Intravenous Thrombolysis with Tenecteplase for the Treatment of Acute Ischemic Stroke.

OBJECTIVE: Intravenous thrombolysis (IVT) with tenecteplase has been associated with better clinical outcomes in acute ischemic stroke (AIS) patients with confirmed large vessel occlusions compared to IVT with alteplase. However, the utility of tenecteplase for the treatment of all AIS patients eligible for IVT has not been established. METHODS: We compared the safety and efficacy of tenecteplase versus alteplase in AIS patients by analyzing propensity score matched data from 20 centers participating in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register. Patients receiving IVT with tenecteplase were matched with up to 3 patients receiving alteplase from the same center. The primary outcome of interest was the distribution of 3-month functional outcomes. Secondary outcomes included the rates of patients with symptomatic intracranial hemorrhage (SICH) in the first 24 hours, excellent (modified Rankin Scale [mRS] score = 0-1) or good (mRS score = 0-2) functional outcome, and all-cause mortality at 3 months. RESULTS: A total of 331 tenecteplase-treated AIS patients were matched to 797 patients treated with alteplase (median age = 70 years, 43.9% women, median National Institutes of Health Stroke Scale score = 11, interquartile range = 6-17). Patients treated with tenecteplase had better 3-month functional outcomes (common odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.18-2.00) with higher odds of good functional outcome (OR = 2.00, 95% CI = 1.45-2.77) and a lower likelihood of all-cause mortality (OR = 0.43, 95% CI = 0.27-0.67) at 3 months, compared to alteplase-treated patients. No difference was found in the likelihood of the 3-month excellent functional outcomes (OR = 1.31, 95% CI = 0.96-1.78) and 24-hour SICH (1.0% vs 1.3%, OR = 0.72, 95% CI = 0.20-2.64). INTERPRETATION: IVT with tenecteplase was associated with better 3-month clinical outcomes compared to IVT with alteplase in AIS patients, with no increased risk of symptomatic intracranial bleeding. ANN NEUROL 2022;92:349-357.

Screening for silent aspiration in hyperacute stroke: A feasibility study of clinical swallowing examination and cough reflex testing.

BACKGROUND: Silent aspiration (SA) is common post-stroke and associated with increased risk of pneumonia, length of stay and healthcare costs. Clinical swallow examinations (CSEs) are unreliable measures of SA. There is no consensus on the clinical components that best detect SA. Cough reflex testing (CRT) is an alternative/adjunct whose SA detection accuracy also lacks consensus. AIMS: To investigate the feasibility of CSE versus CRT against gold standard flexible endoscopic evaluation of swallowing (FEES) for SA identification and to estimate its prevalence in a hyperacute stroke setting. METHODS & PROCEDURES: A single-arm preliminary, prospective, feasibility study of patients less than 72 h post-stroke, over a 31-day period on a hyperacute stroke unit: the Royal Victoria Infirmary, Newcastle-upon-Tyne, UK. Ethical approval for the study was obtained. The study tested the feasibility and acceptability of introducing CRT and developing a standardized CSE. Consent/assent was obtained for all participants. Patients unfit for study were excluded. OUTCOMES & RESULTS: A total of 62% of patients less than 72 h post-stroke (n = 61) were eligible. A total of 75% of those approached (n = 30) consented. A total of 23 patients completed all tests. The principal barrier was anxiety regarding FEES. Mean test time for CRT = 6 min; CSE = 8 min; FEES = 17 min. Patients rated CRT and FEES on average as moderately uncomfortable. A total of 30% (n = 7) of participants who received FEES presented with SA. CONCLUSIONS & IMPLICATIONS: CRT, CSE and FEES are feasible in 58% of hyperacute stroke patients in this setting. FEES anxiety is the main recruitment barrier and is not always well tolerated. Results support further work to establish optimum methods and differential sensitivity/specificity of CRT and CSE in hyperacute stroke for SA identification. WHAT THIS PAPER ADDS: What is already known on this subject SA significantly increases the risk of pneumonia in the early days post-stroke. CSEs are unreliable for identification of SA risk in this population. CRT is gaining popularity as a potential tool to identify stroke patients at risk of SA, though there are questions regarding the efficacy of the clinical protocol currently being used in the UK. What this study adds to existing knowledge This study demonstrates that it is practical and feasible to carry out a larger scale study in this setting to compare CSE and CRT including a consideration of an approach combining both methods for clinical identification of SA versus FEES. Preliminary findings suggest that CSE may have higher levels of sensitivity than CRT for SA identification. What are the potential or actual clinical implications of this work? The results of this study suggest that further work is needed to establish the optimum methods and differential sensitivity/specificity of clinical tools for SA detection in hyperacute stroke.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Hypothalamic expression of GnRH-I and GnIH in the Eurasian tree sparrow over a single long day.

Seasonal reproductive cycles of most birds are regulated by photoperiod via neuroendocrine control. The present study aims to investigate the role of a single long day in triggering hypothalamic expressions of GnRH-I and GnIH in the Eurasian tree sparrow (Passer montanus). Sparrows were divided into two groups (n = 24 each) and pre-treated under short days (9L: 15D) for 4 days. On the fifth day, one group was exposed to long day (14L: 10D), while other was continued under short day for another 1 day. Birds of both the groups were sacrificed and perfused on fifth day at different time points, i.e., ZT 14, ZT 16 and ZT 18 and the expressions of GnRH-I and GnIH mRNAs and peptides were studied using real-time PCR and immunohistochemistry, respectively. In addition, testicular size was measured to know testicular development. Observations revealed that birds exposed to a single long day (14L: 10D) showed an increase in hypothalamic expressions of GnRH-I mRNA and peptide and decrease in levels of GnIH mRNA only at ZT 16 and ZT 18 with no significant change in GnIH peptide. However, no significant change in GnRH-I or GnIH expression was observed at any time point under short day and birds maintained high and low expression levels of GnIH and GnRH-I, respectively. Our results clearly indicate that the photoperiodic response system of sparrow is highly sensitive to light and responds even to single long day. Furthermore, they suggest that the GnRH-I and GnIH are expressed in the hypothalamus of tree sparrow in an anti-phasic manner and switching over of their expression occurs at late hours of exposure of birds to single long day.

Enhancing the Understanding of Soil Nitrogen Fate Using a 3D-Electrospray Sensor Roll Casted with a Thin-Layer Hydrogel.

Accurate and continuous monitoring of soil nitrogen is critical for determining its fate and providing early warning for swift soil nutrient management. However, the accuracy of existing electrochemical sensors is hurdled by the immobility of targeted ions, ion adsorption to soil particles, and sensor reading noise and drifting over time. In this study, polyacrylamide hydrogel with a thickness of 0.45 µm was coated on the surface of solid-state ion-selective membrane (S-ISM) sensors to absorb water contained in soil and, consequently, enhance the accuracy (R2 > 0.98) and stability (drifting < 0.3 mV/h) of these sensors monitoring ammonium (NH4+) and nitrate (NO3-) ions in soil. An ion transport model was built to simulate the long-term NH4+ dynamic process (R2 > 0.7) by considering the soil adsorption process and soil complexity. Furthermore, a soil-based denoising data processing algorithm (S-DDPA) was developed based on the unique features of soil sensors including the nonlinear mass transfer and ion diffusion on the heterogeneous sensor-hydrogel-soil interface. The 14 day tests using real-world soil demonstrated the effectiveness of S-DDPA to eliminate false signals and retrieve the actual soil nitrogen information for accurate (error: <2 mg/L) and continuous monitoring.

Age, gender, peers, life skills and quality of life influence risk of cell phone addiction among college teachers in Karnataka, India : a state level epidemiological analysis.

BACKGROUND: Cell phones are an integral part of modern day life and have become companions for individuals irrespective of age, gender and socio-economic status. In this study, we assessed the factors affecting risk of cell phone addiction among teachers attending Life Skills Training and Counselling Services (LSTCS) program in Karnataka. METHODS: This cross sectional secondary data analysis utilised data from baseline assessment of trainees attending a Life Skills Training and Counselling Services program (LSTCP). Various factors hypothesised to be affecting risk of cell phone addiction (outcome) was analysed using univariate and multivariable logistic regression analysis. All the analysis was done using STATA 12.0 software. RESULTS: Multivariable logistic regression analysis was conducted with risk of cell phone addiction as outcome. A conceptual framework of hypothesized exposure variables was developed based on expert consultation and literature review. Overall, data of 1981 participants was utilized. Gender (AOR=1.91; 95% CI=1.27-2.77), number of peers (AOR=1.01; 95 CI=1-1.008) and social quality of life (AOR=1.01; 95% CI=1.00-1.03) were associated with increased risk of cell phone addiction. Age (AOR=0.98; 95%CI=0.96-1.00), empathy (AOR=0.96;95%;CI=0.93-0.99), communication skills(AOR=0.92, 95%;CI=0.88-0.96) and physical quality of life (AOR=0.96; 95% CI=0.95-0.98) were associated with reduced risk of cell phone addiction. CONCLUSIONS: This study on precursors of risk of cell phone addiction, conducted mostly among apparently healthy individuals, provide important insights into interventions to reduce risk of cell phone addiction. The complexity of associations between peers, gender, quality of life and risk of cell phone addiction needs further exploration.

Characteristics and outcomes of COVID-19 associated stroke: a UK multicentre case-control study.

OBJECTIVE: We set out to determine which characteristics and outcomes of stroke are associated with COVID-19. METHODS: This case-control study included patients admitted with stroke to 13 hospitals in England and Scotland between 9 March and 5 July 2020. We collected data on 86 strokes (81 ischaemic strokes and 5 intracerebral haemorrhages) in patients with evidence of COVID-19 at the time of stroke onset (cases). They were compared with 1384 strokes (1193 ischaemic strokes and 191 intracerebral haemorrhages) in patients admitted during the same time period who never had evidence of COVID-19 (controls). In addition, the whole group of stroke admissions, including another 37 patients who appeared to have developed COVID-19 after their stroke, were included in two logistic regression analyses examining which features were independently associated with COVID-19 status and with inpatient mortality. RESULTS: Cases with ischaemic stroke were more likely than ischaemic controls to occur in Asians (18.8% vs 6.7%, p<0.0002), were more likely to involve multiple large vessel occlusions (17.9% vs 8.1%, p<0.03), were more severe (median National Institutes of Health Stroke Scale score 8 vs 5, p<0.002), were associated with higher D-dimer levels (p<0.01) and were associated with more severe disability on discharge (median modified Rankin Scale score 4 vs 3, p<0.0001) and inpatient death (19.8% vs 6.9%, p<0.0001). Recurrence of stroke during the patient's admission was rare in cases and controls (2.3% vs 1.0%, NS). CONCLUSIONS: Our data suggest that COVID-19 may be an important modifier of the onset, characteristics and outcome of acute ischaemic stroke.

Morphological and Ultrastructural Studies of Pecten in the Eurasian Tree Sparrow.

We studied the fine histological structures of pecten oculi of the Eurasian tree sparrow using various microscopy techniques. The pecten of the tree sparrow was found to be of a pleated type comprising of pleats, bridges, and base. The light microscopic study revealed further that the pleats consist of capillaries of varying sizes, blood vessels, and numerous pigmented cells that give them a black color. Histochemical studies of pecten showed a large deposition of lipid droplets, which were more abundant in the basal area. The transmission electron microscopy displayed capillaries and blood vessels that remain surrounded by a thick fibrous basal membrane. They are formed of endothelial cells having a large lumen and abluminal area with microfolds. Interstitial spaces were found filled with rounded melanocytes, electron-dense pigment granules, and mitochondria. Observations under the scanning electron microscope revealed the presence of a dense vascular network of capillaries and vessels. In addition, large hyalocytes were also observed on the surface of the pleats. The above observations suggest that the histological structure of the pecten of the tree sparrow resembles those present in the pecten of other diurnal birds. However, further investigation is required to ascertain its functional role in birds.

Effect of Recanalization on Cerebral Edema in Ischemic Stroke Treated With Thrombolysis and/or Endovascular Therapy.

Background and Purpose- A large infarct and expanding cerebral edema (CED) due to a middle cerebral artery occlusion confers a 70% mortality unless treated surgically. Reperfusion may cause blood-brain barrier disruption and a risk for cerebral edema and secondary parenchymal hemorrhage (PH). We aimed to investigate the effect of recanalization on development of early CED and PH after recanalization therapy. Methods- From the SITS-International Stroke Treatment Registry, we selected patients with signs of artery occlusion at baseline (either Hyperdense Artery Sign or computed tomography/magnetic resonance imaging angiographic occlusion). We defined recanalization as the disappearance of radiological signs of occlusion at 22 to 36 hours. Primary outcome was moderate to severe CED and secondary outcome was PH on 22- to 36-hour imaging scans. We used logistic regression with adjustment for baseline variables and PH. Results- Twenty two thousand one hundred eighty-four patients fulfilled the inclusion criteria (n=18 318 received intravenous thrombolysis, n=3071 received intravenous thrombolysis+thrombectomy, n=795 received thrombectomy). Recanalization occurred in 64.1%. Median age was 71 versus 71 years and National Institutes of Health Stroke Scale score 15 versus 16 in the recanalized versus nonrecanalized patients respectively. Recanalized patients had a lower risk for CED (13.0% versus 23.6%), adjusted odds ratio (aOR), 0.52 (95% CI, 0.46-0.59), and a higher risk for PH (8.9% versus 6.5%), adjusted odds ratio, 1.37 (95% CI, 1.22-1.55), than nonrecanalized patients. Conclusions- In patients with acute ischemic stroke, recanalization was associated with a lower risk for early CED even after adjustment for higher rate for PH in recanalized patients.

Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2).

BACKGROUND: Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute-chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study. METHODS: We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2-13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation. FINDINGS: Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures. INTERPRETATION: Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials. FUNDING: ReNeuron, Innovate UK (application no 32074-222145). TRIAL REGISTRATION NUMBER: EudraCT Number: 2012-003482-18.

Circadian versus circannual rhythm in the photoperiodic programming of seasonal responses in Eurasian tree sparrow (Passer montanus).

Experiments were performed on the subtropical tree sparrow (Passer montanus) to investigate whether day length, as a proximate factor, involves circadian rhythm in timing seasonal responses or these events are programmed by the mediation of an endogenous circannual rhythm. The experiments began from the two equinoxes, i.e. March and September, and continued for about 18 months. In each equinox, one group of wild birds of both sex was exposed to near simulated day length as it varies in nature at Shillong (Latitude 25°34'N, Longitude 91°53'E), and the other group was given a photoperiodic treatment in the reverse order corresponding to natural variation in day length from the other equinox. The birds exposed to near simulated day lengths in March and September showed gonadal, bill colour and molting responses, as observed in the wild birds in nature. Moreover, when photosensitive birds of March were given photoperiodic treatment in the reverse order (i.e., natural variation in day lengths beginning from September), they maintained their photosensitivity and responded only when they received increasing day length in the following September. However, when the photorefractory birds of September were exposed to reverse photoperiodic treatment (i.e. natural day length as it varies from March), they terminated their photorefractoriness after receiving decreasing day length in March the next year and responded when they again received increasing day length in the following September. These results strongly suggest that photoperiodic regulation of seasonal responses in the tree sparrow involves an endogenous circadian rhythm and exclude the possibility of circannual rhythm generation.

Safety and Outcome of Intravenous Thrombolysis in Stroke Patients on Prophylactic Doses of Low Molecular Weight Heparins at Stroke Onset.

Background and Purpose- There are limited data on intravenous thrombolysis treatment in patients with ischemic stroke who have received prophylactic doses of low molecular weight heparins (LMWHs). We aimed to evaluate the safety and outcomes of intravenous thrombolysis treatment in stroke patients taking thromboprophylactic doses of LMWH. Methods- We analyzed 109 291patients treated with intravenous thrombolysis, recorded in the Safe Implementation of Treatments in Stroke International Thrombolysis Register between 2003 and 2017 not taking oral anticoagulants or therapeutic doses of heparin at stroke onset. One thousand four hundred eleven patients (1.3%) were on prophylactic LMWH for deep venous thrombosis prevention. Outcome measures were symptomatic intracerebral hemorrhage, parenchymal hematoma, death within 7 days and 3 months, and functional dependency at 3 months. Results- Patients on LMWH were older, had more severe strokes, more prestroke disability, and comorbidities than patients without LMWH. There was no significant increase in adjusted odds ratios (aOR) for symptomatic intracerebral hemorrhage (aOR, 1.02 [95% CI, 0.48-2.17] as per Safe Implementation of Treatments in Stroke -MOST, aOR, 0.95 [0.59-1.53] per ECASS II]), nor for 7-day mortality (aOR, 1.14 [0.82-1.59]), in the prophylactic LMWH group. The LMWH group had a higher aOR for 3-month mortality (aOR, 1.94 [1.49-2.53]) and functional dependency, aOR, 1.44 (1.10-1.90). Propensity score analysis matching patients on baseline characteristics removed differences between groups on all outcomes except 3-month mortality. Conclusions- Intravenous thrombolysis in patients with acute ischemic stroke on treatment with prophylactic doses of LMWH at stroke onset is not associated with an increased risk of symptomatic intracerebral hemorrhage or early death.

Glucose Modifies the Effect of Endovascular Thrombectomy in Patients With Acute Stroke.

Background and Purpose- Hyperglycemia is a negative prognostic factor after acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy (EVT) in patients with large-vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of EVT in acute stroke. Methods- Seven randomized trials compared EVT with standard care between 2010 and 2017 (HERMES Collaboration [highly effective reperfusion using multiple endovascular devices]). One thousand seven hundred and sixty-four patients with large-vessel stroke were allocated to EVT (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome (modified Rankin Scale range, 0-6; lower scores indicating less disability) at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level. Results- Median (interquartile range) serum glucose on admission was 120 (104-140) mg/dL (6.6 mmol/L [5.7-7.7] mmol/L). EVT was better than standard care in the overall pooled-data analysis adjusted common odds ratio (acOR), 2.00 (95% CI, 1.69-2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose < or >90 mg/dL (5.0 mmol/L; P=0.019 for interaction; acOR, 3.81; 95% CI, 1.73-8.41 for patients < 90 mg/dL versus 1.83; 95% CI, 1.53-2.19 for patients >90 mg/dL), and glucose < or >100 mg/dL (5.5 mmol/L; P=0.004 for interaction; acOR, 3.17; 95% CI, 2.04-4.93 versus acOR, 1.72; 95% CI, 1.42-2.08) but not between subgroups above these levels of glucose. Conclusions- EVT improved stroke outcomes compared with standard treatment regardless of glucose levels, but the treatment effects were larger at lower glucose levels, with significant interaction effects persisting up to 90 to 100 mg/dL (5.0-5.5 mmol/L). Whether tight control of glucose improves the efficacy of EVT after large-vessel stroke warrants appropriate testing.

A mixed methodology, non-interventional study to evaluate the use of direct oral anticoagulants in UK clinical practice for patients with a first stroke associated with non-valvular atrial fibrillation: study protocol.

BACKGROUND: Treatment with anticoagulants, including direct oral anticoagulants (DOACs), should be considered for patients diagnosed with atrial fibrillation (AF) deemed at risk of ischaemic stroke. There are limited real world data related to the characteristics of patients with non-valvular AF who were not taking anticoagulants at the time of first ischaemic stroke and their subsequent DOAC treatment for the secondary prevention of stroke. Furthermore, little is known about patient adherence and experiences of DOAC treatment, especially for patients with non-valvular AF receiving DOAC therapy for the secondary prevention of stroke. METHODS: This is a UK mixed methodology, non-interventional study, involving retrospective and prospective medical record reviews and a prospective patient survey, in progress in six UK National Health Service secondary/tertiary care centres. The study comprises two groups of patients. Group 1 will include 300 eligible consenting patients with a first ischaemic stroke associated with non-valvular AF untreated with anticoagulants in the 12 months prior to stroke. Group 2 will include a subgroup of 150 patients from Group 1 initiated on one of the DOACs targeting activated Factor X (n = 50 on apixaban, n = 50 on edoxaban and n = 50 on rivaroxaban). The primary endpoint of the study is the CHA2DS2-VASc Risk Score prior to initiation of anticoagulation for patients included in Group 1. Secondary endpoints to be evaluated in Group 1 include patient demographics, clinical characteristics, relevant medical history, anticoagulant therapy initiated for secondary prevention of stroke, and relevant concomitant medication. Secondary endpoints to be evaluated in Group 2 include the time between stroke and DOAC initiation; prescribing of DOACs, other anticoagulants and concomitant medication; clinical assessments and hospital resource use; patient reported outcome measures, including the Morisky Medication Adherence Scale questionnaire and the Treatment Satisfaction Questionnaire for Medication. DISCUSSION: This mixed methodology study will provide new real world insights into the characteristics and management pathways and patient-reported experiences of this important group of patients. It is anticipated that the results of this study will provide the medical community and patients with important information to inform clinical decision-making and help facilitate meaningful improvements in the care of patients with non-valvular AF.

Temperature modulates photoperiodic seasonal responses in the subtropical tree sparrow, Passer montanus.

We studied the effects of temperature on the photoperiodic regulation of seasonal reproduction and related events in the subtropical tree sparrow at Shillong, India. In the first experiment, one group of birds was maintained in an outdoor open aviary receiving natural photoperiod and temperature conditions, while the other group was exposed to natural photoperiod and constant temperature of 17 ± 2 °C in an outdoor closed aviary for 12 months. Although both sexes achieved peak gonadal growth at the same time (May) under the two conditions, gonadal regression and feathers molt were delayed under the temperature controlled condition. In the second experiment, the groups of birds were exposed to three different temperatures (17, 25 and 30 °C) under both long (LD-14L:10D) and short (SD-9L:15D) day lengths for 7 months. Birds showed relatively small but significant gonadal growth, darkening of bill color and feathers molt only at 30 °C under SD. However, they behaved as though they were under natural conditions and exhibited the above responses significantly at all temperatures under LD. There was delayed gonadal regression at the lower temperature (17 °C), while feathers molt delayed with increasing temperature (25, 30 °C) under LD. These results clearly indicate that temperature modulates photoperiodic seasonal responses in the tree sparrow.

Photoperiodic control of GnRH-I expression in seasonal reproduction of the Eurasian tree sparrow.

Day length has been shown to be a major source of temporal information regulating seasonal reproduction in the Eurasian tree sparrow (Passer montanus). The present study aims to investigate the photoperiodic expression of gonadotropin-releasing hormone-I (GnRH-I), and how it mediates seasonal reproduction in male tree sparrows. In different experiments, we studied photoperiod-induced changes in GnRH-I expressing neurons in the hypothalamic preoptic area (POA), together with changes in testicular size under both natural and artificial photoperiodic conditions. Experiment 1, which involved studying changes in GnRH-I expression and testicular volume during different phases of the annual reproductive cycle under natural day length (NDL), revealed that sparrows possess a definite seasonal cycle of GnRH-I peptide expression that runs parallel to testicular size. Birds showed significantly higher levels of GnRH-I expression in the breeding phase when compared to the non-breeding phase. In experiment 2, photosensitive birds were exposed to artificial short (SD: 9L/15D) and long (LD: 14L/10D) day lengths for 240 days to investigate the photoperiodic regulation of GnRH-I expression. They exhibited a significant increase followed by a decrease in GnRH-I expression and testicular size under LD but not SD, suggesting photoperiodic regulation. In experiment 3, when photosensitive birds were exposed to increasing photoperiods (9L/15D, 10L/14D, 10.5L/13.5D, 11L/13D, 12L/12D) for 30 days to find out the critical photoperiod for GnRH-I expression, they responded only when the daily photoperiod was 11 h or more. These results clearly indicate that tree sparrows are capable of fine discrimination of photoperiodic information and use day length for GnRH-I expression to control their seasonal reproduction.

Endovascular therapy for acute ischaemic stroke: the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial.

OBJECTIVE: The Pragmatic Ischaemic Thrombectomy Evaluation (PISTE) trial was a multicentre, randomised, controlled clinical trial comparing intravenous thrombolysis (IVT) alone with IVT and adjunctive intra-arterial mechanical thrombectomy (MT) in patients who had acute ischaemic stroke with large artery occlusive anterior circulation stroke confirmed on CT angiography (CTA). DESIGN: Eligible patients had IVT started within 4.5 hours of stroke symptom onset. Those randomised to additional MT underwent thrombectomy using any Conformité Européene (CE)-marked device, with target interval times for IVT start to arterial puncture of <90 min. The primary outcome was the proportion of patients achieving independence defined by a modified Rankin Scale (mRS) score of 0-2 at day 90. RESULTS: Ten UK centres enrolled 65 patients between April 2013 and April 2015. Median National Institutes of Health Stroke Scale score was 16 (IQR 13-21). Median stroke onset to IVT start was 120 min. In the intention-to-treat analysis, there was no significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). Secondary analyses showed significantly greater likelihood of full neurological recovery (mRS 0-1) at day 90 (OR 7.6, 95% CI 1.6 to 37.2, p=0.010). In the per-protocol population (n=58), the primary and most secondary clinical outcomes significantly favoured MT (absolute difference in mRS 0-2 of 22% and adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021). CONCLUSIONS: The trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival. TRIAL REGISTRATION NUMBER: NCT01745692; Results.

Role of GnIH in photoperiodic regulation of seasonal reproduction in the Eurasian tree sparrow.

Seasonal reproductive cycles of most birds are regulated by photoperiod via neuroendocrine control. Gonadotropin-inhibitory hormone (GnIH) in the hypothalamus has been reported to act as neuroendocrine integrator of photoperiodic cues. In this study, both captive and field investigations were carried out to understand the effects of photoperiod and seasonality on GnIH expression in subtropical tree sparrows. Monthly observations of GnIH mRNA and peptide expression in wild birds over a year revealed a significant increase in GnIH mRNA level and number of GnIH-ir neurons during the non-breeding season when compared with their expression in the breeding season. GnIH-ir neurons were found primarily in the paraventricular nucleus (PVN) with their fibers projecting into the median eminence and some other areas of the brain. In an 8 month-long experiment, birds exposed to short days had higher GnIH expression compared with birds exposed to long days regardless of sampling month. Long-day birds with regressed testes had similar GnIH levels to short-day birds. Though the number of GnIH peptide-expressing neurons ran almost parallel to the levels of GnIH mRNA, they were inversely related to gonadal size in both sexes under natural and artificial photoperiodic conditions. These results clearly indicate an inhibitory role of GnIH in photoperiodic regulation of seasonal reproduction in the tree sparrow.

Photoperiodic time measurement and photoentrainment of a circadian locomotor activity rhythm in subtropical tree sparrows.

Experiments were performed on the subtropical tree sparrow (Passer montanus) to investigate the involvement of an endogenous circadian rhythm in photoperiodic time measurement during the initiation of gonadal growth and functions and also to study the photic entrainment of the circadian activity rhythm. Groups of photosensitive birds of both sexes were exposed to different "night-interruption" light-dark regimes of 24 h duration viz., G1 - 6L/5D/1L/12D, G2 - 6L/6D/1L/11D, G3 - 6L/7D/1L/10D, G4 - 6L/8D/1L/9D, G5 - 6L/10D/1L/7D, G6 - 6L/12D/1L/5D, G7 - 6L/14D/1L/3D and G8 - 6L/16D/1L/1D for 30 days in which 17 h long nights were interrupted by 1 h light pulse falling at different ZTs (i.e., 11, 12, 13, 14, 16, 18, 20 and 22). A control group, for each sex, was maintained under 7L/17D. The birds of all groups behaved as though they had been exposed to a stimulatory photoperiod except those of G1, G8 and the control. Furthermore, the serum levels of testosterone in males and estradiol-17ß in females ran almost parallel to changes in the gonadal size. Birds, when exposed to 12L/12D, showed entrainment of their locomotor activity rhythm with the activity confined mainly during the light phase. However, various characteristics of the activity rhythm differed significantly upon transfer of birds to various night interruption regimes. These results suggest the involvement of the endogenous circadian rhythm in photoperiodic time measurement during the induction of gonadal growth and functions in the tree sparrow. Also, there is photic entrainment of the locomotor activity rhythm that shows variations in various circadian characteristics under different night interruption cycles suggesting that the photoinducible phase is differentially sensitive to light.

Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke.

BACKGROUND AND PURPOSE: Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke. METHODS: Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl-Meyer Assessment-Upper Extremity). RESULTS: Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl-Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, -0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl-Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6). CONCLUSIONS: This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01669161.