Search results for: conversion curve
Commenced in January 2007
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Edition: International
Paper Count: 2207

Search results for: conversion curve

17 An Engaged Approach to Developing Tools for Measuring Caregiver Knowledge and Caregiver Engagement in Juvenile Type 1 Diabetes

Authors: V. Howard, R. Maguire, S. Corrigan

Abstract:

Background: Type 1 Diabetes (T1D) is a chronic autoimmune disease, typically diagnosed in childhood. T1D puts an enormous strain on families; controlling blood-glucose in children is difficult and the consequences of poor control for patient health are significant. Successful illness management and better health outcomes can be dependent on quality of caregiving. On diagnosis, parent-caregivers face a steep learning curve as T1D care requires a significant level of knowledge to inform complex decision making throughout the day. The majority of illness management is carried out in the home setting, independent of clinical health providers. Parent-caregivers vary in their level of knowledge and their level of engagement in applying this knowledge in the practice of illness management. Enabling researchers to quantify these aspects of the caregiver experience is key to identifying targets for psychosocial support interventions, which are desirable for reducing stress and anxiety in this highly burdened cohort, and supporting better health outcomes in children. Currently, there are limited tools available that are designed to capture this information. Where tools do exist, they are not comprehensive and do not adequately capture the lived experience. Objectives: Development of quantitative tools, informed by lived experience, to enable researchers gather data on parent-caregiver knowledge and engagement, which accurately represents the experience/cohort and enables exploration of questions that are of real-world value to the cohort themselves. Methods: This research employed an engaged approach to address the problem of quantifying two key aspects of caregiver diabetes management: Knowledge and engagement. The research process was multi-staged and iterative. Stage 1: Working from a constructivist standpoint, literature was reviewed to identify relevant questionnaires, scales and single-item measures of T1D caregiver knowledge and engagement, and harvest candidate questionnaire items. Stage 2: Aggregated findings from the review were circulated among a PPI (patient and public involvement) expert panel of caregivers (n=6), for discussion and feedback. Stage 3: In collaboration with the expert panel, data were interpreted through the lens of lived experience to create a long-list of candidate items for novel questionnaires. Items were categorized as either ‘knowledge’ or ‘engagement’. Stage 4: A Delphi-method process (iterative surveys) was used to prioritize question items and generate novel questions that further captured the lived experience. Stage 5: Both questionnaires were piloted to refine wording of text to increase accessibility and limit socially desirable responding. Stage 6: Tools were piloted using an online survey that was deployed using an online peer-support group for caregivers for Juveniles with T1D. Ongoing Research: 123 parent-caregivers completed the survey. Data analysis is ongoing to establish face and content validity qualitatively and through exploratory factor analysis. Reliability will be established using an alternative-form method and Cronbach’s alpha will assess internal consistency. Work will be completed by early 2024. Conclusion: These tools will enable researchers to gain deeper insights into caregiving practices among parents of juveniles with T1D. Development was driven by lived experience, illustrating the value of engaged research at all levels of the research process.

Keywords: caregiving, engaged research, juvenile type 1 diabetes, quantified engagement and knowledge

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16 Bicycle Tourism and Sharing Economy (C2C-Tourism): Analysis of the Reciprocity Behavior in the Case of Warmshowers

Authors: Jana Heimel, Franziska Drescher, Lauren Ugur, Graciela Kuchle

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Sharing platforms are a widely investigated field. However, there is a research gap with a lack of focus on ‘real’ (non-profit-orientated) sharing platforms. The research project addresses this gap by conducting an empirical study on a private peer-to-peer (P2P) network to investigate cooperative behavior from a socio-psychological perspective. In recent years the conversion from possession to accessing is increasingly influencing different sectors, particularly the traveling industry. The number of people participating in hospitality exchange platforms like Airbnb, Couchsurfing, and Warmshowers (WS) is rapidly growing. WS is an increasingly popular online community that is linking cycling tourists and locals. It builds on the idea of the “sharing economy” as a not-for-profit hospitality network for bicycle tourists. Hosts not only provide a sleeping berth and warm shower free of charge but also offer additional services to their guests, such as cooking and washing clothes for them. According to previous studies, they are motivated by the idea of promoting cultural experience and forming new friendships. Trust and reciprocity are supposed to play major roles in the success of such platforms. The objective of this research project is to analyze the reciprocity behavior within the WS community. Reciprocity is the act of giving and taking among each other. Individuals feel obligated to return a favor and often expect to increase their own chances of receiving future benefits for themselves. Consequently, the drivers that incite giving and taking, as well as the motivation for hosts and guests, are examined. Thus, the project investigates a particular tourism offer that contributes to sustainable tourism by analyzing P2P resp. cyclist-to-cyclist, C2C) tourism. C2C tourism is characterized by special hospitality and generosity. To find out what motivations drive the hosts and which determinants drive the sharing cycling economy, an empirical study has been conducted globally through an online survey. The data was gathered through the WS community and comprised responses from more than 10,000 cyclists around the globe. Next to general information mostly comprising quantitative data on bicycle tourism (year/tour distance, duration and budget), qualitative information on traveling with WS as well as hosting was collected. The most important motivations for a traveler is to explore the local culture, to save money, and to make friends. The main reasons to host a guest are to promote the use of bicycles and to make friends, but also to give back and pay forward. WS members prefer to stay with/host cyclists. The results indicate that C2C tourists share homogenous characteristics and a similar philosophy, which is crucial for building mutual trust. Members of WS are generally extremely trustful. The study promotes an ecological form of tourism by combining sustainability, regionality, health, experience and the local communities' cultures. The empirical evidence found and analyzed, despite evident limitations, enabled us to shed light, especially on the issue of motivations and social capital, and on the functioning of ‘sharing’ platforms. Final research results are intended to promote C2C tourism around the globe to further replace conventional by sustainable tourism.

Keywords: bicycle tourism, homogeneity, reciprocity, sharing economy, trust

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15 Production of Bioethanol from Oil PalmTrunk by Cocktail Carbohydrases Enzyme Produced by Thermophilic Bacteria Isolated from Hot spring in West Sumatera, Indonesia

Authors: Yetti Marlida, Syukri Arif, Nadirman Haska

Abstract:

Recently, alcohol fuels have been produced on industrial scales by fermentation of sugars derived from wheat, corn, sugar beets, sugar cane etc. The enzymatic hydrolysis of cellulosic materials to produce fermentable sugars has an enormous potential in meeting global bioenergy demand through the biorefinery concept, since agri-food processes generate millions of tones of waste each year (Xeros and Christakopoulos 2009) such as sugar cane baggase , wheat straw, rice straw, corn cob, and oil palm trunk. In fact oil palm trunk is one of the most abundant lignocellulosic wastes by-products worldwide especially come from Malaysia, Indonesia and Nigeria and provides an alternative substrate to produce useful chemicals such as bioethanol. Usually, from the ages 3 years to 25 years, is the economical life of oil palm and after that, it is cut for replantation. The size of trunk usually is 15-18 meters in length and 46-60 centimeters in diameter. The trunk after cutting is agricultural waste causing problem in elimination but due to the trunk contains about 42% cellulose, 34.4%hemicellulose, 17.1% lignin and 7.3% other compounds,these agricultural wastes could make value added products (Pumiput, 2006).This research was production of bioethanol from oil palm trunk via saccharafication by cocktail carbohydrases enzymes. Enzymatic saccharification of acid treated oil palm trunk was carried out in reaction mixture containing 40 g treated oil palm trunk in 200 ml 0.1 M citrate buffer pH 4.8 with 500 unit/kg amylase for treatment A: Treatment B: Treatment A + 500 unit/kg cellulose; C: treatment B + 500 unit/kgg xylanase: D: treatment D + 500 unit/kg ligninase and E: OPT without treated + 500 unit/kg amylase + 500 unit/kg cellulose + 500 unit/kg xylanase + 500 unit/kg ligninase. The reaction mixture was incubated on a water bath rotary shaker adjusted to 600C and 75 rpm. The samples were withdraw at intervals 12 and 24, 36, 48,60, and 72 hr. For bioethanol production in biofermentor of 5L the hydrolysis product were inoculated a loop of Saccharomyces cerevisiae and then incubated at 34 0C under static conditions. Samples are withdraw after 12, 24, 36, 48 and 72 hr for bioethanol and residual glucose. The results of the enzymatic hidrolysis (Figure1) showed that the treatment B (OPT hydrolyzed with amylase and cellulase) have optimum condition for glucose production, where was both of enzymes can be degraded OPT perfectly. The same results also reported by Primarini et al., (2012) reported the optimum conditions the hydrolysis of OPT was at concentration of 25% (w /v) with 0.3% (w/v) amylase, 0.6% (w /v) glucoamylase and 4% (w/v) cellulase. In the Figure 2 showed that optimum bioethanol produced at 48 hr after incubation,if time increased the biothanol decreased. According Roukas (1996), a decrease in the concentration of ethanol occur at excess glucose as substrate and product inhibition effects. Substrate concentration is too high reduces the amount of dissolved oxygen, although in very small amounts, oxygen is still needed in the fermentation by Saccaromyces cerevisiae to keep life in high cell concentrations (Nowak 2000, Tao et al. 2005). The results of the research can be conluded that the optimum enzymatic hydrolysis occured when the OPT added with amylase and cellulase and optimum bioethanol produced at 48 hr incubation using Saccharomyses cerevicea whereas 18.08 % bioethanol produced from glucose conversion. This work was funded by Directorate General of Higher Education (DGHE), Ministry of Education and Culture, contract no.245/SP2H/DIT.LimtabMas/II/2013

Keywords: oil palm trunk, enzymatic hydrolysis, saccharification

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14 The Prospects of Optimized KOH/Cellulose 'Papers' as Hierarchically Porous Electrode Materials for Supercapacitor Devices

Authors: Dina Ibrahim Abouelamaiem, Ana Jorge Sobrido, Magdalena Titirici, Paul R. Shearing, Daniel J. L. Brett

Abstract:

Global warming and scarcity of fossil fuels have had a radical impact on the world economy and ecosystem. The urgent need for alternative energy sources has hence elicited an extensive research for exploiting efficient and sustainable means of energy conversion and storage. Among various electrochemical systems, supercapacitors attracted significant attention in the last decade due to their high power supply, long cycle life compared to batteries and simple mechanism. Recently, the performance of these devices has drastically improved, as tuning of nanomaterials provided efficient charge and storage mechanisms. Carbon materials, in various forms, are believed to pioneer the next generation of supercapacitors due to their attractive properties that include high electronic conductivities, high surface areas and easy processing and functionalization. Cellulose has eco-friendly attributes that are feasible to replace man-made fibers. The carbonization of cellulose yields carbons, including activated carbon and graphite fibers. Activated carbons successively are the most exploited candidates for supercapacitor electrode materials that can be complemented with pseudocapacitive materials to achieve high energy and power densities. In this work, the optimum functionalization conditions of cellulose have been investigated for supercapacitor electrode materials. The precursor was treated with potassium hydroxide (KOH) at different KOH/cellulose ratios prior to the carbonization process in an inert nitrogen atmosphere at 850 °C. The chalky products were washed, dried and characterized with different techniques including transmission electron microscopy (TEM), x-ray tomography and nitrogen adsorption-desorption isotherms. The morphological characteristics and their effect on the electrochemical performances were investigated in two and three-electrode systems. The KOH/cellulose ratios of 0.5:1 and 1:1 exhibited the highest performances with their unique hierarchal porous network structure, high surface areas and low cell resistances. Both samples acquired the best results in three-electrode systems and coin cells with specific gravimetric capacitances as high as 187 F g-1 and 20 F g-1 at a current density of 1 A g-1 and retention rates of 72% and 70%, respectively. This is attributed to the morphology of the samples that constituted of a well-balanced micro-, meso- and macro-porosity network structure. This study reveals that the electrochemical performance doesn’t solely depend on high surface areas but also an optimum pore size distribution, specifically at low current densities. The micro- and meso-pore contribution to the final pore structure was found to dominate at low KOH loadings, reaching ‘equilibrium’ with macropores at the optimum KOH loading, after which macropores dictate the porous network. The wide range of pore sizes is detrimental for the mobility and penetration of electrolyte ions in the porous structures. These findings highlight the influence of various morphological factors on the double-layer capacitances and high performance rates. In addition, they open a platform for the investigation of the optimized conditions for double-layer capacitance that can be coupled with pseudocapacitive materials to yield higher energy densities and capacities.

Keywords: carbon, electrochemical performance, electrodes, KOH/cellulose optimized ratio, morphology, supercapacitor

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13 Effect of Selenium Source on Meat Quality of Bonsmara Bull Calves

Authors: J. van Soest, B. Bruneel, J. Smit, N. Williams, P. Swiegers

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Selenium (Se) is an essential trace mineral involved in reducing oxidative stress, enhancing immune status, improving reproduction, and regulating growth. During finishing period, selenium supplementation can be applied to improve meat quality. Dietary selenium can be provided in inorganic or organic forms. Specifically, L-selenomethionine (organic selenium) allows for selenium storage in animal protein which supports the animal during periods of high oxidative stress. The objective of this study was to investigate the effects of synthetically produced, single amino acid, L-selenomethionine (Excential Selenium 4000, Orffa Additives BV) on production parameters, health status, and meat quality of Bonsmara bull calves. 24 calves, 7 months of age, completed a 60-day initial growing period at a commercial feedlot, after which they were transported to research station Rumen-8 (Bethlehem, South-Africa). After a ten-day adaptation period, the bulls were allocated to a control (n=12) or treatment (n=12) group. Each group was divided over 3 pens based on weight. Both groups received Total Mixed Ration supplemented with 5.25 mg Se/head per day. The control group was supplemented with sodium selenite as Se source, whilst the treatment group was supplemented with L-selenomethionine (Excential Selenium 4000, Orffa Additives BV). Animals were limited to 10 kg feed intake per head per day to ensure similar Se intake. Treatment period lasted 1.5 months. A beta-adrenergic agonist was included in the feed for the last 30 days. During the treatment period, average daily gain, average daily feed intake, and feed conversion ratio were recorded. Blood parameters were measured at day 1, day 25, and before slaughter (day 47). After slaughter, carcass weight, dressing percentage, grading, and meat quality (pH, tenderness, colour, odour, purge, proximate analyses, acid detergent fibre, and neutral detergent fibre) were determined. No differences between groups were found in performance. A higher number of animals with cortisol levels below detection limit (27.6 nmol/l) was recorded for the treatment group. Other blood parameters showed no differences. No differences were found regarding carcass weight and dressing percentage. Important parameters of meat quality were significantly improved in the treatment group: instrumental tenderness at 14 days ageing was 2.8 and 3.4 for treatment and control respectively (P=0.010), and a 0.5% decrease in purge (of fresh samples) was shown, 1.5% and 2.0% for treatment group and control respectively (p=0.029). Besides, pH was shown to be numerically reduced in the treatment group. In summary, supplementation with L-selenomethionine as selenium source improved meat quality compared to sodium selenite. Lower instrumental tenderness (Warner Bratzler Shear Force, WBSF) was recorded for the treatment group. This indicates less tough meat and highest consumer satisfaction. Regarding purge, control was just below 2.0%, an important threshold for consumer acceptation. Treatment group scored 0.5% lower for purge than control, indicating higher consumer satisfaction. The lower pH in the treatment group could be an indication of higher glycogen reserves in muscle which could contribute to a reduced risk of Dark Firm Dry carcasses. More animals showed cortisol levels below detection limit in the treatment group, indicating lower levels of stress when animals receive L-selenomethionine.

Keywords: calves, meat quality, nutrition, selenium

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12 Utilization of Functionalized Biochar from Water Hyacinth (Eichhornia crassipes) as Green Nano-Fertilizers

Authors: Adewale Tolulope Irewale, Elias Emeka Elemike, Christian O. Dimkpa, Emeka Emmanuel Oguzie

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As the global population steadily approaches the 10billion mark, the world is currently faced with two major challenges among others – accessing sustainable and clean energy, and food security. Accessing cleaner and sustainable energy sources to drive global economy and technological advancement, and feeding the teeming human population require sustainable, innovative, and smart solutions. To solve the food production problem, producers have relied on fertilizers as a way of improving crop productivity. Commercial inorganic fertilizers, which is employed to boost agricultural food production, however, pose significant ecological sustainability and economic problems including soil and water pollution, reduced input efficiency, development of highly resistant weeds, micronutrient deficiency, soil degradation, and increased soil toxicity. These ecological and sustainability concerns have raised uncertainties about the continued effectiveness of conventional fertilizers. With the application of nanotechnology, plant biomass upcycling offers several advantages in greener energy production and sustainable agriculture through reduction of environmental pollution, increasing soil microbial activity, recycling carbon thereby reducing GHG emission, and so forth. This innovative technology has the potential for a circular economy and creating a sustainable agricultural practice. Nanomaterials have the potential to greatly enhance the quality and nutrient composition of organic biomass which in turn, allows for the conversion of biomass into nanofertilizers that are potentially more efficient. Water hyacinth plant harvested from an inland water at Warri, Delta State Nigeria were air-dried and milled into powder form. The dry biomass were used to prepare biochar at a pre-determined temperature in an oxygen deficient atmosphere. Physicochemical analysis of the resulting biochar was carried out to determine its porosity and general morphology using the Scanning Transmission Electron Microscopy (STEM). The functional groups (-COOH, -OH, -NH2, -CN, -C=O) were assessed using the Fourier Transform InfraRed Spectroscopy (FTIR) while the heavy metals (Cr, Cu, Fe, Pb, Mg, Mn) were analyzed using Inductively Coupled Plasma – Optical Emission Spectrometry (ICP-OES). Impregnation of the biochar with nanonutrients were achieved under varied conditions of pH, temperature, nanonutrient concentrations and resident time to achieve optimum adsorption. Adsorption and desorption studies were carried out on the resulting nanofertilizer to determine kinetics for the potential nutrients’ bio-availability to plants when used as green fertilizers. Water hyacinth (Eichhornia crassipes) which is an aggressively invasive aquatic plant known for its rapid growth and profusion is being examined in this research to harness its biomass as a sustainable feedstock to formulate functionalized nano-biochar fertilizers, offering various benefits including water hyacinth biomass upcycling, improved nutrient delivery to crops and aquatic ecosystem remediation. Altogether, this work aims to create output values in the three dimensions of environmental, economic, and social benefits.

Keywords: biochar-based nanofertilizers, eichhornia crassipes, greener agriculture, sustainable ecosystem, water hyacinth

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11 Measuring the Biomechanical Effects of Worker Skill Level and Joystick Crane Speed on Forestry Harvesting Performance Using a Simulator

Authors: Victoria L. Chester, Usha Kuruganti

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The forest industry is a major economic sector of Canada and also one of the most dangerous industries for workers. The use of mechanized mobile forestry harvesting machines has successfully reduced the incidence of injuries in forest workers related to manual labor. However, these machines have also created additional concerns, including a high machine operation learning curve, increased the length of the workday, repetitive strain injury, cognitive load, physical and mental fatigue, and increased postural loads due to sitting in a confined space. It is critical to obtain objective performance data for employers to develop appropriate work practices for this industry, however ergonomic field studies of this industry are lacking mainly due to the difficulties in obtaining comprehensive data while operators are cutting trees in the woods. The purpose of this study was to establish a measurement and experimental protocol to examine the effects of worker skill level and movement training speed (joystick crane speed) on harvesting performance using a forestry simulator. A custom wrist angle measurement device was developed as part of the study to monitor Euler angles during operation of the simulator. The device of the system consisted of two accelerometers, a Bluetooth module, three 3V coin cells, a microcontroller, a voltage regulator and an application software. Harvesting performance and crane data was provided by the simulator software and included tree to frame collisions, crane to tree collisions, boom tip distance, number of trees cut, etc. A pilot study of 3 operators with various skill levels was tested to identify factors that distinguish highly skilled operators from novice or intermediate operators. Dependent variables such as reaction time, math skill, past work experience, training movement speed (e.g. joystick control speeds), harvesting experience level, muscle activity, and wrist biomechanics were measured and analyzed. A 10-channel wireless surface EMG system was used to monitor the amplitude and mean frequency of 10 upper extremity muscles during pre and postperformance on the forestry harvest stimulator. The results of the pilot study showed inconsistent changes in median frequency pre-and postoperation, but there was the increase in the activity of the flexor carpi radialis, anterior deltoid and upper trapezius of both arms. The wrist sensor results indicated that wrist supination and pronation occurred more than flexion and extension with radial-ulnar rotation demonstrating the least movement. Overall, wrist angular motion increased as the crane speed increased from slow to fast. Further data collection is needed and will help industry partners determine those factors that separate skill levels of operators, identify optimal training speeds, and determine the length of training required to bring new operators to an efficient skill level effectively. In addition to effective and employment training programs, results of this work will be used for selective employee recruitment strategies to improve employee retention after training. Further, improved training procedures and knowledge of the physical and mental demands on workers will lead to highly trained and efficient personnel, reduced risk of injury, and optimal work protocols.

Keywords: EMG, forestry, human factors, wrist biomechanics

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10 Recurrent Torsades de Pointes Post Direct Current Cardioversion for Atrial Fibrillation with Rapid Ventricular Response

Authors: Taikchan Lildar, Ayesha Samad, Suraj Sookhu

Abstract:

Atrial fibrillation with rapid ventricular response results in the loss of atrial kick and shortened ventricular filling time, which often leads to decompensated heart failure. Pharmacologic rhythm control is the treatment of choice, and patients frequently benefit from the restoration of sinus rhythm. When pharmacologic treatment is unsuccessful or a patient declines hemodynamically, direct cardioversion is the treatment of choice. Torsades de pointes or “twisting of the points'' in French, is a rare but under-appreciated risk of cardioversion therapy and accounts for a significant number of sudden cardiac death each year. A 61-year-old female with no significant past medical history presented to the Emergency Department with worsening dyspnea. An electrocardiogram showed atrial fibrillation with rapid ventricular response, and a chest X-ray was significant for bilateral pulmonary vascular congestion. Full-dose anticoagulation and diuresis were initiated with moderate improvement in symptoms. A transthoracic echocardiogram revealed biventricular systolic dysfunction with a left ventricular ejection fraction of 30%. After consultation with an electrophysiologist, the consensus was to proceed with the restoration of sinus rhythm, which would likely improve the patient’s heart failure symptoms and possibly the ejection fraction. A transesophageal echocardiogram was negative for left atrial appendage thrombus; the patient was treated with a loading dose of amiodarone and underwent successful direct current cardioversion with 200 Joules. The patient was placed on telemetry monitoring for 24 hours and was noted to have frequent premature ventricular contractions with subsequent degeneration to torsades de pointes. The patient was found unresponsive and pulseless; cardiopulmonary resuscitation was initiated with cardioversion, and return of spontaneous circulation was achieved after four minutes to normal sinus rhythm. Post-cardiac arrest electrocardiogram showed sinus bradycardia with heart-rate corrected QT interval of 592 milliseconds. The patient continued to have frequent premature ventricular contractions and required two additional cardioversions to achieve a return of spontaneous circulation with intravenous magnesium and lidocaine. An automatic implantable cardioverter-defibrillator was subsequently implanted for secondary prevention of sudden cardiac death. The backup pacing rate of the automatic implantable cardioverter-defibrillator was set higher than usual in an attempt to prevent premature ventricular contractions-induced torsades de pointes. The patient did not have any further ventricular arrhythmias after implantation of the automatic implantable cardioverter-defibrillator. Overdrive pacing is a method utilized to treat premature ventricular contractions-induced torsades de pointes by preventing a patient’s susceptibility to R on T-wave-induced ventricular arrhythmias. Pacing at a rate of 90 beats per minute succeeded in controlling the arrhythmia without the need for traumatic cardiac defibrillation. In our patient, conversion of atrial fibrillation with rapid ventricular response to normal sinus rhythm resulted in a slower heart rate and an increased probability of premature ventricular contraction occurring on the T-wave and ensuing ventricular arrhythmia. This case highlights direct current cardioversion for atrial fibrillation with rapid ventricular response resulting in persistent ventricular arrhythmia requiring an automatic implantable cardioverter-defibrillator placement with overdrive pacing to prevent a recurrence.

Keywords: refractory atrial fibrillation, atrial fibrillation, overdrive pacing, torsades de pointes

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9 Saving Lives from a Laptop: How to Produce a Live Virtual Media Briefing That Will Inform, Educate, and Protect Communities in Crisis

Authors: Cory B. Portner, Julie A. Grauert, Lisa M. Stromme, Shelby D. Anderson, Franji H. Mayes

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Introduction: WASHINGTON state in the Pacific Northwest of the United States is internationally known for its technology industry, fisheries, agriculture, and vistas. On January 21, 2020, Washington state also became known as the first state with a confirmed COVID-19 case in the United States, thrusting the state into the international spotlight as the world came to grips with the global threat of this disease presented. Tourism is Washington state’s fourth-largest industry. Tourism to the state generates over 1.8 billion dollars (USD) in local and state tax revenue and employs over 180,000 people. Communicating with residents, stakeholders, and visitors on the status of disease activity, prevention measures, and response updates was vital to stopping the pandemic and increasing compliance and awareness. Significance: In order to communicate vital public health updates, guidance implementation, and safety measures to the public, the Washington State Department of Health established routine live virtual media briefings to reach audiences via social media, internet television, and broadcast television. Through close partnership with regional broadcast news stations and the state public affairs news network, the Washington State Department of Health hosted 95 media briefings from January 2020 through September 2022 and continues to regularly host live virtual media briefings to accommodate the needs of the public and media. Methods: Our methods quickly evolved from hosting briefings in the cement closet of a military base to being able to produce and stream the briefings live from any home-office location. The content was tailored to the hot topic of the day and to the reporter's questions and needs. Virtual media briefings hosted through inexpensive or free platforms online are extremely cost-effective: the only mandatory components are WiFi, a laptop, and a monitor. There is no longer a need for a fancy studio or expensive production software to achieve the goal of communicating credible, reliable information promptly. With minimal investment and a small learning curve, facilitators and panelists are able to host highly produced and engaging media availabilities from their living rooms. Results: The briefings quickly developed a reputation as the best source for local and national journalists to get the latest and most factually accurate information about the pandemic. In the height of the COVID-19 response, 135 unique media outlets logged on to participate in the briefing. The briefings typically featured 4-5 panelists, with as many as 9 experts in attendance to provide information and respond to media questions. Preparation was always a priority: Public Affairs staff for the Washington State Department of Health produced over 170 presenter remarks, including guidance on talking points for 63 expert guest panelists. Implication For Practice: Information is today’s most valuable currency. The ability to disseminate correct information urgently and on a wide scale is the most effective tool in crisis communication. Due to our role as the first state with a confirmed COVID-19 case, we were forced to develop the most accurate and effective way to get life-saving information to the public. The cost-effective, web-based methods we developed can be applied in any crisis to educate and protect communities under threat, ultimately saving lives from a laptop.

Keywords: crisis communications, public relations, media management, news media

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8 Multimodal Integration of EEG, fMRI and Positron Emission Tomography Data Using Principal Component Analysis for Prognosis in Coma Patients

Authors: Denis Jordan, Daniel Golkowski, Mathias Lukas, Katharina Merz, Caroline Mlynarcik, Max Maurer, Valentin Riedl, Stefan Foerster, Eberhard F. Kochs, Andreas Bender, Ruediger Ilg

Abstract:

Introduction: So far, clinical assessments that rely on behavioral responses to differentiate coma states or even predict outcome in coma patients are unreliable, e.g. because of some patients’ motor disabilities. The present study was aimed to provide prognosis in coma patients using markers from electroencephalogram (EEG), blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) and [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). Unsuperwised principal component analysis (PCA) was used for multimodal integration of markers. Methods: Approved by the local ethics committee of the Technical University of Munich (Germany) 20 patients (aged 18-89) with severe brain damage were acquired through intensive care units at the Klinikum rechts der Isar in Munich and at the Therapiezentrum Burgau (Germany). At the day of EEG/fMRI/PET measurement (date I) patients (<3.5 month in coma) were grouped in the minimal conscious state (MCS) or vegetative state (VS) on the basis of their clinical presentation (coma recovery scale-revised, CRS-R). Follow-up assessment (date II) was also based on CRS-R in a period of 8 to 24 month after date I. At date I, 63 channel EEG (Brain Products, Gilching, Germany) was recorded outside the scanner, and subsequently simultaneous FDG-PET/fMRI was acquired on an integrated Siemens Biograph mMR 3T scanner (Siemens Healthineers, Erlangen Germany). Power spectral densities, permutation entropy (PE) and symbolic transfer entropy (STE) were calculated in/between frontal, temporal, parietal and occipital EEG channels. PE and STE are based on symbolic time series analysis and were already introduced as robust markers separating wakefulness from unconsciousness in EEG during general anesthesia. While PE quantifies the regularity structure of the neighboring order of signal values (a surrogate of cortical information processing), STE reflects information transfer between two signals (a surrogate of directed connectivity in cortical networks). fMRI was carried out using SPM12 (Wellcome Trust Center for Neuroimaging, University of London, UK). Functional images were realigned, segmented, normalized and smoothed. PET was acquired for 45 minutes in list-mode. For absolute quantification of brain’s glucose consumption rate in FDG-PET, kinetic modelling was performed with Patlak’s plot method. BOLD signal intensity in fMRI and glucose uptake in PET was calculated in 8 distinct cortical areas. PCA was performed over all markers from EEG/fMRI/PET. Prognosis (persistent VS and deceased patients vs. recovery to MCS/awake from date I to date II) was evaluated using the area under the curve (AUC) including bootstrap confidence intervals (CI, *: p<0.05). Results: Prognosis was reliably indicated by the first component of PCA (AUC=0.99*, CI=0.92-1.00) showing a higher AUC when compared to the best single markers (EEG: AUC<0.96*, fMRI: AUC<0.86*, PET: AUC<0.60). CRS-R did not show prediction (AUC=0.51, CI=0.29-0.78). Conclusion: In a multimodal analysis of EEG/fMRI/PET in coma patients, PCA lead to a reliable prognosis. The impact of this result is evident, as clinical estimates of prognosis are inapt at time and could be supported by quantitative biomarkers from EEG, fMRI and PET. Due to the small sample size, further investigations are required, in particular allowing superwised learning instead of the basic approach of unsuperwised PCA.

Keywords: coma states and prognosis, electroencephalogram, entropy, functional magnetic resonance imaging, machine learning, positron emission tomography, principal component analysis

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7 Predicting Open Chromatin Regions in Cell-Free DNA Whole Genome Sequencing Data by Correlation Clustering  

Authors: Fahimeh Palizban, Farshad Noravesh, Amir Hossein Saeidian, Mahya Mehrmohamadi

Abstract:

In the recent decade, the emergence of liquid biopsy has significantly improved cancer monitoring and detection. Dying cells, including those originating from tumors, shed their DNA into the blood and contribute to a pool of circulating fragments called cell-free DNA. Accordingly, identifying the tissue origin of these DNA fragments from the plasma can result in more accurate and fast disease diagnosis and precise treatment protocols. Open chromatin regions are important epigenetic features of DNA that reflect cell types of origin. Profiling these features by DNase-seq, ATAC-seq, and histone ChIP-seq provides insights into tissue-specific and disease-specific regulatory mechanisms. There have been several studies in the area of cancer liquid biopsy that integrate distinct genomic and epigenomic features for early cancer detection along with tissue of origin detection. However, multimodal analysis requires several types of experiments to cover the genomic and epigenomic aspects of a single sample, which will lead to a huge amount of cost and time. To overcome these limitations, the idea of predicting OCRs from WGS is of particular importance. In this regard, we proposed a computational approach to target the prediction of open chromatin regions as an important epigenetic feature from cell-free DNA whole genome sequence data. To fulfill this objective, local sequencing depth will be fed to our proposed algorithm and the prediction of the most probable open chromatin regions from whole genome sequencing data can be carried out. Our method integrates the signal processing method with sequencing depth data and includes count normalization, Discrete Fourie Transform conversion, graph construction, graph cut optimization by linear programming, and clustering. To validate the proposed method, we compared the output of the clustering (open chromatin region+, open chromatin region-) with previously validated open chromatin regions related to human blood samples of the ATAC-DB database. The percentage of overlap between predicted open chromatin regions and the experimentally validated regions obtained by ATAC-seq in ATAC-DB is greater than 67%, which indicates meaningful prediction. As it is evident, OCRs are mostly located in the transcription start sites (TSS) of the genes. In this regard, we compared the concordance between the predicted OCRs and the human genes TSS regions obtained from refTSS and it showed proper accordance around 52.04% and ~78% with all and the housekeeping genes, respectively. Accurately detecting open chromatin regions from plasma cell-free DNA-seq data is a very challenging computational problem due to the existence of several confounding factors, such as technical and biological variations. Although this approach is in its infancy, there has already been an attempt to apply it, which leads to a tool named OCRDetector with some restrictions like the need for highly depth cfDNA WGS data, prior information about OCRs distribution, and considering multiple features. However, we implemented a graph signal clustering based on a single depth feature in an unsupervised learning manner that resulted in faster performance and decent accuracy. Overall, we tried to investigate the epigenomic pattern of a cell-free DNA sample from a new computational perspective that can be used along with other tools to investigate genetic and epigenetic aspects of a single whole genome sequencing data for efficient liquid biopsy-related analysis.

Keywords: open chromatin regions, cancer, cell-free DNA, epigenomics, graph signal processing, correlation clustering

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6 Microfluidic Plasmonic Device for the Sensitive Dual LSPR-Thermal Detection of the Cardiac Troponin Biomarker in Laminal Flow

Authors: Andreea Campu, Ilinica Muresan, Simona Cainap, Simion Astilean, Monica Focsan

Abstract:

Acute myocardial infarction (AMI) is the most severe cardiovascular disease, which has threatened human lives for decades, thus a continuous interest is directed towards the detection of cardiac biomarkers such as cardiac troponin I (cTnI) in order to predict risk and, implicitly, fulfill the early diagnosis requirements in AMI settings. Microfluidics is a major technology involved in the development of efficient sensing devices with real-time fast responses and on-site applicability. Microfluidic devices have gathered a lot of attention recently due to their advantageous features such as high sensitivity and specificity, miniaturization and portability, ease-of-use, low-cost, facile fabrication, and reduced sample manipulation. The integration of gold nanoparticles into the structure of microfluidic sensors has led to the development of highly effective detection systems, considering the unique properties of the metallic nanostructures, specifically the Localized Surface Plasmon Resonance (LSPR), which makes them highly sensitive to their microenvironment. In this scientific context, herein, we propose the implementation of a novel detection device, which successfully combines the efficiency of gold bipyramids (AuBPs) as signal transducers and thermal generators with the sample-driven advantages of the microfluidic channels into a miniaturized, portable, low-cost, specific, and sensitive test for the dual LSPR-thermographic cTnI detection. Specifically, AuBPs with longitudinal LSPR response at 830 nm were chemically synthesized using the seed-mediated growth approach and characterized in terms of optical and morphological properties. Further, the colloidal AuBPs were deposited onto pre-treated silanized glass substrates thus, a uniform nanoparticle coverage of the substrate was obtained and confirmed by extinction measurements showing a 43 nm blue-shift of the LSPR response as a consequence of the refractive index change. The as-obtained plasmonic substrate was then integrated into a microfluidic “Y”-shaped polydimethylsiloxane (PDMS) channel, fabricated using a Laser Cutter system. Both plasmonic and microfluidic elements were plasma treated in order to achieve a permanent bond. The as-developed microfluidic plasmonic chip was further coupled to an automated syringe pump system. The proposed biosensing protocol implicates the successive injection inside the microfluidic channel as follows: p-aminothiophenol and glutaraldehyde, to achieve a covalent bond between the metallic surface and cTnI antibody, anti-cTnI, as a recognition element, and target cTnI biomarker. The successful functionalization and capture of cTnI was monitored by LSPR detection thus, after each step, a red-shift of the optical response was recorded. Furthermore, as an innovative detection technique, thermal determinations were made after each injection by exposing the microfluidic plasmonic chip to 785 nm laser excitation, considering that the AuBPs exhibit high light-to-heat conversion performances. By the analysis of the thermographic images, thermal curves were obtained, showing a decrease in the thermal efficiency after the anti-cTnI-cTnI reaction was realized. Thus, we developed a microfluidic plasmonic chip able to operate as both LSPR and thermal sensor for the detection of the cardiac troponin I biomarker, leading thus to the progress of diagnostic devices.

Keywords: gold nanobipyramids, microfluidic device, localized surface plasmon resonance detection, thermographic detection

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5 Recrystallization Behavior and Microstructural Evolution of Nickel Base Superalloy AD730 Billet during Hot Forging at Subsolvus Temperatures

Authors: Marcos Perez, Christian Dumont, Olivier Nodin, Sebastien Nouveau

Abstract:

Nickel superalloys are used to manufacture high-temperature rotary engine parts such as high-pressure disks in gas turbine engines. High strength at high operating temperatures is required due to the levels of stress and heat the disk must withstand. Therefore it is necessary parts made from materials that can maintain mechanical strength at high temperatures whilst remain comparatively low in cost. A manufacturing process referred to as the triple melt process has made the production of cast and wrought (C&W) nickel superalloys possible. This means that the balance of cost and performance at high temperature may be optimized. AD730TM is a newly developed Ni-based superalloy for turbine disk applications, with reported superior service properties around 700°C when compared to Inconel 718 and several other alloys. The cast ingot is converted into billet during either cogging process or open die forging. The semi-finished billet is then further processed into its final geometry by forging, heat treating, and machining. Conventional ingot-to-billet conversion is an expensive and complex operation, requiring a significant amount of steps to break up the coarse as-cast structure and interdendritic regions. Due to the size of conventional ingots, it is difficult to achieve a uniformly high level of strain for recrystallization, resulting in non-recrystallized regions that retain large unrecrystallized grains. Non-uniform grain distributions will also affect the ultrasonic inspectability response, which is used to find defects in the final component. The main aim is to analyze the recrystallization behavior and microstructural evolution of AD730 at subsolvus temperatures from a semi-finished product (billet) under conditions representative of both cogging and hot forging operations. Special attention to the presence of large unrecrystallized grains was paid. Double truncated cones (DTCs) were hot forged at subsolvus temperatures in hydraulic press, followed by air cooling. SEM and EBSD analysis were conducted in the as-received (billet) and the as-forged conditions. AD730 from billet alloy presents a complex microstructure characterized by a mixture of several constituents. Large unrecrystallized grains present a substructure characterized by large misorientation gradients with the formation of medium to high angle boundaries in their interior, especially close to the grain boundaries, denoting inhomogeneous strain distribution. A fine distribution of intragranular precipitates was found in their interior, playing a key role on strain distribution and subsequent recrystallization behaviour during hot forging. Continuous dynamic recrystallization (CDRX) mechanism was found to be operating in the large unrecrystallized grains, promoting the formation intragranular DRX grains and the gradual recrystallization of these grains. Evidences that hetero-epitaxial recrystallization mechanism is operating in AD730 billet material were found. Coherent γ-shells around primary γ’ precipitates were found. However, no significant contribution to the overall recrystallization during hot forging was found. By contrast, strain presents the strongest effect on the microstructural evolution of AD730, increasing the recrystallization fraction and refining the structure. Regions with low level of deformation (ε ≤ 0.6) were translated into large fractions of unrecrystallized structures (strain accumulation). The presence of undissolved secondary γ’ precipitates (pinning effect), prior to hot forging operations, could explain these results.

Keywords: AD730 alloy, continuous dynamic recrystallization, hot forging, γ’ precipitates

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4 Supplier Carbon Footprint Methodology Development for Automotive Original Equipment Manufacturers

Authors: Nur A. Özdemir, Sude Erkin, Hatice K. Güney, Cemre S. Atılgan, Enes Huylu, Hüseyin Y. Altıntaş, Aysemin Top, Özak Durmuş

Abstract:

Carbon emissions produced during a product’s life cycle, from extraction of raw materials up to waste disposal and market consumption activities are the major contributors to global warming. In the light of the science-based targets (SBT) leading the way to a zero-carbon economy for sustainable growth of the companies, carbon footprint reporting of the purchased goods has become critical for identifying hotspots and best practices for emission reduction opportunities. In line with Ford Otosan's corporate sustainability strategy, research was conducted to evaluate the carbon footprint of purchased products in accordance with Scope 3 of the Greenhouse Gas Protocol (GHG). The purpose of this paper is to develop a systematic and transparent methodology to calculate carbon footprint of the products produced by automotive OEMs (Original Equipment Manufacturers) within the context of automobile supply chain management. To begin with, primary material data were collected through IMDS (International Material Database System) corresponds to company’s three distinct types of vehicles including Light Commercial Vehicle (Courier), Medium Commercial Vehicle (Transit and Transit Custom), Heavy Commercial Vehicle (F-MAX). Obtained material data was classified as metals, plastics, liquids, electronics, and others to get insights about the overall material distribution of produced vehicles and matched to the SimaPro Ecoinvent 3 database which is one of the most extent versions for modelling material data related to the product life cycle. Product life cycle analysis was calculated within the framework of ISO 14040 – 14044 standards by addressing the requirements and procedures. A comprehensive literature review and cooperation with suppliers were undertaken to identify the production methods of parts used in vehicles and to find out the amount of scrap generated during part production. Cumulative weight and material information with related production process belonging the components were listed by multiplying with current sales figures. The results of the study show a key modelling on carbon footprint of products and processes based on a scientific approach to drive sustainable growth by setting straightforward, science-based emission reduction targets. Hence, this study targets to identify the hotspots and correspondingly provide broad ideas about our understanding of how to integrate carbon footprint estimates into our company's supply chain management by defining convenient actions in line with climate science. According to emission values arising from the production phase including raw material extraction and material processing for Ford OTOSAN vehicles subjected in this study, GHG emissions from the production of metals used for HCV, MCV and LCV account for more than half of the carbon footprint of the vehicle's production. Correspondingly, aluminum and steel have the largest share among all material types and achieving carbon neutrality in the steel and aluminum industry is of great significance to the world, which will also present an immense impact on the automobile industry. Strategic product sustainability plan which includes the use of secondary materials, conversion to green energy and low-energy process design is required to reduce emissions of steel, aluminum, and plastics due to the projected increase in total volume by 2030.

Keywords: automotive, carbon footprint, IMDS, scope 3, SimaPro, sustainability

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3 Circular Nitrogen Removal, Recovery and Reuse Technologies

Authors: Lina Wu

Abstract:

The excessive discharge of nitrogen in sewage greatly intensifies the eutrophication of water bodies and threatens water quality. Nitrogen pollution control has become a global concern. The concentration of nitrogen in water is reduced by converting ammonia nitrogen, nitrate nitrogen and nitrite nitrogen into nitrogen-containing gas through biological treatment, physicochemical treatment and oxidation technology. However, some wastewater containing high ammonia nitrogen including landfill leachate, is difficult to be treated by traditional nitrification and denitrification because of its high COD content. The core process of denitrification is that denitrifying bacteria convert nitrous acid produced by nitrification into nitrite under anaerobic conditions. Still, its low-carbon nitrogen does not meet the conditions for denitrification. Many studies have shown that the natural autotrophic anammox bacteria can combine nitrous and ammonia nitrogen without a carbon source through functional genes to achieve total nitrogen removal, which is very suitable for removing nitrogen from leachate. In addition, the process also saves a lot of aeration energy consumption than the traditional nitrogen removal process. Therefore, anammox plays an important role in nitrogen conversion and energy saving. The short-range nitrification and denitrification coupled with anaerobic ammoX ensures total nitrogen removal. It improves the removal efficiency, meeting the needs of society for an ecologically friendly and cost-effective nutrient removal treatment technology. In recent years, research has found that the symbiotic system has more water treatment advantages because this process not only helps to improve the efficiency of wastewater treatment but also allows carbon dioxide reduction and resource recovery. Microalgae use carbon dioxide dissolved in water or released through bacterial respiration to produce oxygen for bacteria through photosynthesis under light, and bacteria, in turn, provide metabolites and inorganic carbon sources for the growth of microalgae, which may lead the algal bacteria symbiotic system save most or all of the aeration energy consumption. It has become a trend to make microalgae and light-avoiding anammox bacteria play synergistic roles by adjusting the light-to-dark ratio. Microalgae in the outer layer of light particles block most of the light and provide cofactors and amino acids to promote nitrogen removal. In particular, myxoccota MYX1 can degrade extracellular proteins produced by microalgae, providing amino acids for the entire bacterial community, which helps anammox bacteria save metabolic energy and adapt to light. As a result, initiating and maintaining the process of combining dominant algae and anaerobic denitrifying bacterial communities has great potential in treating landfill leachate. Chlorella has a brilliant removal effect and can withstand extreme environments in terms of high ammonia nitrogen, high salt and low temperature. It is urgent to study whether the algal mud mixture rich in denitrifying bacteria and chlorella can greatly improve the efficiency of landfill leachate treatment under an anaerobic environment where photosynthesis is stopped. The optimal dilution concentration of simulated landfill leachate can be found by determining the treatment effect of the same batch of bacteria and algae mixtures under different initial ammonia nitrogen concentrations and making a comparison. High-throughput sequencing technology was used to analyze the changes in microbial diversity, related functional genera and functional genes under optimal conditions, providing a theoretical and practical basis for the engineering application of novel bacteria-algae symbiosis system in biogas slurry treatment and resource utilization.

Keywords: nutrient removal and recovery, leachate, anammox, Partial nitrification, Algae-bacteria interaction

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2 Gamification Beyond Competition: the Case of DPG Lab Collaborative Learning Program for High-School Girls by GameLab KBTU and UNICEF in Kazakhstan

Authors: Nazym Zhumabayeva, Aleksandr Mezin, Alexandra Knysheva

Abstract:

Women's underrepresentation in STEM is critical, worsened by ineffective engagement in educational practices. UNICEF Kazakhstan and GameLab KBTU's collaborative initiatives aim to enhance female STEM participation by fostering an inclusive environment. Learning from LEVEL UP's 2023 program, which featured a hackathon, the 2024 strategy pivots towards non-competitive gamification. Although the data from last year's project showed higher than average student engagement, observations and in-depth interviews with participants showed that the format was stressful for the girls, making them focus on points rather than on other values. This study presents a gamified educational system, DPG Lab, aimed at incentivizing young women's participation in STEM through the development of digital public goods (DPGs). By prioritizing collaborative gamification elements, the project seeks to create an inclusive learning environment that increases engagement and interest in STEM among young women. The DPG Lab aims to find a solution to minimize competition and support collaboration. The project is designed to motivate female participants towards the development of digital solutions through an introduction to the concept of DPGs. It consists of a short online course, a simulation videogame, and a real-time online quest with an offline finale at the KBTU campus. The online course offers short video lectures on open-source development and DPG standards. The game facilitates the practical application of theoretical knowledge, enriching the learning experience. Learners can also participate in a quest that encourages participants to develop DPG ideas in teams by choosing missions throughout the quest path. At the offline quest finale, the participants will meet in person to exchange experiences and accomplishments without engaging in comparative assessments: the quest ensures that each team’s trajectory is distinct by design. This marks a shift from competitive hackathons to a collaborative format, recognizing the unique contributions and achievements of each participant. The pilot batch of students is scheduled to commence in April 2024, with the finale anticipated in June. It is projected that this group will comprise 50 female high-school students from various regions across Kazakhstan. Expected outcomes include increased engagement and interest in STEM fields among young female participants, positive emotional and psychological impact through an emphasis on collaborative learning environments, and improved understanding and skills in DPG development. GameLab KBTU intends to undertake a hypothesis evaluation, employing a methodology similar to that utilized in the preceding LEVEL UP project. This approach will encompass the compilation of quantitative metrics (conversion funnels, test results, and surveys) and qualitative data from in-depth interviews and observational studies. For comparative analysis, a select group of participants from the previous year's project will be recruited to engage in the DPG Lab. By developing and implementing a gamified framework that emphasizes inclusion, engagement, and collaboration, the study seeks to provide practical knowledge about effective gamification strategies for promoting gender diversity in STEM. The expected outcomes of this initiative can contribute to the broader discussion on gamification in education and gender equality in STEM by offering a replicable and scalable model for similar interventions around the world.

Keywords: collaborative learning, competitive learning, digital public goods, educational gamification, emerging regions, STEM, underprivileged groups

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1 MANIFEST-2, a Global, Phase 3, Randomized, Double-Blind, Active-Control Study of Pelabresib (CPI-0610) and Ruxolitinib vs. Placebo and Ruxolitinib in JAK Inhibitor-Naïve Myelofibrosis Patients

Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

Abstract:

Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

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