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Telehealth is defined as “the use of electronic information and telecommunications technologies to support long distance healthcare, patient and professional health-related education, public health and health administration” (2). This technology has proven to be a promising method of providing continuing education for healthcare providers (3) as well as supporting clinical services for patients (4). Multiple studies demonstrate effective distance education to rural locations in the United States using telehealth (5–7). However, there remains limited evidence of the cost-effectiveness and the acceptability by both patients and health-care providers of using this technology, and most research to date has been conducted within higher income countries. Recent studies have begun to show promise in addressing the disparity of medical specialists in LMICs by expanding access to sub-specialty training through telehealth (8, 9). Several organizations link multiple groups across geographical and cultural boundaries to provide educational videoconferencing, including the Reseau en Afrique Francophone pour la Telemedicine (10–12), the KwaZulu-Natal Experience (13), and the Global Educational Toxicology Uniting Project (14). Additionally, several programs have explored collaborations between academic institutions/hospitals in higher income countries and LMICs to provide medical education via teleconference, including in specialties such as obstetrics and gynecology (15), emergency and trauma care (16), anesthesia (17), and surgical skills training (18). While much of the rapidly expanding research for Internet-based remote education in LMICs is focused on the continuing medical education of physicians and trainees, a study in Malaysia showed that nurses and their remote lecturers responded positively to e-learning, noting that communication and interaction are key components to a teleconferencing format of teaching (19). Furthermore, during the recent Ebola epidemic, a tablet computer tutorial application was successfully used to train frontline health workers by improving knowledge and attitudes surrounding the virus (20). While telehealth technology holds great promise in educating health professionals in LMICs, very few studies have assessed the feasibility and acceptability of this teaching method with frontline health workers such as CHNs.
|
review
| 99.9 |
Our organization, the Center for Global Health at the Colorado School of Public Health, has partnered with a local agricultural company, AgroAmerica, in the coastal lowlands of southwest Guatemala to create a health center and community health program that improve general health and access to healthcare to several small communities that make up a rural population of approximately 30,000 people (21). This area in Guatemala is cultivated with crops for export, primarily bananas and palm oil, owned by large agro-business enterprises, and the rural population struggles with poverty and lack of access to health, education, and reliable clean water. Our partnership is a unique relationship between a university, a private business, and a community. The program is largely funded by the Guatemalan agricultural company with our university establishing and supporting medical services through a Guatemalan-staffed clinic, laboratory, and pharmacy as well as community-based health programs for maternal and early childhood health. The CHNs in our program conduct home and group visits for pregnant women and children up to 3 years of age. They follow women throughout pregnancy, monitoring expectant mothers and providing interventions that improve prenatal care and delivery. Once the baby is born, the mother and child transition to an early childhood health and development segment of the program that combines a series of neonatal home visits, community education sessions, and mother–child interactive group visits to enhance the health and development of children from birth to 3 years of age. CHNs travel throughout the communities performing assessments of general health, child development and anthropometrics, and providing anticipatory guidance and basic health advice.
|
other
| 99.75 |
In the summers of 2014 and 2015, a general lack of lactation knowledge and support was identified within our program. As a result, team members from our institution provided in-person breastfeeding training to the CHNs while present in Guatemala as baseline education. Following the 2015 program, both the CHNs and the instructors wanted to continue the breastfeeding educational program. However, as in many rural health-center locations in LMICs, a great deal of time and resources are needed to send instructors to the local site for in-person trainings. As many rural health centers reach communities outside of main cities and common thoroughfares, travel to these sites frequently involves extended time and costs, limiting teaching faculty to a few longer trips and limiting teaching to short periods of intense training. From our organization, it costs approximately 3000 USD to send one faculty member to Guatemala for 2 weeks, which includes airfare, room and board, and local transportation but does not even include faculty salary, which varies considerably. In the initial years of program development and implementation, our institution would spend around 50,000 USD annually to send faculty members to our rural site, which quickly became a financial limitation. For programs using local faculty, instructors can provide sustained regular contact with CHNs allowing for interactive discussions over time, including case reviews related to the teaching. For distance programs and partnerships such as ours, however, regular training of CHNs creates the need for a more innovative and cost-effective education delivery method using information and communication technology such as telehealth.
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other
| 99.44 |
For this reason, continuation of the initial breastfeeding curriculum was initiated via a videoconferencing software program at our institution. Developed in response to the expressed needs of the CHNs, topics then expanded to more generalized child health topics in rotation with breastfeeding lectures. The initial pilot period of July–November 2015 demonstrated general feasibility and satisfaction among team members and CHNs, and the team proceeded with a planned curriculum that included knowledge assessments and formal evaluations. The current program evaluation for this telehealth curriculum aimed to prove knowledge gains in child health topics, assess satisfaction and convenience with telehealth technology, demonstrate connection between learners and instructors, and identify challenges in delivery.
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other
| 98.06 |
This pilot was considered to be program evaluation rather than human subject research by the Colorado Multiple Institutional Review Board, and therefore, informed consent was not required. The CHNs were aware of the evaluation process during the program. The program evaluation took place between February and May 2016. Child health lectures were organized into two blocks of five topics each and were selected based on CHN preferences and instructor ability. Lectures covered the following topics: anemia, ear infections, zinc, urinary tract infections, antibiotics, vaccines, obesity, vitamin A, injury prevention, and burns. We used the videoconferencing software program Vidyo© (22), licensed by the Telehealth Department at our institution and available free of charge to our program. Vidyo© is a high-definition videoconferencing platform with an encrypted signal between several computers or mobile devices. The system has smoothing capabilities due to an iterative signal to allow for more natural communication. The platform runs on our institution’s secure network. One of the team members acted as lead instructor by using the Vidyo© platform and sharing the screen with supplementary documents or slides on the topic. Other team members joined lectures as assistant instructors or observers. The lectures consisted of approximately 30 min of didactic teaching with an additional 15 min for questions, case presentations, and discussions of current cases and experiences in the community, providing a total time of approximately 45 min connected via telehealth. Learners viewed the shared supplementary teaching materials and the instructors simultaneously on their screen. The lead instructor viewed the learners as well as the instructor’s home screen with supplementary teaching materials (Figure 1). Lectures were given in Spanish, the native language of the learners, but there was intermittent discussion among instructors in English for clarification. Learners were able to access the teaching documents after the lecture. The educational sessions were not recorded due to the need to maximize bandwidth availability at the Guatemala location.
|
study
| 99.6 |
Internet connection for the instructors was home or office Wi-Fi or cellular network on their personal or work computers, tablets, or phones. The devices connected securely to our institution’s network through Vidyo©. The CHNs used an established Wi-Fi connection at the clinic campus in Guatemala freely available to employees. The Internet at the clinic costs 5,300 Guatemalan Quetzales or approximately 700 USD per month for connection speeds of 6 mbps, which is paid by the Guatemalan agricultural company. This Internet connection is used for maintaining electronic medical records at the clinic and data downloads for multiple ongoing research studies. There were no additional costs to our program for the use of the clinic Internet. No evaluation of specific bandwidth usage was done for this assessment.
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other
| 99.8 |
Evaluation of the program consisted of pre- and post-knowledge assessments by the learners as well as quality and satisfaction evaluations by both learners and instructors. All testing and evaluations were done through Google Forms© (Google Docs, RRID:SCR_005886). The anonymous survey data were collected and stored in Google Docs and then further processed in Microsoft Excel©. Two blocks of five lectures were given. Each block was preceded by a pre-test, consisted of one lecture per week for 5 weeks and was followed by a posttest after the last lecture was given. Pre- and posttests assessed knowledge of each of the five topics per block, with 20 points available per topic and an overall 100 points per test for each of the two blocks. Each lecture was followed by a quality and satisfaction evaluation assessing content, technology, and connection between instructors and learners on a 4-point Likert scale. Instructors completed a separate evaluation assessing technology, convenience, and connection. Both evaluations requested details on technology difficulties and general feedback on the teaching. As technical problems can affect the students’ perceptions of quality (23), technical quality (e.g., audio, video, and time to connect) was measured with each lecture. All surveys and tests were completed anonymously to allow for candid responses.
|
study
| 99.94 |
Survey responses from instructors and learners were combined across 10 lectures for mean Likert scores (1–4 range) with population SD. Percent of “agree” responses (scores 3 and 4) was also calculated per survey question. Survey questions were grouped into assessments of lecture content, technology, and connection among instructors and learners. Knowledge gain was measured by percent improvement per subject and overall pre- to posttest scores. Due to the small number of students, instructors, and lectures, correlation among survey responses per lecture was not performed.
|
study
| 99.94 |
The seven CHN learners in this program had completed either auxiliary nursing school (n = 4, 1 year post high school) or professional nursing school (n = 3, 3 years post high school). All CHNs were female, averaging 25 years of age and 5 years post-completion of nursing school. The lead instructor was a pediatrician at our institution (Kelly A. McConnell). Additional instructors were pediatricians (Maya Bunik and Gretchen J. Domek), a pediatric nurse practitioner (Maureen Lenssen), and a recent medical school graduate from Guatemala (Saskia Bunge Montes). All instructors had been to the site in rural Guatemala and had been involved with the implementation of the community health program.
|
other
| 99.9 |
The percent increase of the mean for each lecture ranged from 1.4 to 19.9% (Figure 2) with an overall average increase of 10.7% among all topics. Overall, the correct score for each lecture improved from a mean of 13.9 to 15.4 out of 20 possible points. Test responses were not paired or adjusted for non-attendance of certain lectures as surveys and tests remained anonymous.
|
study
| 99.94 |
There was an average of 5.5 learners present per lecture. Responses from the learners were overall positive, especially regarding lecture content with 98% or greater agreement with each positive statement (Table 1). The technology questions regarding ease of use and convenience were also strongly positive with at least 98% agreement. The ability to hear the instructor (94.5% agreement) was greater than the ability to see the instructor (87.3% agreement), likely due to greater signal strength required for video compared to audio delivery. Statements related to the connection to the instructor were agreed upon 100% of the time except when asked if the lecture via telehealth was as good as in person (94.5% agreement). The amount of time to connect to the system was most frequently 5–10 min but took up to 15 min. Three lectures were rescheduled due to a lack of Internet connection at the site in Guatemala; two were done later in the same day and one was rescheduled to a different day. Overall, the CHNs were extremely satisfied with the lecture delivery via telehealth as well as the direct teaching.
|
study
| 99.94 |
An average of two instructors was present for each lecture, one lead instructor and generally one additional team member. Audio quality was again reported to be better than video quality with “I could see the learners well” agreed upon only 59.1% of responses compared to 86.4% for audio (Table 1). Ease and convenience statements were 100% agreed upon, reflective of the system in which instructors joined from their personal or work computers or phones at their convenience if available. The amount of time to connect was nearly immediate in all reports from the instructors except two instances in which an observer was not able to connect. Feelings of connection to the learners by the instructors were lower at 86.4% than was reported from learners who reported 100% agreement.
|
study
| 99.94 |
Our pilot evaluation contributes important results on the feasibility and acceptability of using telehealth technology to train CHNs in a rural LMIC, an area where very little research currently exists. In fact, we are not aware of another study using telehealth to train CHNs in a LMIC via an academic partnership. Our study shows that with an overall improvement of more than 10% in pre- to posttest knowledge scores, teaching CHNs through telehealth was effective for knowledge gain specific to the 10 topics taught. CHNs also reported that these teachings were useful and would be impactful for their daily work in the community. Some lectures had a greater improvement than others, which may be related to the difficulty of the test questions, baseline knowledge, quality of the technology, and lecture content. Knowledge gain did not seem to be influenced by the amount of time between each lecture and the final posttest.
|
study
| 100.0 |
High rates of satisfaction and convenience with the telehealth system were demonstrated in our surveys from both learners and instructors. This is a critical component of feasibility and program evaluation, enabling continued investment from both parties. As telehealth involves remote interaction, connection is both difficult and important to maintain. Our instructors are culturally much more experienced with in-person teaching, while the CHNs have less experience with typical classroom didactic education, possibly reducing expectations. This may explain the higher satisfaction from the CHNs compared to the instructors. Overall, a sense of personal connection in regards to the teaching was felt by both parties, and importantly, the CHNs felt that the instructors cared about their learning. We think that there is likely a correlation between video quality and feelings of connection, but our dataset is not large enough for this analysis.
|
other
| 92.94 |
A major strength of our study was the low start-up costs and minimal resources needed to develop and implement a telehealth program. We used existing institutional computer equipment, Internet connections, teleconferencing software, and office space, including a well-established videoconferencing system, Vidyo© (22), as well as Internet access readily available to each participant. This substantially reduced the costs of initiation. While Vidyo© is provided free-of-charge at our institution, other videoconferencing software programs, such as Skype, have basic software packages that are easily accessible, free, and have been used by other e-learning programs (15, 17). Our team also had access and support from the Telehealth Department at our institution, providing infrastructure, technical expertise, and connection troubleshooting, all of which are critical elements to any e-learning programs. In general, Internet connectivity was strong during our study with few failed connections or technical difficulties experienced. Additionally, our educational sessions were all scheduled during protected academic time for our faculty and regular working hours for our CHNs, adding no further salary costs.
|
study
| 99.94 |
Another major strength to our program was the interactive, repetitive, and case-based learning style that we incorporated into each educational session. Research has shown the importance of active-learning exercises, personal interactions and feedback, intensive practice and repetition, and peer discussion in improving learning outcomes (24–26). A major advantage to using telehealth technology over web-based e-learning is the ability to have real-time interaction and active participation that facilitates asking questions, receiving clarifications, and discussing case presentations. In a review of e-learning in LMICs (27), lack of face-to-face interaction is discussed as a challenge to educational effectiveness. Additionally, all members of our team have traveled to the site in Guatemala, met the CHNs in-person, and been involved in multiple elements of the project, allowing a stronger connection, we believe, compared to telehealth contact alone. This participation with and knowledge of the community health program also allowed the team to create content directly applicable to the situations in which the CHNs worked daily.
|
study
| 99.9 |
While not assessed in our small pilot evaluation, there are likely to be significant economic, environmental, and personal benefits to such a program. We believe that increased education will improve the work of the nurses within the community since the lectures were targeted to improve CHN identification of common illnesses, determination of referral needs, and education of families for home treatments and health maintenance. Additional economic benefits include reduced travel of university faculty to the site, including lost work (clinical or teaching) time and travel and accommodation costs. A concept of planetary health linking human health, flourishing civilizations and the environment, described in the Lancet commission on planetary health (28), must be considered in our global health work to ensure the health of the environment as well as populations. This is especially true as the people most hurt by climate change are likely to be the communities we are working to help. Using telehealth to provide education allows for reduced carbon emissions related to travel, and if used on a large scale could have a positive effect on the environment. Additionally, this program evaluation started as Zika virus concerns were raised resulting in reduction in travel to endemic locations, including our site where Zika transmission is reported. The ability to deliver education remotely has far reaching benefits from direct costs to planetary health to personal health.
|
study
| 99.94 |
A major limitation to this study was that a specific cost-effectiveness analysis was not performed as the set-up of equipment, bandwidth, licensing of software, and faculty and CHN salaries were all included free-of-charge to our program. While most economic evaluations of telemedicine have failed to show significant cost savings (29), there is a paucity of data overall and especially in the educational (non-direct patient care) usage of telehealth. This is likely due to the fact that equipment, time, and software used are typically shared among projects in an academic setting, and there is no clear tracking of costs spent or saved with the specific telehealth program. Additionally, instructor and learner time commitments were not calculated for our evaluation. While further research exploring cost-effectiveness will be critical to future program expansion and replication, such studies remain a challenge to conduct. This is especially true in the academic setting where the actual costs of shared university resources and faculty time commitments for a specific telehealth program are hard to quantify, making it particularly difficult to estimate the future costs of scale-up, to generalize any findings and to replicate the study results in other non-academic settings.
|
study
| 99.94 |
Another limitation of our study was that the CHNs completed the surveys and tests anonymously, preventing pairing of pre- and posttest scores or the ability to adjust for lecture attendance. This was, however, done to encourage full participation and to remove concerns about job performance, which we feel aided in more candid survey responses. Furthermore, our dataset of surveys and tests was small, as it was designed as a pilot program evaluation, limiting our ability to calculate further correlation or data beyond central tendency. We do not know from our small pilot study whether the knowledge gain by the CHNs translated into better work performance and for what duration of time the knowledge gain persisted. This will be another important area of future exploration.
|
study
| 99.8 |
We are limited in the sustainability of this project which could provide additional quality improvement cycles as well as more detailed data collection, especially as these additional research questions arise. As this program developed in response to an expressed need, our team had several champions for CHN education. This is the main project of a Global Health postdoctoral fellow, who has moved to a different practice location. The program would benefit from an assigned hub of responsibility such as each oncoming fellow, a resident in our global health program or another long-term champion. The project is likely to continue but not necessarily with the same structure or data collection.
|
other
| 99.9 |
Several lectures were followed by informal discussions regarding the overall telehealth experience. These discussions informed the following lectures in an unofficial improvement cycle. Throughout our experience with telehealth for education, we observed that the learners were much more engaged if the didactic portion was limited to 30 min and interspersed with interactive questions supplied by the instructor and real patient cases brought by the CHNs. Engagement was not specifically measured by the instructors but was discussed after lectures among team members. Also, limiting the use of video and audio transmission for those instructors not directly teaching improved the clarity and focus of the lead instructor and allowed the lead instructor to see and hear the learners better. This allowed for reengagement, questions, and breaks as necessary, similar to the way a live teacher can respond to a class. The CHNs reported preference for a larger screen for viewing, especially compared to a small laptop screen as was most commonly used. In the future, it will be important to provide a larger screen and speakers to allow for better video conferencing at the rural LMIC site. Flexibility and patience from both the learners and instructors were also important since some lectures had to be delayed or postponed due to poor connectivity, although this was rare. Anecdotally, the instructors noted that experience with telehealth, especially in understanding the delay in videoconferencing, allowed for better interactions and stronger feelings of connection.
|
other
| 99.6 |
Our program evaluation shows that telehealth may be an effective and low-cost method of delivering education to frontline health workers, specifically CHNs in rural Guatemala. Post graduate nursing education targeted to current fieldwork was delivered using existing technology systems and easily available resources during work hours with high satisfaction among instructors and learners as well as knowledge improvement among learners from pre- to posttest scores. There are likely to be significant economic benefits to such a telehealth program, including improved fieldwork by CHNs and decreased travel costs by faculty. While larger studies are needed to quantify the duration and benefits of specific knowledge gains and to perform a cost-effectiveness analysis of the program, our initial pilot results are encouraging and show that a telehealth program between an academic university in a high-income country and a rural community health program in a LMIC is both feasible and acceptable. The relationship between the faculty at the US-based Center for Global Health and the frontline health workers at the rural LMIC site in Guatemala is integral to the continued success of this international partnership and community health program, which provides critical health-care access to a rural and impoverished population. The frequent interactions and time and effort given to these educational sessions provide ongoing CHN training in support of the community health program goals and display concern and support for the daily work of the CHNs, contributing to the continuation and longevity of this important partnership.
|
study
| 88.06 |
All authors participated in multiple meetings regarding the design of the educational program and the program evaluation. KM was the instructor for all teaching sessions in this program evaluation, with supervision and approval of materials by GD. All authors participated in teaching, primarily MB and ML, prior to this specific program evaluation. LK coordinated educational sessions and analyzed the data with KM. SM, a Guatemala native, assisted with translation and creation of educational materials as well as communication with CHNs. KM did the primary writing, closely working with author GD. All authors reviewed the manuscript and gave final approval.
|
other
| 99.94 |
It is widely acknowledged that “the best solvent is no solvent”; however, running a reaction under neat conditions is very challenging from the points of view of mass transfer and temperature gradients [1–2]. Therefore, sustainable chemical technologies are often related to the use of a green non-harmful solvent , water. In principle, green chemistry refers to (1) the employment of raw material (substrates) in an efficient manner, (2) decreasing the resulting waste or undesired byproducts, and (3) using cheap and environment friendly solvents (i.e., water). Generally, using water as a solvent is an acceptable choice for green chemistry [4–6]. Indeed, water is attractive from both economic and environmental points of view, and is not taken into account when the E-factor (defined as mass ratio of waste to desired product) for a chemical process is determined [7–8]. This is to be true for chemical processes where the utility of water is limited to the work-up at the end of the process and not when used as a reaction medium. However, it should be noted that the utility of water as a reaction medium is the safest, but not the greenest choice. Unfortunately, most organic compounds and catalysts are not soluble in water, limiting its utility for most reactions [9–10]. For this reason, scientists across academia and industry have proposed many solutions in order to maximize the outcome of reactions (i.e., yields, enantioselectivities, etc.) in water and, thereby, harness its utility for further applications. The abovementioned issues are particularly relevant in the field of asymmetric catalysis, which besides overcoming catalyst compatibility also has to deal with cost issues [11–12]. Research on asymmetric catalysis has been mainly focused on performing catalytic reactions with high enantioselectivity and efficiency [13–14]. As a result, a wide range of chiral catalysts have been established [15–16]. Chiral catalysts are, however, not only incompatible with aqueous solutions, but also expensive due to the structural complexity of the ligands used and the usage of transition metals. Finding an approach to utilize chiral catalysts in water while minimizing their cost (i.e., recycling) is still a big challenge. In order to accomplish this, various strategies have been proposed and applied [17–19]. One significant, well-established and widely used strategy, is the use of site-isolated techniques, i.e., creating a separate micro environment [20–22] for catalysts to (1) allow their use in incompatible media, (2) to reduce their costs by recycling them, and (3) avoid any unfavorable environmental influences that might affect reaction yield and output [23–24]. Indeed, such a strategy proved to be advantageous for performing reactions in water and minimizing both reaction waste and cost [25–26].
|
review
| 99.9 |
Attempts to support homogeneous metal complexes onto organic or inorganic surfaces to facilitate their removal/extraction from the reaction mixture has proven to be successful [27–28]. In fact, the utility of catalytic supports has been fundamental to the concept of entrapping catalysts in organic nanodomains and bringing the notion of catalytic nanoreactors to light [29–30]. In recent years the use of nanocontainers/reactors wherein catalysts are entrapped and physically separated in an isolated compartment has appeared to be an excellent facile approach to enhance performance of reactions in water [31–34]. Pioneering examples in this field include small molecule host–guest containers such as cavitands [35–37], and calixarenes [38–39]. Besides these supramolecular cage structures compartmentalization can also be achieved in macromolecular nanoreactors. The advantage of employing these polymeric structures is their improved robustness and loading capacity, which makes recycling and efficient usage of catalytic species more achievable. Nanocompartments such as polymersomes , micelles , dendrimers , and nanogels [43–44] represent smart and compact devices to carry out reactions in aqueous media. Besides, their facile recyclability make them very suitable as nanoreactors for a multitude of applications in synthetic chemistry . In a recent study the E-factors for different traditional coupling reactions used in the pharmaceutical industry were reported and compared to those achieved in micellar nanoreactors , showing for the latter a decrease of at least an order of magnitude, which underlines their considerable potential in green catalysis (Table 1).
|
review
| 99.8 |
In this review we will focus on the application of polymeric nanoreactors in green catalysis by highlighting their structure and ability to encapsulate and shield catalysts. Four different types of nanoreactors will be described, namely micelles, polymersomes, dendrimers and nanogels. The choice of discussing these nanoreactors stems from their accredited relevance in the field of catalysis and the significant number of examples published in literature. The advantageous aspects of these four classes of nanoreactors over non-supported homogeneous systems include: 1) the site isolation of reactive components (enabling cascade reactions), 2) the ability to convert hydrophobic substrates in water (under green conditions), and 3) the facile catalyst recovery. All these attractive features are covered in this review. Moreover, in this review we have not attempted to be comprehensive, but we rather want to illustrate the application potential of these nanoreactors with some illustrative examples of the most relevant classes of organic reactions (performed in water), which should interest both academia and industry.
|
review
| 99.9 |
Catalysis, in general, is divided into two major types, homogenous and heterogeneous. In homogeneous catalysis catalyst and substrates are both present and molecularly dissolved in the same phase (typically a liquid phase) . Homogeneous catalysis involves the use of biocatalysts (enzymes), organocatalysts and metal catalysts . Catalysis is defined as heterogeneous when catalysts are in an aggregated state, and are thus in a different phase than the reactants . Heterogeneous catalysts typically consist of a solid carrier, the so called “support”, on which catalytic sites are dispersed [49–50]. Homogeneous catalysis is generally performed under milder operative conditions than heterogeneous catalysis . In fact, heterogeneous catalysts generally possess very high decomposition temperatures (above 100 °C) . The presence of a solid phase often results in the formation of temperature gradients when using high temperatures, which leads to an increase in reactant diffusion and a consequent hampering of mass transfer . Furthermore, the catalytic sites in heterogeneous catalysis are often not as well-defined as in homogeneous catalysis. Therefore, homogeneous catalysis usually results in better selectivity and less byproducts .
|
review
| 99.9 |
Although homogenous catalysis ensures high selectivity and a better reaction outcome, yet it is expensive (catalyst recycling is not always an option) and it requires the utility of harmful solvents, yielding high E-factors . In order to lower the E-factor, water should be used in the work-up procedure and separation. It has to be pointed out, however, that the presence of water during the process and its purification afterwards, especially when coming from industrial wastes, poses stringent limitations from an economical and environmental point of view.
|
other
| 99.8 |
A good method for homogeneous catalysts separation and reuse is offered by the use of biphasic liquid–liquid systems. Recycling can be achieved in the reactor when the organic phase is sampled out, while the aqueous phase containing the catalyst is retained into the vessel, enabling for continuous processing. The main issue that has to be solved in such set-up is the tolerability of the catalyst to water (its solubility, its activity, etc.) . A strategy to overcome this problem is the inclusion and confinement of the homogeneous catalysts into a host nano-architecture . Compartmentalization enables catalyst segregation and shielding, and ensures its facile removal from the reaction mixture after the reaction has taken place ; this facilitates reactions to be performed in water followed by liquid–liquid separation of products and catalyst . Moreover, shielding and segregation of catalysts in a nanoreactor facilitates one-pot tandem reactions that, in most cases, require two or more incompatible catalysts . Catalyst confinement leads to a high local concentration of the substrate at the active site, which results in higher reaction rates and better conversion . In this review we will highlight some typical nanoreactors that are used to accommodate homogeneous catalysts, holding promise in green organic synthesis. A division will be made between self-assembled nanoreactors, section 2, and covalent systems, section 3.
|
review
| 99.9 |
Self-assembled nanoreactors are macromolecular architectures that are non-covalently assembled from their constituent building units [58–59]. Such nanoreactors allow for physical confinement of catalysts, shielding them from their surroundings . Compartmentalization of catalysts in supramolecular nanoreactors is advantageous from kinetic (faster catalytic process) and thermodynamic (lower transition state of reaction) catalysis points of view. Segregation and isolation of catalysts inside nanoreactors guarantee, in most cases, a valuable platform for catalyst recycling . In the following section we will discuss the utility of some of the well-established catalytic nanoreactors towards green(er) chemistry .
|
review
| 99.9 |
Micelles are supramolecular architectures that are assembled of amphiphilic molecules . Above the critical micellar concentration (CMC), surfactants with the appropriately designed hydrophilic head (neutral, anionic and cationic) and hydrophobic chain organize themselves in micelles . Micelles have been extensively studied and their utility as nanoreactors is well-established . Various micellar morphologies can be obtained depending on the ‘packing parameter’ [56–61], which is defined as p = v/ao lc, where v is the volume, lc is the length of the hydrophobic chain and ao is the optimal area of the head groups . As a general rule, if p ≤ 1/3 spherical micelles are obtained, while cylindrical micelles, or the so-called worm-like micelles, form when 1/3 ≤ p ≤ 1/2. A typical micelle acquires a hydrophobic core that is able to accommodate hydrophobic catalysts, providing thermodynamic and kinetic control over chemical reactions . Moreover, carrying out reactions in such a hydrophobic core leads to a concentration effect for hydrophobic substrates, which ensures higher reaction rates than those performed in bulk . Besides, the structure of any micellar catalytic environment is governed by the arrangement of the amphiphilic molecules, creating, in many cases, a regioselective environment (Figure 1) that affects the outcome of some reactions .
|
study
| 91.5 |
Assembly of catalyst-functionalized amphiphilic block copolymers into polymer micelles and vesicles. Characteristics of a nanoreactor system are shown using the polymer micelles including (a) the catalysts are protected and isolated from each other by the micellar shell, (b) substrates are effectively sequestered by the core from the surrounding environment, creating a highly concentrated environment for confined catalysis, (c) the nanostructure shell may regulate the access of substrates to the catalyst-containing micelle core. Reprinted with permission from reference .
|
study
| 67.06 |
Non-spherical, high aspect ratio micelles are preferred for catalysis as such structures provide large surface area where reactions could take place . This has been particularly the case for dehydration reactions . Due to the combination of the structures’ high aspect ratio and the hydrophobic effect, water could effectively diffuse away from the catalytic site, which enabled the enhanced formation of product. .
|
study
| 99.94 |
Lipshutz and co-workers have successfully exploited micelles not only as nanoreactors, but as an outstanding platform for achieving greener organic reactions [26,65–66]. They have shown, for example, C–N cross-coupling reactions between heteroaryl bromides, chlorides or iodides and carbamate, sulfonamide or urea derivatives to be successfully realized in water using palladium-loaded TPGS-750-M (dl-α-tocopherol methoxypolyethylene glycol succinate) micelles (Scheme 1). Moreover, this micellar catalytic system allowed for catalyst recycling, minimizing the amount of the used organic solvent and generated waste .
|
study
| 99.94 |
The same group reported another interesting catalytic micelle system, which is based on PTS (polyoxyethanyl α-tocopheryl sebacate) . Using PTS-based micelles, they showed the amination of allylic ethers in water (Table 2 and Table 3). The reaction of different ethers with naphthylmethylamine resulted in excellent yields (Table 2). Comparable yields were obtained when different amines reacted with trans-cinnamyl phenyl ether (Table 3). In both of the cases micelles were used to protect the very sensitive and unstable [Pd(allyl)Cl]2 intermediate from air.
|
study
| 100.0 |
aReactions were carried out under air at rt in 2 wt % PTS/water in the presence of [Pd(allyl)Cl]2 (0.5 mol %), bis[(2-diphenylphosphino)phenyl] ether (DPEphos, 1 mol %), ether (1 equiv), naphthylmethylamine (1.5 equiv), K2CO3 (1.5 equiv) and HCO2Me (4 equiv). Adapted from reference .
|
study
| 99.9 |
aReactions were carried out under air at rt in 2 wt % PTS/water in the presence of [Pd(allyl)Cl]2 (0.5 mol %), DPEphos (1 mol %), trans-cinnamyl phenyl ether (1 equiv), amine (1.5 equiv), K2CO3 (1.5 equiv) and HCO2Me (4 equiv). bIsolated yields. cDoubly allylated product. Adapted from reference .
|
study
| 99.6 |
Micelles were also used to perform cross-coupling between benzyl and aryl halides in water . This reaction is known to result in very limited yields due to the undesired homo-coupling reaction between electron-rich and electron-poor benzyl bromides . This draw-back has been circumvented by using Pd-catalytic micelles, which were assembled in water using TMEDA (tetramethylethylenediamine) as additive. TMEDA was used to stabilize the Pd catalyst by chelation and indeed, presence of TMEDA resulted in higher yield . High catalytic efficiency of these Pd-catalytic micelles was also achieved while catalyzing reactions involving less reactive or sterically hindered species.
|
study
| 100.0 |
Handa et al. described a self-assembled TPGS-750M micelle (shown in Scheme 1), that allowed for copper-catalyzed Suzuki–Myaura coupling of aryl iodides (Scheme 2) . When the reaction was conducted in inert atmosphere, no product was formed. However, the reaction was performed successfully in the presence of air, suggesting that the actual mechanistic pathway involved the formation of a P–(O)–N species on the ligand. The presence of traces of Pd was also needed in this process, as 200 ppm of Pd(OAc)2 worked like a co-catalyst being beneficial either for the reaction rate and the yields, and no product was observed without the Pd source. Furthermore, the recyclability of the catalyst was improved and the experiments could be repeated up to 5 runs with yields >90%. Contrary to the results obtained in bulk, using micelles resulted in higher yields even after catalyst recycling, providing a promising catalytic platform for these coupling reactions .
|
study
| 100.0 |
Lee et al. described an approach to perform catalysis in micelles based on rod–coil block copolymers . Micelles were assembled from hydrophilic poly(ethylene oxide) (PEO) and hexa-p-phenylene, providing a platform for Suzuki reactions with the hydrophobic core acting as a suitable pocket for apolar aromatic guests [71–72]. With such a platform, full conversion was achieved at room temperature in water. Almost quantitative yields were observed when aryl chloride coupling was performed with arylboronic acids. This is indeed remarkable as aryl chlorides are generally not as reactive as aryl bromides or aryl iodides.
|
study
| 99.94 |
Lipshutz and Ghorai developed a micellar system called PQS to perform aldol reactions in water . As depicted in Figure 2, PQS (4a) has an OH moiety that allows for its linkage to the organocatalyst proline 4b. Also, PQS has a lipophilic component that acts as a reaction solvent for hydrophobic dienes. The latter feature allows aldol reactions to take place efficiently in water.
|
study
| 100.0 |
The aldol reaction between cyclohexanone and p-nitrobenzaldehyde was chosen to verify the performance of this nanoreactor. PQS-proline and the analogous mixed diester derivative of 4-hydroxyproline were prepared and tested in this process. The aldol product was achievable only by using the proline compound 4b, therefore different substrates were subsequently tested using 10 mol % of this catalyst in water at room temperature. The achievement of this study was not only on the stereoselectivity of the catalysts, but also on the substrate selectivity (Table 4): the preferred substrates are water-insoluble, suggesting that the reaction is occurring in the lipophilic pocket and not in water. The authors also demonstrated the ability of the PQS system to be recycled up to 10 times without loss in its catalytic activity.
|
study
| 100.0 |
aThe reactions were performed with aldehyde (0.01 mmol), ketone (0.5 mmol), and catalyst 4b (0.01 mmol) at rt. bCombined yield of isolated diastereomers. cDetermined by 1H NMR of the crude product. dDetermined by chiral-phase HPLC analysis for anti-products. Adapted from reference . Copyright 2012 American Chemical Society.
|
other
| 99.1 |
Catalytic micelles were also prepared by O’Reilly et al. when a novel amphiphilic Sulfur–Carbon–Sulfur (SCS) pincer Pd catalyst together with a PAA (poly(acrylic acid)) based polymer self-assembled in water . The catalytic activity of the nanostructures was compared to the results achieved with the small molecule analogues of the pincer Pd complex, in a Suzuki–Miyaura coupling. When the reaction of vinyl epoxide with phenylboronic acid was realized with 2% of pincer catalyst, the rate was 100 times higher for the water-based micellar system compared to the same reaction in organic solvent with the unsupported Pd-complex. A 100 times lower amount of catalyst was also loaded (0.02%), and still the reaction rate achieved was higher than the ones in organic media. This remarkable kinetic effect was attributed to two factors: 1) the small particle radius which increased the nanoreactor’s surface area, and 2) the creation of a more hydrophobic local pocket, as the catalyst was facing directly the hydrophobic membrane. Furthermore, the nanosystem also facilitated catalyst recycling by normal extraction.
|
study
| 100.0 |
Polymeric vesicles or polymersomes are synthetic bilayered hollow architectures that are self-assembled from amphiphilic block copolymers . The synthetic nature of polymersomes allows for facile tuning of their properties such as size , membrane permeability and stability . Various copolymers have been reported for polymersome formation such as poly(ethylene glycol)-b-polystyrene (PEG-b-PS) , polystyrene-b-polyisocyanopeptide (PS-b-PIAT)[21–22] and poly(N-isopropylacrylamide)-b-poly(ethylene oxide) (PNIPAM-b-PEO) . The term “polymersomes” is derived from liposomes because of the structural resemblance. Compared to liposomes, polymersomes are mechanically robust vesicles and therefore considered to be highly attractive for nanoreactor applications . Polymersomes comprise an aqueous lumen and hydrophobic membrane. Such hydrophilic and hydrophobic compartments are capable of accommodating hydrophilic (e.g., enzymes) or hydrophobic catalysts (e.g., metal catalysts) in their lumen or bilayer, respectively . In an aqueous environment the hydrophobic membrane attracts hydrophobic substrates and brings them in proximity to the membrane-bound catalyst, leading to faster reaction rates. The presence of multicompartments in one system is interesting from a catalysis point of view as multistep cascades using incompatible catalysts can be achieved in one polymersome nanoreactor . The compositional versatility of polymersomes thus allows for several applications in catalysis by encapsulating in or tethering catalysts to their compartments . Polymersomes preserve and protect catalysts in their compartments improving, most of the times, catalytic activity and their performance in incompatible solvents such as water .
|
review
| 99.8 |
Catalysis in polymersomes: Polymersomes have been most often used as biocatalytic nanoreactors [22,81–83]. Polymersome nanoreactors were also employed in Pickering emulsions . Pickering emulsions are emulsions stabilized by colloidal particles that adsorb at the water–oil interface. They are more stable than classical emulsions and do not require the usage of small molecule surfactants. This is a big advantage in downstream processing and product and catalyst recovery. The enzyme Candida antarctica lipase B (CalB) was encapsulated in the lumen of the polymersomes or in the Pickering emulsion water droplet. The esterification reaction of 1-hexanol and hexanoic acid was used to evaluate the catalytic performance of the CalB-loaded Pickering emulsions. Higher enzymatic activity was observed when CalB was encapsulated and the best results were achieved when the enzyme was in the lumen (Figure 3b), highlighting the advantage of enzyme compartmentalization and shielding. The explanation for this improved performance is the enlarged contact area between (hydrophobic) substrate and (water soluble) enzyme. Moreover, the system was recycled for at least 9 times without any loss in enzymatic activity.
|
study
| 99.94 |
3a) Schematic representation of a Pickering emulsion with the enzyme in the water phase (i), or with the enzyme inside the polymersome lumen (ii). 3b) Chart of the specific activities of CalB dissolved in the water phase of the polymersome Pickering emulsion (left), CalB in a biphasic water/toluene system (middle,) and CalB encapsulated in the lumen of the polymersome Pickering emulsion (right). Adapted with permission from .
|
other
| 99.5 |
Polymersomes have proven to be very useful for the performance of multistep catalytic conversions, in particular with enzymes . Voit et al. studied the use of cross-linked pH sensitive polymersomes for the conversion of glucose in a tandem reaction . The hydrophilic block of their polymersomes was PEG, and the hydrophobic block contained both poly[2-(diethylamino)ethyl methacrylate] (PDEAEM) which is pH responsive, and poly[4-(3,4-dimethylmaleimido)butyl methacrylate] (PDMIBM) as cross-linker. The activity of glucose oxidase (GOx) to convert glucose into D-glucono-δ-lactone and hydrogen peroxide was the first step of the reaction (Scheme 3A); subsequently, myoglobin (Myo) employed the hydrogen peroxide produced to oxidize guaiacol to quinone and water (Scheme 3B).
|
study
| 100.0 |
When the pH was below 7, the permeability of the cross-linked membrane allowed for substrate/product diffusion, but at basic pH the membrane collapsed and prevented any transport of small molecules. Two different activity tests were performed: 1) GOx and Myo were both entrapped inside the polymersome lumen; 2) GOx and Myo were individually incorporated into the polymersomes and mixed together in solution; in both of the cases the final product formation was monitored by UV–vis spectroscopy. The control over the pH allowed the regulation of the enzymatic cascade (no product was observed at pH 8 in both of the reactive systems), as the diffusion through the membrane was not possible. Moreover, the crosslinking enabled stabilization of the enzymes, which remained active also after 10 days.
|
study
| 100.0 |
Polymersome nanoreactors have also been used to perform many types of non-enzymatic catalytic reactions, such as the proline-catalyzed asymmetric aldol reaction of cyclohexanone and 4-nitrobenzaldehyde . Cross-linked polymersome nanoreactors were also used to perform asymmetric cyclopropanation reactions in water . These products are highly desired intermediates in the preparation of agrochemicals and pharmaceuticals [84–86]. To perform cyclopropanation reactions in polymersomes, the membrane was cross-linked with bisoxazoline (BOX) ligands complexing the copper catalyst. Cyclopropanation reactions were efficiently performed in water, resulting in high yields and enantioselectivities, comparable to those when the reaction was carried out in organic solvent (Figure 4).
|
study
| 100.0 |
As depicted in Table 5, substrate selectivity was observed when catalytic polymersomes were used, reasonably ascribed to a concentration effect, with more hydrophobic substrates leading to an increased local concentration around the catalyst in the hydrophobic membrane and as a consequence a higher reaction rate.
|
study
| 100.0 |
aReactions carried out in 3.0 mL of Milli-Q water with 5.0 equiv of styrene and 1.0 equiv of ethyl diazoacetate. bCatalyst loading in mol %. cConversion of ethyl diazoacetate into cyclopropane product. dDetermined by 1H NMR using triethylene glycol dimethyl ether as an internal standard. eDetermined by chiral GC. fPolymersomes started to precipitate after 15 min. gConfiguration of the product was (1S,2S). hIsolated yields. iDetermined by chiral HPLC. Adapted from reference .
|
study
| 99.9 |
Dergunov et al. reported on the design of a porous polymeric nanoreactor with a lipid bilayer for coupling reactions . These nanocapsules were loaded with palladium catalysts and successfully used in Suzuki, Sonogashira and Heck cross-coupling reactions. Catalytic activity was compared to the activity of the freshly prepared free catalyst, and the palladium entrapment did not affect either the conversion or the yields of the reaction . The catalyst immobilization also allowed facile Pd removal from the final product and catalyst recycling.
|
study
| 100.0 |
Polymeric nanoreactors were also used to perform ring-opening polymerization (ROP) in water. Nallani et al. reported on the enzymatic polymerization of lactones using CalB, which was immobilized in both the polymersome lumen and bi-layer . Nanoreactors for ROP were prepared from polystyrene-polyisocyanopeptide (PS-PIAT) and CalB was incorporated within either the lumen or polymer membrane (Figure 5).
|
study
| 100.0 |
ROP is usually performed in organic solvent so that hydrolysis reactions can be avoided . However, when nanoreactors were used, polymerization proceeded efficiently in water and without formation of any undesired products, providing a platform for aqueous ROP .
|
other
| 90.5 |
As shown in this section, polymersomes have been applied as a platform towards greener reactions , either by allowing reactions to be performed in water or by providing a recyclable catalytic system . As they contain both hydrophobic and aqueous compartments, they are especially useful for the immobilization of different catalysts, such as organocatalysts and enzymes that require different microenvironments for their optimal performance.
|
review
| 99.75 |
Dendrimers are a class of highly branched molecules with high degree of symmetry . They consist of different generations in which every generation is twice the molecular weight of the previous one. Dendritic architectures comprise three regions: a core, inner shell and outer shell . The properties of dendrimers such as hydrophobicity can be tuned by varying their initial molecular components or the number of generations they possess [91–92]. They can assemble in a spherical shape, and within the three-dimensional structure, an interior void is present wherein to accommodate other molecules .
|
review
| 92.5 |
Catalysis in dendrimers: The controlled synthesis of dendrimers and their applications as nanoreactors and catalyst carriers have been extensively studied over the last decades [94–96]. Fan and co-workers incorporated a bis(oxazoline)-copper(II) complex in the hydrophobic core of a polyether dendrimer . The copper catalytic complex was used to carry out asymmetric Mukaiyama aldol reactions. Although this system did not result in any substantial improvements in yields or enantioselectivities, it allowed for facile catalyst recovery and recycling.
|
study
| 99.25 |
Dendrimers were also used to encapsulate bimetallic catalysts to attain highly selective reactions . The first successful attempt was reported by Chung and Rhee, in which they showed the encapsulation of a bimetallic Pt–Pd catalyst in a highly branched PMAM-OH dendrimer corona . These catalytic dendrimers were employed in partial hydrogenation of 1,3-cyclooctadiene into cyclooctene. The utility of these dendrimers in hydrogenation reactions resulted in efficient reactions that proceeded with unprecedented selectivity of 99%. Moreover, this system is one of the first of bimetallic catalytic systems to be used for hydrogenation reactions in water.
|
study
| 100.0 |
Water soluble dendrimer-stabilized nanoparticles (DSN) have been shown to be highly efficient in the catalysis of olefin hydrogenation and in Suzuki coupling reactions [98–99]. Ornelas et al. entrapped a palladium catalyst with dendrimers containing triazole groups (DSN) (Figure 6) .
|
study
| 99.94 |
The aim here was to provide a platform to perform hydrogenation in water. By using only 0.01% of palladium at room temperature, the hydrogenation of allyl alcohol was realized . DSNs were recycled for up to 10 times without loss in activity. DSN nanoreactors were later shown to be utilized for catalysing Suzuki coupling reactions between PhB(OH)2 and PhX (X = I or Br) in water .
|
study
| 100.0 |
Other examples of water-soluble dendrimers are peptide- and glycol-based dendrimers [102–103]. As a result of their compositional versatility, they have been reported in many applications for biomedical engineering (e.g., glycopeptide dendrimers for drug delivery ).
|
review
| 99.3 |
The ability of peptide dendrimers to perform catalysis in an aqueous environment has also been investigated . Many different libraries of peptide dendrimers have been used for biocatalytic applications, such as hydrolysis and aldolase reactions [105–108], showing their potential in green catalysis.
|
review
| 99.06 |
Peptide dendrimers including aspartate, histidine and serine were utilized by Reymond et al. as catalytic esterase triad. Using fluorogenic 8-acyloxypyrene-1,3,6-trisulfonates as substrate (Figure 7) at the pH optimum of 5.5, triads’ activity was successfully demonstrated .
|
study
| 100.0 |
A noticeable rate enhancement was observed, related to a large apparent reactivity increase per catalytic site. Such an enhanced activity could be explained by the relatively high hydrophobic binding of the acyl group and the presence of histidine side chains that act as catalytic groups and as electrostatic substrate binding sites in their basic and acidic forms, respectively.
|
study
| 99.94 |
Nanogels are hydrophilic polymer networks which can swell in the presence of water . They can be crosslinked by either chemical bonds or physical methods, such as non-covalent interactions, entanglements and crystalline domains. The nanogels display excellent swelling behavior and are shape resistant . Due to these unique properties they have mostly been studied as materials in biomedical applications such as controlled drug delivery . Nanogels show promise as nanoreactors as they not only are colloidal stable particle in water but also can be prepared form a wide range of components and in many different sizes and shapes. They have been used for the templated synthesis of metal nanoparticles, via which the shape and size of the nanogel directed the formation of the corresponding particle with similar morphology . The metal nanoparticle core is covered by polymeric brushes, the length and the grafting are important factors which can affect the reaction, as discussed in the following paragraph, and the easy manufacturing of metal nanoparticles makes the preparation of these core-brushes nanosystems suitable for many applications [113–115].
|
review
| 99.9 |
Catalysis in nanogels: Nanogels have intrinsic properties that make them well suited for green chemistry [116–117]. Water-compatible gels are usually based on poly(N-isopropylacrylamide) (PNIPAM), poly(N-vinylcaprolactam) (PVCL) or other water-soluble polymers . For instance, PNIPAM is a thermo-responsive polymer, which has a lower critical solution temperature (LCST) of 32 °C. Above the LCST, individual polymer chains switch from a swollen coil configuration to a collapsed globular one, providing a nano-environment that is suitable for either hydrophobic or hydrophilic substrates . Water forces PNIPAM brushes to become hydrophobic, acting as a suitable environment for most organic reactions ; it allows hydrophobic substrates to diffuse towards the encapsulated catalysts, leading to a concentration effect that directly contributes to an efficient aqueous reaction .
|
study
| 99.7 |
The preparation of catalytic nanocomposite hydrogels has been widely reviewed . Several examples showing their utility as nanoreactors for various reactions such as coupling, oxidation and reduction reactions have been reported . Wei et al. described a nanogel composed of poly(N-isopropylacrylamide) brushes grafted on Pd-NPs (Pd@PNIPAM) to carry out coupling reactions in water under mild conditions . They showed highly efficient coupling of several hydrophobic aryl halides with phenylboronic acid, which in all cases resulted in yields above 70%. Moreover, the Pd@PNIPAM nanoreactors could be easily recycled thanks to the reversible phase-transition of the polymeric brushes .
|
review
| 99.9 |
Que et al. reported the synthesis of gold nanoparticles (Au NPs) sheltered in PEG-PS nanogels for the reduction of 4-nitrophenol (4NP) . Thiol functionalized PEG blocks were immobilized on Au NPs. PS segments improved the stability of the system and provided the necessary hydrophobic environment that is required to undertake the reduction reaction in water. The outcome of using Au@PEG-PS as nanoreactors was compared to those resulting from using both uncoated and PEG-coated Au NPs. While Au@PEG-PS resulted in quantitative conversions for 5 subsequent cycles, both uncoated and PEG45 coated Au NPs resulted in full and 61% conversions only for the first cycle, respectively. Recycling of uncoated and PEG45 coated Au NPs was not possible, highlighting the significance of the nanoreactor design (Figure 8).
|
study
| 100.0 |
Superior catalytic activity of Au@PEG-b-PS was observed in the reduction reaction of 4-nitrophenol to 4-aminophenol. The catalytic activity increased with the decrease in the chain length of the PS block. In addition, the high stability imparted by the PS layer endowed Au@PEG-b-PS with good reusability in catalysis without the loss of catalytic activity, and prevented from electrolyte-induced aggregation, making the system very attractive as nanoreactor.
|
study
| 100.0 |
Following on the previous work, He et al. synthesized cross-linked nanogels that were based on poly(acrylamide-co-acryl acid) (poly(AAm-co-AAc)) . These nanogels were transformed into their catalytic counterparts by growing silver nanoparticles (Ag NPs) inside the cross-linked polymeric network. These catalytic nanogels were also used to catalyse the reduction of 4-nitrophenol to 4-aminophenol in water. The activity of these nanoreactors was tuned by varying the Ag NPs loading and the cross-linking density; higher activities were achieved by increasing the amount of Ag NPs loaded and decreasing the degree of polymer cross-linking. Such conditions facilitated the diffusion of water and substrates through the hydrogels and increased the probability of the reactant to be in contact with the catalyst (Ag NPs).
|
study
| 100.0 |
In this review we have discussed the utility of supramolecular polymersomes, micelles, dendrimers and nanogels in catalysis. Over the past decades, many groups have demonstrated the specific features which make these nanoreactors an advantageous choice for chemical synthesis. In particular, they combine a high active surface area with a good dispersion in solution and therefore are ideal structures for facile diffusion of reactants. Furthermore, the compartments protect the catalyst from undesired interactions with the environment, which can be either the solvent, specifically water, or other catalytic species. As a result they allow reactions to proceed in water and often at room temperature, with excellent yields and selectivities, which traditionally can only be achieved by performing catalysed reactions in organic media. Moreover, although they are homogenously dispersed in the solvent, the nanoreactors are still large enough to be separated from the reaction mixture using standard filtration protocols. Therefore, they enable a facile purification and catalyst reuse.
|
review
| 99.9 |
This latter feature has potentially both an economic and environmental impact, deriving from a lower consumption of organic solvents, as lowering the E-factor in a process is a must for the modern chemical industry. Despite these many advantages, nanoreactors have not yet found widespread use in industry. A number of reasons can account for this. First of all, the construction of the nanoreactors is not always a cost-efficient process. Scalability and reproducibility in nanoreactor production also are key factors that have to be addressed. The recyclability and cost price should be improved to allow competition with existing heterogeneous and homogeneous processes. Furthermore, in most cases only model reactions have been studied. The improvement of a process that is highly relevant for industry would aid in a further acceptance of this technology by the end users. Another issue is that the specific characteristics of nanoreactors should be employed more effectively. Physical protection and separation of catalytic species will allow the performance of multistep conversions in one-pot reactors. This would then enable continuous flow processing, as intermediate work-up steps and solvent switching procedures can be prevented. Although this requires still much development, it is to be expected that in the near future nanoreactors will be key to a more sustainable production of fine chemicals.
|
review
| 99.56 |
Prostate cancer is the second most common cancer and the leading cause of cancer-related death in men worldwide. Continuous androgen deprivation therapy (ADT) is recommended as first-line treatment for metastatic and hormone-naive disease. These patients eventually gain resistance to ADT. The level of PSA of patients increase, the levels of testosterone areat castration, and the disease progress in a few years. Currently, chemotherapy (CT) is often recommended in combination with ADT as the initial treatment for metastatic prostate cancer castre-resistance prostate cancer (mCRPC) with high tumor volume.1
|
review
| 99.9 |
Taxane based regimen (TBR) is the first option in patients with metastatic prostate cancer. Taxanes inhibit mitosis by decreasing the depolymerization of β-tubulin.1,2 There are several studies showing improved overall survival (OS) with TBR while some patients may not respond to this treatment.
|
review
| 99.7 |
Some signaling pathways such as phosphoinositide 3-kinase (PI3K) and hedgehog are activated during the metastatic process and resistance to drugs in various cancers. OPN as well as STMHN1 have been reported to be playing an important role through activation of the PI3K/Akt pathway in metastasis and resistance to chemotherapeutics (CTs) in cell lines.3-6
|
study
| 99.9 |
There are several studies on the effects of vinca alkaloids on microtubules in cell lines, and on clinical outcomes with tailored treatment modification according to predictive markers in several types of cancer.3,7 Overexpression of STHMN1 and/or OPN may be a marker of proliferation and resistance to TBR in mCRPC.
|
study
| 96.4 |
All the cases were provided retrospectively from the records of Firat University, Faculty of Medicine, Medical Oncology Department between 2009 and 2015. This study was approved by the Ethical Committee of Firat University. The patients included in the present study were diagnosed with PC and had received at least 6 cycles of TBR (75 mg, taxane mg/m2, every 21 days, intravenous infusion, together with 10 mg/day prednisone, peroral, continue) for mCRPC. All cases were evaluated every three cycles.
|
study
| 99.94 |
A total of 30 cases were included in the study. The patients were divided into two groups as responders and non-responders. The group of responders was evaluated in three categories as patients with response, stable disease and flare phenomenon based on the PSA working group consensus criteria as follows: a) Response: ≥50% PSA reduction from baseline, b) Stable disease: <50-0% PSA reduction from baseline or absence of any reduction, c) Flare phenomenon: ≥50% PSA reduction from baseline followed by increased PSA levels with subsequent PSA reduction below the baseline values.8 In addition, patients were also stratified into two groups according to GS as the intermediate-risk group (GS: 7) and the as high-risk group (GS: 8-10).1,9
|
study
| 100.0 |
Immunohistochemical (IHC) evaluation: 4-5 μm sections of paraffin blocks were obtained from the cases. The sections were placed on slides coated with poly-L-lysine. Slides were incubated for 10-15 minutes at 60°C in the incubator. Preparations were stained with OPN (Boster, rabbit polyclonal anti-spp1, 100 µL, 1/20, USA) and Bcl-2 (Boster, rabbit Ig G polyclonal antibody for stathmin (STHMN1), 100 µL, 1/50, USA) by means of an automated staining device (ventana medical system, SN: 712299, REF: 750-700, Arizona, USA). Positive controls were prepared with endometrial cancer tissues for STHMN1 and OPN antibodies, and we also used normal prostate epithelium as internal positive control to both antibodies. The slides were evaluated by an independent, blinded pathologist to re-confirm the diagnosis, GS, and the outcome of patients. Slides stained for STHMN1 and OPN were evaluated under a light microscope. STHMN1 and OPN expression ratios were examined in 4 categories:It was identified as 0 (no staining) negative; <10%, “+” weak; 10-50%, “++” mild; and >50%, “+++” extensive). The staining intensity was assessed and scored as negative (no staining), weak(+1, +2) and strong (+3).10
|
study
| 100.0 |
The software package, International Business Machines, Statistical Package for the Social Sciences, 22.0, was used for the statistical analysis of the data. OS was defined as the time from the date of diagnosis to death or the final visit. Kaplan-Meier analysis was used to assess survival and the log-rank test was usedfor statistical analysis. Values of p<0.05 with a 95% confidence interval were considered as statistically significant.
|
study
| 99.9 |
Osteopontin, SS: 2 (Gleason Score 3+4 (Haematoxylin and Eosin (HE) X 100), Immunoperoxidase X 100) 1b: Osteopontin SS:3, (Gleason Score 5+5 (HE X 200), Immunoperoxidase X 200), 1c. Stathmin-1, SS:2, (Gleason Score 5+5 (HE X 200), Immunoperoxidase X 200), 1d: Stathmin-1, SS:3, (Gleason Score 5+5 (HE X 200), Immunoperoxidase X 200), 1e: The speciemens of prostate transurethral resection, aciner adenocarcinoma (Gleason Score 5+5 (HE X200), Immunuperoxidase X 200)
|
other
| 99.9 |
The longest survival was 129 months. Median survival was 96 months (95% CI: not estimated) for the mild STHMN1 expression group (EG) and 56 months (95% CI: 11.375-100.625) for the strong STHMN1 EG. In this study, STHMN1 EGs showed no significant correlation with OS, (p-values: 0.723), (Fig.2a). Median survival was 96 months (95% CI: not estimated) for the mild OPN EG and 34 months (95% CI: 0.528-67.483) for the strong OPN EG. There was no significant correlation between the OPN EGs and OS (p-values: 0.132), (Fig.2b). When it was assessed overall survival (OS) according to together expressions of OPN and STHMN1(high OPN and high STHMN1 as one group; high OPN and low STHMN1, low OPN and high STHMN1, low OPN and low STHMN1 as another one group), none of combine group (OPN, STHMN1) predicted OS (p>0.005), (Fig.3).
|
study
| 100.0 |
Median survival was 28 months (95% CI: 18. 49-37.50) in the intermediate-risk GS group and 96 months (95% CI: 49.13-142.86) in the high-risk GS group. There was no statistically significant difference between the GS groups in terms of OS as assessed by the Kaplan-Meier method (p-value: 0.156).
|
study
| 100.0 |
There are limited options for treatment with cytotoxic regimens as prostate cancer is a highly chemoresistant malignancy.1 Currently, TBR plays a major role in the treatment of metastatic prostate cancer. Although this cytotoxic agent has been demonstrated to improve OS, it is associated with several difficulties such as dose-dependent adverse reactions, CT resistance and no response to treatment.1,2,11
|
review
| 99.8 |
The underlying molecular mechanisms of CT resistance has not been fully clarified. Genetic and non-genetic alterations have been suspected to be involved in the development of drug resistance in previous studies.12,13 Although this resistance appears to be multifactorial; defects in tubulin and microtubule-associated proteins (MAPs), dysregulated cell cycle and apoptotic signaling pathways are among the factors thought to be responsible for taxane resistance.14 Researchers have demonstrated the relationship between taxane resistance and the overexpression of MAPs, tau protein, STHMN1 and OPN with in vitro and in vivo studies.4,6 We investigated whether STHMN1 and OPN expressions could be predictive markers for cancer metastasis and resistance to TBR in mCRPC. It has been reported that OPN plays an important role in the progression of several cancers through the regulation of vascular endothelial growth factor (VEGF) release in the PI3K signaling pathway and the effectiveness of various physiological processes.4,15
|
study
| 100.0 |
Several studies have shown the interaction between OPN and VEGF in the metastatic process and the existing/acquired resistance to CTs.11,12,15 Researchers reported a potential relationship between proliferation, tumorigenicity and level of OPN expression in cell line studies.4 In our study, we also found positive OPN expression in all patients tissue samples. Similar to the literature reports, strong OPN expression was identified in 25/30 (83.4%) of the cases. Although an important role has been shown for OPN in regulating chemotherapeutic drug resistance through increased drug transporter expression, no relationship was observed between OPN and response to treatment in our study. Long-term treatment with cytotoxic drugs may further upregulate OPN release from tumor cells. Therefore, researchers suggested that OPN could be a therapeutic target for cancer treatment and avoid drug resistance. In recent studies, OPN knockdown has been shown to increase the activity of CT drugs and inhibit p-glycoprotein expression. The researchers also found that the levels of OPN could be increased, which were antagonized by the addition of various chemical agents in PI3K/AKT pathway, during endogenous secretion of OPN in the prostate cancer cells line.4,16,17 Most of the studies which have demonstrated findings associated with resistance to CTs are mainly cell culture studies rather than definitive clinical studies. Hence, we focused on the OPN expression level as a possible marker of drug resistance. However, our results indicate no relationship between OPN and response to TBR while a statistically significant difference is seen in terms of increased OPN overexpression with low GS in contrast to the findings of some previous studies.18
|
study
| 100.0 |
STHMN1 is a major cytosolic phosphoprotein and a microtubule-depolymerizing molecule involved in the metastatic process of various cancers; however, the mechanism of its regulation has not been fully clarified. The activity of STHMN1 is controlled by PI3K, which requires maintaining a stable microtubule network during migration.6 Phosphorylation of STHMN1 is mediated by a number of protein kinases including p27, an inhibitor of cyclin-dependent kinase complexes. In the absence of PI3K/Akt activity, captured microtubules are progressively broken down and cells lose their ability to follow the chemotactic gradient. The relationship between STHMN1 and p27 was identified in previous studies.19,20 Researchers reported that STHMN1 binds to p27 cells, and that cells with strong STHMN1 expression and weak p27 expression display increased proliferation and invasion capacity in tumor tissue. STMN1 was also shown to be activated by the Ras-mitogen-activated protein kinase and hedgehog signaling pathway in some studies.21 Researchers observed thiostrepton got over to TBR by blocking transition from G1 to S phase in cell lines.22 Treatment with low-dose anti-STHMN1 therapy and taxane was shown to halt tumor invasion in a breast cancer xenograft.23
|
study
| 99.94 |
In our study, strong STHMN1 expression was identified in 26/30 (86.6%) of the patients while 4/30 (13.2%) of the cases had mild STMN1 expression; however, there was no difference in terms of response to treatment across these expression levels. Positive STHMN1 expression was observed in all of the tissue samples obtained from the patients in the present study. Hence, we considered that all tumor samples were the phosphorylated form of STHMN1; however we could not determine any relationship between STHMN1 expression and response to treatment. Eighteen (60%) of patients exhibited non response to TBR. A key role may be suggested for STHMN1 expression in the metastatic process as STHMN1 expression was observed in all of our patients, as seen in the literature.
|
study
| 100.0 |
Firstly, we evaluated the relationship between response to TBR and the expression of STHMN1 and OPN by analyzing pathology specimens obtained from the patients at the time of diagnosis. Resistance to taxanes may be intrinsic or acquired due to long term exposure to this chemotherapeutic agent. We may have overlooked acquired resistance in the specimens in this study. There may be alterations in these specimens during the progression of metastatic process or the long term use of cytotoxic regimens. Specimens obtained by a second biopsy during the progressive period could have provided further findings. Taken together, to the best of our knowledge, heterogeneity of primary tumor specimens of cases diagnosed with mCRPC has not been observed to date. This issue may be clarified further in prospective studies.
|
study
| 100.0 |
Secondly, the present study was conducted with a limited number of specimens. If we had a sufficient number of patients for this study, perhaps it would have been possible to establish a statistically significant relationship between OS and the expression level of OPN. The present study does not support the results obtained both with in vivo studies and in vitro experiments conducted for this subject matter. Most of the previous studies were carried out with cancer cell lines. These cell lines are thought to be not fully reflecting all characteristics of human cancer cells. The present study is the first study in the literature to show that there is no relationship between OPN and STHMN1 expression and the response to TBR in mCRPC.
|
study
| 99.94 |
The overexpression of STHMN1 and OPN are very important in cancer metastasis. There is no relationship between resistance to TBR and the expression level of OPN or STHMN1 according to our study. OPN and STHMN1 are not suitable markers to predict response to TBR. Furthermore, our findings suggest that the evaluation of these two proteins may be a useful predictor of poor prognosis in patients with mCRPC.
|
study
| 100.0 |
Many wildlife species are reservoirs of pathogens and may transmit infectious agents to sympatric domesticated species (“reverse spill-back”) or endangered wildlife species or humans . Managing the risk of further disease emergence requires improved understanding of the diversity and prevalence of circulating pathogens in natural populations, and the complexity of these multifaceted relationships.
|
other
| 99.9 |
Avian pox (APV) is a viral infection that causes proliferative lesions in wild and domestic bird species worldwide. Poxvirus infections are commonly cutaneous, though they may also produce virulent diphtheritic forms. The disease exists at very low prevalence where it is endemic and it has little impact on affected birds . However the infection can cause economic losses in domestic poultry and the introduction of APV, and other pathogens, to remote island archipelagos (e.g. Galapagos and Hawaii) has caused dramatic declines to the immunologically naïve, not to mention rare, avifauna of those island groups[3–5]. The disease is caused by Avipoxvirus, a genus of enveloped double-stranded DNA viruses. Transmission is mainly via arthropod vectors, though it can also occur via respiratory aerosols or contact with infected birds or contaminated surfaces like perches or nests . Poxvirus is extremely resistant to desiccation, and can survive in the environment for long periods which may facilitate its transmission.
|
review
| 99.75 |
The International Committee on Taxonomy of viruses (ICTV) recognises 10 species in the genus Avipoxvirus , all named according to the first host where they were described. Phylogenetic analysis based on polymorphism of both P4b (major core protein) and DNA polymerase genes indicate the existence of three major clades, A (Fowlpox-like viruses), B (Canarypox-like viruses) and C (Psittacinepox-like viruses), and some recently described subclades . Conventionally, APV was considered to be host-species or host-order specific although many ecological and historical processes may modulate this pattern . For instance, Canarypox virus (CNPV) was thought to preferentially infect passerines, while Fowlpox virus (FWPV) affected chickens and turkeys. Taxonomy of genus Avipoxvirus was based on this concept until recent studies showed that Accipitriformes, Columbiformes, Otidiformes and Passeriformes, can be infected by a high diversity of strains [7–10]. More in depth knowledge about the genetic diversity of APV strains is necessary because combined mutations and recombination among well characterized APV strains have been proposed as the source of the variability which may provide new strains with different pathogenicity . Strain diversity in a single host may be very high, for instance, at least 17 genotypes have been described from houbara bustards, including both CNPV and FWPV genotypes . Because of some APV strains may be found in several bird species the introduction of domestic birds may be a threat for wild birds, especially in isolated populations. Conversely, wild birds may be an infection source for poultry .
|
review
| 98.5 |
The epidemiology of avian pox infection and their distribution in natural populations is not well known because there are a number of biotic and abiotic factors that affect their distribution and prevalence . A handful of studies have investigated the prevalence of poxvirus infections in wild birds around the world, most of them based on the visual observation of affected individuals. In continental birds, modal prevalence ranged from 2% to 16% in different bird species, mainly passerines [3,12–16]. The highest prevalence of pox-like lesions has been found in remote islands, such as the Canary Islands, where 50% of lesser short-toed larks (Calandrella rufescens) trapped around farmyards showed cutaneous lesions or the Laysan albatross in Hawaii with over 88% of the individuals infected in wet years . The prevalence of avian pox may be influenced by human land-use as shown in Galapagos finches where prevalence increased 8-fold in agriculture areas. The authors argued that changes in innate immune function were correlated to human land-uses types and this may have determined changes in disease susceptibility. Nevertheless, other studies have obtained contradictory results about the degree of infection in urban birds .
|
review
| 99.44 |
Here, we studied the prevalence of cutaneous pox-like lesions and the diversity of APV strains in house sparrows, a widespread peridomestic bird, with high abundance in urban centres, around livestock and in cereal farms. Passer domesticus is ideal for studying the prevalence of avian pox lesions and the dynamics of a circulating pathogen because of their abundance, ubiquity and their association with human settlements. They are known to host diverse APV strains from both the CNPV and FWPV clades . We examine whether prevalence, or strain type, varies along an urban to agricultural habitat gradient. This will provide a base level assessment for future comparison, and identify whether specific habitat types pose a higher risk for APV transmission. Sampling was carried out at different landscape types (urban, agricultural and natural) near both to farms and to the Doñana National Park in South Spain (Huelva province), which is a breeding ground and transit point for approximately 300 different species of birds. Additionally, we studied the prevalence and diversity of APV genotypes in several sites in central Spain.
|
study
| 100.0 |
Two areas of the Iberian Peninsula (south and central regions) were sampled in order to determine prevalence and genetic diversity of APV in house sparrows. In central Spain (Madrid and Caceres provinces) we surveyed seven different locations between November (2012) and June (2013). In South Spain (Huelva province) 15 different sites were surveyed from July to October 2013 and from June to August 2014. Some of the sampling sites were located inside or close to protected areas, including the Doñana National Park and wetlands included in the Natura 2000 Network. In South Spain, sampling sites were geographically clustered in trios formed of an urban area (human inhabited areas in small towns or villages), an agricultural area (areas with a high presence of farm animals, usually cows, horses and/or hens) and natural areas (with low presence of humans and livestock). There were five clusters totalling 15 different sampling areas.
|
study
| 99.94 |
House sparrows were individually marked with unique identifying rings, weighed, aged and sexed based on plumage and skull pneumatization characteristics . House sparrows were classed as: 1) yearlings, birds in their first year of life; 2) adults, birds in at least their second year of life and 3) birds that could not be classified, including adult birds and yearlings with a completed moult and ossified skull pneumatisation . Blood samples were obtained from the jugular vein of each bird using sterile syringes. Samples from yearlings were used for the molecular identification of the sex of individuals. The volume of blood extracted depended on bird size but never exceeded 1% of avian body mass. Blood was collected in Eppendorf tubes and maintained in cold boxes in the field and at 4°C for 24 hours. After that, blood was centrifuged for 10 minutes at 4,000 rpm to separate the serum and cellular fractions. Samples were frozen at -20°C until subsequent analysis.
|
study
| 100.0 |
Birds showing evidence of potential poxvirus infection (i.e. cutaneous lesions such as hyperplastic nodules on unfeathered portions of legs, feet or head suspicious of viral infection) were recorded. Cutaneous lesions were swabbed or biopsied using sterile swabs placed in virus transport buffer (PBS, 1% of a dilution of 200mM L-glutamine, 10.000 U penicillin and 10 mg streptomycin/ml, and 0.5% gelatine) for samples obtained in the southern Spain. Swab samples from central Spain were placed in PBS and tissue samples were stored dry. Swabs were rubbed vigorously against the surface of the skin lesion. For tissue samples, a minimally invasive biopsy was excised from the edges of lesions, and great care was taken to not cause bleeding. In the infrequent event of haemostasis, digital pressure was applied to the site of the bleeding, taking care not to break the fragile avian bones. All samples were immediately frozen in portable liquid nitrogen containers or kept in cold-boxes and subsequently frozen in the laboratory on the same day. Samples were stored at -80°C awaiting molecular analysis.
|
study
| 99.94 |
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