Search results for: bloodstream expression site

Authors: Ling Ai, Ziyu Zhao, Zeyu Zhou, Xiaochen Yang, Heng Zhai, Stuart Holmes

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Optimizing the catalyst layer structure is crucial for enhancing the performance of proton exchange membrane fuel cells (PEMFCs) with low Platinum (Pt) loading. Current works focused on the utilization, durability, and site activity of Pt particles on support, and performance enhancement has been achieved by loading Pt onto porous support with different morphology, such as graphene, carbon fiber, and carbon black. Some schemes have also incorporated cost considerations to achieve lower Pt loading. However, the design of the catalyst layer (CL) structure in the membrane electrode assembly (MEA) must consider the interactions between the layers. Addressing the crucial aspects of water management, low contact resistance, and the establishment of effective three-phase boundary for MEA, multi-walled carbon nanotubes (MWCNTs) are promising CL support due to their intrinsically high hydrophobicity, high axial electrical conductivity, and potential for ordered alignment. However, the drawbacks of MWCNTs, such as strong agglomeration, wall surface chemical inertness, and unopened ends, are unfavorable for Pt nanoparticle loading, which is detrimental to MEA processing and leads to inhomogeneous CL surfaces. This further deteriorates the utilization of Pt and increases the contact resistance. Robust chemical oxidation or nitrogen doping can introduce polar functional groups onto the surface of MWCNTs, facilitating the creation of open tube ends and inducing defects in tube walls. This improves dispersibility and load capacity but reduces length and conductivity. Consequently, a trade-off exists between maintaining the intrinsic properties and the degree of functionalization of MWCNTs. In this work, MWCNTs were modified based on the operational requirements of the MEA from the viewpoint of interlayer interactions, including the search for the optimal degree of oxidation, N-doping, and micro-arrangement. MWCNT were functionalized by oxidizing, N-doping, as well as micro-alignment to achieve lower contact resistance between CL and proton exchange membrane (PEM), better hydrophobicity, and enhanced performance. Furthermore, this work expects to construct a more continuously distributed three-phase boundary by aligning MWCNT to form a locally ordered structure, which is essential for the efficient utilization of Pt active sites. Different from other chemical oxidation schemes that used HNO3:H2SO4 (1:3) mixed acid to strongly oxidize MWCNT, this scheme adopted pure HNO3 to partially oxidize MWCNT at a lower reflux temperature (80 ℃) and a shorter treatment time (0 to 10 h) to preserve the morphology and intrinsic conductivity of MWCNT. The maximum power density of 979.81 mw cm-2 was achieved by Pt loading on 6h MWCNT oxidation time (Pt-MWCNT6h). This represented a 59.53% improvement over the commercial Pt/C catalyst of 614.17 (mw cm-2). In addition, due to the stronger electrical conductivity, the charge transfer resistance of Pt-MWCNT6h in the electrochemical impedance spectroscopy (EIS) test was 0.09 Ohm cm-2, which was 48.86% lower than that of Pt/C. This study will discuss the developed catalysts and their efficacy in a working fuel cell system. This research will validate the impact of low-functionalization modification of MWCNTs on the performance of PEMFC, which simplifies the preparation challenges of CL and contributing for the widespread commercial application of PEMFCs on a larger scale.

Keywords: carbon nanotubes, electrocatalyst, membrane electrode assembly, proton exchange membrane fuel cell

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Authors: Federica Verna, Alessandra Pautasso, Maria Caramelli, Cristiana Maurella, Walter Mignone, Cristina Casalone

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Mosquito-Borne Diseases (MBDs) are dangerously increasing in prevalence, geographical distribution and severity, representing an emerging threat for both humans and animals. Interaction between multiple disciplines is needed for an effective early warning, surveillance and control of MBDs, according to the One Health concept. This work reports the integrated surveillance system enforced by IZSPLV in Piedmont, Liguria and Valle d’Aosta regions (Northwestern Italy) in order to control MDBs spread. Veterinary services and local human health authority are involved in an information network, to connect the surveillance of human clinical cases with entomological surveillance and veterinary monitoring in order to implement control measures in case of outbreak. A systematic entomological surveillance is carried out during the vector season using mosquitoes traps located in sites selected according to risk factors. Collected mosquitoes are counted, identified to species level by morphological standard classification keys and pooled by collection site, date and species with a maximum of 100 individuals. Pools are analyzed, after RNA extraction, by Real Time RT-PCR distinctive for West Nile Virus (WNV) Lineage 1 and Lineage 2, Real Time RT-PCR USUTU virus (USUV) and a traditional flavivirus End-point RT-PCR. Positive pools are sequenced and the related sequences employed to perform a basic local alignment search tool (BLAST) in the GenBank library. Positive samples are sent to the National Reference Centre for Animal Exotic Diseases (CESME, Teramo) for confirmation. With particular reference to WNV, after the confirmation, as provided by national legislation, control measures involving both local veterinary and human health services are activated: equine sera are randomly sampled within a 4 km radius from the positive collection sites and tested with ELISA kit and WNV NAT screening of blood donors is introduced. This surveillance network allowed to detect since 2011 USUV circulation in this area of Italy. WNV was detected in Piedmont and Liguria for the first time in 2014 in mosquitoes. During the 2015 vector season, we observed the expansion of its activity in Piedmont. The virus was detected in almost all Provinces both in mosquitoes (6 pools) and animals (19 equine sera, 4 birds). No blood bag tested resulted infected. The first neuroinvasive human case occurred too. Competent authorities should be aware of a potentially increased risk of MBDs activity during the 2016 vector season. This work shows that this surveillance network allowed to early detect the presence of MBDs in humans and animals, and provided useful information to public authorities, in order to apply control measures. Finally, an additional value of our diagnostic protocol is the ability to detect all viruses belonging to the Flaviviridae family, considering the emergence caused by other Flaviviruses in humans such as the recent Zika virus infection in South America. Italy has climatic and environmental features conducive to Zika virus transmission, the competent vector and many travellers from Brazil reported every year.

Keywords: integrated surveillance, mosquito borne disease, West Nile virus, Zika virus

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Authors: Evelyn Castle, Adam Thompson

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Background: In 2013, the Kano State Primary Health Care Management Board redesigned its Routine immunization supply chain from diffused pull to direct delivery push. It addressed issues around stockouts and reduced time spent by health facility staff collecting, and reporting on vaccine usage. The health care board sought the help of a 3PL for twice-monthly deliveries from its cold store to 484 facilities across 44 local governments. eHA’s Health Delivery Systems group formed a 3PL to serve 326 of these new facilities in partnership with the State. We focused on designing and implementing a technology system throughout. Basic methodologies: GIS Mapping: - Planning the delivery of vaccines to hundreds of health facilities requires detailed route planning for delivery vehicles. Mapping the road networks across Kano and Bauchi with a custom routing tool provided information for the optimization of deliveries. Reducing the number of kilometers driven each round by 20%, - reducing cost and delivery time. Direct Delivery Information System: - Vaccine Direct Deliveries are facilitated through pre-round planning (driven by health facility database, extensive GIS, and inventory workflow rules), manager and driver control panel customizing delivery routines and reporting, progress dashboard, schedules/routes, packing lists, delivery reports, and driver data collection applications. Move: Last Mile Logistics Management System: - MOVE has improved vaccine supply information management to be timely, accurate and actionable. Provides stock management workflow support, alerts management for cold chain exceptions/stock outs, and on-device analytics for health and supply chain staff. Software was built to be offline-first with user-validated interface and experience. Deployed to hundreds of vaccine storage site the improved information tools helps facilitate the process of system redesign and change management. Findings: - Stock-outs reduced from 90% to 33% - Redesigned current health systems and managing vaccine supply for 68% of Kano’s wards. - Near real time reporting and data availability to track stock. - Paperwork burdens of health staff have been dramatically reduced. - Medicine available when the community needs it. - Consistent vaccination dates for children under one to prevent polio, yellow fever, tetanus. - Higher immunization rates = Lower infection rates. - Hundreds of millions of Naira worth of vaccines successfully transported. - Fortnightly service to 326 facilities in 326 wards across 30 Local Government areas. - 6,031 cumulative deliveries. - Over 3.44 million doses transported. - Minimum travel distance covered in a round of delivery is 2000 kms & maximum of 6297 kms. - 153,409 kms travelled by 6 drivers. - 500 facilities in 326 wards. - Data captured and synchronized for the first time. - Data driven decision making now possible. Conclusion: eHA’s Vaccine Direct delivery has met challenges in Kano and Bauchi State and provided a reliable delivery service of vaccinations that ensure t health facilities can run vaccination clinics for children under one. eHA uses innovative technology that delivers vaccines from Northern Nigerian zonal stores straight to healthcare facilities. Helped healthcare workers spend less time managing supplies and more time delivering care, and will be rolled out nationally across Nigeria.

Keywords: direct delivery information system, health delivery system, GIS mapping, Northern Nigeria, vaccines

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Authors: Claudio Clemente, Valentina Gargiulo, Alessio Occhicone, Giovanni Piero Pepe, Giovanni Ausanio, Michela Alfè

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Volatile organic compound (VOC) emissions represent a serious risk to human health and the integrity of the ecosystems, especially at high concentrations. For this reason, it is very important to continuously monitor environmental quality and develop fast and reliable portable sensors to allow analysis on site. Chemiresistors have become promising candidates for VOC sensing as their ease of fabrication, variety of suitable sensitive materials, and simple sensing data. A chemoresistive gas sensor is a transducer that allows to measure the concentration of an analyte in the gas phase because the changes in resistance are proportional to the amount of the analyte present. The selection of the sensitive material, which interacts with the target analyte, is very important for the sensor performance. The most used VOC detection materials are metal oxides (MOx) for their rapid recovery, high sensitivity to various gas molecules, easy fabrication. Their sensing performance can be improved in terms of operating temperature, selectivity, and detection limit. Metal-organic frameworks (MOFs) have attracted a lot of attention also in the field of gas sensing due to their high porosity, high surface area, tunable morphologies, structural variety. MOFs are generated by the self-assembly of multidentate organic ligands connecting with adjacent multivalent metal nodes via strong coordination interactions, producing stable and highly ordered crystalline porous materials with well-designed structures. However, most MOFs intrinsically exhibit low electrical conductivity. To improve this property, MOFs can be combined with organic and inorganic materials in a hybrid fashion to produce composite materials or can be transformed into more stable structures. MOFs, indeed, can be employed as the precursors of metal oxides with well-designed architectures via the calcination method. The MOF-derived MOx partially preserved the original structure with high surface area and intrinsic open pores, which act as trapping centers for gas molecules, and showed a higher electrical conductivity. Core-shell heterostructures, in which the surface of a metal oxide core is completely coated by a MOF shell, forming a junction at the core-shell heterointerface, can also be synthesized. Also, nanocomposite in which MOF structures are intercalated with graphene related materials can also be produced, and the conductivity increases thanks to the high mobility of electrons of carbon materials. As MOF structures, zinc-based MOFs belonging to the ZIF family were selected in this work. Several Zn-based materials based and/or derived from MOFs were produced, structurally characterized, and arranged in a chemo resistive architecture, also exploring the potentiality of different approaches of sensing layer deposition based on PLD (pulsed laser deposition) and, in case of thermally labile materials, MAPLE (Matrix Assisted Pulsed Laser Evaporation) to enhance the adhesion to the support. The sensors were tested in a controlled humidity chamber, allowing for the possibility of varying the concentration of ethanol, a typical analyte chosen among the VOCs for a first survey. The effect of heating the chemiresistor to improve sensing performances was also explored. Future research will focus on exploring new manufacturing processes for MOF-based gas sensors with the aim to improve sensitivity, selectivity and reduce operating temperatures.

Keywords: chemiresistors, gas sensors, graphene related materials, laser deposition, MAPLE, metal-organic frameworks, metal oxides, nanocomposites, sensing performance, transduction mechanism, volatile organic compounds

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Authors: Joel Rookwood

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Sports mega events have become increasingly significant in sporting, political and economic terms, with analysis often focusing on issues including resource expenditure, development, legacy and sustainability. Transnational tournaments can inspire interest from a variety of demographics, and the operational management of such events can involve contributions from a range of personnel. In addition to television audiences events also attract attending spectators, and in football contexts the temporary migration of fans from potentially rival nations and teams can present event organising committees and security personnel with various challenges in relation to crowd management. The behaviour, interaction and control of supporters has previously led to incidents of disorder and hooliganism, with damage to property as well as injuries and deaths proving significant consequences. The Heysel tragedy at the 1985 European Cup final in Brussels is a notable example, where 39 fans died following crowd disorder and mismanagement. Football disasters and disorder, particularly in the context of international competition, have inspired responses from police, law makers, event organisers, clubs and associations, including stadium improvements, legislative developments and crowd management practice to improve the effectiveness of spectator safety. The growth and internationalisation of fandom and developments in event management and tourism have seen various responses to the evolving challenges associated with hosting large numbers of visiting spectators at mega events. In football contexts ‘fan parks’ are a notable example. Since the first widespread introduction in European football competitions at the 2006 World Cup finals in Germany, these facilities have become a staple element of such mega events. This qualitative, longitudinal, multi-continent research draws on extensive semi-structured interview and observation data. As a frame of reference, this work considers football events staged before and after the development of fan parks. Research was undertaken at four World Cup finals (Japan 2002, Germany 2006, South Africa 2010 and Brazil 2014), four European Championships (Portugal 2004, Switzerland/Austria 2008, Poland/Ukraine 2012 and France 2016), four other confederation tournaments (Ghana 2008, Qatar 2011, USA 2011 and Chile 2015), and four European club finals (Istanbul 2005, Athens 2007, Rome 2009 and Basle 2016). This work found that these parks are typically temporarily erected, specifically located zones where supporters congregate together irrespective of allegiances to watch matches on large screens, and partake in other forms of organised on-site entertainment. Such facilities can also allow organisers to control the behaviour, confine the movement and monitor the alcohol consumption of supporters. This represents a notable shift in policy from previous football tournaments, when the widely assumed causal link between alcohol and hooliganism which frequently shaped legislative and police responses to disorder, also dissuaded some authorities from permitting fans to consume alcohol in and around stadia. It also reflects changing attitudes towards modern football fans. The work also found that in certain contexts supporters have increasingly engaged with such provision which impacts fan behaviour, but that this is relative to factors including location, facilities, management and security.

Keywords: event, facility, fan, management, park

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Authors: Vincent Schlageter, Maroua Mestiri, Florian Denzinger, Hugo Raetzo, Michel Demierre

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Precise landslide monitoring with differential global navigation satellite system (GNSS) is well known, but technical or economic reasons limit its application by geotechnical companies. This study demonstrates the reliability and the usefulness of Geomon (Infrasurvey Sàrl, Switzerland), a stand-alone and cost-effective rover network. The system permits deploying up to 15 rovers, plus one reference station for differential GNSS. A dedicated radio communication links all the modules to a base station, where an embedded computer automatically provides all the relative positions (L1 phase, open-source RTKLib software) and populates an Internet server. Each measure also contains information from an internal inclinometer, battery level, and position quality indices. Contrary to standard GNSS survey systems, which suffer from a limited number of beacons that must be placed in areas with good GSM signal, Geomon offers greater flexibility and permits a real overview of the whole landslide with good spatial resolution. Each module is powered with solar panels, ensuring autonomous long-term recordings. In this study, we have tested the system on several sites in the Swiss mountains, setting up to 7 rovers per site, for an 18 month-long survey. The aim was to assess the robustness and the accuracy of the system in different environmental conditions. In one case, we ran forced blind tests (vertical movements of a given amplitude) and compared various session parameters (duration from 10 to 90 minutes). Then the other cases were a survey of real landslides sites using fixed optimized parameters. Sub centimetric-accuracy with few outliers was obtained using the best parameters (session duration of 60 minutes, baseline 1 km or less), with the noise level on the horizontal component half that of the vertical one. The performance (percent of aborting solutions, outliers) was reduced with sessions shorter than 30 minutes. The environment also had a strong influence on the percent of aborting solutions (ambiguity search problem), due to multiple reflections or satellites obstructed by trees and mountains. The length of the baseline (distance reference-rover, single baseline processing) reduced the accuracy above 1 km but had no significant effect below this limit. In critical weather conditions, the system’s robustness was limited: snow, avalanche, and frost-covered some rovers, including the antenna and vertically oriented solar panels, leading to data interruption; and strong wind damaged a reference station. The possibility of changing the sessions’ parameters remotely was very useful. In conclusion, the rover network tested provided the foreseen sub-centimetric-accuracy while providing a dense spatial resolution landslide survey. The ease of implementation and the fully automatic long-term survey were timesaving. Performance strongly depends on surrounding conditions, but short pre-measures should allow moving a rover to a better final placement. The system offers a promising hazard mitigation technique. Improvements could include data post-processing for alerts and automatic modification of the duration and numbers of sessions based on battery level and rover displacement velocity.

Keywords: GNSS, GSM, landslide, long-term, network, solar, spatial resolution, sub-centimeter.

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Authors: Zdravko Trivic, John Chye Fung, Ruzica Bozovic-Stamenovic

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Within the context of rapidly ageing population in Singapore and the pressing demands on both caregivers and care providers, an integrated approach to ageing-friendly and ability-sensitive enabling environment becomes an imperative. This particularly applies to nursing home environments and their immediate surroundings, as they are becoming one of the main available options of long-term care for many senior adults who are unable to age at home. Yet, despite the considerable efforts to break the still predominant clinical approach to eldercare and to introduce more home-like design and person-centric care model, nursing homes keep being stigmatised and perceived as not so desirable environments to grow old in. The challenges are further emphasised by the associated physical, sensorial, psychological and cognitive declines that are the common consequences of ageing. Such declines have an immense impact on almost all aspects of older adults’ daily functioning, including problems with mobility and spatial orientation, difficulties in communication, withdrawal from social interaction, higher level of depression and decreased sense of independence and autonomy. However, typical nursing home designs tend to neglect the full capacities of balanced and carefully integrated multisensory stimuli as active component of care and ability building. This paper outlines part of a larger multi-disciplinary study of six nursing homes in Singapore, with overarching objectives to create new models of supportive nursing home environments that go beyond the clinical care model and encourage community integration with the nursing home settings. The paper focuses on the largely neglected aspects of sensorial comfort and multi-sensorial properties of nursing homes, including both indoor and immediate outdoor spaces (boundaries). The objective was to investigate the sensory rhythms and explore their role in nursing home users’ daily routine and therapeutic capacities. Socio-sensory rhythms were captured and analysed through a combination of on-site sensory recordings of “objective” quantitative sensory data (air temperature and humidity, sound level and luminance) using multi-function environment meter, perceived experienced data, spatial mapping, first-person observations of nursing home users’ activity patterns, and interviews. This was done in addition to employment of available assessment tools, such as Wisconsin Person Directed Care assessment tool, Dementia Quality of Life [DQoL] instrument, and Resident Environment Impact Scale [REIS], as these tools address the issues of sensorial experience insufficiently and selectively. Key findings indicate varied levels of sensory comfort, as well as diversity, intensity, and customisation of multi-sensory conditions within different nursing home spaces. Sensory stimulation is typically concentrated in communal living areas of the nursing homes or in the areas that often provide controlled or limited access, including specifically designed sensory rooms and outdoor green spaces (gardens and terraces). Opportunities for sensory stimulation are particularly limited for bed-bound senior residents and within more functional areas, such as corridors. This suggests that the capacities of nursing home designs to provide more diverse and better integrated pleasant sensory conditions as integrated “therapeutic devices” to build nursing home residents’ physical and mental abilities, encourage activity and improve wellbeing are far from exhausted.

Keywords: ageing-supportive environment, enabling design, multi-sensory assessment, nursing home environment

Procedia PDF Downloads 123

Authors: Marcela Davalos Lopez

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The history of the circulation of hygienic knowledge and the consolidation of public health in Latin American cities towards the end of the 19th century is well known. Among them, Mexico City was inserted in international politics, strengthened institutions, medical knowledge, applied parameters of modernity and built sanitary engineering works. Despite the power that this hygienist system achieved, its scope was relative: it cannot be generalized to all cities. From a comparative and contextual analysis, it will be shown that conclusions derived from modern urban historiography present, from our contemporary observations, fractures. Between 1890 and 1930, the small cities and areas surrounding the Mexican capital adapted in their own way the international and federal public health regulations. This will be shown for neighborhoods located around Mexico City and in a medium city, close to the Mexican capital (about 80 km), called Cuernavaca. While the inhabitants of the neighborhoods kept awaiting the evolutionary process and the forms that public hygiene policies were taking (because they were witnesses and affected in their territories), in Cuernavaca, the dictates came as an echo. While the capital was drained, large roads were opened, roundabouts were erected, residents were expelled, and drains, sewers, drinking water pipes, etc., were built; Cuernavaca was sheltered in other times and practices. What was this due to? Undoubtedly, the time and energy that it took politicians and the group of "scientists" to carry out these enormous works in the Mexican capital took them away from addressing the issue in remote villages. It was not until the 20th century that the federal hygiene policy began to be strengthened. Despite this, there are other factors that emphasize the particularities of each site. I would like to draw attention here to the different receptions that each town prepared on public hygiene. We will see that Cuernavaca responded to its own semi-rural culture, history, orography and functions, prolonging for much longer, for example, the use of its deep ravines as sewers. For their part, the neighborhoods surrounding the capital, although affected and excluded from hygienist policies, chose to move away from them and solve the deficiencies with their own resources (they resorted to the waste that was left from the dried lake of Mexico to continue their lake practices). All of this points to a paradox that shapes our contemporary concerns: on the one hand, the benefits derived from medical knowledge and its technological applications (in this work referring particularly to the urban health system) and, on the other, the alteration it caused in environmental settings. Places like Cuernavaca (classified by the nineteenth-century and hygienists of the first decades of the twentieth century as backward), as well as landscapes such as neighborhoods, affected by advances in sanitary engineering, keep in their memory buried practices that we observe today as possible ways to reestablish environmental balances: alternative uses of water; recycling of organic materials; local uses of fauna; various systems for breaking down excreta, and so on. In sum, what the nineteenth and first half of the twentieth centuries graduated as levels of backwardness or progress, turn out to be key information to rethink the routes of environmental conservation. When we return to the observations of the scientists, politicians and lawyers of that period, we find historically rejected cultural alterity. Populations such as Cuernavaca that, due to their history, orography and/or insufficiency of federal policies, kept different relationships with the environment, today give us clues to reorient basic elements of cities: alternative uses of water, waste of raw materials, organic or consumption of local products, among others. It is, therefore, a matter of unearthing the rejected that cries out to emerge to the surface.

Keywords: sanitary hygiene, Mexico city, cultural alterity, environmental conservation, environmental history

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Authors: Berrachid Dounia, Bellihi Hassan

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The financial crisis made a barrier in front of small projects that are looking for funding, but in the other hand it has had at least an interesting side effect which is the rise of alternative and increasingly creative forms of financing. The traditional forms of financing has known a recession due to the new difficult situation of economical recession that all parts of the world have known. Having an innovating idea that has an effect on both sides, the economic one and social one is very beneficial for those who wants to get rid of the economical crisis. In this case, entrepreneurs who want to be successful are looking for the means of financing that are going to get their projects to the reality. The financing could be various, whether the entrepreneur can use his own resources, or go to the three “Fs”(Family, friends, and fools),look for Angel Investors, or try for the academic solution like universities and private incubators, but sometimes, entrepreneurs feels uncomfortable about those means and start looking to newer, less traditional forms of financing their projects. In the last few years, people have shown a great interest to the use of internet for many reasons (information, social networking, communication, entertainment, transaction, etc.). The use of internet facilitates relations between people and eases the maintenance of existing relationships ,it increases also the number of exchanges which leads to a “collective creativity”, moreover, internet gives an opportunity to create new tool for mobilizing civil society, which makes the participation in a project company much easier. The new atmosphere of business forces the project leaders to look for new solution of financing that cut out the financial intermediaries. Using platforms in order to finance projects is an alternative that is changing the traditional solutions of financing projects. New creative ways of lending money appears like Peer to Peer (person to person or P2P)lending. This digital directly intermediary got his origins from microcredit principles. Crowdfunding also, like P2P, involves getting individuals to pool their resources to finance a project without a typical financial intermediary. For Lambert and Schwienbacher "Crowdfunding involves an open call, essentially through the Internet, for the provision of financial resources either in the form of donations (without rewards) or in exchange for some form of reward and/or voting rights in order to support initiatives for specific purposes". The idea of this proposal for investors and entrepreneurs is to encourage small contributions from a large number of funders "the crowd" in order to raise money to fund projects. All those conditions made from crowdfunding a useful alternative to project leaders, and especially the ones who are carrying special ideas that need special funds. As mentioned before by Laflamme. S. et Lafortune. S. internet is a tool for mobilizing civil society. In our case, the crowdfunding is the tool that funds social entrepreneurship, in the case of not for profit organizations, it focuses his attention on social problems which could be resolved by mobilizing different resources, creating innovative initiatives, and building new social arrangements which call up the civil society. Social entrepreneurs are mostly the ones who goes onto crowdfunding web site, so they propose the amount which is expected to realize their project and then they receive the funds from crowd funders. Something the crowd funders expect something in return, like a product from the business (a sample from a product (case of a cooperative) or a CD (in the case of films or songs)), but not their money back. Thus, we cannot say that their lands are donations, because a donator did not expect anything back. However, in order to encourage "crowd-funders", rewards motivates people to get interested by projects and made some money from internet. The operation of crowd funding is making all parts satisfied investors, entrepreneurs and also crowdfunding sites owners. This paper aims to give a view of the mechanism of crowdfunding, by clarifying the techniques and its different categories, and social entrepreneurship as a sponsor of social development. Also, it aims to show how this alternative of financing could be beneficial for social entrepreneurs and how it is bringing a solution to fund social projects. The article concludes with a discussion of the contribution of crowdfunding in social entrepreneurship especially in the Moroccan context.

Keywords: crowd-funding, social entrepreneurship, projects funding, financing

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Authors: Angshuman Raha, Abesh Kumar Sanyal, Uttaran Bandyopadhyay, Kaushik Mallick, Kamalika Bhattacharyya, Subrata Gayen, Gaurab Nandi Das, Mohd. Ali, Kailash Chandra

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Indian Himalayan Region (IHR), due to its sheer latitudinal and altitudinal expanse, acts as a mixing ground for different zoogeographic faunal elements. The innumerable unique and distributional restricted rare species of IHR are constantly being threatened with extinction by the ongoing climate change scenario. Many of which might have faced extinction without even being noticed or discovered. Monitoring the community dynamics of a suitable taxon is indispensable to assess the effect of this global perturbation at micro-habitat level. Lepidoptera, particularly moths are suitable for this purpose due to their huge diversity and strict herbivorous nature. The present study aimed to collate scattered historical records of moths from IHR and spatially disseminate the same in Geographic Information System (GIS) domain. The study also intended to identify moth species with significant altitudinal shifts which could be prioritised for monitoring programme to assess the effect of climate change on biodiversity. A robust database on moths recorded from IHR was prepared from voluminous secondary literature and museum collections. Historical sampling points were transformed into richness grids which were spatially overlaid on altitude, annual precipitation and vegetation layers separately to show moth richness patterns along major environmental gradients. Primary samplings were done by setting standard light traps at 11 Protected Areas representing five Indian Himalayan biogeographic provinces. To identify significant altitudinal shifts, past and present altitudinal records of the identified species from primary samplings were compared. A consolidated list of 4107 species belonging to 1726 genera of 62 families of moths was prepared from a total of 10,685 historical records from IHR. Family-wise assemblage revealed Erebidae to be the most speciose family with 913 species under 348 genera, followed by Geometridae with 879 species under 309 genera and Noctuidae with 525 species under 207 genera. Among biogeographic provinces, Central Himalaya represented maximum records with 2248 species, followed by Western and North-western Himalaya with 1799 and 877 species, respectively. Spatial analysis revealed species richness was more or less uniform (up to 150 species record per cell) across IHR. Throughout IHR, the middle elevation zones between 1000-2000m encompassed high species richness. Temperate coniferous forest associated with 1500-2000mm rainfall zone showed maximum species richness. Total 752 species of moths were identified representing 23 families from the present sampling. 13 genera were identified which were restricted to specialized habitats of alpine meadows over 3500m. Five historical localities with high richness of >150 species were selected which could be considered for repeat sampling to assess climate change influence on moth assemblage. Of the 7 species exhibiting significant altitudinal ascend of >2000m, Trachea auriplena, Diphtherocome fasciata (Noctuidae) and Actias winbrechlini (Saturniidae) showed maximum range shift of >2500m, indicating intensive monitoring of these species. Great Himalayan National Park harbours most diverse assemblage of high-altitude restricted species and should be a priority site for habitat conservation. Among the 13 range restricted genera, Arichanna, Opisthograptis, Photoscotosia (Geometridae), Phlogophora, Anaplectoides and Paraxestia (Noctuidae) were dominant and require rigorous monitoring, as they are most susceptible to climatic perturbations.

Keywords: altitudinal shifts, climate change, historical records, Indian Himalayan region, Lepidoptera

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Authors: Qiaosi Li, Frankie Kwan Kit Wong, Tung Fung

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Lightweight unmanned aerial vehicle (UAV) loading with novel sensors offers a low cost approach for data acquisition in complex environment. This study established a framework for applying UAV system in complex environment quick mapping and assessed the performance of UAV-based hyperspectral image and digital surface model (DSM) derived from photogrammetric point clouds for 13 species classification in wetland area Mai Po Inner Deep Bay Ramsar Site, Hong Kong. The study area was part of shallow bay with flat terrain and the major species including reedbed and four mangroves: Kandelia obovata, Aegiceras corniculatum, Acrostichum auerum and Acanthus ilicifolius. Other species involved in various graminaceous plants, tarbor, shrub and invasive species Mikania micrantha. In particular, invasive species climbed up to the mangrove canopy caused damage and morphology change which might increase species distinguishing difficulty. Hyperspectral images were acquired by Headwall Nano sensor with spectral range from 400nm to 1000nm and 0.06m spatial resolution image. A sequence of multi-view RGB images was captured with 0.02m spatial resolution and 75% overlap. Hyperspectral image was corrected for radiative and geometric distortion while high resolution RGB images were matched to generate maximum dense point clouds. Furtherly, a 5 cm grid digital surface model (DSM) was derived from dense point clouds. Multiple feature reduction methods were compared to identify the efficient method and to explore the significant spectral bands in distinguishing different species. Examined methods including stepwise discriminant analysis (DA), support vector machine (SVM) and minimum noise fraction (MNF) transformation. Subsequently, spectral subsets composed of the first 20 most importance bands extracted by SVM, DA and MNF, and multi-source subsets adding extra DSM to 20 spectrum bands were served as input in maximum likelihood classifier (MLC) and SVM classifier to compare the classification result. Classification results showed that feature reduction methods from best to worst are MNF transformation, DA and SVM. MNF transformation accuracy was even higher than all bands input result. Selected bands frequently laid along the green peak, red edge and near infrared. Additionally, DA found that chlorophyll absorption red band and yellow band were also important for species classification. In terms of 3D data, DSM enhanced the discriminant capacity among low plants, arbor and mangrove. Meanwhile, DSM largely reduced misclassification due to the shadow effect and morphological variation of inter-species. In respect to classifier, nonparametric SVM outperformed than MLC for high dimension and multi-source data in this study. SVM classifier tended to produce higher overall accuracy and reduce scattered patches although it costs more time than MLC. The best result was obtained by combining MNF components and DSM in SVM classifier. This study offered a precision species distribution survey solution for inaccessible wetland area with low cost of time and labour. In addition, findings relevant to the positive effect of DSM as well as spectral feature identification indicated that the utility of UAV-borne hyperspectral and photogrammetry deriving 3D data is promising in further research on wetland species such as bio-parameters modelling and biological invasion monitoring.

Keywords: digital surface model (DSM), feature reduction, hyperspectral, photogrammetric point cloud, species mapping, unmanned aerial vehicle (UAV)

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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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Authors: Leila Safazadeh, Brad Berron

Abstract:

Self-assembled monolayers have tremendous impact in interfacial science, due to the unique opportunity they offer to tailor surface properties. Low-density self-assembled monolayers are an emerging class of monolayers where the environment-interfacing portion of the adsorbate has a greater level of conformational freedom when compared to traditional monolayer chemistries. This greater range of motion and increased spacing between surface-bound molecules offers new opportunities in tailoring adsorption phenomena in sensing systems. In particular, we expect low-density surfaces to offer a unique opportunity to intercalate surface bound ligands into the secondary structure of protiens and other macromolecules. Additionally, as many conventional sensing surfaces are built upon gold surfaces (SPR or QCM), these surfaces must be compatible with gold substrates. Here, we present the first stable method of generating low-density self assembled monolayer surfaces on gold for the analysis of their interactions with protein targets. Our approach is based on the 2:1 addition of thiol-yne chemistry to develop new classes of y-shaped adsorbates on gold, where the environment-interfacing group is spaced laterally from neighboring chemical groups. This technique involves an initial deposition of a crystalline monolayer of 1,10 decanedithiol on the gold substrate, followed by grafting of a low-packed monolayer on through a photoinitiated thiol-yne reaction in presence of light. Orthogonality of the thiol-yne chemistry (commonly referred to as a click chemistry) allows for preparation of low-density monolayers with variety of functional groups. To date, carboxyl, amine, alcohol, and alkyl terminated monolayers have been prepared using this core technology. Results from surface characterization techniques such as FTIR, contact angle goniometry and electrochemical impedance spectroscopy confirm the proposed low chain-chain interactions of the environment interfacing groups. Reductive desorption measurements suggest a higher stability for the click-LDMs compared to traditional SAMs, along with the equivalent packing density at the substrate interface, which confirms the proposed stability of the monolayer-gold interface. In addition, contact angle measurements change in the presence of an applied potential, supporting our description of a surface structure which allows the alkyl chains to freely orient themselves in response to different environments. We are studying the differences in protein adsorption phenomena between well packed and our loosely packed surfaces, and we expect this data will be ready to present at the GRC meeting. This work aims to contribute biotechnology science in the following manner: Molecularly imprinted polymers are a promising recognition mode with several advantages over natural antibodies in the recognition of small molecules. However, because of their bulk polymer structure, they are poorly suited for the rapid diffusion desired for recognition of proteins and other macromolecules. Molecularly imprinted monolayers are an emerging class of materials where the surface is imprinted, and there is not a bulk material to impede mass transfer. Further, the short distance between the binding site and the signal transduction material improves many modes of detection. My dissertation project is to develop a new chemistry for protein-imprinted self-assembled monolayers on gold, for incorporation into SPR sensors. Our unique contribution is the spatial imprinting of not only physical cues (seen in current imprinted monolayer techniques), but to also incorporate complementary chemical cues. This is accomplished through a photo-click grafting of preassembled ligands around a protein template. This conference is important for my development as a graduate student to broaden my appreciation of the sensor development beyond surface chemistry.

Keywords: low-density self-assembled monolayers, thiol-yne click reaction, molecular imprinting

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Authors: David J. Foran, Nhan Do, Samuel Ajjarapu, Wenjin Chen, Tahsin Kurc, Joel H. Saltz

Abstract:

The large-scale data and computational requirements of investigators throughout the clinical and research communities demand an informatics infrastructure that supports both existing and new investigative and translational projects in a robust, secure environment. In some subspecialties of medicine and research, the capacity to generate data has outpaced the methods and technology used to aggregate, organize, access, and reliably retrieve this information. Leading health care centers now recognize the utility of establishing an enterprise-wide, clinical data warehouse. The primary benefits that can be realized through such efforts include cost savings, efficient tracking of outcomes, advanced clinical decision support, improved prognostic accuracy, and more reliable clinical trials matching. The overarching objective of the work presented here is the development and implementation of a flexible Intelligent Retrieval and Interrogation System (IRIS) that exploits the combined use of computational imaging, genomics, and data-mining capabilities to facilitate clinical assessments and translational research in oncology. The proposed System includes a multi-modal, Clinical & Research Data Warehouse (CRDW) that is tightly integrated with a suite of computational and machine-learning tools to provide insight into the underlying tumor characteristics that are not be apparent by human inspection alone. A key distinguishing feature of the System is a configurable Extract, Transform and Load (ETL) interface that enables it to adapt to different clinical and research data environments. This project is motivated by the growing emphasis on establishing Learning Health Systems in which cyclical hypothesis generation and evidence evaluation become integral to improving the quality of patient care. To facilitate iterative prototyping and optimization of the algorithms and workflows for the System, the team has already implemented a fully functional Warehouse that can reliably aggregate information originating from multiple data sources including EHR’s, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology PAC systems, Digital Pathology archives, Unstructured Clinical Documents, and Next Generation Sequencing services. The System enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information about patient tumors individually or as part of large cohorts to identify patterns that may influence treatment decisions and outcomes. The CRDW core system has facilitated peer-reviewed publications and funded projects, including an NIH-sponsored collaboration to enhance the cancer registries in Georgia, Kentucky, New Jersey, and New York, with machine-learning based classifications and quantitative pathomics, feature sets. The CRDW has also resulted in a collaboration with the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) at the U.S. Department of Veterans Affairs to develop algorithms and workflows to automate the analysis of lung adenocarcinoma. Those studies showed that combining computational nuclear signatures with traditional WHO criteria through the use of deep convolutional neural networks (CNNs) led to improved discrimination among tumor growth patterns. The team has also leveraged the Warehouse to support studies to investigate the potential of utilizing a combination of genomic and computational imaging signatures to characterize prostate cancer. The results of those studies show that integrating image biomarkers with genomic pathway scores is more strongly correlated with disease recurrence than using standard clinical markers.

Keywords: clinical data warehouse, decision support, data-mining, intelligent databases, machine-learning.

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Authors: Fatima Saeed, Abdullah Mudassar

Abstract:

Introduction: Patient safety remains a global priority in the ever-evolving healthcare landscape. At the forefront of this endeavor are the International Patient Safety Goals (IPSGs), a standardized framework designed to mitigate risks and elevate the quality of care. Doctors, positioned as primary caregivers, wield a pivotal role in upholding and adhering to IPSGs, underscoring the critical significance of their knowledge and understanding of these goals. This research embarks on a comprehensive exploration into the depth of Doctors ' comprehension of IPSGs, aiming to unearth potential gaps and provide insights for targeted educational interventions. Established by influential healthcare bodies, including the World Health Organization (WHO), IPSGs represent a universally applicable set of objectives spanning crucial domains such as medication safety, infection control, surgical site safety, and patient identification. Adherence to these goals has exhibited substantial reductions in adverse events, fostering an overall enhancement in the quality of care. This study operates on the fundamental premise that an informed Doctors workforce is indispensable for effectively implementing IPSGs. A nuanced understanding of these goals empowers Doctors to identify potential risks, advocate for necessary changes, and actively contribute to a safety-centric culture within healthcare institutions. Despite the acknowledged importance of IPSGs, there is a growing concern that nurses may need more knowledge to integrate these goals into their practice seamlessly. Methodology: A Comprehensive research methodology covering study design, setting, duration, sample size determination, sampling technique, and data analysis. It introduces the philosophical framework guiding the research and details material, methods, and the analysis framework. The descriptive quantitative cross-sectional study in teaching care hospitals utilized convenient sampling over six months. Data collection involved written informed consent and questionnaires, analyzed with SPSS version 23, presenting results graphically and descriptively. The chapter ensures a clear understanding of the study's design, execution, and analytical processes. Result: The survey results reveal a substantial distribution across hospitals, with 34.52% in MTIKTH and 65.48% in HMC MTI. There is a notable prevalence of patient safety incidents, emphasizing the significance of adherence to IPSGs. Positive trends are observed, including 77.0% affirming the "time-out" procedure, 81.6% acknowledging effective healthcare provider communication, and high recognition (82.7%) of the purpose of IPSGs to improve patient safety. While the survey reflects a good understanding of IPSGs, areas for improvement are identified, suggesting opportunities for targeted interventions. Discussion: The study underscores the need for tailored care approaches and highlights the bio-socio-cultural context of 'contagion,' suggesting areas for further research amid antimicrobial resistance. Shifting the focus to patient safety practices, the survey chapter provides a detailed overview of results, emphasizing workplace distribution, patient safety incidents, and positive reflections on IPSGs. The findings indicate a positive trend in patient safety practices with areas for improvement, emphasizing the ongoing need for reinforcing safety protocols and cultivating a safety-centric culture in healthcare. Conclusion: In summary, the survey indicates a positive trend in patient safety practices with a good understanding of IPSGs among participants. However, identifying areas for potential improvement suggests opportunities for targeted interventions to enhance patient safety further. Ongoing efforts to reinforce adherence to safety protocols, address identified gaps, and foster a safety culture will contribute to continuous improvements in patient care and outcomes.

Keywords: infection control, international patient safety, patient safety practices, proper medication

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Authors: Chiu-Yin Leung

Abstract:

This research investigates a complex assemblage among indigenous identities, socio-political organization and national apparatus in the border landscape of post-colonial Hong Kong. This former British colony had designated a transient mode of governance in its New Territories and particularly the northernmost borderland in 1951-2012. With a discriminated system of land provisions for the indigenous villagers, the place has been inherited with distinctive village-based culture, historic monuments and agrarian practices until its sovereignty return into the People’s Republic of China. In its latest development imperatives by the national strategic planning, the frontier area of Hong Kong has been identified as a strategy site for regional economic integration in South China, with cross-border projects of innovation and technology zones, mega-transport infrastructure and inter-jurisdictional arrangement. Contemporary literature theorizes borders as the material and discursive production of territoriality, which manifest in state apparatus and the daily lives of its citizens and condense in the contested articulations of power, security and citizenship. Drawing on the concept of assemblage, this paper attempts to tract how the border regime and infrastructure in Hong Kong as a city are deeply ingrained in the everyday lived spaces of the local communities but also the changing urban and regional strategies across different longitudinal moments. Through an intensive ethnographic fieldwork among the borderland villages since 2008 and the extensive analysis of colonial archives, new development plans and spatial planning frameworks, the author navigates the genealogy of the border landscape in Ta Kwu Ling frontier area and its implications as the milieu for new state space, covering heterogeneous fields particularly in indigenous rights, heritage preservation, rural sustainability and regional economy. Empirical evidence suggests an apparent bias towards indigenous power and colonial representation in classifying landscape values and conserving historical monuments. Squatter and farm tenants are often deprived of property rights, statutory participation and livelihood option in the planning process. The postcolonial bureaucracies have great difficulties in mobilizing resources to catch up with the swift, political-first approach of the mainland counterparts. Meanwhile, the cultural heritage, lineage network and memory landscape are not protected altogether with any holistic view or collaborative effort across the border. The enactment of land resumption and compensation scheme is furthermore disturbed by lineage-based customary law, technocratic bureaucracy, intra-community conflicts and multi-scalar political mobilization. As many traces of colonial misfortune and tyranny have been whitewashed without proper management, the author argues that postcolonial justice is yet reconciled in this fragmented border landscape. The assemblage of border in mainstream representation has tended to oversimplify local struggles as a collective mist and setup a wider production of schizophrenia experiences in the discussion of further economic integration among Hong Kong and other mainland cities in the Pearl River Delta Region. The research is expected to shed new light on the theorizing of border regions and postcolonialism beyond Eurocentric perspectives. In reassembling the borderland experiences with other arrays in state governance, village organization and indigenous identities, the author also suggests an alternative epistemology in reconciling socio-spatial differences and opening up imaginaries for positive interventions.

Keywords: heritage conservation, indigenous communities, post-colonial borderland, regional development, rural sustainability

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

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