays could be performed (week 4 post-induction). We have also performed a cell viability assay and fluorescence-activated cell sorting (FACS) using four cell-surface markers (CD184, CD44, CD15, and CD24) to select a neuronal population. At least 70% of the cells were viable in the isolated neuron population. Conclusion: We have found that these iPSC-derived neurons recapitulate mature neuronal phenotypes and demonstrate functionality. Thus, this represents a patient-derived ex vivo neuronal model to investigate the molecular mechanisms of clinical TIPN.

Keywords: chemotherapy, iPSC-derived neurons, peripheral neuropathy, taxane, paclitaxel

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Authors: Ifeoma Anozie, Teka Apalata, Dominic Abaver

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Introduction: Despite use of Anti-retroviral therapy to reduce the incidence of opportunistic infections among HIV/AIDS patients, rapid episodes of re-infection after deworming are still common occurrences because pharmaceutical intervention alone does not prevent reinfection. Unsafe water and inadequate personal hygiene and parasitic infections are widely expected to accelerate the progression of HIV infection. This is because the chronic immunosuppression of HIV infection encourages susceptibility to opportunistic (including parasitic) infections which is linked to CD4+ cell count of <200 cells/μl. Intestinal parasites such as G. intestinalis and Entamoeba spp are ubiquitous protozoa that remain infectious over a long time in an environment and show resistance to standard disinfection. To control re-infection, the social factors that underpin the prevention need to be controlled. This study aims at prevention of intestinal parasites in people living with HIV/AIDS by using a treatment, hygiene education and sanitation (THEdS) bundle approach. Methods: This study was conducted in four clinics (Ngangelizwe health centre, Tsolo gateway clinic, Idutywa health centre and Nqamakwe health centre) across the seven districts in Eastern cape, South Africa. The four clinics were divided in two: experimental and control, for the purpose of intervention. Data was collected from March 2019 to February 2020. Six hundred participants were screened for intestinal parasitic infections. Stool samples were collected and analysed twice: before (Pre-test infection screening) and after (Post-test re-infection) THEdS bundle intervention. The experimental clinics received full intervention package, which include therapeutic treatment, health education on personal hygiene and sanitation training, while the control clinics received only therapeutic treatment for those found with intestinal parasitic infections. Results: Baseline prevalence of Intestinal Parasites isolated shows 12 intestinal parasites with overall frequency of 65, with Ascaris lumbricoides having most frequency (44.6%). The intervention had a cure rate of 60%, with odd ratio of 1.42, which indicates that the intervention group is 1.42 times more likely of parasite clearing as compared to the control group. The relative risk ratio of 1.17 signifies that there is 1.17 times more likelihood to clear intestinal parasite if there no intervention. Discussion and conclusion: Infection with multiple parasites can cause health defects, especially among HIV/AIDS patients. Efficiency of some HIV vaccines in HIV/AIDS patients is affected because treatment of re-infection amplifies drug resistance, affects the efficacy of the front-line drugs, and still permits transmission. In South Africa, treatment of intestinal parasites is usually offered to clinic attending HIV/AIDS patients upon suspicion but not as a mandate for patients being initiated into Antiretroviral (ART) program. The effectiveness of THEdS bundle advocates for inclusiveness of mandatory screening for intestinal parasitic infections among attendees of HIV/Aids clinics on regular basis.

Keywords: cure rate, , HIV/AIDS patients, intestinal parasites, intervention studies, reinfection rate

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Authors: Esther Friedlander, Philip Friedlander

Abstract:

The use of immunotherapy that inhibits programmed death-1 (PD-1) or its ligand PD-L1 confers survival benefits in patients with non-small cell lung cancer (NSCLC). However, approximately 45% of patients experience primary treatment resistance, necessitating the development of strategies to improve efficacy. While the renin-angiotensin system (RAS) has systemic hemodynamic effects, tissue-specific regulation exists along with modulation of immune activity in part through regulation of myeloid cell activity, leading to the hypothesis that RAS inhibition may improve anti-PD-1/L-1 efficacy. A retrospective analysis was conducted that included 173 advanced solid tumor cancer patients treated at Valley Hospital, a community Hospital in New Jersey, USA, who were treated with a PD-1/L-1 inhibitor in a defined time period showing a statistically significant relationship between RAS pathway inhibition (RASi through concomitant treatment with an ACE inhibitor or angiotensin receptor blocker) and positive efficacy to the immunotherapy that was independent of age, gender and cancer type. Subset analysis revealed strong numerical benefit for efficacy in both patients with squamous and nonsquamous NSCLC as determined by documented clinician assessment of efficacy and by duration of therapy. A PUBMED literature search was now conducted to identify studies assessing the effect of RAS pathway inhibition on anti-PD-1/L1 efficacy in advanced solid tumor patients and compare these findings to those seen in the Valley Hospital retrospective study with a focus on NSCLC specifically. A total of 11 articles were identified assessing the effects of RAS pathway inhibition on the efficacy of checkpoint inhibitor immunotherapy in advanced cancer patients. Of the 11 studies, 10 assessed the effect on survival of RASi in the context of treatment with anti-PD-1/PD-L1, while one assessed the effect on CTLA-4 inhibition. Eight of the studies included patients with NSCLC, while the remaining 2 were specific to genitourinary malignancies. Of the 8 studies, two were specific to NSCLC patients, with the remaining 6 studies including a range of cancer types, of which NSCLC was one. Of these 6 studies, only 2 reported specific survival data for the NSCLC subpopulation. Patient characteristics, multivariate analysis data and efficacy data seen in the 2 NSLCLC specific studies and in the 2 basket studies, which provided data on the NSCLC subpopulation, were compared to that seen in the Valley Hospital retrospective study supporting a broader effect of RASi on anti-PD-1/L1 efficacy in advanced NSLCLC with the majority of studies showing statistically significant benefit or strong statistical trends but with one study demonstrating worsened outcomes. This comparison of studies extends published findings to the community hospital setting and supports prospective assessment through randomized clinical trials of efficacy in NSCLC patients with pharmacodynamic components to determine the effect on immune cell activity in tumors and on the composition of the tumor microenvironment.

Keywords: immunotherapy, cancer, angiotensin, efficacy, PD-1, lung cancer, NSCLC

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Authors: Arsyam Mawardi, Sony Suhandono, Azzania Fibriani, Fifi Fitriyah Masduki

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Malaria is an infectious disease caused by Plasmodium sp. This disease has a high prevalence in Indonesia, especially in Jayapura. The vaccine that is currently being developed has not been effective in overcoming malaria. This is due to the high polymorphism in the Plasmodium genome especially in areas that encode Plasmodium surface proteins. Merozoite Surface Protein 1 (MSP1) Plasmodium falciparum is a surface protein that plays a role in the invasion process in human erythrocytes through the interaction of Glycophorin A protein receptors and sialic acid in erythrocytes with Reticulocyte Binding Proteins (RBP) and Duffy Adhesion Protein (DAP) ligands in merozoites. MSP1 can be targeted to be a specific antigen and predicted epitope area which will be used for the development of diagnostic and malaria vaccine therapy. MSP1 consists of 17 blocks, each block is dimorphic, and has been marked as the K1 and MAD20 alleles. Exceptions only in block 2, because it has 3 alleles, among others K1, MAD20 and RO33. These polymorphisms cause allelic variations and implicate the severity of patients infected P. falciparum. In addition, polymorphism of MSP1 in Jayapura isolates has not been reported so it is interesting to be further identified and projected as a specific antigen. Therefore, in this study, we analyzed the allele polymorphism as well as detected the MSP1 epitope antigen candidate on block 2 P. falciparum. Clinical samples of selected malaria patients followed the consecutive sampling method, examining malaria parasites with blood preparations on glass objects observed through a microscope. Plasmodium DNA was isolated from the blood of malarial positive patients. The block 2 MSP1 gene was amplified using PCR method and cloned using the pGEM-T easy vector then transformed to TOP'10 E.coli. Positive colonies selection was performed with blue-white screening. The existence of target DNA was confirmed by PCR colonies and DNA sequencing methods. Furthermore, DNA sequence analysis was done through alignment and formation of a phylogenetic tree using MEGA 6 software and insilico analysis using IEDB software to predict epitope candidate for P. falciparum. A total of 15 patient samples have been isolated from Plasmodium DNA. PCR amplification results show the target gene size about ± 1049 bp. The results of MSP1 nucleotide alignment analysis reveal that block 2 MSP1 genes derived from the sample of malarial patients were distributed in four different allele family groups, K1 (7), MAD20 (1), RO33 (0) and MSP1_Jayapura (10) alleles. The most commonly appears of the detected allele is MSP1_Jayapura single allele. There was no significant association between sex variables, age, the density of parasitemia and alel variation (Mann Whitney, U > 0.05), while symptomatic signs have a significant difference as a trigger of detectable allele variation (U < 0.05). In this research, insilico study shows that there is a new epitope antigen candidate from the MSP1_Jayapura allele and it is predicted to be recognized by B cells with 17 amino acid lengths in the amino acid sequence 187 to 203.

Keywords: epitope candidate, insilico analysis, MSP1 P. falciparum, polymorphism

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Authors: Sahar Nasr, Lin Li, Edwin Wang

Abstract:

Bladder cancer (BLCA) is known as the 13th cause of death among cancer patients worldwide, and ~575,000 new BLCA cases are diagnosed each year. Urothelial carcinoma (UC) is the most prevalent subtype among BLCA patients, which can be categorized into muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Currently, various therapeutic options are available for UC patients, including (1) transurethral resection followed by intravesical instillation of chemotherapeutics or Bacillus Calmette-Guérin for NMIBC patients, (2) neoadjuvant platinum-based chemotherapy (NAC) plus radical cystectomy is the standard of care for localized MIBC patients, and (3) systematic chemotherapy for metastatic UC. However, conventional treatments may lead to several challenges for treating patients. As an illustration, some patients may suffer from recurrence of the disease after the first line of treatment. Recently, immune checkpoint therapy (ICT) has been introduced as an alternative treatment strategy for the first or second line of treatment in advanced or metastatic BLCA patients. Although ICT showed lucrative results for a fraction of BLCA patients, ~80% of patients were not responsive to it. Therefore, novel treatment methods are required to augment the ICI response rate within BLCA patients. It has been shown that the infiltration of T-cells into the tumor microenvironment (TME) is positively correlated with the response to ICT within cancerous patients. Therefore, the goal of this study is to enhance the infiltration of cytotoxic T-cells into TME through the identification of target genes within the tumor that are responsible for the non-T-cell inflamed TME and their inhibition. BLCA bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and immune score for TCGA samples were used to determine the Pearson correlation score between the expression of different genes and immune score for each sample. The genes with strong negative correlations were selected (r < -0.2). Thereafter, the correlation between the expression of each gene and survival in BLCA patients was calculated using the TCGA data and Cox regression method. The genes that are common in both selected gene lists were chosen for further analysis. Afterward, BLCA bulk and single-cell RNA-sequencing data were ranked based on the expression of each selected gene and the top and bottom 25% samples were used for pathway enrichment analysis. If the pathways related to the T-cell infiltration (e.g., antigen presentation, interferon, or chemokine pathways) were enriched within the low-expression group, the gene was included for downstream analysis. Finally, the selected genes will be used to calculate the correlation between their expression and the infiltration rate of the activated CD+8 T-cells, natural killer cells and the activated dendric cells. A list of potential target genes has been identified and ranked based on the above-mentioned analysis and criteria. SUN-1 got the highest score within the gene list and other identified genes in the literature as benchmarks. In conclusion, inhibition of SUN1 may increase the tumor-infiltrating lymphocytes and the efficacy of ICI in BLCA patients. BLCA tumor cells with and without SUN-1 CRISPR/Cas9 knockout will be injected into the syngeneic mouse model to validate the predicted SUN-1 effect on increasing tumor-infiltrating lymphocytes.

Keywords: data analysis, gene expression analysis, gene identification, immunoinformatic, functional genomics, transcriptomics

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Authors: Niklas Ravn-Boess, Nainita Bhowmick, Takamitsu Hattori, Shohei Koide, Christopher Park, Dimitris Placantonakis

Abstract:

Background: Glioblastoma (GBM) is the most common and deadly primary brain malignancy in adults. Tumor propagation, brain invasion, and resistance to therapy critically depend on GBM stem-like cells (GSCs); however, the mechanisms that regulate GSC self-renewal are incompletely understood. Given the aggressiveness and poor prognosis of GBM, it is imperative to find biomarkers that could also translate into novel drug targets. Along these lines, we have identified a cell surface antigen, CD97 (ADGRE5), an adhesion G protein-coupled receptor (GPCR), that is expressed on GBM cells but is absent from non-neoplastic brain tissue. CD97 has been shown to promote invasiveness, angiogenesis, and migration in several human cancers, but its frequency of expression and functional role in regulating GBM growth and survival, and its potential as a therapeutic target has not been investigated. Design: We assessed CD97 mRNA and protein expression in patient derived GBM samples and cell lines using publicly available RNA-sequencing datasets and flow cytometry, respectively. To assess CD97 function, we generated shRNA lentiviral constructs that target a sequence in the CD97 extracellular domain (ECD). A scrambled shRNA (scr) with no predicted targets in the genome was used as a control. We evaluated CD97 shRNA lentivirally transduced GBM cells for Ki67, Annexin V, and DAPI. We also tested CD97 KD cells for their ability to self-renew using clonogenic tumorsphere formation assays. Further, we utilized synthetic Abs (sAbs) generated against the ECD of CD97 to test for potential antitumor effects using patient-derived GBM cell lines. Results: CD97 mRNA expression was expressed at high levels in all GBM samples available in the TCGA cohort. We found high levels of surface CD97 protein expression in 6/6 patient-derived GBM cell cultures, but not human neural stem cells. Flow cytometry confirmed downregulation of CD97 in CD97 shRNA lentivirally transduced cells. CD97 KD induced a significant reduction in cell growth in 3 independent GBM cell lines representing mesenchymal and proneural subtypes, which was accompanied by reduced (~20%) Ki67 staining and increased (~30%) apoptosis. Incubation of GBM cells with sAbs (20 ug/ ml) against the ECD of CD97 for 3 days induced GSC differentiation, as determined by the expression of GFAP and Tubulin. Using three unique GBM patient derived cultures, we found that CD97 KD attenuated the ability of GBM cells to initiate sphere formation by over 300 fold, consistent with an impairment in GSC self-renewal. Conclusion: Loss of CD97 expression in patient-derived GBM cells markedly decreases proliferation, induces cell death, and reduces tumorsphere formation. sAbs against the ECD of CD97 reduce tumorsphere formation, recapitulating the phenotype of CD97 KD, suggesting that sAbs that inhibit CD97 function exhibit anti-tumor activity. Collectively, these findings indicate that CD97 is necessary for the proliferation and survival of human GBM cells and identify CD97 as a promising therapeutically targetable vulnerability in GBM.

Keywords: adhesion GPCR, CD97, GBM stem cell, glioblastoma

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Authors: Lacramioara Ochiuz, Manuela Hortolomei, Aurelia Vasile, Iulian Stoleriu, Marcel Popa, Cristian Peptu

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Local antibiotherapy is one of the most effective acne therapies. Erythromycin (ER) is a macrolide antibiotic topically administered for over 30 years in the form of gel, ointment or hydroalcoholic solution for the acne therapy. The use of ER as a base for topical dosage forms raises some technological challenges due to the physicochemical properties of this substance. The main disadvantage of ER is the poor water solubility (2 mg/mL) that limits both formulation using hydrophilic bases and skin permeability. Cyclodextrins (CDs) are biocompatible cyclic oligomers of glucose, with hydrophobic core and hydrophilic exterior. CDs are used to improve the bioavailability of drugs by increasing their solubility and/or their rate of dissolution after including the poorly water soluble substances (such as ER) in the hydrophobic cavity of CDs. Adding CDs leads to the increase of solubility and improved stability of the drug substance, increased permeability of substances of low water solubility, decreased toxicity and even to active dose reduction as a result of increased bioavailability. CDs increase skin tolerability by reducing the irritant effect of certain substances. We have included ER to lactide modified β-cyclodextrin, in order to improve the therapeutic effect of topically administered ER. The aims of the present study were to synthesise and describe a new complex with prolonged release of ER with lactide modified β-cyclodextrin (CD-LA_E), to investigate the CD-LA_E complex by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR), to analyse the effect of semisolid base on the in vitro and ex vivo release characteristics of ER in the CD-LA_E complex by assessing the permeability coefficient and the release kinetics by fitting on mathematical models. SEM showed that, by complexation, ER changes its crystal structure and enters the amorphous phase. FTIR analysis has shown that certain specific bands of some groups in the ER structure move during the incapsulation process. The structure of the CD-LA_E complex has a molar ratio of 2.12 to 1 between lactide modified β-cyclodextrin and ER. The three semisolid bases (2% Carbopol, 13% Lutrol 127 and organogel based on Lutrol and isopropyl myristate) show a good capacity for incorporating the CD-LA_E complex, having a content of active ingredient ranging from 98.3% to 101.5% as compared to the declared value of 2% ER. The results of the in vitro dissolution test showed that the ER solubility was significantly increased by CDs incapsulation. The amount of ER released from the CD-LA_E gels was in the range of 76.23% to 89.01%, whereas gels based on ER released a maximum percentage of 26.01% ER. The ex vivo dissolution test confirms the increased ER solubility achieved by complexation, and supports the assumption that the use of this process might increase ER permeability. The highest permeability coefficient was obtained in ER released from gel based on 2% Carbopol: in vitro 33.33 μg/cm2/h, and ex vivo 26.82 μg/cm2/h, respectively. The release kinetics of complexed ER is performed by Fickian diffusion, according to the results obtained by fitting the data in the Korsmeyer-Peppas model.

Keywords: erythromycin, acne, lactide, cyclodextrin

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Authors: Natalia C. E. S. Nascimento, Mercia L. Oliveira, Fernando R. A. Lima, Leonardo T. C. do Nascimento, Marina B. Silveira, Brigida G. A. Schirmer, Andrea V. Ferreira, Carlos Malamut, Juliana B. da Silva

Abstract:

Tissue hypoxia is a common characteristic of solid tumors leading to decreased sensitivity to radiotherapy and chemotherapy. In the clinical context, tumor hypoxia assessment employing the positron emission tomography (PET) tracer ¹⁸F-fluoromisonidazole ([¹⁸F]FMISO) is helpful for physicians for planning and therapy adjusting. The aim of this work was to implement the synthesis of 18F-FMISO in a TRACERlab® MXFDG module and also to establish the quality control procedure. [¹⁸F]FMISO was synthesized at Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN/Brazil) using an automated synthesizer (TRACERlab® MXFDG, GE) adapted for the production of [¹⁸F]FMISO. The FMISO chemical standard was purchased from ABX. 18O- enriched water was acquired from Center of Molecular Research. Reagent kits containing eluent solution, acetonitrile, ethanol, 2.0 M HCl solution, buffer solution, water for injections and [¹⁸F]FMISO precursor (dissolved in 2 ml acetonitrile) were purchased from ABX. The [¹⁸F]FMISO samples were purified by Solid Phase Extraction method. The quality requirements of [¹⁸F]FMISO are established in the European Pharmacopeia. According to that reference, quality control of [¹⁸F]FMISO should include appearance, pH, radionuclidic identity and purity, radiochemical identity and purity, chemical purity, residual solvents, bacterial endotoxins, and sterility. The duration of the synthesis process was 53 min, with radiochemical yield of (37.00 ± 0.01) % and the specific activity was more than 70 GBq/µmol. The syntheses were reproducible and showed satisfactory results. In relation to the quality control analysis, the samples were clear and colorless at pH 6.0. The spectrum emission, measured by using a High-Purity Germanium Detector (HPGe), presented a single peak at 511 keV and the half-life, determined by the decay method in an activimeter, was (111.0 ± 0.5) min, indicating no presence of radioactive contaminants, besides the desirable radionuclide (¹⁸F). The samples showed concentration of tetrabutylammonium (TBA) < 50μg/mL, assessed by visual comparison to TBA standard applied in the same thin layer chromatographic plate. Radiochemical purity was determined by high performance liquid chromatography (HPLC) and the results were 100%. Regarding the residual solvents tested, ethanol and acetonitrile presented concentration lower than 10% and 0.04%, respectively. Healthy female mice were injected via lateral tail vein with [¹⁸F]FMISO, microPET imaging studies (15 min) were performed after 2 h post injection (p.i), and the biodistribution was analyzed in five-time points (30, 60, 90, 120 and 180 min) after injection. Subsequently, organs/tissues were assayed for radioactivity with a gamma counter. All parameters of quality control test were in agreement to quality criteria confirming that [¹⁸F]FMISO was suitable for use in non-clinical and clinical trials, following the legal requirements for the production of new radiopharmaceuticals in Brazil.

Keywords: automatic radiosynthesis, hypoxic tumors, pharmacopeia, positron emitters, quality requirements

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Authors: Li Jiuen Ong, Magdalin Cheong, Sri Rahayu, Lek Alexander, Pei Ting Tan

Abstract:

Background: Previous programme evaluations from the diabetes training programme conducted in Changi General Hospital revealed that healthcare professionals (HCPs) are keen to receive advance diabetes training and education, specifically in medical, nutritional therapy. HCPs also expressed a preference for interactive activities over didactic teaching methods to enhance their learning. Since the War on Diabetes was initiated by MOH in 2016, HCPs are challenged to be actively involved in continuous education to be better equipped to reduce the growing burden of diabetes. Hence, streamlining training to incorporate an element of fun is of utmost importance. Aim: The nutrition programme incorporates game play using an interactive board game that aims to provide a more conducive and less stressful environment for learning. The board game could be adapted for training of community HCPs, health ambassadors or caregivers to cope with the increasing demand of diabetes care in the hospital and community setting. Methodology: Stages for game’s conception (Jaffe, 2001) were adopted in the development of the interactive board game ‘Sweet Score™ ’ Nutrition concepts and topics in diabetes self-management are embedded into the game elements of varying levels of difficulty (‘Easy,’ ‘Medium,’ ‘Hard’) including activities such as a) Drawing/ sculpting (Pictionary-like) b)Facts/ Knowledge (MCQs/ True or False) Word definition) c) Performing/ Charades To study the effects of game play on knowledge acquisition and perceived experiences, participants were randomised into two groups, i.e., lecture group (control) and game group (intervention), to test the difference. Results: Participants in both groups (control group, n= 14; intervention group, n= 13) attempted a pre and post workshop quiz to assess the effectiveness of knowledge acquisition. The scores were analysed using paired T-test. There was an improvement of quiz scores after attending the game play (mean difference: 4.3, SD: 2.0, P<0.001) and the lecture (mean difference: 3.4, SD: 2.1, P<0.001). However, there was no significance difference in the improvement of quiz scores between gameplay and lecture (mean difference: 0.9, 95%CI: -0.8 to 2.5, P=0.280). This suggests that gameplay may be as effective as a lecture in terms of knowledge transfer. All the13 HCPs who participated in the game rated 4 out of 5 on the likert scale for the favourable learning experience and relevance of learning to their job, whereas only 8 out of 14 HCPs in the lecture reported a high rating in both aspects. 16. Conclusion: There is no known board game currently designed for diabetes training for HCPs.Evaluative data from future training can provide insights and direction to improve the game format and cover other aspects of diabetes management such as self-care, exercise, medications and insulin management. Further testing of the board game to ensure learning objectives are met is important and can assist in the development of awell-designed digital game as an alternative training approach during the COVID-19 pandemic. Learning through gameplay increases opportunities for HCPs to bond, interact and learn through games in a relaxed social setting and potentially brings more joy to the workplace.

Keywords: active learning, game, diabetes, nutrition

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Authors: Xu Qian

Abstract:

This abstract examines the concept of resilience in adolescents from both adolescent medicine and child psychology perspectives. It discusses the role of healthcare providers in fostering resilience among adolescents, encompassing physical, psychological, and social aspects. The paper highlights evidence-based interventions and practical strategies for promoting resilience in this population. Introduction: Resilience plays a crucial role in the healthy development of adolescents, enabling them to navigate through the challenges of this transitional period. This abstract explores the concept of resilience from the perspectives of adolescent medicine and child psychology, shedding light on the collective efforts of healthcare providers in fostering resilience. By integrating the principles and practices of these two disciplines, this abstract emphasizes the multidimensional nature of resilience and its significance in the overall well-being of adolescents. Methods: A comprehensive literature review was conducted, encompassing research articles, empirical studies, and expert opinions from both adolescent medicine and child psychology fields. The search included databases such as PubMed, PsycINFO, and Google Scholar, focusing on publications from the past decade. The review aimed to identify evidence-based interventions and practical strategies employed by healthcare providers to promote resilience among adolescents. Results: The review revealed several key findings regarding the promotion of resilience in adolescents. Firstly, resilience is a dynamic process influenced by individual characteristics, environmental factors, and the interaction between the two. Secondly, healthcare providers play a critical role in fostering resilience by addressing the physical, psychological, and social needs of adolescents. This entails comprehensive healthcare services that integrate medical care, mental health support, and social interventions. Thirdly, evidence-based interventions such as cognitive-behavioral therapy, social skills training, and positive youth development programs have shown promising outcomes in enhancing resilience. Discussion: The integration of adolescent medicine and child psychology perspectives provides a comprehensive framework for promoting resilience in adolescents. By acknowledging the interplay between physical health, psychological well-being, and social functioning, healthcare providers can tailor interventions to address the specific needs and challenges faced by adolescents. Collaborative efforts between medical professionals, psychologists, educators, and families are vital in creating a supportive environment that fosters resilience. Additionally, the findings highlight the importance of early identification and intervention, emphasizing the need for routine screening and assessment to identify adolescents at risk and provide timely support. Conclusion: Promoting resilience in adolescents requires a holistic approach that integrates adolescent medicine and child psychology perspectives. By recognizing the multifaceted nature of resilience, healthcare providers can implement evidence-based interventions and practical strategies to enhance the well-being of adolescents. The collaboration between healthcare professionals from different disciplines, alongside the involvement of families and communities, is crucial for creating a resilient support system. By investing in the promotion of resilience during adolescence, we can empower young individuals to overcome adversity and thrive in their journey toward adulthood.

Keywords: psychology, clinical psychology, child psychology, adolescent psychology, adolescent

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Authors: Farrah Putri Salmanida, Mei-Li Wu, Rika Wahyuningtyas, Wen-Bin Chung, Hso-Chi Chaung, Ko-Tung Chang

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Within the field of immunotherapy, oncolytic virotherapy (OVT) employs dual approaches that directly eliminate tumor cells while preserving healthy ones and indirectly reprogram the tumor microenvironment (TME) to elicit antitumor responses. Within the TME, tumor associated macrophages (TAMs) manifest characteristics akin to those of anti-inflammatory M2 macrophages, thus earning the designation of M2-like TAMs. In prior research, two antigens denoted as A1 (g6Ld10T) and A3 (ORF6L5), derived from a complete sequence of ORF5 with partial sequence of ORF6 in Porcine Reproductive and Respiratory Syndrome Virus Genotype 2 (PRRSV-2), demonstrated the capacity to repolarize M2-type porcine alveolar macrophages (PAMs) into M1 phenotypes. In this study, we sought for utilizing OVT strategies by introducing A1 or A3 on TAMs to endow them with the anti-tumor traits of M1 macrophages while retaining their capacity to target cancer cells. Upon exposing human THP-1-derived M2 macrophages to a cross-species test with 2 µg/ml of either A1 or A3 for 24 hours, real time PCR revealed that A3, but not A1, treated cells exhibited upregulated gene expressions of M1 markers (CCR7, IL-1ß, CCL2, Cox2, CD80). These cells reacted to virus-derived antigen, as evidenced by increased expression of pattern-recognition receptors TLR3, TLR7, and TLR9, subsequently providing feedback in the form of type I interferon responses like IFNAR1, IFN-ß, IRF3, IRF7, OAS1, Mx1, and ISG15. Through an MTT assay, only after 15 µg/ml of A3 treatment could the cell viability decrease, with a predicted IC50 of 16.96 µg/ml. Interestingly, A3 caused dose-dependent toxicity to a rat C6 glial cancer cell line even at doses as low as 2.5 µg/ml and reached its IC50 at 9.419 µg/ml. Using Annexin V/7AAD staining and PCR test, we deduced that a significant proportion of C6 cells were undergoing the early apoptosis phase predominantly through the intrinsic apoptosis cascade involving Bcl-2 family proteins. Following this stage, we conducted a test on A3’s repolarization ability, which revealed a significant rise in M1 gene expression markers, such as TNF, CD80, and IL-1ß, in M2-like TAMs generated in vitro from murine RAW264.7 macrophages grown with conditioned medium of 4T1 breast cancer cells. This was corroborated by the results of transcriptome analysis, which revealed that the primary subset among the top 10 to top 30 significantly upregulated differentially expressed genes (DEGs) dominantly consisted of M1 macrophages profiles, including Ccl3, Ccl4, Csf3, TNF, Bcl6b, Stc1, and Dusp2. Our findings unveiled the remarkable potential of the PRRSV-derived antigen A3 to repolarize macrophages while also being capable of selectively inducing apoptosis in cancerous cells. While further in vivo study is needed for A3, it holds promise as an adjuvant by its dual effects in cancer therapy modalities.

Keywords: cancer cell apoptosis, interferon responses, macrophage repolarization, recombinant protein

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Authors: Rafia S. Al-lamki, Jun Wang, Simon Pacey, Jordan Pober, John R. Bradley

Abstract:

Tumor necrosis factor alpha (TNF), signaling through TNFR2, may act an autocrine growth factor for renal tubular epithelial cells. Clear cell renal carcinomas (ccRCC) contain cancer stem cells (CSCs) that give rise to progeny which form the bulk of the tumor. CSCs are rarely in cell cycle and, as non-proliferating cells, resist most chemotherapeutic agents. Thus, recurrence after chemotherapy may result from the survival of CSCs. Therapeutic targeting of both CSCs and the more differentiated bulk tumor populations may provide a more effective strategy for treatment of RCC. In this study, we hypothesized that TNFR2 signaling will induce CSCs in ccRCC to enter cell cycle so that treatment with ligands that engage TNFR2 will render CSCs susceptible to chemotherapy. To test this hypothesis, we have utilized wild-type TNF (wtTNF) or specific muteins selective for TNFR1 (R1TNF) or TNFR2 (R2TNF) to treat either short-term organ cultures of ccRCC and adjacent normal kidney (NK) tissue or cultures of CD133+ cells isolated from ccRCC and adjacent NK, hereafter referred to as stem cell-like cells (SCLCs). The effect of cyclophosphamide (CP), currently an effective anticancer agent, was tested on CD133+SCLCs from ccRCC and NK before and after R2TNF treatment. Responses to TNF were assessed by flow cytometry (FACS), immunofluorescence, and quantitative real-time PCR, TUNEL, and cell viability assays. Cytotoxic effect of CP was analyzed by Annexin V and propidium iodide staining with FACS. In addition, we assessed the effect of TNF on isolated SCLCs differentiation using a three-dimensional (3D) culture system. Clinical samples of ccRCC contain a greater number SCLCs compared to NK and the number of SCSC increases with higher tumor grade. Isolated SCLCs show expression of stemness markers (oct4, Nanog, Sox2, Lin28) but not differentiation markers (cytokeratin, CD31, CD45, and EpCAM). In ccRCC organ cultures, wtTNF and R2TNF increase CD133 and TNFR2 expression and promote cell cycle entry whereas wtTNF and R1TNF increase TNFR1 expression and promote cell death of SCLCs. Similar findings are observed in SCLCs isolated from NK but the effect was greater in SCLCs isolated from ccRCC. Application of CP distinctly triggered apoptotic and necrotic cell death in SLCSs pre-treatment with R2TNF as compared to CP treatment alone, with SCLCs from ccRCC more sensitive to CP compared to SLCS from NK. Furthermore, TNF promotes differentiation of SCLCs to an epithelial phenotype in 3D cultures, confirmed by cytokeratin expression and loss of stemness markers Nanog and Sox2. The differentiated cells show positive expression of TNF and TNFR2. These findings provide evidence that selective engagement of TNFR2 drive CSCs to cell proliferation/differentiation, and targeting of cycling cells with TNFR2 agonist in combination with anti-cancer agents may be a potential therapy for RCC.

Keywords: cancer stem cells, ccRCC, cell cycle, cell death, TNF, TNFR1, TNFR2, CD133

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Authors: Alok Bapatla, Pamela Lutting, Mariastella Serrano

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Background: Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain associated with altered bowel habits in the absence of an underlying organic cause. Although the exact etiology of IBS is not fully understood, one of the leading theories postulates a pathology within the Brain-Gut Axis that leads to an overall increase in gastrointestinal sensitivity and pejorative changes in gastrointestinal motility. Research and clinical practice have shown that Gut Directed Hypnotherapy (GDH) has a beneficial clinical role in improving Mind-Gut control and thereby comorbid conditions such as anxiety, abdominal pain, constipation, and diarrhea. Aims: This study presents a 17-year old male with underlying anxiety and a one-year history of IBS-Constipation Predominant Subtype (IBS-C), who has demonstrated impressive improvement of symptoms following GDH treatment following refractory trials with medications including bisacodyl, senna, docusate, magnesium citrate, lubiprostone, linaclotide. Method: The patient was referred to a licensed clinical psychologist specializing in clinical hypnosis and cognitive-behavioral therapy (CBT), who implemented “The Standardized Hypnosis Protocol for IBS” developed by Dr. Olafur S. Palsson, Psy.D at the University of North Carolina at Chapel Hill. The hypnotherapy protocol consisted of a total of seven weekly 45-minute sessions supplemented with a 20-minute audio recording to be listened to once daily. Outcome variables included the GAD-7, PHQ-9 and DCI-2, as well as self-ratings (ranging 0-10) for pain (intensity and frequency), emotional distress about IBS symptoms, and overall emotional distress. All variables were measured at intake prior to administration of the hypnosis protocol and at the conclusion of the hypnosis treatment. A retrospective IBS Questionnaire (IBS Severity Scoring System) was also completed at the conclusion of the GDH treatment for pre-and post-test ratings of clinical symptoms. Results: The patient showed improvement in all outcome variables and self-ratings, including abdominal pain intensity, frequency of abdominal pain episodes, emotional distress relating to gut issues, depression, and anxiety. The IBS Questionnaire showed a significant improvement from a severity score of 400 (defined as severe) prior to GDH intervention compared to 55 (defined as complete resolution) at four months after the last session. IBS Questionnaire subset questions that showed a significant score improvement included abdominal pain intensity, days of pain experienced per 10 days, satisfaction with bowel habits, and overall interference of life affected by IBS symptoms. Conclusion: This case supports the existing research literature that GDH has a significantly beneficial role in improving symptoms in patients with IBS. Emphasis is placed on the numerical results of the IBS Questionnaire scoring, which reflects a patient who initially suffered from severe IBS with failed response to multiple medications, who subsequently showed full and sustained resolution

Keywords: pediatrics, constipation, irritable bowel syndrome, hypnotherapy, gut-directed hypnosis

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Authors: Vitaliy Petrov, Natalia Shusharina, Vitaliy Kasymov, Maksim Patrushev, Evgeny Bogdanov

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The leading worldwide death reasons are ischemic heart disease and other cardiovascular illnesses. Generally, the common symptom is high blood pressure. Long-time blood pressure control is very important for the prophylaxis, correct diagnosis and timely therapy. Non-invasive methods which are based on Korotkoff sounds are impossible to apply often and for a long time. Implantable devices can combine longtime monitoring with high accuracy of measurements. The main purpose of this work is to create a real-time monitoring system for decreasing the death rate from cardiovascular diseases. These days implantable electronic devices began to play an important role in medicine. Usually implantable devices consist of a transmitter, powering which could be wireless with a special made battery and measurement circuit. Common problems in making implantable devices are short lifetime of the battery, big size and biocompatibility. In these work, blood pressure measure will be the focus because it’s one of the main symptoms of cardiovascular diseases. Our device will consist of three parts: the implantable pressure sensor, external transmitter and automated workstation in a hospital. The Implantable part of pressure sensors could be based on piezoresistive or capacitive technologies. Both sensors have some advantages and some limitations. The Developed circuit is based on a small capacitive sensor which is made of the technology of microelectromechanical systems (MEMS). The Capacitive sensor can provide high sensitivity, low power consumption and minimum hysteresis compared to the piezoresistive sensor. For this device, it was selected the oscillator-based circuit where frequency depends from the capacitance of sensor hence from capacitance one can calculate pressure. The external device (transmitter) used for wireless charging and signal transmission. Some implant devices for these applications are passive, the external device sends radio wave signal on internal LC circuit device. The external device gets reflected the signal from the implant and from a change of frequency is possible to calculate changing of capacitance and then blood pressure. However, this method has some disadvantages, such as the patient position dependence and static using. Developed implantable device doesn’t have these disadvantages and sends blood pressure data to the external part in real-time. The external device continuously sends information about blood pressure to hospital cloud service for analysis by a physician. Doctor’s automated workstation at the hospital also acts as a dashboard, which displays actual medical data of patients (which require attention) and stores it in cloud service. Usually, critical heart conditions occur few hours before heart attack but the device is able to send an alarm signal to the hospital for an early action of medical service. The system was tested with wireless charging and data transmission. These results can be used for ASIC design for MEMS pressure sensor.

Keywords: MEMS sensor, RF power, wireless data, oscillator-based circuit

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Authors: Masoume Ehsani, Ning Zhu, Huu Doan, Ali Lohi, Amira Abdelrasoul

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Membrane fouling poses severe challenges in membrane-based wastewater treatment applications. Ultrasound (US) has been considered an effective fouling remediation technique in filtration processes. Bubble cavitation in the liquid medium results from the alternating rarefaction and compression cycles during the US irradiation at sufficiently high acoustic pressure. Cavitation microbubbles generated under US irradiation can cause eddy current and turbulent flow within the medium by either oscillating or discharging energy to the system through microbubble explosion. Turbulent flow regime and shear forces created close to the membrane surface cause disturbing the cake layer and dislodging the foulants, which in turn improve the cleaning efficiency and filtration performance. Therefore, the number, size, velocity, and oscillation pattern of the microbubbles created in the liquid medium play a crucial role in foulant detachment and permeate flux recovery. The goal of the current study is to gain in depth understanding of the influence of the US power intensity and frequency on the microbubble dynamics and its characteristics generated under US irradiation. In comparison with other imaging techniques, the synchrotron in-line Phase Contrast Imaging technique at the Canadian Light Source (CLS) allows in-situ observation and real-time visualization of microbubble dynamics. At CLS biomedical imaging and therapy (BMIT) polychromatic beamline, the effective parameters were optimized to enhance the contrast gas/liquid interface for the accuracy of the qualitative and quantitative analysis of bubble cavitation within the system. With the high flux of photons and the high-speed camera, a typical high projection speed was achieved; and each projection of microbubbles in water was captured in 0.5 ms. ImageJ software was used for post-processing the raw images for the detailed quantitative analyses of microbubbles. The imaging has been performed under the US power intensity levels of 50 W, 60 W, and 100 W, in addition to the US frequency levels of 20 kHz, 28 kHz, and 40 kHz. For the duration of 2 seconds of imaging, the effect of the US power and frequency on the average number, size, and fraction of the area occupied by bubbles were analyzed. Microbubbles’ dynamics in terms of their velocity in water was also investigated. For the US power increase of 50 W to 100 W, the average bubble number and the average bubble diameter were increased from 746 to 880 and from 36.7 µm to 48.4 µm, respectively. In terms of the influence of US frequency, a fewer number of bubbles were created at 20 kHz (average of 176 bubbles rather than 808 bubbles at 40 kHz), while the average bubble size was significantly larger than that of 40 kHz (almost seven times). The majority of bubbles were captured close to the membrane surface in the filtration unit. According to the study observations, membrane cleaning efficiency is expected to be improved at higher US power and lower US frequency due to the higher energy release to the system by increasing the number of bubbles or growing their size during oscillation (optimum condition is expected to be at 20 kHz and 100 W).

Keywords: bubble dynamics, cavitational bubbles, membrane fouling, ultrasonic cleaning

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Authors: Mohamad F. Jamiluddin, Emeline Sarry, Ana Bejanariu, Cécile Bauche

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Introduction: Over 360 million people are chronically infected with hepatitis B virus (HBV), of whom 1 million die each year from HBV-associated liver cirrhosis or hepatocellular carcinoma. Current treatment options for chronic hepatitis B depend on interferon-α (IFNα) or nucleos(t)ide analogs, which control virus replication but rarely eliminate the virus. Treatment with PEG-IFNα leads to a sustained antiviral response in only one third of patients. After withdrawal of the drugs, the rebound of viremia is observed in the majority of patients. Furthermore, the long-term treatment is subsequently associated with the appearance of drug resistant HBV strains that is often the cause of the therapy failure. Among the new therapeutic avenues being developed, therapeutic vaccine aimed at inducing immune responses similar to those found in resolvers is of growing interest. The high prevalence of chronic hepatitis B necessitates the design of better vaccination strategies capable of eliciting broad-spectrum of cell-mediated immunity(CMI) and humoral immune response that can control chronic hepatitis B. Induction of HBV-specific T cells and B cells by therapeutic vaccination may be an innovative strategy to overcome virus persistence. Lentiviral vectors developed and optimized by THERAVECTYS, due to their ability to transduce non-dividing cells, including dendritic cells, and induce CMI response, have demonstrated their effectiveness as vaccination tools. Method: To develop a HBV therapeutic vaccine that can induce a broad but specific immune response, we generated recombinant lentiviral vector carrying IRES(Internal Ribosome Entry Site)-containing bicistronic constructs which allow the coexpression of two vaccine products, namely HBV T- cell epitope vaccine and HBV virus like particle (VLP) vaccine. HBV T-cell epitope vaccine consists of immunodominant cluster of CD4 and CD8 epitopes with spacer in between them and epitopes are derived from HBV surface protein, HBV core, HBV X and polymerase. While HBV VLP vaccine is a HBV core protein based chimeric VLP with surface protein B-cell epitopes displayed. In order to evaluate the immunogenicity, mice were immunized with lentiviral constructs by intramuscular injection. The T cell and antibody immune responses of the two vaccine products were analyzed using IFN-γ ELISpot assay and ELISA respectively to quantify the adaptive response to HBV antigens. Results: Following a single administration in mice, lentiviral construct elicited robust antigen-specific IFN-γ responses to the encoded antigens. The HBV T- cell epitope vaccine demonstrated significantly higher T cell immunogenicity than HBV VLP vaccine. Importantly, we demonstrated by ELISA that antibodies are induced against both HBV surface protein and HBV core protein when mice injected with vaccine construct (p < 0.05). Conclusion: Our results highlight that THERAVECTYS lentiviral vectors may represent a powerful platform for immunization strategy against chronic hepatitis B. Our data suggests the likely importance of Lentiviral vector based novel bicistronic construct for further study, in combination with drugs or as standalone antigens, as a therapeutic lentiviral based HBV vaccines. THERAVECTYS bicistronic HBV vaccine will be further evaluated in animal efficacy studies.

Keywords: chronic hepatitis B, lentiviral vectors, therapeutic vaccine, virus-like particle

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Authors: Tran Tran

Abstract:

Mental health issues are prevalent among Vietnamese undergraduate students, and they are greatly exacerbated during the COVID-19 pandemic for this population. While there is empirical evidence supporting the effectiveness and efficiency of therapy on mental health issues among college students, the rates of Vietnamese college students seeking professional mental health services were alarmingly low. Multiple factors can prevent those in need from finding support. The Internalized Stigma Model posits that public stigma directly affects intentions to seek psychological help via self-stigma and attitudes toward seeking help. However, little research has focused on what factors can predict public stigma toward seeking professional psychological support, especially among this population. A potential predictor is academic majors since academic majors can influence undergraduate students' perceptions, attitudes, and intentions. A study suggested that students who have completed two or more psychology courses have a more positive attitude toward seeking care for mental health issues and reduced stigma, which might be attributed to increased mental health literacy. In addition, research has shown that women are more likely to utilize mental health services and have lower stigma than men. Finally, studies have also suggested that experience of mental health services can increase endorsement of perceived need and lower stigma. Thus, it is expected that perceived helpfulness from past service uses can reduce stigma. This study aims to address this gap in the literature and investigate which factors can predict public stigma, specifically academic major, gender, and perceived helpfulness, potentially suggesting an avenue of prevention and ultimately improving the well-being of Vietnamese college students. The sample includes 408 undergraduate students (Mage = 20.44; 80.88% female) Hanoi city, Vietnam. Participants completed a pen-and-paper questionnaire. Students completed the Stigma Scale for Receiving Psychological Help, which yielded a mean public stigma score. Participants also completed a measurement assessing their perceived helpfulness of their university’s counseling center, which included eight subscales: future self-development, learning issues, career counseling, medical and health issues, mental health issues, conflicts between teachers and students, conflicts between parents and students, and interpersonal relationships. Items were summed to create a composite perceived helpfulness score. Finally, participants provided demographic information. This included gender, which was dichotomized between female and other. Additionally, it included academic major, which was also similarly dichotomized between psychology and other (e.g., natural science, social science, and pedagogy & social work). Linear relationships between public stigma and gender, academic major, and perceived helpfulness were analyzed individually with a regression model. Findings suggested that academic major, gender, and perceived counseling center's helpfulness predicted stigma against seeking professional psychological help. Specifically, being a psychology major predicted lower levels of public stigma (β = -.25, p < .001). Additionally, gender female predicted lower levels of public stigma (β = -.11, p < .05). Lastly, higher levels of perceived helpfulness of the counseling center also predicted lower levels of public stigma (β = -.16, p < .01). The study’s results offer potential intervention avenues to help reduce stigma and increase well-being for Vietnamese college students.

Keywords: stigma, vietnamese college students, counseling services, help-seeking

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Authors: Meenakshi Barsaul Chauhan, Aastha Chauhan, Shilpa Hurmade, Rajeev Sen, Jyotsna Sen, Monika Dalal

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Introduction: Ovarian masses are common forms of neoplasm in women and represent 2/3rd of gynaecological malignancies. A pre-operative suggestion of malignancy can guide the gynecologist to refer women with suspected pelvic mass to a gynecological oncologist for appropriate therapy and optimized treatment, which can improve survival. In the younger age group preoperative differentiation into benign or malignant pathology can decide for conservative or radical surgery. Imaging modalities have a definite role in establishing the diagnosis. By using International Ovarian Tumor Analysis (IOTA) classification with sonography, costly radiological methods like Magnetic Resonance Imaging (MRI) / computed tomography (CT) scan can be reduced, especially in developing countries like India. Thus, this study is being undertaken to evaluate the role of clinical methods and sonography for diagnosis of the nature of the ovarian tumor. Material And Methods: This prospective observational study was conducted on 40 patients presenting with ovarian masses, in the Department of Obstetrics and Gynaecology, at a tertiary care center in northern India. Functional cysts were excluded. Ultrasonography and color Doppler were performed on all the cases.IOTA rules were applied, which take into account locularity, size, presence of solid components, acoustic shadow, dopper flow etc . Magnetic Resonance Imaging (MRI) / computed tomography (CT) scans abdomen and pelvis were done in cases where sonography was inconclusive. In inoperable cases, Fine needle aspiration cytology (FNAC) was done. The histopathology report after surgery and cytology report after FNAC was correlated statistically with the pre-operative diagnosis made clinically and sonographically using IOTA rules. Statistical Analysis: Descriptive measures were analyzed by using mean and standard deviation and the Student t-test was applied and the proportion was analyzed by applying the chi-square test. Inferential measures were analyzed by sensitivity, specificity, negative predictive value, and positive predictive value. Results: Provisional diagnosis of the benign tumor was made in 16(42.5%) and of the malignant tumor was made in 24(57.5%) patients on the basis of clinical findings. With IOTA simple rules on sonography, 15(37.5%) were found to be benign, while 23 (57.5%) were found to be malignant and findings were inconclusive in 2 patients (5%). FNAC/Histopathology reported that benign ovarian tumors were 14 (35%) and 26(65%) were malignant, which was taken as the gold standard. The clinical finding alone was found to have a sensitivity of 66.6% and a specificity of 90.9%. USG alone had a sensitivity of 86% and a specificity of 80%. When clinical findings and IOTA simple rules of sonography were combined (excluding inconclusive masses), the sensitivity and specificity were 83.3% and 92.3%, respectively. While including inconclusive masses, sensitivity came out to be 91.6% and specificity was 89.2. Conclusion: IOTA's simple sonography rules are highly sensitive and specific in the prediction of ovarian malignancy and also easy to use and easily reproducible. Thus, combining clinical examination with USG will help in the better management of patients in terms of time, cost and better prognosis. This will also avoid the need for costlier modalities like CT, and MRI.

Keywords: benign, international ovarian tumor analysis classification, malignant, ovarian tumours, sonography

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Authors: Inna Kornienko, Svetlana Guryeva, Anatoly Shekhter, Elena Petersen

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Transplantation is an effective treatment option for patients suffering from different end-stage diseases. However, it is plagued by a constant shortage of donor organs and the subsequent need of a lifelong immunosuppressive therapy for the patient. Currently some researchers look towards using of pig organs to replace human organs for transplantation since the matrix derived from porcine organs is a convenient substitute for the human matrix. As an initial step to create a new ex vivo tissue engineered model, optimized protocols have been created to obtain organ-specific acellular matrices and evaluated their potential as tissue engineered scaffolds for culture of normal cells and tumor cell lines. These protocols include decellularization by perfusion in a bioreactor system and immersion-agitation on an orbital shaker with use of various detergents (SDS, Triton X-100) and freezing. Complete decellularization – in terms of residual DNA amount – is an important predictor of probability of immune rejection of materials of natural origin. However, the signs of cellular material may still remain within the matrix even after harsh decellularization protocols. In this regard, the matrices obtained from tissues of low-immunogenic pigs with α3Galactosyl-tranferase gene knock out (GalT-KO) may be a promising alternative to native animal sources. The research included a study of induced effect of frozen and fresh fragments of GalT-KO skin on healing of full-thickness plane wounds in 80 rats. Commercially available wound dressings (Ksenoderm, Hyamatrix and Alloderm) as well as allogenic skin were used as a positive control and untreated wounds were analyzed as a negative control. The results were evaluated on the 4th day after grafting, which corresponds to the time of start of normal wound epithelization. It has been shown that a non-specific immune response in models treated with GalT-Ko pig skin was milder than in all the control groups. Research has been performed to measure technical skin characteristics: stiffness and elasticity properties, corneometry, tevametry, and cutometry. These metrics enabled the evaluation of hydratation level, corneous layer husking level, as well as skin elasticity and micro- and macro-landscape. These preliminary data may contribute to development of personalized transplantable organs from GalT-Ko pigs with significantly limited potential of immune rejection. By applying growth factors to a decellularized skin sample it is possible to achieve various regenerative effects based on the particular situation. In this particular research BMP2 and Heparin-binding EGF-like growth factor have been used. Ideally, a bioengineered organ must be biocompatible, non-immunogenic and support cell growth. Porcine organs are attractive for xenotransplantation if severe immunologic concerns can be bypassed. The results indicate that genetically modified pig tissues with knock-outed α3Galactosyl-tranferase gene may be used for production of low-immunogenic matrix suitable for transplantation.

Keywords: decellularization, low-immunogenic, matrix, scaffolds, transplants

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