\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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To make an information system that can recognize human emotion requires elemental technologies such as natural language understanding, social computing, etc.
\r\n\r\n\tThis book gives a lot of knowledge of the latest information processing and artificial intelligence techniques that can be applied to the recognition of human emotion. The main topics include text understanding, emotion recognition and generation from a text by using information processing and artificial intelligence techniques. Besides, other themes such as social media analysis, nursing management systems and applications of sentiment analysis in corporations are included.
\r\n\r\n\tRelated fields or theme also include: affective computing, sentiment analysis systems, sentiment analysis text mining, natural language processing, information retrieval, information extraction advanced intelligence, neural computing, deep learning, cloud computing, swarm intelligence chatbot, personality analysis, dialogue breakdown, dialogue control nursing management systems, clinical pathways systems, medical text mining.
\r\n\t
The bulk of milk production in the world is supplied from the cows. Besides the fact that genetic is the most important factor in a cow’s milk productivity; feeding and environmental factors are also considered as crucial factors. Because of these points, calving and increasing reproductive performance has become the most fundamental issue for milk industry. For the animal breeders both having milk and obtaining a calf throughout a year is indispensable. To accomplish this, there should not be a problem in a herd from the aspect of reproduction. But many factors like diseases and environmental agents in cows in post partum period cause decrease in fertility. Among the reasons of reduction in fertility; there are factors like indetermination of estrus in time or detection of estrus in wrong time, premature estrus, subestrus, anestrus, delaying of ovulation, failure of ovulation and fertilization, inadequacy of communication between embryo and uterus, poor body condition score, heat stress, dystocia, retained placenta, delayed uterine involution, metritis, endometritis, and other illnesses. Although a great deal of studies has been done to lower the infertility caused by these factors, this problem has not been eradicated completely up to these days [1-6].
The reasons mentioned above are associated with female animals and environmental conditions. Together with this, fertility is dependent not only to the female but also to the male. There should not be a problem in male’s genital organs and the male must have the ability to produce sperms to fertilize the ovum. If artificial insemination is carried out, morphologic structures, numbers, motilities of the sperms should be normal [7-10].
Progestagens and Prostaglandin F2 alpha (PGF2α) have been used to prevent the disorders related to estrus. But observation of estrus is necessary in both administrations. For this reason researchers have dealt with developing protocols without estrus observation. Ovulations have been synchronized with a method developed in Wisconsin University, and this method was named as Ovsynch. Later, this method has been modified by the combined use of both progestagens and prostaglandins and many modified ovsynch protocols have been derived [11-12].
Nowadays, one of the methods used by the veterinarians to increase the percentage of pregnancy in cows is GnRH and hCG application just before the artificial insemination, together with the insemination or 1st – 15th days after insemination because hormonal balance is very crucial in early embryonic period. Nearly, 25% of cattle embryos die within the first three weeks of pregnancy [4, 13-15]. In this period, continuation of progesterone release by corpus luteum is vital for the life of embryo [16]. For this reason, researchers have strived to keep the progesterone level sufficient enough in early pregnancy by administering GnRH and hCG in different days of estrus cycle. hCG application is done to animals during the insemination or luteal period in order to provide the rupture of Graafian follicle, to abolish functional insufficiencies of corpus luteum and to rise the endogenous progesterone production to the most effective level, and as a result of these applications it has been stated that pregnancy rate has increased in some studies [17-18]. In the same way, with the GnRH application before, during and post insemination in different days, it has been notified that pregnancy rate has been increased by means of stimulating folliculogenesis, ovulation and luteal structures [19-21].
The latest method to regulate maternal and fetal relation, to retard or inhibit luteolysis, to maintain high progesterone levels and as a result; to enhance pregnancy rate is application of Nonsteroid Anti-inflammatory Drugs (NSAID) in critical days of pregnancy. Estrus cycle’s hormonal mechanism should be very well known for the good management of this process.
Cows are polyestrous animals throughout the year. They show estrus within 18-24 day periods only if they are not pregnant. Estrus cycle is controlled and managed by hormones released by hypothalamus, hypophysis, ovaries and uterus [22].
In the start of estrus cycle GnRH plays the most important role [23]. By giving GnRH released from hypothalamus in each 30 – 120 minute periods to hypophysis system, it induces synthesis and release of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). With the FSH effect follicles in the ovaries start to grow. Follicular development is observed in waves. In each wave just one follicle passes to dominant state from the many developed follicles, rarely two follicles passes to preovulatory stage. Follicular development or atresia is not seen in other follicles in follicular wave. While estradiol produced from preovulatory follicle induces LH release, it inhibits FSH release [3, 5, 24]. But FSH release is not only regulated by estradiol and GnRH, inhibin which is an ovary originated peptide also inhibits FSH release just like estradiol. Moreover, activin which is a peptide hormone found in follicular liquid induces FSH release, but follistatin inhibits it [5].
Released estrogen both causes physiological changes in genital canal and emergence of overt estrus signs. Ovulation in cows takes place 24 to 30 hours after the peak of LH. Ovulated follicle undergoes structural and functional change with the effect of LH and metamorphoses to corpus luteum. Developing corpus luteum releases progesterone, and so, it makes a negative feedback to hypothalamus and by hindering FSH and LH release it also follicular activities in ovaries. In the meantime, by inhibiting contractions of uterus and stimulating the glands in endometrium, it causes the liquid so called uterus milk to be released. As a result it prepares a suitable ambient and provides the continuation of gestation [5, 22, 25-28].
If there is not a live embryo in uterus in the 16th -18th days of cycle, PGF2α is synthesized, and causes the corpus luteum’s regression and decreases the progesterone secretion. Decrease in progesterone causes LH peak and this increase in LH results in increase of estradiol level. While luteolysis is progressing, a new preovulatory follicle develops and cycle resumes. If the animal gets pregnant, PGF2α secretion is blocked and progesterone level stays in the level enough for sustain the gestation [16, 24, 25, 27].
Gestation is a process which starts with fertilisation and completed with birth of the young. Fertilization is the name given to the event of forming a diploid chromosome cell from two haploid chromosome cells by entering of spermatozoon into oocyte [29].
Fertilization takes place in oviduct ampulla in domestic mammals. It happens approximately in 12 hours. In the end, zygote forms [30-31].
Zygote undergoes a set of mitotic division which is called “segmentation”. With the first segmentation division, blastomere which is a two cell embryo forms. When the blastomeres proliferate in countless numbers it is called morula. Then, water diffusion starts in morula and a liquid filled blank which is called blastocele forms. When this blank forms, embryo is called as blastocyte [30, 32].
When blastocyte undergoes a mitotic division, liquid continues to accumulate in the blastocele and for this reason pressure inside the embryo increases. Proteolytic enzymes and blastocyte contraction and relaxation movements cause the tear of zona pelucida. When there is a little tear in zona pellucida, blastocyte goes out. This prolapsus which is called as hatching takes place between 9th and 11th days in cows. After this stage, embryo lives freely in uterus until implantation and feeds with uterus milk [14, 24, 30, 32].
15th to 17th days of the gestation is considered as the critical period. Embryonic deaths taking place in this stage causes dramatic economic losses. During this period, unless the signal to prevent the production of PGF2α is sent, endometrial luteolytic PGF2α release will be realized. For the continuation of gestation this endometrial PGF2α production must be hindered. Biology of this critical period is complex and affected from very different events. Forming of luteolysis or continuation of gestation is dependent on hormonal, cellular and molecular factors belonging to both mother and the embryo. In order to increase the pregnancy rate in artificial insemination and embryo transfer, hCG, eCG and GnRH applications are done in this critical period. In these applications, while increasing progesterone amount, decreasing plasma estradiol 17 beta amounts and inhibiting PGF2α synthesis from endometrium is aimed [16].
Blockage of luteolysis during the recognition of gestation can be possible by inhibition of estradiol production because existence of estradiol is obligatory for luteolysis. Estradiol induces PGF2α secretion. When compared with cyclic animals, follicular development and concentration of plasma estradiol are less in pregnant animals. How does estradiol affects PGF2α secretion in cellular and molecular levels is not known. However, estradiol has got a central role in luteolysis. For this reason; while antilteolytic strategies are developed, for the retardation or inhibition of luteolysis decrease of estradiol level is aimed [16].
Progesterone amount circulating in cows provides maternal recognition. This situation shows the importance of high level progesterone for the recognition of pregnancy in critical period. Another factor for the pregnancy recognition is bovine interferon-tau which is released by the embryo. Bovine interferon-tau is also known as bovine trophoblast protein-1 (bTP-1). Bovine interferon-tau which is secreted to lumen of uterus inhibits the release of PGF2α from the endometrium in critical period. Stimulating of progesterone to bovine interferon-tau is another possible mechanism for the maternal recognition. In the cows, which have higher levels of progesterone in the critical period, more bovine interferon-tau is produced by the embryo [16, 32].
Interferon-tau shows its affect by hindering estradiol receptors. Subsequently, oxytocin receptors diminish and cyclooxygenase inhibitors get activated. Interferon-tau insures the production of some endometrial proteins crucial for the life of embryo. The first of these proteins is bovine granulocyte protein-2. Second one is ubiquitin cross-reactive protein (UCRP). UCRP conjugates with cytosolic endometrial proteins in response to pregnancy and interferon-tau. Proteins conjugated with UCRP become a target for processing by proteasome. This affect of interferon-tau is mediated by the induction of signal transducer and activation of transcription 1 (STAT-1), STAT-2, and interferon regulatory factor 1. UCRP, alpha chemokines and induction of these transcription factors procure pregnancy recognition by mother [33].
Embryonic death is the most important source of reproductive losses. During the first three weeks of pregnancy embryonic deaths occur by means of several factors. If embryonic deaths take place between the 24th and 50th days, it is called as late embryonic death [4, 13].
Even in healthy cows in the first three weeks of pregnancy, more than 25% of the embryos cannot continue its development. While fertilization rate in cows with first service is 90%, calving rate is about 50-60% [4, 14]. In a study associated with this topic, it is reported that calving rate is 70% after insemination and most of the 30% of embryo losses take place in between 6th and 18th days [34]. If embryonic death happens before 16th - 17th days, cows continue to show estrus within normal intervals. However, if embryonic death happens after 16th - 17th days, returning back to estrus cycle takes longer and cycle interval becomes irregular [4].
There are plenty of factors that cause embryonic death in cows. These are; endocrine, genetic, intrinsic and extrinsic environmental factors, climate, stress, age, insemination time, semen quality, infectious agents, nutrition, chromosomal anomalies. Especially, abnormal progesterone and estrogen profiles cause embryonic deaths. Moreover, in high producing cows steroid metabolism is faster because of liver blood circulation increase. And this causes lower levels of progesterone in luteal period of estrus cycle [4, 35].
Low progesterone levels lead to death of embryo by causing excessive estradiol and PGF2α secretion. It is required that luteolytic effects of estradiol and PGF2α should be decreased in the early period after insemination in order for maternal recognition of pregnancy [36].
Researchers assert that low progesterone concentration before insemination period causes abnormal follicular development, elicit abnormal oocyte development in ovulatory follicle and ultimately, it causes early embryonic death [37-38].
Adequate secretion of progesterone in luteal period is vital for healthy ovulation, nutrition and survival of developing embryo. Low level of progesterone leads to embryonic death for reasons of:
Low progesterone levels from ovulation to 6th day after the insemination causes the inhibition of embryo’s development.
If progesterone is insufficient in pre-estrus period, uterus deprives of progesterone receptors. As a result of this, in 4th – 9th days of post insemination excessive PGF2α secretion forms, and this makes both an embryotoxic and luteolytic affect.
In 14th – 17th days which are the days of pregnancy recognition, cause of low pregnancy rate is progesterone inadequacy and excessiveness of estradiol.
Low progesterone levels in late embryonic period indicate imminent embryonic death [36, 39].
Oxytocin produced by corpus luteum stimulates the release of PGF2α from endometrium. PGF2α production depends on reaching of oxytocin receptor number to a threshold value. When these receptors in endometrium reaches a sufficient number, pulsatil secretion of PGF2α occurs in response to luteal oxytocin secretion and luteolysis goes after. For this reason, maternal recognition of pregnancy must take place before luteolysis [32, 40].
Specific proteins (bTP-1) produced by blastocyst in cows are signals preventing luteolysis. bTP-1, inhibits the endometrium cells’ oxytocin receptor production. As a result, oxytocin cannot induce PGF2α release. In addition to this, bTP-1increases protein production from uterine glands. These released proteins into uterus lumen provide nutrition of embryo [32].
NSAIDs NSAID: Nonsteroid Anti-inflammatory Drugs
Metabolism of Prostaglandins.
Nowadays, the most known NSAID is aspirin. The past of Aspirin dates back to hundreds of years. The most important step in the discovery of Aspirin is the identification of salicylic acid in 1860. Following this discovery, sodium salicylate in 1875 and phenyl salicylate in 1886 were first used. But these drugs formed serious side effects in gastrointestinal system. Aspirin or acetyl salicylic acid was discovered by Felix Hoffman in 1897. It was started to be sold under the name of Aspirin by Bayer Company in 1899 [46].
For the first time, it has been identified that prostaglandin inhibitors prevent product of Cox by John Vane in 1971 [44]. Later studies have shown that Cox enzymes have different isoforms and have different functions. Cox-1 is found in stomach, intestine, kidney and thrombocytes, and Cox-2 is secreted in platelets, macrophages, endothelial cells [41, 47]. While classic NSAIDs inhibit both enzymes, Cox-2 inhibitors inhibit inducible Cox-2. Thanks to this, Cox-2 inhibitors can show anti-inflammatory effect without forming any side effects in gastrointestinal system and in other tissues [43]. Existence of Cox-3 enzyme was discovered by Chandrasekharan et al. in 2002 [48]. See table 1.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Cox-1 Specific Agents | \n\t\t\tLow Dose Aspirin | \n\t\t\tIt makes COX-1 inhibition without doing COX-2 inhibition. | \n\t\t
COX Non-specific Agents | \n\t\t\tDiclofenac, Ketorolak, Asetaminofen, Flunixin meglumine. | \n\t\t\tIt inhibits both enzymes. | \n\t\t
COX-2 Selective Agents | \n\t\t\tMeloxicam, Nabumetane, Nimesulid, Carpofren. | \n\t\t\tWith Clinic threpautic doses in human and animals, while doing COX-2 inhibition, in increasing doses they cause COX-1 inhibition. | \n\t\t
COX-2 Specific Agents | \n\t\t\tCelecoxib, Rofecoxib. | \n\t\t\tThey are agents which do not cuase COX-1 inhibition even in maximum threpautic clinical doses. | \n\t\t
Cox inhibitors are used with different aims in reproductive field. Among these are; blocking of ovulation and implantation, preventing post operative adhesions and hindering of premature births (tocolytic) [50-58].
A lot of studies have been done to understand the importance of Cox enzyme in implantation. It has been found out that COX-2 is produced by uterus luminal epithel and stroma which surround blastocyte during implantation in rats. This situation indicates that COX-2 has a fundamental role in implantation [59-60]. Again in another study, it has been identified that female rats which have COX-1 deficiency have normal fertility and young number. Because in the presence of COX-1 enzyme deficiency, COX-2 supplies this deficit [59]. However, female rats which have COX-2 deficiency are infertile. Because lacking of COX-2 enzyme occurs ovulation, fertilization, implantation and desidualization defects [61].
Parallel with the studies done on experiment animals, studies searching the effects of NSAIDs on pregnancy rates of livestock have also been done. In these studies, flunixin meglumine, meloxicam, and carprofen have been used in order to increase pregnancy rate in cows.
Flunixin meglumine is a derivation of nicotinic acid and is also a non-selective cox inhibitor. It is a potent NSAID to keep the inflammation, pain and fever under control. Especially, it is used in visceral pains. In addition to its analgesic effect, it has antiendotoxic and antipyretic effects. Flunixin meglumine’s half-life is between 8 and 12 hours in cows, but it is longer in other animals [49, 62].
Flunixin meglumine is used in cows combined with antibiotics to cure illnesses like; joint ill, transit fever, blackleg, superfoul, mastitis, puerperal metritis, vaginal prolapse, pneumonia, downer cow. Moreover, it is used in pain therapy after small operations [63-64].
Flunixin meglumine is used in cows in ways like intramuscular, intravenous and peros. When it is used orally, the dose is 1 mg/kg. 1.1-2.2 mg/kg dose is used in intravenous way. The most application way is intramuscular injection and the dose is 1.1 mg/kg. This dose of flunixin meglumine is given once in a day or two times by dividing the dose. Flunixin meglumine can be given in 6-8 hour intervals in 0.25-0.50 mg/kg doses. Average therapy period is three days and it can be given 5 days maximum [65-69].
Carprofen is a propionic acid derivative NSAID and a selective cox-2 inhibitor. The drugs in this group take –fen suffix (e.g. ibuprofen, ketoprofen). Carprofen is the safest drug in this group because its peripheral prostaglandin inhibition is weak. It is a long effective NSAID with a clinical effect time of 12 hours. Carprofen in cows administered subcutaneous, in dose of 1.4 mg/kg to body weight [49, 65, 70-72].
Meloxicam is a selective cox-2 inhibitor. It is an oxicam group NSAID. It has anti-inflammatory, analgesic and antipyretic effects. Half-life is 13 hours in cows. It is used in cows by intramuscular, intravenous and subcutaneous ways in single doses of 0.5 mg/kg [65, 70-71].
In many studies about usage of flunixin meglumine, carprofen and meloxicam in different times after post insemination, decreasing PGF2α release, increasing luteal progesterone level and preventing early embryonic deaths are aimed [72-75].
In some of these studies [74-77], deserved pregnancy rates have been accomplished, on the other hand in some other studies [78-80] pregnancy rates have not changed.
In a study [75], in order to prevent early embryonic deaths in cows which are exposed to transportation stress, flunixin meglumine was given. In the study animals were divided into 3 groups as; control, stress (S) and stress +flunixin meglumine (SFM). After the synchronization of the cows’ estrus with MGA - PGF2α, insemination was done by observing the estrus. Animals were exposed to stress 14 days after the insemination. 1.1 mg/kg dose of flunixin meglumine was given to SFM group before transportation. Just transportation stress was formed in S group. When looked at the pregnancy rates (Control 76%, Stress 69% and SFM 84%), it is seen that there is a positive relation between pregnancy rates and flunixin meglumine application.
Merrill et al [76] searched the effects of 1.1mg/kg dose of flunixin meglumine administration on embryonic mortality of stressful and unstressed cows. They used 259 heifers and 127 cows. They designed the application groups as; control, control + flunixin meglumine, stress and stress + flunixin meglumine. In the first experiment, they used 259 angus crossbred heifers. All the heifers were synchronized with Controlled Internal Drug-Release (CIDR®) and PGF2α. In the second experiment, they used 127 angus crossbred cows. All the cows were synchronized with MGA and PGF2α. Applications started 14 days after artificial insemination. While pregnancy rate of animals exposed to transportation stress is 62%, unstressed animals had 64% pregnancy rate. While the pregnancy rate of flunixin meglumine cured animals was 69%, it was 59% in others. In the first experiment they reported that flunixin meglumine given animals had more pregnancy rate than others which were not given. In the second experiment, it was reported that flunixin meglumine applied animals had higher pregnancy rates than others (80% vs. 66%).
In another study, single dose of flunixin meglumine injection (1.1 mg/kg) was done on the 14th day after the insemination to animals which were exposed to transportation stress. The effect of this application on early embryonic deaths and prostaglandin in circulation and cortisol levels were searched. Researchers used 483 beef cows and animals were divided into 4 groups. They designed the groups as; first group transport, second group transport + flunixin meglumine, third group no transport (n=130) and the last group no transport + flunixin meglumine. After the application, transport + flunixin meglumine group had higher pregnancy rate than flunixin meglumine free group (74% vs. 66%) without looking at transportation. Just flunixin meglumine administered cows’ pregnancy rates were found higher than non-flunixin meglumine cows (71% vs. 61%). Cortisol concentration in cows exposed to transportation stress got increased but pregnancy rate did not change. In flunixin meglumine given subjects prostaglandin concentration was found lower than not givens. As a result researchers came to conclusion that NSAID applications would increase the pregnancy rate [77] .
Odensvik et al [81] have reported that application of flunixin meglumine both orally and parentally supports luteal function. They administered 2, 3 or 4 oral doses 2.2 mg/kg flunixin meglumine to heifers. They started the 9 day-therapy period 14-15 days of the estrus. As a result, they have found that estrus cycle is prolonged in groups of 3 and 4 doses administration. Luteolysis have taken place when 2 or 3 doses of flunixin meglumine have been applied. But in 4 dose give groups luteolysis have been postponed. The first cycle of the animals was evaluated as control and the 2nd cycle was evaluated as therapy cycle. Before the experiment, cycles of the animals were synchronized by PGF2α.
Dogruer et al. [82] synchronized repeat breeder heifers by applying two dose PGF2α. 48 hours after PGF2α, they administered GnRH (buserelin acetate) and after 12 – 14 hours they made fixed time artificial insemination. Then, they divided the heifers into two groups randomly and they injected a group flunixin meglumine on the 15th and 16th days. They used the other group as control. They made a pregnancy test to animals on the 29th day and in the end, they identified 50% pregnancy rate in therapy group, and 20% in the control group.
Güzeloğlu et al [74] gave GnRH on the 48th hour after synchronisation with PGF2α to 52 Holstein heifers and they inseminated them after 12-14 hours. Following this application, they administered 1.1 mg/kg dose of flunixin meglumine after artificial insemination on 15th days evening and 16th days morning via intramuscular way. Pregnancy test was done on the 29th day and, 20 pregnant animals in the treatment group and 13 pregnant animals in the control group was found.
In a study by Lucacin et al [78], they administered 1.1 mg/kg dose of flunixin meglumine to animals between the estrus cycle’s 11th and 16th days. Saline solution was given to animals in the control group. The estrus cycle of the animals was synchronized by the applications of estradiol benzoate + CIDR + PGF2α and then, fixed time artificial insemination was done. Researchers did not find any difference between progesterone concentrations and pregnancy rates of treatment group and control group.
Rabaglino et al. [79] synchronized the heifers with Cosynch+CIDR protocol, they gave half of them double dose of flunixin meglumine (400 mg) on the 15th and 16th days after artificial insemination. At the end of this application, 59.4% pregnancy was reached in control group, 59.5% pregnancy rate was reached in Flunixin meglumine given group.
Geary et al. [80] searched the effects of flunixin meglumine on the pregnancy rates in a study done on Angus heifers. In the first experiment they synchronized the animals with MGA and PGF2α. Animals were inseminated 12 hours after the observation of estrus. 13 days after the artificial insemination they injected single dose of flunixin meglumine to animals. While pregnancy rate was 72% in control group, it remained 66% in flunixin meglumine group. In the second experiment, Angus cows were synchronized via Select Synch or Select Synch + CIDR method. After that, they were inseminated by observing estrus. Around 13 days after artificial insemination they were injected flunixin meglumine. In the pregnancy test done on the 47th day, no difference was observed between the control and subject group (57% vs. 58%). In the third experiment both the heifers and the cows were used as materials. While Heifers were synchronized through Select Synch + CIDR protocol, cows were synchronized with Co-Synch + CIDR protocol. Pregnancy test was done on the 29th day; it was confirmed on the 75th day in heifers and 99th day in cows by ultrasound examination. As the conclusion of the experiment, no difference was found between flunixin meglumine and control group (50% vs. 48%).
Kruger and Heuwiser [83] made a study to assess the carprofen and flunixin meglumine’s effect on pregnancy rate of dairy cattle. They injected animals with carprofen and flunixin meglumine on 14th, 15th and 16th days after the insemination. In the first experiment, 413 Holstein-Friesian heifers were used. The cycles of these animals were synchronized with PGF2α and they were inseminated by observing their estrus. 2.2 mg/kg dose of flunixin meglumine was given to therapy group animals after the insemination’s 14th-15th days or 15th-16th days. No application was done to animals in the control group. At the end of this experiment, pregnancy rate in the control group was 58.7% and 58.6% in the treatment group. Serum progesterone levels on 14-15days and 21-22 days after insemination were compared in both pregnant and non-pregnant animals. It was observed that on the 21-22 days progesterone levels of pregnant animals were higher. In the second experiment researchers used 380 Holstein cows and these animals were synchronized by ovsynch protocol. After 16 hours from the second GnRH injection, fixed time artificial insemination was done. 1.4 mg/kg dose of carprofen was given via subcutaneous on the 15th day after the insemination to the treatment group. No therapy was applied to control group. It was identified that while pregnancy rate in carprofen given group was 33%, it was 35.5 in control group. Researchers come to the idea that NSAID application does not affect the reproductive performance.
Heuwieser et al. [72] made a study on 970 cows. They divided the animals into three groups. They administered 1.4 mg/kg dose of carprofen subcutaneous following artificial insemination. 1.4 mg/kg dose of carprofen was given into the uterus 12-24 hours after the insemination to the 2nd group. 3rd group was left as control. After the first insemination the pregnancy rates were found as 42.2%, 38.3% and 45.1%, respectively. As a result they reported that, subcutaneous carprofen therapy did not affect the pregnancy rate but intrauterine therapy had a negative effect on the pregnancy rate.
Amiridis et al. [73] applied flunixin meglumine, ketoprofen and meloxicam to heifers. In the end, they came to conclusion that meloxicam administered animals have the longest estrus cycle and meloxicam is much more potent than other NSAIDs. The same researchers made a study on repeat breeder cows; 1st group was GnRH, 2nd group was progesterone, 3rd group was meloxicam and the 4th group was GnRH + progesterone + meloxicam. They reported that the highest pregnancy rates were seen in 4th group.
In another study on Holstein heifers, 0.5 mg/kg dose of meloxicam was administered subcutaneous on the 15th day following the insemination. Finally, it was identified that pregnancy rate was 24.3% in meloxicam cured group and 52% in control group. In the light of these data, researchers reported that meloxicam application during the time of maternal recognition will be harmful to pregnancy [84].
In a study aimed at increasing pregnancy rate and progesterone synthesis by inhibiting prostaglandin synthesis, a fixed time artificial insemination was done by synchronising cycles of Nelore cows. Researchers divided the animals into 8 groups and they designed the groups as follows. 1st group constitutes the control and given saline on 7th and 16th days; to the 2nd group, saline on the 7th day and flunixin meglumine on the 16th day; to the 3rd group, bST on the 7th day and saline on the 16th day, to the 4th group, bST on the 7th day and flunixin meglumine on the 16th day, to the 5th group, hCG on the 7th day and saline on the 16th day, to the 6th group, hCG on the 7th day and flunixin meglumine on the 16th day, to the 7th group, bST + hCG on the 7th day and saline on the 16th day, to the last group, bST + hCG on the 7th day and flunixin meglumine on the 16th day were administered. It was found out that the group only cured with hCG on the 7th day showed a higher rate of pregnancy [85].
Tek et al. [86] searched the effects of flunixin meglumine and oxytetracyclin combinations on the cows diagnosed with subclinical endometritis. They applied intramuscular flunixin meglumine (2 mg/kg) and oxytetracyclin (300 mg). They inseminated the animals in the first estrus seen after the application. When compared with the control group, pregnancy rates were higher in flunixin meglumine and oxytetracyclin administered group (25% vs. 55%).
In another study, animals with puerperal metritis were injected with ceftiofur (CEF) and/or flunixin meglumine. CEF was given to the first group for three days. A single dose of flunixin meglumine (2.2 mg/kg) was given intravenous in addition to CEF to the animals in the second group. At the end of the study, researchers came to a conclusion that flunixin meglumine application does not have a beneficial effect on clinical recovery and reproductive performance [87].
Preparing a suitable environment inside uterus is aimed with NSAIDs applied in different times before embryo transfer to cows and heifers. In most of these studies, while flunixin meglumine or ibuprofen applications just before the embryo transfer increase the pregnancy rate has been reported [88-90], in a study it has been reported that it is ineffective [91], and in another study [91] it has been reported that pregnancy rate has diminished.
Elli et al. [88] investigated whether ibuprofen application increases implantation rates during embryo transfer in cattle. In their study done on 100 heifers, they gave half of them 5 mg/kg dose of intramuscular ibuprofen 1 hour before embryo transfer. Pregnancy rate in the treatment group reached 82% but stayed 56% in control group.
Purcell et al. [89], in a study they made on beef cattle applied either 500 mg dose of flunixin meglumine 2-12 minute before embryo transfer or they inserted CIDR shortly after the embryo transfer. The first of four groups was remained as control group, CIDR to 2nd group, flunixin meglumine to 3rd group, both flunixin meglumine given and CIDR inserted to 4th group. Pregnancy rates were found as 65%, 60,7%, 74.7% and 69.8%, respectively. The average pregnancy rates of flunixin meglumine administered animals (3rd and 4th group) and unapplied animals (1st and 2nd group) were identified as 72.3% and 63%.
In another study [90], 10 ml flunixin meglumine was injected to beef cattle 2-5 minutes before the embryo transfer and when it was compared with control group, it was found that pregnancy rate was higher in flunixin meglumine given group (51.1% vs. 63.8%).
McNaughtan [91] injected 10 ml flunixin meglumine to heifers just before the embryo transfer. He identified that during the pregnancy examination 90 days after the embryo transfer, the difference between the therapy and control group (n: 165) was nonsignificant (50% vs. 45%).
Bulbul et al [92] gave 500 mg flunixin meglumine intramuscular five minutes before embryo transfer in a study done on 39 brown Swiss. As a result of the pregnancy examination on the 30th day by means of ultrasound, they reported that pregnancy rate in the flunixin meglumine given group was lower in comparison to control group (50% vs. 52.6%).
Artificial insemination is the first biotechnologic application used in domestic animal. It was first performed by Ivanow in 1899 in Russia on farm animals. This procedure was adopted in 1940s by animal breeders and then it has become prominent all over the world. Such associated technologies as cryopreservation, invitro fertilization and embryo transfer have then started to develop and they have resulted in successful pregnancies (93). NSAID implementations have been used in recent years among the assisted reproductive technologies. NSAIDs are applied as a new strategy to increase the pregnancy rates of cows in artificial insemination. Nevertheless, the results obtained from the previous studies conflict with each other. Especially, there are different studies stating that flunixin application increases, does not change or decreases the pregnancy rate. For this reason, NSAIDs relation with interferon tau and endometrial proteins should be investigated in a more detailed way. Thus, from where the difference in pregnancy rates originate can be found and taking of necessary precautions can be possible.
In the United States (US), stroke is the fifth leading cause of mortality with a stroke occurring approximately every 40 seconds and stroke-related death approximately every 4 minutes [1, 2]. In 2011, stroke was found to be the leading cause of disability in the US, with around 7 million stroke survivors [3]. In 2016, the World Health Organization designated stroke as the second leading cause of mortality worldwide. Acute ischemic strokes account for about 80% of all stroke-related deaths [4]. Intravenous tissue plasminogen activator (tPA) has been shown to improve outcomes in acute ischemic stroke [5, 6]. In patients who receive tPA, early administration has been shown to reduce morbidity, mortality, and adverse events such as intracranial hemorrhages, promoting early discharges and higher rates of independent ambulation at discharge [5, 7]. Mechanical thrombectomies performed by neuro-interventionists have shown to improve outcomes for patients with proximal intracranial arterial occlusion [8, 9, 10, 11] and have become the standard of care for patients who qualify for intervention. However, this procedure is performed only at tertiary care centers and is not available at smaller hospitals around the country.
\nDespite the obvious benefits of tPA administration, only a small percentage of patients presenting with acute ischemic strokes are eligible to receive it [12, 13, 14, 15]. The most common reason attributed to this is a delay between the development of stroke symptoms and the patient seeking treatment at a hospital [16, 17]. There are also marked rural–urban disparities in stroke care [18, 19, 20]. These disparities are, in part, a result of the scarcity of neurologists [21, 22, 23, 24]. Studies have shown better outcomes in stroke patients under the care of neurologists as compared to physicians of other specialties, such as Internal Medicine or Family Medicine [22, 25, 26]. Telestroke aims to bridge this gap by providing neurology expertise in remote areas around the world through high-quality audio-video conferencing and digital image sharing.
\nCommunication of medical information across long distances has occurred throughout history. It is well documented that bonfires and heliographs were used to send communications about the bubonic plague in Europe [27]. Telegraph communication was used in the civil war and radio communication was used in World War I, and wars thereafter, to send information about casualties and to request medical dispatches and transport for wounded soldiers [28]. Telemedicine in its current form was developed by NASA to monitor the physiologic states of astronauts during manned space missions [29]. The first interactive video telemedicine systems were established for psychiatry [30] and radiology [31] but later expanded to critical care [32] and oncology [33] to bridge the shortage of specialists in these fields. In 1999, the term
Before discussing telestroke models, it is important to understand the terminology used to describe telestroke systems, as described by the American Telemedicine Association [39].
Distant site: the distant telestroke provider location.
Originating site: the site where the patient is initially located.
Telestroke network: a group of primary, secondary, and tertiary care settings that provide acute stroke care to patient populations. Telestroke networks consist of originating sites where the patients are located and distant sites where the telestroke provider is located.
Spoke: the affiliate or partner site in a telestroke network that is underserviced or under-supported by neurologists where patient services are delivered.
Hub: a comprehensive tertiary care center where vascular neurologists and other acute stroke specialists compose a call panel delivering telestroke services to network partner sites (i.e., spoke sites). This is also the center where the patient may be transferred if a higher level of care is needed.
Several different telestroke models have been described and are listed below [38, 39].
Hub and spoke within a single healthcare system.
Hub and spoke with external sites.
Horizontal hubless network: interconnected sites within a large hospital system for on-call clinical coverage.
Third-party distribution model: telestroke services are provided to multiple originating sites through arrangements with an independent corporation or an affiliated network of telestroke providers.
Supervisory training model: academic teleneurology programs to assist trainees within the hospital system.
Hub and Spoke with external sites and third-party distribution models are the most commonly used models within telestroke [35]. In telestroke networks, the majority of spoke sites are small hospitals (i.e., 0–99 beds) [37], but the spoke hospital size may vary from 25 to 500 beds in different telestroke networks [17]. A telestroke consult typically starts with a patient presenting to a spoke site with a suspected stroke. After an initial assessment by the physician at the spoke site, a triage process is conducted through telephone operators, followed by a video teleconferencing call with the neurologist at the distant site [see flow diagram of a telestroke system]. After reviewing the National Institute of Health Stroke Scale (NIHSS) and brain imaging (typically a non-contrasted CT scan of the head) and reviewing the patient’s history for indications/contraindications for tPA, a decision is made for administration of tPA. After this initial process, the decision of transferring the patient to the hub site is made, depending upon the need for further investigation, possible thrombectomy/neurosurgical intervention, or requirement of a higher level of care as compared to the spoke site. The term “Drip and Ship” is often used to describe transfer from spoke to hub sites, where after receiving the bolus dose of tPA, the patient is started on tPA drip and transferred emergently for further management [40].
\nThe majority of the hospitals in telestroke systems have formal written contracts between the hub and the spoke site with a closed-loop communication system in place [37]. A vast array of Food and Drug Administration (FDA) approved two-way video-conferencing modalities with picture archiving and communication system are available for use by these networks that provide Health Insurance Portability and Accountability Act (HIPPA) compliant, secure, encrypted multipoint data sharing with evolving functionality through the use of desktops, robotic carts, laptops, tablets, and even mobile phones with provider-to-provider interfaces [37, 38].
\nMore recent advancements in telestroke systems include an ambulance-based telemedicine system that provides a feasible tool for prehospital stroke assessment [41, 42, 43, 44]. Early attempts at prehospital telestroke consults were limited due to technical difficulties [44]. Newer studies have shown a high level of agreement in evaluation and treatment by mobile stroke units with a vascular neurologist on board compared to telestroke consults by a vascular neurologist [45] at a distant site who guides immediate treatment [46]. The data, however, is still limited and requires further investigation before the utility and efficacy of telestroke programs can be ascertained.
\nThe primary goal of telestroke models is to establish a network of neurology consults across underserved areas that do not have in-house neurology consultants available, thereby expediting the initial stroke exam and care. As the effective tPA window is time-sensitive, and early administration of tPA is known to improve outcomes [5, 6, 13, 47], delay in transport of patients to tertiary care centers can lead to loss of the crucial intervention time window in acute ischemic stroke patients. After adequate training, the use of telestroke systems to measure NIHSS scores is viable and scoring is reliable, with inter-rater reliability comparable to that of in-person measurements [48, 49] even in telemedicine-naïve stroke practitioners [50]. Such assessment has also been found to be reliable when performed by neurology trained nurse practitioners [51], on laptop-based workstations [52], or even mobile-based video telestroke consults [53, 54]. Also, the FDA has approved teleradiology systems that enable effective and rapid evaluation of images by stroke specialists [55]. Stroke specialist evaluation via teleradiology systems has been found to be comparable to assessment by a neuroradiologist in aiding the decision making for tPA administration [56, 57].
\nStudies have shown that telestroke facilitated administration of tPA to patients in community hospitals and rural hospitals (as small as 100 beds or less) has outcomes comparable to those of in-person treatment at comprehensive stroke care centers [58, 59, 60, 61]. Even with in a stroke network, the performance of spoke sites is similar regardless of the bedsize [62]. Also, the use of telestroke at rural hospitals can provide patients with comparable or reduced time between symptom onset and tPA administration [door-to-needle time (DTN)] compared to those directly presenting to tertiary care centers [63]. A non-blinded randomized control trial in the Telemedic Pilot Project for Integrative Stroke Care (TEMPiS) network in Germany showed that patients treated in telestroke network hospitals had significantly fewer poor outcomes compared to patients treated in community hospitals without telestroke capabilities [64]. Telestroke consults are becoming exceedingly cost-effective in dealing with acute strokes in the community [65, 66, 67, 68, 69].
\nTelestroke consults also have utility beyond acute stroke. Patients receiving tPA or those with subacute strokes with milder symptoms not requiring emergent intravascular intervention can remain at the spoke site for further investigation. Telestroke follow-up consults can aid in guiding the physicians at the spoke sites to continue further stroke workup and discharge patients from the spoke site. This may also reduce the cost of transport and limit patients being transferred to hub sites to only those requiring urgent neurosurgical/intravascular intervention. A randomized control trial by Evans et al. showed that the management of stroke patients in dedicated stroke units showed better outcomes for large vessel infarcts but not for small lacunar infarcts when compared to those in general medical wards with stroke team support [70]. Based on this hypothesis, small lacunar strokes could potentially be managed by the medical team at spokes sites with telestroke consults and follow-ups. The Telemedicine in Stroke in Swabia Project and The Order of St. Francis Stroke Network study experience demonstrated the safety and reliability of such telestroke models [71, 72]. Even for patients requiring treatment in an intensive care unit, teleneurointensive care units are providing valuable support for prevention, diagnosis, and the timely management of cerebrovascular conditions induced secondary to neurologic injuries [73] and have shown improved outcomes [74].
\nTelestroke has also been studied in in-home and ambulatory post-stroke rehabilitation settings for serial neurologic assessments and timely adjustments of therapies. These studies have shown that telerehabilitation approaches are comparable to conventional rehabilitation in improving activities of daily living and motor function for stroke survivors [75, 76]. Virtual neurovascular clinics aimed at secondary stroke prevention are another evolving avenue for follow-up visits for stroke patients [77].
\nIn the field of clinical research, telestroke consults may aid in identifying patients who are eligible for trials of therapies for ischemic or hemorrhagic strokes, neuroprotective agents, or innovative diagnostic tests, thereby facilitating expedited enrollment at the originating sites after transfer to stroke centers [78]. Telestroke models are being incorporated into the education and training of neurologists, emergency teams, and nursing staff [77, 79, 80, 81, 82]. With the ever-expanding horizons of telestroke, training in telemedicine will likely become mainstream for all future physician and medical personnel training programs. However, the data regarding the use of telestroke beyond acute stroke care is still limited and needs further investigation.
\nZaidi et al. showed that outcomes at 90 days were no different between patients treated with tPA by telemedicine and patients treated by the same neurologists over the same time interval at the stroke center hub hospital [83]. They also found no difference in time from stroke onset to treatment. Switzer et al. found that the average time between symptom onset and treatment at the spoke sites in their telestroke system was lower than the emergency department at their hub site [63]. As previously mentioned, several studies have found post-tPA outcomes at spoke sites were comparable to those of in-person treatment at comprehensive stroke care centers [58, 59, 60, 61]. Implementation of a standardized regional telestroke program in a community setting increased utilization of alteplase, improved DTN time, decreased length of stay, and significantly increased the chances of patients going home [84].
\nEstablishing a telestroke network requires infrastructure and technology-related expenses along with the expenses of round-the-clock neurology coverage and the cost of transport. Initial projects around the country were supported by government funds and research grants, but to develop a self-sustaining model, telestroke networks need to be cost-effective. For a Danish telestroke system consisting of five hubs and five spokes, a 2008 study by Ehlers et al. calculated an incremental cost-effectiveness ratio (the cost of thrombolysis per quality-adjusted life year [QALY]) to be approximately US$50,000 after 1 year [69]. In 2011, Nelson et al. conducted cost data analyses of telestroke networks in rural Arizona and Utah and found the incremental cost-effectiveness ratio using a 90-day horizon of $108,363 per QALY and a lifetime horizon of $2449 per QALY [66], which reflected a high initial cost but overall long-term cost reduction, likely due to rehabilitation cost reduction from early tPA administration. Also, the highest cost-effectiveness was seen in the most severe stroke cases. In a 2013 study by Switzer et al., cost savings of $358,435 per year over 5 years were observed in a telestroke system consisting of one hub and seven spokes, as well as an improvement in patients’ quality of life associated with increased numbers of individuals being discharged to home [67]. Growing evidence for the cost-effectiveness of telestroke networks and improved patient outcomes has spurred the growth of telestroke networks around the world.
\nContinuous quality improvement is a key element for any successful telestroke program. Several elements play a role in this improvement, including adaptation to local laws and statues, effective training programs, identification of competency issues, and overcoming challenges with technical and manpower issues at both provider and recipient sites. In 1988, Donebedian was the first to describe the model of structure, process, and outcomes measurements for assessing the quality of healthcare [85]. Systematic collection and analysis of quality data has been shown to improve the quality of stroke care that is delivered [86], and telestroke is no exception to this. Several quality measures help assess and quantify the overall function of telestroke systems. Most hub hospitals have stroke certification and emergency and ICU staff training through standards set by the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) process.
\nThe capacity of the healthcare system, staffing ratios of specialists, availability of specialized units and equipment, and the organization structure with hospital networking should all be carefully studied and analyzed for any telehealth network systems. Defined protocols should be in place both at the originating and distant sites.
\nAnalogous to the traditional stroke pathway, the key global component of telestroke quality is still DTN time. Median DTN with telestroke varies from 106 to 121 minutes, even though the recommendation is less than 1 hour [58]. Several aspects of stroke chain-of-care that play an important role in DTN include Emergency Department (ED) door to CT scan (D-CT) time, ED door to teleneurologist consult time, teleneurologist to camera/phone time, and teleconsult duration (Con).
\nClear definitions of these times are important as no uniform definitions currently exist. In some centers, a consult with teleneurologist occurs after CT scan results are obtained, while in other centers, a consult is initiated even before the CT scan is ordered. The time from ED to consult differs in these situations, which can affect these measures. Similarly, the definition of consult time varies between centers. At some centers, consult time is defined as the time spent on camera evaluating patients, and at other centers, it is defined as time spent on camera along with the time spent reviewing the images and other diagnostic results. Because of these variations, consult duration varied from 14 to 32 minutes in different studies [87, 88]. Studies showed that telestroke by itself might not decrease the DTN as there are variations in the subsects of stroke chain-of-care [89].
\nIt has been shown that D-NC and Con play a major role in DTN [90]. Various factors including, when the consultant is notified, the time a consultant takes to interview the patient, and the experience level of the staff aiding with the examination will have to be considered while analyzing such data. The percentage of patients transferred after a telestroke consult to a destination hospital is also an important factor as it involves significant costs [67]. Data should be collected quantifying the rate of transfers after the consult and steps should be taken to minimize unnecessary transfers.
\nThe success of any program is ultimately decided by measuring outcomes, which could be patient related or system related. A modified Rankin scale, which is measured 90 days after a stroke, is the most commonly used measurement of stroke outcome [83]. Steps should be taken to ensure a 90-day follow-up on all the telestroke treated patients. No significant differences in mortality or morbidity were noted in patients in the hub and spoke hospitals of the TEMPiS network [91]. Even though 90-day outcomes after stroke are reported in most clinical trials, this data is not routinely collected by hospitals because of the cost and complexity involved. Data on stroke mimics that were treated by telestroke networks is an important factor as it plays a big role in minimizing costs, even though tPA administration might not increase the risk to these patients. Similarly, data on the percentage of patients receiving tPA through telestroke networks is very useful to compare with in-person stroke treatment numbers. In a study that examined several telestroke networks, the rate of tPA via telestroke was 18–36% compared to the national average tPA administration rate of 5–8% [91].
\nData collection regarding patient characteristics, NIHSS score pre/post-treatment and before discharge, length of hospital stay, discharge disposition (home vs. rehab vs. sub-acute rehab), readmission rate, complications including intracranial hemorrhage, other significant hemorrhages, mortality, and 90-day follow-up outcomes are recommended by the American Heart Association and the American Stroke Association [92]. One of the highest priorities for several healthcare systems is patient satisfaction. Attempts should be made to follow-up with the treated patients and family members about their satisfaction with the telestroke process. LaMonte et al. found that the telestroke process enhanced patient satisfaction in their study [93]. Measuring provider satisfaction is equally important for improving telestroke service quality. Studies showed that patients are more enthusiastic about telemedicine compared to providers even though both of the groups were satisfied [94]. Providers having less of a personal benefit was one of the possible reasons behind this discrepancy [92].
\nIn a good telestroke program, the technology involved is as important as the physicians’ clinical expertise. Video and audio conferencing equipment quality, transmission clarity, internet speed, user-friendliness of the software, accessibility of personnel training modules, and encryption of patient information in transit to protect patient privacy all play a role for effective delivery of telestroke care. All technical difficulties, failures, and limitations should be continuously monitored, documented, and analyzed promptly to prevent repeated occurrences.
\nLastly, apart from the issues unique to telestroke, data on regular measures as recommended by National Quality Forum for stroke patients, including use of tPA, anti-thrombolysis therapy by day 2, thromboembolism prophylaxis, lipid-lowering medications on discharge, anti-thrombotic therapy on discharge, anticoagulation in the setting of atrial fibrillation, rehabilitation evaluation, and stroke education should be collected and evaluated regularly [95].
\nThere are still challenges with current models. In the last 15 years, there has been a substantial improvement in stroke quality measures. Most of the measures are already being performed with a high compliance rate and innovation. They should be expanded to pre-hospitalization and post-hospitalization settings as well as to telestroke for further improvement of stroke care [62, 96, 97, 98, 99]. Universal guidelines about definitions of times in stroke chain-of-care, protocols for consultant notification, and specific standard stepwise processes that can be applied universally for telestroke networks will be useful in standardizing telestroke models. As telestroke is becoming more popular in delivering care for acute stroke patients, there is a need for strict quality metrics to ensure safe and effective care for the patients. Even though in several aspects telestroke is as effective as in-person stroke care, there are several issues pertinent to telestroke like technology, policies, and challenges with data collection due to distant participating sites that need to be refined for effective and timely management of stroke patients.
\nLack of neurology coverage is not unique to the US; it is a problem worldwide [100]. Several countries in Europe have developed efficient telestroke networks [59, 64, 69, 101, 102, 103], with the TEMPiS network in Germany showing remarkable results [64, 104, 105]. The Telestroke Committee of the European Stroke Organization has recently published recommendations regarding telestroke networks in Europe concerning infrastructure, teleconsultation service, transfer options, standard operating procedures, professional training, and quality monitoring and improvement. They have also made recommendations about the technical and ethical aspects of telemedicine [106], which are similar to ones in the US.
\nAsia is quite heterogeneous in terms of variability in language, governments, culture, historical links, socioeconomic development, and organization of health services. In China, the National Telestroke Center, established in 2014, was designed to provide neurological coverage to 300 rural hospitals throughout the country through the telestroke network [107]. This was also the first platform where Google Glasses were used for real-time telestroke consults. The system is still evolving and data from China is still limited. In India, telestroke systems are still uncommon, but they show prospects for expansion, aiming to provide care to rural communities that are limited in their resources [108, 109]. Japan, Singapore, and South Korea have rather advanced nationwide medical systems, but telemedicine experience in these countries is still limited [110, 111, 112]. Teleneurology and telestroke have great potential to extend neurology expertise to underserved populations in the world; however, further investment in creating infrastructure and technology is needed before their impact on healthcare is realized.
\nIn December 2019, the first case of the novel coronavirus COVID-19 was identified in China [113]. Since then, the rapid spread of the virus has led to a worldwide pandemic [114]. The US has become the epicenter of this pandemic with the largest number of reported cases worldwide. Of all COVID-19 cases, an estimated 19% are healthcare personnel [115]. The COVID-19 pandemic has put a significant strain on healthcare personnel in providing in-person care, especially in an acute setting. Several States in the US and countries around the world have implemented stay-at-home orders. Hospitals have canceled elective procedures and outpatient in-person clinic visits to minimize the exposure risk to patients and healthcare workers. Additionally, COVID-19 is associated with an increased risk of thromboembolic complications [116]. This puts neurologists at risk of exposure while assessing patients with acute neurological deficits. Screening for symptoms of COVID-19 has also become difficult in the setting of neurological deficits, especially aphasia and encephalopathy. Most countries around the world, including the US, already suffer from a lack of adequate neurology coverage [100] and COVID-19 exposure not only puts neurologists’ wellbeing and life at risk but also exacerbates this deficiency. This pandemic has brought the need and utility of telemedicine, teleneurology, and telestroke into the limelight [117, 118, 119, 120]. Teleconsults are an effective way of providing outpatient care as well was acute care inside the hospitals, limiting the exposure risk to physicians and patients, as well as limiting the use of personal protective equipment which is in short supply. The pandemic may change the paradigm of teleneurology and telestroke permanently and force the system to adapt to its growing need at a much faster pace.
\nDespite the utility and efficacy of telestroke networks, there exist significant hurdles in establishing and efficiently sustaining a viable telestroke program.
\nThe most important hurdle is third party reimbursement. It took decades for the concept of telemedicine to come to fruition, and pay parity kept telemedicine programs across the country from flourishing, sustaining, and expanding [121, 122, 123, 124, 125, 126]. Without appropriate reimbursement, the burden of financial overhead in maintaining the high-quality video interface, teleneurology and teleradiology coverage, and costs of emergent care including imaging, tPA, and transportation to hub hospitals would make telestroke network unsustainable. The Centers for Medicare and Medicaid Services (CMS) has addressed the need for reimbursement for telemedicine services and third-party payers have followed suit [37, 121]. Appropriate reimbursement for teleservices remains a concern among providers [127] and continues to be a barrier for the expansion of telestroke networks to underserved areas of the country.
\nLicensure and hospital credentialing, often across state lines, further burdens physicians and hospitals to spend resources, thus putting additional constraints on the expansion of these services. Physicians are required to maintain a license in the state where the spoke site is located in addition to the hub site where they usually work. This requires unrestricted licensure to be maintained in every state where the teleconsult is requested. A national or multistate license for telemedicine would reduce the necessity for a consultant to be licensed in multiple individual states, but this kind of license does not currently exist [128]. In 2011, CMS began allowing credentialing and privileging by proxy at small and critical-access hospitals, which has allowed these hospitals to rely on the credentialing and privileging process performed at the hub site [92, 129]. However, this policy needs to be adopted by all 50 states to mitigate the onus of licensing and credentialing on physicians and small hospitals. Also, reimbursement in cases where the patient receives tPA at the spoke site and is transferred to the hub hospital remains an issue, as neither the spoke nor hub facility is eligible to bill the higher Medicare diagnosis-related group codes that are associated with thrombolytic administration [128].
\nEstablishing and maintaining the infrastructure for high-quality video conferencing in small rural hospitals also adds to the financial burden on these hospitals. There is also marked heterogeneity in the platforms available, which spoke sites need to take into account before joining a telestroke model [37, 128]. Platform differences also limit the flexibility of these rural hospitals in terms of associating with more than one network or transitioning to a different network as the platforms utilized by these networks may be incompatible. Additionally, to comply with CMS billing requirements, a high-quality, two-way video connection is recommended and a minimum frame rate of at least 20 frames per second has been suggested [130]. Thus, high-speed internet is an essential component of telestroke networks. The availability of high-speed internet connections in rural parts of the country is limited and is a separate problem limiting the implementation of telestroke networks. These issues become exceedingly challenging in resource-limited countries around the world.
\nConvincing the leadership of potential spoke sites of the cost-effectiveness of joining a telestroke system requires time and effort on the part of the hub telestroke providers. Joining a telestroke system not only requires investment in infrastructure but also requires extensive training and development of protocols for teleconsults and transfers. These requirements may appear daunting to the leadership and hospital staff, especially at small rural hospitals with limited resources. However, the literature supporting the safety, cost-effectiveness, and improved patient outcomes related to telestroke networks may help encourage their buy-in to such programs. Joining such a system implies a long-term partnership between the hub and the spoke sites. Trust also needs to be established between the spoke site ED staff and consulting neurologists. Endorsements and testimony from the leadership of existing spoke sites in similar settings, hearing patient experiences from those who benefitted from these networks, and meeting with the team of consulting neurologists may prove useful in building this trust.
\nAlong with the establishment of infrastructure for telestroke, medical staff at spokes sites need to be trained for ever-evolving telestroke protocols and joint commission requirements. They need to be able to recognize the early signs and symptoms of acute stroke, perform NIHSS exams, screen for eligibility for tPA, and to be proficient at using the teleconsult interface to facilitate the process efficiently. Telestroke systems can include stroke patient management training to spoke medical staff on education NIHSS exam demonstrations, reviews of alteplase reconstitution, administration and considerations, alteplase dosage calculations and telemedicine cart demonstration and review. Other patient management training can be provided to paramedics local to the spoke sites, these sessions typically include; impact of and time sensitivity of strokes, what is a stroke, types of stroke, stroke mimics, EMS neurological assessments, stroke management/prehospital guidelines and telemedicine and alteplase through an organizational system of care.
\nGiven the wide variability of telestroke systems based on AHA/ASA guidelines and local governing factors, each network should develop an standard operating protocol (SOP) that suits their needs (Tables 1–3) [131]. The volume of teleconsults can vary greatly between the spoke hospitals, thus training needs to be reinforced at specified intervals to ensure efficient and seamless consults and to maintain high-quality patient care. This may lead to telemedicine fatigue in the staff at low-volume hospitals that needs to be mitigated during the training by emphasizing the importance of their work in the teleconsult system in their community at improving outcomes in patients who may have otherwise not had an opportunity for timely stroke intervention due to time lost in transportation to larger centers.
\nAmerican College of Cardiology/American Heart Association class of recommendation and level of evidence to clinical strategies, interventions, treatments, or diagnostic testing in patient care*\n | \n
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American Heart Association summary of recommendations for telestrokes [131].
The outcome or result of the intervention should be specified (an improved clinical outcome or increased diagnostic accuracy or incremental prognostic information).
For comparative-effectiveness recommendations (COR I and IIa; LOE A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.
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The method of assessing quality is evolving, including the application of standardized, widely used, and preferably validated evidence grading tools; and for systematic reviews, the incorporation of an Evidence Review Committee.
COR, class of recommendation; EO, expert opinion; LD, limited data; LOE, level of evidence; NR, nonrandomized; R, randomized; and RCT, randomized controlled trial.
Class of recommendation (COR) and level of evidence (LOE) are determined independently (any COR may be paired with any LOE). A recommendation with LOE C does not imply that the recommendation is weak. Many important clinical questions addressed in guidelines do not lend themselves to clinical trials. Although RCTs are unavailable, there may be a very clear clinical consensus that a specific test or therapy is useful or effective.
Telemedicine | \nCOR | \nLOE | \n
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1. For sites without in-house imaging interpretation expertise, teleradiology systems approved by the US Food and Drug Administration are recommended for timely review of brain imaging in patients with suspected acute stroke. | \nI | \nA | \n
2. When implemented within a telestroke network, teleradiology systems approved by the US Food and Drug Administration are useful in supporting rapid imaging interpretation in time for IV alteplase administration decision making. | \nI | \nA | \n
3. Telestroke/teleradiology evaluations of acute ischemic stroke (AIS) patients can be effective for correct IV alteplase eligibility decision making. | \nIIa | \nB-R | \n
4. Administration of IV alteplase guided by telestroke consultation for patients with AIS may be as safe and as beneficial as that of stroke centers. | \nIIb | \nB-NR | \n
5. Providing alteplase decision-making support via telephone consultation to community physicians is feasible and safe and may be considered when a hospital has access to neither an in-person stroke team nor a telestroke system. | \nIIb | \nC-LD | \n
6. Telestroke networks may be reasonable for triaging patients with AIS who may be eligible for interfacility transfer to be considered for acute mechanical thrombectomy. | \nIIb | \nB-NR | \n
American Heart Association/American Stroke Association guidelines for telemedicine [131].
Telestroke networks, like traditional practices, are required to be compliant with HIPAA, which governs protected health information in the US. Given that telestroke networks rely on real-time data sharing between the spoke and the hub, data security becomes a concern. Data security requires end-to-end encryption on the sharing platform, reliable documentation and storage, strict control of access to users within the network, and cooperation between the information technology staff at both sites. To ensure 24-hour coverage, consulting physicians often use a mobile device for such calls and must be cognizant of their surroundings while consulting remotely. For example, most telestroke systems provide home accessibility for physician consults. Currently due to HIPPA rules the use of hand held mobile phones remains limited for detection of stroke. Given the renewed interest in telehealth with the COVID-19 pandemic, there is a potential for use of mobile phone application technology.
\nHealthcare data breaches have been on the rise with larger and teaching hospitals being at a greater risk [132, 133]. Given multiple points of entry and the potential for data breaches in telestroke networks, extra care is needed at the hub and spokes sites to ensure data safety. Despite these challenges, telestroke networks have shown to provide safe, efficient, and cost-effective stroke care to underserved communities. There is still enormous potential for telestroke networks to expand into rural areas of the country as well as around the world.
\nSince its conception, telestroke has expanded greatly in its scope and utility in bridging the gap in stroke care between the rural and urban communities, in both acute and continued care. Despite the challenges faced in establishing and sustaining telestroke networks, these networks are flourishing and expanding, creating an ever-evolving paradigm for stroke care throughout the country and around the world.
\nThe authors have no conflicts of interest to disclose.
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