PREVALENCE OF OCULAR ABNORMALITIES AND NORMAL DIAGNOSTIC PARAMETERS IN TWO GROUPS OF PANAMANIAN GOLDEN FROGS (ATELOPUS ZETEKI).

Panamanian golden frog (PGF) (Atelopus zeteki) is a critically endangered species. The Maryland Zoo in Baltimore houses two groups of PGF originating from distinct geographic locations as an assurance colony, with the goal of upholding genetics for future release of individuals back to their native environment. The purpose of this cross-sectional study was to characterize the prevalence of ocular abnormalities in these two zoo-housed populations of PGF as well as to establish normal parameters for selected diagnostic tests in these groups. Twenty-five females and 25 males were randomly selected from each group (100 PGF; 200 eyes in total) to undergo ocular examination using slit lamp biomicroscopy and direct ophthalmoscopy. Endodontic absorbent paper point test (EAPPT) and intraocular pressure (IOP) and Rose Bengal stain diagnostic tests were also performed. Reference ranges for tear production (EAPPT, 0.5-3 mm/min) and IOP (14-26 mmHg) were calculated in the nondiseased PGF eyes (n = 160 eyes). Rose Bengal stain uptake was negative on all eyes. In total, 40 eyes of 30 PGF were found to have some form of ocular abnormality (28% of PGF, 20% of eyes). The most frequently observed ocular abnormalities were cataract (9% of PGF, 6% of eyes) and keratitis (nonlipid keratopathy; 10% of PGF, 5.5% of eyes). There was no significant difference in overall ocular abnormality prevalence between the two groups studied (P = 0.37) or between the sexes (P = 0.76). The median age of an eye with cataract and keratitis (nonlipid keratopathy) was 10.35 and 7.7 yr, respectively. Ocular abnormalities are common in these two populations of PGF. Documentation of these ocular abnormalities and establishment of diagnostic reference ranges have not previously been published and may be important for maintaining the health of this endangered species.

CASE DEFINITION AND TREATMENT TRIAL OF TETANY SYNDROME IN PANAMANIAN GOLDEN FROGS (ATELOPUS ZETEKI).

The mass extinction of amphibians necessitates specialized programs to ensure species' survival. Maryland Zoo in Baltimore houses the largest assurance population of the critically endangered Panamanian golden frog (Atelopus zeteki). However, individuals in this population experience a tetany-like syndrome, characterized by rigid/inappropriately positioned limbs and difficulty hopping, swimming, and righting. In this study, a syndrome case definition was assigned and the associated clinical signs were described. Then, four different treatments were systematically assessed in order to find the most effective protocol for treatment and begin to elucidate its underlying causes. Eighty-three frogs fulfilled the case definition and were treated orally for 14 d with either calcium gluconate, magnesium chloride, supplemental gavage feeding, or combination of calcium, magnesium, and vitamin B complex. Frogs were tested with a defined protocol assessing hopping, righting, and swimming abilities. Testing was performed at symptom onset and repeated weekly until resolution occurred. Analyses revealed that combination treatment was significantly more effective in eliminating clinical signs of tetany syndrome. Results show the most effective way to treat this syndrome, but do not help elucidate the underlying cause. Future work will focus on examining factors (e.g., diet, husbandry) that may elicit the syndrome for a more complete understanding of its etiology.

No Sex Differences in the Prevalence of Intracranial Aneurysms in Patients with Ascending Thoracic Aortic Aneurysms: A Multi-Center Experience.

BACKGROUND: Previous studies suggest a coprevalence of intracranial aneurysms (IA) in patients with infrarenal abdominal aortic aneurysms (AAA). We reviewed our multicenter experience in the detection/treatment of IAs in patients with ascending thoracic aortic aneurysms (ATAA) relative to patients without ATAA. METHODS: Surgical cases of ATAA repaired at 3 sites from January 1998 to December 2018 were retrospectively reviewed. Out of these patients, those with intracranial vascular imaging were selected for our study, and these individuals were concurrently randomly matched with a control group of patients who underwent intracranial vascular imaging without an ATAA in a 1:1 ratio by age, sex, smoking history, and year of intracranial vascular imaging. Conditional logistic regression was used to calculate odds ratios (OR). RESULTS: We reviewed 2176 ATAA repairs. 74% (n = 1,615) were men. Intracranial vascular imaging was available in 298 (13.7%) patients. Ninteen patients were found to have 22 IAs for a prevalence of 6.4%. Mean size of IA was 4.6 ± 3.3 mm; mean age at IA detection, 63.4 ± 12.1 years. IA was present on head imaging in 4.7% of male and 12.5% of female patients. Eleven (58%) patients were men. The OR of having IA in female versus male patients is 2.90, 95% confidence interval [CI] [1.08-7.50], P = 0.029. Time from IA diagnosis to ATAA repair was 1.7 ± 116.2 months. Two patients underwent treatment for IA, one ruptured and one unruptured. All were diagnosed before ATAA repair. Treatment included 1 clipping and 1 coiling with subsequent reintervention of the coiling using a flow diversion device. In the matched group of patients who had intracranial vascular imaging without ATAA, the rate of IA is 5.0%. IA was detected in 3.8% of males and 9.4% of female patients for an OR of 2.59, 95% CI [0.84-7.47], P = 0.083. Association within our study and matched groups, the OR of developing an IA with and without ATAA was not statistically significant 1.29, 95% CI [0.642.59], P = 0.48. There was also no evidence of sex differences in the association of ATAA with IA (interaction P = 0.88). The OR for the association of ATAA with IA was 1.33, 95% CI [0.46-3.84], P = 0.59 in females and 1.25, 95% CI [0.49-3.17], P = 0.64 in males. CONCLUSIONS: Our study found that IA was present in 6.4% of patients with ATAA who had intracranial vascular imaging available. The odds of IA were 1.29 times higher than a matched cohort of patients who had intracranial vascular imaging without ATAA but this failed to achieve statistical significance. We found that the odds of IA were more than 2 times higher in females than males for both those with ATAA (OR = 2.90) and those without ATAA (OR = 2.59); however, it only reached statistical significance in those with ATAA.

Systematic Review on Magnetic Resonance Angiography with Vessel Wall Imaging for the Characterization of Symptomatic Carotid Artery Plaque.

BACKGROUND: To perform a systematic literature review to assess the usefulness of performing magnetic resonance angiography (MRA) with vessel wall imaging (VWI) sequences for the assessment of symptomatic carotid artery plaques and the identification of risky plaque features predisposing for stroke. METHODS: We performed a systematic review of the literature pertaining to MRA with VWI techniques in patients with carotid artery disease, focusing on symptomatic patients' plaque features and morphology. Independent reviewers screened and analyzed data extracted from eligible studies, and a modified Newcastle-Ottawa Scale was used to appraise the quality of the design and content of the selected manuscripts to achieve an accurate interpretation. RESULTS: This review included nineteen peer-reviewed manuscripts, all of them including MRA and VWI assessments of the symptomatic carotid artery plaque. We focused on patients' comorbidities and reviewed plaque features, including intraplaque hemorrhage, a lipid-rich necrotic core, a ruptured fibrous cap, and plaque ulceration. CONCLUSIONS: MRA with VWI is a useful tool in the evaluation of carotid artery plaques. This imaging technique allows clinicians to identify plaques at risk of causing a neurovascular event. The presence of intraplaque hemorrhage, plaque ulceration, a ruptured fibrous cap, and a lipid-rich necrotic core are associated with neurovascular symptoms. The timely identification of these features could have a positive impact on neurovascular event prevention.

Greater burden of white matter lesions and silent infarcts ipsilateral to carotid stenosis.

OBJECTIVES: Carotid stenosis may cause silent cerebrovascular disease (CVD) through atheroembolism and hypoperfusion. If so, revascularization may slow progression of silent CVD. We aimed to compare the presence and severity of silent CVD to the degree of carotid bifurcation stenosis by cerebral hemisphere. MATERIALS AND METHODS: Patients age ≥40 years with carotid stenosis >50% by carotid ultrasound who underwent MRI brain from 2011-2015 at Mayo Clinic were included. Severity of carotid stenosis was classified by carotid duplex ultrasound as 50-69% (moderate), 70-99% (severe), or occluded. White matter lesion (WML) volume was quantified using an automated deep-learning algorithm applied to axial T2 FLAIR images. Differences in WML volume and prevalent silent infarcts were compared across hemispheres and severity of carotid stenosis. RESULTS: Of the 183 patients, mean age was 71±10 years, and 39.3% were female. Moderate stenosis was present in 35.5%, severe stenosis in 46.5% and occlusion in 18.0%. Patients with carotid stenosis had greater WML volume ipsilateral to the side of carotid stenosis than the contralateral side (mean difference, 0.42±0.21cc, p=0.046). Higher degrees of stenosis were associated with greater hemispheric difference in WML volume (moderate vs. severe; 0.16±0.27cc vs 0.74±0.31cc, p=0.009). Prevalence of silent infarct was 23.5% and was greater on the side of carotid stenosis than the contralateral side (hemispheric difference 8.8%±3.2%, p=0.006). Higher degrees of stenosis were associated with higher burden of silent infarcts (moderate vs severe, 10.8% vs 31.8%; p=0.002). CONCLUSIONS: WML and silent infarcts were greater on the side of severe carotid stenosis.

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Looking for opportunities to co-enroll: The DISCOVERY study experience.

BACKGROUND: Conducting high-quality stroke trials is complex and costly. Often these trials compete for the attention of researchers and the availability of patients. Enrolling patients in more than one study concurrently has the potential to accelerate recruitment into individual studies. DISCOVERY is a multicenter, inception cohort study of cognitive impairment and dementia following ischemic or hemorrhagic stroke. At the request of site investigators, a DISCOVERY committee reviews individual studies for approval of possible concurrent co-enrollment into DISCOVERY. The purpose of this report is to summarize the characteristics and outcomes of studies reviewed by committee for possible co-enrollment. METHODS: This analysis covers studies reviewed from 07/01/2020 to 04/26/2022 by the Site Management Committee (SMC) of the DISCOVERY Recruitment and Retention Core. Characterization of each study included study type, number and length of follow-up visits, and whether there were protocol-required blood draws, brain imaging studies, or cognitive tests. Studies were scored for patient burden and scientific overlap with Discovery. The primary outcome was SMC approval to co-enroll. RESULTS: 59 studies were reviewed, and 69.5% (n = 41, 21 clinical trials; 20 observational studies) were found by the SMC to be appropriate for co-enrollment. Higher patient burden and greater scientific overlap with DISCOVERY reduced the rates of approval for co-enrollment. CONCLUSION: A large number of diverse stroke studies are being run concurrently across the DISCOVERY study network, however, about two-thirds of the studies were considered appropriate for consideration of co-enrollment. Future studies should study how co-enrollment might improve trial network efficiency.

Higher Risk for Reintervention in Patients after Stenting for Radiation-Induced Internal Carotid Artery Stenosis: A Single-Center Analysis and Systematic Review.

BACKGROUND: This study aimed to review short- and long-term outcomes of all carotid artery stenting (CAS) in patients with radiation-induced (RI) internal carotid artery (ICA) stenosis compared with patients with atherosclerotic stenosis (AS). METHODS: We performed a single-center, multisite case-control study of transfemoral carotid artery intervention in patients stented for RI or AS. Cases of stented RI carotid arteries were identified using a CAS database covering January 2000 to December 2019. These patients were randomly matched 2:1 with stented patients because of AS by age, sex, and year of CAS. A conditional logistic regression model was performed to estimate the odds of reintervention in the RI group. Finally, a systematic review was performed to assess the outcomes of RI stenosis treated with CAS. RESULTS: There were 120 CAS in 113 patients because of RI ICA stenosis. Eighty-nine patients (78.8%) were male, and 68 patients (60.2%) were symptomatic. The reasons for radiation included most commonly treatment for diverse malignancies of the head and neck in 109 patients (96.5%). The mean radiation dose was 58.9 ± 15.6 Gy, and the time from radiation to CAS was 175.3 ± 140.4 months. Symptoms included 31 transient ischemic attacks (TIAs), 21 strokes (7 acute and 14 subacute), and 17 amaurosis fugax. The mean National Institutes of Health Stroke Scale in acute strokes was 8.7 ± 11.2. In asymptomatic patients, the indication for CAS was high-grade stenosis determined by duplex ultrasound. All CAS were successfully completed. Reinterventions were more frequent in the RI ICA stenosis cohort compared with the AS cohort (10.1% vs. 1.4%). Reinterventions occurred in 14 vessels, and causes for reintervention were restenosis in 12 followed by TIA/stroke in two vessels. On conditional regression modeling, patients with RI ICA stenosis were at a higher risk for reintervention (odds ratio = 7.1, 95% confidence interval = 2.1-32.8; P = 0.004). The mean follow-up was 33.7 ± 36.9 months, and the mortality across groups was no different (P = 0.12). CONCLUSIONS: In our single-center, multisite cohort study, patients who underwent CAS for RI ICA stenosis experienced a higher rate of restenosis and a higher number of reinterventions compared with CAS for AS. Although CAS is safe and effective for this RI ICA stenosis cohort, further data are needed to reduce the risk of restenosis, and close patient surveillance is warranted. In our systematic review, CAS was considered an excellent alternative option for the treatment of patients with RI ICA stenosis. However, careful patient selection is warranted because of the increased risk of restenosis on long-term follow-up.

Cilostazol Versus Aspirin for Secondary Stroke Prevention: Systematic Review and Meta-Analysis.

OBJECTIVES: Cilostazol has promise as an alternative to aspirin for secondary stroke prevention given its vasodilatory and anti-inflammatory properties in addition to platelet aggregation inhibition. We aimed to conduct a systematic review and meta-analysis to estimate the efficacy and safety of cilostazol compared to aspirin for stroke prevention in patients with previous stroke or transient ischemic attack (TIA). MATERIALS AND METHODS: We searched PubMed and the Cochrane Central Register of Controlled Trials from 1996 to 2019. Randomized clinical trials that compared cilostazol to aspirin and reported the endpoints of ischemic stroke, intracranial hemorrhage and any bleeding were included. A random-effects estimate was computed based on the Mantel-Haenszel method. The pooled risk estimates with 95% confidence intervals were compared between cilostazol and aspirin. RESULTS: The search identified 5 randomized clinical trials comparing cilostazol vs. aspirin for secondary stroke prevention that collectively enrolled 7240 patients, all from Asian countries (3615 received cilostazol and 3625 received aspirin). Pooled results from the random-effects model showed that cilostazol was associated with significantly lower risk of recurrent ischemic stroke (RR 0.68; 95% CI, 0.54 to 0.87), intracranial hemorrhage (RR 0.42; 95% CI, 0.27 to 0.65) and any bleeding (RR 0.71; 95% CI, 0.55 to 0.91). CONCLUSIONS: This meta-analysis suggests that cilostazol is more effective than aspirin in preventing recurrent ischemic stroke with lower risk of intracranial hemorrhage and other bleeding. Since all trials to date are from Asian countries, confirmatory trials of cilostazol for secondary stroke prevention in other populations are needed.

Non-Adherence to Antihypertensive Guidelines in Patients with Asymptomatic Carotid Stenosis.

IMPORTANCE: Hypertension and carotid stenosis are both risk factors for stroke, but the presence of carotid stenosis might dampen enthusiasm for tight control of hypertension because of concerns for hypoperfusion. OBJECTIVE: To determine the extent to which there are opportunities to potentially improve pharmacotherapy for hypertension in patients known to have asymptomatic high-grade carotid stenosis. DESIGN: We examined anti-hypertensive medication prescription and adherence to evidence-based hypertension treatment guidelines in a cross-sectional analysis of baseline data of patients enrolled in a clinical trial. SETTING: The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) is a multicenter prospective randomized open blinded end-point clinical trial of intensive medical management with or without revascularization by endarterectomy or stenting for asymptomatic high-grade carotid stenosis. PARTICIPANTS: 1479 participants (38.6% female; mean age 69.8 years) from 132 clinical centers enrolled in the CREST-2 trial as of April 6, 2020 who were taking ≥1 antihypertensive drug at baseline. EXPOSURES: Pharmacotherapy for hypertension. MAIN OUTCOME: Adherence to evidence-based guidelines for treating hypertension. RESULTS: Of 1458 participants with complete data, 26% were on one, 31% on 2, and 43% on ≥3 antihypertensive medications at trial entry. Thirty-two percent of participants were prescribed thiazide; 74%, angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB); 38%, calcium channel blocker (CCB); 56%, a beta blocker; 11%, loop diuretic; and 27%, other. Of those prescribed a single antihypertensive medication, the proportion prescribed thiazide was 5%; ACEI or ARB, 55%, and CCB, 11%. The prevalence of guideline-adherent regimens was 34% (95% CI, 31-36%). CONCLUSIONS AND RELEVANCE: In a diverse cohort with severe carotid disease and hypertension, non-adherence to hypertension guidelines was common. All preferred classes of antihypertensive drug were under-prescribed. Using staged iterative guideline-based care for hypertension, CREST-2 will characterize drug tolerance and stroke rates under these conditions. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT02089217.

Higher Long-Term Mortality with Carotid Artery Stenting in Asymptomatic Male Compared with Female Patients in the Southeastern Vascular Study Group.

BACKGROUND: To review the sex differences among symptomatic and asymptomatic patients treated with carotid endarterectomy (CEA) and carotid artery stenting (CAS) in the Southeastern Vascular Study Group (SEVSG), a regional quality group of the Vascular Quality Initiative (VQI). METHODS: All cases reported by the SEVSG members of symptomatic and asymptomatic patients were included in this retrospective review of CEA and CAS. Primary end point was 3-year survival difference between male and female patients. Secondary end points included in-hospital myocardial infarction (MI), transient ischemic attack (TIA)/stroke, and mortality differences between symptomatic and asymptomatic male and female patients. Cox proportional hazard regression was used to assess 3-year survival differences. RESULTS: There were 8,303 CEA and 1,876 CAS procedures performed in 29 centers from January 2011 to December 2018. From those, 4,650 (56.0%) and 938 (50.1%) were asymptomatic CEA and CAS, respectively. There were 2,760 (59.4%) male patients in the asymptomatic CEA and 597 (63.9%) in the asymptomatic CAS groups. After CEA, the rates of in-hospital MI (P = 0.034), TIA/stroke (P < 0.001), and death (P < 0.001) were significantly higher in symptomatic patients. MIs were more frequent in females with asymptomatic disease (P = 0.041). After CAS, the rate of TIA/stroke was higher in symptomatic patients (P = 0.030). There were no differences according to sex in the CAS group. On follow-up, asymptomatic male patients treated with CAS had a higher 3-year all-cause mortality compared with their female counterparts (7.0% vs. 1.8%; P = 0.015). On multivariable Cox regression analysis, male sex (HR = 2.63 [95% CI = 1.058-6.536]; P = 0.038) and lower hemoglobin levels (HR = 0.72 [95% CI = 0.597-0.857]; P < 0.001) were predictors of death in asymptomatic male patients treated with CAS. CONCLUSIONS: In our SEVSG region, postoperative MIs, TIA/stroke, and deaths were higher in symptomatic CEA patients. MIs were more frequent in asymptomatic CEA females. Postoperative TIA/stroke was more frequent in symptomatic CAS patients. After CAS, asymptomatic male patients had higher 3-year all-cause mortality than female patients. On multivariable Cox regression analysis, male sex and lower hemoglobin levels were predictors of death in these asymptomatic male patients treated with CAS. Long-term mortality risk in asymptomatic males should be considered before offering CAS. Further national VQI analysis of our asymptomatic and symptomatic male and female patients treated with CEA and CAS would be warranted.

Incorporation of Telestroke into Neurology Residency Training: "Time Is Brain and Education".

Background: With increasing demand for neurologists, nontraditional health care delivery mechanisms have been developed to leverage this limited resource. Introduction: Telemedicine has emerged as an effective digital solution. Over the past three decades, telemedicine use has steadily grown; however, neurologists often learn on the job, rather than as part of their medical training. The current literature regarding telestroke training during neurology training is sparse, focusing on cerebrovascular fellowship curricula. We sought to enhance telestroke training in our neurology residency by incorporating real-life application. Materials and Methods: We implemented a formal educational model for neurology residents to use telemedicine for remote acquisition of the National Institutes of Health Stroke Scale (NIHSS) for patients with suspected acute ischemic stroke (AIS) before arrival at our comprehensive stroke center. This three-phase educational model involved multidisciplinary classroom didactics, simulation exercises, and real-world experience. Training and feedback were provided by neurologists experienced in telemedicine. Results: All residents completed formal training in telemedicine prehospital NIHSS acquisition and had the opportunity to participate in additional simulation exercises. Currently, residents are gaining additional experience by performing prehospital NIHSS acquisition for patients in whom AIS is suspected. Our preliminary data indicate that resident video encounters average 10.6 min in duration, thus saving time once patients arrive at our hospital. Discussion: To our knowledge, this is the first report of a telestroke-integrated neurology residency program in a comprehensive stroke center resulting in shortened time to treatment in patients with suspected AIS. Conclusions: We present a model that can be adopted by other neurology residency programs as it provides real-world telemedicine training critical to future neurologists.

British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

Stroke Caused by Extracranial Disease.

Extracranial internal carotid artery atherosclerotic occlusive disease is a common ischemic stroke mechanism. Vascular risk factor control remains the cornerstone of stroke prevention in patients with both asymptomatic and symptomatic carotid occlusive diseases. Intensive medical therapy refers to the contemporary approach of antiplatelet therapy, blood pressure control, low-density lipoprotein reduction, and lifestyle modification to reduce stroke risk. Carotid revascularization with endarterectomy or angioplasty and stenting are established treatments for patients with symptomatic carotid stenosis ≥70%. Previously accepted ischemic stroke preventative strategies, such as carotid revascularization for asymptomatic carotid stenosis, require reassessment given advances in both medical therapy and surgical techniques. The purpose of this review is to describe contemporary approaches to the management of extracranial carotid atherosclerotic occlusive disease and the basis of these recommendations. Results from recently published clinical trials will be highlighted in addition to updated information from clinical trials addressing knowledge gaps in prevention of stroke caused by extracranial disease.

Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial.

Importance: Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. Objectives: To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. Design, Setting, and Participants: The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ≥150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Interventions: Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n = 581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n = 570) for up to 72 hours. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Results: Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P = .55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Conclusions and Relevance: Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT01369069.

Pharmacotherapy for Patients with Atrial Fibrillation and Cerebral Microbleeds.

BACKGROUND: Patients with cerebral microbleeds have increased risk of intracranial hemorrhage and ischemic stroke. No trial specifically informs antithrombotic therapy for patients with cerebral microbleeds and atrial fibrillation. We investigated the safety of anticoagulation versus no anticoagulation with regard to cerebrovascular outcomes and mortality. METHODS: All consecutive atrial fibrillation patients from 2015 to 2018 with MRI evidence of ≥1 cerebral microbleed at time of imaging were reviewed. Patients were treated with warfarin, direct oral anticoagulants, or neither. Primary outcome was all-cause mortality informed by National Death Registry and the composite of ischemic and hemorrhagic stroke. All statistical tests were 2-sided and significant at P < .05. RESULTS: The median interval from patient identification until the end of electronic health record surveillance was 9.93 months (interquartile range, 2.83-19.17 months). We identified 308 atrial fibrillation patients with cerebral microbleeds; 128(41.6%) were on warfarin, 88(28.6%) on direct oral anticoagulants, and 92(29.9%) on neither. Over the surveillance interval, 87 deaths, 51 ischemic strokes, and 14 hemorrhagic strokes occurred. The estimated likelihoods of the composite stroke outcome and ischemic stroke only did not differ significantly among the 3 groups. However, patients taking direct oral anticoagulants had a significantly smaller likelihood of all-cause mortality than patients who were not anticoagulated (adjusted hazard ratio: .44[.23, .83], P=.012). CONCLUSIONS: In patients with coprevalent atrial fibrillation and cerebral microbleeds, we did not detect differences in subsequent ischemic stroke, hemorrhagic stroke, or both, comparing warfarin, direct oral anticoagulants, or neither. Patients treated with direct oral anticoagulants had better survival than nonanticoagulated patients.

Comparison of Stroke Outcomes of Hub and Spoke Hospital Treated Patients in Mayo Clinic Telestroke Program.

PURPOSE: To examine telemedicine as it applies to acute ischemic stroke care at a spoke hospital and the effect on patient outcomes, including the timeliness of response, quality of care, safety, morbidity, and mortality when compared to standard hub hospital stroke center care. METHODS: Retrospective review of prospectively entered quality/performance stroke/telestroke patient catalog data were completed for 1000 adult patients who presented with an acute ischemic stroke to the Mayo Clinic Hospitals (500 patients) or to one of thirteen Mayo Clinic affiliated telestroke spoke hospitals in the regions (500 patients). The primary outcome of interest was the percentage of accurate decision making for eligibility of IV alteplase administration assessed by blinded adjudication and the secondary outcomes pertained to complications, discharge parameters, and standard quality metrics. RESULTS: There was no difference in the spoke hospital versus hub hospital groups in identifying and making the correct decision regarding which patients were eligible for IV alteplase administration (96% [95% confidence interval (CI): 94%-97%] versus 97% [95% CI: 95%-98%]; P = 0.32). There was no difference among the groups in proportion receiving IV alteplase, sustaining symptomatic intracranial hemorrhage, and mortality. Patients in the spoke group were less likely to have a favorable outcome at discharge, as defined by National Institutes of Health Stroke Scale (NIHSS): 0-1 or mRS: 0-1 or Glasgow Outcome Scale (GOS): 0-1 (21% versus, 35%; P < 0.001), were less likely to have venous thromboembolism prophylaxis (46% versus 63%; P < 0.01), were less likely to have received antithrombotic therapy (85% versus 90%; P = .02), were less likely to be discharged on anticoagulation when indicated (56% versus 64%; P = .01), and were less likely to be prescribed cholesterol reducing treatment (68% versus 72%; P < .001). The initial acute care hospital length of stay was longer for the spoke hospital group by one day (median: 4 versus 3; P < .001). CONCLUSION: The key findings were that evidence-based stroke thrombolysis eligibility decision making, thrombolysis administration, and thrombolysis emergency stroke metrics were uniformly excellent for the spoke hospital group when compared to the standard hub hospital group. However, evidence-based stroke hospitalization and discharge metrics were inferior for the spoke hospital group when compared to the standard hub hospital.

Factors Associated With Time to Site Activation, Randomization, and Enrollment Performance in a Stroke Prevention Trial.

BACKGROUND AND PURPOSE: Multicenter clinical trials attempt to select sites that can move rapidly to randomization and enroll sufficient numbers of patients. However, there are few assessments of the success of site selection. METHODS: In the CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trials), we assess factors associated with the time between site selection and authorization to randomize, the time between authorization to randomize and the first randomization, and the average number of randomizations per site per month. Potential factors included characteristics of the site, specialty of the principal investigator, and site type. RESULTS: For 147 sites, the median time between site selection to authorization to randomize was 9.9 months (interquartile range, 7.7, 12.4), and factors associated with early site activation were not identified. The median time between authorization to randomize and a randomization was 4.6 months (interquartile range, 2.6, 10.5). Sites with authorization to randomize in only the carotid endarterectomy study were slower to randomize, and other factors examined were not significantly associated with time-to-randomization. The recruitment rate was 0.26 (95% confidence interval, 0.23-0.28) patients per site per month. By univariate analysis, factors associated with faster recruitment were authorization to randomize in both trials, principal investigator specialties of interventional radiology and cardiology, pre-trial reported performance >50 carotid angioplasty and stenting procedures per year, status in the top half of recruitment in the CREST trial, and classification as a private health facility. Participation in StrokeNet was associated with slower recruitment as compared with the non-StrokeNet sites. CONCLUSIONS: Overall, selection of sites with high enrollment rates will likely require customization to align the sites selected to the factor under study in the trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02089217.

THE PHARMACOKINETICS OF TOPICAL ITRACONAZOLE IN PANAMANIAN GOLDEN FROGS (ATELOPUS ZETEKI).

Chytridiomycosis is caused by the fungus Batrachochytrium dendrobatidis and is one of the primary causes of the global decline in amphibian populations and specifically of the Panamanian golden frog ( Atelopus zeteki ). Itraconazole has been demonstrated to be an effective treatment for chytridiomycosis by inhibiting cytochrome P450, a major enzyme important for the structure of B. dendrobatidis zoospores' plasma membranes. However, anecdotal reports of toxicity in this and other amphibian species have been reported at the 0.01% concentration. This study is the first to determine pharmacokinetics of 0.01% and 0.001% itraconazole in the Panamanian golden frog. Frogs were bathed 10 min, euthanized, and skin, liver, and heart were collected at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 36 hr. Itraconazole concentrations were measured using high performance liquid chromatography, and the minimum inhibitory concentration (MIC) of itraconazole (0.032 µg/ml) for B. dendrobatidis was used to determine whether therapeutic concentrations were attained. Itraconazole was detected in all tissues at both concentrations, indicating systemic absorption. At the 0.01% itraconazole bath, itraconazole concentrations in all tissues exceeded the MIC at all time points, and the lack of decline until the end of the study at 36 hr precluded determining a disappearance half-life. With the 0.001% bath, itraconazole exceeded the MIC and declined with a disappearance half-life that markedly varied (14.1-1,244 min). This study augments the growing literature base on chytridiomycosis and seeks to aid in further experimental attempts to find the most-optimal treatment protocol for this disease.