The Role of Multimodality Imaging in Cardiomyopathy.

PURPOSE OF REVIEW: There has been increasing use of multimodality imaging in the evaluation of cardiomyopathies. RECENT FINDINGS: Echocardiography, cardiac magnetic resonance (CMR), cardiac nuclear imaging, and cardiac computed tomography (CCT) play an important role in the diagnosis, risk stratification, and management of patients with cardiomyopathies. Echocardiography is essential in the initial assessment of suspected cardiomyopathy, but a multimodality approach can improve diagnostics and management. CMR allows for accurate measurement of volumes and function, and can easily detect unique pathologic structures. In addition, contrast imaging and parametric mapping enable the characterization of tissue features such as scar, edema, infiltration, and deposition. In non-ischemic cardiomyopathies, metabolic and molecular nuclear imaging is used to diagnose rare but life-threatening conditions such amyloidosis and sarcoidosis. There is an expanding use of CCT for planning electrophysiology procedures such as cardioversion, ablations, and device placement. Furthermore, CCT can evaluate for complications associated with advanced heart failure therapies such as cardiac transplant and mechanical support devices. Innovations in multimodality cardiac imaging should lead to increased volumes and better outcomes.

Safety and comparative efficacy of initiating low-molecular-weight heparin within 24 hours of injury or surgery for venous thromboembolism prophylaxis in patients with spinal cord injury: a prospective TRACK-SCI registry study.

OBJECTIVE: Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a significant clinical concern. This study sought to determine the incidence of VTE and hemorrhagic complications among patients with SCI who received low-molecular-weight heparin (LMWH) within 24 hours of injury or surgery and identify variables that predict VTE using the prospective Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database. METHODS: The TRACK-SCI database was queried for individuals with traumatic SCI from 2015 to 2022. Primary outcomes of interest included rates of VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and in-hospital hemorrhagic complications that occurred after LWMH administration. Secondary outcomes included intensive care unit and hospital length of stay, discharge location type, and in-hospital mortality. RESULTS: The study cohort consisted of 162 patients with SCI. Fifteen of the 162 patients withdrew from the study, leading to loss of data for certain variables for these patients. One hundred thirty patients (87.8%) underwent decompression and/or fusion surgery for SCI. DVT occurred in 11 (7.4%) of 148 patients, PE in 9 (6.1%) of 148, and any VTE in 18 (12.2%) of 148 patients. The analysis showed that admission lower-extremity motor score (p = 0.0408), injury at the thoracic level (p = 0.0086), admission American Spinal Injury Association grade (p = 0.0070), and younger age (p = 0.0372) were significantly associated with VTE. There were 3 instances of postoperative spine surgery-related bleeding (2.4%) in the 127 patients who had spine surgery with bleeding complication data available, with one requiring return to surgery (0.8%). Thirteen (8.8%) of 147 patients had a bleeding complication not related to spine surgery. There were 2 gastrointestinal bleeds associated with nasogastric tube placement, 3 cases of postoperative non-spine-related surgery bleeding, and 8 cases of other bleeding complications (5.4%) not related to any surgery. CONCLUSIONS: Initiation of LMWH within 24 hours was associated with a low rate of spine surgery-related bleeding. Bleeding complications unrelated to SCI surgery still occur with LMWH administration. Because neurosurgical intervention is typically the limiting factor in initializing chemical DVT prophylaxis, many of these bleeding complications would have likely occurred regardless of the protocol.

Hypotension requiring vasopressor treatment and increased cardiac complications in elderly spinal cord injury patients: a prospective TRACK-SCI registry study.

OBJECTIVE: Increasing life expectancy has led to an older population. In this study, the authors analyzed complications and outcomes in elderly patients following spinal cord injury (SCI) using the established multi-institutional prospective study Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database collected in the Department of Neurosurgical Surgery at the University of California, San Francisco. METHODS: TRACK-SCI was queried for elderly individuals (≥ 65 years of age) with traumatic SCI from 2015 to 2019. Primary outcomes of interest included total hospital length of stay, perioperative complications, postoperative complications, and in-hospital mortality. Secondary outcomes included disposition location, and neurological improvement based on the American Spinal Injury Association Impairment Scale (AIS) grade at discharge. Descriptive analysis, Fisher's exact test, univariate analysis, and multivariable regression analysis were performed. RESULTS: The study cohort consisted of 40 elderly patients. The in-hospital mortality rate was 10%. Every patient in this cohort experienced at least 1 complication, with a mean of 6.6 separate complications (median 6, mode 4). The most common complication categories were cardiovascular, with a mean of 1.6 complications (median 1, mode 1), and pulmonary, with a mean of 1.3 (median 1, mode 0) complications, with 35 patients (87.5%) having at least 1 cardiovascular complication and 25 (62.5%) having at least 1 pulmonary complication. Overall, 32 patients (80%) required vasopressor treatment for mean arterial pressure (MAP) maintenance goals. The use of norepinephrine correlated with increased cardiovascular complications. Only 3 patients (7.5%) of the total cohort had an improved AIS grade compared with their acute level at admission. CONCLUSIONS: Given the increased frequency of cardiovascular complications associated with vasopressor use in elderly SCI patients, caution is warranted when targeting MAP goals in these patients. A downward adjustment of blood pressure maintenance goals and prophylactic cardiology consultation to select the most appropriate vasopressor agent may be advisable for SCI patients ≥ 65 years of age.

A phase Ib dose escalation study of oral monotherapy with KX2-391 in elderly patients with acute myeloid leukemia.

Poor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. This multi-center phase Ib open-label safety and activity study involved elderly patients with relapsed or refractory AML, or who declined standard chemotherapy. Twenty-four patients averaging 74 years of age were enrolled. The majority previously received hypomethylating agents. Five doses were tested: 40 mg (n = 1), 80 mg (n = 2), 120 mg (n = 8), 140 mg (n = 12), and 160 mg (n = 1). Seven patients were treated for 12 days or less, nine for 15-29 days, five for 33-58 days, and three for 77-165 days. One patient receiving 120 mg for 165 days had reduced splenomegaly and survived 373 days. Another had no evidence of disease progression for 154 days. One patient receiving 160 mg for 12 days remained treatment-free for about 18 months. Dose-limiting toxicities occurred in eight patients at: 120 mg (transaminitis, hyperbilirubinemia), 140 mg (mucositis, allergic reaction, transaminitis, acute kidney injury), and 160 mg (mucositis). The maximum tolerated dose for KX2-391 was 120 mg once daily. KX2-391 bone marrow concentrations were approximately similar to plasma concentrations. This is the first study to evaluate the safety of KX2-391 in elderly patients with AML. Further studies are warranted, including alternative dosing phase I trials evaluating shorter courses at higher doses and phase II trials. (Clinical Trial Registration:The study was registered at ClinicalTrials.gov: NCT01397799 (July 20, 2011)).

Decision tree-based machine learning analysis of intraoperative vasopressor use to optimize neurological improvement in acute spinal cord injury.

OBJECTIVE: Previous work has shown that maintaining mean arterial pressures (MAPs) between 76 and 104 mm Hg intraoperatively is associated with improved neurological function at discharge in patients with acute spinal cord injury (SCI). However, whether temporary fluctuations in MAPs outside of this range can be tolerated without impairment of recovery is unknown. This retrospective study builds on previous work by implementing machine learning to derive clinically actionable thresholds for intraoperative MAP management guided by neurological outcomes. METHODS: Seventy-four surgically treated patients were retrospectively analyzed as part of a longitudinal study assessing outcomes following SCI. Each patient underwent intraoperative hemodynamic monitoring with recordings at 5-minute intervals for a cumulative 28,594 minutes, resulting in 5718 unique data points for each parameter. The type of vasopressor used, dose, drug-related complications, average intraoperative MAP, and time spent in an extreme MAP range (< 76 mm Hg or > 104 mm Hg) were collected. Outcomes were evaluated by measuring the change in American Spinal Injury Association Impairment Scale (AIS) grade over the course of acute hospitalization. Features most predictive of an improvement in AIS grade were determined statistically by generating random forests with 10,000 iterations. Recursive partitioning was used to establish clinically intuitive thresholds for the top features. RESULTS: At discharge, a significant improvement in AIS grade was noted by an average of 0.71 levels (p = 0.002). The hemodynamic parameters most important in predicting improvement were the amount of time intraoperative MAPs were in extreme ranges and the average intraoperative MAP. Patients with average intraoperative MAPs between 80 and 96 mm Hg throughout surgery had improved AIS grades at discharge. All patients with average intraoperative MAP > 96.3 mm Hg had no improvement. A threshold of 93 minutes spent in an extreme MAP range was identified after which the chance of neurological improvement significantly declined. Finally, the use of dopamine as compared to norepinephrine was associated with higher rates of significant cardiovascular complications (50% vs 25%, p < 0.001). CONCLUSIONS: An average intraoperative MAP value between 80 and 96 mm Hg was associated with improved outcome, corroborating previous results and supporting the clinical verifiability of the model. Additionally, an accumulated time of 93 minutes or longer outside of the MAP range of 76-104 mm Hg is associated with worse neurological function at discharge among patients undergoing emergency surgical intervention for acute SCI.

Expert-augmented automated machine learning optimizes hemodynamic predictors of spinal cord injury outcome.

Artificial intelligence and machine learning (AI/ML) is becoming increasingly more accessible to biomedical researchers with significant potential to transform biomedicine through optimization of highly-accurate predictive models and enabling better understanding of disease biology. Automated machine learning (AutoML) in particular is positioned to democratize artificial intelligence (AI) by reducing the amount of human input and ML expertise needed. However, successful translation of AI/ML in biomedicine requires moving beyond optimizing only for prediction accuracy and towards establishing reproducible clinical and biological inferences. This is especially challenging for clinical studies on rare disorders where the smaller patient cohorts and corresponding sample size is an obstacle for reproducible modeling results. Here, we present a model-agnostic framework to reinforce AutoML using strategies and tools of explainable and reproducible AI, including novel metrics to assess model reproducibility. The framework enables clinicians to interpret AutoML-generated models for clinical and biological verifiability and consequently integrate domain expertise during model development. We applied the framework towards spinal cord injury prognostication to optimize the intraoperative hemodynamic range during injury-related surgery and additionally identified a strong detrimental relationship between intraoperative hypertension and patient outcome. Furthermore, our analysis captured how evolving clinical practices such as faster time-to-surgery and blood pressure management affect clinical model development. Altogether, we illustrate how expert-augmented AutoML improves inferential reproducibility for biomedical discovery and can ultimately build trust in AI processes towards effective clinical integration.

Nasopharyngeal cancer in non-endemic areas: Impact of treatment intensity within a large retrospective multicentre cohort.

AIM: Recommendations for managing patients with nasopharyngeal carcinoma (NPC) in non-endemic areas are largely derived from studies conducted in endemic areas. We analysed the impact of treatment approaches on survival in non-endemic areas. METHODS: In an international, multicentre, retrospective study, we analyse consecutive patients with NPC diagnosed between 2004 and 2017 in 36 hospitals from 11 countries. Treatment was categorised as non-intensive (NIT), including radiotherapy alone or concomitant chemoradiotherapy (cCRT), and intensive (IT) including cCRT preceded by and/or followed by chemotherapy (CT). The impact of IT on overall survival (OS) and disease-free survival (DFS) was adjusted for all the available potential confounders. RESULTS: Overall, 1021 and 1113 patients were eligible for overall survival (OS) and disease-free survival (DFS) analyses, respectively; 501 and 554 with Epstein Barr-encoded RNA (EBER) status available. In the whole group, 5-year OS was 84% and DFS 65%. The use of NIT was associated with a risk of death or recurrence 1.37 times higher than patients receiving IT. Patients submitted to NIT and induction CT + concurrent concomitant chemo and three-dimensional Conformal Radiation Therapy (3DCRT) had a risk of death or recurrence 1.5 and 1.7 times higher than patients treated with induction CT + cCRT with intensity-modulated radiotherapy (IMRT), respectively. The IT had no impact on OS in neither patients with EBER+ nor in patients with EBER-; IT showed better DFS in EBER+ but not in patients with EBER-. CONCLUSIONS: In low-incidence areas, patients with NPC treated with induction CT followed by concurrent IMRT cCRT achieved the highest DFS rate. The benefit of IT on DFS was restricted to patients with EBER+, suggesting that additional therapy offers no advantages in EBER- cases.

Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury.

Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients. Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods. Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery. Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention. Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).

Spinal cord injury is a devastating condition that involves damage to the nerve fibers connecting the brain with the spinal cord, often leading to permanent changes in strength, sensation and body functions, and in severe cases paralysis. Scientists around the world work hard to find ways to treat or even repair spinal cord injuries but few patients with complete immediate paralysis recover fully. Immediate paralysis is caused by direct damage to neurons and their extension in the spinal cord. Previous research has shown that blood pressure regulation may be key in saving these damaged neurons, as spinal cord injuries can break the communication between nerves that is involved in controlling blood pressure. This can lead to a vicious cycle of dysregulation of blood pressure and limit the supply of blood and oxygen to the damaged spinal cord tissue, exacerbating the death of spinal neurons. Management of blood pressure is therefore a key target for spinal cord injury care, but so far, the precise thresholds to enable neurons to recover are poorly understood. To find out more, Torres-Espin, Haefeli et al. used machine learning software to analyze previously recorded blood pressure and heart rate data obtained from 118 patients that underwent spinal cord surgery after acute spinal cord injury. The analyses revealed that patients who suffered from either low or high blood pressure during surgery had poorer prospects of recovery. Statistical models confirming these findings showed that the optimal blood pressure range to ensure recovery lies between 76 to 104-117 mmHg. Any deviation from this narrow window would dramatically worsen the ability to recover. These findings suggests that dysregulated blood pressure during surgery affects to odds of recovery in patients with a spinal cord injury. Torres-Espin, Haefeli et al. provide specific information that could improve current clinical practice in trauma centers. In the future, such machine learning tools and models could help develop real-time models that could predict the likelihood of a patient's recovery following spinal cord injury and related neurological conditions.

Minimally Invasive Endoscopic Intracerebral Hemorrhage Evacuation.

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and poor functional outcomes, largely because there are no evidence-based treatment options for this devastating disease process. In the past decade, a number of minimally invasive surgeries have emerged to address this issue, one of which is endoscopic evacuation. Stereotactic ICH Underwater Blood Aspiration (SCUBA) is a novel endoscopic evacuation technique performed in a fluid-filled cavity using an aspiration system to provide an additional degree of freedom during the procedure. The SCUBA procedure utilizes a suction device, endoscope, and sheath and is divided into two phases. The first phase involves maximal aspiration and minimal irrigation to decrease clot burden. The second phase involves increasing irrigation for visibility, decreasing aspiration strength for targeted aspiration without disturbing the cavity wall, and cauterizing any bleeding vessels. Using the endoscope and aspiration wand, this technique aims to maximize hematoma evacuation while minimizing collateral damage to the surrounding brain. Advantages of the SCUBA technique include the use of a low-profile endoscopic sheath minimizing brain disruption and improved visualization with a fluid-filled cavity rather than an air-filled one.

Diagnostic Accuracy of Spiral Whole-Heart Quantitative Adenosine Stress Cardiovascular Magnetic Resonance With Motion Compensated L1-SPIRIT.

BACKGROUND: Variable density spiral (VDS) pulse sequences with motion compensated compressed sensing (MCCS) reconstruction allow for whole-heart quantitative assessment of myocardial perfusion but are not clinically validated. PURPOSE: Assess performance of whole-heart VDS quantitative stress perfusion with MCCS to detect obstructive coronary artery disease (CAD). STUDY TYPE: Prospective cross sectional. POPULATION: Twenty-five patients with chest pain and known or suspected CAD and nine normal subjects. FIELD STRENGTH/SEQUENCE: Segmented steady-state free precession (SSFP) sequence, segmented phase sensitive inversion recovery sequence for late gadolinium enhancement (LGE) imaging and VDS sequence at 1.5 T for rest and stress quantitative perfusion at eight short-axis locations. ASSESSMENT: Stenosis was defined as ≥50% by quantitative coronary angiography (QCA). Visual and quantitative analysis of MRI data was compared to QCA. Quantitative analysis assessed average myocardial perfusion reserve (MPR), average stress myocardial blood flow (MBF), and lowest stress MBF of two contiguous myocardial segments. Ischemic burden was measured visually and quantitatively. STATISTICAL TESTS: Student's t-test, McNemar's test, chi-square statistic, linear mixed-effects model, and area under receiver-operating characteristic curve (ROC). RESULTS: Per-patient visual analysis demonstrated a sensitivity of 84% (95% confidence interval [CI], 60%-97%) and specificity of 83% [95% CI, 36%-100%]. There was no significant difference between per-vessel visual and quantitative analysis for sensitivity (69% [95% CI, 51%-84%] vs. 77% [95% CI, 60%-90%], P = 0.39) and specificity (88% [95% CI, 73%-96%] vs. 80% [95% CI, 64%-91%], P = 0.75). Per-vessel quantitative analysis ROC showed no significant difference (P = 0.06) between average MPR (0.68 [95% CI, 0.56-0.81]), average stress MBF (0.74 [95% CI, 0.63-0.86]), and lowest stress MBF (0.79 [95% CI, 0.69-0.90]). Visual and quantitative ischemic burden measurements were comparable (P = 0.85). DATA CONCLUSION: Whole-heart VDS stress perfusion demonstrated good diagnostic accuracy and ischemic burden evaluation. No significant difference was seen between visual and quantitative diagnostic performance and ischemic burden measurements. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Functional Outcome After Minimally Invasive Endoscopic Evacuation of Thalamic Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most devastating form of stroke, with thalamic hemorrhages carrying the worst outcomes. Minimally invasive (MIS) endoscopic ICH evacuation is a promising new therapy for the condition. However, it remains unclear whether therapy success is location dependent. Here we present long-term functional outcomes after MIS evacuation of spontaneous thalamic hemorrhages. METHODS: Patients presenting to a single urban health system with spontaneous ICH were triaged to a central hospital for management of ICH. Operative criteria for MIS evacuation included hemorrhage volume ≥15 mL, age ≥18, National Institutes of Health Stroke Scale ≥6, and baseline modified Rankin Score (mRS) ≤3. Demographic, radiographic, and clinical data were collected prospectively, and descriptive statistics were performed retrospectively. Functional outcomes were assessed using 6-month mRS scores. RESULTS: Endoscopic ICH evacuation was performed on 21 patients. Eleven patients had hemorrhage confined to the thalamus, whereas 10 patients had hemorrhages in the thalamus and surrounding structures. Eighteen patients (85.7%) had intraventricular extension. The average preoperative volume was 39.8 mL (standard deviation [SD]: 31.5 mL) and postoperative volume was 3.8 mL (SD: 6.1 mL), resulting in an average evacuation rate of 91.4% (SD: 11.1%). One month after hemorrhage, 2 patients (9.5%) had expired and all other patients remained functionally dependent (90.5%). At 6-month follow-up, 4 patients (19.0%) had improved to a favorable outcome (mRS ≤ 3). CONCLUSION: Among patients with ICH undergoing medical management, those with thalamic hemorrhages have especially poor outcomes. This study suggests that MIS evacuation can be safely performed in a thalamic population. It also presents long-term functional outcomes that can aid in planning randomization schemes or subgroup analyses in future MIS evacuation clinical trials.

Phase I/II study of bendamustine in combination with ofatumumab, carboplatin, etoposide (BOCE) for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.

We developed an outpatient salvage chemotherapy regimen using bendamustine, ofatumumab, carboplatin and etoposide (BOCE) to treat relapsed/refractory non-Hodgkin lymphoma (RR NHL) in a single-center phase I/II study. Primary objectives were safety, tolerability and overall response rate (ORR). Thirty-five RR NHL patients (57% de novo large cell [DLBCL] or grade 3B follicular [FL], 26% transformed DLBCL, 9% grade 3A FL, 3% mantle cell; median age = 62, median prior therapies = 1) were treated. Median follow-up was 24.1 months. ORR was 69% (CR = 49%, PR = 20% [ORR = 70%, CR = 50%, PR = 20% in the de novo DLBCL/grade 3B FL subgroup]). Median progression-free survival was 5.1 months and overall-survival 26.2 months. Twelve patients subsequently underwent stem cell transplantation. The most common non-hematologic grade 3-4 toxicities were neutropenic fever and hypophosphatemia. There were no treatment-related deaths. In conclusion, BOCE is a safe and effective outpatient salvage regimen for patients with RR NHL and serves as an effective bridge to stem cell transplantation.

New-onset atrial fibrillation and outcomes following isolated coronary artery bypass surgery: A systematic review and meta-analysis.

Prior meta-analyses have shown that new-onset atrial fibrillation (NOAF) occurs in up to 40% of patients following cardiac surgery and is associated with substantial major adverse cardiovascular events. The stroke and mortality implications of NOAF in isolated CABG without concomitant valve surgery is not known. We thought that NOAF would be associated with increased risk of stroke and mortality, even in patients undergoing isolated CABG. A blinded review of studies from MEDLINE, CENTRAL, and Web of Science was done by two independent investigators. Stroke, 30-day/hospital mortality, long-term cardiovascular mortality, and long-term (>1 year) all-cause mortality were analyzed. We used Review Manager Version 5.3 to perform pooled analysis of outcomes. Of 4461 studies identified, 19 studies (n = 129 628) met inclusion criteria. NOAF incidence ranged from 15% to 36%. NOAF was associated with increased risk of stroke (unadjusted OR 2.15 [1.82, 2.53] [P < .00001]; adjusted OR 1.88 [1.02, 3.46] [P = .04]). NOAF was associated with increased 30-day/hospital mortality (OR 2.35 [1.67, 3.32] [P < .00001]) and long-term cardiovascular mortality (OR 2.04 [1.35, 3.09] [P = .0007]) NOAF was associated with increased long-term all-cause mortality (unadjusted OR 1.79 [1.63, 1.96] [P < .00001]; adjusted OR 1.58 [1.24, 2.00] [P = .0002]). We found that the incidence of NOAF following isolated CABG is high and is associated with increased stroke rate and mortality. Early recognition and management of NOAF could improve outcomes.

Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice.

BACKGROUND: Postoperative cognitive decline (PCD) requires microglial activation. Voltage-gated Kv1.3 potassium channels are involved in microglial activation. We determined the role of Kv1.3 in PCD and the efficacy and safety of inhibiting Kv1.3 with phenoxyalkoxypsoralen-1 (PAP-1) in preventing PCD in a mouse model. METHODS: After institutional approval, we assessed whether Kv1.3-deficient mice (Kv1.3-/-) exhibited PCD, evidenced by tibial-fracture surgery-induced decline in aversive freezing behaviour, and whether PAP-1 could prevent PCD and postoperative neuroinflammation in PCD-vulnerable diet-induced obese (DIO) mice. We also evaluated whether PAP-1 altered either postoperative peripheral inflammation or tibial-fracture healing. RESULTS: Freezing behaviour was unaltered in postoperative Kv1.3-/- mice. In DIO mice, PAP-1 prevented postoperative (i) attenuation of freezing behaviour (54 [17.3]% vs 33.4 [12.7]%; P=0.03), (ii) hippocampal microglial activation by size (130 [31] pixels vs 249 [49]; P<0.001) and fluorescence intensity (12 000 [2260] vs 20 800 [5080] absorbance units; P<0.001), and (iii) hippocampal upregulation of interleukin-6 (IL-6) (14.9 [5.7] vs 25.6 [10.4] pg mg-1; P=0.011). Phenoxyalkoxypsoralen-1 neither affected surgery-induced upregulation of plasma IL-6 nor cartilage and bone components of the surgical fracture callus. CONCLUSIONS: Microglial-mediated PCD requires Kv1.3 activity, determined by genetic and pharmacological targeting approaches. Phenoxyalkoxypsoralen-1 blockade of Kv1.3 prevented surgery-induced hippocampal microglial activation and neuroinflammation in mice known to be vulnerable to PCD. Regarding perioperative safety, these beneficial effects of PAP-1 treatment occurred without impacting fracture healing. Kv1.3 blockers, currently undergoing clinical trials for other conditions, may represent an effective and safe intervention to prevent PCD.

Dexmedetomidine Exerts an Anti-inflammatory Effect via α2 Adrenoceptors to Prevent Lipopolysaccharide-induced Cognitive Decline in Mice.

BACKGROUND: Clinical studies have shown that dexmedetomidine ameliorates cognitive decline in both the postoperative and critical care settings. This study determined the mechanism(s) for the benefit provided by dexmedetomidine in a medical illness in mice induced by lipopolysaccharide. METHODS: Cognitive decline, peripheral and hippocampal inflammation, blood-brain barrier permeability, and inflammation resolution were assessed in male mice. Dexmedetomidine was administered in the presence of lipopolysaccharide and in combination with blockers. Cultured macrophages (RAW 264.7; BV-2) were exposed to lipopolysaccharide ± dexmedetomidine ± yohimbine; tumor necrosis factor α release into the medium and monocyte NFκB activity was determined. RESULTS: In vivo, lipopolysaccharide-induced cognitive decline and inflammation (mean ± SD) were reversed by dexmedetomidine (freezing time, 55.68 ± 12.31 vs. 35.40 ± 17.66%, P = 0.0286, n = 14; plasma interleukin [IL]-1ß: 30.53 ± 9.53 vs. 75.68 ± 11.04 pg/ml, P < 0.0001; hippocampal IL-1ß: 3.66 ± 1.88 vs. 28.73 ± 5.20 pg/mg, P < 0.0001; n = 8), which was prevented by α2 adrenoceptor antagonists. Similar results were found in 12-month-old mice. Lipopolysaccharide also increased blood-brain barrier leakage, inflammation-resolution orchestrator, and proresolving and proinflammatory mediators; each lipopolysaccharide effect was attenuated by dexmedetomidine, and yohimbine prevented dexmedetomidine's attenuating effect. In vitro, lipopolysaccharide-induced tumor necrosis factor α release (RAW 264.7: 6,308.00 ± 213.60 vs. 7,767.00 ± 358.10 pg/ml, P < 0.0001; BV-2: 1,075.00 ± 40.41 vs. 1,280.00 ± 100.30 pg/ml, P = 0.0003) and NFκB-p65 activity (nuclear translocation [RAW 264.7: 1.23 ± 0.31 vs. 2.36 ± 0.23, P = 0.0031; BV-2: 1.08 ± 0.26 vs. 1.78 ± 0.14, P = 0.0116]; phosphorylation [RAW 264.7: 1.22 ± 0.40 vs. 1.94 ± 0.23, P = 0.0493; BV-2: 1.04 ± 0.36 vs. 2.04 ± 0.17, P = 0.0025]) were reversed by dexmedetomidine, which was prevented by yohimbine. CONCLUSIONS: Preclinical studies suggest that the cognitive benefit provided by dexmedetomidine in mice administered lipopolysaccharide is mediated through α2 adrenoceptor-mediated anti-inflammatory pathways.

Native T1 Mapping, Extracellular Volume Mapping, and Late Gadolinium Enhancement in Cardiac Amyloidosis: A Meta-Analysis.

OBJECTIVES: This study aimed to compare the diagnostic and prognostic performance of native T1 mapping (T1), extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging for evaluating cardiac amyloidosis (CA). BACKGROUND: CA is a progressive infiltrative process in the extracellular space that is often underdiagnosed and holds a poor prognosis. Cardiac magnetic resonance (CMR) offers novel techniques for detecting and quantifying the disease burden of CA. METHODS: We searched PubMed for published studies using native T1, ECV, or LGE to diagnose and prognosticate CA. A total of 18 diagnostic (n = 2,015) and 13 prognostic studies (n = 1,483) were included for analysis. Pooled sensitivities, specificities, diagnostic odds ratios (DORs) of all diagnostic tests were assessed by bivariate analysis. Pooled hazard ratios (HRs) for mortality for the 3 techniques were determined. RESULTS: Bivariate comparison showed that ECV (DOR: 84.6; 95% confidence interval [CI]: 30.3 to 236.2) had a significantly higher DOR for CA than LGE (DOR: 20.1; 95% CI: 9.1 to 44.1; p = 0.03 vs. ECV). There was no significant difference between LGE and native T1 for sensitivity, specificity, and DOR. HR was significantly higher for ECV (HR: 4.27; 95% CI: 2.87 to 6.37) compared with LGE (HR: 2.60; 95% CI: 1.90 to 3.56; p = 0.03 vs. ECV) and native T1 (HR: 2.04; 95% CI: 1.24 to 3.37; p = 0.01 vs. ECV). CONCLUSIONS: ECV demonstrates a higher diagnostic OR for assessing cardiac amyloid than LGE and a higher HR for adverse events compared with LGE and native T1. In addition, native T1 showed similar sensitivity and specificity as ECV and LGE without requiring contrast material. Although limited by study heterogeneity, this meta-analysis suggests that ECV provides high diagnostic and prognostic utility for the assessment of cardiac amyloidosis.

Advanced Techniques for Endoscopic Intracerebral Hemorrhage Evacuation: A Technical Report With Case Examples.

BACKGROUND: Multiple surgical techniques to perform minimally invasive intracerebral hemorrhage (ICH) evacuation are currently under investigation. The use of an adjunctive aspiration device permits controlled suction through an endoscope, minimizing collateral damage from the access tract. As with increased experience with any new procedure, performance of endoscopic minimally invasive ICH evacuation requires development of a unique set of operative tenets and techniques. OBJECTIVE: To describe operative nuances of endoscopic minimally invasive ICH evacuation developed at a single center over an experience of 80 procedures. METHODS: Endoscopic minimally invasive ICH evacuation was performed on 79 consecutive eligible patients who presented a single Health System between March 2016 and May 2018. We summarize 4 core operative tenets and 4 main techniques used in 80 procedures. RESULTS: A total of 80 endoscopic minimally invasive ICH evacuations were performed utilizing the described surgical techniques. The average preoperative and postoperative volumes were 49.5 mL (standard deviation [SD] 31.1 mL, interquartile range [IQR] 30.2) and 5.4 mL (SD 9.6, mL IQR 5.1), respectively, with an average evacuation rate of 88.7%. All cause 30-d mortality was 8.9%. CONCLUSION: As experience builds with endoscopic minimally invasive ICH evacuation, academic discussion of specific surgical techniques will be critical to maximizing its safety and efficacy.

Long-term functional outcome following minimally invasive endoscopic intracerebral hemorrhage evacuation.

BACKGROUND AND PURPOSE: Preclinical studies suggest that clot removal may mitigate primary and secondary brain injury following intracerebral hemorrhage (ICH). Although the MISTIE trial did not demonstrate an overall outcome benefit, it did demonstrate outcome benefit from effective reduction of clot burden. Minimally invasive endoscopic ICH evacuation may provide an alternative option for clot evacuation. METHODS: Patients presenting to a single healthcare system from December 2015 to October 2018 with supratentorial spontaneous ICH were evaluated for minimally invasive endoscopic evacuation. Inclusion and exclusion criteria were prospectively established by a multidisciplinary group in the healthcare system. The prespecified primary analysis was the proportion of patients with modified Rankin Score (mRS) 0-3 at 6 months. RESULTS: One hundred patients met the inclusion and exclusion criteria and underwent minimally invasive endoscopic ICH evacuation. The mean (SD) hematoma size was 49.7 (30.6) mL, the mean (SD) evacuation percentage was 88.2 (20.3)%, and 86% of patients had postoperative residual hematoma ≤15 mL. At 6 months the proportion of patients with an mRS of 0-3 was 46%. CONCLUSIONS: This study suggests that minimally invasive endoscopic ICH evacuation may produce favorable long-term functional outcomes. Further evaluation of this technique in a randomized clinical trial is necessary.