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ISEB-SWTINT1 exam Dumps Source : ISEB Intermediate Certificate in(R) Software Testing

Test Code : ISEB-SWTINT1
Test title : ISEB Intermediate Certificate in(R) Software Testing
Vendor title : ISEB
: 43 existent Questions

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ISEB ISEB Intermediate Certificate in(R)

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The ISEB check administration certification is the next stage of competency in application trying out after the ISEB foundation and ISEB Intermediate levels. earning this certification makes employment candidates greater effective and marketable, because it signifies a tenacious capacity to analyse, synthesize and evaluate tasks concerning application testing management. These information are indispensable to the profession development of software testers, notably in this age of international competition and economic uncertainty.

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The test management analyze package includes a finished analyze guide, keep assessments, 56 dual-sided flashcards, situation query papers, exam counsel, prize material, 90 days replete training abet in the private locality of the company’s IT certification forum, and more. moreover, the package is available in numerous genesis strategies – instant download, set of CDs, or everything provided in a sure, replete colour booklet (with the prize material on a CD).

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what is ITIL? Your bespeak to the IT Infrastructure Library | killexams.com existent Questions and Pass4sure dumps

what is ITIL?

The IT Infrastructure Library (ITIL) is a library of volumes describing a framework of choicest practices for supplying IT capabilities. ITIL has gone through a brace of revisions in its heritage and presently includes 5 books, each protecting a variety of approaches and tiers of the IT provider lifecycle. ITIL’s systematic approach to IT provider administration can back groups control possibility, toughen customer family members, set up low-budget practices, and construct a tenacious IT ambiance that allows for boom, scale and change.

Developed via the British govt's significant computing device and Telecommunications company (CCTA) throughout the 1980s, the ITIL first consisted of greater than 30 books, developed and released over time, that codified optimal practices in suggestions technology collected from many sources (together with carriers' optimum practices) around the globe. IBM, as an instance, says that its 4-volume string on programs-management concepts, A management outfit for counsel techniques, usual because the Yellow Books, provided vital input into the original ITIL books.

In April 2001, CCTA, along with a number of other businesses, own been rolled into the office of government Commerce (OGC), which is now commonly used as the cabinet workplace. The OGC adopted the assignment as a allotment of its mission to drudgery with the U.k. public sector as a ferment to achieve effectivity, value for cash in traffic actions, and enhanced success in the start of classes and initiatives.

The kick wasn't to create a proprietary product that may well be commercialized; reasonably, it changed into to acquire most effective practices that might assist with what the govt identified changed into an increasing dependence in the executive on IT combined with a painful lack of usual methods that own been expanding expenses and allowing mistakes to perpetuate. It promptly grew to be obvious that distributing these optimal practices would profit both public and personal-sector organizations.

through the years, ITIL's credibility and utility grew to become identified, and in 2005 its practices contributed to and aligned with the ISO/IEC 20000 service administration typical, the primary overseas ordinary for IT carrier management; it is in keeping with British regular BS15000.

since 2013, ITIL is owned via Axelos — a joint venture between the cupboard workplace and Capita. Axelos gives companies the license to accomplish exercise of the ITIL framework, while managing updates and technique changes. however, to exercise ITIL internally, corporations shouldn't own a license. ITIL v3 was released in 2011, beneath the cupboard workplace, bringing updates to the 2007 edition published beneath OGC.

In 2018, Axelos introduced ITIL four – a colossal overhaul to the whole framework and the greatest trade due to the fact ITIL v3 turned into published in 2007. ITIL 4, which each and every started rolling out in Q1 of 2019, offers a extra agile, bendy and customizable edition of ITIL it truly is up to date for up to date corporations. The newest edition encourages much less siloes, greater collaboration, communique throughout the whole company and integrating agile and DevOps into ITSM ideas.

What's in the ITIL?

The ITIL has gone through a brace of revisions in its history. The common 30 books of the ITIL had been first condensed in 2000 (when ITIL V2 became launched) to seven books, every wrapped around a side of IT administration. Later, the ITIL Refresh project in 2007 consolidated the ITIL to five volumes which includes 26 manner and capabilities – here is mentioned because the ITIL 2007 edition. In 2011, yet another replace — dubbed ITIL 2011 — become published beneath the cupboard office. The 5 volumes remained, and ITIL 2007 and ITIL 2011 remained equivalent.

ITIL 4, which became launched in 2019, continues the identical focus on automating procedures, improving carrier management and integrating the IT department into the enterprise. youngsters, it likewise updates the framework to accommodate and reply to up to date technology, outfit and utility. when you account that ITIL’s eventual update, the IT fork has grown to develop into essential to each enterprise and the brand unusual framework accommodates this via being more agile, elastic and collaborative.

ITIL 4 consists of 9 guiding ideas that had been adopted from essentially the most fresh ITIL Practitioner examination, which covers organizational trade administration, communication and size and metrics. These ideas consist of:

  • focal point on cost
  • Design for adventure
  • start the state you're
  • Work holistically
  • progress iteratively
  • take a notice at at once
  • Be clear
  • Collaborate
  • maintain it essential
  • The latest edition of ITIL specializes in company tradition and integrating IT into the ordinary enterprise constitution. It encourages collaboration between IT and different departments, peculiarly as other traffic units increasingly weigh on expertise to fetch drudgery completed. ITIL four additionally emphasizes customer remarks, since it’s easier than ever for companies to assume into account their public belief, client delight and dissatisfaction.

    For extra counsel on the merits of the newest version of ITIL, observe “ITIL four: ITSM receives agile.”

    How conclude I achieve ITIL into follow?

    ITIL is a collection of e-books, but in simple terms going on a analyzing spree may not improve your IT operations. First, you own to wrap your mind around the ideas and then fetch body of workers buy-in. Getting some IT personnel to undertake unusual techniques may likewise be enjoy herding cats, however there are outfit that may support.

    along with the ITIL comes a whole suite of consulting, practicing and certification functions. From the early Nineteen Nineties, certifications had been administered through two impartial bodies: EXIN and ISEB, counting on your region. the two bodies shaped an alliance on the recess of 2006 to extra IT service management.

    considering 2014, Axelos is the proprietor of the ITIL personnel certification and checks are administered via authorized working towards groups (ATOs). Accreditations are administered by means of Strategic Examination Institutes (EIs). EIs should be accredited directly with the aid of Axelos with a purpose to tender accreditation to ATOs.

    before imposing ITIL at your organizations, there are a number of questions accomplish positive to reply, corresponding to what complications your corporation is attempting to decipher and what is your path to chronic service improvement.

    For a deeper study placing ITIL into apply, observe "7 inquiries to inquire earlier than implementing ITIL" and "the pass to fetch each and every started with ITIL."

    what is ITIL certification and is it worth it?

    The ITIL v3 certification scheme in the past consisted of 5 levels: basis, Practitioner, Intermediate, skilled and grasp. each stage required an improved depth of competencies and understanding of ITIL. The certification scheme under ITIL 4 has been streamlined to encompass the ITIL groundwork and the ITIL master assessments. The ITIL basis examination has two paths, ITIL Managing professional (MP) or ITIL Strategic leader (SL), which each and every own their personal modules and checks.

    The ITIL Managing professional (MP) examination is designed for IT practitioners who're involved with know-how and digital groups each and every the pass through the organization, now not simply within the IT department. This direction will school experts every thing they should learn about working successful IT tasks, groups and workflows.

    Modules encompass:

  • ITIL expert – Create, deliver and assist
  • ITIL specialist – drive Stakeholder value
  • ITIL professional – elevated velocity IT
  • ITIL Strategist – Direct, scheme & improve
  • The ITIL Strategic leader (SL) exam is designed for those that assume care of “all digitally enabled functions,” and not simply people that plunge beneath IT operations. This path makes a speciality of how technology directs company approach and the pass IT performs into that.

    Modules consist of:

  • ITIL Strategist – Direct, scheme & improve
  • ITIL leader – Digital & IT method
  • both paths can result in the ITIL master exam, which is the maximum degree of certification that you may obtain with ITIL 4.

    For those already in the middle of working towards a ITIL v3 certifications, credits will switch over to the unusual certifications. Axelos recommends that each one ITIL certification candidates proceed the route towards ITIL master.

    For in-depth analysis of ITIL certification, observe "What ITIL certifications imply to your IT management practices."

    How can ITIL multiply my enterprise's enterprise efficiency?

    A neatly-run IT arduous that manages casual and maintains the infrastructure humming now not handiest saves cash, but it surely likewise permits the traffic individuals to conclude their jobs extra comfortably. as an instance, brokerage company Pershing reduced its incident response time by using 50 percent within the first year after restructuring its carrier desk according to ITIL guidelines, enabling clients with complications to fetch lower back to drudgery much more instantly.

    ITIL provides a scientific and professional approach to the administration of IT service provision, and offers the following advantages:

  • reduced IT prices
  • superior IT features by using proven top-rated succeed procedures
  • superior client pride via a extra expert approach to provider delivery
  • necessities and counsel
  • enhanced productivity
  • enhanced exercise of abilities and adventure
  • more desirable start of third-party features through the specification of ITIL or BS15000 as the universal for provider delivery in functions procurements
  • in line with Axelos, ITIL can likewise assist corporations multiply features by pass of:

  • helping groups control risk, disruption and failure
  • strengthening client family members through “offering efficient capabilities that meet their needs”
  • setting up cost-efficient practices
  • building a tenacious atmosphere that quiet makes it viable for for increase, scale and alter.
  • For a deeper study the pass to fetch probably the most from ITIL, observe "5 steps to successful ITIL adoption."

    what will ITIL charge?

    Getting began includes the buy of the ITIL either as hardcopy, PDF, ePub or through an online subscription at once from Axelos. Then there may be the can charge of training, which fluctuates each yr. The course resulting in the preparatory groundwork certificates usually runs for 2 days, and courses leading to higher certifications will likewise be a week or more.

    Add to that the inevitable charge of re-engineering some processes to conform to ITIL guidelines, and adjustment of abet desk or other software to snare the information you want for tracking and producing metrics.

    there's, incidentally, no such issue as "ITIL-compliant" utility; the ITIL is a framework, no longer a typical. Some aid desk and management utility has been engineered with ITIL practices in mind, however, and so will lend themselves superior to groups working inside the framework.

    Examples of utility and functions designed with ITIL and ITSM in mind encompass:

  • Samange: offers carrier desk automation with the ITIL framework in mind
  • InvGate provider Desk: a web-based ITIL-able carrier that boasts a person-pleasant interface
  • ManageEngine ServiceDesk Plus: net-primarily based aid desk and asset management software it truly is purchasable in an ITIL version
  • imaginative and prescient Helpdesk: A multifunction carrier desk answer with ITIL integration
  • How long will an ITIL venture take?

    ITIL is not a "mission"; it be an ongoing adventure to enrich IT service administration. greatest practices should be baked into everything, and they exigency to evolve as the enterprise evolves. With IT group of workers purchase-in, alterations can commence once personnel are expert, and a few effects should quiet be obvious inside weeks or months. process alterations conclude assume time, youngsters, as entrenched perilous practices are rooted out and modified (and, doubtlessly, team of workers alterations circle up), but many businesses own pronounced substantial heed downs after their first 12 months.

    To fetch a much better conception of what it is going to assume to undertake and implement ITIL, which you could flick thru case studies on the Axelos site. fresh case reports comprise organizations enjoy Sony and Disney — two corporations with huge IT operations to manipulate.

    What savings can i are expecting?

    companies and public sector companies that own correctly implemented ITIL optimal practices file large heed downs.

    as an instance, in its merits of ITIL paper, purple Elephant stories that Procter and Gamble saved about $500 million over four years via reducing aid desk calls and enhancing working techniques. Nationwide coverage finished a 40 % discount in device outages and estimates a $4.3 million ROI over three years, and Capital One reduced its "enterprise essential" incidents by pass of 92 % over two years. After three years of ITIL implementation, forest products company MeadWestvaco claimed to own eradicated greater than $one hundred,000 annually in IT renovation contracts and recognized a ten % gain in operational balance thanks to ITIL.

    with out buy-in and cooperation from IT body of workers, youngsters, any implementation is bound to fail. Bringing foremost practices into a arduous is as an Awful lot a PR job as it is a technical recreation.

    other criticisms consist of the fact that it’s inconceivable to scheme for each failure, event or incident so it’s no longer an accurate science. truly, you gained’t comprehend the accurate ROI on ITIL unless you implement it within your corporation and exercise it without difficulty. subsequently, in view that ITIL is a framework, it will probably most effective be as a hit as company buy-in makes it viable for. Embracing certifications, working towards and investing in the shift will abet multiply the probabilities of success and heed downs.


    what is an ISEB certificate? | killexams.com existent Questions and Pass4sure dumps

    what is an ISEB manager's certificate in IT carrier administration? and can you inform me what ITIL is? These each had been requested in a fresh job description.For suggestions about the ISEB supervisor's certificate in IT carrier management, gladden observe this web web page. you will likewise wish to examine the guidelines at this website.

    so far as i will tell, here is knowledgeable building exertion that mixes training and checks to enhance already-certified managers -- who own to first acquire an ISEB/EXIN foundation certificate in IT service administration (or the ISEB network carrier management certificates, which offers exemption) -- into greater senior certifications in the specific areas of provider abet or provider beginning.

    as far as ITIL goes, that refers to the IT Infrastructure Library, a largely European strategy to managing IT capabilities, supported by British ordinary 15000 (BS15000). observe this web site for extra suggestions.

    It sounds enjoy you're given that employment someplace within the European Union, if no longer in the UK. decent success and hope that helps!


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    Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals | killexams.com existent questions and Pass4sure dumps

    A plastic scheme for organic synthesis

    The infrastructure for chemical synthesis typically lies at either recess of a spectrum: small-scale studies in ad hoc assemblies of glassware or large-scale production in capital-intensive custom reactors. Kitson et al. report a hybrid protocol that customizes a blueprint for synthesis of a target compound in a string of interconnected plastic modules, which can be assembled en masse by 3D printing (see the Perspective by Hornung). The approach, demonstrated for the commercial muscle relaxant baclofen, establishes a systematic workflow that is potentially amenable to automation: each and every that is necessary for synthesis and purification is the introduction of stock solutions and variation of temperature or pressure.

    Science, this issue p. 314; observe likewise p. 273

    Abstract

    Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. They present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code. This in circle guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations. They demonstrate the approach for the γ-aminobutyric acid receptor agonist, (±)-baclofen, establishing a concept that paves the pass for the local manufacture of drugs outside of specialist facilities.

    The manufacture of dynamic pharmaceutical ingredients (APIs) is vital for modern health care, yet censorious drugs are regularly manufactured for a finite epoch in a limited number of sites. The manufacture of chemical products—whether bulk, fine, or specialty chemicals, such as APIs—is currently based on a model whereby a central plant is exclusively designed for the manufacture of the product, or range of products, sold by that particular company (1). This model holds whether the manufacturer is a large pharmaceutical company or, as is increasingly the case, a condense research organization operating large chemical manufacturing plants to order from the pharmaceutical industry. This process leads to safety issues around both the storage and transport of such materials, as well as the issues inherent in the large-scale manufacture of chemicals (2). In addition, these large-scale plants are often at the lenity of complicated and global supply chains of raw materials, the failure of which at any point will reduce or halt the capacity of the plant to produce materials and deliver them effectively (3, 4). Also, when a given complicated intermediate or API goes out of production, the plants are often repurposed and the manufacturing capacity is lost. The reinstatement of the process would require, in the best case, substantial capital investment to reconfigure a chemical plant for its synthesis. To alleviate this issue, they pose a concept whereby the large-scale manufacturing process of complicated fine chemicals, such as APIs, is augmented by distributed, point-of-use manufacturing in self-contained cartridges, requiring limited user interaction to produce the desired products on demand. To achieve this, they developed a methodology for the translation of bench-scale synthesis procedures into a step-by-step workflow that could be used to create digital designs for custom reactionware that can be fabricated by using three-dimensional (3D) printing technologies. In this way, they even to coast beyond the preserve of industrial manufacturing and prototyping applications (5), to revolutionize the relationship between the design, manufacture, and operation of functional devices (6–11) and exploit the increasing exercise of 3D printing in the automation of the chemical sciences (12–15). This methodology, which is in stark contrast to both large- and medium-scale traditional chemical manufacture, and likewise to the exercise of continuous-flow and microreactor approaches (1, 16, 17), allows for the distribution of simple chemical precursors and solvents rather than the complicated products themselves. These precursors could then continue to profit from the economies of scale brought by traditional manufacturing processes while complicated products with short shelf lives, or lower and more distributed demand, can be produced locally. This has added benefits in terms of manufacture of the final products as the synthesis of smaller quantities is inherently safer than large-scale processes and poses less risk to both operators and infrastructure. Further, the translation of these synthetic approaches into a digitally defined format, where the reactor design and, eventually, an automated synthesis procedure are encoded, could allow the digitization of each and every chemical products into a very low-cost manufacturing format. This could allow large numbers of discontinued APIs to be made available as they can be brought back into production on a diminutive scale by the fabrication and exercise of the appropriate cartridges (18, 19).

    As a proof of principle, they present a process by which the traditional laboratory-scale synthesis of a commercially available API can be translated into the design of an integrated cartridge. To conclude this, each and every the reaction steps and intrasynthesis purification processes are encoded into the 3D architecture of the cartridge so that the chemical reactions, work-ups, and purification are done with minimal user intervention and exposure automatically. They own demonstrated this process in the replete synthesis of the anticonvulsant medication (±)-baclofen (see below).

    This routine for translating traditional laboratory syntheses into a profile that can be encapsulated in a separate cartridge is split into three layers of consideration, which were iteratively reevaluated during the cartridge development process. The first is the “conceptual layer,” where the chemical reactions and processes necessary are identified and developed. The second is the “digital layer,” in which these processes are translated into digital 3D models of the final cartridge devices. Finally, a “physical layer,” where the digital models are realized as either a modular implementation or a monolithic implementation, is used to generate the finalized cartridge, which can be used to outcome the designed synthesis (Fig. 1). These physical systems can then be tested for efficacy as a final implementation, before iterating the process to develop reliable cartridge syntheses.

    Fig. 1 Schematic representation of the translation of a multistep synthesis from conception through to implementation as a reaction cartridge.

    Reactions necessary for the synthesis are identified (A→B→C→D, top left panel) and the specific chemical and physical processes and reaction parameters necessary for each reaction are laid out (conditions i. – iii., left panel). These processes are then translated into bespoke reaction modules designed to accomplish one or more of the chemical processes identified in the previous step (top perquisite panel). The modules are then designed as 3D CAD models (lower focus panel), with libraries of module components to accommodate the required reaction parameters. These digital models can then be fabricated to produce either a modular or monolithic implementation (lower perquisite panel) of the process.

    First, the fundamental chemistry required for the transformations is considered and optimized to minimize the necessary interstep purification for the completion of the replete synthesis. This approach is similar to that taken to develop telescoped (i.e., consecutive transformations in a separate reactor or sequence of reactors without isolation and purification of intermediates) and “one-pot” syntheses (20, 21), often used in process chemistry, both of which even to maximize the efficiency of the synthetic route. Although here it is not necessary to produce genuinely telescoped syntheses, as modules for interstep purification can be built into the cartridge design, the synthesis of the desired compound, including each and every reagents and starting materials for each and every the necessary steps, must be considered as a unified process. The choice of synthetic route to any target compound will be dictated by a number of factors, including the relative availability and cost of starting materials, reagents, and solvents, as well as the compatibility of reaction and purification sequences with the reactor modules produced. In any wide-scale application of their approach, a cost analysis of any proposed synthetic route will own to be performed to ensure its viability for the product. Once the chemistry for the synthesis is developed, a sequence can be produced where the physical processes and reaction parameters—such as heating, cooling, aspect separations, reaction volumes, and times—can be identified.

    Vital to the success of these modules is the compatibility of the cartridge material with the chemistry being performed. Whereas traditional laboratory syntheses assume state mostly in glassware, they exercise polypropylene (PP) as a basic structural material for the fabrication of the cartridges. They own organize that this polyolefinic material, while demonstrating a robust range of chemical compatibility for traditional synthetic organic reactions, is likewise a suitable substrate for 3D printing applications (22–24). This gives the best equipoise of chemical resistance and material properties for 3D printing. Therefore, the first step in the design process is testing the reactions necessary for compatibility in the reactor materials. Future iterations of the concept could expand on the materials and fabrication processes available for the reaction modules to further develop the range of chemistries feasible in this system, using, for example, perfluorinated polymers to multiply the chemical resistance of the module.

    To demonstrate the feasibility of incorporating these PP reactors into the production of APIs, they tested a number of reactions that lead to such targets in test modules fabricated from PP (Fig. 2). They tested reactions for the synthesis of three APIs: the central nervous system inhibitor (±)-baclofen (25), the anticonvulsant lamotrigine (26), and the gastroprotective agent zolimidine (27). As can be seen, each and every of the reactions tested were observed to work, but with slightly lower efficiency in PP reactors than in traditional glass reactors, owing to physical loss of material on the relatively jagged PP surface hampering product recovery. Surface roughness is inherent in the 3D printed process; however, exercise of other, as yet undeveloped, materials or different manufacturing techniques could reduce this issue. The zolimidine reactions, particularly the copper-catalyzed iodination reaction, experienced a pronounced reduction in efficiency, compared to (±)-baclofen or lamotrigine. They surmised that this was due to side reactions of the iodine with the polypropylene. These issues highlight that the process of translation from glassware must assume into account both the physical and chemical properties and limitations of the reactor substrate (23). For this reason, the first two syntheses were selected for further development into reaction cartridges to explore the concept.

    Fig. 2 Comparison of glass reactors with plastic reactionware for the optimized synthetic routes to (±)-baclofen (top), lamotrigine (middle), and zolimidine (bottom) with reaction yields for each step (reaction yields in PP vessels given in parentheses).

    Single (top right) or double (bottom right) chambered polypropylene reaction test cartridges were used. PP, polypropylene; TBAF, tetrabutylammonium fluoride; THF, tetrahydrofuran.

    Once the processes needed for the reaction sequence are identified, the combined continuous protocol is mapped onto the 3D digital designs for the target-specific cartridge. The sequence of processes is split into a string of modules, with each representing a telescoped string of processes that can assume state in a separate chamber of the 3D printed system. Each process module is then created as a digital model that can be manipulated to provide the remedy physical dimensions necessary for the reaction scheme. The 3D models of the cartridges used in this study were created with OpenSCAD software, an open-source framework for CSG (constructive solid geometry) modeling that allows a highly elastic and configurable approach to create all-around libraries of components as reusable pieces of code. Once defined, these pieces of code can be manipulated by the software, allowing the generation of complicated reactor geometries with minimal human inputs. For example, in this study, they designed a module library consisting of interchangeable top and bottom components with varying features that can be easily combined to produce reaction vessels with different shapes and features. From a separate line of code, an entire module can be created, with 18 different shapes available (i.e., three different tops and six different bottoms can be selected; Fig. 3). The modules were designed around simple chambers where each reaction or process could be performed in as nigh a manner as viable to the pass it would be carried out with traditional batch chemical techniques, easing the transition between published synthesis in glassware and “cartridge” synthesis. Typically, a yardstick module would own an opening on the top of the wall of the chamber for transfer of reaction mixtures from previous modules and an opening at the bottom of the chamber for expelling material from the module subsequent to the completion of the desired process. The transfer of material between modules is facilitated by a further opening in the roof of the compartment, which can be used to apply pressure that forces the reaction medium out of the chamber via the outlet at the bottom. The opening at the top otherwise equalizes pressure throughout the device to forestall the premature transfer of material, and likewise allows for application of vacuum to remove and exchange solvents. These modules can then be combined in sequences by exercise of further components of their module library such as siphon tubes for the transfer of material from one reaction module to another.

    Fig. 3 Parameterized approach to the design of individual process modules.

    Digital libraries of module components (top) can be easily assembled to produce a wide range of module geometries dictated by the specific process and reaction parameters (e.g., solvent volumes, number of inputs and outputs, etc.) (bottom). Hydrophobic filters for aspect separation are shown in red, and fritted glass filters are shown in blue. DCM, dichloromethane. HR, reactor height.

    Once a reaction chamber is created, unusual features can be introduced by subtracting or adding shapes to the module. For example, a filtration device can be made from a module with a top input, a round bottom with a port, and a glass filter. To achieve this feature, a cylindrical model conforming to the dimensions of the physical filter to be inserted is created and subsequently subtracted from the model of a reaction chamber, producing a void space in the model into which the filter fits (see supplementary materials). aspect separation modules were achieved in a similar manner by using hydrophobic frit inserts that effectively sunder organic and aqueous phases for product extractions. In keeping with their wish to design synthesis cartridges that can be produced outside traditional manufacturing regimes, they own exploited their group’s development of 3D printed reactors—reactionware—for synthetic chemical applications as a routine of prototyping the physical reactors (28, 29). Three-dimensional printing–based fabrication approaches own the added handicap of being intimately linked to the design process.

    Fabrication of the modular system was carried out on low-cost (~$2000) 3D printers, Ultimaker 2 and 2+, although many other fused deposition modeling (FDM) printers could print the 3D modules produced through this approach. If it is necessary to incorporate nonprinted materials during 3D printing of the final module, a preprogrammed recess in the printing process is instigated at a point just above the designed void, and the component is inserted in this space before the resumption of printing. Upon completion of printing, the inlet and outlet ports were tapped with a ¼ inch unified national fine (UNF) thread to allow ease of integration with the external infrastructure for performing the reaction sequences. Using yardstick ports allowed us to attach either yardstick fluidic tubing connectors such as those organize in traditional flood synthesis setups, or widely used Luer lock adapters. These Luer lock connectors are easily reconfigurable, facilitating feedback into the design process.

    The API chosen to accomplish a complete end-to-end synthesis was the central nervous system depressant and antispastic medication (±)-baclofen (30, 31) [RS-β-(4-chlorophenyl)-γ-aminobutyric acid] (4) (Fig. 4), a derivative of γ-aminobutyric acid (GABA) that modulates the action of this central inhibitory neurotransmitter (25). This target was chosen as an case to demonstrate that even relatively short syntheses require a disproportionately larger set of chemical processing steps to outcome the replete synthesis; in the future, they envision that the synthesis of larger numbers of compounds and compound classes will greatly expand the scope of this approach. (±)-Baclofen has organize a number of applications since its first reported synthesis and is currently being investigated beyond its traditional use, as a high-dose treatment for alcoholism (32). Many syntheses of (±)-baclofen own been published since it was first reported, often proceeding through the formation, and subsequent hydrolysis, of β-(4-chlorophenyl)-γ-butyrolactam (3). They own modified such a traditional synthesis of (±)-baclofen starting from the commercially available material methyl 4-chloro-cinammate (1), and proceeding via the Michael addition of nitromethane to profile 4-nitro-3-(4-chlorophenyl)butanoic acid (2), followed by nickel-catalyzed reductive lactamization and subsequent acid hydrolysis to produce the final product in its commercially available racemic profile as a hydrochloride salt. This three–reaction-step sequence contains 12 individual processing steps that must be incorporated into the reactionware device to complete the synthesis (Fig. 4). This sequence was designed to be particularly amenable to translation into the modular or monolithic system as at each stage, the reactions are either sufficiently clean, or reaction impurities that would impinge on subsequent process in the synthesis could be readily removed by aspect partition. The final product is purified through a methanol–diethyl ether crystallization, which yields a crystalline solid that can be retrieved directly from the cartridge device. An animation of the entire process, showing the passage of reagents, processes, and work-ups, is shown in movie S1.

    Fig. 4 Synthesis of (±)-baclofen in a string reaction cartridges.

    (Top) Conceptual synthetic procedure for the synthesis of (±)-baclofen under the conditions described in Fig. 2, showing the necessary processing sequence to outcome this synthetic pathway. These processes were then split into modules (a) to (e) (indicated by gray boxes in the process sequences), which they translated into a digital design (middle left) and finally fabricated as either a modular (middle right) or monolithic (bottom left) implementation. A partially fabricated monolithic cartridge is likewise shown indicating the placement of non-3D printed components and internal fluidic pathways (bottom focus and right). Both modular and monolithic cartridges are shown with Luer taper–compatible valving for interfacing with external fluidic inputs and pressure or vacuum lines.

    Each of these processes was translated into operations that could be successfully embodied in one or more reaction or purification modules. The specific reaction modules used for the synthesis of (±)-baclofen were (a) a combined Michael addition, evaporation and ether extraction module; (b) a combined solvent exchange and reduction module; (c) a aspect separation and filtration module; (d) a combined solvent exchange and hydrolysis module; and (e) a filtration module. Individual modules were fabricated for a “plug-and-play” approach to the reaction process development by using Luer lock fittings to connect individual modules and Luer taper–compatible valves to interface with pressure or vacuum systems. This design allowed testing of each individual process in isolation before the modules were combined to build up the replete synthesis. Finally, the module designs were “digitally stitched together” by using the developed CAD libraries for internal fluidic pathways to create the design for a monolithic synthesis cartridge. Once fabricated, the individual modules and the monolithic cartridges were evacuated and filled with a nitrogen atmosphere to ensure an inert environment for the subsequent chemistry.

    The first chamber, (a), consists of a lower volume (4.9 ml) where the initial reaction can assume state and is separated from the upper outlet by a hydrophobic frit. Reactor modules (b) and (d) consist of a separate unbroken reaction chamber (31.8 ml) with adequate volume to accommodate the reaction volumes and extraction solvents from the previous processes before concentration under reduced pressure. Extraction module (c) consists of a chamber of adequate volume (4.7 ml) to hold the aqueous aspect from the previous chamber, which has a drain at the bottom covered by a hydrophobic frit that prevents both solid material and aqueous solution from passing into the next chamber or module. The final module is a filtration module for separating and retrieving the final product. This separate module can be either open to the atmosphere or enclosed as required. During the fabrication process, chambers or modules that required stirring were equipped with a PTFE (polytetrafluoroethylene)–coated magnetic stirring bead (length 10 mm) to enable mixing of the contents. Each module or chamber of the monolith was equipped with a ¼ inch UNF threaded port carrying a female Luer lock adapter, which was used to interject an inert (dry, N2) atmosphere, or reduced pressure, into the system. The modular system was designed such that there was a separate fluidic path through the reactor; flood from one chamber into the next was induced either by pressure from excess solvent, in the case of the aspect separation processes, or the introduction of nitrogen pressure incompatibility between the pertinent chambers to thrust the reaction blend through an embedded channel running from the bottom of one chamber to the top of the next.

    Starting materials were prepared as simple solutions and transferred to the cartridge via yardstick Luer syringes. The cooling and heating required for the reaction sequence were achieved by the immersion of the reaction cartridge or module in an ice or sand bath, respectively, and the temperature required for the reactions can be achieved automatically on a stirring-hotplate. The exact sequence of operations, positioning of the module in the heating or cooling bath, and time intervals necessary for completing the synthesis are outlined in the supplementary materials (figs. S12 and S13 and table S3).

    Performing the synthesis starting from 200 mg of 1 in the manner described yielded 98 mg (39% yield over three reaction steps and 12 processing steps from 1 with ≥95% purity as determined by high-performance liquid chromatography) of (±)-baclofen hydrochloride salt, which is more than 1 day’s maximum dosage of the drug. Better efficiency of reaction can be achieved with lower concentrations of starting materials (using a similar cartridge at half concentration, i.e., 100-mg scale, gave a 44% yield over three steps of similar purity). Increasing the volume of the reactor as well increases the quantity of (±)-baclofen obtained [a 300-mg scale synthesis yielded 133 mg (35%) (±)-baclofen]. The integration of the reaction processing steps into the design of the modules greatly simplifies the operations required to achieve the reaction sequence compared to traditional bench synthesis and simultaneously reduces the even of technical skills required to achieve the process down to simple operations that conclude not require the specific skills of a trained synthetic chemist. Although the total time for the reaction sequence is around 40 hours in this case, including each and every intermediate operations, the workflow is constrained by the geometry of the device, so each and every human interaction is limited to simple interventions at specific time periods, and it should be viable to curtail the interaction time further. The exercise of such bespoke, single-use cartridges would greatly reduce the time spent on glassware preparation, liquid handling, and other ancillary tasks associated with the majority of chemical syntheses at this scale. Also, by using the geometry of the reactor to constrain the operation of the synthesis, they reduce the human decision making involved in the synthesis processes, making the sequence more reproducible. Given adequate facilities, several instances of the synthesis cartridge could be used at once, achieving scalability by numbering-up arrays of cartridges, and using these in parallel to multiply the output. As a result of the capacity to parameterize and encode multistep organic synthesis reactions with work-ups embedded, they envisage that a digital programmable universal heater-stirrer-solvent-reagent plug-and-play device can be constructed into which only the cartridge, specific to a given synthesis, can be plugged in.

    The (±)-baclofen synthesis necessitated liquid handling and separation of reaction chambers to outcome the replete reaction sequence. In some cases, however, syntheses can be conducted in separate reaction cartridges, depending on the nature and attribute of the interstep purification required. For example, the synthesis of lamotrigine (Fig. 2) can be achieved in a separate cartridge as the intermediate material is insoluble in the reaction solvent at low temperatures. In a single, closed, filtration module, the initial reaction product could be washed and processed in situ before introduction of the solvent for the subsequent cyclization step. This stands in contrast to the traditional procedure, which requires the solid product of the first step to be removed from the initial reactor to be filtered, dried, and then reintroduced to a reactor for the second step of the synthesis. Performing the synthesis of lamotrigine on a 250-mg scale of starting material yields 112 mg (46% over two reaction steps) of the final product, giving an off-white crystalline powder.

    The digital approach to the design of the system that they own adopted allows the blueprints for these cartridges to be stored electronically for implementation as and when required. The distribution model for fine and specialty chemicals, such as the APIs implied by this approach, would lead to a decentralizing of logistical approaches to chemical manufacture. Here, any location with access to a sufficiently diverse market of chemical precursors and suitable cartridge fabrication facilities could be used to produce chemical products, which could previously be achieved only in a fully equipped synthesis laboratory with highly trained staff. This approach not only holds engage for eventually delivering on-demand personalized medicines manufactured at, or near, the point of use, but likewise has short-term potential applications in the synthesis of APIs that are currently out of production. An immediate repercussion of digitization is that the cost for synthesis at the bench scale (milligrams) could reduce markedly owing to savings in labor and infrastructure with only a one-off digitization cost (and allow operators to accomplish 5 to 10 different products at the selfsame time). Once the saving meets the digitization cost, the efforts of the expert chemist will shift from bespoke on-demand chemical manufacturing to chemical digitization (see supplementary materials for an economic analysis). Their methodology will own the most rapid repercussion for chemicals that are currently produced on exact in diminutive batches and that occupy a gap in the market where the exact for a product is adequate for it to be commercially viable but insufficient to justify plant-scale production. This gap lies between the elevated cost of bench-scale versus reactor-scale synthesis, and thus the digitization profit of compounds in this zone is high.

    The regulatory framework necessary to produce complicated materials in this vogue will exigency thorough attention; indeed, their approach would require a completely unusual system for the regulation of API manufacture. This system would own to be developed alongside the evolution of this approach as a routine for pharmaceutical synthesis, which they own presented here in proof-of-concept form; however, they can envision a situation in which regulatory agencies certify specific cartridge or module designs as soon as a digitized process is fully established (including the embedded quality-control protocols), independent of the physical location of person who uses the cartridge. This approach has multiple benefits. First, the framework can adopt well-established methods of digital kick certification from the information technology universe (e.g., digital signing with asymmetric ciphers). Second, no explicit certification would be needed for each unusual “facility” (which might be a hospital or a private house) that would exigency the drug. Third, existing methods for protecting and manipulating digital content provide much more efficient models for distribution and regulation compared to the retail and patent system, respectively. These regulatory issues surrounding the commercial or clinical application of this approach are not trivial, and care must be taken to ensure that end-user safety is not compromised. However, they believe that the benefits in terms of efficiency of delivery, robustness of supply, and range of materials available could lead to the digitization of chemical synthesis.

    Acknowledgments: They concede the abet of S. Marshall in compiling their analysis of the economic repercussion of their methodology. Supplementary materials comprise a PDF document detailing the materials and methods used in this article; the STL and OpenSCAD files used to generate each and every 3D printed objects mentioned; a schematic movie illustrating the process of baclofen synthesis in the monolithic cartridge; and Python code that can be used to automate the stirrer-hotplate operations for the baclofen synthesis. They gratefully concede fiscal back from the Engineering and Physical Sciences Research Council (grant nos. EP/H024107/1, EP/J015156/1, EP/K021966/1, EP/L015668/1, EP/L023652/1) and European Research Council (project 670467 SMART-POM). This research was developed with funding from the Defense Advanced Research Projects Agency (DARPA). The views, opinions and/or findings expressed are those of the author and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. L.C. is the founder and director of CroninGroupPLC and is listed as an inventor on a patent application filed by The University of Glasgow (GB 1800299.8). L.C. conceived the initial concept and the design approach; P.J.K. designed the reactionware with abet from J.P.F. and S.Z.; G.M. and R.C.S. telescoped the methods, porting them from glass to plastic; and P.J.K. developed the monolithic cartridges with abet from S.Z. J.S.M. helped evaluate the purity of the products, and P.J.K. coordinated the team with abet from L.C.


    Late Preterm Infants and Neurodevelopmental Outcomes at Kindergarten | killexams.com existent questions and Pass4sure dumps

    Late Preterm Infants and Neurodevelopmental Outcomes at Kindergarten | Articles | Pediatrics

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