Prehospital exenatide in hyperglycemic stroke-A randomized trial

Objectives Hyperglycemia is a predictor for poor stroke outcome. Hyperglycemic stroke patients treated with thrombolysis have an increased risk of intracranial hemorrhage. Insulin is the gold standard for treating hyperglycemia but comes with a risk of hypoglycemia. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are drugs used in type 2 diabetes that have a low risk of hypoglycemia and have been shown to exert neuroprotective effects. The primary objective was to determine whether prehospital administration of the GLP-1RA exenatide could lower plasma glucose in stroke patients. Secondary objective was to study tolerability and safety. Materials & Methods Randomized controlled trial comparing exenatide administrated prehospitally with a control group receiving standard care for hyperglycemia. Patients with Face Arm Speech Test >= 1 and glucose >= 8 mmol/L were randomized. Glucose was monitored for 24 hours. All adverse events were recorded. Results Nineteen patients were randomized, eight received exenatide. An interim recruitment failure analysis with subsequent changes of the protocol was made. The study was stopped prematurely due to slow inclusion. No difference was observed in the main outcome of plasma glucose at 4 hours, control vs exenatide (mean, SD); 7.0 +/- 1.9 vs 7.6 +/- 1.6; P = .56). No major adverse events were reported. Conclusions We found no evidence that prehospital exenatide had effect on hyperglycemia. However, it was given without adverse events in this study with limited sample size that was prematurely stopped due to slow inclusion.Peer reviewe

Did we see it coming? An evaluation of the Swedish early awareness and alert system

Early awareness and alert (EAA) systems have been established in many countries but evidence on their ability to accurately prioritize new medicines (for early assessment) is limited. The purpose of this study is to assess whether the Swedish EAA System identified and prioritized (i.e. produced early assessment reports for) new medicines that would go on to have a substantial economic impact. Methods We adapted a study design commonly used in the assessment of diagnostic test accuracy. The prioritization made by the Swedish EAA System prior to marketing authorization comprised the index test and national drug sales data in the second year post-authorization served as the reference standard. All initial marketing authorization applications for medicinal products processed by the European Medicines Agency (EMA) between 2010 and 2015 (study population) were classified using the index test and the reference standard. Results Two hundred and fifty-three new medicinal products processed by EMA comprised the study population. Of these, 71 were prioritized by the Swedish EAA System and 21 were classified as having a substantial economic impact. The sensitivity and positive predictive value were 76.2% and 22.5%, respectively. Subgroup analyses showed that the accuracy of prioritization, in terms of sensitivity, was 100% for antineoplastic/immunomodulating agents. Conclusions The Swedish EAA System identified all new medicines that would go on to have a substantial economic impact and prioritized most of these medicines. Our findings provide reassurance to decision makers who rely on the outputs of the Swedish EAA System to keep informed about new medicines. Moreover, this study also provides valuable insights to stakeholders willing to establish and/or evaluate their own EAA activities and systems

Early awareness and alert system in Sweden : history and current status

Abstract Summary: We describe the evolution and the current state of the Swedish Early Awareness and Alert System for new drugs, a national level EAA system successfully implemented in a country with decentralized health care managed by 21 regions. Our work is of interest to countries already having EAA systems in place as well as for those seeking to establish EAA activities. Introduction: Over the past decades, early awareness and alert (EAA) activities and systems have gained importance and become a key early health technology assessment (HTA) tool. While a pioneer in HTA, Sweden had no national level EAA activities until recently. We describe the evolution and current status of the Swedish EAA System. Methods: This was a historical analysis based on the knowledge and experience of the authors supplemented by a targeted review of published and grey literature as well as documents produced by or relating to the Swedish EAA System. Key milestones and a description of the current state of the Swedish EAA System is presented. Results: Initiatives to establish a system for the identification and assessment of emerging health technologies in Sweden date back to the 1980s. Since the 90s, the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) supported the development of EuroScan and was one of its founder members. In the mid-00s, an independent regional initiative, driven by the Stockholm Drug and Therapeutics Committee, resulted in the establishment of a regional horizon scanning unit. By 2009, this work had expanded to a collaboration between the four biggest regions in Sweden. The following year it was further expanded to the national level. Today, the Swedish EAA System carries out identification, filtration and prioritization of new drugs, early assessment of the prioritized drugs, and dissemination of the information. Its outputs are used to select new drugs for inclusion in the Swedish national process for managed introduction and follow-up. Conclusions: The Swedish EAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the System today is its complete integration into the national process for managed introduction and follow-up of new drugs. The System will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international levels

The emerging role of AMPK in the regulation of breathing and oxygen supply

Regulation of breathing is critical to our capacity to accommodate deficits in oxygen availability and demand during, for example, sleep and ascent to altitude. It is generally accepted that a fall in arterial oxygen increases afferent discharge from the carotid bodies to the brainstem and thus delivers increased ventilatory drive, which restores oxygen supply and protects against hypoventilation and apnoea. However, the precise molecular mechanisms involved remain unclear. We recently identified as critical to this process the AMP-activated protein kinase (AMPK), which is key to the cell-autonomous regulation of metabolic homoeostasis. This observation is significant for many reasons, not least because recent studies suggest that the gene for the AMPK-α1 catalytic subunit has been subjected to natural selection in high-altitude populations. It would appear, therefore, that evolutionary pressures have led to AMPK being utilized to regulate oxygen delivery and thus energy supply to the body in the short, medium and longer term. Contrary to current consensus, however, our findings suggest that AMPK regulates ventilation at the level of the caudal brainstem, even when afferent input responses from the carotid body are normal. We therefore hypothesize that AMPK integrates local hypoxic stress at defined loci within the brainstem respiratory network with an index of peripheral hypoxic status, namely afferent chemosensory inputs. Allied to this, AMPK is critical to the control of hypoxic pulmonary vasoconstriction and thus ventilation–perfusion matching at the lungs and may also determine oxygen supply to the foetus by, for example, modulating utero-placental blood flow

The Association of Pre-stroke Psychosis and Post-stroke Levels of Health, Resource Utilization, and Care Process: A Register-Based Study

Background: While approximately one percent of the global population is formally diagnosed with psychosis or schizophrenia, the actual number is expected to be significantly higher. These patients often consume more healthcare resources and have poorer somatic health. In this study, we analyze potential differences in health, resources, and care process between stroke patients with and without a previous diagnosis of psychosis or schizophrenia.Methods: Ischemic stroke patients from seven regions in Sweden were identified via ICD-10 codes (I63.0-9) in regional administrative systems and the Swedish Stroke Register, and approximately 70% of all ischemic stroke cases in Sweden during 2008–2011 were included (n = 46,350). Relevant patient-level data from national registries were linked to enable multivariate regression analysis, including data on socioeconomics, mortality, municipality services, and filled prescriptions. History of psychosis or schizophrenia was defined via ICD-10 codes F20-29 (n = 389).Results: Patient-reported functional outcomes at 3 months and 1 year were significantly lower in the psychosis subgroup, and stroke recurrence was higher. Patients with pre-stroke psychosis did not receive the same levels of reperfusion treatment as the non-psychosis group. Time at the stroke unit was the same, as were first-year levels of somatic care, but dispensation of antihypertensives was less common.Conclusion: Our findings emphasize the importance of taking mental comorbidity into account during stroke treatment as well as when evaluating indicators for health, resources, and the care process, since mental comorbidity such as psychosis or schizophrenia may have a significant impact the year preceding and the year succeeding the stroke event

Experimental spinal cord injuries : a histopathological, neurological, and pharmacological study in the rat

Photochemically-induced ischemic lesions and compression-induced traumatic injuries in the mid-thoracic spinal cord were studied in female rats. The histopathological development of the injuries was found to be similar to that described in other experimental spinal cord injury models and in human post-mortem material. Edema, evidenced with albumin immunoreactivity, increased during the first 24 hours and decreased 72 hours post-lesion. During the first week post-lesion the tissue within the lesion disintegrated and degenerated and axonal retraction bulbs were found adjacent to the lesion. At 3 weeks post-injury gliosis was observed around the lesion, as evidenced by increased immunoreactivity against glial fibrillary acidic protein. The gliosis became more pronounced at 6 weeks post-ischemia at which time geminocytes were also found in the viable tissue surrounding the lesion. The functional capacity following spinal cord injury was tested in rats with photochemically-induced ischemic lesions. A test protocol, the Motor Performance Score (MPS), was developed for fast, easy, and reliable evaluation of motor function in spinal cord injured rats. The MPS was shown to correlate well with morphological descriptors of lesion size in both ischemic and compressive injuries. Regrowing axons were found within the lesion cavity from two weeks post-lesion. To evaluate the amount of regeneration a novel stereological tool utilizing isotropic virtual planes was adapted to estimate neurofilament-immunoreactive fibers within a CNS lesion. Using this tool spontaneous regeneration of axons of central origin could be demonstrated after spinal cord lesions in the rat. The axonal sprouting and/or elongation was extensive between 1 and 5 weeks post-ischemia. Part of this regeneration was abortive but a large number of axons was present even at 15 weeks after the lesion. The axonal nature of the neurofilament-positive fibers was verified in ultra-structural studies and Schwann cells and oligodendrocytes were found adjacent to the axons. Both the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and the non-NMDA antagonist NBQX was found to improve motor function in rats with ischemic lesions. Moreover, for the first time NBQX was demonstrated to protect spinal cord tissue from secondary degeneration to the same degree as MK-801, reducing the lesion volume by 50%. To investigate the protective effect of a clinically used drug, rats with ischemic or traumatic spinal cord injuries were treated with the non competitive NMDA antagonist, memantine. No protective effect was found at doses that have been reported to be protective in cerebral ischemia models. Due to hazardous side effects, higher doses could not be used in our model. The affinity of memantine was shown to be significantly lower for NMDA receptors in the rat spinal cord than for those in the brain. The affinity of memantine to human spinal NMDA receptors was found to be even lower which disqualifies this drug for clinical use in spinal cord injury treatment

Sex Differences in Ischemic Stroke Within the Younger Age Group : A Register-Based Study

Background: Stroke incidence is decreasing in most developing countries. However, worrisome trends of an increase in the younger population have been described. Aim: To investigate sex differences and longitudinal changes in ischemic stroke regarding incidence, cardiovascular risk factors, and outcome, in the young. Methods: This is an observational study based on the data from the Swedish national stroke registry, Riksstroke. Patients, 18–54 years of age, having ischemic stroke between 2005 and 2018 were included, resulting in a study population of 16,210 patients. Results: The incidence was higher in men than in women (30.6 vs. 19.1 per 100,000, P < 0.001). After an initial increase, the incidence stabilized and then decreased, resulting in a similar level in 2018 as in 2005. Atrial fibrillation, diabetes, and usage of anti-hypertensives at stroke onset were more common among men and did not change over time. Smoking was common and slightly more so in women, but with a reduced prevalence in both men and women during the study period. Dependency in Activities of Daily Living (ADL) and case fatality showed no clear trends or sex differences. Conclusions: The results show that there are sex differences in ischemic stroke in the younger age group regarding incidence and vascular risk factors, particularly smoking. Temporal trends in stroke incidence are difficult to interpret as fluctuations are substantial, largely due to stroke being quite uncommon in the younger population

Clinical Study Sex, Diastolic Blood Pressure, and Outcome after Thrombolysis for Ischemic Stroke

Background. The goal of this study was to identify differences in risk factors and functional outcome between the two sexes in patients treated with thrombolysis for ischemic stroke. Methods. This cohort study audited data from patients treated with thrombolysis for ischemic stroke during a 3-year period at Södersjukhuset, Stockholm. Results. Of the 355 patients included in the study, 162 (45%) were women and 193 (54%) were men. Women were older with a median age of 76 years; median age for men was 69 years ( < 0.0001). Diastolic blood pressure was lower for women compared to men ( = 0.001). At admission fewer women had a favorable modified Rankin Scale score compared to men (93.8% versus 99%, = 0.008). Three months after discharge functional status did not differ significantly between the two sexes. Diastolic blood pressure was associated to functional outcome only in men when sex specific odds ratios were calculated (OR, 5.7; 95% CI,. Conclusion. The study indicates that females appear to gain a relatively greater benefit from thrombolytic therapy than men due to a better functional recovery. A higher diastolic blood pressure increases the risk for a worse prospective functional status in men