Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Superfluidity of Light and Its Breakdown in Optical Mesh Lattices.

Hydrodynamic phenomena can be observed with light thanks to the analogy between quantum gases and nonlinear optics. In this Letter, we report an experimental study of the superfluid-like properties of light in a (1+1)-dimensional nonlinear optical mesh lattice, where the arrival time of optical pulses plays the role of a synthetic spatial dimension. A spatially narrow defect at rest is used to excite sound waves in the fluid of light and measure the sound speed. The critical velocity for superfluidity is probed by looking at the threshold in the deposited energy by a moving defect, above which the apparent superfluid behavior breaks down. Our observations establish optical mesh lattices as a promising platform to study fluids of light in novel regimes of interdisciplinary interest, including non-Hermitian and/or topological physics.

A support programme for secondary prevention in patients with transient ischaemic attack and minor stroke (INSPiRE-TMS): an open-label, randomised controlled trial.

BACKGROUND: Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. METHODS: INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. FINDINGS: From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75-1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77-1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62-1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). INTERPRETATION: Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. FUNDING: German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation.

Collapse on the line - how synthetic dimensions influence nonlinear effects.

Power induced wave collapse is one of the most fascinating phenomena in optics as it provides extremely high intensities, thus stimulating a range of nonlinear processes. For low power levels, propagation of beams in bulk media is dominated by diffraction, while above a certain threshold self-focusing is steadily enhanced by the action of a positive nonlinearity. An autocatalytic blow-up occurs, which is only stopped by saturation of the nonlinearity, material damage or the inherent medium discreteness. In the latter case, this leads to energy localization on a single site. It is commonly believed that for cubic nonlinearities, this intriguing effect requires at least two transverse dimensions to occur and is thus out of reach in fiber optics. Following the concept of synthetic dimensions, we demonstrate that mixing short and long-range interaction resembles a two-dimensional mesh lattice and features wave collapse at mW-power levels in a genuine 1D system formed by coupled fiber loops.

2D Solitons in PT-Symmetric Photonic Lattices.

Over the last few years, parity-time (PT) symmetry has been the focus of considerable attention. Ever since, pseudo-Hermitian notions have permeated a number of fields ranging from optics to atomic and topological physics, as well as optomechanics, to mention a few. Unlike their Hermitian counterparts, nonconservative systems do not exhibit a priori real eigenvalues and hence unitary evolution. However, once PT symmetry is introduced, such dissipative systems can surprisingly display a real eigenspectrum, thus ensuring energy conservation during evolution. In optics, PT symmetry can be readily established by incorporating, in a balanced way, regions having an equal amount of optical gain and loss. However, thus far, all optical realizations of such PT symmetry have been restricted to a single transverse dimension (1D), such as arrays of optical waveguides or active coupled cavity arrangements. In most cases, only the loss function was modulated-a restrictive aspect that is only appropriate for linear systems. Here, we present an experimental platform for investigating the interplay between PT symmetry and nonlinearity in two-dimensional (2D) environments, where nonlinear localization and soliton formation can be observed. In contrast to typical dissipative solitons, we demonstrate a one-parameter family of soliton solutions that are capable of displaying attributes similar to those encountered in nonlinear conservative arrangements. For high optical powers, this new family of PT solitons tends to collapse on a discrete network-thus giving rise to an amplified, self-accelerating structure.

Observation of Time Reversed Light Propagation by an Exchange of Eigenstates.

As time flow dictates all evolution, its effective reversal is a topic of active research in a broad range of disciplines, including acoustics, hydrodynamics and optics. This multifarious set of environments is reflected by a great diversity of approaches to observe various echoes of wave functions. Here, we experimentally demonstrate time reversal of a pulse sequence propagating through a photonic mesh lattice realized by two coupled loops of telecommunication fibres. Our system features a symmetric band structure, which allows for almost perfect reversal of its evolution by exchanging the population between two opposing bands. The protocol applied is based on a non-adiabatic and instantaneous exchange of eigenstates resulting in highly efficient time reversal of a pulse chain.

Observation of Bloch oscillations in complex PT-symmetric photonic lattices.

Light propagation in periodic environments is often associated with a number of interesting and potentially useful processes. If a crystalline optical potential is also linearly ramped, light can undergo periodic Bloch oscillations, a direct outcome of localized Wannier-Stark states and their equidistant eigenvalue spectrum. Even though these effects have been extensively explored in conservative settings, this is by no means the case in non-Hermitian photonic lattices encompassing both amplification and attenuation. Quite recently, Bloch oscillations have been predicted in parity-time-symmetric structures involving gain and loss in a balanced fashion. While in a complex bulk medium, one intuitively expects that light will typically follow the path of highest amplification, in a periodic system this behavior can be substantially altered by the underlying band structure. Here, we report the first experimental observation of Bloch oscillations in parity-time-symmetric mesh lattices. We show that these revivals exhibit unusual properties like secondary emissions and resonant restoration of PT symmetry. In addition, we present a versatile method for reconstructing the real and imaginary components of the band structure by directly monitoring the light evolution during a cycle of these oscillations.

Observation of optical solitons in PT-symmetric lattices.

Controlling light transport in nonlinear active environments is a topic of considerable interest in the field of optics. In such complex arrangements, of particular importance is to devise strategies to subdue chaotic behaviour even in the presence of gain/loss and nonlinearity, which often assume adversarial roles. Quite recently, notions of parity-time (PT) symmetry have been suggested in photonic settings as a means to enforce stable energy flow in platforms that simultaneously employ both amplification and attenuation. Here we report the experimental observation of optical solitons in PT-symmetric lattices. Unlike other non-conservative nonlinear arrangements where self-trapped states appear as fixed points in the parameter space of the governing equations, discrete PT solitons form a continuous parametric family of solutions. The possibility of synthesizing PT-symmetric saturable absorbers, where a nonlinear wave finds a lossless path through an otherwise absorptive system is also demonstrated.

Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS): a protocol for a randomised controlled trial.

BACKGROUND: Patients with recent stroke or TIA are at high risk for new vascular events. Several evidence based strategies in secondary prevention of stroke are available but frequently underused. Support programs with multifactorial risk factor modifications after stroke or TIA have not been investigated in large-scale prospective controlled trials so far. INSPiRE-TMS is a prospective, multi-center, randomized open intervention trial for intensified secondary prevention after minor stroke and TIA. METHODS/DESIGN: Patients with acute TIA or minor stroke admitted to the participating stroke centers are screened and recruited during in-hospital stay. Patients are randomised in a 1:1 ratio to intervention (support program) and control (usual care) arms. Inclusion of 2.082 patients is planned. The support program includes cardiovascular risk factor measurement and feedback, monitoring of medication adherence, coaching in lifestyle modifications, and active involvement of relatives. Standardized motivational interviewing is used to assess and enhance patients' motivation. Primary objective is a reduction of new major vascular events defined as nonfatal stroke and myocardial infarction or vascular death. Recruitment time is planned for 3.5 years, follow up time is at least 2 years for every patient resulting in a total study time of 5 years (first patient in to last patient out). DISCUSSION: Given the high risk for vascular re-events in acute stroke and the available effective strategies in secondary prevention, the INSPIRE-TMS support program has the potential to lead to a relevant reduction of recurrent events and a prolongation of the event-free survival time. The trial will provide the basis for the decision whether an intensified secondary prevention program after stroke should be implemented into regular care. A cost-effectiveness evaluation will be performed. TRIAL REGISTRATION: clinicaltrials.gov: 01586702.

Can telemedicine contribute to fulfill WHO Helsingborg Declaration of specialized stroke care?

BACKGROUND: Providing stroke unit treatment for all stroke patients is a cross-national goal as stated in the WHO Helsingborg Declaration. In order to achieve specialized stroke care for a large area, two stroke centers and 12 community hospitals established an integrative stroke network. This evaluation was performed to analyze achieved advances in stroke management. METHODS: Core network elements are: (1) establishing stroke wards in all hospitals; (2) continuous training in stroke treatment; (3) telemedicine service staffed by a 24 h/day 'strokologist' with capability for high-speed videoconferencing and transfer of CT/MRI images. Data were prospectively documented in the databank of the telestroke service, in the Bavarian Stroke Registry and in the controlling departments. RESULTS: In 2003, 4,179 stroke patients were admitted to the regional network hospitals. Between February 2003 and January 2004 a total of 2,182 teleconsultations were conducted. 250 teleconsultations yielded a nonvascular diagnosis. Indicators for stroke management quality improved compared with other hospitals without stroke unit: the frequency of CT/MRI within 3 h was 59% compared to 46%, frequency of speech therapy 36% (21%), and of occupational therapy 38% (12%). Eighty-six (2.1%) of the patients received systemic thrombolysis compared to 10 patients in the preceding year. Mean length of in-hospital stay decreased from 12.4 in 2002 to 9.7 days in 2003. CONCLUSIONS: This stroke network concept leads to a substantial improvement of stroke management. Telemedicine contributes to an early etiological assessment and fills the gap of specialized stroke expertise in neurologically underserved areas.

Identification of Chlamydia pneumoniae in intracranial and extracranial arteries in patients with stroke and in controls: combined immunohistochemical and polymerase chain reaction analyses.

An association of the obligatory intracellular gram-negative pathogen Chlamydia pneumoniae with coronary artery disease, myocardial infarction, and atherosclerosis was suggested. The presence of C pneumoniae was determined in different arteries (n = 165) from 23 control cases and 10 patients with stroke including coronary arteries, carotid arteries, basilar artery, and middle cerebral arteries of normal controls and patients with stroke using nested polymerase chain reaction (PCR) and immunohistochemistry (IHC). Atherosclerosis was detected in 51.5% of all investigated arteries. No significant differences were detected between controls (59.1% by IHC, 45.5% by nested PCR) and patients with stroke (40% by IHC, 40% by nested PCR). This is the first investigation demonstrating C pneumoniae by IHC and nested PCR in different intracerebral arteries in control persons and patients with stroke. No significant correlation between the presence of chlamydial DNA or antigens in arteries and stroke could be demonstrated. The presence of the C pneumoniae is indicative of a correlation between infection and atherosclerosis, but not of a specific vascular neuropathology such as stroke.

Progression in lacunar stroke is related to elevated acute phase parameters.

BACKGROUND AND PURPOSE: Despite the small size of lacunar infarcts, progression of neurological deficits is a common problem in this stroke subtype. This investigation studied the frequency and the course of neurological deterioration as well as predictors and possible underlying pathomechanisms of early progression in lacunar stroke. METHODS: Fourty-six consecutive patients with acute lacunar stroke were prospectively evaluated by daily clinical neurological examination including the National Institutes of Health Stroke Scale (NIHSS) and follow-up using the Barthel Index after 3 months. Progressive neurological deficit was defined as worsening by > or =1 point in the NIHSS for motor function. Progressive and stable patients were compared regarding clinical profile, inflammatory parameters (leukocytes, body temperature, C-reactive protein), coagulation parameters (fibrinogen, D-dimer, vWF, PTT), and glutamate plasma concentration, as well as blood glucose and blood pressure. RESULTS: Eleven patients (23.9%) showed progression of stroke symptoms, 9 of these within the first 24 h after admission. The score on the NIHSS on admission was similar in patients with progressive stroke and stable patients, but significantly higher in the progressive stroke group on days 2 (p = 0.01), 3 (p = 0.001) and at discharge (p = 0.003). Deterioration was significantly associated with a higher leukocyte count (p = 0.012), higher body temperature (p = 0.031) and a higher fibrinogen concentration (p = 0.046) on admission. Barthel Index at discharge (p = 0.001) and after 90 days (p < 0.001) was significantly worse in the progressive stroke group. CONCLUSIONS: Progression in lacunar stroke usually occurs within 24 h and may be related to an acute-phase response. The long-term prognosis of progressive stroke patients is persistently worse compared with patients with nonprogressive stroke.

L-arginine-mediated vasoreactivity in patients with a risk of stroke.

OBJECTIVES: L-arginine is the substrate for nitric oxide (NO) production and has been shown to induce an endothelium-dependent increase in cerebral blood flow in humans. We studied the hypothesis that L-arginine-mediated vasoreactivity is impaired in patients with cardiovascular risk factors and a risk of stroke. METHODS: 55 patients with cardiovascular risk factors (mean age 63.0 +/- 8.5 years) were included in the study. 45 of them had a history of previous minor stroke or transient ischemic attack (TIA) while 10 patients had cardiovascular risk factors but no previous cerebral ischemic event. Endothelium-dependent changes in cerebral blood flow during the infusion of 30 g L-arginine were assessed by continuous transcranial Doppler sonography of both middle cerebral arteries, intima-media thickness (IMT) of the common carotid artery, by Duplex sonography. Associations between risk factors, IMT, L-arginine reactivity and previous cerebrovascular events were analyzed by stepwise multiple linear regression analysis and patient groups were compared. RESULTS: Normal young volunteers showed an L-arginine-mediated increase in mean flow velocity of 22 +/- 8%; L-arginine reactivity of the 55 patients was 28 +/- 10%. Patients with a history of stroke or TIA had significantly higher flow velocity responses to L-arginine (29 +/- 10%) than patients with cardiovascular risk factors but no previous cerebrovascular event (21 +/- 8%, p < 0.05). Stepwise multiple linear regression analysis showed a significant association of enhanced L-arginine reactivity with previous stroke/TIA (p < 0.001) and elevated fibrinogen levels (p < 0.05) but not with age, IMT, hypertension, cholesterol or other risk factors. The same regression model showed an association between IMT and previous stroke/TIA (p < 0.001) and serum cholesterol levels (p < 0.05) but not L-arginine reactivity. CONCLUSIONS: L-arginine reactivity of the cerebral vessels may be assessed by Doppler sonography and was enhanced in patients with a history of stroke or TIA. It was independent of IMT of the carotid arteries. We conclude that enhanced L-arginine reactivity is a potential marker for cerebral endothelial dysfunction and an independent indicator for an increased risk of stroke.

Complications following acute ischemic stroke.

The objective of this study was to assess typical early-onset complications following ischemic stroke in a large, hospital-based cohort to provide clinical data for future randomized trials and quality standards in clinical routine. 3,866 patients with acute ischemic stroke were prospectively documented in 14 Neurology Departments with an acute stroke unit. Within the first week after admission, increased intracranial pressure (7.6%) and recurrent cerebral ischemia (5.1%) were the most frequent neurological complications. Fever >38 degrees C (13.2%), severe arterial hypertension (7.5%) and pneumonia (7.4%) were the most frequent medical complications. Multivariate regression analysis yielded brain stem infarction and large-artery atherosclerosis as independent predictors for early recurrent ischemic stroke. This study provides representative data on onset and severity of early neurological and medical complications as well as possible predictors for early recurrent cerebral ischemia following acute ischemic stroke.

The low normothermia concept--maintaining a core body temperature between 36 and 37 degrees C in acute stroke unit patients.

Elevated body temperature increases mortality and worsens outcome in acute stroke patients. In animal models of stroke, even slight hypothermia was shown to be neuroprotective. Pharmacological treatment alone (paracetamol, metamizol) usually fails to lower core body temperature below 37 degrees C. The purpose of this study was to establish the feasibility and safety of continuous body surface cooling towards low normothermic temperatures in noncomatose, nonventilated stroke unit patients. Eighteen acute stroke patients (15 ischemic infarcts, 3 hemorrhages) with baseline body core temperatures >37.0 degrees C (taken in the urinary bladder) were laid on a water-perfused cooling mattress and received pethidine and dihydroergotoxine in order to avoid shivering and peripheral vasoconstriction. The target range for core body temperature was between 36 and 37 degrees C for 24 hours. None of the patients was treated with antipyretic drugs during the cooling period. Median baseline National Institutes of Health Stroke Scale score (NIHSSS) was 15.5 (8-24). Three patients had core temperatures >38 degrees C. A temperature in the target range could be reached within 3.3 hours (median) and maintained in all but two patients. Major procedure-related adverse events were vomiting (n = 2), drop in mean arterial blood pressure >20% (n = 2), pneumonia (n = 2), and a rise in central venous pressure >20 cm H2O (n = 3) totaling 9 events in 8 of 18 patients (44%). No patient died within the first week; mortality after three months was 12%. Continuous body core temperature reduction of 1-2 degrees C may safely be attained by a cooling mattress in nonventilated stroke unit patients. Critically high temperature values can be avoided. The neuroprotective potential of this method has to be assessed in a controlled trial.