Sex differences in stroke reperfusion therapy in Aotearoa (New Zealand).

BACKGROUND AND AIMS: Stroke is a leading cause of death in Aotearoa (New Zealand), and stroke reperfusion therapy is a key intervention. Sex differences in stroke care have previously been asserted internationally. This study assessed potential differences in stroke reperfusion rates and quality metrics by sex in Aotearoa (New Zealand). METHODS: This study used data from three overlapping sources. The National Stroke Reperfusion Register provided 4-year reperfusion data from 2018 to 2021 on all patients treated with reperfusion therapy (intravenous thrombolysis and thrombectomy), including time delays, treatment rates, mortality and complications. Linkage to Ministry of Health administrative and REGIONS Care study data provided an opportunity to control for confounders and explore potential mechanisms. T-test and Wilcoxon rank-sum analyses were used for continuous variables, while the chi-squared test and logistic regression were used for comparing dichotomous variables. RESULTS: Fewer women presented with ischaemic stroke (12 186 vs 13 120) and were 4.2 years older than men (median (interquartile range (IQR)) 79 (68-86) vs 73 (63-82) years). Women were overall less likely to receive reperfusion therapy (13.9% (1704) vs 15.8% (2084), P < 0.001) with an adjusted odds ratio of 0.83 (0.77-0.90), P < 0.001. The adjusted odds ratio for thrombolysis was lower for women (0.82 (0.76-0.89), P < 0.001), but lower rates of thrombectomy fell just short of statistical significance ((0.89 (0.79-1.00), P = 0.05). There were no significant differences in complications, delays or documented reasons for non-thrombolysis. CONCLUSIONS: Women were less likely to receive thrombolysis, even after adjusting for age and stroke severity. We found no definitive explanation for this disparity.

Comparison of Stroke Care Costs in Urban and Nonurban Hospitals and Its Association With Outcomes in New Zealand: A Nationwide Economic Evaluation.

BACKGROUND: Although geographical differences in treatment and outcomes after stroke have been described, we lack evidence on differences in the costs of treatment between urban and nonurban regions. Additionally, it is unclear whether greater costs in one setting are justified given the outcomes achieved. We aimed to compare costs and quality-adjusted life years in people with stroke admitted to urban and nonurban hospitals in New Zealand. METHODS: Observational study of patients with stroke admitted to the 28 New Zealand acute stroke hospitals (10 in urban areas) recruited between May and October 2018. Data were collected up to 12 months poststroke including treatments in hospital, inpatient rehabilitation, other health service utilization, aged residential care, productivity, and health-related quality of life. Costs in New Zealand dollars were estimated from a societal perspective and assigned to the initial hospital that patients presented to. Unit prices for 2018 were obtained from government and hospital sources. Multivariable regression analyses were conducted when assessing differences between groups. RESULTS: Of 1510 patients (median age 78 years, 48% female), 607 presented to nonurban and 903 to urban hospitals. Mean hospital costs were greater in urban than nonurban hospitals ($13 191 versus $11 635, P=0.002), as were total costs to 12 months ($22 381 versus $17 217, P<0.001) and quality-adjusted life years to 12 months (0.54 versus 0.46, P<0.001). Differences in costs and quality-adjusted life years remained between groups after adjustment. Depending on the covariates included, costs per additional quality-adjusted life year in the urban hospitals compared to the nonurban hospitals ranged from $65 038 (unadjusted) to $136 125 (covariates: age, sex, prestroke disability, stroke type, severity, and ethnicity). CONCLUSIONS: Better outcomes following initial presentation to urban hospitals were associated with greater costs compared to nonurban hospitals. These findings may inform greater targeted expenditure in some nonurban hospitals to improve access to treatment and optimize outcomes.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Ultra-Long Transfers for Endovascular Thrombectomy-Mission Impossible?: The Australia-New Zealand Experience.

BACKGROUND: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. METHODS: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). RESULTS: There were 131 patients; the median age was 64 [53-74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12-22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1-3] versus 3 [1-6] in the patients selected with noncontrast CT+CT angiography, P=0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01-0.19]; P<0.01). CONCLUSIONS: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.

Clinical outcomes of delayed mechanical thrombectomy: Descriptive analysis and development of a screening tool.

BACKGROUND AND PURPOSE: Limited data guide the selection of patients with large vessel occlusion ischaemic stroke who may benefit from referral to a distant tertiary centre for mechanical thrombectomy (MT). We aimed to characterize this population, describe clinical outcomes and develop a screening system to identify patients most likely to benfit from delayed mechanical thrombectomy (MT). METHODS: We undertook a retrospective cohort analysis enrolling patients transferred from regional sites to one of two MT comprehensive stroke units with a time from non-contrast computed tomography (NCCT) of the brain to reperfusion of 4 h or more. We describe Alberta Stroke Programme Early Computed Tomography Score (ASPECTS), National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) in our patients and compare these patients to those in extended-time-window trials. Lastly, we developed and validated a scoring model to help clinicians identify appropriate patients based on variables associated with poor outcomes. RESULTS: We included 563 patients, 46% of whom received thrombolysis; the median (interquartile range [IQR]) ASPECTS was 8 (7-10) and the median (IQR) NIHSS score was 16 (11-20). The median (IQR) symptom to mechanical reperfusion time was 390 (300-580) min. Eight patients (1%) had a symptomatic haemorrhage. We achieved good clinical outcome (defined as mRS score ≤2) in 299 patients (54%). Age, diabetes, NIHSS score and ASPECTS were used to create a weighted scoring system with a validated area under the curve of 0.83 (95% confidence interval 0.74-0.92). CONCLUSION: Our study shows, in highly selected patients, that delayed MT many hours after baseline NCCT is associated with good clinical outcomes. However, older patients with diabetes, high NIHSS score and low ASPECTS may not benefit from transfer to a hub centre many hours away for MT in this model of care.

Impact considerations of post-production processes on cell and gene drug products.

Cell and gene therapies are demonstrating clinical efficacy, but prohibitive product costs and operational complexity bottlenecks may limit expanded patient access to these innovative and transformative products. An initial survey and subsequent article published through the International Society for Cell & Gene Therapy in 2017 presented a roadmap on how specific steps, from tissue procurement and material acquisition to facility operation and production, contribute to the high cost of cell and gene therapies. Herein the authors expanded the investigation to provide considerations to better understand how post-production procedures can impact a product's accessibility to patients. The administration of a drug product to and follow-up in a patient involve key decisions in several post-production process areas, such as product storage, distribution and handling logistics and compliance, across the value chain through integrated data management solutions. Understanding as well as carefully evaluating these specific components is not widely considered during early process development but is critical in developing a viable product life cycle.

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

BACKGROUND: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype. OBJECTIVE: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST. METHODS: This study used a systematic cross-sectional analysis of clinical and molecular features. RESULTS: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation). CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.

Routine Use of Tenecteplase for Thrombolysis in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: In ischemic stroke, intravenous tenecteplase is noninferior to alteplase in selected patients and has some practical advantages. Several stroke centers in New Zealand changed to routine off-label intravenous tenecteplase due to improved early recanalization in large vessel occlusion, inconsistent access to thrombectomy within stroke networks, and for consistency in treatment protocols between patients with and without large vessel occlusion. We report the feasibility and safety outcomes in tenecteplase-treated patients. METHODS: We performed a retrospective analysis of consecutive patients thrombolyzed with intravenous tenecteplase at 1 comprehensive and 2 regional stroke centers from July 14, 2018, to February 29, 2020. We report the baseline clinical characteristics, rates of symptomatic intracranial hemorrhage, and angioedema. These were then compared with patient outcomes with those treated with intravenous alteplase at 2 other comprehensive stroke centers. Multivariable mixed-effects logistic regression models were performed assessing the association of tenecteplase with symptomatic intracranial hemorrhage and independent outcome (modified Rankin Scale score, 0-2) at day 90. RESULTS: There were 165 patients treated with tenecteplase and 254 with alteplase. Age (75 versus 74 years), sex (56% versus 60% male), National Institutes of Health Stroke Scale scores (8 versus 10), median door-to-needle times (47 versus 48 minutes), or onset-to-needle time (129 versus 130 minutes) were similar between the groups. Symptomatic intracranial hemorrhage occurred in 3 (1.8% [95% CI, 0.4-5.3]) tenecteplase patients compared with 7 (2.7% [95% CI, 1.1-5.7]) alteplase patients (P=0.75). There were no differences between tenecteplase and alteplase in the rates of angioedema (4 [2.4%; 95% CI, 0.7-6.2] versus 1 [0.4%; 95% CI, 0.01-2.2], P=0.08) or 90-day functional independence (100 [61%] versus 140 [57%], P=0.47), respectively. In mixed-effects logistic regression models, there was no significant association between thrombolytic choice and symptomatic intracranial hemorrhage (odds ratio tenecteplase, 0.62 [95% CI, 0.14-2.80], P=0.53) or functional independence (odds ratio tenecteplase, 1.20 [95% CI, 0.74-1.95], P=0.46). CONCLUSIONS: Routine use of tenecteplase for stroke thrombolysis was feasible and had comparable safety profile and outcome to alteplase.

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 .).

Functional neurological disorders presenting as emergencies to secondary care.

BACKGROUND: Functional neurological disorders (FND) represent a significant proportion of presentations to outpatient adult neurology services. There is little information relating to patients presenting to acute inpatient care. METHODS: We identified patients presenting as acute admissions with FND to Christchurch Hospital, Christchurch, New Zealand, from 2016 to 2018. We analyzed relevant demographic and clinical data from electronic records and measured incidence of presentation to secondary care and healthcare utilization. RESULTS: One hundred sixty-two patients presented on 173 occasions with FND, representing 9% of all admissions to the neurology service during the 3-year study period. The mean age was 40 (SD 17) years, 111 (69%) patients were female and the median length of stay was 3 (IQR 2-4) days. A total of 92 computed tomography brain scans, 77 magnetic resonance imaging brain scans and 42 electroencephalograms were carried out. On 22 (13%) occasions, patients were referred for outpatient psychological therapy. In the 3 years prior to each patient's last presentation in the study period, these 162 patients had a total of 671 presentations to the emergency department. Healthcare demand did not decrease after the index admission. The rate of acute inpatient admission for FND was 10 per 100,000 per year for the total Christchurch Hospital catchment, 6/100,000/year in rural areas, and 11/100,000/year in urban areas. CONCLUSION: FND represented almost 1 in 10 acute neurology admissions with significant inpatient healthcare resource utilization.

Left Atrial Appendage Thrombus Detected During Hyperacute Stroke Imaging Is Associated With Atrial Fibrillation.

BACKGROUND AND PURPOSE: Left atrial appendage (LAA) is the likely embolic source in atrial fibrillation (AF)-related cardioembolic strokes. We sought to determine the prevalence of LAA thrombus on hyperacute stroke imaging and its association with AF. METHODS: We retrospectively examined the clinical and radiological features of patients assessed through the hyperacute stroke imaging pathway over a 12-month period at Christchurch Hospital. The LAA was included in the computed tomography angiogram scan-range as part of the multimodal imaging protocol. Two radiological readers blinded to clinical information independently assessed for the presence of LAA thrombus. The association between AF and LAA thrombus was determined by multivariable logistic regression analysis. RESULTS: Of 303 patients included in the analysis, the overall prevalence of LAA thrombus was 6.6% and 14.9% in patients with known AF. Patients with LAA thrombus were older (85 versus 75 years, P<0.01), more commonly had known or newly diagnosed AF (75% versus 30%, P<0.01) and heart failure (30% versus 8%, P=0.01), and was associated with intracranial large vessel occlusion (65% versus 39%, P=0.02). In the multivariable model, AF (odds ratio, 3.71 [95% CI, 1.25-11.01] P=0.02) was independently associated with LAA thrombus after adjusting for age and congestive heart failure. Interrater reliability was moderate (kappa=0.56). CONCLUSIONS: LAA thrombus is a potential radiological marker of AF and can be assessed as a part of hyperacute stroke imaging.

Dabigatran Reversal Before Intravenous Tenecteplase in Acute Ischemic Stroke.

Background and Purpose- Reversal of dabigatran before intravenous thrombolysis in patients with acute ischemic stroke has been well described using alteplase but experience with intravenous tenecteplase is limited. Tenecteplase seems at least noninferior to alteplase in patients with intracranial large vessel occlusion. We report on the experience of dabigatran reversal before tenecteplase thrombolysis for acute ischemic stroke. Methods- We included consecutive patients with ischemic stroke receiving dabigatran prestroke treated with intravenous tenecteplase after receiving idarucizumab. Patients were from 2 centers in New Zealand and Australia. We reported the clinical, laboratory, and radiological characteristics and their functional outcome. Results- We identified 13 patients receiving intravenous tenecteplase after dabigatran reversal. Nine (69%) were male, median age was 79 (interquartile range, 69-85) and median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 4-21). Atrial fibrillation was the indication for dabigatran therapy in all patients. All patients had a prolonged thrombin clotting time (median, 80 seconds [interquartile range, 57-113]). Seven patients with large vessel occlusion were referred for endovascular thrombectomy, 2 of these patients (29%) had early recanalization with tenecteplase abrogating thrombectomy. No patients had parenchymal hemorrhage or symptomatic hemorrhagic transformation. Favorable functional outcome (modified Rankin Scale score, 0-2) occurred in 8 (62%) patients. Two deaths occurred from large territory infarction. Conclusions- Our experience suggests intravenous thrombolysis with tenecteplase following dabigatran reversal using idarucizumab may be safe in selected patients with acute ischemic stroke. Further studies are required to more precisely estimate the efficacy and risk of clinically significant hemorrhage.

Primary lateral sclerosis: consensus diagnostic criteria.

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.

Endovascular Therapy for Ischemic Stroke Can Be Successfully Performed by Peripheral Vascular Interventionalists.

PURPOSE: To describe interventionalist and workflow characteristics of an acute stroke endovascular thrombectomy (EVT) center without a dedicated interventional neuroradiology service and report clinical and radiologic outcomes. MATERIALS AND METHODS: Retrospective review was performed of all patients receiving EVT at Christchurch Hospital, New Zealand, from June 2014 to the end of December 2019 from a prospective reperfusion registry. During the study period, 5 peripheral vascular interventional radiologists, 2 of whom had experience in other neuroendovascular procedures, performed 210 EVT procedures. Median age of patients was 76 years (interquartile range: 64-83 y), and 107 (51%) were men. RESULTS: The most commonly occluded vessel was the M1 middle cerebral artery (n = 114; 54%). Successful reperfusion (Modified Treatment In Cerebral Ischemia score 2b-3) was achieved in 180 (86%) procedures. Favorable 90-day outcome (modified Rankin Scale score 0-2) was achieved in 102 (54%) patients with no disability before stroke. Symptomatic intracranial hemorrhage occurred in 3 (1.4%) patients. Treatment rates in the local catchment area increased from 6 per 100,000 population in 2017 to 15 per 100,000 in 2019. CONCLUSIONS: The results of this study suggest peripheral vascular interventional radiologists with specific training can successfully perform EVT resulting in a significant increase in EVT provision.

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.

The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.

A roadmap for cost-of-goods planning to guide economic production of cell therapy products.

Cell therapy products are frequently developed and produced without incorporating cost considerations into process development, contributing to prohibitively costly products. Herein we contextualize individual process development decisions within a broad framework for cost-efficient therapeutic manufacturing. This roadmap guides the analysis of cost of goods (COG) arising from tissue procurement, material acquisition, facility operation, production, and storage. We present the specific COG considerations related to each of these elements as identified through a 2013 International Society for Cellular Therapy COG survey, highlighting the differences between autologous and allogeneic products. Planning and accounting for COG at each step in the production process could reduce costs, allowing for more affordable market pricing to improve the long-term viability of the cell therapy product and facilitate broader patient access to novel and transformative cell therapies.

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.

BACKGROUND: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. METHODS: Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. RESULTS: Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. CONCLUSIONS: Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.

Rationalizing resources a framework and a process.

To meet the demands of population health and value-based care, healthcare organizations may soon be compelled to take steps to rationalize their service and resource offerings.

Mandatory bundled payment getting into formation for value-based care.

Succeeding under Medicare's enterprise Comprehensive Care for Joint Replacement Model will require collaboration among caregivers and financial arrangements to align incentives Priorities for most organization's transition to becoming a value-based hospitals will be care redesign, supply-purchasing strategy, and post-acute care provider partnering. Pursuing value for your joint replacement program will chart a path for other service lines and lead your organization's transition to becoming a value-based enterprise.