Hemorrhagic Transformation in Noncardioembolic Acute Ischemic Stroke: MRI Analysis From PACIFIC-STROKE.

BACKGROUND: In the phase 2 PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), asundexian, an oral factor XIa inhibitor, did not increase the risk of hemorrhagic transformation (HT). In this secondary analysis, we aimed to investigate the frequency, types, and risk factors of HT on brain magnetic resonance imaging (MRI). METHODS: This was a secondary analysis of the PACIFIC-STROKE trial. Patients with mild-to-moderate acute noncardioembolic ischemic stroke were randomly assigned to asundexian or placebo plus guideline-based antiplatelet therapy. Brain MRIs were required at baseline (≤120 hours after stroke onset) and at 26 weeks or end-of-study. HT was defined using the Heidelberg classification and classified as early HT (identified on baseline MRI) or late HT (new HT by 26 weeks) based on iron-sensitive sequences. Multivariable logistic regression models were used to test factors that are associated with early HT and late HT, respectively. RESULTS: Of 1745 patients with adequate baseline brain MRI (mean age, 67 years; mean National Institutes of Health Stroke Scale score, 2.8), early HT at baseline was detected in 497 (28.4%). Most were hemorrhagic infarctions (hemorrhagic infarction type 1: 15.2%; HI2: 12.7%) while a few were parenchymal hematomas (parenchymal hematoma type 1: 0.4%; parenchymal hematoma type 2: 0.2%). Early HT was more frequent with longer symptom onset-to-MRI interval. Male sex, diabetes, higher National Institutes of Health Stroke Scale large (>15 mm) infarct size, cortical involvement by infarct, higher number of acute infarcts, presence of chronic brain infarct, cerebral microbleed, and chronic cortical superficial siderosis were independently associated with early HT in the multivariable logistic regression model. Of 1507 with follow-up MRI, HT was seen in 642 (42.6%) overall, including 361 patients (23.9%) with late HT (new HT: 306; increased grade of baseline HT: 55). Higher National Institutes of Health Stroke Scale, large infarct size, cortical involvement of infarct, and higher number of acute infarcts predicted late HT. CONCLUSIONS: About 28% of patients with noncardioembolic stroke had early HT, and 24% had late HT detectable by MRI. Given the high frequency of HT on MRI, more research is needed on how it influences treatment decisions and outcomes.

Impact of Self-Reported Loss of Balance and Gait Disturbance on Outcomes following Adult Spinal Deformity Surgery.

Background: The objective of this study was to evaluate if imbalance influences complication rates, radiological outcomes, and patient-reported outcomes (PROMs) following adult spinal deformity (ASD) surgery. Methods: ASD patients with baseline and 2-year radiographic and PROMs were included. Patients were grouped according to whether they answered yes or no to a recent history of pre-operative loss of balance. The groups were propensity-matched by age, pelvic incidence-lumbar lordosis (PI-LL), and surgical invasiveness score. Results: In total, 212 patients were examined (106 in each group). Patients with gait imbalance had worse baseline PROM measures, including Oswestry disability index (45.2 vs. 36.6), SF-36 mental component score (44 vs. 51.8), and SF-36 physical component score (p < 0.001 for all). After 2 years, patients with gait imbalance had less pelvic tilt correction (-1.2 vs. -3.6°, p = 0.039) for a comparable PI-LL correction (-11.9 vs. -15.1°, p = 0.144). Gait imbalance patients had higher rates of radiographic proximal junctional kyphosis (PJK) (26.4% vs. 14.2%) and implant-related complications (47.2% vs. 34.0%). After controlling for age, baseline sagittal parameters, PI-LL correction, and comorbidities, patients with imbalance had 2.2-times-increased odds of PJK after 2 years. Conclusions: Patients with a self-reported loss of balance/unsteady gait have significantly worse PROMs and higher risk of PJK.

Factors Associated with the Maintenance of Cost-Effectiveness at 5 Years in Adult Spinal Deformity Corrective Surgery.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To evaluate factors associated with the long-term durability of cost-effectiveness (CE) in ASD patients. BACKGROUND: A substantial increase in costs associated with the surgical treatment for adult spinal deformity (ASD) has given precedence to scrutinize the value and utility it provides. METHODS: We included 327 operative ASD patients with 5-year (5 Y) follow-up. Published methods were used to determine costs based on CMS.gov definitions and were based on the average DRG reimbursement rates. Utility was calculated using quality-adjusted life-years (QALY) utilizing the Oswestry Disability Index (ODI) converted to Short-Form Six-Dimension (SF-6D), with a 3% discount applied for its decline with life expectancy. The CE threshold of $150,000 was used for primary analysis. RESULTS: Major and minor complication rates were 11% and 47% respectively, with 26% undergoing reoperation by 5 Y. The mean cost associated with surgery was $91,095±$47,003, with a utility gain of 0.091±0.086 at 1Y, QALY gained at 2 Y of 0.171±0.183, and at 5 Y of 0.42±0.43. The cost per QALY at 2 Y was $414,885, which decreased to $142,058 at 5 Y.With the threshold of $150,000 for CE, 19% met CE at 2 Y and 56% at 5 Y. In those in which revision was avoided, 87% met cumulative CE till life expectancy. Controlling analysis depicted higher baseline CCI and pelvic tilt (PT) to be the strongest predictors for not maintaining durable CE to 5 Y (CCI OR: 1.821 [1.159-2.862], P=0.009) (PT OR: 1.079 [1.007-1.155], P=0.030). CONCLUSIONS: Most patients achieved cost-effectiveness after four years postoperatively, with 56% meeting at five years postoperatively. When revision was avoided, 87% of patients met cumulative cost-effectiveness till life expectancy. Mechanical complications were predictive of failure to achieve cost-effectiveness at 2 Y, while comorbidity burden and medical complications were at 5 Y.

Stronger association of objective physical metrics with baseline patient-reported outcome measures than preoperative standing sagittal parameters for adult spinal deformity patients.

OBJECTIVE: Sagittal alignment measured on standing radiography remains a fundamental component of surgical planning for adult spinal deformity (ASD). However, the relationship between classic sagittal alignment parameters and objective metrics, such as walking time (WT) and grip strength (GS), remains unknown. The objective of this work was to determine if ASD patients with worse baseline sagittal malalignment have worse objective physical metrics and if those metrics have a stronger relationship to patient-reported outcome metrics (PROMs) than standing alignment. METHODS: The authors conducted a retrospective review of a multicenter ASD cohort. ASD patients underwent baseline testing with the timed up-and-go 6-m walk test (seconds) and for GS (pounds). Baseline PROMs were surveyed, including Oswestry Disability Index (ODI), Patient-Reported Outcomes Measurement Information System (PROMIS), Scoliosis Research Society (SRS)-22r, and Veterans RAND 12 (VR-12) scores. Standard spinopelvic measurements were obtained (sagittal vertical axis [SVA], pelvic tilt [PT], and mismatch between pelvic incidence and lumbar lordosis [PI-LL], and SRS-Schwab ASD classification). Univariate and multivariable linear regression modeling was performed to interrogate associations between objective physical metrics, sagittal parameters, and PROMs. RESULTS: In total, 494 patients were included, with mean ± SD age 61 ± 14 years, and 68% were female. Average WT was 11.2 ± 6.1 seconds and average GS was 56.6 ± 24.9 lbs. With increasing PT, PI-LL, and SVA quartiles, WT significantly increased (p < 0.05). SRS-Schwab type N patients demonstrated a significantly longer average WT (12.5 ± 6.2 seconds), and type T patients had a significantly shorter WT time (7.9 ± 2.7 seconds, p = 0.03). With increasing PT quartiles, GS significantly decreased (p < 0.05). SRS-Schwab type T patients had a significantly higher average GS (68.8 ± 27.8 lbs), and type L patients had a significantly lower average GS (51.6 ± 20.4 lbs, p = 0.03). In the frailty-adjusted multivariable linear regression analyses, WT was more strongly associated with PROMs than sagittal parameters. GS was more strongly associated with ODI and PROMIS Physical Function scores. CONCLUSIONS: The authors observed that increasing baseline sagittal malalignment is associated with slower WT, and possibly weaker GS, in ASD patients. WT has a stronger relationship to PROMs than standing alignment parameters. Objective physical metrics likely offer added value to standard spinopelvic measurements in ASD evaluation and surgical planning.

Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials.

BACKGROUND: Phase II trials of asundexian were underpowered to detect important differences in bleeding. OBJECTIVES: The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding. METHODS: We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. RESULTS: In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding. CONCLUSIONS: Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

Machine learning clustering of adult spinal deformity patients identifies four prognostic phenotypes: a multicenter prospective cohort analysis with single surgeon external validation.

BACKGROUND CONTEXT: Among adult spinal deformity (ASD) patients, heterogeneity in patient pathology, surgical expectations, baseline impairments, and frailty complicates comparisons in clinical outcomes and research. This study aims to qualitatively segment ASD patients using machine learning-based clustering on a large, multicenter, prospectively gathered ASD cohort. PURPOSE: To qualitatively segment adult spinal deformity patients using machine learning-based clustering on a large, multicenter, prospectively gathered cohort. STUDY DESIGN/SETTING: Machine learning algorithm using patients from a prospective multicenter study and a validation cohort from a retrospective single center, single surgeon cohort with complete 2-year follow up. PATIENT SAMPLE: About 805 ASD patients; 563 patients from a prospective multicenter study and 242 from a single center to be used as a validation cohort. OUTCOME MEASURES: To validate and extend the Ames-ISSG/ESSG classification using machine learning-based clustering analysis on a large, complex, multicenter, prospectively gathered ASD cohort. METHODS: We analyzed a training cohort of 563 ASD patients from a prospective multicenter study and a validation cohort of 242 ASD patients from a retrospective single center/surgeon cohort with complete two-year patient-reported outcomes (PROs) and clinical/radiographic follow-up. Using k-means clustering, a machine learning algorithm, we clustered patients based on baseline PROs, Edmonton frailty, age, surgical history, and overall health. Baseline differences in clusters identified using the training cohort were assessed using Chi-Squared and ANOVA with pairwise comparisons. To evaluate the classification system's ability to discern postoperative trajectories, a second machine learning algorithm assigned the single-center/surgeon patients to the same 4 clusters, and we compared the clusters' two-year PROs and clinical outcomes. RESULTS: K-means clustering revealed four distinct phenotypes from the multicenter training cohort based on age, frailty, and mental health: Old/Frail/Content (OFC, 27.7%), Old/Frail/Distressed (OFD, 33.2%), Old/Resilient/Content (ORC, 27.2%), and Young/Resilient/Content (YRC, 11.9%). OFC and OFD clusters had the highest frailty scores (OFC: 3.76, OFD: 4.72) and a higher proportion of patients with prior thoracolumbar fusion (OFC: 47.4%, OFD: 49.2%). ORC and YRC clusters exhibited lower frailty scores and fewest patients with prior thoracolumbar procedures (ORC: 2.10, 36.6%; YRC: 0.84, 19.4%). OFC had 69.9% of patients with global sagittal deformity and the highest T1PA (29.0), while YRC had 70.2% exhibiting coronal deformity, the highest mean coronal Cobb Angle (54.0), and the lowest T1PA (11.9). OFD and ORC had similar alignment phenotypes with intermediate values for Coronal Cobb Angle (OFD: 33.7; ORC: 40.0) and T1PA (OFD: 24.9; ORC: 24.6) between OFC (worst sagittal alignment) and YRC (worst coronal alignment). In the single surgeon validation cohort, the OFC cluster experienced the greatest increase in SRS Function scores (1.34 points, 95%CI 1.01-1.67) compared to OFD (0.5 points, 95%CI 0.245-0.755), ORC (0.7 points, 95%CI 0.415-0.985), and YRC (0.24 points, 95%CI -0.024-0.504) clusters. OFD cluster patients improved the least over 2 years. Multivariable Cox regression analysis demonstrated that the OFD cohort had significantly worse reoperation outcomes compared to other clusters (HR: 3.303, 95%CI: 1.085-8.390). CONCLUSION: Machine-learning clustering found four different ASD patient qualitative phenotypes, defined by their age, frailty, physical functioning, and mental health upon presentation, which primarily determines their ability to improve their PROs following surgery. This reaffirms that these qualitative measures must be assessed in addition to the radiographic variables when counseling ASD patients regarding their expected surgical outcomes.

Are insufficient corrections a major factor in distal junctional kyphosis? A simulated analysis of cervical deformity correction using in-construct measurements.

OBJECTIVE: The present study utilized recently developed in-construct measurements in simulations of cervical deformity surgery in order to assess undercorrection and predict distal junctional kyphosis (DJK). METHODS: A retrospective review of a database of operative cervical deformity patients was analyzed for severe DJK and mild DJK. C2-lower instrumented vertebra (LIV) sagittal angle (SA) was measured postoperatively, and the correction was simulated in the preoperative radiograph in order to match the C2-LIV by using the planning software. Linear regression analysis that used C2 pelvic angle (CPA) and pelvic tilt (PT) determined the simulated PT that matched the virtual CPA. Linear regression analysis was used to determine the C2-T1 SA, C2-T4 SA, and C2-T10 SA that corresponded to DJK of 20° and cervical sagittal vertical axis (cSVA) of 40 mm. RESULTS: Sixty-nine cervical deformity patients were included. Severe and mild DJK occurred in 11 (16%) and 22 (32%) patients, respectively; 3 (4%) required DJK revision. Simulated corrections demonstrated that severe and mild DJK patients had worse alignment compared to non-DJK patients in terms of cSVA (42.5 mm vs 33.0 mm vs 23.4 mm, p < 0.001) and C2-LIV SVA (68.9 mm vs 57.3 mm vs 36.8 mm, p < 0.001). Linear regression revealed the relationships between in-construct measures (C2-T1 SA, C2-T4 SA, and C2-T10 SA), cSVA, and change in DJK (all R > 0.57, p < 0.001). A cSVA of 40 mm corresponded to C2-T4 SA of 10.4° and C2-T10 SA of 28.0°. A DJK angle change of 10° corresponded to C2-T4 SA of 5.8° and C2-T10 SA of 20.1°. CONCLUSIONS: Simulated cervical deformity corrections demonstrated that severe DJK patients have insufficient corrections compared to patients without DJK. In-construct measures assess sagittal alignment within the fusion separate from DJK and subjacent compensation. They can be useful as intraoperative tools to gauge the adequacy of cervical deformity correction.

Development of a modified frailty index for adult spinal deformities independent of functional changes following surgical correction: a true baseline risk assessment tool.

PURPOSE: To develop a simplified, modified frailty index for adult spinal deformity (ASD) patients dependent on objective clinical factors. METHODS: ASD patients with baseline (BL) and 2-year (2Y) follow-up were included. Factors with the largest R2 value derived from multivariate forward stepwise regression were including in the modified ASD-FI (clin-ASD-FI). Factors included in the clin-ASD-FI were regressed against mortality, extended length of hospital stay (LOS, > 8 days), revisions, major complications and weights for the clin-ASD-FI were calculated via Beta/Sullivan. Total clin-ASD-FI score was created with a score from 0 to 1. Linear regression correlated clin-ASD-FI with ASD-FI scores and published cutoffs for the ASD-FI were used to create the new frailty cutoffs: not frail (NF: < 0.11), frail (F: 0.11-0.21) and severely frail (SF: > 0.21). Binary logistic regression assessed odds of complication or reop for frail patients. RESULTS: Five hundred thirty-one ASD patients (59.5 yrs, 79.5% F) were included. The final model had a R2 of 0.681, and significant factors were: < 18.5 or > 30 BMI (weight: 0.0625 out of 1), cardiac disease (0.125), disability employment status (0.3125), diabetes mellitus (0.0625), hypertension (0.0625), osteoporosis (0.125), blood clot (0.1875), and bowel incontinence (0.0625). These factors calculated the score from 0 to 1, with a mean cohort score of 0.13 ± 0.14. Breakdown by clin-ASD-FI score: 51.8% NF, 28.1% F, 20.2% SF. Increasing frailty severity was associated with longer LOS (NF: 7.0, F: 8.3, SF: 9.2 days; P < 0.001). Frailty independently predicted occurrence of any complication (OR: 9.357 [2.20-39.76], P = 0.002) and reop (OR: 2.79 [0.662-11.72], P = 0.162). CONCLUSIONS: Utilizing an existing ASD frailty index, we proposed a modified version eliminating the patient-reported components. This index is a true assessment of physiologic status, and represents a superior risk factor assessment compared to other tools for both primary and revision spinal deformity surgery as a result of its immutability with surgery, lack of subjectivity, and ease of use.

Predictors of pelvic tilt normalization: a multicenter study on the impact of regional and lower-extremity compensation on pelvic alignment after complex adult spinal deformity surgery.

OBJECTIVE: The objective was to determine the degree of regional decompensation to pelvic tilt (PT) normalization after complex adult spinal deformity (ASD) surgery. METHODS: Operative ASD patients with 1 year of PT measurements were included. Patients with normalized PT at baseline were excluded. Predicted PT was compared to actual PT, tested for change from baseline, and then compared against age-adjusted, Scoliosis Research Society-Schwab, and global alignment and proportion (GAP) scores. Lower-extremity (LE) parameters included the cranial-hip-sacrum angle, cranial-knee-sacrum angle, and cranial-ankle-sacrum angle. LE compensation was set as the 1-year upper tertile compared with intraoperative baseline. Univariate analyses were used to compare normalized and nonnormalized data against alignment outcomes. Multivariable logistic regression analyses were used to develop a model consisting of significant predictors for normalization related to regional compensation. RESULTS: In total, 156 patients met the inclusion criteria (mean ± SD age 64.6 ± 9.1 years, BMI 27.9 ± 5.6 kg/m2, Charlson Comorbidity Index 1.9 ± 1.6). Patients with normalized PT were more likely to have overcorrected pelvic incidence minus lumbar lordosis and sagittal vertical axis at 6 weeks (p < 0.05). GAP score at 6 weeks was greater for patients with nonnormalized PT (0.6 vs 1.3, p = 0.08). At baseline, 58.5% of patients had compensation in the thoracic and cervical regions. Postoperatively, compensation was maintained by 42% with no change after matching in age-adjusted or GAP score. The patients with nonnormalized PT had increased rates of thoracic and cervical compensation (p < 0.05). Compensation in thoracic kyphosis differed between patients with normalized PT at 6 weeks and those with normalized PT at 1 year (69% vs 35%, p < 0.05). Those who compensated had increased rates of implant complications by 1 year (OR [95% CI] 2.08 [1.32-6.56], p < 0.05). Cervical compensation was maintained at 6 weeks and 1 year (56% vs 43%, p = 0.12), with no difference in implant complications (OR 1.31 [95% CI -2.34 to 1.03], p = 0.09). For the lower extremities at baseline, 61% were compensating. Matching age-adjusted alignment did not eliminate compensation at any joint (all p > 0.05). Patients with nonnormalized PT had higher rates of LE compensation across joints (all p < 0.01). Overall, patients with normalized PT at 1 year had the greatest odds of resolving LE compensation (OR 9.6, p < 0.001). Patients with normalized PT at 1 year had lower rates of implant failure (8.9% vs 19.5%, p < 0.05), rod breakage (1.3% vs 13.8%, p < 0.05), and pseudarthrosis (0% vs 4.6%, p < 0.05) compared with patients with nonnormalized PT. The complication rate was significantly lower for patients with normalized PT at 1 year (56.7% vs 66.1%, p = 0.02), despite comparable health-related quality of life scores. CONCLUSIONS: Patients with PT normalization had greater rates of resolution in thoracic and LE compensation, leading to lower rates of complications by 1 year. Thus, consideration of both the lower extremities and thoracic regions in surgical planning is vital to preventing adverse outcomes and maintaining pelvic alignment.

Persistent Lower Extremity Compensation for Sagittal Imbalance After Surgical Correction of Complex Adult Spinal Deformity: A Radiographic Analysis of Early Impact.

BACKGROUND AND OBJECTIVES: Achieving spinopelvic realignment during adult spinal deformity (ASD) surgery does not always produce ideal outcomes. Little is known whether compensation in lower extremities (LEs) plays a role in this disassociation. The objective is to analyze lower extremity compensation after complex ASD surgery, its effect on outcomes, and whether correction can alleviate these mechanisms. METHODS: We included patients with complex ASD with 6-week data. LE parameters were as follows: sacrofemoral angle, knee flexion angle, and ankle flexion angle. Each parameter was ranked, and upper tertile was deemed compensation. Patients compensating and not compensating postoperatively were propensity score matched for body mass index, frailty, and T1 pelvic angle. Linear regression assessed correlation between LE parameters and baseline deformity, demographics, and surgical details. Multivariate analysis controlling for baseline deformity and history of total knee/hip arthroplasty evaluated outcomes. RESULTS: Two hundred and ten patients (age: 61.3 ± 14.1 years, body mass index: 27.4 ± 5.8 kg/m2, Charlson Comorbidity Index: 1.1 ± 1.6, 72% female, 22% previous total joint arthroplasty, 24% osteoporosis, levels fused: 13.1 ± 3.8) were included. At baseline, 59% were compensating in LE: 32% at hips, 39% knees, and 36% ankles. After correction, 61% were compensating at least one joint. Patients undercorrected postoperatively were less likely to relieve LE compensation (odds ratio: 0.2, P = .037). Patients compensating in LE were more often undercorrected in age-adjusted pelvic tilt, pelvic incidence, lumbar lordosis, and T1 pelvic angle and disproportioned in Global Alignment and Proportion (P < .05). Patients matched in sagittal age-adjusted score at 6 weeks but compensating in LE were more likely to develop proximal junctional kyphosis (odds ratio: 4.1, P = .009) and proximal junctional failure (8% vs 0%, P = .035) than those sagittal age-adjusted score-matched and not compensating in LE. CONCLUSION: Perioperative lower extremity compensation was a product of undercorrecting complex ASD. Even in age-adjusted realignment, compensation was associated with global undercorrection and junctional failure. Consideration of lower extremities during planning is vital to avoid adverse outcomes in perioperative course after complex ASD surgery.

Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes.

BACKGROUND: Exploratory analysis of the phase 2 PACIFIC-Stroke (Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-Non-Cardioembolic Stroke) randomized trial suggested that asundexian, an oral factor XIa inhibitor, prevents recurrent stroke and transient ischemic attacks in patients with atherosclerotic stroke. In this post hoc exploratory analysis, we hypothesized that asundexian would be more effective in patients enrolled with large, multiple, or cortical acute infarcts on magnetic resonance imaging than in patients enrolled with a single small subcortical acute infarct, and asundexian would prevent incident cortical covert infarcts. METHODS: In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug. RESULTS: Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]). CONCLUSIONS: These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.

Postoperative Discharge to Acute Rehabilitation or Skilled Nursing Facility Compared With Home Does Not Reduce Hospital Readmissions, Return to Surgery, or Improve Outcomes Following Adult Spine Deformity Surgery.

STUDY DESIGN: Retrospective review of a prospective multicenter adult spinal deformity (ASD) study. OBJECTIVE: The aim of this study was to evaluate 30-day readmissions, 90-day return to surgery, postoperative complications, and patient-reported outcomes (PROs) for matched ASD patients receiving nonhome discharge (NON), including acute rehabilitation (REHAB), and skilled nursing facility (SNF), or home (HOME) discharge following ASD surgery. SUMMARY OF BACKGROUND DATA: Postoperative disposition following ASD surgery frequently involves nonhome discharge. Little data exists for longer term outcomes for ASD patients receiving nonhome discharge versus patients discharged to home. MATERIALS AND METHODS: Surgically treated ASD patients prospectively enrolled into a multicenter study were assessed for NON or HOME disposition following hospital discharge. NON was further divided into REHAB or SNF. Propensity score matching was used to match for patient age, frailty, spine deformity, levels fused, and osteotomies performed at surgery. Thirty-day hospital readmissions, 90-day return to surgery, postoperative complications, and 1-year and minimum 2-year postoperative PROs were evaluated. RESULTS: A total of 241 of 374 patients were eligible for the study. NON patients were identified and matched to HOME patients. Following matching, 158 patients remained for evaluation; NON and HOME had similar preoperative age, frailty, spine deformity magnitude, surgery performed, and duration of hospital stay ( P >0.05). Thirty-day readmissions, 90-day return to surgery, and postoperative complications were similar for NON versus HOME and similar for REHAB (N=64) versus SNF (N=42) versus HOME ( P >0.05). At 1-year and minimum 2-year follow-up, HOME demonstrated similar to better PRO scores including Oswestry Disability Index, Short-Form 36v2 questionnaire Mental Component Score and Physical Component Score, and Scoliosis Research Society scores versus NON, REHAB, and SNF ( P <0.05). CONCLUSIONS: Acute needs must be considered following ASD surgery, however, matched analysis comparing 30-day hospital readmissions, 90-day return to surgery, postoperative complications, and PROs demonstrated minimal benefit for NON, REHAB, or SNF versus HOME at 1- and 2-year follow-up, questioning the risk and cost/benefits of routine use of nonhome discharge. LEVEL OF EVIDENCE: Level III-prognostic.

Transcranial Doppler ultrasound to evaluate the risk of hyperperfusion after endovascular stroke thrombectomy.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) has been reported in up to 50% of acute ischemic stroke (AIS) patients with a large vessel occlusion (LVO) treated with endovascular thrombectomy (EVT). HT may be driven by postrecanalization hyperperfusion injury and is independently associated with worse functional outcomes. Strategies to identify patients at risk for HT may assist in developing preventive therapies. METHODS: We prospectively included adult AIS patients with an anterior circulation LVO achieving successful recanalization after EVT. Consenting participants received transcranial Doppler ultrasound (TCD) within 18 hours of procedure completion. We compared flow velocities according to the presence of HT on the computed tomography scan performed within the first 24±12 hours from the end of EVT. We also evaluated the association of flow velocities with systemic blood pressure (BP) readings at the time of insonation. RESULTS: A total of 48 patients consented to participate in the study. Six (12%) were excluded due to the absence of temporal windows. HT was detected in 20 participants (48%). Those with HT had higher peak systolic velocities on the middle cerebral arteries compared to those without HT for both the symptomatic (107±42 vs. 82±25 cm/second, p = .024) and asymptomatic (97±21 vs. 81±25 cm/second, p = .040) sides. No correlation of flow velocities on either the symptomatic or asymptomatic side and BP measurements at the time of insonation was detected. CONCLUSION: TCD can identify patients at risk of HT following successful EVT. TCD could serve as an inexpensive ancillary test to guide participant selection for clinical trials targeting postprocedural reperfusion injury.

Chronic ischemic lesions and presence of patent foramen ovale in young adults with embolic stroke of undetermined source: Results of the young ESUS patient registry.

BACKGROUND: Chronic ischemic lesions (CILs) are frequent findings in patients with acute ischemic stroke, but their phenotypes and relevance in young adults with embolic stroke of undetermined source (Y-ESUS) remains uncertain. We aimed to compare Y-ESUS patients with CIL to those without CIL and assessed the association of CIL and its phenotypes with the presence of patent foramen ovale (PFO). METHODS: This prospective longitudinal, multicenter cohort study enrolled consecutive patients 50 years and younger with ESUS from October 2017 to October 2019 in 41 stroke research centers in 13 countries. Local investigators adjudicated presence and phenotypes of CIL on routine brain imaging (either magnetic resonance imaging (MRI) or computed tomography (CT)). RESULTS: Overall, 535 patients were enrolled (mean age = 40.4 (standard deviation (SD) = 7.3) years, 238 (44%) female). CILs were present in 76/534 (14.2%) patients with a median count CIL count of 1.0 (interquartile range (IQR) = 1-2), 42/76 (55%) had at least one cortical phenotype and 38/76 (50%) at least one non-cortical phenotype. Y-ESUS with CIL were less often female (32% vs 47% in non-CIL Y-ESUS), were older (mean 43 vs 40 years), had more often hypertension (42% vs 19%), diabetes (17% vs 7%), and hyperlipidemia (34% vs 18%). CIL Y-ESUS were independently associated with lower stroke recurrence (relative risk (RR) = 0.17 (0.05-0.61)). In Y-ESUS with PFO, CILs were less frequent in probable pathogenic PFO than with probable non-pathogenic PFO (6.1% vs 30% p< 0.001). CONCLUSION: One in seven Y-ESUS patients has additional CIL. CILs were associated with several vascular risk factors, lower probability of a pathogenic PFO, and lower stroke recurrence.

Determining the best vertebra for measuring pelvic incidence and spinopelvic parameters in adult spinal deformity patients with transitional anatomy.

OBJECTIVE: The aim of this study was to determine if spinal deformity patients with L5 sacralization should have pelvic incidence (PI) and other spinopelvic parameters measured from the L5 or S1 endplate. METHODS: This study was a multicenter retrospective comparative cohort study comprising a large database of adult spinal deformity (ASD) patients and a database of asymptomatic individuals. Linear regression modeling was used to determine normative T1 pelvic angle (TPA) and PI - lumbar lordosis (LL) mismatch (PI-LL) based on PI and age in a database of asymptomatic subjects. In an ASD database, patients with radiographic evidence of L5 sacralization had the PI, LL, and TPA measured from the superior endplate of S1 and then also from L5. The differences in TPA and PI-LL from normative were calculated in the sacralization cohort relative to L5 and S1 and correlated to the Oswestry Disability Index (ODI). Patients were grouped based on the Scoliosis Research Society (SRS)-Schwab PI-LL modifier (0, +, or ++) using the L5 PI-LL and S1 PI-LL. Baseline ODI and SF-36 Physical Component Summary (PCS) scores were compared across and within groups. RESULTS: Among 1179 ASD patients, 276 (23.4%) had transitional anatomy, 176 with sacralized L5 (14.9%) and 100 (8.48%) with lumbarization of S1. The 176 patients with sacralized L5 were analyzed. When measured using the L5 superior endplate, pelvic parameters were significantly smaller than those measured relative to S1 (PI: 24.5° ± 11.0° vs 55.7° ± 12.0°, p = 0.001;TPA: 11.2° ± 12.0° vs 20.3° ± 12.5°, p = 0.001; and PI-LL: 0.67° ± 21.1° vs 11.4° ± 20.8°, p = 0.001). When measured from S1, 76 (43%), 45 (25.6%), and 55 (31.3%) patients had SRS-Schwab PI-LL modifiers of 0, +, and ++, respectively, compared with 124 (70.5%), 22 (12.5%), and 30 (17.0%), respectively, when measured from L5. There were significant differences in ODI and PCS scores as the SRS-Schwab grade increased regardless of L5 or S1 measurement. The L5 group had lower PCS functional scores for SRS-Schwab modifiers 0 and ++ relative to same grades in the S1 group. Offset from normative TPA (0.5° ± 11.1° vs 9.6° ± 10.8°, p = 0.001) and PI-LL (4.5° ± 20.4° vs 15.2° ± 19.3°, p = 0.001) were smaller when measuring from L5. Moreover, S1 measurements were more correlated with health status by ODI (TPA offset from normative: S1, R = 0.326 vs L5, R = 0.285; PI-LL offset from normative: S1, R = 0.318 vs L5, R = 0.274). CONCLUSIONS: Measuring the PI and spinopelvic parameters at L5 in sacralized anatomy results in underestimating spinal deformity and is less correlated with health-related quality of life. Surgeons may consider measuring PI and spinopelvic parameters relative to S1 rather than at L5 in patients with a sacralized L5.

Patient-specific Cervical Deformity Corrections With Consideration of Associated Risk: Establishment of Risk Benefit Thresholds for Invasiveness Based on Deformity and Frailty Severity.

STUDY DESIGN/SETTING: This was a retrospective cohort study. BACKGROUND: Little is known of the intersection between surgical invasiveness, cervical deformity (CD) severity, and frailty. OBJECTIVE: The aim of this study was to investigate the outcomes of CD surgery by invasiveness, frailty status, and baseline magnitude of deformity. METHODS: This study included CD patients with 1-year follow-up. Patients stratified in high deformity if severe in the following criteria: T1 slope minus cervical lordosis, McGregor's slope, C2-C7, C2-T3, and C2 slope. Frailty scores categorized patients into not frail and frail. Patients are categorized by frailty and deformity (not frail/low deformity; not frail/high deformity; frail/low deformity; frail/high deformity). Logistic regression assessed increasing invasiveness and outcomes [distal junctional failure (DJF), reoperation]. Within frailty/deformity groups, decision tree analysis assessed thresholds for an invasiveness cutoff above which experiencing a reoperation, DJF or not achieving Good Clinical Outcome was more likely. RESULTS: A total of 115 patients were included. Frailty/deformity groups: 27% not frail/low deformity, 27% not frail/high deformity, 23.5% frail/low deformity, and 22.5% frail/high deformity. Logistic regression analysis found increasing invasiveness and occurrence of DJF [odds ratio (OR): 1.03, 95% CI: 1.01-1.05, P =0.002], and invasiveness increased with deformity severity ( P <0.05). Not frail/low deformity patients more often met Optimal Outcome with an invasiveness index <63 (OR: 27.2, 95% CI: 2.7-272.8, P =0.005). An invasiveness index <54 for the frail/low deformity group led to a higher likelihood of meeting the Optimal Outcome (OR: 9.6, 95% CI: 1.5-62.2, P =0.018). For the frail/high deformity group, patients with a score <63 had a higher likelihood of achieving Optimal Outcome (OR: 4.8, 95% CI: 1.1-25.8, P =0.033). There was no significant cutoff of invasiveness for the not frail/high deformity group. CONCLUSIONS: Our study correlated increased invasiveness in CD surgery to the risk of DJF, reoperation, and poor clinical success. The thresholds derived for deformity severity and frailty may enable surgeons to individualize the invasiveness of their procedures during surgical planning to account for the heightened risk of adverse events and minimize unfavorable outcomes.

Role of corticosteroids in skin physiology and therapeutic potential of an 11ß-HSD1 inhibitor: A review.

Skin is a major site of cortisol bioconversion by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzymes which catalyze intracellular inactive cortisone into physiologically active cortisol. 11ß-HSD1 is highly expressed in skin, especially in dermal fibroblasts, epidermal keratinocytes, melanocytes, and hair follicles, and plays important roles in regulating keratinocytes, fibroblast proliferation, and has roles in skin aging. Inhibition of 11ß-HSD1 may reverse decreased collagen levels observed in extrinsically and intrinsically aged skin. Inhibitors of 11ß-HSD1 may also have the potential to reverse decreased collagen observed in skin atrophy induced by glucocorticoid treatment. This systematic review aimed to summarize the current knowledge of roles for 11ß-HSD1 inhibitor in skin physiology and potential for future use in medications. Studies have demonstrated that immediately following experimental insult in an animal model, there is increased expression of 11ß-HSD1, and that topical application of an 11ß-HSD1 inhibitor increases the rate of healing, increases skin collagen content, increases dermal fibroblasts, and increases dermal thickness. Furthermore, in patients with type 2 diabetes mellitus, 11ß-HSD1 inhibitors reduce wound diameter after injury. Further development of 11ß-HSD1 inhibitors appears to be a promising area for treating aging skin, aiding wound healing, and mitigating effects of systemic glucocorticoid use. Both topically and orally administered 11ß-HSD1 inhibitors appear to be viable avenues for future research.

Efficacy of Varying Surgical Approaches on Achieving Optimal Alignment in Adult Spinal Deformity Surgery.

BACKGROUND: The Roussouly, SRS-Schwab, and Global Alignment and Proportion (GAP) classifications define alignment by spinal shape and deformity severity. The efficacy of different surgical approaches and techniques to successfully achieve these goals is not well understood. PURPOSE: Identify the impact of surgical approach and/or technique on meeting complex realignment goals in adult spinal deformity (ASD) corrective surgery. STUDY DESIGN/SETTING: Retrospective study. MATERIALS AND METHODS: Included patients with ASD fused to pelvis with 2-year data. Patients were categorized by: (1) Roussouly: matching current and theoretical spinal shapes, (2) improving in SRS-Schwab modifiers (0, +, ++), and (3) improving GAP proportionality by 2 years. Analysis of covariance and multivariable logistic regression analyses controlling for age, levels fused, baseline deformity, and 3-column osteotomy usage compared the effect of different surgical approaches, interbody, and osteotomy use on meeting realignment goals. RESULTS: A total of 693 patients with ASD were included. By surgical approach, 65.7% were posterior-only and 34.3% underwent anterior-posterior approach with 76% receiving an osteotomy (21.8% 3-column osteotomy). By 2 years, 34% matched Roussouly, 58% improved in GAP, 45% in SRS-Schwab pelvic tilt (PT), 62% sagittal vertical axis, and 70% pelvic incidence-lumbar lordosis. Combined approaches were most effective for improvement in PT [odds ratio (OR): 1.7 (1.1-2.5)] and GAP [OR: 2.2 (1.5-3.2)]. Specifically, anterior lumbar interbody fusion (ALIF) below L3 demonstrated higher rates of improvement versus TLIFs in Roussouly [OR: 1.7 (1.1-2.5)] and GAP [OR: 1.9 (1.3-2.7)]. Patients undergoing pedicle subtraction osteotomy at L3 or L4 were more likely to improve in PT [OR: 2.0 (1.0-5.2)] and pelvic incidence-lumbar lordosis [OR: 3.8 (1.4-9.8)]. Clinically, patients undergoing the combined approach demonstrated higher rates of meeting SCB in Oswestry Disability Index by 2 years while minimizing rates of proximal junctional failure, most often with an ALIF at L5-S1 [Oswestry Disability Index-SCB: OR: 1.4 (1.1-2.0); proximal junctional failure: OR: 0.4 (0.2-0.8)]. CONCLUSIONS: Among patients undergoing ASD realignment, optimal lumbar shape and proportion can be achieved more often with a combined approach. Although TLIFs, incorporating a 3-column osteotomy, at L3 and L4 can restore lordosis and normalize pelvic compensation, ALIFs at L5-S1 were most likely to achieve complex realignment goals with an added clinical benefit and mitigation of junctional failure.

Cost Benefit of Implementation of Risk Stratification Models for Adult Spinal Deformity Surgery.

STUDY DESIGN/SETTING: Retrospective cohort study. OBJECTIVE: Assess the extent to which defined risk factors of adverse events are drivers of cost-utility in spinal deformity (ASD) surgery. METHODS: ASD patients with 2-year (2Y) data were included. Tertiles were used to define high degrees of frailty, sagittal deformity, blood loss, and surgical time. Cost was calculated using the Pearl Diver registry and cost-utility at 2Y was compared between cohorts based on the number of risk factors present. Statistically significant differences in cost-utility by number of baseline risk factors were determined using ANOVA, followed by a generalized linear model, adjusting for clinical site and surgeon, to assess the effects of increasing risk score on overall cost-utility. RESULTS: By 2 years, 31% experienced a major complication and 23% underwent reoperation. Patients with ≤2 risk factors had significantly less major complications. Patients with 2 risk factors improved the most from baseline to 2Y in ODI. Average cost increased by $8234 per risk factor (R2 = .981). Cost-per-QALY at 2Y increased by $122,650 per risk factor (R2 = .794). Adjusted generalized linear model demonstrated a significant trend between increasing risk score and increasing cost-utility (r2 = .408, P < .001). CONCLUSIONS: The number of defined patient-specific and surgical risk factors, especially those with greater than two, were associated with increased index surgical costs and diminished cost-utility. Efforts to optimize patient physiology and minimize surgical risk would likely reduce healthcare expenditures and improve the overall cost-utility profile for ASD interventions.Level of evidence: III.

Multiphasic exercise prehabilitation for patients undergoing surgery for head and neck cancer: a hybrid effectiveness-implementation study protocol.

Head and neck cancer (HNC) treatment often consists of major surgery followed by adjuvant therapy, which can result in treatment-related side effects, decreased physical function, and diminished quality of life. Perioperative nutrition interventions and early mobilization improve recovery after HNC treatment. However, there are few studies on prehabilitation that include exercise within the HNC surgical care pathway. We have designed a multiphasic exercise prehabilitation intervention for HNC patients undergoing surgical resection with free flap reconstruction. We will use a hybrid effectiveness-implementation study design guided by the RE-AIM framework to address the following objectives: (1) to evaluate intervention benefits through physical function and patient-reported outcome assessments; (2) to determine the safety and feasibility of the prehabilitation intervention; (3) to evaluate the implementation of exercise within the HNC surgical care pathway; and (4) to establish a post-operative screening and referral pathway to exercise oncology resources. The results of this study will provide evidence for the benefits and costs of a multiphasic exercise prehabilitation intervention embedded within the HNC surgical care pathway. This paper describes the study protocol design, multiphasic exercise prehabilitation intervention, planned analyses, and dissemination of findings. Trial registration: https://clinicaltrials.gov/NCT04598087.