Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomised controlled trial

Background: Current evidence supports the use of intravenous thrombolysis with alteplase in patients with wake-up stroke selected with MRI or perfusion imaging and is recommended in clinical guidelines. However, access to advanced imaging techniques is often scarce. We aimed to determine whether thrombolytic treatment with intravenous tenecteplase given within 4·5 h of awakening improves functional outcome in patients with ischaemic wake-up stroke selected using non-contrast CT. Methods: TWIST was an investigator-initiated, multicentre, open-label, randomised controlled trial with blinded endpoint assessment, conducted at 77 hospitals in ten countries. We included patients aged 18 years or older with acute ischaemic stroke symptoms upon awakening, limb weakness, a National Institutes of Health Stroke Scale (NIHSS) score of 3 or higher or aphasia, a non-contrast CT examination of the head, and the ability to receive tenecteplase within 4·5 h of awakening. Patients were randomly assigned (1:1) to either a single intravenous bolus of tenecteplase 0·25 mg per kg of bodyweight (maximum 25 mg) or control (no thrombolysis) using a central, web-based, computer-generated randomisation schedule. Trained research personnel, who conducted telephone interviews at 90 days (follow-up), were masked to treatment allocation. Clinical assessments were performed on day 1 (at baseline) and day 7 of hospital admission (or at discharge, whichever occurred first). The primary outcome was functional outcome assessed by the modified Rankin Scale (mRS) at 90 days and analysed using ordinal logistic regression in the intention-to-treat population. This trial is registered with EudraCT (2014–000096–80), ClinicalTrials.gov (NCT03181360), and ISRCTN (10601890). Findings: From June 12, 2017, to Sept 30, 2021, 578 of the required 600 patients were enrolled (288 randomly assigned to the tenecteplase group and 290 to the control group [intention-to-treat population]). The median age of participants was 73·7 years (IQR 65·9–81·1). 332 (57%) of 578 participants were male and 246 (43%) were female. Treatment with tenecteplase was not associated with better functional outcome, according to mRS score at 90 days (adjusted OR 1·18, 95% CI 0·88–1·58; p=0·27). Mortality at 90 days did not significantly differ between treatment groups (28 [10%] patients in the tenecteplase group and 23 [8%] in the control group; adjusted HR 1·29, 95% CI 0·74–2·26; p=0·37). Symptomatic intracranial haemorrhage occurred in six (2%) patients in the tenecteplase group versus three (1%) in the control group (adjusted OR 2·17, 95% CI 0·53–8·87; p=0·28), whereas any intracranial haemorrhage occurred in 33 (11%) versus 30 (10%) patients (adjusted OR 1·14, 0·67–1·94; p=0·64). Interpretation: In patients with wake-up stroke selected with non-contrast CT, treatment with tenecteplase was not associated with better functional outcome at 90 days. The number of symptomatic haemorrhages and any intracranial haemorrhages in both treatment groups was similar to findings from previous trials of wake-up stroke patients selected using advanced imaging. Current evidence does not support treatment with tenecteplase in patients selected with non-contrast CT. Funding: Norwegian Clinical Research Therapy in the Specialist Health Services Programme, the Swiss Heart Foundation, the British Heart Foundation, and the Norwegian National Association for Public Health

Adapting The Sniffin' Sticks Olfactory Test To Diagnose Parkinson's Disease In Estonia

The aim of the study was to develop a culturally adapted translation of the 12-item smell identification test from Sniffin' Sticks (SS-12) for the Estonian population in order to help diagnose Parkinson's disease (PD). Methods: A standard translation of the SS-12 was created and 150 healthy Estonians were questioned about the smells used as response options in the test. Unfamiliar smells were replaced by culturally familiar options. The adapted SS-12 was applied to 70 controls in all age groups, and thereafter to 50 PD patients and 50 age- and sex-matched controls. Results: 14 response options from 48 used in the SS-12 were replaced with familiar smells in an adapted version, in which the mean rate of correct response was 87% (range 73-99) compared to 83% with the literal translation (range 50-98). In PD patients, the average adapted SS-12 score (5.4/12) was significantly lower than in controls (average score 8.9/12), p<0.0001. A multiple linear regression using the score in the SS-12 as the outcome measure showed that diagnosis and age independently influenced the result of the SS-12. A logistic regression using the SS-12 and age as covariates showed that the SS-12 (but not age) correctly classified 79.0% of subjects into the PD and control category, using a cut-off of <7 gave a sensitivity of 76% and specificity of 86% for the diagnosis of PD. Conclusions: The developed SS-12 cultural adaption is appropriate for testing olfaction in Estonia for the purpose of PD diagnosis. © 2014 Elsevier Ltd.208830833Soudrya, Y., Lemogne, C., Malinvaud, D., Consoli, S.-M., Bonfils, P., Olfactory system and emotion: common substrates (2011) Eur Ann Otorhinolaryngol Head Neck Dis, 128, pp. 18-23Kovács, T., Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders (2004) Ageing Res Rev, 3, pp. 215-232Chaudhuri, K.R., Odin, P., The challenge of non-motor symptoms in Parkinson's disease (2010) Prog Brain Res, 184, pp. 325-341Bohnen, N.I., Studenski, S.A., Constantine, G.M., Moore, R.Y., Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case-control study (2008) Eur J Neurol, 15 (7), pp. 685-691Silveira-Moriyama, L., de Jesus Carvalho, M., Katzenschlager, R., Petrie, A., Ranvaud, R., Barbosa, E.R., The use of smell identification tests in the diagnosis of Parkinson's disease in Brazil (2008) Mov Disord, 23, pp. 2328-2334Silveira-Moriyama, L., Schwingenschuh, P., O'Donnell, A., Schneider, S.A., Mir, P., Carrillo, F., Olfaction in patients with suspected Parkinsonism and scans without evidence of dopaminergic deficit (SWEDDs) (2009) JNeurol Neurosurg Psychiatry, 80 (7), pp. 744-748Doty, R.L., Shaman, P., Kimmelman, C., Dann, M.S., University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic (1984) Laryngoscope, 94, pp. 176-178Doty, R.L., Marcus, A., Lee, W.W., Development of the 12-Item cross-cultural smell identification test (CC-SIT) (1996) Laryngoscope, 106, pp. 353-356Hummel, T., Konnerth, C.G., Rosenheim, K., Kobal, G., Screening of olfactory function using a 4 minute odor identification test: reliability, normative data, and investigations in patients with olfactory loss (2001) Ann Otol Rhinol Laryngol, 110, pp. 976-981Nordin, S., Bramerson, A., Liden, E., Bende, M., The Scandinavian odor-identification test: development, reliability, validity and normative data (1998) Acta Otolaryngol, 118, pp. 226-234Simmen, D., Briner, H.R., Hess, K., Screeningtest des Geruchssinnes mit Riechdiskette (1999) Laryngorhinootologie, 78, pp. 125-130Hummel, C., Zucco, G.M., Iannilli, E., Maboshe, W., Landis, B.N., Hummel, T., OLAF: standardization of international olfactory tests (2012) Eur Arch Otorhinolaryngol, 269 (3), pp. 871-880Cho, J.H., Jeong, Y.S., Lee, Y.J., Hong, S.C., Yoon, J.H., Kim, J.K., The Korean version of the Sniffin' stick (KVSS) test and its validity in comparison with the cross-cultural smell identification test (CC-SIT) (2009) Auris Nasus Larynx, 36, pp. 280-286Shu, C.H., Yuan, B.C., Lin, S.H., Lin, C.Z., Cross-cultural application of the "Sniffin' Sticks" odor identification test (2007) Am J Rhinol, 21 (5), pp. 570-573Silveira-Moriyama, L., Sirisena, D., Gamage, P., Ranjanie Gamage, R., Silva, R., Lees, A.J., Adapting the sniffin' sticks to diagnose PD in Sri Lanka (2009) Mov Disord, 24 (8), pp. 1229-1233Mackay-Sim, A., Grant, L., Owen, C., Chant, D., Silburn, P., Australian norms for a quantitative olfactory function test (2004) JClin Neurosci, 11, pp. 874-879Neumann, C., Tsioulos, K., Merkonidis, C., Salam, M., Clark, A., Philpott, C., Validation study of the "Sniffin' Sticks" olfactory test in a British population: a preliminary communication (2012) Clin Otolaryngol, 37 (1), pp. 23-27Eibenstein, A., Fioretti, A.B., Lena, C., Rosati, N., Ottaviano, I., Fusetti, M., Olfactory screening test: experience in 102 Italian subjects (2005) Acta Otorhinolaryngol Ital, 25 (1), pp. 18-22Boesveldt, S., Verbaan, D., Knol, D.L., Visser, M., van Rooden, S.M., van Hilten, J.J., Acomparative study of odor identification and odor discrimination deficits in Parkinson's disease (2008) Mov Disord, 23 (14), pp. 1984-1990Boesveldt, S., de Muinck Keizer, R.J., Knol, D.L., Wolters, E., Berendse, H.W., Extended testing across, not within, tasks raises diagnostic accuracy of smell testing in Parkinson's disease (2009) Mov Disord, 24 (1), pp. 85-90Hummel, T., Kobal, G., Gudziol, H., Mackay-Sim, A., Normative data for the "Sniffin' Sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects (2007) Eur Arch Otorhinolaryngol, 264, pp. 237-243Doty, R.L., Olfactory dysfunction in Parkinson disease (2012) Nat Rev Neurol, 8 (6), pp. 329-339Brand, G., Millot, J.L., Sex differences in human olfaction: between evidence and enigma (2001) QJ Exp Psychol B, 54 (3), pp. 259-270Larsson, M., Nilsson, L.G., Olofsson, J.K., Nordin, S., Demographic and cognitive predictors of cued odor identification: evidence from a population-based study (2004) Chem Senses, 29 (6), pp. 547-554Doty, R.L., Cameron, E.L., Sex differences and reproductive hormone influences on human odor perception (2009) Physiol Behav, 97 (2), pp. 213-228Orhan, K.S., Karabulut, B., Keles, N., Deger, K., Evaluation of factors concerning the olfaction using the sniffin' sticks test (2012) Otolaryngol Head Neck Surg, 146 (2), pp. 240-246Frye, R.E., Schwartz, B.S., Doty, R.L., Dose-related effects of cigarette smoking on olfactory function (1990) JAMA, 263, pp. 1233-1236Katotomichelakis, M., Balatsouras, D., Tripsianis, G., Davris, S., Maroudias, N., Danielides, V., The effect of smoking on the olfactory function (2007) Rhinology, 45, pp. 273-280Bower, J.H., Maraganore, D.M., Peterson, B.J., Ahlskog, J.E., Rocca, W.A., Immunologic diseases, anti-inflammatory drugs, & Parkinson disease: a case-control study (2006) Neurology, 67 (3), pp. 494-496Sedig, L., Leibner, J., Ramjit, A.L., Wu, S.S., Dai, Y., Okun, M.S., Is rhinorrhea an under-recognized intrinsic symptom of Parkinson disease? A prospective pilot study (2010) Int J Neurosci, 120 (4), pp. 258-26

Shape Restoration Effect in Ag–SiO₂ Core–Shell Nanowires

The combination of two different materials in a single composite core–shell heterostructure can lead to improved or even completely novel properties. In this work we demonstrate the enhancement of the mechanical properties of silver (Ag) nanowires (NW) achieved by coating them with a silica (SiO₂) shell. In situ scanning electron microscope (SEM) nanomechanical tests of Ag–SiO₂ core–shell nanowires reveal an improved fracture resistance and an electron-beam induced shape restoration effect. In addition, control experiments are conducted separately on uncoated Ag NWs and on empty SiO₂ shells in order to gain deeper insight into the peculiar properties of Ag–SiO₂. Test conditions are simulated using finite-element methods; possible mechanisms responsible for the shape restoration and the enhanced fracture resistance are discussed

Odor Identification Test in Idiopathic REM-Behavior Disorder and Parkinson's Disease in China

Olfactory dysfunction is common in Parkinson's disease (PD) and idiopathic rapid eye movement sleep behavior disorder (iRBD), which is a risk factor in the development of PD. However, a few studies have conflicting results when comparing dysosmia in the patients with iRBD and PD. There is no study investigating the olfactory function in Chinese patients with iRBD. Additionally, the Sniffin' Sticks screening 12 test (SS-12) contains several odors that are not familiar to people in different cultures.Odor identification was evaluated in iRBD patients (n = 54), PD patients (n = 54) and healthy controls (n = 54). With the identification data, a brief odor identification test was established and then validated in other subjects.Odor identification scores in iRBD patients were significantly higher than those in PD patients (P<0.001) but lower than those in controls (P<0.001). At the cut-off value of 7.5, the Sniffin' Sticks clearly differentiated iRBD and PD patients from the controls, and the brief test could increase the specificity in diagnosing PD. Neither the Sniffin' Sticks nor the brief test could clearly differentiate PD and iRBD patients from each other.Olfaction is more impaired in PD patients than in iRBD patients, possibly due to the heterogeneity of iRBD patients. The Sniffin' Sticks could be a useful tool for differentiating iRBD patients from the healthy population, and it could be useful for screening people at high-risk of PD in China, especially when combined with polysomnography. To reduce the expense and time required for the Sniffin' Sticks test, this study shows that a brief test is feasible