The studies providing the animals were funded by the UK Department for Food, Environment and Rural Affairs and the European Union (through funding of the EU TSE Reference Laboratory). We acknowledge the support of the project managers, Dr. M. Simmons and Dr. M. Jeffrey.

1. Assessment of Posture
<ol>
	<li>Assess the posture of the animal whilst undisturbed.</li>
	<li>Animals affected by TSEs may stand with wide-based limbs, may appear hunched, or may stand with a low head carriage.</li>
</ol>
2. Assessment of Behavior
<ol>
	<li>Study the animal&#8217;s behavior, when left alone, when approached, and when handled.</li>
	<li>TSE-affected animals may display altered mentation by standing separately from other sheep or not immediately following other sheep.</li>
	<li>When the animal is approached, it may run away and collapses, or it collapses to the floor when handled. Compulsive clockwise or counter-clockwise circling may be seen in sheep with atypical scrapie.</li>
</ol>
3. Menace Response Testing
<ol>
	<li>Hold the animal&#8217;s head for testing of the menace response: move the hand or several fingers several times towards each eye of the animal to induce a blink response but be careful not to touch any facial hairs or create any air turbulence that may cause the animal to blink.</li>
	<li>The menace response may be absent in scrapie-affected animals, particularly in sheep with atypical scrapie. Although testing of the menace response is the only cranial nerve testing used as part of the protocol, visual inspection of the face during this procedure may reveal other signs of neurologic deficits not normally seen in scrapie, e.g. facial paralysis. If the animal does not blink in response to the menace it is advisable to test the palpebral reflex by touching the eyelids to ensure that the animal&#8217;s inability to blink is not caused by facial paralysis.</li>
</ol>
4. Testing of the Scratch Response
<ol>
	<li>Ensure the animal is calm during this procedure because the test cannot be interpreted in a struggling animal.</li>
	<li>Scratch areas of the back at the thoracic, lumbar, and sacral regions, pausing between each scratching episode.</li>
	<li>If the animal responds with rhythmical head or body movements, or moves or licks its lips upon scratching of one particular area, repeat the scratch test to confirm reproducibility of the scratch response.</li>
	<li>A repeatable response is usually elicited in animals that are pruritic, which usually includes sheep with classical scrapie or goats with the pruritic form of scrapie, but there is generally no response in sheep with atypical scrapie unless other pruritic skin conditions or ectoparasites are present.</li>
</ol>
5. Checking for Wool Loss and Skin Lesions
<ol>
	<li>Inspect the skin.</li>
	<li>Pruritus due to scrapie usually causes hair loss, which may be on the poll, back, rump, side of chest or abdomen due to excessive rubbing or scratching where the underlying skin appears normal.</li>
	<li>Abrasions may appear later if the animal has the opportunity to rub on sharp objects. Bite wounds may appear, particularly on the limbs, due to excessive nibbling of the limbs.</li>
</ol>
6. Scoring Body Condition
<ol>
	<li>Assess the animal&#8217;s body condition by palpating the dorsal and transverse processes of the lumbar vertebrae.</li>
	<li>Scrapie may cause a progressive loss of body condition where the transverse processes of the lumbar vertebrae can be easily felt individually, and the ends of the processes appear sharp.</li>
</ol>
7. Blindfolding the Animal
<ol>
	<li>Cover the animal&#8217;s eyes with a hood, which can be made by using any nonsee-through bag where one corner is cut off to allow breathing of the animal.</li>
	<li>Release the animal only if there are no safety concerns, and there is no risk of injury due to a panicking animal; otherwise keep hold of the sheep and study animal movements whilst still in control of the animal.</li>
	<li>Blindfolding may exacerbate signs of a vestibular system or cerebellar dysfunction, which may be obscured by the animal&#8217;s ability to compensate through its vision. Loss of balance, incoordination, or circling may be elicited, particularly in otherwise clinically unremarkable sheep with atypical scrapie.</li>
</ol>
8. Assessment of the Animal&#8217;s Movement
<ol>
	<li>Study the animal&#8217;s gait and muscle movements when it moves freely.</li>
	<li>Incoordination may be characterized by wide-based movements of the hind limbs, hopping with both hind limbs, or swaying excessively in the hind quarters, which may result in stumbling or briefly sitting down.</li>
	<li>The presence of a head tremor is often subtle when the animal is undisturbed but may become more noticeable during or after completion of the clinical examination.</li>
</ol>
9. Interpretation
<ol>
	<li>Consider the significance of the findings with respect to scrapie.</li>
	<li>Although the presence of individual signs, such as a repeatable response to scratching, tremor, abnormal behavior, circling, collapsing episodes, ataxia, or an absent menace response, may have various causes, the combined occurrence of two or more of these signs is highly suggestive of scrapie in sheep or goats.</li>
</ol>

<ol>
	<li>Benestad, S. L., Arsac, J. N., Goldmann, W., N&#246;remark, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Atypical/Nor98+scrapie:+properties+of+the+agent,+genetics,+and+epidemiology.">Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology.</a> Vet Res.. 39 (4), 19 (2008).</li><li>D&#39;Angelo, A., Maurella, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+clinical+criteria+to+diagnose+scrapie+in+Italy.">Assessment of clinical criteria to diagnose scrapie in Italy.</a> Vet. J. 174 (1), 106-112 (2007).</li><li>Eloit, M., Adjou, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=BSE+agent+signatures+in+a+goat.">BSE agent signatures in a goat.</a> Vet. Rec. 156 (16), 523-524 (2005).</li><li>Fediaevsky, A., Maurella, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+prevalence+of+atypical+scrapie+in+sheep+from+positive+flocks+is+not+higher+than+in+the+general+sheep+population+in+11+European+countries.">The prevalence of atypical scrapie in sheep from positive flocks is not higher than in the general sheep population in 11 European countries.</a> BMC Vet. Res. 6, 9 (2010).</li><li>Healy, A. M., Weavers, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+clinical+neurology+of+scrapie+in+Irish+sheep.">The clinical neurology of scrapie in Irish sheep.</a> J. Vet. Intern. Med. 17 (6), 908-916 (2003).</li><li>Houston, E. F., Gravenor, M. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+signs+in+sheep+experimentally+infected+with+scrapie+and+BSE.">Clinical signs in sheep experimentally infected with scrapie and BSE.</a> 152 (11), 333-334 (2003).</li><li>Kittelberger, R., Chaplin, M. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Atypical+scrapie/Nor98+in+a+sheep+from+New+Zealand.">Atypical scrapie/Nor98 in a sheep from New Zealand.</a> J. Vet. Diagn. Invest. 22 (6), 863-875 (2010).</li><li>Konold, T., Bone, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Associations+of+clinical+signs+and+prion+protein+genotypes+in+British+sheep+with+scrapie.">Associations of clinical signs and prion protein genotypes in British sheep with scrapie.</a> Dtsch. Tier&#228;rztl. Wochenschr. 116 (11), 380-388 (2009).</li><li>Konold, T., Bone, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Scrapie+in+goats.">Scrapie in goats.</a> Vet. Rec. 161 (11), 395-396 (2007).</li><li>Konold, T., Bone, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pruritus+is+a+common+feature+in+sheep+infected+with+the+BSE+agent.">Pruritus is a common feature in sheep infected with the BSE agent.</a> BMC Vet. Res. 4, 16 (2008).</li><li>Konold, T., Bone, G. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Monitoring+of+clinical+signs+in+goats+with+transmissible+spongiform+encephalopathies.">Monitoring of clinical signs in goats with transmissible spongiform encephalopathies.</a> BMC Vet. Res. 6, 13 (2010).</li><li>Konold, T., Davis, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+findings+in+two+cases+of+atypical+scrapie+in+sheep:+a+case+report.">Clinical findings in two cases of atypical scrapie in sheep: a case report.</a> BMC Vet. Res. 3, 1 (2007).</li><li>Passler, T., Walz, P. H., Pugh, D. G., Pugh, D. G., Baird, A. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Diseases of the Neurologic System. In: Sheep and Goat Medicine. , 361-405 (2012).</li><li>Russel, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Body+condition+scoring+of+sheep.">Body condition scoring of sheep.</a> In Pract. 6 (3), 91-93 (1984).</li><li>Simmons, H. A., Simmons, M. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Atypical+scrapie+in+sheep+from+a+UK+research+flock+which+is+free+from+classical+scrapie.">Atypical scrapie in sheep from a UK research flock which is free from classical scrapie.</a> BMC Vet. Res. 5, 8 (2009).</li><li>Simmons, M. M., Konold, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+natural+atypical+scrapie+phenotype+is+preserved+on+experimental+transmission+and+sub-passage+in+PRNP+homologous+sheep.">The natural atypical scrapie phenotype is preserved on experimental transmission and sub-passage in PRNP homologous sheep.</a> BMC Vet. Res. 6, 14 (2010).</li><li>Spiropoulos, J., Lockey, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolation+of+prion+with+BSE+properties+from+farmed+goat.">Isolation of prion with BSE properties from farmed goat.</a> Emerg. Infect. Dis. 17 (12), 2253-2261 (2011).</li><li>Ulvund, M. J., H&#246;rnlimann, B., Riesner, D., Kretzschmar, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Clinical Findings in Scrapie. In: Prions in humans and animals. , 398-407 (2006).</li></ol>

All procedures involving animals were carried out in accordance with the Animal (Scientific Procedures) Act 1986, under license from the UK Government Home Office. 
The authors declare that they have no competing financial interests.

Scrapie is a listed disease by the World Health Organization for Animal Health (OIE), which, in the absence of a quick and reliable ante mortem test, relies on the farmers&#8217; or veterinarians&#8217; ability to recognize the clinical signs associated with this disease. Most scrapie cases, particularly atypical scrapie cases, however, are currently found by targeted TSE surveillance, i.e. by brain examination of small ruminants subject to slaughter or fallen stock animals. Breeding sheep for resistance to classical scrapie, which reduced the number of classical scrapie cases, most likely also reduced people&#8217;s awareness for the disease so that it is less often considered in the differential diagnosis of neurologic disorders in sheep. Atypical scrapie also has a low prevalence with approximately five cases in abattoirs and eight cases in fallen stock per 10,000 tested in Europe4. In addition, pruritus, usually evident as alopecia with or without excoriation, is often considered a characteristic sign of scrapie13. Thus, a neurologic disease without concomitant pruritus as observed in atypical scrapie12 or the nonpruritic form of caprine scrapie11 may not raise suspicion of scrapie.
This examination protocol was designed to identify clinical signs of TSE in sheep by evaluating specific clinical signs associated with various types of scrapie (atypical and classical scrapie, the latter represented by an atypical BSE-inoculated sheep, which presented with classical scrapie-like signs). In classical scrapie, the percentage of cases that displayed a positive scratch response (&#8220;nibble reflex&#8221;) ranged from 50-77 in over 100 sheep studied5,8. Movement disorders can be observed in up to 81% of classical scrapie cases based on various studies18. Incoordination is also a major sign in various naturally occurring cases of atypical scrapie, often accompanied by behavioral changes1, but additional signs reported in both naturally and experimentally infected atypical scrapie sheep were circling and visual impairment12,15,16, which is why blindfolding and the testing of the menace response is included in the examination protocol. Scoring the body condition, for example using a 6 point scoring system14, enables evaluation of emaciation, which may be observed in scrapie-affected sheep5. Although clinical criteria to aid in the detection of scrapie in sheep have been proposed previously2, these only related to the detection of classical scrapie and took the clinical history into account, which may not be available if animals are presented at an abattoir.
The current protocol allows screening of many animals for signs of scrapie within a short period of time. Furthermore, the examination protocol can be applied to experimental studies of scrapie in sheep and goats to monitor clinical onset, progression, and end-point. However, it does not replace a more detailed physical and neurologic examination with appropriate recording of the clinical case history, possibly followed by ancillary diagnostic tests (examination of blood and cerebrospinal fluid; more sophisticated imaging techniques if appropriate), which may be necessary subsequently to rule out various other conditions in small ruminants that present with similar signs, such as metabolic or inflammatory neurological diseases, brain abscesses, or tumors.
Although a clinical examination is generally less sensitive in detecting TSE-affected animals than post mortem tests based on detection of prion protein2,11, particularly in an early stage of the incubation period, this is currently the only detection method in live animals and most relevant to those countries that do not have a targeted surveillance system in place to identify TSE-affected small ruminants.

Scrapie is a transmissible spongiform encephalopathy (TSE) of sheep and goats, which belongs to the group of protein misfolding disorders, like bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease in deer, and Creutzfeldt-Jakob disease in humans. The diagnosis is made post mortem by detecting the abnormal form of the prion protein, which is proteinase-resistant, usually in the brain. Two major naturally occurring scrapie forms can be distinguished, which are epidemiologically, pathologically, and biochemically different: classical scrapie and atypical scrapie. In addition, a neurological disease with classical scrapie-like clinical signs can be induced in sheep and goats by experimental infection with the BSE agent6,10-11. In fact, naturally occurring BSE has been diagnosed in goats3,17. Control of classical scrapie (and BSE in sheep if it occurred naturally) has been achieved by breeding for genetic resistance targeting the prion protein gene, but this is more difficult for atypical scrapie, which is believed to be a sporadic disease and has been diagnosed in countries considered to be free from classical scrapie, e.g. New Zealand7.
Scrapie is a neurologic disease of adult sheep and goats resulting in changes in behavior, sensation, and movement, but the disease is slowly progressive, and clinical signs are often not recognized because the animal keeper or veterinary surgeon may not be familiar with the clinical signs, or scrapie is not considered at all in the differential diagnosis of neurologic diseases in small ruminants.
The proposed examination protocol was designed to aid in the clinical diagnosis of scrapie with two purposes in mind: it should be considerably brief to allow scanning of many animals within a short period of time but specific enough to allow detection of scrapie-affected animals, which is achieved by assessing the presence of clinical signs frequently encountered in scrapie-affected animals. This protocol is a slight modification from the one used to monitor goats for signs of classical scrapie11 and includes blindfolding of the animal, which may exacerbate clinical signs not normally associated with scrapie9.

clinical examination protocol to detect atypical and classical scrapie in sheep

The diagnosis of scrapie, a transmissible spongiform encephalopathy (TSEs) of sheep and goats, is currently based on the detection of disease-associated prion protein by post mortem tests. Unless a random sample of the sheep or goat population is actively monitored for scrapie, identification of scrapie cases relies on the reporting of clinical suspects, which is dependent on the individual&#39;s familiarization with the disease and ability to recognize clinical signs associated with scrapie. Scrapie may not be considered in the differential diagnosis of neurological diseases in small ruminants, particularly in countries with low scrapie prevalence, or not recognized&#160;if it presents as nonpruritic form like atypical scrapie. To aid in the identification of clinical suspects, a short examination protocol is presented to assess the display of specific clinical signs associated with pruritic and nonpruritic forms of TSEs in sheep, which could also be applied to goats. This includes assessment of behavior, vision (by testing of the menace response), pruritus (by testing the response to scratching), and movement (with and without blindfolding). This may lead to a more detailed neurologic examination&#160;of reporting animals as scrapie suspects. It&#160;could also be used in experimental TSE studies of sheep or goats to evaluate disease progression or to identify clinical end-point.

Clinically healthy sheep. Poll Dorset wether from a scrapie-free flock intracerebrally inoculated with bovine brain of New Zealand origin and examined at 49 months post inoculation. This sheep has a normal posture, behaves normally, displays a normal menace response (Figure 1), does not react to the scratch test, has an intact fleece, and a very good body condition. It is clinically unremarkable when blindfolded and shows no signs of a movement disorder.
Atypical scrapie sheep presenting with the nonpruritic form of TSEs in sheep. Cheviot wether from a scrapie-free flock intracerebrally inoculated with brain homogenate from an atypical scrapie field case of the same prion protein genotype (AHQ/AHQ) and examined at 36 months post inoculation. This sheep also has a normal posture but behaves differently to the other sheep in the pen and circles in clockwise direction. It does not blink when the menace response is tested. Scratching does not elicit any response, and no fleece changes are apparent, but the body condition is only fair. It circles clockwise when blindfolded (Figure 2) and loses balance. The gait is ataxic, and a fine head tremor is visible.
Atypical BSE sheep presenting with the pruritic form of TSEs in sheep, which is clinically similar to the clinical presentation of classical scrapie-affected sheep. For this reason, a classical scrapie case is not included. Poll Dorset wether from a scrapie-free flock intracerebrally inoculated with bovine atypical (L-type) BSE brain homogenate and examined at 50 months post inoculation. This sheep stands slightly hunched, tends to keep the hind limbs wide-based and falls on the floor when caught. The menace response is weak. Scratching of various areas of the back elicits head or lip movements (Figure 3), and there is wool loss with minor skin trauma on the poll. The body condition is good. When blindfolded, it is reluctant to move and rests its rear end on the hurdle to maintain balance. The sheep is ataxic and displays fore limb hypermetria.
<img alt="Figure 1" fo:content-width="5in" fo:src="/files/ftp_upload/51101/51101fig1highres.jpg" src="/files/ftp_upload/51101/51101fig1.jpg" /> 
Figure 1.&#160;Menace response testing. Menacing gesture towards the animal&#8217;s eye induces a blink response. <a href="https://www.jove.com/files/ftp_upload/51101/51101fig1highres.jpg" target="_blank">Click here to view larger image.</a>
<img alt="Figure 2" fo:content-width="5in" fo:src="/files/ftp_upload/51101/51101fig2highres.jpg" src="/files/ftp_upload/51101/51101fig2.jpg" /> 
Figure 2.&#160;Blindfolding. Clockwise circling elicited by blindfolding the sheep with a hood. <a href="https://www.jove.com/files/ftp_upload/51101/51101fig2highres.jpg" target="_blank">Click here to view larger image.</a>
<img alt="Figure 3" fo:content-width="5in" fo:src="/files/ftp_upload/51101/51101fig3highres.jpg" src="/files/ftp_upload/51101/51101fig3.jpg" /> 
Figure 3.&#160;Testing of the scratch response. Scratching of the back elicits lip licking with sideward movements of the head <a href="https://www.jove.com/files/ftp_upload/51101/51101fig3highres.jpg" target="_blank">Click here to view larger image.</a>

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Clinical Examination Protocol to Detect Atypical and Classical Scrapie in Sheep

A short clinical examination protocol is presented to aid in the detection of classical and atypical scrapie in sheep and goats.

The diagnosis of scrapie, a transmissible spongiform encephalopathy (TSEs) of sheep and goats, is currently based on the detection of disease-associated ...

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12.7K Views.  Animal Health and Veterinary Laboratories Agency Weybridge. A short clinical examination protocol is presented to aid in the detection of classical and atypical scrapie in sheep and goats.

Video: Clinical Examination Protocol to Detect Atypical and Classical Scrapie in Sheep

Using Visual and Narrative Methods to Achieve Fair Process in Clinical Care

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The Institute of Medicine has targeted patient-centeredness as an important area of quality improvement. A major dimension of patient-centeredness is ...

EEG Mu Rhythm in Typical and Atypical Development

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Common foot and ankle pathologies have been linked to isolated Musculus gastrocnemius tightness (MGT). Various examination techniques have been described ...

Echocardiographic and Histological Examination of Cardiac Morphology in the Mouse

An increasing number of genetically modified mouse models has become available in recent years. Moreover, the number of pharmacological studies performed in mice is high. Phenotypic characterization of these mouse models also requires the examination of cardiac function and morphology. Echocardiography and magnetic resonance imaging (MRI) are commonly used approaches to characterize cardiac function and morphology in mice. Echocardiographic and MRI equipment specialized for use in small rodents is&#160;expensive and requires a dedicated space. This protocol describes cardiac measurements in mice using a clinical echocardiographic system with a 15 MHz human vascular probe. Measurements are performed on anesthetized adult mice. At least three image sequences are recorded and analyzed for each animal in M-mode in the parasternal short-axis view. Afterwards, cardiac histological examination is performed, and cardiomyocyte diameters are determined on hematoxylin-eosin- or wheat germ agglutinin (WGA)-stained paraffin sections. Vessel density is determined morphometrically after Pecam-1 immunostaining. The protocol has been applied successfully to pharmacological studies and different genetic animal models under baseline conditions, as well as after experimental myocardial infarction by the permanent ligation of the left anterior descending coronary artery (LAD). In our experience, echocardiographic investigation is limited to anesthetized animals and is feasible in adult mice weighing at least 25 g.

Echocardiographic examination is frequently used in mice. Expensive high-resolution ultrasound devices have been developed for this purpose. This protocol describes an affordable echocardiographic procedure combined with histological morphometric analyses to determine cardiac morphology.

An increasing number of genetically modified mouse models has become available in recent years. Moreover, the number of pharmacological studies performed ...

Protocol to Create Chronic Wounds in Diabetic Mice

Chronic wounds develop as a result of defective regulation in one or more complex cellular and molecular processes involved in proper healing. They impact ~6.5M people and cost ~$40B/year in the US alone. Although a significant effort has been invested in understanding how chronic wounds develop in humans, fundamental questions remain unanswered. Recently, we developed a novel mouse model for diabetic chronic wounds that have many characteristics of human chronic wounds. Using db/db-/- mice, we can generate chronic wounds by inducing high levels of oxidative stress (OS) in the wound tissue immediately after wounding, using a one-time treatment with inhibitors specific to the antioxidant enzymes catalase and glutathione peroxidase. These wounds have high levels of OS, develop biofilm naturally, become fully chronic within 20 days after treatment and can remain open more for more than 60 days. This novel model has many features of diabetic chronic wounds in humans and therefore can contribute significantly to advancing fundamental understanding of how wounds become chronic. This is a major breakthrough because chronic wounds in humans cause significant pain and distress to patients and result in amputation if unresolved. Moreover, these wounds are very expensive and time-consuming to treat, and lead to significant loss of personal income to patients. Advancements in this field of study through the use of our chronic wound model can significantly improve health care for millions who suffer under this debilitating condition. In this protocol, we describe in great detail the procedure to cause acute wounds to become chronic, which has not been done before.

Chronic wounds are developed from acute wounds on a diabetic mouse model by inducing high levels of oxidative stress after a full-thickness cutaneous wound. The wound is treated with inhibitors for catalase and glutathione peroxidase, resulting in impaired healing and biofilm development by bacteria present in the skin microbiome.

Chronic wounds develop as a result of defective regulation in one or more complex cellular and molecular processes involved in proper healing. They impact ...

A Clinical Trial Assessing the Safety, Efficacy, and Delivery of Olive-Oil-Based Three-Chamber Bags for Parenteral Nutrition

Limited evidence exists to precisely estimate efficacy and safety differences between parenteral nutrition (PN) prepared using olive-oil-based three-chamber bags (3CBs) and soybean-oil-based compounded bags (CoBs) in hospitalized adult patients. We designed a multicenter, randomized, prospective, open-label, noninferiority protocol to compare the efficacy, safety, and distribution of olive-oil-based 3CBs and soybean-oil-based CoB formulations in adult Chinese patients requiring PN during surgical intervention. Subjects were randomized to receive either one of the study treatments using an interactive voice or web-based recognition system in accordance with the randomization code. Randomization was further stratified based on the study site and surgical category. Both treatment groups received similar amounts of calories and protein. In addition, the two study treatments contained a similar composition of the amino-acid component. The only difference between the two PN formulations was the lipid constitution. The duration of administration of study treatments was a minimum of 5 days up to a maximum of 14 days after the surgical procedure. The primary efficacy endpoint was serum prealbumin levels on day 5 of the study. Noninferiority was proved if the anti-log of the lower bound of the 95% confidence interval (CI) of the treatment difference was at least 0.80. Other efficacy measures included treatment preparation time; duration to achieve tolerability of oral nutrition; associated infectious complications; length of hospitalization; and laboratory assessment of markers of nutrition, inflammation, metabolism, and oxidative stress. A total of 458 patients were enrolled in the study. The results showed that olive-oil-based 3CBs were non-inferior to soybean-based CoBs, besides being well tolerated. The infection rate was found to be significantly lower in the olive-oil-based 3CB group. Thus, this study may be used as a reference for future research on lipid emulsion and 3CBs.

Here, we present a protocol for a study comparing the efficacy, safety, and delivery of olive-oil-based 3CB and soybean-oil-based CoB formulations in adults requiring parenteral nutrition. The results revealed that olive-oil-based 3CBs is non-inferior and well tolerated compared to soybean formulations.

Limited evidence exists to precisely estimate efficacy and safety differences between parenteral nutrition (PN) prepared using olive-oil-based ...

Observational Study Protocol for Repeated Clinical Examination and Critical Care Ultrasonography Within the Simple Intensive Care Studies

Longitudinal evaluations of critically ill patients by combinations of clinical examination, biochemical analysis and critical care ultrasonography (CCUS) may detect adverse events of interventions such as fluid overload at an early stage. The Simple Intensive Care Studies (SICS) is a research line that focuses on the prognostic and diagnostic value of combinations of clinical variables.
The SICS-I specifically focused on the use of clinical variables obtained within 24 h of acute admission for prediction of cardiac output (CO) and mortality. Its sequel, SICS-II, focuses on repeated evaluations during ICU admission. The first clinical examination by trained researchers is performed within 3 h after admission consisting of physical examination and educated guessing. The second clinical examination is performed within 24 h after admission and includes physical examination and educated guessing, biochemical analysis and CCUS assessments of heart, lungs, inferior vena cava (IVC) and kidney. This evaluation is repeated at days 3 and 5 after admission. CCUS images are validated by an independent expert, and all data is registered in an online secured database. Follow-up at 90 days includes registration of complications and survival status according to patient&#39;s medical charts and the municipal person registry. The primary focus of SICS-II is the association between venous congestion and organ dysfunction.
The purpose of publishing this protocol is to provide details on the structure and methods of this on-going prospective observational cohort study allowing answering multiple research questions. The design of the data collection of combined clinical examination and CCUS assessments in critically ill patients are explicated. The SICS-II is open for other centers to participate and is open for other research questions that can be answered with our data.

Structured protocols are necessary to provide answers on research questions in critically ill patients. The Simple Intensive Care Studies (SICS) provides an infrastructure for repeated measurements in critically ill patients including clinical examination, biochemical analysis and ultrasonography. SICS projects have specific focus but the structure is flexible to other investigations.

Longitudinal evaluations of critically ill patients by combinations of clinical examination, biochemical analysis and critical care ultrasonography (CCUS) ...

Transthoracic Echocardiographic Examination in the Rabbit Model

Large animal models such as the rabbit are valuable for translational preclinical research. Rabbits have a similar cardiac electrophysiology compared to that of humans and that of other large animal models such as dogs and pigs. However, the rabbit model has the additional advantage of lower maintenance costs compared to other large animal models. The longitudinal evaluation of cardiac function using echocardiography, when appropriately implemented, is a useful methodology for preclinical assessment of novel therapies for heart failure with reduced ejection fraction (e.g. cardiac regeneration). The correct use of this non-invasive tool requires the implementation of a standardized examination protocol following international guidelines. Here we describe, step by step, a detailed protocol supervised by veterinary cardiologists for performing echocardiography in the rabbit model, and demonstrate how to correctly obtain the different echocardiographic views and imaging planes, as well as the different imaging modes available in a clinical echocardiography system routinely used in human and veterinary patients.

Here we describe, step by step, a detailed protocol for performing echocardiography in the rabbit model. We show how to correctly obtain the different echocardiographic views and imaging planes, as well as the different imaging modes available in a clinical echocardiography system routinely used in human and veterinary patients.

Large animal models such as the rabbit are valuable for translational preclinical research. Rabbits have a similar cardiac electrophysiology compared to ...

Clinical Practice Protocol of Creative Music Therapy for Preterm Infants and Their Parents in the Neonatal Intensive Care Unit

Creative music therapy for preterm infants and their parents (CMT) has emerged as a promising family-integrated early intervention involving communicative musicality to improve infant development, parental well-being, and bonding. It aims at relaxing and nurturing the infant as well as promoting safety and social interaction for the parent-infant dyad. A music therapist specially trained in CMT hums or sings in an infant-directed, improvised, lullaby style continually adjusting to the individual needs, expressions, and breathing pattern of the preterm infant. Based on the principles of family-integrated care, the family is incorporated individually in the therapeutic process, namely by delivering CMT during kangaroo care (KC) and by motivating and facilitating parental vocal interaction with their infant to strengthen the parent-infant bonding. CMT aims at relaxing, stimulating, and coregulating premature infants at a time when many other interventions are still risky and can overwhelm the vulnerable patient group. CMT may be advantageous not by educating and teaching parents, but rather by uncovering the intuitive capacities of parenting that are often overshadowed by the traumatic experience of preterm birth. However, CMT can only be provided when the infants are clinically stable. CMT with parental integration is feasible when parents are available and receptive to participate. This paper presents a detailed protocol on how to use CMT to empower preterm infants and their families.

Creative music therapy for preterm infants and their parents has emerged as a promising family-integrated early intervention. We present a detailed protocol on how to use vocal interaction, humming, or singing to empower preterm infants and their families.

Creative music therapy for preterm infants and their parents (CMT) has emerged as a promising family-integrated early intervention involving communicative ...