Rationale and design of the AngeLmed for Early Recognition and Treatment of STEMI trial: a randomized, prospective clinical investigation.

Significant improvements in door-to-balloon times have led to a reduction in mortality in ST-segment elevation myocardial infarction; however, mean symptom-to-door times remain at 2 to 3 hours. An intracardiac electrogram monitoring device may be beneficial in high-risk patients by alerting them to rapidly progressive ST-segment changes indicative of acute coronary occlusion. The Cardiosaver and DETECT phase I clinical studies demonstrated the safety, feasibility, and potential benefit of using an intracardiac electrogram monitoring device to alert the patient to seek medical attention. The goal of the randomized, prospective ALERTS Trial (Clinicaltrials.gov no. NCT00781118) is to evaluate the efficacy of an implantable monitoring device (IMD) in reducing the composite of either cardiac or unexplained death, new Q-wave myocardial infarction, or symptom-to-door time of >2 hours for confirmed thrombotic events. The IMD alerts the patient in real time when ST-segment deviation from a personalized baseline exceeds the trigger threshold. The trial is designed to enroll high-risk post-acute coronary syndrome patients or patients with previous multivessel coronary artery bypass surgery. All patients have the IMD implanted, with 1:1 unblinded randomization to the alerting feature being either turned on versus turned off for the first 6 months. Randomization occurs at the first follow-up visit, 7 to 14 days after the implantation of the IMD. Subjects then return for follow-up visits at months 1, 3, and 6 and thereafter every 6 months until closure of the investigational device exemption. Subjects who cannot be implanted successfully or who have the device explanted are removed from the study and followed up for a minimum of 30 days post-procedure. If a subject experiences a device-related complication and/or adverse experience, the subject is followed up until resolution or until the condition becomes stable and no further change is anticipated.

Concurrent radiological and ultrasonographical findings in the forelimb proximal sesamoid bones and adjacent suspensory ligament branches in yearling and 2-year-old Thoroughbred sales horses.

BACKGROUND: Changes in the proximal sesamoid bones (sesamoids) and the insertional region of the adjacent suspensory ligament branch (branch) are of particular importance in young Thoroughbreds sold at public auction. Little is known about the prevalence of concurrent ultrasonographical branch change, relative to the various grades of radiological sesamoid appearance. OBJECTIVE: To examine the existence of concurrent radiological and ultrasonographical findings in individual sesamoid-branch units in sales horses; to determine whether there are any radiological findings that are consistently accompanied by a particular degree of insertional branch change, and to provide practical recommendations as to when suspensory branch ultrasonography may be warranted in a sales environment. STUDY DESIGN: Prospective cohort study using an enrolled sample. METHODS: Horses were enrolled with consignor permission from a large Thoroughbred yearling sale and five 2-year-old Thoroughbred sales the following year. Data from the radiological evaluation of forelimb sesamoids and the ultrasonographical examination of the adjacent forelimb suspensory branches were described. RESULTS: A total of 2204 yearling forelimb sesamoid-branch units and 1336 2-year-old forelimb sesamoid-branch units were included, from 551 sales yearlings and 334 sales 2-year-olds. The proportion of yearling sesamoids with grade ≤1 vascular channels that had adjacent grade ≥2 fibrillar branch change was 1.2%. The same proportion for 2-year-olds was 3.8%, with medial forelimb sesamoids with grade 1 vascular channels overrepresented in 2-year-olds in this category. In yearlings, 31% of sesamoids with grade 2 vascular channels had adjacent grade ≥2 fibrillar branch change and 59% of sesamoids with grade 3 vascular channels had adjacent grade ≥2 fibrillar branch change. In 2-year-olds, 47% of sesamoids with grade 2 vascular channels had adjacent grade ≥2 fibrillar branch change and 67% of sesamoids with grade 3 vascular channels had the same. Only one yearling sesamoid and one 2-year-old sesamoid with radiological abaxial concavity had grade ≥2 fibrillar branch change. MAIN LIMITATIONS: Hindlimbs were not included. Clinical examinations were not performed and the status of any past or present inflammatory process at the sesamoid-branch enthesis could not be inferred from radiographs and ultrasonographic images alone. CONCLUSIONS: The existence and prevalence of concurrent radiological and ultrasonographical findings in the proximal sesamoid bones and adjacent suspensory ligament branches in yearling and 2-year-old Thoroughbred sales horses has been established. General recommendations have been made for selective branch ultrasonography on the basis of radiological sesamoid appearance. The results support a separate aetiology for radiological sesamoid abaxial concavity that does not primarily involve the suspensory branch insertion.

Radiological findings in the proximal sesamoid bones of yearling and 2-year-old Thoroughbred sales horses: Prevalence, progression and associations with racing performance.

BACKGROUND: Radiological findings in the proximal sesamoid bones (sesamoids) are a persistent source of controversy at Thoroughbred sales, due to inconsistent classification and conflicting assignment of potential clinical importance. OBJECTIVES: To define the prevalence of sesamoid findings on sales repository radiographs in yearling and 2-year-old Thoroughbreds and to analyse associations with racing performance. To track the changes in sesamoid findings between 1 and 2 years of age in horses that present for sale at both ages. STUDY DESIGN: Prospective cohort study using an enrolled sample. METHODS: Horses were enrolled from a 2016 yearling sale and five 2017 2-year-old sales with consignor permission. Radiological findings relating to sesamoid vascular channel appearance, abaxial contour changes and sesamoid fragments were examined. Associations between sesamoid findings and racing performance from 2 to 4 years of age were examined using multivariate regression analyses. Clinical follow-up was sought to ascertain why horses that did not race never started. RESULTS: A total of 2508 yearlings and 436 2-year-olds were included for evaluation. Interobserver agreement using the new grading system was substantial. Yearling findings associated with a significantly reduced probability of starting a race were: Grade 3 vascular channels in forelimb sesamoids (0.52, P < 0.001, 95% confidence interval (CI): 0.37-0.67), abaxial new bone in forelimb sesamoids (0.62, P = 0.01, 95% CI: 0.49-0.73), apical or abaxial fragments in forelimb sesamoids (0.55, P = 0.005, 95% CI: 0.37-0.72). For affected horses that did race, Grade 3 vascular channels in forelimb sesamoids were associated with fewer race starts (9.9 starts, P = 0.03, 95% CI: 8.0-12.2) and Grade 3 vascular channels in hindlimb sesamoids were associated with a delayed start to racing careers (54 days, P = 0.01, 95% CI: 20-89). Abaxial new bone in forelimb sesamoids was associated with a 54% reduction in total earnings (P = 0.003, 95% CI: 24-72) and a 46% reduction in earnings per start (P = 0.002, 95% CI: 21-64). Abaxial concavity occurred predominantly in yearling medial forelimb sesamoids, had no impact on racing performance and mostly resolved by 2-year-old sale. MAIN LIMITATIONS: These findings are applicable to horses presented for sale at public auction and may underestimate the prevalence of severe lesions in non-sales horses. CONCLUSIONS: Grade 3 vascular channels, forelimb sesamoid abaxial new bone and forelimb sesamoid fragments are important findings in sales repository radiology. The new grading scale assigns a numerical grade for vascular channel appearance that matches the number of enlarged vascular channels evident in a given sesamoid. Abaxial contour changes, when present in sesamoids that are Grade 0 for enlarged vascular channels, are noted separately as either abaxial new bone or abaxial concavity. Fragments are also noted and interpreted separately.

Ultrasonography of the suspensory ligament branches in yearling and 2-year-old Thoroughbred sales horses: Prevalence, progression of findings and associations with racing performance.

BACKGROUND: Equine suspensory ligament branch (branch) ultrasonography is becoming increasingly commonplace presale. No ultrasonographical branch reference data exists for Thoroughbred sales horses. OBJECTIVES: To define the prevalence of ultrasonographical findings in the forelimb suspensory branches of yearling and 2-year-old sales Thoroughbreds and to analyse associations with racing performance. To track changes in branch findings between 1 and 2 years of age in horses that present for sale at both ages. STUDY DESIGN: Prospective cohort study using an enrolled sample. METHODS: Horses were enrolled from a 2016 yearling sale and five 2017 2-year-old sales with consignor permission. Ultrasonography was performed immediately prior to the sales. Ultrasonographical findings relating to branch size, fibrillar pattern, the presence of hyperechoic foci, periligamentar tissue thickness and the adjacent proximal sesamoid bone surface were examined. Associations with racing performance from 2 to 4 years of age were investigated using multivariate regression analyses. Clinical follow-up was sought to ascertain why horses that did not race never started. RESULTS: A total of 593 sales yearlings and 367 2-year-olds had forelimb branch ultrasonography performed. Grade ≥2 fibrillar branch change was present in 8.9% of yearlings and 14.4% of 2-year-olds. A 0.25 cm increase in branch width was associated with a 49-day delayed start to racing careers (P < 0.001, 95% confidence interval (95% CI): 21-77 days). The presence of grade 2 hyperechoic foci was associated with significantly lower total earnings (P = 0.01, 95% CI: $2000-$16 022) and lower earnings per start (P = 0.003, 95% CI: $349-$1718) in United States Dollars. Grade 3 fibrillar branch change had clinically important reductions in the probability of racing, the calibre of racing performance and earnings. Grade 1 fibrillar pattern was associated with significantly higher earnings per start (P = 0.004, 95% CI: $2641-$5759). MAIN LIMITATIONS: The findings are applicable to horses prepared for public auction and deemed fit to be entered for sale. The results may underestimate the proportion of severe lesions in horses not entered for sale. CONCLUSIONS: Reference values specific to young Thoroughbreds have been established. Grade 1 fibrillar branch change should be regarded as an acceptable appearance in sales yearlings and 2-year-olds. Approximately one-third of grade 2 yearling branches progressed to a grade 3 lesion. Evidence of enlarged branch width and grade 2 hyperechoic foci at 2-year-old sales constitute a risk to racing performance.

Cadherin-mediated differential cell adhesion controls slow muscle cell migration in the developing zebrafish myotome.

Slow-twitch muscle fibers of the zebrafish myotome undergo a unique set of morphogenetic cell movements. During embryogenesis, slow-twitch muscle derives from the adaxial cells, a layer of paraxial mesoderm that differentiates medially within the myotome, immediately adjacent to the notochord. Subsequently, slow-twitch muscle cells migrate through the entire myotome, coming to lie at its most lateral surface. Here we examine the cellular and molecular basis for slow-twitch muscle cell migration. We show that slow-twitch muscle cell morphogenesis is marked by behaviors typical of cells influenced by differential cell adhesion. Dynamic and reciprocal waves of N-cadherin and M-cadherin expression within the myotome, which correlate precisely with cell migration, generate differential adhesive environments that drive slow-twitch muscle cell migration through the myotome. Removing or altering the expression of either protein within the myotome perturbs migration. These results provide a definitive example of homophilic cell adhesion shaping cellular behavior during vertebrate development.

Implanted Monitor Alerting to Reduce Treatment Delay in Patients With Acute Coronary Syndrome Events.

BACKGROUND: Increased pre-hospital delay during acute coronary syndrome (ACS) events contributes to worse outcome. OBJECTIVES: The purpose of this study was to assess the effectiveness of an implanted cardiac monitor with real-time alarms for abnormal ST-segment shifts to reduce pre-hospital delay during ACS events. METHODS: In the ALERTS (AngeLmed Early Recognition and Treatment of STEMI) pivotal study, subjects at high risk for recurrent ACS events (n = 907) were randomized to control (Alarms OFF) or treatment groups for 6 months, after which alarms were activated in all subjects (Alarms ON). Emergency department (ED) visits with standard-of-care cardiac test results were independently adjudicated as true- or false-positive ACS events. Alarm-to-door (A2D) and symptom-to-door (S2D) times were calculated for true-positive ACS ED visits triggered by 3 possible prompts: alarm only, alarms + symptoms, or symptoms only. RESULTS: The Alarms ON group showed reduced delays, with 55% (95% confidence interval [CI]: 46% to 63%) of ED visits for ACS events <2 h compared with 10% (95% CI: 2% to 27%) in the Alarms OFF group (p < 0.0001). Results were similar when restricted to myocardial infarction (MI) events. Median pre-hospital delay for MI was 12.7 h for Alarms OFF and 1.6 h in Alarms ON subjects (p < 0.0089). Median A2D delay was 1.4 h for asymptomatic MI. Median S2D delay for symptoms-only MI (no alarm) in Alarms ON was 4.3 h. CONCLUSIONS: Intracardiac monitoring with real-time alarms for ST-segment shift that exceeds a subject's self-normative ischemia threshold level significantly reduced the proportion of pre-hospital delays >2 h for ACS events, including asymptomatic MI, compared with symptoms-only ED visits in Alarms OFF. (AngeLmed for Early Recognition and Treatment of STEMI [ALERTS]; NCT00781118).

Scube2 mediates Hedgehog signalling in the zebrafish embryo.

The Hedgehog family of secreted morphogens specifies the fate of a large number of different cell types within invertebrate and vertebrate embryos, including the muscle cell precursors of the embryonic myotome of zebrafish. Formation of Hedgehog-sensitive muscle fates is disrupted within homozygous zebrafish mutants of the "you"-type class, the majority of which disrupt components of the Hedgehog (HH) signal transduction pathway. We have undertaken a phenotypic and molecular characterisation of one of these mutants, you, which we show results from mutations within the zebrafish orthologue of the mammalian gene scube2. This gene encodes a member of the Scube family of proteins, which is characterised by several protein motifs including EGF and CUB domains. Epistatic and molecular analyses position Scube2 function upstream of Smoothened (Smoh), the signalling component of the HH receptor complex, suggesting that Scube2 may act during HH signal transduction prior to, or during, receipt of the HH signal at the plasma membrane. In support of this model we show that scube2 has homology to cubilin, which encodes an endocytic receptor involved in protein trafficking suggesting a possible mode of function for Scube2 during HH signal transduction.

Dystrophin is required for the formation of stable muscle attachments in the zebrafish embryo.

A class of recessive lethal zebrafish mutations has been identified in which normal skeletal muscle differentiation is followed by a tissue-specific degeneration that is reminiscent of the human muscular dystrophies. Here, we show that one of these mutations, sapje, disrupts the zebrafish orthologue of the X-linked human Duchenne muscular dystrophy (DMD) gene. Mutations in this locus cause Duchenne or Becker muscular dystrophies in human patients and are thought to result in a dystrophic pathology through disconnecting the cytoskeleton from the extracellular matrix in skeletal muscle by reducing the level of dystrophin protein at the sarcolemma. This is thought to allow tearing of this membrane, which in turn leads to cell death. Surprisingly, we have found that the progressive muscle degeneration phenotype of sapje mutant zebrafish embryos is caused by the failure of embryonic muscle end attachments. Although a role for dystrophin in maintaining vertebrate myotendinous junctions (MTJs) has been postulated previously and MTJ structural abnormalities have been identified in the Dystrophin-deficient mdx mouse model, in vivo evidence of pathology based on muscle attachment failure has thus far been lacking. This zebrafish mutation may therefore provide a model for a novel pathological mechanism of Duchenne muscular dystrophy and other muscle diseases.

Met and Hgf signaling controls hypaxial muscle and lateral line development in the zebrafish.

Somites give rise to a number of different embryonic cell types, including the precursors of skeletal muscle populations. The lateral aspect of amniote and fish somites have been shown to give rise specifically to hypaxial muscle, including the appendicular muscle that populates fins and limbs. We have investigated the morphogenetic basis for formation of specific hypaxial muscles within the zebrafish embryo and larvae. Transplantation experiments have revealed a developmentally precocious commitment of cells derived from pectoral fin level somites to forming hypaxial and specifically appendicular muscle. The fate of transplanted somites cannot be over-ridden by local inductive signals, suggesting that somitic tissue may be fixed at an early point in their developmental history to produce appendicular muscle. We further show that this restriction in competence is mirrored at the molecular level, with the exclusive expression of the receptor tyrosine kinase met within somitic regions fated to give rise to appendicular muscle. Loss-of-function experiments reveal that Met and its ligand, hepatocyte growth factor, are required for the correct morphogenesis of the hypaxial muscles in which met is expressed. Furthermore, we demonstrate a requirement for Met signaling in the process of proneuromast deposition from the posterior lateral line primordia.