Search results for: behaviour therapy

Authors: M. Testa, L. Peotta, S. Giusiano, B. Lazzolino, U. Manera, A. Canosa, M. Grassano, F. Palumbo, A. Bombaci, S. Cabras, F. Di Pede, L. Solero, E. Matteoni, C. Moglia, A. Calvo, A. Chio

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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of adulthood, which primarily affects the central nervous system and is characterized by progressive bilateral degeneration of motor neurons. The degeneration processes in ALS extend far beyond the neurons of the motor system, and affects cognition, behaviour and language. To outline the prevalence of language deficits in an ALS cohort and explore their profile along with demographic and neuropsychological data. A full neuropsychological battery and language assessment was administered to 56 ALS patients. Neuropsychological assessment included tests of executive functioning, verbal fluency, social cognition and memory. Language was assessed using tests for verbal comprehension, production and pragmatics. Patients were cognitively classified following the Revised Consensus Criteria and divided in three groups showing different levels of language deficits: group 1 - no language deficit; group 2 - one language deficit; group 3 - two or more language deficits. Chi-square for independence and non-parametric measures to compare groups were applied. Nearly half of ALS-CN patients (48%) reported one language test under the clinical cut-off, and only 13% of patents classified as ALS-CI showed no language deficits, while the rest 87% of ALS-CI reported two or more language deficits. ALS-BI and ALS-CBI cases all reported two or more language deficits. Deficits in production and in comprehension appeared more frequent in ALS-CI patients (p=0.011, p=0.003 respectively), with a higher percentage of comprehension deficits (83%). Nearly all ALS-CI reported at least one deficit in pragmatic abilities (96%) and all ALS-BI and ALS-CBI patients showed pragmatic deficits. Males showed higher percentage of pragmatic deficits (97%, p=0.007). No significant differences in language deficits have been found between bulbar and spinal onset. Months from onset and level of impairment at testing (ALS-FRS total score) were not significantly different between levels and type of language impairment. Age and education were significantly higher for cases showing no deficits in comprehension and pragmatics and in the group showing no language deficits. Comparing performances at neuropsychological tests among the three levels of language deficits, no significant differences in neuropsychological performances were found between group 1 and 2; compared to group 1, group 3 appeared to decay specifically on executive testing, verbal/visuospatial learning, and social cognition. Compared to group 2, group 3 showed worse performances specifically in tests of working memory and attention. Language deficits have found to be spread in our sample, encompassing verbal comprehension, production and pragmatics. Our study reveals that also cognitive intact patients (ALS-CN) showed at least one language deficit in 48% of cases. Pragmatic domain is the most compromised (84% of the total sample), present in nearly all ALS-CI (96%), likely due to the influence of executive impairment. Lower age and higher education seem to preserve comprehension, pragmatics and presence of language deficits. Finally, executive functions, verbal/visuospatial learning and social cognition differentiate the group with no language deficits from the group with a clinical language impairment (group 3), while attention and working memory differentiate the group with one language deficit from the clinical impaired group.

Keywords: amyotrophic lateral sclerosis, language assessment, neuropsychological assessment, language deficit

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Authors: Breanna Wright, Peter Bragge

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Diagnostic error rates in healthcare are approximately 10% of cases. Diagnostic errors can cause patient harm due to inappropriate, inadequate or delayed treatment, and such errors contribute heavily to medical liability claims globally. Therefore, addressing diagnostic error is a high priority. In most cases, diagnostic errors are the result of faulty information synthesis rather than lack of knowledge. Specifically, the majority of diagnostic errors involve cognitive factors, and in particular, cognitive biases. Emergency Departments are an environment with heightened risk of diagnostic error due to time and resource pressures, a frequently chaotic environment, and patients arriving undifferentiated and with minimal context. This project aimed to develop a behavioural, evidence-informed intervention to reduce diagnostic error in Emergency Departments through co-design with emergency physicians, insurers, researchers, hospital managers, citizens and consumer representatives. The Forum Process was utilised to address this aim. This involves convening a small (4 – 6 member) expert panel to guide a focused literature and practice review; convening of a 10 – 12 person citizens panel to gather perspectives of laypeople, including those affected by misdiagnoses; and a 18 – 22 person structured stakeholder dialogue bringing together representatives of the aforementioned stakeholder groups. The process not only provides in-depth analysis of the problem and associated behaviours, but brings together expertise and insight to facilitate identification of a behaviour change intervention. Informed by the literature and practice review, the Citizens Panel focused on eliciting the values and concerns of those affected or potentially affected by diagnostic error. Citizens were comfortable with diagnostic uncertainty if doctors were honest with them. They also emphasised the importance of open communication between doctors and patients and their families. Citizens expect more consistent standards across the state and better access for both patients and their doctors to patient health information to avoid time-consuming re-taking of long patient histories and medication regimes when re-presenting at Emergency Departments and to reduce the risk of unintentional omissions. The structured Stakeholder Dialogue focused on identifying a feasible behavioural intervention to review diagnoses in Emergency Departments. This needed to consider the role of cognitive bias in medical decision-making; contextual factors (in Victoria, there is a legislated 4-hour maximum time between ED triage and discharge / hospital admission); resource availability; and the need to ensure the intervention could work in large metropolitan as well as small rural and regional ED settings across Victoria. The identified behavioural intervention will be piloted in approximately ten hospital EDs across Victoria, Australia. This presentation will detail the findings of all review and consultation activities, describe the behavioural intervention developed and present results of the pilot trial.

Keywords: behavioural intervention, cognitive bias, decision-making, diagnostic error

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Authors: R. Yuan, S. Sivasankaran, N. Dutta, K. Ebrahimi

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This paper investigates the software capability and computer-aided engineering (CAE) method of modelling transient heat transfer process occurred in the vehicle underhood region during vehicle thermal soak phase. The heat retention from the soak period will be beneficial to the cold start with reduced friction loss for the second 14°C worldwide harmonized light-duty vehicle test procedure (WLTP) cycle, therefore provides benefits on both CO₂ emission reduction and fuel economy. When vehicle undergoes soak stage, the airflow and the associated convective heat transfer around and inside the engine bay is driven by the buoyancy effect. This effect along with thermal radiation and conduction are the key factors to the thermal simulation of the engine bay to obtain the accurate fluids and metal temperature cool-down trajectories and to predict the temperatures at the end of the soak period. Method development has been investigated in this study on a light-duty passenger vehicle using coupled aerodynamic-heat transfer thermal transient modelling method for the full vehicle under 9 hours of thermal soak. The 3D underhood flow dynamics were solved inherently transient by the Lattice-Boltzmann Method (LBM) method using the PowerFlow software. This was further coupled with heat transfer modelling using the PowerTHERM software provided by Exa Corporation. The particle-based LBM method was capable of accurately handling extremely complicated transient flow behavior on complex surface geometries. The detailed thermal modelling, including heat conduction, radiation, and buoyancy-driven heat convection, were integrated solved by PowerTHERM. The 9 hours cool-down period was simulated and compared with the vehicle testing data of the key fluid (coolant, oil) and metal temperatures. The developed CAE method was able to predict the cool-down behaviour of the key fluids and components in agreement with the experimental data and also visualised the air leakage paths and thermal retention around the engine bay. The cool-down trajectories of the key components obtained for the 9 hours thermal soak period provide vital information and a basis for the further development of reduced-order modelling studies in future work. This allows a fast-running model to be developed and be further imbedded with the holistic study of vehicle energy modelling and thermal management. It is also found that the buoyancy effect plays an important part at the first stage of the 9 hours soak and the flow development during this stage is vital to accurately predict the heat transfer coefficients for the heat retention modelling. The developed method has demonstrated the software integration for simulating buoyancy-driven heat transfer in a vehicle underhood region during thermal soak with satisfying accuracy and efficient computing time. The CAE method developed will allow integration of the design of engine encapsulations for improving fuel consumption and reducing CO₂ emissions in a timely and robust manner, aiding the development of low-carbon transport technologies.

Keywords: ATCT/WLTC driving cycle, buoyancy-driven heat transfer, CAE method, heat retention, underhood modeling, vehicle thermal soak

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Authors: Khulud Alhussain, Anna Gavine, Stephen Macgillivray, Sushila Chowdhry

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Background: Estimates show that by the year 2030, mental illness will account for more than half of the global economic burden, second to non-communicable diseases. Often, the perinatal period is characterised by psychological ambivalence and a mixed anxiety-depressive condition. Maternal mental disorder is associated with perinatal anxiety and depression and affects breastfeeding behaviors. Studies also indicate that maternal mental health can considerably influence a baby's health in numerous aspects and impact the newborn health due to lack of adequate breastfeeding. However, studies reporting factors associated with breastfeeding behaviors are predominantly quantitative. Therefore, it is not clear what literature is available to understand the factors affecting breastfeeding and perinatal women’s perspectives and experiences. Aim: This review aimed to explore the perceptions and experiences of women with perinatal anxiety and depression, as well as how these experiences influence their breastfeeding behaviours. Methods: A systematic literature review of qualitative studies in line with the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ). Four electronic databases (CINAHL, PsycINFO, Embase, and Google Scholar) were explored for relevant studies using a search strategy. The search was restricted to studies published in the English language between 2000 and 2022. Findings from the literature were screened using a pre-defined screening criterion and the quality of eligible studies was appraised using the Walsh and Downe (2006) checklist. Findings were extracted and synthesised based on Braun and Clark. The review protocol was registered on PROSPERO (Ref: CRD42022319609). Result: A total of 4947 studies were identified from the four databases. Following duplicate removal and screening 16 studies met the inclusion criteria. The studies included 87 pregnant and 302 post-partum women from 12 countries. The participants were from a variety of economic, regional, and religious backgrounds, mainly from the age of 18 to 45 years old. Three main themes were identified: Barriers to breastfeeding, breastfeeding facilitators, emotional disturbance, and breastfeeding. Seven subthemes emerged from the data: expectation versus reality, uncertainly about maternal competencies, body image and breastfeeding, lack of sufficient breastfeeding support for family and caregivers’ support, influences positive breastfeeding practices, breastfeeding education, and causes of mental strain among breastfeeding women. Breastfeeding duration is affected in women with mental health disorders, irrespective of their desire to breastfeed. Conclusion: There is significant empirical evidence that breastfeeding behaviour and perinatal mental disturbance are linked. However, there is a lack of evidence to apply the findings to Saudi women due to lack of empirical qualitative information. To improve the psychological well-being of mothers, it is crucial to explore and recognise any concerns with their mental, physical, and emotional well-being. Therefore, robust research is needed so that breastfeeding intervention researchers and policymakers can focus on specifically what needs to be done to help mentally distressed perinatal women and their new-born.

Keywords: pregnancy, perinatal period, anxiety, depression, emotional disturbance, breastfeeding

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Authors: Carmen W. H. Chan, Helen Y. L. Chan, Kai Chow Choi, Ka Ming Chow, Cecilia W. M. Kwan, Nancy H. Y. Ng, Jackie Robinson

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Introduction: In Hong Kong, a significant number of deaths occur in acute care wards, which requires nurses in these settings to provide end-of-life care and lead ACP implementation. However, nurses in these settings, in fact, have very low-level involvement in ACP discussions because of limited training in ACP conversations. Objective: This study aims to assess the impact of a multi-media experiential ACP (MEACP) training program, which is guided by the experiential learning model and theory of planned behaviour, on nurses' knowledge and confidence in assisting patients with ACP. Methodology: The study utilizes a cluster randomized controlled trial with a 12-week follow-up. Eligible nurses working in acute care hospital wards are randomly assigned at the ward level, in a 1:1 ratio, to either the control group (no ACP education) or the intervention group (4-week MEACP training program). The training programme includes training through a webpage and mobile application, as well as a face-to-face training workshop with enhanced lectures and role play, which is based on the Theory of Planned Behavior and Kolb's Experiential Learning Model. Questionnaires were distributed to assess nurses' knowledge (a 10-item true/false questionnaire) and level of confidence (five-point Likert scale) in ACP at baseline (T0), four weeks after the baseline assessment (T1), and 12 weeks after T1 (T2). In this interim report, data analysis was mainly descriptive in nature. Result: The interim report focuses on the preliminary results of 165 nurses at T0 (Control: 74, Intervention: 91) over a 5-month period, 69 nurses from the control group who completed the 4-week follow-up and 65 nurses from the intervention group who completed the 4-week MEACP training program at T1. The preliminary attrition rate is 6.8% and 28.6% for the control and intervention groups, respectively, as some nurses did not complete the whole set of online modules. At baseline, the two groups were generally homogeneous in terms of their years of nursing practice, weekly working hours, working title, and level of education, as well as ACP knowledge and confidence levels. The proportion of nurses who answered all ten knowledge questions correctly increased from 13.8% (T0) to 66.2% (T1) for the intervention group and from 13% (T0) to 20.3% (T1) for the control group. The nurses in the intervention group answered an average of 7.57 and 9.43 questions correctly at T0 and T1, respectively. They showed a greater improvement in the knowledge assessment at T1 with respect to T0 when compared with their counterparts in the control group (mean difference of change score, Δ=1.22). They also exhibited a greater gain in level of confidence at T1 compared to their colleagues in the control group (Δ=0.91). T2 data is yet available. Conclusion: The prevalence of nurses engaging in ACP and their level of knowledge about ACP in Hong Kong is low. The MEACP training program can enrich nurses by providing them with more knowledge about ACP and increasing their confidence in conducting ACP.

Keywords: advance directive, advance care planning, confidence, knowledge, multi-media experiential, randomised control trial

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Authors: Lukasz Szymanski, Zbigniew Kolacinski, Grzegorz Raniszewski, Slawomir Wiak, Lukasz Pietrzak, Dariusz Koza, Karolina Przybylowska-Sygut, Ireneusz Majsterek, Zbigniew Kaminski, Justyna Fraczyk, Malgorzata Walczak, Beata Kolasinska, Adam Bednarek, Joanna Konka

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The aim of this work is to investigate the influence of electromagnetic field from the range of radio frequencies on the desired nanoparticles for cancer therapy. In the article, the development and demonstration of the method and the model device for hyperthermic selective destruction of cancer cells are presented. This method was based on the synthesis and functionalization of carbon nanotubes serving as ferromagnetic material nanocontainers. The methodology of the production carbon - ferromagnetic nanocontainers (FNCs) includes: The synthesis of carbon nanotubes, chemical, and physical characterization, increasing the content of a ferromagnetic material and biochemical functionalization involving the attachment of the key addresses. The ferromagnetic nanocontainers were synthesised in CVD and microwave plasma system. Biochemical functionalization of ferromagnetic nanocontainers is necessary in order to increase the binding selectively with receptors presented on the surface of tumour cells. Multi-step modification procedure was finally used to attach folic acid on the surface of ferromagnetic nanocontainers. Pristine ferromagnetic carbon nanotubes are not suitable for application in medicine and biotechnology. Appropriate functionalization of ferromagnetic carbon nanotubes allows to receiving materials useful in medicine. Finally, a product contains folic acids on the surface of FNCs. The folic acid is a ligand of folate receptors – α which is overexpressed on the surface of epithelial tumours cells. It is expected that folic acids will be recognized and selectively bound by receptors presented on the surface of tumour cells. In our research, FNCs were covalently functionalized in a multi-step procedure. Ferromagnetic carbon nanotubes were oxidated using different oxidative agents. For this purpose, strong acids such as HNO3, or mixture HNO3 and H2SO4 were used. Reactive carbonyl and carboxyl groups were formed on the open sides and at the defects on the sidewalls of FNCs. These groups allow further modification of FNCs as a reaction of amidation, reaction of introduction appropriate linkers which separate solid surface of FNCs and ligand (folic acid). In our studies, amino acid and peptide have been applied as ligands. The last step of chemical modification was reaction-condensation with folic acid. In all reaction as coupling reagents were used derivatives of 1,3,5-triazine. The first trials in the device for hyperthermal RF generator have been done. The frequency of RF generator was in the ranges from 10 to 14Mhz and from 265 to 621kHz. Obtained functionalized nanoparticles enabled to reach the temperature of denaturation tumor cells in given frequencies.

Keywords: cancer colon cells, carbon nanotubes, hyperthermia, ligands

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Authors: Brittany Richardson, Ying Wang

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For physical therapy, exercise prescription, athlete training, and regular fitness training, it is crucial to perform health assessments or fitness assessments periodically. An accurate assessment is propitious for tracking recovery progress, preventing potential injury and making long-range training plans. Assessments include necessary measurements, height, weight, blood pressure, heart rate, body fat, etc. and advanced evaluation, muscle group strength, stability-mobility, and movement evaluation, etc. In the current standard assessment procedures, the accuracy of assessments, especially advanced evaluations, largely depends on the experience of physicians, coaches, and personal trainers. And it is challenging to track clients’ progress in the current assessment. Unlike the tradition assessment, in this paper, we present a deep learning based face recognition algorithm for accurate, comprehensive and trackable assessment. Based on the result from our assessment, physicians, coaches, and personal trainers are able to adjust the training targets and methods. The system categorizes the difficulty levels of the current activity for the client or user, furthermore make more comprehensive assessments based on tracking muscle group over time using a designed landmark detection method. The system also includes the function of grading and correcting the form of the clients during exercise. Experienced coaches and personal trainer can tell the clients' limit based on their facial expression and muscle group movements, even during the first several sessions. Similar to this, using a convolution neural network, the system is trained with people’s facial expression to differentiate challenge levels for clients. It uses landmark detection for subtle changes in muscle groups movements. It measures the proximal mobility of the hips and thoracic spine, the proximal stability of the scapulothoracic region and distal mobility of the glenohumeral joint, as well as distal mobility, and its effect on the kinetic chain. This system integrates data from other fitness assistant devices, including but not limited to Apple Watch, Fitbit, etc. for a improved training and testing performance. The system itself doesn’t require history data for an individual client, but the history data of a client can be used to create a more effective exercise plan. In order to validate the performance of the proposed work, an experimental design is presented. The results show that the proposed work contributes towards improving the quality of exercise plan, execution, progress tracking, and performance.

Keywords: exercise prescription, facial recognition, landmark detection, fitness assessments

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Authors: Omair Anas

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The Persian Gulf has been in turmoil for a long time since the colonial administration has handed over the role to the small and weak kings and emirs who were assured of protection in return of many economic and security promises to them. The regional order, Saudi Arabia evolved was a rentier regional order secured by an expansion of rentier economy and taking responsibility for much of the expenses of the regional order on behalf of relatively poor countries. The two oil booms helped the Saudi state to expand the 'rentier order' driven stability and bring the countries like Egypt, Jordan, Syria, and Palestine under its tutelage. The disruptive misadventure, however, came with Iran's proclamation of the Islamic Revolution in 1979 which it wanted to be exported to its 'un-Islamic and American puppet' Arab neighbours. For Saudi Arabia, even the challenge presented by the socialist-nationalist Arab dictators like Gamal Abdul Nasser and Hafez Al-Assad was not that much threatening to the Saudi Arabia’s then-defensive realism. In the Arab uprisings, the Gulf monarchies saw a wave of insecurity and Iran found it an opportune time to complete the revolutionary process it could not complete after 1979. An alliance of convenience and ideology between Iran and Islamist groups had the real potential to challenge both Saudi Arabia’s own security and its leadership in the region. The disruptive threat appeared at a time when the Saudi state had already sensed an impending crisis originating from the shifts in the energy markets. Low energy prices, declining global demands, and huge investments in alternative energy resources required Saudi Arabia to rationalize its economy according to changing the global political economy. The domestic Saudi reforms remained gradual until the death of King Abdullah in 2015. What is happening now in the region, the Qatar crisis, the Lebanon crisis and the Saudi-Iranian proxy war in Iraq, Syria, and Yemen has combined three immediate objectives, rationalising Saudi economy and most importantly, the resetting the Saudi royal power for Saudi Arabia’s longest-serving future King Mohammad bin Salman. The Saudi King perhaps has no time to wait and watch the power vacuum appearing because of Iran’s expansionist foreign policy. The Saudis appear to be employing an offensive realism by advancing a pro-active regional policy to counter Iran’s threatening influence amid disappearing Western security from the region. As the Syrian civil war is coming to a compromised end with ceding much ground to Iran-controlled militias, Hezbollah and Al-Hashad, the Saudi state has lost much ground in these years and the threat from Iranian proxies is more than a reality, more clearly in Bahrain, Iraq, Syria, and Yemen. This paper attempts to analyse the changing Saudi behaviour in the region, which, the author understands, is shaped by an offensive-realist approach towards finding a favourable security environment for the Saudi-led regional order, a post-rentier order perhaps.

Keywords: terrorism, Saudi Arabia, Rentier State, gulf crisis

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Authors: Faris Algahtani

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Background: In Saudi Arabia, it is essential to know what practices are employed and considered effective by special education teachers working with preschool children with intellectual disabilities, as a prerequisite for identifying areas for improvement. Preschool provision for these children is expanding through a network of Intellectual Disability Centres while, in primary schools, a policy of inclusion is pursued and, in mainstream preschools, pilots have been aimed at enhancing learning in readiness for primary schooling. This potentially widens the attainment gap between preschool children with and without intellectual disabilities, and influences the scope for improvement. Goal: The aim of the study was to explore special education teachers’ practices and perceived perceptions of those practices for preschool children with intellectual disabilities in Saudi Arabia Method: A qualitative interpretive approach was adopted in order to gain a detailed understanding of how special education teachers in an IDC operate in the classroom. Fifteen semi-structured interviews were conducted with experienced and qualified teachers. Data were analysed using thematic analysis, based on themes identified from the literature review together with new themes emerging from the data. Findings: American methods strongly influenced teaching practices, in particular TEACCH (Treatment and Education of Autistic and Communication related handicapped Children), which emphasises structure, schedules and specific methods of teaching tasks and skills; and ABA (Applied Behaviour Analysis), which aims to improve behaviours and skills by concentrating on detailed breakdown and teaching of task components and rewarding desired behaviours with positive reinforcement. The Islamic concept of education strongly influenced which teaching techniques were used and considered effective, and how they were applied. Tensions were identified between the Islamic approach to disability, which accepts differences between human beings as created by Allah in order for people to learn to help and love each other, and the continuing stigmatisation of disability in many Arabic cultures, which means that parents who bring their children to an IDC often hope and expect that their children will be ‘cured’. Teaching methods were geared to reducing behavioural problems and social deficits rather than to developing the potential of the individual child, with some teachers recognizing the child’s need for greater freedom. Relationships with parents could in many instances be improved. Teachers considered both initial teacher education and professional development to be inadequate for their needs and the needs of the children they teach. This can be partly attributed to the separation of training and development of special education teachers from that of general teachers. Conclusion: Based on the findings, teachers’ practices could be improved by the inclusion of general teaching strategies, parent-teacher relationships and practical teaching experience in both initial teacher education and professional development. Coaching and mentoring support from carefully chosen special education teachers could assist the process, as could the presence of a second teacher or teaching assistant in the classroom.

Keywords: special education, intellectual disabilities, early intervention , early childhood

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Authors: Soma Kanta Baral

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Background: Since 1981, when the first AIDS case was reported, worldwide, more than 34 million people have been infected with HIV. Almost 95 percent of the people infected with HIV live in developing countries. As HBV & HIV share similar routes of transmission by sexual intercourse or drug use by parenteral injection, co-infection is common. Because of the limited access to healthcare & HIV treatment in developing countries, HIV-infected individuals are present late for care. Enumeration of CD4+ T cell count at the time of diagnosis has been useful to initiate the therapy in HIV infected individuals. The baseline CD4+ T cell count shows high immunological variability among patients. Methods: This prospective study was done in the serology section of the Department of Microbiology over a period of one year from august 2012 to July 2013. A total of 13037 individuals subjected for HIV test were included in the study comprising of 4982 males & 8055 females. Blood sample was collected by vein puncture aseptically with standard operational procedure in clean & dry test-tube. All blood samples were screened for HIV as described by WHO algorithm by Immuno-chromatography rapid kits. Further confirmation was done by biokit ELISA method as per the manufacturer’s guidelines. After informed consent, HIV positive individuals were screened for HBsAg by Immuno-chromatography rapid kits (Hepacard). Further confirmation was done by biokit ELISA method as per the manufacturer’s guidelines. EDTA blood samples were collected from the HIV sero-positive individuals for baseline CD4+ T count. Then, CD4+ T cells count was determined by using FACS Calibur Flow Cytometer (BD). Results: Among 13037 individuals screened for HIV, 104 (0.8%) were found to be infected comprising of 69(66.34%) males & 35 (33.65%) females. The study showed that the high infection was noted in housewives (28.7%), active age group (30.76%), rural area (56.7%) & in heterosexual route (80.9%) of transmission. Out of total HIV infected individuals, distribution of HBV co-infection was found to be 6(5.7%). All co- infected individuals were married, male, above the age of 25 years & heterosexual route of transmission. Baseline CD4+ T cell count of HIV infected patient was found higher (mean CD4+ T cell count; 283cells/cu.mm) than HBV co-infected patients (mean CD4+ T cell count; 91 cells/cu.mm). Majority (77.2%) of HIV infected & all co-infected individuals were presented in our center late (CD4+ T cell count;< 350/cu. mm) for diagnosis and care. Majority of co- infected 4 (80%) were late presented with advanced AIDS stage (CD4+ count; <200/cu.mm). Conclusions: The study showed a high percentage of HIV sero-positive & co- infected individuals. Baseline CD4+ T cell count of majority of HIV infected individuals was found to be low. Hence, more sustained and vigorous awareness campaigns & counseling still need to be done in order to promote early diagnosis and management.

Keywords: HIV/AIDS, HBsAg, co-infection, CD4+

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Authors: Al Huuskonen, Clio Lake, K. M. Naude, Polina Petlitsyna, Sorsha Henning, Julia Wimmers-Klick

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This project presents the outcomes of a community-based participatory action initiative aimed at advocating for equitable healthcare and human rights for trans, two-spirit, and gender-diverse individuals, building upon the University of British Columbia (UBC) Trans Coalition's ongoing efforts. Participatory Action Research (PAR) was chosen as the research method with the goal of improving trans rights on the UBC campus, particularly regarding equitable access to healthcare. PAR involves active community contribution throughout the research process, which in this case was done by way of liaising with student resource groups and advocacy leaders. The goals of this project were as follows: a) identify gaps in gender-affirming healthcare for UBC students by consulting the community and collaborating with UBC services, b) develop an information package outlining provincial and university-based health insurance for gender-affirming care (including hormone therapy and surgeries), FAQs, and resources for UBC's trans students, c) make this package available to UBC students and other national transgender advocacy organizations. The initiative successfully expanded the UBC AMS Student Health and Dental Plan to include gender-affirming procedural coverage, developed a care access guide for students, and advocated for improved health records inclusivity, mechanisms for trans students to report negative care experiences, and increased access to gender-affirming primary care through the on-campus health clinic. Collaboration with other universities' pride organizations and Trans Care BC yielded positive outcomes through broader coalition building and resource sharing. Ongoing efforts are underway to update provincial policies, particularly through expanding coverage under fair pharma care and addressing the compounding effects of the primary care crisis for trans individuals. The project's tangible results include improved trans rights on campus, especially in terms of healthcare access. Expanding healthcare coverage through student care benefits thousands of students, making the ability to undergo important affirming procedures more affordable. Providing students with information on extended coverage options and communication with their doctors further removes barriers to care and positively impacts student wellbeing. This initiative demonstrates the effectiveness of community-based participatory action in advancing equitable healthcare for trans and gender-diverse individuals and serves as a model for other institutions and organizations striving to promote inclusivity and advocate for marginalized populations' rights.

Keywords: equitable healthcare, trans and gender-diverse individuals, inclusivity, participatory action research project

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Authors: B. Petrović, L. Rutonjski, M. Baucal, M. Teodorović, O. Čudić, B. Basarić

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Purpose/Objective: Radiotherapy treatment planning requires use of CT simulator, in order to acquire CT images. The overall performance of CT simulator determines the quality of radiotherapy treatment plan, and at the end, the outcome of treatment for every single patient. Therefore, it is strongly advised by international recommendations, to set up a quality control procedures for every machine involved in radiotherapy treatment planning process, including the CT scanner/ simulator. The overall process requires number of tests, which are used on daily, weekly, monthly or yearly basis, depending on the feature tested. Materials/Methods: Two phantoms were used: a dedicated phantom CIRS 062QA, and a QA phantom obtained with the CT simulator. The examined CT simulator was Siemens Somatom Definition as Open, dedicated for radiation therapy treatment planning. The CT simulator has a built in software, which enables fast and simple evaluation of CT QA parameters, using the phantom provided with the CT simulator. On the other hand, recommendations contain additional test, which were done with the CIRS phantom. Also, legislation on ionizing radiation protection requires CT testing in defined periods of time. Taking into account the requirements of law, built in tests of a CT simulator, and international recommendations, the intitutional QC programme for CT imulator is defined, and implemented. Results: The CT simulator parameters evaluated through the study were following: CT number accuracy, field uniformity, complete CT to ED conversion curve, spatial and contrast resolution, image noise, slice thickness, and patient table stability.The following limits are established and implemented: CT number accuracy limits are +/- 5 HU of the value at the comissioning. Field uniformity: +/- 10 HU in selected ROIs. Complete CT to ED curve for each tube voltage must comply with the curve obtained at comissioning, with deviations of not more than 5%. Spatial and contrast resultion tests must comply with the tests obtained at comissioning, otherwise machine requires service. Result of image noise test must fall within the limit of 20% difference of the base value. Slice thickness must meet manufacturer specifications, and patient stability with longitudinal transfer of loaded table must not differ of more than 2mm vertical deviation. Conclusion: The implemented QA tests gave overall basic understanding of CT simulator functionality and its clinical effectiveness in radiation treatment planning. The legal requirement to the clinic is to set up it’s own QA programme, with minimum testing, but it remains user’s decision whether additional testing, as recommended by international organizations, will be implemented, so to improve the overall quality of radiation treatment planning procedure, as the CT image quality used for radiation treatment planning, influences the delineation of a tumor and calculation accuracy of treatment planning system, and finally delivery of radiation treatment to a patient.

Keywords: CT simulator, radiotherapy, quality control, QA programme

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Authors: Robert Pečenko, Karin Tomažič, Igor Planinc, Sabina Huč, Tomaž Hozjan

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Timber is favourable structural material due to high strength to weight ratio, recycling possibilities, and green credentials. Despite being flammable material, it has relatively high fire resistance. Everyday engineering practice around the word is based on an outdated design of timber structures considering standard fire exposure, while modern principles of performance-based design enable use of advanced non-standard fire curves. In Europe, standard for fire design of timber structures EN 1995-1-2 (Eurocode 5) gives two methods, reduced material properties method and reduced cross-section method. In the latter, fire resistance of structural elements depends on the effective cross-section that is a residual cross-section of uncharred timber reduced additionally by so called zero strength layer. In case of standard fire exposure, Eurocode 5 gives a fixed value of zero strength layer, i.e. 7 mm, while for non-standard parametric fires no additional comments or recommendations for zero strength layer are given. Thus designers often implement adopted 7 mm rule also for parametric fire exposure. Since the latest scientific evidence suggests that proposed value of zero strength layer can be on unsafe side for standard fire exposure, its use in the case of a parametric fire is also highly questionable and more numerical and experimental research in this field is needed. Therefore, the purpose of the presented study is to use advanced calculation methods to investigate the thickness of zero strength layer and parametric charring rates used in effective cross-section method in case of parametric fire. Parametric studies are carried out on a simple solid timber beam that is exposed to a larger number of parametric fire curves Zero strength layer and charring rates are determined based on the numerical simulations which are performed by the recently developed advanced two step computational model. The first step comprises of hygro-thermal model which predicts the temperature, moisture and char depth development and takes into account different initial moisture states of timber. In the second step, the response of timber beam simultaneously exposed to mechanical and fire load is determined. The mechanical model is based on the Reissner’s kinematically exact beam model and accounts for the membrane, shear and flexural deformations of the beam. Further on, material non-linear and temperature dependent behaviour is considered. In the two step model, the char front temperature is, according to Eurocode 5, assumed to have a fixed temperature of around 300°C. Based on performed study and observations, improved levels of charring rates and new thickness of zero strength layer in case of parametric fires are determined. Thus, the reduced cross section method is substantially improved to offer practical recommendations for designing fire resistance of timber structures. Furthermore, correlations between zero strength layer thickness and key input parameters of the parametric fire curve (for instance, opening factor, fire load, etc.) are given, representing a guideline for a more detailed numerical and also experimental research in the future.

Keywords: advanced numerical modelling, parametric fire exposure, timber structures, zero strength layer

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Authors: Ali Kassem, Yhea Kishik, Ali Hassan, Mohamed Abdelwahab

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Introduction: Accelerated coronary and peripheral vascular atherosclerosis is one of the most common and chronic complications of diabetes mellitus. A recent aspect of coronary artery disease in this condition is its silent nature. The aim of the work: Detection of the prevalence of silent myocardial ischemia (SMI) in Upper Egypt type 2 diabetic males and to select male diabetic population who should be screened for SMI. Patients and methods: 100 type 2 diabetic male patients with a negative history of angina or anginal equivalent symptoms and 30 healthy control were included. Full medical history and thorough clinical examination were done for all participants. Fasting and post prandial blood glucose level, lipid profile, (HbA1c), microalbuminuria, and C-reactive protein were done for all participants Resting ECG, trans-thoracic echocardiography, treadmill exercise ECG, myocardial perfusion imaging were done for all participants and patients positive for one or more NITs were subjected for coronary angiography. Results Twenty nine patients (29%) were positive for one or more NITs in the patients group compared to only one case (3.3%) in the controls. After coronary angiography, 20 patients were positive for significant coronary artery stenosis in the patients group, while it was refused to be done by the patient in the controls. There were statistical significant difference between the two groups regarding, hypertension, dyslipidemia and obesity, family history of DM and IHD with higher levels of microalbuminuria, C-reactive protein, total lipids in patient group versus controls According to coronary angiography, patients were subdivided into two subgroups, 20 positive for SMI (positive for coronary angiography) and 80 negative for SMI (negative for coronary angiography). No statistical difference regarding family history of DM and type of diabetic therapy was found between the two subgroups. Yet, smoking, hypertension, obesity, dyslipidemia and family history of IHD were significantly higher in diabetics positive versus those negative for SMI. 90% of patients in subgroup positive for SMI had two or more cardiac risk factors while only two patients had one cardiac risk factor (10%). Uncontrolled DM was detected more in patients positive for SMI. Diabetic complications were more prevalent in patients positive for SMI versus those negative for SMI. Most of the patients positive for SMI have DM more than 5 years duration. Resting ECG and resting Echo detected only 6 and 11 cases, respectively, of the 20 positive cases in group positive for SMI compared to treadmill exercise ECG and myocardial perfusion imaging that detected 16 and 18 cases respectively, Conclusion: Type 2 diabetic male patients should be screened for detection of SMI when aged above 50 years old, diabetes duration is more than 5 years, presence of two or more cardiac risk factors and/or patients suffering from one or more of the chronic diabetic complications. CRP, is an important parameter for selection of type 2 diabetic male patients who should be screened for SMI. Non invasive cardiac tests are reliable for screening of SMI in these patients in our locality.

Keywords: C-reactive protein, Silent myocardial ischemia, Stress tests, type 2 DM

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Authors: Jennifer Kehinde, Claire O’Donnell, Annmarie Grealish

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Introduction: Breastfeeding has been shown to provide numerous health benefits for both infants and mothers. The decision to breastfeed is influenced by physiological, psychological, and emotional factors. However, the importance of equipping mothers with the necessary knowledge for successful breastfeeding practice cannot be ruled out. The decline in global breastfeeding rate can be linked to a lack of adequate breastfeeding education during the prenatal stage. This systematic review examined the effectiveness of prenatal breastfeeding education on breastfeeding uptake postpartum. Method: This review was undertaken and reported in conformity with the Preferred Reporting Items for Systemic Reviews and Meta-Analysis statement (PRISMA) and was registered on the international prospective register for systematic reviews (PROSPERO: CRD42020213853). A PICO analysis (population, intervention, comparison, outcome) was undertaken to inform the choice of keywords in the search strategy to formulate the review question, which was aimed at determining the effectiveness of prenatal breastfeeding educational programs in improving breastfeeding uptake following birth. A systematic search of five databases (Cumulative Index to Nursing and Allied Health Literature, Medline, Psych INFO, and Applied Social Sciences Index and Abstracts) was searched between January 2014 until July 2021 to identify eligible studies. Quality assessment and narrative synthesis were subsequently undertaken. Results: Fourteen studies were included. All 14 studies used different types of breastfeeding programs; eight used a combination of curriculum-based breastfeeding education programs, group prenatal breastfeeding counselling, and one-to-one breastfeeding educational programs, which were all delivered in person; four studies used web-based learning platforms to deliver breastfeeding education prenatally which were both delivered online and face to face over a period of 3 weeks to 2 months with follow-up periods ranging from 3 weeks to 6 months; one study delivered breastfeeding educational intervention using mother-to-mother breastfeeding support groups in promoting exclusive breastfeeding, and one study disseminated breastfeeding education to participants based on the theory of planned behaviour. The most effective interventions were those that included both theory and hands-on demonstrations. Results showed an increase in breastfeeding uptake, breastfeeding knowledge, an increase in a positive attitude to breastfeeding, and an increase in maternal breastfeeding self-efficacy among mothers who participated in breastfeeding educational programs during prenatal care. Conclusion: Prenatal breastfeeding education increases women’s knowledge of breastfeeding. Mothers who are knowledgeable about breastfeeding and hold a positive approach towards breastfeeding have the tendency to initiate breastfeeding and continue for a lengthened period. Findings demonstrate a general correlation between prenatal breastfeeding education and increased breastfeeding uptake postpartum. The high level of positive breastfeeding outcomes inherent in all the studies can be attributed to prenatal breastfeeding education. This review provides rigorous contemporary evidence that healthcare professionals and policymakers can apply when developing effective strategies to improve breastfeeding rates and ultimately improve the health outcomes of mothers and infants.

Keywords: breastfeeding, breastfeeding programs, breastfeeding self-efficacy, prenatal breastfeeding education

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Authors: Melissa K. Hord, Stephen P. Whiteside

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With lifetime prevalence rates ranging from 6% to 15%, anxiety disorders are among the most common childhood mental health diagnoses. Anxiety disorders diagnosed in childhood generally show an unremitting course, lead to additional psychopathology and interfere with social, emotional, and academic development. Effective evidence-based treatments include cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRI’s). However, if anxious children receive any treatment, it is usually through primary care, typically consists of medication, and very rarely includes evidence-based psychotherapy. Despite the high prevalence of anxiety disorders, there have only been two independent research labs that have investigated long-term results for CBT treatment for all childhood anxiety disorders and two for specific anxiety disorders. Generally, the studies indicate that the majority of youth maintain gains up to 7.4 years after treatment. These studies have not been replicated. In addition, little is known about the additional mental health care received by these patients in the intervening years after anxiety treatment, which seems likely to influence maintenance of gains for anxiety symptoms as well as the development of additional psychopathology during the subsequent years. The original sample consisted of 335 children ages 7 to 17 years (mean 13.09, 53% female) diagnosed with an anxiety disorder in 2010. Medical record review included provider billing records for mental health appointments during the five years after anxiety treatment. The subsample for this study was classified into three groups: 64 children who received CBT in an anxiety disorders clinic, 56 who received treatment from a psychiatrist, and 10 who were seen in a primary care setting. Chi-square analyses resulted in significant differences in mental health care utilization across the five years after treatment. Youth receiving treatment in primary care averaged less than one appointment each year and the appointments continued at the same rate across time. Children treated by a psychiatrist averaged approximately 3 appointments in the first two years and 2 in the subsequent three years. Importantly, youth treated in the anxiety clinic demonstrated a gradual decrease in mental health appointments across time. The nuanced differences will be presented in greater detail. The results of the current study have important implications for developing dissemination materials to help guide parents when they are selecting treatment for their children. By including all mental health appointments, this study recognizes that anxiety is often comorbid with additional diagnoses and that receiving evidence-based treatment may have long-term benefits that are associated with improvements in broader mental health. One important caveat might be that the acuity of mental health influenced the level of care sought by patients included in this study; however, taking this possibility into account, it seems those seeking care in a primary care setting continued to require similar care at the end of the study, indicating little improvement in symptoms was experienced.

Keywords: anxiety, children, mental health, outcomes

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Authors: E. Steen, B. Dewulf, N. Müller, C. Vandycke, Y. Vandekerckhove

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Introduction: The care for a ST-elevation myocardial infarction (STEMI) patient is time-critical. Reperfusion therapy within 90 minutes of initial medical contact is mandatory in the improvement of the outcome. Primary percutaneous coronary intervention (PCI) without previous fibrinolytic treatment, is the preferred reperfusion strategy in patients with STEMI, provided it can be performed within guideline-mandated times. Aim of the study: During a one year period (January 2013 to December 2013) the files of all consecutive STEMI patients with urgent referral from non-PCI facilities for primary PCI were reviewed. Special attention was given to a subgroup of patients with prior out-of-hospital medical contact generated by the 112-system. In an effort to reduce out-of-hospital system delay to definitive care a change in pre-hospital 112 dispatch strategies is proposed for these time-critical patients. Actual time recordings were compared with travel time simulations for two suggested scenarios. A first scenario (SC1) involves the decision by the on scene ground EMS (GEMS) team to transport the out-of-hospital diagnosed STEMI patient straight forward to a PCI centre bypassing the nearest non-PCI hospital. Another strategy (SC2) explored the potential role of helicopter EMS (HEMS) where the on scene GEMS team requests a PCI-centre based HEMS team for immediate medical transfer to the PCI centre. Methods and Results: 49 (29,1% of all) STEMI patients were referred to our hospital for emergency PCI by a non-PCI facility. 1 file was excluded because of insufficient data collection. Within this analysed group of 48 secondary referrals 21 patients had an out-of-hospital medical contact generated by the 112-system. The other 27 patients presented at the referring emergency department without prior contact with the 112-system. The table below shows the actual time data from first medical contact to definitive care as well as the simulated possible gain of time for both suggested strategies. The PCI-team was always alarmed upon departure from the referring centre excluding further in-hospital delay. Time simulation tools were similar to those used by the 112-dispatch centre. Conclusion: Our data analysis confirms prolonged reperfusion times in case of secondary emergency referrals for STEMI patients even with the use of HEMS. In our setting there was no statistical difference in gain of time between the two suggested strategies, both reducing the secondary referral generated delay with about one hour and by this offering all patients PCI within the guidelines mandated time. However, immediate HEMS activation by the on scene ground EMS team for transport purposes is preferred. This ensures a faster availability of the local GEMS-team for its community. In case these options are not available and the guideline-mandated times for primary PCI are expected to be exceeded, primary fibrinolysis should be considered in a non-PCI centre.

Keywords: STEMI, system delay, HEMS, emergency medicine

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Authors: R. Tariq, R. Lee

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Background: Heywood, Middleton & Rochdale Urgent Community Care Team (UCCT)1 is a great example of using a multidisciplinary team to cope with demand. The service reduces unnecessary admissions to hospitals and ensures that patients can leave the hospital quicker by making care more readily available within the community and patient’s homes. The team comprises nurses, community practitioners, and allied health professions, including physiotherapy, occupational therapy, pharmacy, and GPs. The main challenge for a team with a range of experiences and skill sets is to maintain consistency of care, which technology can help address. Allied healthcare professionals (HCPs) are often used in expanded roles with duties mainly involving patient consultations and decision making to ease pressure on doctors. The Clinical Reasoning Platform (CRP) Dem Dx is used to support new as well as experienced professionals in the decision making process. By guiding HCPs through diagnosing patients from an expansive directory of differential diagnoses, patients can receive quality care in the community. Actions on the platform are determined using NICE guidelines along with local guidance influencing the assessment and management of a patient. Objective: To compare the clinical assessment, decisions, and actions taken by the UCCT multidisciplinary team in the community and Dem Dx, using retrospective clinical cases. Methodology: Dem Dx was used to analyse 192 anonymised cases provided by the HMR UCCT. The team’s performance was compared with Dem Dx regarding the quality of the documentation of the clinical assessment and the next steps on the patient’s journey, including the initial management, actions, and any onward referrals made. The cases were audited by two medical doctors. Results: The study found that the actions outlined by the Dem Dx platform were appropriate in almost 87% of cases. When in a direct comparison between DemDX and the actions taken by the clinical team, it was found that the platform was suitable 83% (p<0.001) of the time and could lead to a potential improvement of 66% in the assessment and management of cases. Dem Dx also served to highlight the importance of comprehensive and high quality clinical documentation. The quality of documentation of cases by UCCT can be improved to provide a detailed account of the assessment and management process. By providing step-by-step guidance and documentation at every stage, Dem Dx may ensure that legal accountability has been fulfilled. Conclusion: With the ever expanding workforce in the NHS, technology has become a key component in driving healthcare outcomes. To improve healthcare provision and clinical reasoning, a decision support platform can be integrated into HCPs’ clinical practice. Potential assistance with clinical assessments, the most appropriate next step and actions in a patient’s care, and improvements in the documentation was highlighted by this retrospective study. A further study has been planned to ascertain the effectiveness of improving outcomes using the clinical reasoning platform within the clinical setting by clinicians.

Keywords: allied health professional, assessment, clinical reasoning, clinical records, clinical decision-making, ocumentation

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Authors: Chee Wee Gan, Anthony Herr Cheun Ng, Yee Shan Wong, Subbu Venkatraman, Lynne Hsueh Yee Lim

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Otitis media with effusion (OME) is the leading cause of hearing loss in children worldwide. Surgery to insert grommet tube into the eardrum is usually indicated for OME unresponsive to antimicrobial therapy. It is the most common surgery for children. However, current commercially available grommet tubes are non-bioresorbable, not drug-treated, with unpredictable duration of retention on the eardrum to ventilate middle ear. Their functionality is impaired when clogged or chronically infected, requiring additional surgery to remove/reinsert grommet tubes. We envisaged that a novel fully bioresorbable grommet tube with sustained antibiotic release technology could address these drawbacks. In this study, drug-loaded bioresorbable poly(L-lactide-co-ε-caprolactone)(PLC) copolymer grommet tubes were fabricated by microinjection moulding technique. In vitro drug release and degradation model of PLC tubes were studied. Antibacterial property was evaluated by incubating PLC tubes with P. aeruginosa broth. Surface morphology was analyzed using scanning electron microscopy. A preliminary animal study was conducted using guinea pigs as an in vivo model to evaluate PLC tubes with and without drug, with commercial Mini Shah grommet tube as comparison. Our in vitro data showed sustained drug release over 3 months. All PLC tubes revealed exponential degradation profiles over time. Modeling predicted loss of tube functionality in water to be approximately 14 weeks and 17 weeks for PLC with and without drug, respectively. Generally, PLC tubes had less bacteria adherence, which were attributed to the much smoother tube surfaces compared to Mini Shah. Antibiotic from PLC tube further made bacteria adherence on surface negligible. They showed neither inflammation nor otorrhea after 18 weeks post-insertion in the eardrums of guinea pigs, but had demonstrated severe degree of bioresorption. Histology confirmed the new PLC tubes were biocompatible. Analyses on the PLC tubes in the eardrums showed bioresorption profiles close to our in vitro degradation models. The bioresorbable antibiotic-loaded grommet tubes showed good predictability in functionality. The smooth surface and sustained release technology reduced the risk of tube infection. Tube functional duration of 18 weeks allowed sufficient ventilation period to treat OME. Our ongoing studies include modifying the surface properties with protein coating, optimizing the drug dosage in the tubes to enhance their performances, evaluating their functional outcome on hearing after full resoption of grommet tube and healing of eardrums, and developing animal model with OME to further validate our in vitro models.

Keywords: bioresorbable polymer, drug release, grommet tube, guinea pigs, otitis media with effusion

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Authors: Geum Yeon Sim, Jasal Patel, Anand Kumthekar, Stanley Wainapel

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A 65-year-old right-hand dominant African-American man, formerly employed as a security guard, was referred to Rehabilitation Medicine with bilateral hand stiffness and weakness. His past medical history was only significant for myelofibrosis, diagnosed 4 years earlier, for which he was receiving scheduled blood transfusions. Approximately 2 years ago, he began to notice stiffness and swelling in his non-dominant hand that progressed to pain and decreased strength, limiting his hand function. Similar but milder symptoms developed in his right hand several months later. There was no history of prior injury or exposure to cold. Physical examination showed enlargement of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints with finger flexion contractures, Swan-neck and Boutonniere deformities, and associated joint tenderness. Changes were more prominent in the left hand. X-rays showed mild osteoarthritis of several bilateral PIP joints. Anti-nuclear antibodies, rheumatoid factor, and cyclic citrullinated peptide antibodies were negative. MRI of the hand showed no erosions or synovitis. A rheumatology consultation was obtained, and the cause of his symptoms was attributed to myelofibrosis-related arthropathy with secondary osteoarthritis. The patient was tried on diclofenac cream and received a few courses of Occupational Therapy with limited functional improvement. Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. Rheumatic manifestations of malignancies include direct invasion, paraneoplastic presentations, secondary gout, or hypertrophic osteoarthropathy. PMF causes gradual bone marrow fibrosis with extramedullary metaplastic hematopoiesis in the liver, spleen, or lymph nodes. Musculoskeletal symptoms are not common and are not well described in the literature. The first reported case of myelofibrosis related arthritis was seronegative arthritis due to synovial invasion of myeloproliferative elements. Myelofibrosis has been associated with autoimmune diseases such as systemic lupus erythematosus, progressive systemic sclerosis, and rheumatoid arthritis. Gout has been reported in patients with myelofibrosis, and the underlying mechanism is thought to be related to the high turnover of nucleic acids that is greatly augmented in this disease. X-ray findings in these patients usually include erosive arthritis with synovitis. Treatment of underlying PMF is the treatment of choice, along with anti-inflammatory medications. Physicians should be cognizant of recognizing this rare entity in patients with PMF while maintaining clinical suspicion for more common causes of joint deformities, such as rheumatic diseases.

Keywords: myelofibrosis, arthritis, arthralgia, malignancy

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Authors: Luvuno N. Jele, Warwick W. Hastie, Andrew Green

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Calcarenite is a clastic sedimentary beach rock composed of more than 50% sand sized (0.0625 – 2 mm) carbonate grains. In South Africa, these rocks occur as a narrow belt along most of the coast of KwaZulu-Natal and sporadically along the coast of the Eastern Cape. Calcarenites contain a high percentage of calcium carbonate, and due to a number of its physical and structural features, like porosity, cementing material, sedimentary structures, grain shape, and grain size; they are more prone to chemical and mechanical weathering. The objective of the research is to study the strength and compressibility characteristics of the calcarenites along the coast of KwaZulu-Natal to be able to better understand the geotechnical behaviour of these rocks, which may help to predict areas along the coast which may be potentially susceptible to failure/differential settling resulting in damage to property. A total of 148 cores were prepared and analyzed. Cores were analyzed perpendicular and parallel to bedding. Tests were carried out in accordance with the relevant codes and recommendations of the International Society for Rock Mechanics, American Standard Testing Methods, and Committee of Land and Transport Standard Specifications for Road and Bridge Works for State Road Authorities. Test carried out included: x-ray diffraction, petrography, shape preferred orientation (SPO), 3-D Tomography, rock porosity, rock permeability, ethylene glycol, slake durability, rock water absorption, Duncan swelling index, triaxial compressive strength, Brazilian tensile strength and uniaxial compression test with elastic modulus. The beach-rocks have a uniaxial compressive strength (UCS) ranging from 17,84Mpa to 287,35Mpa and exhibit three types of failure; (1) single sliding shear failure, (2) complete cone development, and (3) splitting failure. Brazilian tensile strength of the rocks ranges from 2.56 Mpa to 12,40 Ma, with those tested perpendicular to bedding showing lower tensile strength. Triaxial compressive tests indicate calcarenites have strength ranging from 86,10 Mpa to 371,85 Mpa. Common failure mode in the triaxial test is a single sliding shear failure. Porosity of the rocks varies from 1.25 % to 26.52 %. Rock tests indicate that the direction of loading, whether it be parallel to bedding or perpendicular to bedding, plays no significantrole in the strength and durability of the calcarenites. Porosity, cement type, and grain texture play major roles.UCS results indicate that saturated cores are weaker in strength compared to dry samples. Thus, water or moisture content plays a significant role in the strength and durability of the beach-rock. Loosely packed, highly porous and low magnesian-calcite bearing calcarenites show a decrease in strength compared to the densely packed, low porosity and high magnesian-calcite bearing calcarenites.

Keywords: beach-rock, calcarenite, cement, compressive, failure, porosity, strength, tensile, grains

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Authors: Alinka Molnár-Tóth, Tímea Tánczos, Regina Barna, Katalin Jakab, Péter Klivényi

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Supported by neuroscientific findings, the so-called Hub-and-Spoke model of the human semantic system is based on two subcomponents of semantic cognition, namely the semantic control process and semantic representation. Our semantic knowledge is multimodal in nature, as the knowledge system stored in relation to a conception is extensive and broad, while different aspects of the conception may be relevant depending on the purpose. The motivation of our research is to develop a new diagnostic measurement procedure based on the preservation of semantic representation, which is appropriate to the specificities of the Hungarian language and which can be used to compare the non-verbal semantic knowledge of healthy and aphasic persons. The development of the test will broaden the Hungarian clinical diagnostic toolkit, which will allow for more specific therapy planning. The sample of healthy persons (n=480) was determined by the last census data for the representativeness of the sample. Based on the concept of the Pyramids and Palm Tree Test, and according to the characteristics of the Hungarian language, we have elaborated a test based on different types of semantic information, in which the subjects are presented with three pictures: they have to choose the one that best fits the target word above from the two lower options, based on the semantic relation defined. We have measured 5 types of semantic knowledge representations: associative relations, taxonomy, motional representations, concrete as well as abstract verbs. As the first step in our data analysis, we examined the normal distribution of our results, and since it was not normally distributed (p < 0.05), we used nonparametric statistics further into the analysis. Using descriptive statistics, we could determine the frequency of the correct and incorrect responses, and with this knowledge, we could later adjust and remove the items of questionable reliability. The reliability was tested using Cronbach’s α, and it can be safely said that all the results were in an acceptable range of reliability (α = 0.6-0.8). We then tested for the potential gender differences using the Mann Whitney-U test, however, we found no difference between the two (p < 0.05). Likewise, we didn’t see that the age had any effect on the results using one-way ANOVA (p < 0.05), however, the level of education did influence the results (p > 0.05). The relationships between the subtests were observed by the nonparametric Spearman’s rho correlation matrix, showing statistically significant correlation between the subtests (p > 0.05), signifying a linear relationship between the measured semantic functions. A margin of error of 5% was used in all cases. The research will contribute to the expansion of the clinical diagnostic toolkit and will be relevant for the individualised therapeutic design of treatment procedures. The use of a non-verbal test procedure will allow an early assessment of the most severe language conditions, which is a priority in the differential diagnosis. The measurement of reaction time is expected to advance prodrome research, as the tests can be easily conducted in the subclinical phase.

Keywords: communication disorders, diagnostic toolkit, neurorehabilitation, semantic knowlegde

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Authors: Aoxue Yang, Weili Tian, Haikun Liu

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Brain tumor stem cells (BTSCs) are resistant to therapy and give rise to recurrent tumors. These rare and elusive cells are likely to disseminate during cancer progression, and some may enter dormancy, remaining viable but not increasing. The identification of dormant BTSCs is thus necessary to design effective therapies for glioblastoma (GBM) patients. Glucocorticoids (GCs) are used to treat GBM-associated edema. However, glucocorticoids participate in the physiological response to psychosocial stress, linked to poor cancer prognosis. This raises concern that glucocorticoids affect the tumor and BTSCs. Identifying markers specifically expressed by brain tumor stem cells (BTSCs) may enable specific therapies that spare their regular tissue-resident counterparts. By ribosome profiling analysis, we have identified that glycerol-3-phosphate dehydrogenase 1 (GPD1) is expressed by dormant BTSCs but not by NSCs. Through different stress-induced experiments in vitro, we found that only dexamethasone (DEXA) can significantly increase the expression of GPD1 in NSCs. Adversely, mifepristone (MIFE) which is classified as glucocorticoid receptors antagonists, could decrease GPD1 protein level and weaken the proliferation and stemness in BTSCs. Furthermore, DEXA can induce GPD1 expression in tumor-bearing mice brains and shorten animal survival, whereas MIFE has a distinct adverse effect that prolonged mice lifespan. Knocking out GR in NSC can block the upregulation of GPD1 inducing by DEXA, and we find the specific sequences on GPD1 promotor combined with GR, thus improving the efficiency of GPD1 transcription from CHIP-Seq. Moreover, GR and GPD1 are highly co-stained on GBM sections obtained from patients and mice. All these findings confirmed that GR could regulate GPD1 and loss of GPD1 Impairs Multiple Pathways Important for BTSCs Maintenance GPD1 is also a critical enzyme regulating glycolysis and lipid synthesis. We observed that DEXA and MIFE could change the metabolic profiles of BTSCs by regulating GPD1 to shift the transition of cell dormancy. Our transcriptome and lipidomics analysis demonstrated that cell cycle signaling and phosphoglycerides synthesis pathways contributed a lot to the inhibition of GPD1 caused by MIFE. In conclusion, our findings raise concern that treatment of GBM with GCs may compromise the efficacy of chemotherapy and contribute to BTSC dormancy. Inhibition of GR can dramatically reduce GPD1 and extend the survival duration of GBM-bearing mice. The molecular link between GPD1 and GR may give us an attractive therapeutic target for glioblastoma.

Keywords: cancer stem cell, dormancy, glioblastoma, glycerol-3-phosphate dehydrogenase 1, glucocorticoid receptor, dexamethasone, RNA-sequencing, phosphoglycerides

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Authors: Ilana Singer, Anastasia Lučić, Julie Leclerc

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Introduction: Tics, characterized by repetitive, sudden, non-voluntary motor movements or vocalizations, are prevalent in chronic tic disorder (CT) and Tourette Syndrome (TS). These neurodevelopmental disorders often coexist with various psychiatric conditions, leading to challenges and reduced quality of life. While medication in conjunction with behavioral interventions, such as Habit Reversal Training (HRT), Exposure Response Prevention (ERP), and Comprehensive Behavioral Intervention for Tics (CBIT), has shown efficacy, a significant proportion of patients experience persistent tics. Thus, innovative treatment approaches are necessary to improve therapeutic outcomes, such as mindfulness-based approaches. Nonetheless, the effectiveness of mindfulness-based interventions in the context of CT and TS remains understudied. Objective: The objective of this scoping review is to provide an overview of the current state of research on mindfulness-based interventions for CT and TS, identify knowledge and evidence gaps, discuss the effectiveness of mindfulness-based interventions with other treatment options, and discuss implications for clinical practice and policy development. Method: Using guidelines from Peters (2020) and the PRISMA-ScR, a scoping review was conducted. Multiple electronic databases were searched from inception until June 2023, including MEDLINE, EMBASE, PsychInfo, Global Health, PubMed, Web of Science, and Érudit. Inclusion criteria were applied to select relevant studies, and data extraction was independently performed by two reviewers. Results: Five papers were included in the study. Firstly, we found that mindfulness interventions were found to be effective in reducing anxiety and depression while enhancing overall well-being in individuals with tics. Furthermore, the review highlighted the potential role of mindfulness in enhancing functional connectivity within the Default Mode Network (DMN) as a compensatory function in TS patients. This suggests that mindfulness interventions may complement and support traditional therapeutic approaches, particularly HRT, by positively influencing brain networks associated with tic regulation and control. Conclusion: This scoping review contributes to the understanding of the effectiveness of mindfulness-based interventions in managing CT and TS. By identifying research gaps, this review can guide future investigations and interventions to improve outcomes for individuals with CT or TS. Overall, these findings emphasize the potential benefits of incorporating mindfulness-based interventions as a smaller subset within comprehensive treatment strategies. However, it is essential to acknowledge the limitations of this scoping review, such as the exclusion of a pre-established protocol and the limited number of studies available for inclusion. Further research and clinical exploration are necessary to better understand the specific mechanisms and optimal integration of mindfulness-based interventions with existing behavioral interventions for this population.

Keywords: scoping reviews, Tourette Syndrome, tics, mindfulness-based, therapy, intervention

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Authors: Shenlun Chen, Leonard Wee

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Tumor grading is an essential reference for colorectal cancer (CRC) staging and survival prognostication. The widely used World Health Organization (WHO) grading system defines histological grade of CRC adenocarcinoma based on the density of glandular formation on whole slide images (WSI). Tumors are classified as well-, moderately-, poorly- or un-differentiated depending on the percentage of the tumor that is gland forming; >95%, 50-95%, 5-50% and <5%, respectively. However, manually grading WSIs is a time-consuming process and can cause observer error due to subjective judgment and unnoticed regions. Furthermore, pathologists’ grading is usually coarse while a finer and continuous differentiation grade may help to stratifying CRC patients better. In this study, a deep learning based automatic differentiation grading algorithm was developed and evaluated by survival analysis. Firstly, a gland segmentation model was developed for segmenting gland structures. Gland regions of WSIs were delineated and used for differentiation annotating. Tumor regions were annotated by experienced pathologists into high-, medium-, low-differentiation and normal tissue, which correspond to tumor with clear-, unclear-, no-gland structure and non-tumor, respectively. Then a differentiation prediction model was developed on these human annotations. Finally, all enrolled WSIs were processed by gland segmentation model and differentiation prediction model. The differentiation grade can be calculated by deep learning models’ prediction of tumor regions and tumor differentiation status according to WHO’s defines. If multiple WSIs were possessed by a patient, the highest differentiation grade was chosen. Additionally, the differentiation grade was normalized into scale between 0 to 1. The Cancer Genome Atlas, project COAD (TCGA-COAD) project was enrolled into this study. For the gland segmentation model, receiver operating characteristic (ROC) reached 0.981 and accuracy reached 0.932 in validation set. For the differentiation prediction model, ROC reached 0.983, 0.963, 0.963, 0.981 and accuracy reached 0.880, 0.923, 0.668, 0.881 for groups of low-, medium-, high-differentiation and normal tissue in validation set. Four hundred and one patients were selected after removing WSIs without gland regions and patients without follow up data. The concordance index reached to 0.609. Optimized cut off point of 51% was found by “Maxstat” method which was almost the same as WHO system’s cut off point of 50%. Both WHO system’s cut off point and optimized cut off point performed impressively in Kaplan-Meier curves and both p value of logrank test were below 0.005. In this study, gland structure of WSIs and differentiation status of tumor regions were proven to be predictable through deep leaning method. A finer and continuous differentiation grade can also be automatically calculated through above models. The differentiation grade was proven to stratify CAC patients well in survival analysis, whose optimized cut off point was almost the same as WHO tumor grading system. The tool of automatically calculating differentiation grade may show potential in field of therapy decision making and personalized treatment.

Keywords: colorectal cancer, differentiation, survival analysis, tumor grading

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Authors: Sudip Kumar Sinha, Saptarshi Ghosh

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While there’s a perpetual buzz around zinc oxide (ZnO) superstructures for their unique optical features, the versatile material has been constantly utilized to manifest tailored electronic properties through rendition of distinct morphologies. And yet, the unorthodox approach of implementing the novel 1D nanostructures of ZnO (pristine or doped) for volatile sensing applications has ample scope to accommodate new unconventional morphologies. In the last two decades, solid-state sensors have attracted much curiosity for their relevance in identifying pollutant, toxic and other industrial gases. In particular gas sensors based on metal oxide semiconducting (wide Eg) nanomaterials have recently attracted intensive attention owing to their high sensitivity and fast response and recovery time. These materials when exposed to air, the atmospheric O2 dissociates and get absorb on the surface of the sensors by trapping the outermost shell electrons. Finally a depleted zone on the surface of the sensors is formed, that enhances the potential barrier height at grain boundary . Once a target gas is exposed to the sensor, the chemical interaction between the chemisorbed oxygen and the specific gas liberates the trapped electrons. Therefore altering the amount of adsorbate is a considerable approach to improve the sensitivity of any target gas/vapour molecule. Likewise, this study presents a spontaneous but self catalytic creation of Sn-doped ZnO hexagonal nanoprisms on Si (100) substrates through thermal evaporation-condensation method, and their subsequent deployment for volatile sensing. In particular, the sensors were utilized to detect molecules of ethanol, acetone and ammonia below their permissible exposure limits which returned sensitivities of around 85%, 80% and 50% respectively. The influence of Sn concentration on the growth, microstructural and optical properties of the nanoprisms along with its role in augmenting the sensing parameters has been detailed. The single-crystalline nanostructures have a typical diameter ranging from 300 to 500 nm and a length that extends up to few micrometers. HRTEM images confirmed the hexagonal crystallography for the nanoprisms, while SAED pattern asserted the single crystalline nature. The growth habit is along the low index <0001>directions. It has been seen that the growth mechanism of the as-deposited nanostructures are directly influenced by varying supersaturation ratio, fairly high substrate temperatures, and specified surface defects in certain crystallographic planes, all acting cooperatively decide the final product morphology. Room temperature photoluminescence (PL) spectra of this rod like structures exhibits a weak ultraviolet (UV) emission peak at around 380 nm and a broad green emission peak in the 505 nm regime. An estimate of the sensing parameters against dispensed target molecules highlighted the potential for the nanoprisms as an effective volatile sensing material. The Sn-doped ZnO nanostructures with unique prismatic morphology may find important applications in various chemical sensors as well as other potential nanodevices.

Keywords: gas sensor, HRTEM, photoluminescence, ultraviolet, zinc oxide

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Authors: Esther Gumboh

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The police play a critical role in society and are an integral aspect of the rule of law. Equally, respect for human rights is an integral part of professional policing. In view of the vast powers that the police enjoy and the attendant risk of abuse and resulting human rights violations, the need for police accountability and civilian police oversight is internationally and regionally recognised. Policing oversight springs from the duty to investigate human rights violations. Those implicated in perpetrating or covering up violations must be disciplined or prosecuted to ensure effective accountability. Police accountability is particularly important in Malawi given the dark history of policing in the country during the 30-year dictatorial era under President Kamuzu Banda. Described as one of the most repressive regimes in Africa, the Banda administration was characterised by gross state-sponsored violence, repressive policing and human rights violations. Indeed, the police were involved in various forms of human rights abuse including arbitrary arrests and unlawful detentions, torture, and excessive use of force in conducting arrests and public order policing. This situation flourished within a culture of police impunity bolstered in part by the absence of clear oversight mechanisms for police accountability. In turn, there was immense public mistrust of the police. Unsurprisingly, the criminal justice system was one of the priority areas for reform when Malawi adopted its first democratic Constitution in 1994. Section 153 of the Constitution envisions a police service that is, for all intents and purposes, there to provide for the protection of public safety and the rights of persons in Malawi according to the prescriptions of the Constitution and any other law. This position reflects the view that the duty to protect and promote human rights is not incompatible with effective policing. Despite this, the police continue to engage in questionable behaviour in public order policing, excessive use of force, deaths in police custody, ill-treatment, torture and other forms of abuse including sexual abuse. Perpetrators of abuses are occasionally punished, but investigations are often delayed, abandoned, or remain inconclusive. Police accountability remains largely elusive. Commendably, the law does subject the police to significant oversight both internally and externally. However, until 2010, Malawi lacked a wholly independent civilian oversight mechanism specifically mandated to monitor the activities of the Malawi Police Service and held it accountable. This void has since been filled by the Independent Complaints Commission established under the Police Act. This is a positive development that reiterates Malawi’s commitment to the investigation of human rights violations by the police and to ending police impunity. This contribution examines the legal framework for this Commission to project the effectiveness of the Commission. While the framework looks promising on various fronts, there are potential challenges that lie ahead. Malawi must pre-emptively deal with these challenges carefully if the Commission is to have any practical significance in transforming police accountability in the country. Drawing on lessons from other jurisdictions like South Africa, the paper makes recommendations for legislative reform to strengthen the Commission’s framework.

Keywords: civilian policing oversight, Malawi, police, police accountability, policing, policing oversight

Procedia PDF Downloads 193

Authors: Jade V. Rushby, Tony Loughland, Tracy L. Durksen, Hoa Nguyen, Robert M. Klassen

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This paper reports a study investigating the development and implementation of an online multi-session ‘scenario-based learning’ (SBL) program administered to preservice teachers in Australia. The transition from initial teacher education to the teaching profession can present numerous cognitive and psychological challenges for early career teachers. Therefore, the identification of additional supports, such as scenario-based learning, that can supplement existing teacher education programs may help preservice teachers to feel more confident and prepared for the realities and complexities of teaching. Scenario-based learning is grounded in situated learning theory which holds that learning is most powerful when it is embedded within its authentic context. SBL exposes participants to complex and realistic workplace situations in a supportive environment and has been used extensively to help prepare students in other professions, such as legal and medical education. However, comparatively limited attention has been paid to investigating the effects of SBL in teacher education. In the present study, the SBL intervention provided participants with the opportunity to virtually engage with school-based scenarios, reflect on how they might respond to a series of plausible response options, and receive real-time feedback from experienced educators. The development process involved several stages, including collaboration with experienced educators to determine the scenario content based on ‘critical incidents’ they had encountered during their teaching careers, the establishment of the scoring key, the development of the expert feedback, and an extensive review process to refine the program content. The 4-part SBL program focused on areas that can be challenging in the beginning stages of a teaching career, including managing student behaviour and workload, differentiating the curriculum, and building relationships with colleagues, parents, and the community. Results from prior studies implemented by the research group using a similar 4-part format have shown a statistically significant increase in preservice teachers’ self-efficacy and classroom readiness from the pre-test to the final post-test. In the current research, professional teaching identity - incorporating self-efficacy, motivation, self-image, satisfaction, and commitment to teaching - was measured over six weeks at multiple time points: before, during, and after the 4-part scenario-based learning program. Analyses included latent growth curve modelling to assess the trajectory of change in the outcome variables throughout the intervention. The paper outlines (1) the theoretical underpinnings of SBL, (2) the development of the SBL program and methodology, and (3) the results from the study, including the impact of the SBL program on aspects of participating preservice teachers’ professional identity. The study shows how SBL interventions can be implemented alongside the initial teacher education curriculum to help prepare preservice teachers for the transition from student to teacher.

Keywords: classroom simulations, e-learning, initial teacher education, preservice teachers, professional learning, professional teaching identity, scenario-based learning, teacher development

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Authors: Jennifer Kehinde, Claire O'donnell, Annmarie Grealish

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Introduction: Breastfeeding has been shown to provide numerous health benefits for both infants and mothers. The decision to breastfeed is influenced by physiological, psychological, and emotional factors. However, the importance of equipping mothers with the necessary knowledge for successful breastfeeding practice cannot be ruled out. The decline in global breastfeeding rate can be linked to lack of adequate breastfeeding education during prenatal stage.This systematic review examined the effectiveness of prenatal breastfeeding education on breastfeeding uptake postpartum. Method: This review was undertaken and reported in conformity with the Preferred Reporting Items for Systemic Reviews and Meta-Analysis statement (PRISMA) and was registered on the international prospective register for systematic reviews (PROSPERO: CRD42020213853). A PICO analysis (population, intervention, comparison, outcome) was undertaken to inform the choice of keywords in the search strategy to formulate the review question which was aimed at determining the effectiveness of prenatal breastfeeding educational programs at improving breastfeeding uptake following birth. A systematic search of five databases (Cumulative Index to Nursing and Allied Health Literature, Medline, Psych INFO, and Applied Social Sciences Index and Abstracts) were searched between January 2014 until July 2021 to identify eligible studies. Quality assessment and narrative synthesis were subsequently undertaken. Results: Fourteen studies were included. All 14 studies used different types of breastfeeding programs; eight used a combination of curriculum based breastfeeding education program, group prenatal breastfeeding counselling and one-to-one breastfeeding educational programs which were all delivered in person; four studies used web-based learning platforms to deliver breastfeeding education prenatally which were both delivered online and face to face over a period of 3 weeks to 2 months with follow-up periods ranging from 3 weeks to 6 months; one study delivered breastfeeding educational intervention using mother-to-mother breastfeeding support groups in promoting exclusive breastfeeding and one study disseminated breastfeeding education to participants based on the theory of planned behaviour. The most effective interventions were those that included both theory and hands-on demonstrations. Results showed an increase in breastfeeding uptake, breastfeeding knowledge, increase in positive attitude to breastfeeding and an increase in maternal breastfeeding self-efficacy among mothers who participated in breastfeeding educational programs during prenatal care. Conclusion: Prenatal breastfeeding education increases women’s knowledge of breastfeeding. Mothers who are knowledgeable about breastfeeding and hold a positive approach towards breastfeeding have the tendency to initiate breastfeeding and continue for a lengthened period. Findings demonstrates a general correlation between prenatal breastfeeding education and increased breastfeeding uptake postpartum. The high level of positive breastfeeding outcome inherent in all the studies can be attributed to prenatal breastfeeding education. This review provides rigorous contemporary evidence that healthcare professionals and policymakers can apply when developing effective strategies to improve breastfeeding rates and ultimately improve the health outcomes of mothers and infants.

Keywords: breastfeeding, breastfeeding programs, breastfeeding self-efficacy, prenatal breastfeedng education

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Authors: Nigar Kantarci Carsibasi

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

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

Procedia PDF Downloads 104