Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the Melbourne Mobile Stroke Unit (TASTE-A): a phase 2, randomised, open-label trial.

BACKGROUND: Mobile stroke units (MSUs) equipped with a CT scanner reduce time to thrombolytic treatment and improve patient outcomes. We tested the hypothesis that tenecteplase administered in an MSU would result in superior reperfusion at hospital arrival, when compared with alteplase. METHODS: The TASTE-A trial is a phase 2, randomised, open-label trial at the Melbourne MSU and five tertiary hospitals in Melbourne, VIC, Australia. Patients (aged ≥18 years) with ischaemic stroke who were eligible for thrombolytic treatment were randomly allocated in the MSU to receive, within 4·5 h of symptom onset, either standard-of-care alteplase (0·9 mg/kg [maximum 90 mg], administered intravenously with 10% as a bolus over 1 min and 90% as an infusion over 1 h), or the investigational product tenecteplase (0·25 mg/kg [maximum 25 mg], administered as an intravenous bolus over 10 s), before being transported to hospital for ongoing care. The primary outcome was the volume of the perfusion lesion on arrival at hospital, assessed by CT-perfusion imaging. Secondary safety outcomes were modified Rankin Scale (mRS) score of 5 or 6 at 90 days, symptomatic intracerebral haemorrhage and any haemorrhage within 36 h, and death at 90 days. Assessors were masked to treatment allocation. Analysis was by intention-to-treat. The trial was registered with ClinicalTrials.gov, NCT04071613, and is completed. FINDINGS: Between June 20, 2019, and Nov 16, 2021, 104 patients were enrolled and randomly allocated to receive either tenecteplase (n=55) or alteplase (n=49). The median age of patients was 73 years (IQR 61-83), and the median NIHSS at baseline was 8 (5-14). On arrival at the hospital, the perfusion lesion volume was significantly smaller with tenecteplase (median 12 mL [IQR 3-28]) than with alteplase (35 mL [18-76]; adjusted incidence rate ratio 0·55, 95% CI 0·37-0·81; p=0·0030). At 90 days, an mRS of 5 or 6 was reported in eight (15%) patients allocated to tenecteplase and ten (20%) patients allocated to alteplase (adjusted odds ratio [aOR] 0·70, 95% CI 0·23-2·16; p=0·54). Five (9%) patients allocated to tenecteplase and five (10%) patients allocated to alteplase died from any cause at 90 days (aOR 1·12, 95% CI 0·26-4·90; p=0·88). No cases of symptomatic intracerebral haemorrhage were reported within 36 h with either treatment. Up to day 90, 13 serious adverse events were noted: five (5%) in patients treated with tenecteplase, and eight (8%) in patients treated with alteplase. INTERPRETATION: Treatment with tenecteplase on the MSU in Melbourne resulted in a superior rate of early reperfusion compared with alteplase, and no safety concerns were noted. This trial provides evidence to support the use of tenecteplase and MSUs in an optimal model of stroke care. FUNDING: Melbourne Academic Centre for Health.

The Mobile Stroke Unit Nurse: An International Exploration of Their Scope of Practice, Education, and Training.

ABSTRACT: BACKGROUND: Mobile stroke units (MSUs) are ambulance-based prehospital stroke care services. Through immediate roadside assessment and onboard brain imaging, MSUs provide faster stroke management with improved patient outcomes. Mobile stroke units have enabled the development of expanded scope of practice for stroke nurses; however, there is limited published evidence about these evolving prehospital acute nursing roles. AIMS: The aim of this study was to explore the expanded scope of practice of nurses working on MSUs by identifying MSUs with onboard nurses; describing the roles and responsibilities, training, and experience of MSU nurses, through a search of the literature; and describing 2 international MSU services incorporating nurses from Memphis, Tennessee, and Melbourne, Australia. METHODS: We searched PubMed, CINAHL, and the Joanna Briggs Institute Evidence-Based Practice database using the terms "mobile stroke unit" and "nurse." Existing MSUs were identified through the PRE-hospital Stroke Treatment Organization to determine models that involved nurses. We describe 2 MSUs involving nurses: one in Memphis and one in Melbourne, led by 2 of our authors. RESULTS: Ninety articles were found describing 15 MSUs; however, staffing details were lacking, and it is unknown how many employ nurses. Nine articles described the role of the nurse, but role specifics, training, and expertise were largely undocumented. The MSU in Memphis, the only unit to be staffed exclusively by onboard nurse practitioners, is supported by a neurologist who consults via telephone. The Melbourne MSU plans to trial a nurse-led telemedicine model in the near future. CONCLUSION: We lack information on how many MSUs employ nurses, and the nurses' scope of practice, training, and expertise. Expert stroke nurse practitioners can safely perform many of the tasks undertaken by the onboard neurologist, making a nurse-led telemedicine model an effective and potentially cost-effective model that should be considered for all MSUs.

Effects of early motivational interviewing on post-stroke depressive symptoms: A pilot randomized study of the Good Mood Intervention program.

AIMS: The aim of this pilot randomized study was to investigate the feasibility of early motivational interviewing, for reducing mood after acute stroke. BACKGROUND: Depression is a frequent consequence of stroke that can adversely affect recovery. METHODS: DESIGN: Pilot randomized study. Intervention group patients received 3, individual motivational interviewing sessions by nurses or social workers prior to hospital discharge. PARTICIPANTS: Adult patients with acute stroke during 2013 to 2014. BLINDING: Research assistant who collected data was blind to group assignment. OUTCOMES: Data were collected at 3 time points: baseline, 1-month, and 3-month follow-up. Outcome measures (anxiety, depression, quality of life) were analysed by descriptive statistics. RESULTS: Forty-eight patients were enrolled, and 79% retention was achieved at 3 months. Eight participants withdrew (16.7%), and 2 were unable to participate (death: 2.1% and new onset aphasia: 2.1%), leaving 38 participants in the final cohort (Intervention: N = 18, Control: N = 20). Anxiety, depression, and quality of life measures did not alter significantly in the study period. CONCLUSIONS: Carefully designed studies are required to investigate the effectiveness of early motivational interviewing for improving mood after stroke. The therapy can be administered by nurses, but significant resources are required in terms of training and fidelity.

Certification of elements in and use of standard reference material 3280 multivitamin/multielement tablets.

Standard Reference Material 3280 Multivitamin/ Multielement Tablets was issued by the National Institute of Standards and Technology in 2009, and has certified and reference mass fraction values for 13 vitamins, 26 elements, and two carotenoids. Elements were measured using two or more analytical methods at NIST with additional data contributed by collaborating laboratories. This reference material is expected to serve a dual purpose: to provide quality assurance in support of a database of dietary supplement products and to provide a means for analysts, dietary supplement manufacturers, and researchers to assess the appropriateness and validity of their analytical methods and the accuracy of their results.

Debilitation and mortality associated with besnoitiosis in four Virginia opossums (Didelphis virginiana).

Besnoitia spp. are coccidian parasites that infect a variety of wild and domestic mammals as well as some reptiles. Although infection with Besnoitia is common in Virginia opossums (Didelphis virginiana), clinical signs or death due to Besnoitia is rare. This manuscript describes four Virginia opossums that had severe clinical disease and inflammation associated with besnoitiosis. Clinical signs included trembling, incoordination, circling, blindness, poor body condition, and sudden death. Gross lesions included parasitic cysts in eyes, skin, and visceral organs. Histologically, cysts were often degenerate and associated with mild to marked inflammation, and amyloidosis was noted in one animal. Polymerase chain reaction and sequencing confirmed Besnoitia darlingi in three of the four opossums.

Continence management in acute stroke: a survey of current practices in Australia.

AIM: The aim of the study was to determine current national urinary incontinence management practices in Australian acute stroke units and their concordance with the National Stroke Foundation guidelines. BACKGROUND: Urinary incontinence is a common consequence after stroke and a statistically significant indicator of poor outcome, including disability and admission to institutional care. The National Stroke Foundation has produced guidelines for the acute and post-acute phase of care, offering Australian nurses evidence-based recommendations regarding stroke management including the management of urinary incontinence. METHOD: In 2007-2008, dedicated acute stroke units in Australia were identified and a senior nurse from each unit was invited to participate in a 10-minute telephone survey to ascertain their current urinary continence management practices. RESULTS: Representatives from 41 acute stroke units participated in the survey (response rate 98%). Participants from less than half of the units reported that they had a formal plan for urinary incontinence management (n=19, 46%), and the majority of those who did not would find a formal plan useful (n=15, 79%). Two-thirds of respondents stated that they would manage urinary incontinence with indwelling catheterization (n=25, 61%). Only 30% (n=12) were 'satisfied' or 'very satisfied' with urinary continence management in their acute stroke unit. CONCLUSION: A large proportion of acute stroke units were yet to establish formal urinary incontinence management plans. The implementation of evidence-based urinary incontinence management plans after stroke is integral to improving patient outcomes. An increase in resources for professional development in the assessment, treatment and management of urinary incontinence is essential to improve and maintain skills in after-stroke care.

Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy.

BACKGROUND: Spontaneous control of human immunodeficiency virus (HIV) infection has been documented in a minority of HIV-infected individuals. The mechanisms behind this outcome remain largely unknown, and a better understanding of them will likely influence future vaccine strategies. METHODS: HIV-specific T cell and antibody responses as well as host genetics were examined in untreated HIV-infected patients who maintain comparatively low plasma HIV RNA levels (hereafter, controllers), including those with levels of < 50 RNA copies/mL (elite controllers, n = 64), those with levels of 50-2000 copies/mL (viremic controllers, n = 60); we also examined HIV-specific T cell and antibody responses as well as host genetics for patients with levels of >10,000 copies/mL (chronic progressors, n = 30). RESULTS: CD8+ T cells from both controller groups preferentially target Gag over other proteins in the context of diverse HLA class I alleles, whereas responses are more broadly distributed in persons with progressive infection. Elite controllers represent a distinct group of individuals who have significantly more CD4 and CD8 T cells that secrete interferon-gamma and interleukin-2 and lower levels of HIV-neutralizing antibodies. Individual responses were quite heterogeneous, and none of the parameters evaluated was uniquely associated with the ability to control viremia. CONCLUSIONS: Elite controllers are a distinct group, even when compared to persons with low level viremia, but they exhibit marked genetic and immunologic heterogeneity. Even low-level viremia among HIV controllers was associated with measurable T cell dysfunction, which has implications for current prophylactic vaccine strategies.

Effect of butorphanol administration on cardiovascular parameters in isoflurane-anesthetized horses - a retrospective clinical evaluation.

OBJECTIVE: To determine cardiovascular responses to administration of butorphanol in isoflurane-anesthetized horses. STUDY DESIGN: Retrospective evaluation of anesthetic records. ANIMALS: Seventy-six horses anesthetized for a variety of clinical surgical procedures. METHODS: Anesthetic records of clinical equine patients anesthetized between January 1999 and December 2003 were searched. The records were reviewed for horses in which anesthesia was induced with ketamine and a benzodiazepine and maintained with isoflurane, and horses that received butorphanol intraoperatively. Exclusion criteria included horses in which the rate of infusion of an inotrope or end-tidal isoflurane concentration was changed 10 minutes before or after the butorphanol bolus. The horses were separated into two groups: group 1 horses received butorphanol at intervals as part of a balanced protocol, group 2 horses had > or = 10% increase in heart rate (HR) or blood pressure within 10 minutes prior to butorphanol administration. RESULTS: Eighty-nine butorphanol administration events matched the criteria for inclusion, 49 in group 1 and 40 in group 2. There were no significant changes after butorphanol administration in systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), and heart rate (HR) in group 1, or in end-tidal carbon dioxide concentration or hemoglobin oxygen saturation in either group. There were significant decreases in SAP (p < 0.0001), MAP (p < 0.0005), and DAP (p < 0.0008) after butorphanol administration in group 2. CONCLUSIONS AND CLINICAL RELEVANCE: The results presented here confirm that butorphanol can be administered to horses during isoflurane anesthesia without adverse effects on HR and arterial blood pressure. The results imply that butorphanol can deepen the plane of anesthesia and obtund sympathetic stimulation from a surgical procedure.

Increased sequence diversity coverage improves detection of HIV-specific T cell responses.

The accurate identification of HIV-specific T cell responses is important for determining the relationship between immune response, viral control, and disease progression. HIV-specific immune responses are usually measured using peptide sets based on consensus sequences, which frequently miss responses to regions where test set and infecting virus differ. In this study, we report the design of a peptide test set with significantly increased coverage of HIV sequence diversity by including alternative amino acids at variable positions during the peptide synthesis step. In an IFN-gamma ELISpot assay, these "toggled" peptides detected HIV-specific CD4(+) and CD8(+) T cell responses of significantly higher breadth and magnitude than matched consensus peptides. The observed increases were explained by a closer match of the toggled peptides to the autologous viral sequence. Toggled peptides therefore afford a cost-effective and significantly more complete view of the host immune response to HIV and are directly applicable to other variable pathogens.

Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction.

In progressive viral infection, antiviral T cell function is impaired by poorly understood mechanisms. Here we report that the inhibitory immunoregulatory receptor CTLA-4 was selectively upregulated in human immunodeficiency virus (HIV)-specific CD4(+) T cells but not CD8(+) T cells in all categories of HIV-infected subjects evaluated, with the exception of rare people able to control viremia in the absence of antiretroviral therapy. CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4(+) T cells to produce interleukin 2 in response to viral antigen. Most HIV-specific CD4(+) T cells coexpressed CTLA-4 and another inhibitory immunoregulatory receptor, PD-1. In vitro blockade of CTLA-4 augmented HIV-specific CD4(+) T cell function. These data, indicating a reversible immunoregulatory pathway selectively associated with CD4(+) T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients.

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.

Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.

Preparation and characterization of a suite of ephedra-containing standard reference materials.

The National Institute of Standards and Technology, the U.S. Food and Drug Administration, Center for Drug Evaluation and Research and Center for Food Safety and Applied Nutrition, and the National Institutes of Health, Office of Dietary Supplements, are collaborating to produce a series of Standard Reference Materials (SRMs) for dietary supplements. A suite of ephedra materials is the first in the series, and this paper describes the acquisition, preparation, and value assignment of these materials: SRMs 3240 Ephedra sinica Stapf Aerial Parts, 3241 E. sinica Stapf Native Extract, 3242 E. sinica Stapf Commercial Extract, 3243 Ephedra-Containing Solid Oral Dosage Form, and 3244 Ephedra-Containing Protein Powder. Values are assigned for ephedrine alkaloids and toxic elements in all 5 materials. Values are assigned for other analytes (e.g., caffeine, nutrient elements, proximates, etc.) in some of the materials, as appropriate. Materials in this suite of SRMs are intended for use as primary control materials when values are assigned to in-house (secondary) control materials and for validation of analytical methods for the measurement of alkaloids, toxic elements, and, in the case of SRM 3244, nutrients in similar materials.