**Author details**

Suchana Akter Jahan\* and Hazim El-Mounayri Purdue School of Engineering and Technology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Multiscale Modeling Framework for Defect Generation in Metal Powder Bed Fusion Process… DOI: http://dx.doi.org/10.5772/intechopen.104493*


**X-Ray N-Beam Takagi-Taupin Dynamical Theory and N-Beam Pinhole Topographs Experimentally Obtained and Computer-Simulated**

Kouhei Okitsu, Yasuhiko Imai and Yoshitaka Yoda

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/47846


**1. Introduction**

The intravascular volume status (i.e., the extent of vascular filling) is a relevant cardiovascular parameter related to the cardiac preload (i.e., the stretch of cardiac tissue in relaxed conditions), which in turn affects cardiac output and arterial blood pressure. Its assessment in critically ill patients is essential to establish and carefully balance the appropriate fluid therapy, whereby fluid supplementation may favor cardiac efficiency, but also increase the rate of complications and mortality [1–3]. Various pathological conditions are characterized by alteration of the volume status, e.g., heart failure causes overload while dehydration leads to volume depletion.

The non invasive evaluation of the volume status is very important, as it allows to inspect a patient in emergency conditions or during the follow-up. An approximate assessment of the volemic condition can be obtained from US imaging of the IVC [4,5]. In fact, the pulsatility of the IVC was found to correlate with the intravascular fluid volume [6]. Moreover, it can be useful for the non-invasive estimation of the central venous pressure [7–9].

However, this non-invasive method has shown limitations [10,11]. Important problems are due to the lack of standardization [12] and to the subjectivity of the measurement [13]. Indeed, both B-mode and M-mode US scans have been used, followed by a subjective identification of the IVC maximal and minimal diameters [6,14]. Specifically, IVC pulsatility can be expressed in terms of the caval index (CI), defined as the variation of the vessel diameter during a respiratory cycle relative to the maximum diameter: minimum and maximum diameters are measured by the operator from a B-mode video or an M-mode trace considering inspiration and expiration, respectively. This clinical approach is not standardized [12,15] (e.g., either long [16] or short axis [17] visualizations are used), and is operator-dependent [13] and prone to measurement errors, e.g., due to movements [18] and non-uniform pulsatility of IVC [15]. In particular, the M-mode registration allows to visualize a section of the vein over time at high frequency along a fixed direction in space [19]. As the IVC moves during respiration, the M-mode approach fails to constantly refer to the same section of the vein. On the other hand, measuring diameters from a B-mode video requires that the operator chooses the frames corresponding to the end of inspiration and expiration, in addition to selecting the sections along which to estimate the diameters (which could be different, if the operator does not compensate for IVC movement).

Moreover, IVC pulsatility may vary considerably in different portions of the vein [15,20], so that a single measurement taken by a manual approach provides limited information.

Some confounding factors have also been documented in case of specific pathologies, e.g., to the respiratory system [21,22] or the heart [23,24]. Indeed, breathing and heartbeats provide the main stimulations affecting IVC pulsatility. Separating the effects of the two contributions could possibly help to counteract these limitations [13,25].

A further problem consists in the shape of the IVC: in different sections along the longitudinal view, the IVC can exhibit very different diameters, as in the case of a saber profile [15,26], and different pulsatilities [20]; the IVC cross-section can be irregular, much different from a circle or an ellipsoid (especially in the case of hypo-volemia), with a large variation of pulsatility in different directions [27,28]. Thus, investigating IVC both in long and short axis views and averaging across different sections or directions could be important to better characterize the vessel and its respirophasic dynamics.

We have carried out a series of studies trying to overcome some of the limitations of the US assessment of IVC. Specifically, we have developed an automated method to track the movements and estimate the borders of the IVC from US video-clips [19,20,28,29]. Data derived from both longitudinal (long axis) and transverse (short axis) sections of the vessel can be processed. The algorithms extract information from either a whole tract of longitudinal section of the vein or a transverse section, respectively. This way, the overall pulsatility can be estimated. Moreover, the border of the vein is found for each frame of the video-clip, so that the vessel pulsations can be investigated over time, obtaining time series which can be processed to estimate further indexes characterizing pulsatility, e.g., induced by either respiration or cardiac stimulation only. Preliminary results indicate that IVC average size and global pulsatility and its respiratory and cardiac components estimated in long axis are strongly related to the right atrial pressure (in contrast with size and pulsatility estimated by standard clinical approaches [30]) and are useful for its non-invasive estimation [25,31].

However, beyond these promising correlations, there is still no stable criterion capable of recognizing pathological problems in the volume status. With this study, we face this aspect and try to propose a classification method based on an automated processing. Specifically, US B-mode video-clips of IVC from long and short axis have been acquired from patients with different volume status. They have been processed, tracking the movements and estimating the border of the vein. Then, indexes characterizing IVC size and pulsatility have been automatically extracted and used to build a classifier able to discriminate patients in either hypo-, eu-, or hyper-volemic conditions.


*2.9.3 Binders in paper making and paper coating*

Starch possesses a binding property and can be used as a binder in papermaking and paper coating. Cooked starch is widely used as paper-making additive and the retention of the cooked starch on the paper matrix is based on starch absorption [108]. However, the amount of starch absorbed is limited by the cellulose substrates absorption saturation. Another problem which might cause operational problems is the high viscosity of the starch paste after cooking. Bloembergen *et al*. [120] revealed that the modified starch possessed better paper binding capacity than cooked starches.

**209**

crops [24].

*Utilization of Starch in Food and Allied Industries in Africa: Challenges and Prospects*

**3. Challenges facing common starch sources and way outs**

suggestions described below are given utmost attention:

and make them readily available for consumption.

products to the larger industries [24].

mycotoxin contamination in starch [108].

Starch is the basis of our food and industrial economy, but the food situation in most developing tropical countries is alarmingly worsening owing to increasing population, fragmented farms with rudimentary technologies, poor pre-harvest and postharvest farm practices and shortage of fertile land [11, 24, 108]. The shortage of food supply has resulted into a high incidence of hunger and malnutrition [12, 13]. It also affected the demand for starch as food, pharmaceutical and industrial uses coupled with the need to attain self-sufficiency in starch production.

However, self-sufficiency in starch production could be attained if the following

i.Some lesser known and unconventional crops could be good sources of nutrients and starch, and even have the potential of broadening the present narrow food base of the human species (Viano *et al*., 1995). *Dioscorea villosa* L (common name wild yam or atlantic yam) is one of the underutilized starch sources, and it is less explored due the presence of anti nutritional factors. Processing techniques can reduce the anti-nutritional factors in food

ii.Efficient and effective development of the various starch based crop value chains such as cassava in order to increase their productivity [24].

production, processing and delivery of high quality and quantity of cassava

iv.Promotion of effective pest/pathogens integrated management programs and reduction of the occurrence of mycotoxin in starch based crops, to prevent emerging and endemic pests and diseases as well as reduction of

v.Access to high yielding, climate-resilient and affordable quality seeds, advances in breeding technology using genomic approaches that is costeffective and field-relevant high throughput phenotyping approaches will accelerate and contribute significantly to mass production starch-based

iii.Encouraging small and medium scale investments in order to enhance

Starch bioconversion into ethanol is a two-step process. Saccharification is the first step, which involves conversion of starch into sugar using an amylolytic microorganism or enzymes such as glucoamylase and α-amylase. Fermentation is the second step, which involves conversion of sugar into ethanol using *Saccharomyces cerevisiae* [121]. An alternative to the conventional multistage process of starch fermentation which offers poor economic feasibility is the use of amylolytic yeasts for the direct fermentation of starch. Despite the fact that there are over 150 amylolytic yeast species, they possess limited industrial use because of their low ethanol tolerance [121]. Therefore, most research effort has been geared towards the development of genetically engineered amylolytic strains of *S. cerevisiae*, and in these strains, heterologous genes encoding α-amylase and glucoamylase from various organisms have been produced including their products and their products [121].

*DOI: http://dx.doi.org/10.5772/intechopen.95020*

*2.9.4 Starch as energy source*

*Utilization of Starch in Food and Allied Industries in Africa: Challenges and Prospects DOI: http://dx.doi.org/10.5772/intechopen.95020*

#### *2.9.4 Starch as energy source*

*Innovation in the Food Sector Through the Valorization of Food and Agro-Food By-Products*

sodium caseinate and gum Arabic [102].

**2.9 Utilization of starch in allied industries**

forced with 2.5% starch nanoparticles.

low cost, and suitable physicochemical properties [31].

*2.9.3 Binders in paper making and paper coating*

*2.9.2 Drug carrier and tablet binder*

*2.8.6 Emulsion stabilizer*

*2.9.1 Packaging component*

condition and the process involves application heat and shear thinning. Therefore, starch which has ability to tolerate acidity, heat, and shear is suitable for these products. Also, lipophilic starch which has potential to stabilize emulsions, other modified starches such as cross-linked starch and stabilized starch are the most commonly used for these products [117]. Lipophilic starch is produced by esterification with n-octenyl succinic anhydrate, which led to a starch structure comprising both hydrophilic and lipophilic properties. This starch can be used for mayonnaise and salad dressing, lipophilic starch might be used to replace animal-derived

A scientific study suggested that starch could be used as a stabilizer in oil-inwater emulsions [117]. The study further revealed that emulsion prepared with equivalent volume ratio of water and paraffin could be stabilized by adding an aliquot of starch dispersion [117]. Kim *et al*. [117] established that the introduction of starch nano particles of more than 0.02% wt kept the emulsion longer than 2 month of storage without coalescence of oil droplets. Starch might be used in various emul-

sions not only for foods but also for cosmetics and pharmaceuticals [117].

Some non food uses of starch in allied industries are described below:

Nanoparticle from starch can be used as a material in barrier films for food packaging. The primary focus of the barrier properties of the packaging films is on water vapor transmission and oxygen permeability [117]. However, a decrease in water vapors permeability was observed when the maize starch was used. Kristo and Biliaderis [118] revealed addition of 30–40% waxy maize starch significantly decreased the water vapor permeability in the component. Similarly, García *et al.* [119] observed a 40% decrease in the permeability of cassava starch film, rein-

Starch has been described as a nontoxic, biodegradable, and biocompatible polymer [117]. Its nanoparticles possess the ability to deliver an ample range of molecules to any location in human body for sustained periods of time. Starch has been useful in tablet formulation and binding due to its relative inertness, abundance,

Starch possesses a binding property and can be used as a binder in papermaking and paper coating. Cooked starch is widely used as paper-making additive and the retention of the cooked starch on the paper matrix is based on starch absorption [108]. However, the amount of starch absorbed is limited by the cellulose substrates absorption saturation. Another problem which might cause operational problems is the high viscosity of the starch paste after cooking. Bloembergen *et al*. [120] revealed that the modified starch possessed better paper binding capacity than

**208**

cooked starches.

Starch bioconversion into ethanol is a two-step process. Saccharification is the first step, which involves conversion of starch into sugar using an amylolytic microorganism or enzymes such as glucoamylase and α-amylase. Fermentation is the second step, which involves conversion of sugar into ethanol using *Saccharomyces cerevisiae* [121]. An alternative to the conventional multistage process of starch fermentation which offers poor economic feasibility is the use of amylolytic yeasts for the direct fermentation of starch. Despite the fact that there are over 150 amylolytic yeast species, they possess limited industrial use because of their low ethanol tolerance [121]. Therefore, most research effort has been geared towards the development of genetically engineered amylolytic strains of *S. cerevisiae*, and in these strains, heterologous genes encoding α-amylase and glucoamylase from various organisms have been produced including their products and their products [121].


**Abstract**

Currently, metabolic diseases are the main public health problem. Obesity is a metabolic imbalance that leads to insulin resistance, hyperinsulinemia, dyslipidemia, hypertension, and proinflammatory and prothrombotic states that can trigger type 2 diabetes as well as cardiovascular diseases. Obesity is the excess of adipose tissue and is considered a risk factor to develop metabolic syndrome. The obesogenic environment that is lived promotes the search for specific solutions that help to control, eradicate, or minimize the negative results in health, making use of the properties of flavonoids, as important sources of antioxidants, with anti-inflammatory, antithrombotic, and antihypertensive effects. Given the above, the objective of this chapter is to highlight the effects of flavonoids on the modulation of lipolysis and lipogenesis altered by a hyperlipidic diet.

**Keywords:** flavonoids, lipolysis, lipogenesis, obesity, inflammation


**2. Eye care in the optometry setting using community based optical coherence tomography and virtual glaucoma clinics**

Current treatment for age related macular disease requires patients to be monitored closely ( usually on a monthly basis ) for recurrence of the disease. This disease affects elderly people, who may be unable to drive due to loss of visual acuity below driving standards. In rural areas, where there is a greater travel burden ( for example in rural Wales ) there is a major challenge for people to keep up with their appointments. Elderly people are increasingly reliant on relatives, neighbours and carers to transport them to clinics, and in many cases ambulance transfer is needed for routine clinic appointments. This causes additional stress and incon‐ venience for these patients. It increases the chance of further health problems as for example increased rate of falls. This costs either the health authorities and/ or the patients for organising and supplying this transport. More CO2 gases are released in the atmosphere from the increased pollution.

The solution for all these issues is to deliver healthcare closer to the home in the community. This can be achieved with community based OCT machines, together with (non- ) mydriatic fundus cameras. In areas with not very dense population or in countries, where the purchase of enough equipment is an issue, this equipment can be integrated into special mobile vans. Mobile vans can visit different areas with a pre- determined schedule, and are the topic of discussion of the next section in this chapter.

The information obtained with this equipment is sufficient for a trained ophthalmologist to assign appropriate treatment or follow up, using modern telemedicine equipment, even if he or she is thousands of miles away. This allows remote diagnosis and management of patients.

Glaucoma is a chronic disease, in which in the majority of cases lifetime follow up is required. This puts a large strain on the ophthalmology clinics. For most of the patients with stable glaucoma follow up in a virtual clinic is possible.

Trained opticians or nurses can check visual acuity, IOP ( Goldman application ), perform visual acuity test, nerve fibre layer scans (OCT, GDX, HRT ) and record fundus photos with a (non)- mydriatic camera. All these tests can be done in the community and after that the information can be digitally transferred to a regional ophthalmology centre, where it can be interpreted by ophthalmologists. In this way patients are not going to have travel long distances. The ophthalmologists will be able to increase the capacity of their clinics. They will have all the required information for changing treatment and assigning follow up appoint‐ ments. Prioritisation of patients who need to be seen for a face to face consultation can be made from the information.

#### **2.1. Optometry and teleophthalmology**

The main problem encountered in the change was the issue of confidentiality. The Caldicott Guardian deemed that the clinical need was greater in these instances, and once the decision

Smart Phone technology has been shown to be useful in the assessment and treatment of eye emergencies. All patients showed improvements in visual acuity ranging from 1 line to 7 lines,

A Consultant opinion was gained quickly in all 12 cases. The costs of patient and hospital transport were saved. There is a role for the use of smart tablets in digital image transfer to provide a larger image, and these could also be used for transfer of retinal optical coherence tomography images in a macular clinic. There is the potential for use of smart phone images

Eye Emergencies can be effectively treated in rural areas by Nurse Practitioners obtaining advice directly from a Consultant through high resolution images of the eye seen on a smart

It is possible to take slit lamp photos by placing the lens of a smart phone against the slit lamp lens; however, the use of an adapter will allows higher quality photographs. This may help to facilitate teleophthalmology for nurse practitioners and optometrists in the primary care

The Keeler Portable Slit Lamp iPhone 4 image adapter has been reported to be compatible with the Haag-Streit 900 BM (older series) and Topcon SL-3F slit lamps. The adapter is not com‐ patible with Topcon SL-D7, Mentor. When using the Keeler adapter, a moderate amount of force has to be applied to attach the adapter to most Haag-Streit slit lamp oculars (the diameter of my slit lamp's ocular is 30 mm and it requires a moderate amount of force to attach).

**2. Eye care in the optometry setting using community based optical**

Current treatment for age related macular disease requires patients to be monitored closely ( usually on a monthly basis ) for recurrence of the disease. This disease affects elderly people, who may be unable to drive due to loss of visual acuity below driving standards. In rural areas, where there is a greater travel burden ( for example in rural Wales ) there is a major challenge for people to keep up with their appointments. Elderly people are increasingly reliant on relatives, neighbours and carers to transport them to clinics, and in many cases ambulance transfer is needed for routine clinic appointments. This causes additional stress and incon‐ venience for these patients. It increases the chance of further health problems as for example

**coherence tomography and virtual glaucoma clinics**

was made, the images were to be deleted form both Smart phones

and complete resolution of symptoms due to prompt diagnosis and therapy.

*1.2.6. Lessons Learnt*

8 Telemedicine

phone.

setting.

in dermatological emergencies

**1.3. Smart phone adapters for slit lamps**

In the UK there are currently 2.3 ophthalmologists per 100 000 population, as described by Kulshrestha and Kelly (2011). This is the lowest pro rata than any other European Union country (www.uems.net). In the UK, optometrists play an important role in managing patients with eye complaints. Most of the patients seen in the Hospital Eye Service (HES) are referred by them either directly or through the patient's general practitioner (GP) (Bell and O'Brien 1997). For example more than 90 % of all suspected cases of primary open angle glaucoma are referred to the HES by optometrists according to Harrison and Wild et al (1988). The National Health Service (NHS) hospitals in the United Kingdom are a part of the public system. Optometry practices are private and have a dual role: they carry sight tests and dispense spectacles and contact lenses. The sight tests are reimbursed by the NHS.

The Hospital Eye Services (HES) in the UK are usually overloaded with patients and have waiting times of several months for new patients. There are also waiting times for follow up appointments. This means that for many patients allocated 6 months follow up appointments, the appointment may be delayed by a number of months. This is called slippage, and slippage has increased in recent years due to the introduction of new NICE guidance for glaucoma, which has increased referrals into HES from primary care. In addition, increased workload from the Vasoactive Endothelial Growth Factor antagonist treatment of wet age related macular disease has overloaded the service due to the demands of monthly OCT scanning and injections. This service is now affecting appointments in general ophthalmology clinics where glaucoma patients are seen.

Teleophthalmology provides us with the opportunity for these patients to be reviewed directly by the consultant and the HES staff who are already trained to do this by using virtual glaucoma clinics. At the Portsmouth-based glaucoma refinement scheme (Trickha et al 2012) designated refinement scheme optometrist examined the patients followed by a standard Humphrey 24-2 visual field (SITA fast) (Carl Zeiss Meditec,Dublin, CA, USA), applanation tonometry assessment of IOP (Goldmann model; Haag-Streit, Bern, Switzerland), and a digital disc photograph (Topcon, Tokyo, Japan). All the information is processed digitally to a named consultant, who takes the decision at a specially designated virtual glaucoma clinic, whether the patient needs an appointment at the HES or can be discharged and followed up in the community by a community optometrist. In this project only 11 % of the referrals to the virtual clinic needed an appointment in the HES and the other 89% did not need it. The positive predictive rate of the refinement scheme was 0.78 compared to 0.37 for the unrefined one.

Teleophthalmology: Eye Care in the Community

http://dx.doi.org/10.5772/55788

11

In addition to refining patient referrals, teleophthalmology can be used for glaucoma patients follow up in the community. In a study performed by Bunduchi et al. (2010) in Scotland, stable glaucoma patients were followed up in the community by a designated optometrist.They had visual acuities, visual fields test, intraocular pressure measurement and fundus photograph of the eye done at a local optometrist sometimes many miles away from the HES. All the information was transferred via secure electronic information exchange system to the hospital where the information was assessed by the consultant or trained hospital staff at a virtual glaucoma clinic. In the virtual glaucoma clinic more patients can be assessed compared to a standard glaucoma clinic. In this way more slots were available for the unstable glaucoma patients. This can reduce the waiting time for follow up appointments and reduce the necessity for the patients to travel long distances usually every 6 months with all the associated

Teleophthalmology provides the opportunity of setting up an efficient glaucoma referral refinement and follow up system under the care of consultant ophthalmologist. In this way patients can receive quality specialised hospital services in their local community without the need for travel. This can lead to savings for the NHS and the patient, as it can increase the

The optical coherence tomography (OCT) is the gold standard for diagnosis and follow up of many macular diseases. Many community optometry practices have OCT machines currently. In a study performed by Kelly at al. (2011) fundus photos and OCT scans were transferred by secure file transfer email (National Health Service or NHS mail) to the hospital ophthalmolo‐ gist. The images transferred via email are with superior quality compared to the standard method of communication (faxing) and are much faster than posting of hard copies or using a CD. In 96 % of cases in this study analysis of the referrals and a working diagnosis/care pathway was provided by the ophthalmologist to the optometrist within the next calendar day. In the cases where ophthalmic examination was required patients were referred through the GP. In some cases on the basis of information provided by the optometrist urgent oph‐

drawbacks.

capacity of the existing glaucoma services.

thalmology appointments were scheduled.

**2.3. Teleophthalmology and macular diseases**

With an aging population (baby-boomers are currently retiring) and financial strain on the NHS hospital services, new technological and organizational solutions are in need of imple‐ mentation to solve the capacity problems brought about by an increased demand on services. Involving optometrists as part of a team is one potential solution. To ensure that quality is guaranteed, this can be done under the direct supervision of the consultant ophthalmologist (or other trained HES trained staff) with the help of an IT teleophthalmology connection between them. In addition to assisting the Hospital Eye Service by using the human, techno‐ logical and the space capacity available at the optometry practices in urban areas, teleoph‐ thalmology provides invaluable benefits in rural areas. The availability of ophthalmology services at the community reduces the need of transport (cost and carbon emissions) and reduces the inconvenience (need of accompanying relative/ absence from work).

For example in the Hywel Dda Health Board, patients from Wales have to travel sometimes more than 1 hour in each direction for a HES appointment. Ophthalmology patients are usually elderly, some with impaired eyesight and not fit to drive. Even if they are fit to drive they usually need somebody accompanying them, because of the need for pupillary dilation. Very often the general health of these patients is impaired as well which makes the journeys even more unpleasant and add to the psychological burden on the patient. Many of the ophthal‐ mology conditions are chronic and need multiple follow up appointments (sometimes monthly visits) or on a lifelong basis (for example glaucoma). Waiting times for optometric appointments are usually a few days and these practices are situated in the community.

The teleophthalmology connection between HES and optometry practices can be significant‐ ly helpful in managing patients with 1) Glaucoma 2) Macular diseases 3) Emergency eye conditions.

#### **2.2. Teleophthalmology in glaucoma patients**

Management of patients with glaucoma and ocular hypertension is a significant part of the everyday workload in the glaucoma clinics. The North London Eye study and other population based surveys estimate that patients with ocular hypertension or primary open angle glaucoma (POAG) will increase by one third by 2021, as demonstrated by Morley and Murdoch (2006). According to Lockwood et al (2010) the positive predictive rate in the diagnosis of glaucoma and ocular hypertension was 0.37 before the National Institute of Clinical Excellence (NICE) guidelines published in April 2009 and has dropped to 0.2 after that. There are several glaucoma refinement schemes such as the Manchester, and Carmarthenshire Refinement Scheme, which rely on a specially trained optometrist to reduce the number of false positive glaucoma referrals and increase the positive predictive rate of HES referrals as described by Hensen et al (2003) and Devarajan et al (2011).In these schemes specially trained optometrists take the decision on which patients are to be referred to HES and which have to be discharged. Teleophthalmology provides us with the opportunity for these patients to be reviewed directly by the consultant and the HES staff who are already trained to do this by using virtual glaucoma clinics. At the Portsmouth-based glaucoma refinement scheme (Trickha et al 2012) designated refinement scheme optometrist examined the patients followed by a standard Humphrey 24-2 visual field (SITA fast) (Carl Zeiss Meditec,Dublin, CA, USA), applanation tonometry assessment of IOP (Goldmann model; Haag-Streit, Bern, Switzerland), and a digital disc photograph (Topcon, Tokyo, Japan). All the information is processed digitally to a named consultant, who takes the decision at a specially designated virtual glaucoma clinic, whether the patient needs an appointment at the HES or can be discharged and followed up in the community by a community optometrist. In this project only 11 % of the referrals to the virtual clinic needed an appointment in the HES and the other 89% did not need it. The positive predictive rate of the refinement scheme was 0.78 compared to 0.37 for the unrefined one.

In addition to refining patient referrals, teleophthalmology can be used for glaucoma patients follow up in the community. In a study performed by Bunduchi et al. (2010) in Scotland, stable glaucoma patients were followed up in the community by a designated optometrist.They had visual acuities, visual fields test, intraocular pressure measurement and fundus photograph of the eye done at a local optometrist sometimes many miles away from the HES. All the information was transferred via secure electronic information exchange system to the hospital where the information was assessed by the consultant or trained hospital staff at a virtual glaucoma clinic. In the virtual glaucoma clinic more patients can be assessed compared to a standard glaucoma clinic. In this way more slots were available for the unstable glaucoma patients. This can reduce the waiting time for follow up appointments and reduce the necessity for the patients to travel long distances usually every 6 months with all the associated drawbacks.

Teleophthalmology provides the opportunity of setting up an efficient glaucoma referral refinement and follow up system under the care of consultant ophthalmologist. In this way patients can receive quality specialised hospital services in their local community without the need for travel. This can lead to savings for the NHS and the patient, as it can increase the capacity of the existing glaucoma services.

#### **2.3. Teleophthalmology and macular diseases**

which has increased referrals into HES from primary care. In addition, increased workload from the Vasoactive Endothelial Growth Factor antagonist treatment of wet age related macular disease has overloaded the service due to the demands of monthly OCT scanning and injections. This service is now affecting appointments in general ophthalmology clinics where

With an aging population (baby-boomers are currently retiring) and financial strain on the NHS hospital services, new technological and organizational solutions are in need of imple‐ mentation to solve the capacity problems brought about by an increased demand on services. Involving optometrists as part of a team is one potential solution. To ensure that quality is guaranteed, this can be done under the direct supervision of the consultant ophthalmologist (or other trained HES trained staff) with the help of an IT teleophthalmology connection between them. In addition to assisting the Hospital Eye Service by using the human, techno‐ logical and the space capacity available at the optometry practices in urban areas, teleoph‐ thalmology provides invaluable benefits in rural areas. The availability of ophthalmology services at the community reduces the need of transport (cost and carbon emissions) and

For example in the Hywel Dda Health Board, patients from Wales have to travel sometimes more than 1 hour in each direction for a HES appointment. Ophthalmology patients are usually elderly, some with impaired eyesight and not fit to drive. Even if they are fit to drive they usually need somebody accompanying them, because of the need for pupillary dilation. Very often the general health of these patients is impaired as well which makes the journeys even more unpleasant and add to the psychological burden on the patient. Many of the ophthal‐ mology conditions are chronic and need multiple follow up appointments (sometimes monthly visits) or on a lifelong basis (for example glaucoma). Waiting times for optometric appointments are usually a few days and these practices are situated in the community.

The teleophthalmology connection between HES and optometry practices can be significant‐ ly helpful in managing patients with 1) Glaucoma 2) Macular diseases 3) Emergency eye

Management of patients with glaucoma and ocular hypertension is a significant part of the everyday workload in the glaucoma clinics. The North London Eye study and other population based surveys estimate that patients with ocular hypertension or primary open angle glaucoma (POAG) will increase by one third by 2021, as demonstrated by Morley and Murdoch (2006). According to Lockwood et al (2010) the positive predictive rate in the diagnosis of glaucoma and ocular hypertension was 0.37 before the National Institute of Clinical Excellence (NICE) guidelines published in April 2009 and has dropped to 0.2 after that. There are several glaucoma refinement schemes such as the Manchester, and Carmarthenshire Refinement Scheme, which rely on a specially trained optometrist to reduce the number of false positive glaucoma referrals and increase the positive predictive rate of HES referrals as described by Hensen et al (2003) and Devarajan et al (2011).In these schemes specially trained optometrists take the decision on which patients are to be referred to HES and which have to be discharged.

reduces the inconvenience (need of accompanying relative/ absence from work).

glaucoma patients are seen.

10 Telemedicine

conditions.

**2.2. Teleophthalmology in glaucoma patients**

The optical coherence tomography (OCT) is the gold standard for diagnosis and follow up of many macular diseases. Many community optometry practices have OCT machines currently. In a study performed by Kelly at al. (2011) fundus photos and OCT scans were transferred by secure file transfer email (National Health Service or NHS mail) to the hospital ophthalmolo‐ gist. The images transferred via email are with superior quality compared to the standard method of communication (faxing) and are much faster than posting of hard copies or using a CD. In 96 % of cases in this study analysis of the referrals and a working diagnosis/care pathway was provided by the ophthalmologist to the optometrist within the next calendar day. In the cases where ophthalmic examination was required patients were referred through the GP. In some cases on the basis of information provided by the optometrist urgent oph‐ thalmology appointments were scheduled.

In the last few years wet age related macular degeneration (AMD) and the intravitreal anti-VEGF injection treatment has put unprecedented strain on the ophthalmology services worldwide. Even when the patients do not need treatment they have to be followed up on monthly basis, because of the possibility of recurrence. Stable wet AMD patients can be followed up locally with their community optometrist. Optometrists can examine the patients; take OCT scans and fundus photos and all this information can be transferred digitally via secure connection to the eye clinic. Consultants or other trained staff at the HES virtual AMD clinic can assess the information and manage the patients appropriately. In this way the current capacity of the eye clinics can be increased.

transferred to a grading centre in Cardiff. In Exeter there is a mobile glaucoma service which has been developed to provide additional clinic capacity, run by Glaucoma Nurse Practition‐ ers. In York there is a Box Van where patients are seen to have OCT scanning and lucentis

Teleophthalmology: Eye Care in the Community

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13

In Wales all diabetic patients undergo annual screening in local community hospitals or GP surgeries depending on the rural location. Digital fundus imaging is carried out with dilated pupils. The photographs are saved onto laptops with strict security access codes. Images are stored in data centres in North Wales, (Canaervon), Mid and South West Wales (Carmarthen) and Trefforest near Cardiff at Fairway Court which is the main centre to which all images are sent for data backup. These centres are linked through a DAWN2METRO VPN. Graders at

Any patients with sight threatening diabetic retinopathy are referred to their local eye clinic by a fax or letter referral depending on the urgency and the patients are seen appropriately in specialised diabetic eye clinics within the hospital eye service. Patients with background diabetic retinopathy or no retinopathy at all have annual follow up screening assessments. This has proved to be a world class, efficient and well coordinated screening service for all diabetics in Wales. Consultant Ophthalmologists throughout Wales have regular group meetings to discuss how the service is to be delivered and improved, and provide regular training for all the Graders at Trefforest. In addition, it has standardised ophthalmic care for diabetics throughout the whole country. Consultants may view images at the local Screening Centre. There are now developments in place to allow the images to be digitally transferred to individual clinics from the main centre, so Consultants can visualise them in the clinic setting

This service was set up to screening for new referrals and follow up care of stable patients according to NICE standards The Royal Devon & Exeter Hospital Wonford have a dedicated Mobile Eye Unit which goes out across the community which screens new referrals and provides follow up care of stable patients. It is Nurse led, the Specialist Glaucoma Nurses

injections in the van.

**3.1. Diabetic retinopathy screening service for Wales**

Trefforest carry out primary and secondary retinal screening.

**3.2. Exeter mobile glaucoma service**

**•** Visual field assessments,

**•** Goldman tonometry,

**•** Pupil assessment,

**•** Heidelberg Retinal Tomography,

**•** visual acuity,

**•** gonioscopy,

**•** Pachymetry,

carrying out investigations in the mobile unit including:

#### **2.4. Teleophthalmology and urgent ophthalmology referrals**

Many of the patients with eye complaints present initially at the optometrists practices. Sometimes the cases can be solved just with the advice of the ophthalmologist. The percentage of these cases can be increased significantly by using the opportunities of teleophthalmology. In this way unnecessary appointments at the HES and travel can be avoided. If emergency phone calls from the optometrists are accompanied by anterior segment photo or fundus photo the hospital ophthalmologist will receive much more information and can take immediate decision in most of the cases, whether to see the patient as an emergency or even to give appropriate management plan to the optometrist.

Most of the referral to the HES, even if they come from the GP are seen prior by their optom‐ etrists. If most of the referrals are accompanied by digital information received at the hospital the prioritisation consultant can more easily detect urgent cases, so they can receive sooner appointment.

Optometrists have the expertise to manage ophthalmology patients and with the help of teleophthalmology technology these skills can be expanded. The variety of patients managed in the community setting under the direct teleophthalmology supervision of a hospital consultant can be increased. In this way more resources at the hospitals can be spared for more challenging cases. On the other hand patients can receive high quality hospital service at their local community.


*4.3. Presence of Ultramafic Rocks*

From the seismic section that crosses the São Francisco Craton from East to West (Figure 1b), the interpretations done by several authors agree on the identification of the Bambuí group (Figure 3). This unit is about 1200–1300 m deep in the area of the H2G seepage zone and lies on the Jequitaí formation which itself lies on the poorly identified older Proterozoic succession, the Macaúbas and possibly the Espinhaço formations (Solon et al., 2015 [23]).

**Figure 3.** Three interpretations of the same reflection seismic section across the São Francisco craton (see Figure 1b for the location) from East "E" to West "W". From top to bottom: (**a**) Romeiro-Silva and Zalán (2005 [24]), (**b**) Coelho et al. (2008 [39]) and (**c**) Alkmim and Martins-Neto (2012 [40]). The locations of the exploration well A-RF-1-MG are shown in (**a**) and the gas seepage H2G (blue triangle) is reported for all cases. On all illustrations, the depth is expressed in two-way travel time (TWT).

The basal Paranoá–Upper Espinhaço sequence consists of continental sediments and volcanic rocks associated with anorogenic plutons. Mesoproterozoic anorogenic magmatism associated with multiple rifting episodes might represent a manifestation of the Columbia supercontinent breakup, which started around 1.6 Ga and ended between 1.3 and 1.2 Ga (Reis et al., 2017a, b [41,42]). The Espinhaço Supergroup is exposed on the East of the São Francisco Basin. The two basal formations of the Espinhaço sequence are composed of alluvial sandstones, conglomerates and pelites and form a ca. 300-m-thick of two coarsening-upward sequences. Despite the potential presence of K-rich alkaline volcanic and intrusives rocks (Chemal et al., 2012 [43]), this formation does not seem suitable for H2 production.

The basement rocks of the São Francisco basin are dominated by Archaean to Palaeoproterozoic migmatites, amphibolite to granulite-grade gneisses, and granite–greenstones (Teixeira et al., 2017 [20]). For example, the Rio Itapicuru low-grade supra-crustal greenstone belt has several lithostratigraphic subdivisions, including a basal mafic volcanic unit composed of massive and pillowed basaltic flows intercalated with chert, banded iron-formation, and carbonaceous shale (Oliveira et al., 2019 [44]). The banded iron-formation is mainly composed of oxidized iron Fe(III) forming a possible mix of hematite and magnetite, which can produce a strong magnetic anomaly (Pereira and Fuck, 2005 [45]) (purple zones in Figure 4).

**Figure 4.** Magnetometric map (modified from Correa, 2019 [46]). Note that "MG" stands for "Minas Gerais".

In this area, the Bouguer anomaly map exhibits predominantly negative anomalies (Figure 5) which correlate with granitoids resulting from the crustal rejuvenation of the area, associated with partial re-fusion of the crust during past thermal events. This also suggests that major magmatic sequences affected the basement of the southern part of the São Franscico Basin, which is compatible with the magnetic anomalies (Figure 4). Since the Quadrilátero Ferrífero (a mineral-rich region with extensive deposits of iron ore) and the "greenstone" belts present the same gravimetric signature, they could have the same origin (Pinto et al., 2007 [47]). Here again, the basement rock composition presents a high potential for H2 production.


**3. Results and Discussion**

Aluminum alloys are known for their high affinity to hydrogen at high temperature, promoting the appearance of numerous inclusions in the microstructure after solidification, with porosity being the most relevant and harmful defect compromising the strength of the component [4,30,31]. To assess the similarity of the porosity levels in samples, the melts were degassed before pouring at the desired temperature (700 ± 5 ◦C [31]), using the Multi-Mode Frequency, Modulated (MMM) ultrasonic technology, to ensure that the density of the bath was identical for every experiment. The average density reached in the experiments was 2.68 ± 0.1 (0.5% ± 0.07 porosity).

Figure 3 shows the variation of the α-Al grain size and circularity of AlSi7Mg0.3 alloy processed by ultrasound, with an average frequency of 19.9 ± 0.2 kHz and 40% of the system power (400 W—corresponding to approximately 60 μm), evaluated in a longitudinal section of the feeder (V#1 to V#3 samples, according to Figure 1). The respective microstructures are shown in Figure 4a–c.

**Figure 3.** Variation of the α-Al grain size and circularity with the distance to the acoustic radiator in the feeder.

**Figure 4.** Examples of microstructures of AlSi7Mg0.3 alloy processed by ultrasound, at 19.9 ± 0.2 kHz average frequency evaluated in a vertical section of the feeder: (**a**) V#1; (**b**) V#2 and (**c**) V#3 samples, according to Figure 1.

The experimental results suggest that the feeder (central zone of the feeder and directly below the acoustic radiator) presents a microstructure with a well-defined globular morphology. Overall, the variation of grain size and circularity apparent was minimal, as can confirmed by the standard deviations presented in Figure 3. Indeed, the average grain size and circularity for all characterized positions were, respectively, 120 μm and 0.8. As demonstrated by Puga et al. [32] and Eskin et al. [29] the zone below the flat acoustic radiator is able to promote extremely intense cavitation, being able to

promote nucleation and further to this, an increase in the quantity of α-Al grains, and consequently, the reduction of their diameter and a globular morphology.

Figure 5 shows the variation of the α-Al grain size and circularity of AlSi7Mg0.3 alloy processed by ultrasound, at the average frequency of 19.9 ± 0.2 kHz (resonance frequency at high temperature), with the distance to the acoustic radiator in the feeder (H#1 to H#3 samples, according to Figure 1). The respective microstructures are shown in Figure 6a–c.

**Figure 5.** Variation of the α-Al grain size and circularity with the distance to the acoustic radiator in the feeder.

**Figure 6.** Examples of microstructures of AlSi7Mg0.3 alloy processed by ultrasound, at 19.9 ± 0.2 kHz average frequency evaluated in a horizontal section of the feeder: (**a**) H#1, (**b**) H#2 and (**c**) H#3 samples, according to Figure 1.

The results presented suggest that with increasing distance to the acoustic radiator the α-Al grain size tends to increase, and the grain circularity tends to decrease. Although the grain size tends to increase, the matrix continues to present a quasi-globular morphology with some indications of rosette grains. This is an opposite tendency compared to what happens with the traditional processes of sand casting, where the matrix tends to present a dendritic morphology, even after chemical melt treatments.

Furthermore, the results presented in Figures 5 and 6 suggest that the cooling rate influences the grain morphology. Although the effect of ultrasound promotes a globular matrix, the fast cooling rates in thinner sections (e.g., position H#3 with a section solidification module 0.41) tends to overlap the effect of ultrasound. However, this effect also allows the formation of a thinner but non-dendritic microstructure, which is beneficial for the mechanical properties. However, in sections directly affected by the acoustic radiator (e.g., feeder—Figures 3 and 4), it is suggested that the morphology of the Al matrix (grain size and circularity) may be directly affected by the cavitation mechanism.

Contrary to the traditional process of refinement, where the addition of the master alloy Al-Ti-B is generally used, in the present approach this issue is not considered. Overall, the applied acoustic intensity is sufficient for: (i) converting the displacement of piezoelectric into kinetic energy in the liquid; (ii) creating acoustic cavitation and acoustic streams able to promote the nucleation and homogenization in the melt; (iii) increasing the temperature of the medium due to bubble collapse, which can promote and accelerate the α-Al grains.

A numerical simulation study was performed to validate the aforementioned hypothesis and experimental results. Figure 7 presents the numerical results of the axial displacement (evaluated in solid parts and the acoustic pressure in the melt), for the whole system, when the acoustic radiator was immersed in water at a depth of 15 mm, according to the boundary conditions represented in Figure 2.

**Figure 7.** Numerical results of the solid displacement and acoustic pressure obtained for the ultrasonic system apparatus.

According to the eigenfrequency results of the acoustic radiator, the first longitudinal compression mode was located at 20.23 kHz. This matches well with the operation frequency of the transducer, as can be proved by the experimental electrical impedance results measured by the authors. Thus, in order to numerically quantify the acoustic pressure in the medium, a domain frequency study was performed at *f* 0 = 20.20 kHz. Figure 8a,b presents the numerical values of acoustic pressure along the horizontal section with the distance to the acoustic radiator in the feeder (H#1 to H#2) and the vertical component beneath the feeder (V#1 to V#3).

**Figure 8.** Numerical results of the acoustic pressure obtained in the (**a**) vertical and (**b**) horizontal directions.

As can be observed in Figure 8a, a sinusoidal curve with a positive and negative acoustic pressure of at least 5 MPa in the vertical component is reached in the melt. According to Eskin's work [29] the threshold of acoustic pressure to verify cavitation is around 2 MPa. Indeed, according to experimental results for parameters numerically evaluated, the level of cavitation and acoustic streams at 40% system power (using the same acoustic radiator that numerically simulated) is totally defined, as can be observed in Figure 9. It may be clearly observed that in corresponding conditions (i.e., similar fluid and boundary conditions) that are initially resting (Figure 9a), it is possible to promote streaming and cavitation effects by the use of the detailed ultrasonic system.

**Figure 9.** Photograph of resonance cavitation field in the experimental container (400 W): (**a**) No-US, (**b**) with US activated.

Contrary to high values of acoustic pressure measured along the longitudinal section of the feeder (V#1 to V#3), in the horizontal cylindrical section (H#1 to H#2) the maximum acoustic pressure registered was 1 MPa (Figure 8b). Considering the high level of cavitation and acoustic streams created below the flat surface of the acoustic radiator, as well as the long interval time of solidification, it is suggested that a mixing and distribution of nuclei can travel along the cylindrical shape and contribute to the refining of Al grain reported in results of Figures 5 and 6. Furthermore, according to Figure 10, there is a correlation between the acoustic pressure and the grain size. It is shown that as the pressure increases, the grain size tends to decrease by an exponential decay function.

**Figure 10.** Effect of acoustic pressure versus grain size.

It is suggested that there is a threshold for the acoustic pressure grain refinement effect. In these particular conditions, it is apparent that for acoustic pressures higher than 2 MPa there are no significant benefits in terms of grain refinement.

## **4. Conclusions**

This study explored the influence of acoustic pressure in the overall refinement of sand cast aluminum alloys, using experimental and numerical approaches to detail the overall pressure distribution and distance to acoustic excitation. According to the results, the following conclusions may be drawn:

(1) The mechanism of refinement/modification of the α-Al matrix is a consequence of the acoustic activation caused in the liquid metal directly below the face of the acoustic radiator and is able to be distributed by different mold cavity area branches.

(2) In areas near the feeder there is a clear homogeneity in the morphology of the α-Al with respect to grain size and grain circularity. That is, the influence of the acoustic radiator in the liquid medium immediately below its top flat face is evident.

(3) In areas that are more distant to the feeder, the acoustic pressure directly caused by the acoustic radiator tends not to induce significant alteration in the grain size due to the lower pressure; however, this is compensated for by the higher cooling rates.

(4) Knowledge of the acoustic pressure profile, together with the analysis of the positioning of the acoustic radiator for refinement/modification the α-Al matrix validated through the use of numerical models, will allow high integrity castings to be obtained, with a tendency towards increased mechanical properties when compared to traditional treatment methods.

**Author Contributions:** Conceptualization, V.H.C. and H.P.; Methodology, V.H.P. and H.P.; Validation, H.P. and J.B.; Formal analysis, V.H.C. and H.P.; Resources, H.P.; Data curation, V.H.P. and J.B.; Writing—original draft preparation, V.H.P. and H.P.

**Funding:** This research received no external funding.

**Acknowledgments:** This work was supported by FCT funding through the project PTDC/EMEEME/30967/2017 (NORTE-0145-FEDER-030967) and by FEDER funding through COMPETE 2020, NORTE2020, PORTUGAL2020 – Programa Operacional Competitividade e Internacionalização (POCI). Additionally, this work was supported by FCT with the reference project UID/EEA/04436/2019.

**Conflicts of Interest:** The authors declare no conflicts of interest.


**2. Experimental Methods**

The organic synaptic transistors based on a floating-gate OFET architecture were fabricated with dinaphtho[2,3-b:20 ,30 -f]thieno[3,2-b]thiophene (DNTT) semiconductor (Figure 1a), according to the bottom-gate, top-contact structure depicted in Figure 1b. A key to this device is the utilization of the ultra-thin, flat Al nanolayer, which is surface-oxidized to form an Al/AlOx stack [16]. The device fabrication processes are summarized as follows. The gate substrate is prepared as a flexible and transparent polyethylene terephthalate (PET) sheet, which has a predeposited conducting indium tin oxide (ITO) film (130 nm) (surface resistivity 60 Ω/sq, Sigma-Aldrich). The ITO surface was planarized by a 40-nm thick poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS, Clevios™, Heraeus) buffer layer to reduce the gate leakage. Then, insulating poly(methyl methacrylate) (PMMA, M.W. = 120,000, Sigma-Aldrich) was spin-coated from a toluene solution to serve as a blocking dielectric (410 nm). The Al functional layer with a nominal thickness of 3 nm was thermally evaporated and exposed to ambient air for oxidation. DNTT (sublimed grade, 99%, Sigma-Aldrich) was vacuum-evaporated for a hole-transporting molecular channel (50 nm). Finally, the Au source/drain electrodes (30 nm) were evaporated through a shadow mask. ultra-thin, flat Al nanolayer, which is surface-oxidized to form an Al/AlOx stack [16]. The device fabrication processes are summarized as follows. The gate substrate is prepared as a flexible and transparent polyethylene terephthalate (PET) sheet, which has a predeposited conducting indium tin oxide (ITO) film (130 nm) (surface resistivity 60 Ω/sq, Sigma-Aldrich). The ITO surface was planarized by a 40-nm thick poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS, Clevios™, Heraeus) buffer layer to reduce the gate leakage. Then, insulating poly(methyl methacrylate) (PMMA, M.W. = 120,000, Sigma-Aldrich) was spin-coated from a toluene solution to serve as a blocking dielectric (410 nm). The Al functional layer with a nominal thickness of 3 nm was thermally evaporated and exposed to ambient air for oxidation. DNTT (sublimed grade, 99%, Sigma-Aldrich) was vacuumevaporated for a hole-transporting molecular channel (50 nm). Finally, the Au source/drain electrodes (30 nm) were evaporated through a shadow mask.

bottom-gate, top-contact structure depicted in Figure 1b. A key to this device is the utilization of the

**Figure 1.** (**a**) Chemical structure of dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT), used as an active molecular material in organic synaptic transistors. (**b**) Cross-sectional illustration of the device structure. (**c**) Circuit diagram employed for the measurement of voltage-dependent synaptic plasticity. (**d**) Model illustration: Biological processes relevant to the neuronal signal transmission through release and re-uptake of neurotransmitters and the electronic processes that mimic such properties through trapping-mediated hole transport at the semiconductor channel. **Figure 1.** (**a**) Chemical structure of dinaphtho[2,3-b:20 ,30 -f]thieno[3,2-b]thiophene (DNTT), used as an active molecular material in organic synaptic transistors. (**b**) Cross-sectional illustration of the device structure. (**c**) Circuit diagram employed for the measurement of voltage-dependent synaptic plasticity. (**d**) Model illustration: Biological processes relevant to the neuronal signal transmission through release and re-uptake of neurotransmitters and the electronic processes that mimic such properties through trapping-mediated hole transport at the semiconductor channel.

For emulating the STP behavior, we used the quasi-two-terminal electrical configuration shown in Figure 1c. Here, the gate and drain electrodes were externally wired and connected to a common computer controlled source-measure unit (Keithely 2400). The synaptic voltage (*V*syn) pulses were generated by using a LabVIEW code, for them to have a specific number of sharp spike-like electrical stimulation stages with varying frequencies. The synaptic current (*I*syn) was measured as a function of time as the output signal. For emulating the STP behavior, we used the quasi-two-terminal electrical configuration shown in Figure 1c. Here, the gate and drain electrodes were externally wired and connected to a common computer controlled source-measure unit (Keithely 2400). The synaptic voltage (*V*syn) pulses were generated by using a LabVIEW code, for them to have a specific number of sharp spike-like electrical stimulation stages with varying frequencies. The synaptic current (*I*syn) was measured as a function of time as the output signal.

#### **3. Results and Discussion 3. Results and Discussion**

Materials characterization including atomic force microscopy (AFM) and transmission electron microscopy (TEM) as well as the basic transistor characterization such as transfer, output, mobility measurements has been reported in our previous paper [16]. Here, we introduce a numerical model that is applied to analyze the experimental STP. It is based on the functional model initially developed for nanoparticle organic memory field-effect transistors (NOMFET), by Bichler and co-workers [21]. In this study, we modify the notations and introduce the correlative parametrization approach, so Materials characterization including atomic force microscopy (AFM) and transmission electron microscopy (TEM) as well as the basic transistor characterization such as transfer, output, mobility measurements has been reported in our previous paper [16]. Here, we introduce a numerical model that is applied to analyze the experimental STP. It is based on the functional model initially developed for nanoparticle organic memory field-effect transistors (NOMFET), by Bichler and co-workers [21]. In this study, we modify the notations and introduce the correlative parametrization approach, so that

it can better describe our synaptic devices. Let's first recapitulate the physical meaning of such a model, by drawing a parallel between a biological synapse and a synaptic transistor channel. As shown in Figure 1d, the communication through a biological synapse is signaled by the action potential of the presynaptic neuron, which in turn activates the release of neurotransmitters toward the postsynaptic neuron. Part of these chemical messengers are eventually pulled back into the presynaptic neuron through re-uptake. Therefore, a specific time-domain pattern of neural signals conditions the dynamic variation of synaptic strength. Similarly, in our OFETs, holes accumulated at the DNTT channel serve as electronic signal carriers. Since the *V*syn is bound to drain and gate, part of the transporting holes are trapped into the Al floating gate when a spike arrives. These trapped carriers can be easily detrapped into the channel, which is a key feature of our transistors with an ultra-thin tunnel oxide. Therefore, the STP behavior can be emulated by adjusting the input *V*syn pulses.

For the square-type input *V*syn waveform consisting of varying frequency and duty cycles, the direct relationship between the *n*th synaptic current *In* and the (*n* + 1)th one *I*n+1 can be iteratively established. As an intermediate, the current *In*+ is the value at the falling edge of each synaptic spike and is dictated by how much the floating gate is charged during that pulse, which is written as

$$I\_{n+} = I\_n \exp\left(-\frac{\mathcal{W}}{\tau\_t}\right) + I\_0 \left[\exp\left(-\frac{\Delta E\_F}{kT}\right) \left\{1 - \exp\left(-\frac{\mathcal{W}}{\tau\_t}\right)\right\}\right] \tag{1}$$

where *W* is the activation pulse width, τ*t* is the trapping time constant, *I*0 is the initial current, ∆*EF* is the semiconductor Fermi-level shift at the fully charged state of the floating gate, *k* is the Boltzmann constant, and *T* is the absolute temperature. Between two pulses (while *V*syn = 0 V), the carriers now leave the floating gate by natural detrapping, partially recovering the channel current, expressed as

$$I\_{n+1} = I\_{n+} \exp\left(-\frac{T\_p - \mathcal{W}}{\tau\_d}\right) + I\_0 \left[1 - \exp\left(-\frac{T\_p - \mathcal{W}}{\tau\_d}\right)\right] \tag{2}$$

where *Tp* is the pulse time period and τ*d* is the detrapping time constant. Merging Equations (1) and (2) gives the final model

$$I\_{n+1} = I\_{\rm tr} \exp\{-\frac{\mathcal{W}}{\tau\_{\rm t}}\} \exp\{-\frac{T\_{\rm f} - \mathcal{W}}{\tau\_{\rm d}}\} + I\_0 \left[\exp\{-\frac{\Lambda E\_F}{kT}\} \{1 - \exp\{-\frac{\mathcal{W}}{\tau\_{\rm t}}\}\} \exp\{-\frac{T\_{\rm f} - \mathcal{W}}{\tau\_{\rm d}}\} + \left\{1 - \exp\{-\frac{T\_{\rm f} - \mathcal{W}}{\tau\_{\rm d}}\}\right\}\right].\tag{3}$$

To gain insights into the voltage-dependent signal transmission properties, we experimentally recorded the STP behavior of the same transistor, at four different magnitudes of *V*syn as −4, −6, −8, and −10 V. The composition of the input signals (i.e., the frequency sequence and the number of spikes at each stage) was kept the same except for the voltage magnitude. Our test input waveforms consisted of six stages with the frequencies of 5, 1, 0.2, 2, 4, and 0.5 Hz. These frequencies determine the value of *Tp*, and *W* was fixed as 20 ms. Therefore, the remaining task in modeling is to fit the experimental *I*syn data by determining four parameters, which are *I*0, ∆*EF*, τ*t* , and τ*d*. Instead of setting all these fitting parameters free, we employed a correlative extraction approach for more physically reliable results. The main idea is that the asymptotic final current *I*0exp(−∆*EF*/*kT*) should reflect the same amount of trapped carriers, and therefore have a quadratic dependence on the *V*syn magnitude considering the forced saturation-regime transistor operation. To systematically apply this method, we first extracted the four fitting parameters from the data set at the lowest value of *V*syn = −4 V. Then, we calculated the *I*0exp(−∆*EF*/*kT*) value for *V*syn = −4 V, and then let this base asymptotic limit quadratically increase with increasing *V*syn. Therefore, for the three other data sets (*V*syn = −6, −8, and −10 V), the apparent initial *I*0 value together with the prefixed *I*0exp(−∆*EF*/*kT*) value allowed for the unambiguous calculation of ∆*EF* for each *V*syn.

Figure 2a shows that *I*0 monotonously increases in magnitude with increasing *V*syn values, which is accounted for by the channel current flow enhanced by both gate (free carrier density) and drain voltages (lateral electric field) [18]. Interestingly, the ∆*EF* follows a similar trend before experiencing a small drop at a high *V*syn. This evidences that gate-induced trapping (decreasing the free carriers) and gate-enhanced hole accumulation act together to set the right balance for the Fermi level approachable at the fully charged state [22]. The inset of Figure 2a confirms that the magnitude of *V*syn and the asymptotic synaptic current follows the quadratic dependence, evidenced by slope 2 on this log-log representation. a small drop at a high *V*syn. This evidences that gate-induced trapping (decreasing the free carriers) and gate-enhanced hole accumulation act together to set the right balance for the Fermi level approachable at the fully charged state [22]. The inset of Figure 2a confirms that the magnitude of *V*syn and the asymptotic synaptic current follows the quadratic dependence, evidenced by slope 2 on this log-log representation.

**Figure 2.** (**a**) The change of *I*0 and Δ*EF* as a function of voltage, estimated by the correlative approaches. Inset: the log-log plot showing the quadratic dependence of the final current on the synaptic voltage. (**b**) The extracted time constants for the trapping and detrapping processes. **Figure 2.** (**a**) The change of *I*0 and ∆*EF* as a function of voltage, estimated by the correlative approaches. Inset: the log-log plot showing the quadratic dependence of the final current on the synaptic voltage. (**b**) The extracted time constants for the trapping and detrapping processes.

Having determined the values of *I*0 and Δ*EF*, the two timing constants were estimated by performing global fitting to the experimental results. Figure 2b shows that despite the ultra-thin nature of our AlOx favoring spontaneous relaxation, the detrapping time constant *τd* is greater than the trapping counterpart *τt* at all voltage biases considered. Another important finding here is that the magnitude of *V*syn can substantially influence the ratio between *τd* and*τt* values, implying a direct impact on the STP modulation. Having determined the values of *I*0 and ∆*EF*, the two timing constants were estimated by performing global fitting to the experimental results. Figure 2b shows that despite the ultra-thin nature of our AlOx favoring spontaneous relaxation, the detrapping time constant τ*d* is greater than the trapping counterpart τ*t* at all voltage biases considered. Another important finding here is that the magnitude of *V*syn can substantially influence the ratio between τ*d* and τ*t* values, implying a direct impact on the STP modulation.

Figure 3 shows the direct comparison between the experimental STP results and the model currents reproduced by inserting the parameters in Figure 2 into Equation (3). Similar STP behaviors have been observed in several field-effect synaptic transistors [14–16]. In brief, we can notice that even with the constant magnitude of *V*syn, the produced *I*syn quite significantly changes its magnitude responding to the spiking frequency. At a high *V*syn frequency, a monotonous decrease in current is monitored because the negative gate pulse traps holes from the channel into the floating gate. When this frequency decreases, the amount of holes escaping the traps (per time) can exceed that of the holes being trapped into the floating gate, so that the *I*syn gradually recovers its strength. In Figure 3, the model-calculated values are in a broad agreement with the measurements, and showed a similar trend in STP modulation. With increasing *V*syn, the overall magnitude of output current *I*syn went up, and it was necessary to introduce different timing parameters at each test voltage to fully explain the voltage-dependent transmission behavior. As shown in Figure 2b, the evolution of *τd* was more dramatic than that of *τt*, which is reflected in Figure 3 as the suppressed potentiation at *V*syn = −8 or −10 V. This result also indicates that further optimization in synaptic voltages or structural engineering of nanoscale trapping media [23] may enable a switchable short-term and long-term neuromorphic behavior out of the same base architecture. Figure 3 shows the direct comparison between the experimental STP results and the model currents reproduced by inserting the parameters in Figure 2 into Equation (3). Similar STP behaviors have been observed in several field-effect synaptic transistors [14–16]. In brief, we can notice that even with the constant magnitude of *V*syn, the produced *I*syn quite significantly changes its magnitude responding to the spiking frequency. At a high *V*syn frequency, a monotonous decrease in current is monitored because the negative gate pulse traps holes from the channel into the floating gate. When this frequency decreases, the amount of holes escaping the traps (per time) can exceed that of the holes being trapped into the floating gate, so that the *I*syn gradually recovers its strength. In Figure 3, the model-calculated values are in a broad agreement with the measurements, and showed a similar trend in STP modulation. With increasing *V*syn, the overall magnitude of output current *I*syn went up, and it was necessary to introduce different timing parameters at each test voltage to fully explain the voltage-dependent transmission behavior. As shown in Figure 2b, the evolution of τ*d* was more dramatic than that of τ*t* , which is reflected in Figure 3 as the suppressed potentiation at *V*syn = −8 or −10 V. This result also indicates that further optimization in synaptic voltages or structural engineering of nanoscale trapping media [23] may enable a switchable short-term and long-term neuromorphic behavior out of the same base architecture.

*Electronics* **2020**, *9*, 4 5 of 6

**Figure 3.** Comparing the experimental and model-reproduced STP (short-term plasticity) in organic synaptic transistors, with the magnitude of *V*syn being (**a**) −4 V, (**b**) −6 V, (**c**) −8 V, and (**d**) −10 V. The test measurements consisted of six steps, the frequencies of which are denoted in (a). The same test condition applies to all the other panels. **Figure 3.** Comparing the experimental and model-reproduced STP (short-term plasticity) in organic synaptic transistors, with the magnitude of *V*syn being (**a**) −4 V, (**b**) −6 V, (**c**) −8 V, and (**d**) −10 V. The test measurements consisted of six steps, the frequencies of which are denoted in (a). The same test condition applies to all the other panels.

#### **4. Conclusion 4. Conclusions**

We have reported on a combined experimental and theoretical analysis of the voltage-dependent synaptic plasticity in flexible OFETs. An iterative model was used in conjunction with the correlative extraction to understand the STP characteristics at different voltages. It was found that the applied voltage has a significant impact on *I*0, Δ*EF*, and timing constants. Among them, the *τd* experienced a particularly remarkable rise, turning the device into a practically depressing synapse at large voltages. At the same time, we have noticed the limited applicability of the model, evidenced by fitting errors. This indicates that an advanced model will need to be developed based on the physical characteristics of each complex trapping mechanism, which may for instance include the multiple time constants with a direct functional link to the materials and operational conditions. We have reported on a combined experimental and theoretical analysis of the voltage-dependent synaptic plasticity in flexible OFETs. An iterative model was used in conjunction with the correlative extraction to understand the STP characteristics at different voltages. It was found that the applied voltage has a significant impact on *I*0, ∆*EF*, and timing constants. Among them, the τ*d* experienced a particularly remarkable rise, turning the device into a practically depressing synapse at large voltages. At the same time, we have noticed the limited applicability of the model, evidenced by fitting errors. This indicates that an advanced model will need to be developed based on the physical characteristics of each complex trapping mechanism, which may for instance include the multiple time constants with a direct functional link to the materials and operational conditions.

**Author Contributions:** Conceptualization, S.L. and C.-H.K.; methodology, C.-H.K.; validation, S.L. and C.-H.K.; formal analysis, S.L. and C.-H.K.; investigation, S.L. and C.-H.K.; writing—original draft preparation, C.-H.K.; writing—review and editing, S.L. and C.-H.K. All authors have read and agreed to the published version of the manuscript. **Author Contributions:** Conceptualization, S.L. and C.-H.K.; methodology, C.-H.K.; validation, S.L. and C.-H.K.; formal analysis, S.L. and C.-H.K.; investigation, S.L. and C.-H.K.; writing—original draft preparation, C.-H.K.; writing—review and editing, S.L. and C.-H.K. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the Gachon University research fund of 2019 (GCU-2019-0361), and also by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-**Funding:** This work was supported by the Gachon University research fund of 2019 (GCU-2019-0361), and also by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2019R1C1C1003356).

2019R1C1C1003356). **Conflicts of Interest:** The authors declare no conflict of interest. **Conflicts of Interest:** The authors declare no conflict of interest.


**5. Dislocation Emission from Grain Boundaries in Nanocrystalline Materials**

Finally, utilizing the brief discussion provided in previous sections we consider the Dislocation Emission from GBs in NC materials in some detail. Rapid development of NC materials has raised the question of the role that dislocation pile-ups and other modes of dislocation production play in determining the strength of the materials, vis-a-vis the HP effect. For this purpose, we divide the region in two subsections. First, we consider deformation mechanisms, ultrafine grains, typically between 20 to 100 nm, and later grains finer than that.