Tenecteplase Improves Reperfusion across Time in Large Vessel Stroke.

OBJECTIVE: Tenecteplase improves reperfusion compared to alteplase in patients with large vessel occlusions. To determine whether this improvement varies across the spectrum of thrombolytic agent to reperfusion assessment times, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates. METHODS: Patients with large vessel occlusion and treatment with thrombolysis were pooled from the Melbourne Stroke Registry, and the EXTEND-IA and EXTEND-IA TNK trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at imaging reassessment. We compared the treatment effect of tenecteplase and alteplase, accounting for thrombolytic to assessment exposure times, via Poisson modeling. We compared 90-day outcomes of patients who achieved reperfusion with a thrombolytic to patients who achieved reperfusion via endovascular therapy using ordinal logistic regression. RESULTS: Among 893 patients included in the primary analysis, thrombolytic-induced reperfusion was observed in 184 (21%) patients. Tenecteplase was associated with higher rates of reperfusion (adjusted incidence rate ratio [aIRR] = 1.50, 95% confidence interval [CI] = 1.09-2.07, p = 0.01). Findings were consistent in patient subgroups with first segment (aIRR = 1.41, 95% CI = 0.93-2.14) and second segment (aIRR = 2.07, 95% CI = 0.98-4.37) middle cerebral artery occlusions. Increased thrombolytic to reperfusion assessment times were associated with reperfusion (tenecteplase: adjusted risk ratio [aRR] = 1.08 per 15 minutes, 95% CI = 1.04-1.13 vs alteplase: aRR = 1.06 per 15 minutes, 95% CI = 1.00-1.13). No significant treatment-by-time interaction was observed (p = 0.87). Reperfusion via thrombolysis was associated with improved 90-day modified Rankin Scale scores (adjusted common odds ratio = 2.15, 95% CI = 1.54-3.01) compared to patients who achieved reperfusion following endovascular therapy. INTERPRETATION: Tenecteplase, compared to alteplase, increases prethrombectomy reperfusion, regardless of the time from administration to reperfusion assessment. Prethrombectomy reperfusion is associated with better clinical outcomes. ANN NEUROL 2023;93:489-499.

Mediation of Successful Reperfusion Effect through Infarct Growth and Cerebral Edema: A Pooled, Patient-Level Analysis of EXTEND-IA Trials and SELECT Prospective Cohort.

OBJECTIVE: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. METHODS: In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. RESULTS: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR = 0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (ß = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23-0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86-3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95-2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. INTERPRETATION: In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804.

On-road driving remediation following acquired brain injury: a randomized controlled trial.

OBJECTIVE: To investigate the relationship between on-road driving remediation and achieving fitness to drive following acquired brain injury. DESIGN: Randomized controlled trial. SETTING: Tertiary hospital outpatient driver assessment and rehabilitation service, Australia. PARTICIPANTS: Thirty-five participants (54.3% male), aged 18-65 years, 41 days-20 years post-acquired brain injury (including stroke, aneurysm, traumatic brain injury) recommended for on-road driving remediation following occupational therapy driver assessment were randomly assigned to intervention (n = 18) and waitlist control (n = 17) groups. INTERVENTION: Intervention group received on-road driving remediation delivered by a qualified driving instructor in a dual-control vehicle. The waitlist control group completed a 6 week period of no driving-related remediation. MAIN MEASURE: Fitness to drive rated following the conduct of an on-road occupational therapy driver assessment with a qualified driving instructor where outcome assessors were blinded to group allocation. RESULTS: The intervention group were significantly more likely to achieve a fit to drive recommendation than no driving specific intervention (p = 0.003). CONCLUSION: Following comprehensive assessment, individualized on-road driving remediation programs devised by an occupational therapist with advanced training in driver assessment and rehabilitation and delivered by a qualified driving instructor are significantly associated with achieving fitness to drive after acquired brain injury.

Endovascular Thrombectomy Versus Medical Management in Isolated M2 Occlusions: Pooled Patient-Level Analysis from the EXTEND-IA Trials, INSPIRE, and SELECT Studies.

OBJECTIVE: The objective of this study was to evaluate functional and safety outcomes of endovascular thrombectomy (EVT) versus medical management (MM) in patients with M2 occlusion and examine their association with perfusion imaging mismatch and stroke severity. METHODS: In a pooled, patient-level analysis of 3 randomized controlled trials (EXTEND-IA, EXTEND-and IA-TNK parts 1 and 2) and 2 prospective nonrandomized studies (INSPIRE and SELECT), we evaluated EVT association with 90-day functional independence (modified Rankin Scale [mRS] = 0-2) in isolated M2 occlusions as compared to medical management overall and in subgroups by mismatch profile status and stroke severity. RESULTS: We included 517 patients (EVT = 195 and MM = 322), baseline median (interquartile range [IQR]) National Institutes of Health Stroke Scale (NIHSS) was 13 (8-19) in EVT versus 10 (6-15) in MM, p < 0.001. Pretreatment ischemic core did not differ (EVT = 10 [0-24] ml vs MM = 9 [3-21] ml, p = 0.59). Compared to MM, EVT was more frequently associated with functional independence (68.3 vs 61.6%, adjusted odds ratio [aOR] = 2.42, 95% confidence interval [CI] = 1.25-4.67, p = 0.008, inverse probability of treatment weights [IPTW]-OR = 1.75, 95% CI = 1.00-3.75, p = 0.05) with a shift toward better mRS outcomes (adjusted cOR = 2.02, 95% CI:1.23-3.29, p = 0.005), and lower mortality (5 vs 10%, aOR = 0.32, 95% CI = 0.12-0.87, p = 0.025). EVT was associated with higher functional independence in patients with a perfusion mismatch profile (EVT = 70.7% vs MM = 61.3%, aOR = 2.29, 95% CI = 1.09-4.79, p = 0.029, IPTW-OR = 2.02, 1.08-3.78, p = 0.029), whereas no difference was found in those without mismatch (EVT = 43.8% vs MM = 62.7%, p = 0.17, IPTW-OR: 0.71, 95% CI = 0.18-2.78, p = 0.62). Functional independence was more frequent with EVT in patients with moderate or severe strokes, as defined by baseline NIHSS above any thresholds from 6 to 10, whereas there was no difference between groups with milder strokes below these thresholds. INTERPRETATION: In patients with M2 occlusion, EVT was associated with improved clinical outcomes when compared to MM. This association was primarily observed in patients with a mismatch profile and those with higher stroke severity. ANN NEUROL 2022;91:629-639.

Impact of increasing total knee replacement constraint within a single implant line on coronal stability: an ex vivo investigation.

INTRODUCTION: Despite the existence of diverse total knee implant designs, few data is available on the relationship between the level of implant constraint and the postoperative joint stability in the frontal plane and strain in the collateral ligaments. The current study aimed to document this relation in an ex vivo setting. MATERIALS AND METHODS: Six fresh-frozen lower limbs underwent imaging for preparation of specimen-specific surgical guides. Specimens were dissected and assessed for joint laxity using the varus-valgus stress tests at fixed knee flexion angles. A handheld dynamometer applied tensile loads at the ankle, thereby resulting in a knee abduction-adduction moment of 10 Nm. Tibiofemoral kinematics were calculated using an optical motion capture system, while extensometers attached to medial collateral (MCL) and lateral collateral ligament (LCL) measured strain. Native joint testing was followed by four TKA designs from a single implant line-cruciate retaining, posterior stabilised, varus-valgus constrained and hinged knee (HK)-and subsequent testing after each implantation. Repeated measures linear mixed-models (p < 0.05) were used to compare preoperative vs. postoperative data on frontal plane laxity and collateral ligament strain. RESULTS: Increasing implant constraint reduced frontal plane laxity across knee flexion, especially in deep flexion (r2 > 0.76), and MCL strain in extension; however, LCL strain reduction was not consistent. Frontal plane laxity increased with knee flexion angle, but similar trends were inconclusive for ligament strain. HK reduced joint laxity and ligament strain as compared to the native condition consistently across knee flexion angle, with significant reductions in flexion (p < 0.024) and extension (p < 0.001), respectively, thereby elucidating the implant design-induced joint stability. Ligament strain exhibited a strong positive correlation with varus-valgus alignment (r2 = 0.96), notwithstanding knee flexion angle or TKA implant design. CONCLUSION: The study demonstrated that increasing the constraint of a TKA resulted in lower frontal plane laxity of the knee. With implant features impacting laxity in the coronal plane, consequentially affecting strain in collateral ligaments, surgeons must consider these factors when deciding a TKA implant, especially for primary TKA. LEVEL OF EVIDENCE: V.

Microvascular Dysfunction in Blood-Brain Barrier Disruption and Hypoperfusion Within the Infarct Posttreatment Are Associated With Cerebral Edema.

BACKGROUND: Factors contributing to cerebral edema in the post-hyperacute period of ischemic stroke (first 24-72 hours) are poorly understood. Blood-brain barrier (BBB) disruption and postischemic hyperperfusion reflect microvascular dysfunction and are associated with hemorrhagic transformation. We investigated the relationships between BBB integrity, cerebral blood flow, and space-occupying cerebral edema in patients who received acute reperfusion therapy. METHODS: We performed a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK and EXTEND-IA TNK part 2 trials who had MRI with dynamic susceptibility contrast-enhanced perfusion-weighted imaging 24 hours after treatment. We investigated the associations between BBB disruption and cerebral blood flow within the infarct with cerebral edema assessed using 2 metrics: first midline shift (MLS) trichotomized as an ordinal scale of negligible (<1 mm), mild (≥1 to <5 mm), or severe (≥5 mm), and second relative hemispheric volume (rHV), defined as the ratio of the 3-dimensional volume of the ischemic hemisphere relative to the contralateral hemisphere. RESULTS: Of 238 patients analyzed, 133 (55.9%) had negligible, 93 (39.1%) mild, and 12 (5.0%) severe MLS at 24 hours. The associated median rHV was 1.01 (IQR, 1.00-1.028), 1.03 (IQR, 1.01-1.077), and 1.15 (IQR, 1.08-1.22), respectively. MLS and rHV were associated with poor functional outcome at 90 days (P<0.002). Increased BBB permeability was independently associated with more edema after adjusting for age, occlusion location, reperfusion, parenchymal hematoma, and thrombolytic agent used (MLS cOR, 1.12 [95% CI, 1.03-1.20], P=0.005; rHV ß, 0.39 [95% CI, 0.24-0.55], P<0.0001), as was reduced cerebral blood flow (MLS cOR, 0.25 [95% CI, 0.10-0.58], P=0.001; rHV ß, -2.95 [95% CI, -4.61 to -11.29], P=0.0006). In subgroup analysis of patients with successful reperfusion (extended Treatment in Cerebral Ischemia 2b-3, n=200), reduced cerebral blood flow remained significantly associated with edema (MLS cOR, 0.37 [95% CI, 0.14-0.98], P=0.045; rHV ß, -2.59 [95% CI, -4.32 to -0.86], P=0.004). CONCLUSIONS: BBB disruption and persistent hypoperfusion in the infarct after reperfusion treatment is associated with space-occupying cerebral edema. Further studies evaluating microvascular dysfunction during the post-hyperacute period as biomarkers of poststroke edema and potential therapeutic targets are warranted.

Reduced Severity of Tissue Injury Within the Infarct May Partially Mediate the Benefit of Reperfusion in Ischemic Stroke.

BACKGROUND: Emerging data suggest tissue within the infarct lesion is not homogenously damaged following ischemic stroke but has a gradient of injury. Using blood-brain-barrier (BBB) disruption as a marker of tissue injury, we tested whether therapeutic reperfusion improves clinical outcome by reducing the severity of tissue injury within the infarct in patients with ischemic stroke. METHODS: In a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) and EXTEND-IA part-2 (Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke) trials, post-treatment BBB permeability at 24 hours was calculated based on the extent of T1-brightening by extravascular gadolinium on T2* perfusion-weighted imaging and measured within the diffusion-weighted-imaging lesion. First, to determine the clinical significance of BBB disruption as a marker of severity of tissue injury, we examined the association between post-treatment BBB permeability and functional outcome. Second, we performed an exploratory (reperfusion, BBB permeability, functional outcome) mediation analysis to estimate the proportion of the reperfusion-outcome relationship that is mediated by change in BBB permeability. RESULTS: In the 238 patients analyzed, an increased BBB permeability measured within the infarct at 24 hours was associated with a reduced likelihood of favorable outcome (90-day modified Rankin Scale score of ≤2) after adjusting for age, baseline National Institutes of Health Stroke Scale, premorbid modified Rankin Scale, infarct topography, laterality, thrombolytic agent, sex, parenchymal hematoma, and follow-up infarct volume (adjusted odds ratio, 0.86 [95% CI, 0.75-0.98]; P=0.023). Mediation analysis suggested reducing the severity of tissue injury (as estimated by BBB permeability) accounts for 18.2% of the association between reperfusion and favorable outcome, as indicated by a reduction in the regression coefficient of reperfusion after addition of BBB permeability as a covariate. CONCLUSIONS: In patients with ischemic stroke, reduced severity of tissue injury within the infarct, as determined by assessing the integrity of the BBB, is independently associated with improved functional outcome. In addition to reducing diffusion-weighted imaging-defined infarct volume, reperfusion may also improve clinical outcome by reducing tissue injury severity within the infarct.

Prospective Observational Cohort Study of Tenecteplase Versus Alteplase in Routine Clinical Practice.

BACKGROUND: A 10-hospital regional network transitioned to tenecteplase as the standard of care stroke thrombolytic in September 2019 because of potential workflow advantages and reported noninferior clinical outcomes relative to alteplase in meta-analyses of randomized trials. We assessed whether tenecteplase use in routine clinical practice reduced thrombolytic workflow times with noninferior clinical outcomes. METHODS: We designed a prospective registry-based observational, sequential cohort comparison of tenecteplase- (n=234) to alteplase-treated (n=354) stroke patients. We hypothesized: (1) an increase in the proportion of patients meeting target times for target door-to-needle time and transfer door-in-door-out time, and (2) noninferior favorable (discharge to home with independent ambulation) and unfavorable (symptomatic intracranial hemorrhage, in-hospital mortality or discharge to hospice) in the tenecteplase group. Total hospital cost associated with each treatment was also compared. RESULTS: Target door-to-needle time within 45 minutes for all patients was superior for tenecteplase, 41% versus 29%; adjusted odds ratio, 1.85 (95% CI, 1.27-2.71); P=0.001; 58% versus 41% by Get With The Guidelines criteria. Target door-in-door-out time within 90 minutes was superior for tenecteplase 37% (15/43) versus 14% (9/65); adjusted odds ratio, 3.62 (95% CI, 1.30-10.74); P=0.02. Favorable outcome for tenecteplase fell within the 6.5% noninferiority margin; adjusted odds ratio, 1.26 (95% CI, 0.89-1.80). Unfavorable outcome was less for tenecteplase, 7.3% versus 11.9%, adjusted odds ratio, 0.77 (95% CI, 0.42-1.37) but did not fall within the prespecified 1% noninferior boundary. Net benefit (%favorable-%unfavorable) was greater for the tenecteplase sample: 37% versus 27%. P=0.02. Median cost per hospital encounter was less for tenecteplase cases ($13 382 versus $15 841; P<0.001). CONCLUSIONS: Switching to tenecteplase in routine clinical practice in a 10-hospital network was associated with shorter door-to-needle time and door-in-door-out times, noninferior favorable clinical outcomes at discharge, and reduced hospital costs. Evaluation in larger, multicenter cohorts is recommended to determine if these observations generalize.

Considerations for the Implementation of a Telestroke Network: A Systematic Review.

The application of telestroke has matured considerably since its inception in 1999. The use of telestroke is now recommended in several published guidelines. Consequently, jurisdictions without a telestroke service are seeking practical information on the best approach to implement telestroke. French et al. (2013) reviewed the challenges of implementing a telestroke network including studies between 2000 and 2010. At the time, telestroke networks were largely limited to the UK, USA, Canada and Europe and only one process evaluation had been conducted. Given the prolific expansion of telestroke services since 2010, we conducted a systematic review to determine factors associated with successful establishment, management, and sustainability of a contemporary telestroke services. A comprehensive search of telestroke studies was conducted in July 2021. Empirical studies published between 2010 and 2021 were included if they contained descriptive, evaluation or operational data on the implementation of a telestroke network. Studies were subsequently evaluated using the Consolidated Framework for Implementation Research (CFIR). The initial literature search revealed a total of 7415 potential studies; 38 of which met the inclusion criteria. The past decade of process evaluation studies has enabled a more nuanced investigations into how to implement and sustain a telestroke network. Pre-implementation planning is crucial to ensure clear telestroke processes, governance structures and stakeholder engagement. Sustainability of networks relies on securing long-term investment, providing adequate resources, and maintaining staff motivation and willingness. Recommendations are provided to overcome commonly identified barriers related to technology, staffing, planning and standardisation of processes, evaluation, and sustainability and scale-up. Further research needs to explore how new advancements in stroke care such as endovascular clot retrieval (EVT) and advanced brain imaging can be considered and planned for during the implementation of a new telestroke service.

The role of medial ligaments and tibialis posterior in stabilising the medial longitudinal foot arch: a cadaveric gait simulator study.

BACKGROUND: Debate exists whether adult acquired flatfoot deformity develops secondary to tibialis posterior (TibPost) tendon insufficiency, failure of the ligamentous structures, or a combination of both. AIM: The aim of this study is to determine the contribution of the different medial ligaments in the development of acquired flatfoot pathology. Also to standardise cadaveric flatfoot models for biomechanical research and orthopaedic training. METHODS: Five cadaveric feet were tested on a dynamic gait simulator. Following tests on the intact foot, the medial ligaments - fascia plantaris (FP), the spring ligament complex (SLC) and interosseous talocalcaneal ligament (ITCL) - were sectioned sequentially. Joint kinematics were analysed for each condition, with and without force applied to TibPost. RESULTS: Eliminating TibPost resulted in higher internal rotation of the calcaneus following the sectioning of FP and SLC (d>1.28, p = 0.08), while sectioning ITCL resulted in higher external rotation without TibPost (d = 1.24, p = 0.07). Sequential ligament sectioning induced increased flattening of Meary's angle. CONCLUSION: Function of TibPost and medial ligaments is not mutually distinctive. The role of ITCL should not be neglected in flatfoot pathology; it is vital to section this ligament to develop flatfoot in cadaveric models.

Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke.

BACKGROUND: Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion. METHODS: We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage. RESULTS: Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group. CONCLUSIONS: Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .).

Can Intraoperative Intra-Articular Loads Predict Postoperative Knee Joint Laxity Following Total Knee Arthroplasty? A Cadaver Study with Smart Tibial Trays.

Ligament balancing during total knee arthroplasty (TKA) often relies on subjective surgeon experience. Although instrumented tibial trays facilitate an objective assessment of intraoperative joint balance through quantification of intra-articular joint loads, postoperative clinical assessment of joint balance relies on passive stress tests quantifying varus-valgus joint laxity. This study aimed at correlating the intraoperative and postoperative metrics used to assess joint balance while also comparing joint loads obtained during passive assessment and active functional motions. Four experienced surgical fellows were assigned a fresh-frozen lower limb each to plan and perform posterior-stabilised TKA. An instrumented tibial insert measured intraoperative intra-articular loads. Specimens were then subjected to passive flexion-extension, open-chain extension, active squatting, and varus-valgus laxity tests on a validated knee simulator. Intra-articular loads were recorded using the instrumented insert and tibiofemoral kinematics using an optical motion capture system. A negative correlation was observed between mean intraoperative intra-articular loads and corresponding mean postoperative tibial abduction angle during laxity tests (medial: R = -0.93, p = 0.02; lateral: R = -0.88, p = 0.04); however, this was not observed for each specimen. Peak intra-articular load distribution for active squatting was lateral-heavy, contrasting to the medial-heavy distribution observed in passive intraoperative measurements, for all specimens. These aspects should be given due consideration while assessing intraoperative and postoperative joint stability following TKA.

SCreg: a registration-based platform to compare unicondylar knee arthroplasty SPECT/CT scans.

BACKGROUND: A combination of conventional computed tomography and single photon emitted computed tomography (SPECT/CT) provides simultaneous data on the intensity and location of osteoblastic activity. Currently, since SPECT/CT scans are not spatially aligned, scans following knee arthroplasty are compared by extracting average and maximal values of osteoblastic activity intensity from large subregions of the structure of interest, which leads to a loss of resolution, and hence, information. Therefore, this paper describes the SPECT/CT registration platform (SCreg) based on the principle of image registration to spatially align SPECT/CT scans following unicondylar knee arthroplasty (UKA) and allow full resolution intra-subject and inter-subject comparisons. METHODS: SPECT-CT scans of 20 patients were acquired before and 1 year after UKA. Firstly, scans were pre-processed to account for differences in voxel sizes and divided in volumes of interest. This was followed by optimization of registration parameters according to their volumetric agreement, and alignment using a combination of rigid, affine and non-rigid registration. Finally, radiotracer uptakes were normalized, and differences between pre-operative and post-operative activity were computed for each voxel. Wilcoxon signed rank sum test was performed to compare Dice similarity coefficients pre- and post-registration. RESULTS: Qualitative and quantitative validation of the platform assessing the correct alignment of SPECT/CT scans resulted in Dice similarity coefficient values over 80% and distances between predefined anatomical landmarks below the fixed threshold of (2;2;0) voxels. Locations of increased and decreased osteoblastic activity obtained during comparisons of osteoblastic activity before and after UKA were mainly consistent with literature. CONCLUSIONS: Thus, a full resolution comparison performed on the platform could assist surgeons and engineers in optimizing surgical parameters in view of bone remodeling, thereby improving UKA survivorship.

The Effect of Surgical Treatments for Trapeziometacarpal Osteoarthritis on Wrist Biomechanics: A Cadaver Study.

PURPOSE: Studies have shown the effects of surgical treatments for trapeziometacarpal osteoarthritis on thumb biomechanics; however, the biomechanical effects on the wrist have not been reported. This study aimed to quantify alterations in wrist muscle forces following trapeziectomy with or without ligament reconstruction and replacement. METHODS: A validated physiological wrist simulator replicated cyclic wrist motions in cadaveric specimens by applying tensile loads to 6 muscles. Muscle forces required to move the intact wrist were compared with those required after performing trapeziectomy, suture suspension arthroplasty, prosthetic replacement, and ligament reconstruction with tendon interposition (LRTI). RESULTS: Trapeziectomy required higher abductor pollicis longus forces in flexion and higher flexor carpi radialis forces coupled with lower extensor carpi ulnaris forces in radial deviation. Of the 3 surgical reconstructions tested post-trapeziectomy, wrist muscle forces following LRTI were closest to those observed in the intact case throughout the range of all simulated motions. CONCLUSIONS: This study shows that wrist biomechanics were significantly altered following trapeziectomy, and of the reconstructions tested, LRTI most closely resembled the intact biomechanics in this cadaveric model. CLINICAL RELEVANCE: Trapeziectomy, as a standalone procedure in the treatment of trapeziometacarpal osteoarthritis, may result in the formation of a potentially unfilled trapezial gap, leading to higher wrist muscle forces. This biomechanical alteration could be associated with clinically important outcomes, such as pain and/or joint instability.

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial.

Importance: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase. Objective: To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke. Design, Setting, and Participants: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria. Interventions: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy. Main Outcomes and Measures: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death. Results: All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]). Conclusions and Relevance: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned. Trial Registration: ClinicalTrials.gov Identifier: NCT03340493.

Disparities in Antihypertensive Prescribing After Stroke: Linked Data From the Australian Stroke Clinical Registry.

Background and Purpose- Despite evidence to support the prescription of antihypertensive medications before hospital discharge to promote medication adherence and prevent recurrent events, many patients with stroke miss out on these medications at discharge. We aimed to examine patient, clinical, and system-level differences in the prescription of antihypertensive medications at hospital discharge after stroke. Methods- Adults with acute ischemic stroke or intracerebral hemorrhage alive at discharge were included (years 2009-2013) from 39 hospitals participating in the Australian Stroke Clinical Registry. Patient comorbidities were identified using the International Statistical Classification of Diseases and Related Health Problems (Tenth Edition, Australian Modification) codes from the hospital admissions and emergency presentation data. The outcome variable and other system factors were derived from the Australian Stroke Clinical Registry dataset. Multivariable, multilevel logistic regression was used to examine factors associated with the prescription of antihypertensive medications at hospital discharge. Results- Of the 10 315 patients included, 79.0% (intracerebral hemorrhage, 74.1%; acute ischemic stroke, 79.8%) were prescribed antihypertensive medications at discharge. Prescription varied between hospital sites, with 6 sites >2 SDs below the national average for provision of antihypertensives at discharge. Prescription was also independently associated with patient and clinical factors including history of hypertension, diabetes mellitus, management in an acute stroke unit, and discharge to rehabilitation. In patients with acute ischemic stroke, females (odds ratio, 0.85; 95% CI, 0.76-0.94), those who had greater stroke severity (odds ratio, 0.81; 95% CI 0.72-0.92), or dementia (odds ratio, 0.65; 95% CI, 0.52-0.81) were less likely to be prescribed. Conclusions- Prescription of antihypertensive medications poststroke varies between hospitals and according to patient factors including age, sex, stroke severity, and comorbidity profile. Implementation of targeted quality improvement initiatives at local hospitals may help to reduce the variation in prescription observed.

Response to Late-Window Endovascular Revascularization Is Associated With Collateral Status in Basilar Artery Occlusion.

Background and Purpose- The benefit of endovascular therapy in extended time windows has been demonstrated in patients with anterior circulation large vessel occlusion ischemic stroke and favorable imaging profile. We evaluated whether collaterals and thrombus burden influence the associations between revascularization, time-to-treatment, and outcome in endovascular therapy-treated patients with basilar artery occlusion. Methods- We retrospectively analyzed clinical and imaging data of consecutive endovascular therapy-treated patients with basilar artery occlusion included in the multicenter Basilar Artery Treatment and Management Collaboration. The BATMAN (Basilar Artery on Computed Tomography Angiography score, which evaluates thrombus burden and collaterals) and the PC-CS (Posterior Circulation Collateral score, which evaluates collaterals) were assessed on computed tomography angiography, blinded to clinical outcome. Good outcome was defined as modified Rankin Scale score of ≤3 within 3 months; revascularization (successful reperfusion) as modified Thrombolysis in Cerebral Infarction 2b-3 (or TIMI [Thrombolysis in Myocardial Infarction] 2-3 in the BASICS [Basilar Artery International Cooperation Study] registry). Results- We included 172 patients with basilar artery occlusion treated with endovascular therapy (124 with mechanical thrombectomy): mean (SD) age 65 (13) years, median National Institutes of Health Stroke Scale 22 (interquartile range 12-30), 64 (37%) treated >6 hours. Revascularization (achieved in 79% of patients) was associated with good outcome (P=0.003). The use of new generation thrombectomy devices was associated with good outcome (P=0.03). In patients who achieved revascularization, 29/46 (63%) of patients with a favorable BATMAN score and 26/51 (51%) with favorable PC-CS had good outcomes. In logistic regression analysis (adjusted for age, National Institutes of Health Stroke Scale, and time-to-treatment ≤6/>6 hours), revascularization was associated with good outcome in patients with favorable BATMAN score (odds ratio, 15.8; 95% CI, 1.4-175; P=0.02) or PC-CS (odds ratio, 9.4; 95% CI, 1.4-64; P=0.02). In patients who achieved revascularization, early (time-to-treatment ≤6 hours) but not late treatment was associated with improved outcome in patients with unfavorable BATMAN score (18/52 [35%]; odds ratio, 15; 95% CI, 1.9-124; P=0.01) or PC-CS (16/44 [36%]; odds ratio, 5.5; 95% CI, 1.4-21; P=0.01). Conclusions- Revascularization is associated with good outcome in patients with basilar artery occlusion with good collaterals and less extensive occlusion, even >6 hours after onset.

Meeting unmet needs following minor stroke: the SUN randomised controlled trial protocol.

BACKGROUND: Whilst there are comprehensive guidelines for the rehabilitation of people with severe impairments from stroke, there has been less attention on the health and rehabilitation needs of people with minor stroke. Our study will assess whether a new multi-component service pathway using an integrated model based around primary care will reduce unmet need following minor stroke compared with usual care 1 and 3 months post-hospital discharge. METHODS: One hundred ten patients with minor stroke will be recruited within a parallel, randomised controlled trial design comparing a new service pathway and usual care. The new service pathway will comprise a self-management kit, customised General Practitioner checklist, and a series of minor stroke educational topics. Participants will complete assessments pre-hospital discharge and 1 and 3 months later. The primary outcome measure will be the Survey of Unmet Needs and Service Usage. Secondary outcome measures will include assessments of ability, adjustment and participation; social group connectedness; return to work; health-related quality of life; and perceptions of the new service pathway (intervention group only). Mixed model repeated measures will be used to analyse within and between group differences at each time point. Return to work will be analysed using Chi square tests. Perceptions of the new service pathway will be analysed qualitatively. DISSEMINATION OF RESULTS: The project will produce an evidence-based, multicomponent service pathway for minor stroke patients, applicable to other health services nationally and internationally. Dissemination will include publications and presentations. TRIAL REGISTRATION: Prospectively registered - Australian New Zealand Clinical Trials Registry (ACTRN12619000133134p) 30 January 2019.

The Basilar Artery on Computed Tomography Angiography Prognostic Score for Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: Basilar artery occlusion is associated with high risk of disability and mortality. This study aimed to assess the prognostic value of a new radiological score: the Basilar Artery on Computed Tomography Angiography (BATMAN) score. METHODS: A retrospective analysis of consecutive stroke patients with basilar artery occlusion diagnosed on computed tomographic angiography was performed. BATMAN score is a 10-point computed tomographic angiography-based grading system which incorporates thrombus burden and the presence of collaterals. Reliability was assessed with intraclass coefficient correlation. Good outcome was defined as modified Rankin Scale score of ≤3 at 3 months and successful reperfusion as thrombolysis in cerebral infarction 2b-3. BATMAN score was externally validated and compared with the Posterior Circulation Collateral score. RESULTS: The derivation cohort included 83 patients with 41 in the validation cohort. In receiver operating characteristic (ROC) analysis, BATMAN score had an area under receiver operating characteristic curve of 0.81 (95% confidence interval [CI], 0.7-0.9) in derivation cohort and an area under receiver operating characteristic curve of 0.74 (95% CI, 0.6-0.9) in validation cohort. In logistic regression adjusted for age and clinical severity, BATMAN score of <7 was associated with poor outcome in derivation cohort (odds ratio, 5.5; 95% CI, 1.4-21; P=0.01), in validation cohort (odds ratio, 6.9; 95% CI, 1.4-33; P=0.01), and in endovascular patients, after adjustment for recanalization and time to treatment (odds ratio, 4.8; 95% CI, 1.2-18; P=0.01). BATMAN score of <7 was not associated with recanalization. Interrater agreement was substantial (intraclass coefficient correlation, 0.85; 95% CI, 0.8-0.9). BATMAN score had greater accuracy compared with Posterior Circulation Collateral score (P=0.04). CONCLUSIONS: The addition of collateral quality to clot burden in BATMAN score seems to improve prognostic accuracy in basilar artery occlusion patients.

Simultaneous Multiple Intracerebral Hemorrhages (SMICH).

BACKGROUND AND PURPOSE: Simultaneous multiple intracerebral hemorrhages (SMICHs) are uncommon. Few single-center studies have analyzed characteristics and outcome of SMICH. We analyzed clinical characteristics and outcome of SMICH patients from 2 comprehensive stroke centers. METHODS: Baseline imaging from consecutive intracerebral hemorrhage (ICH) patients (n=1552) from Helsinki ICH study and Royal Melbourne Hospital ICH study was screened for SMICH. ICH pathogenesis was classified according to the structural lesion, medication, amyloid angiopathy, systemic/other disease, hypertension, undetermined classification system (SMASH-U). ICH caused by trauma, tumor, and aneurysmal rupture was excluded. Baseline clinical and radiological characteristics and 90-day mortality were compared between SMICH and single ICH patients. Association of SMICH with 90-day mortality was assessed in multivariable logistic regression models adjusted for predictors of ICH outcome. RESULTS: Of 1452 patients, 85 (5.9%) were classified as SMICH. SMICH were more often female (58% versus 42%; P=0.004), had lower baseline Glasgow Coma Scale (12 versus 14; P=0.008), and more frequent lobar location (59% versus 34%; P<0.001) compared with single ICH. The SMASH-U pathogenesis of SMICH patients was less often hypertensive (20% versus 37%; P=0.001), more often systemic coagulopathy (12% versus 3%; P<0.001), and trended toward more cerebral amyloid angiopathy (32% versus 23%; P=0.071). SMICH was not associated with 90-day mortality on univariate (37% versus 35%; P=0.610), multivariable (odds ratio, 0.783; 95% confidence interval, 0.401-1.529; P=0.473), or propensity score-matched analyses (odds ratio, 0.760; 95% confidence interval, 0.352-1.638; P=0.484). CONCLUSIONS: SMICH occurs in ≈1 in 20 ICH, more commonly with lobar located hematomas and systemic coagulopathy with less hypertensive angiopathy. The associated mortality is similar to single ICH. Given varied etiologies, SMICH management should target the underlying pathology.