A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke.

BACKGROUND: The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS: We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS: The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS: In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.).

Diagnostic accuracy of an artificial intelligence algorithm versus radiologists for fracture detection on cervical spine CT.

OBJECTIVES: To compare diagnostic accuracy of a deep learning artificial intelligence (AI) for cervical spine (C-spine) fracture detection on CT to attending radiologists and assess which undetected fractures were injuries in need of stabilising therapy (IST). METHODS: This single-centre, retrospective diagnostic accuracy study included consecutive patients (age ≥18 years; 2007-2014) screened for C-spine fractures with CT. To validate ground truth, one radiologist and three neurosurgeons independently examined scans positive for fracture. Negative scans were followed up until 2022 through patient files and two radiologists reviewed negative scans that were flagged positive by AI. The neurosurgeons determined which fractures were ISTs. Diagnostic accuracy of AI and attending radiologists (index tests) were compared using McNemar. RESULTS: Of the 2368 scans (median age, 48, interquartile range 30-65; 1441 men) analysed, 221 (9.3%) scans contained C-spine fractures with 133 IST. AI detected 158/221 scans with fractures (sensitivity 71.5%, 95% CI 65.5-77.4%) and 2118/2147 scans without fractures (specificity 98.6%, 95% CI 98.2-99.1). In comparison, attending radiologists detected 195/221 scans with fractures (sensitivity 88.2%, 95% CI 84.0-92.5%, p < 0.001) and 2130/2147 scans without fracture (specificity 99.2%, 95% CI 98.8-99.6, p = 0.07). Of the fractures undetected by AI 30/63 were ISTs versus 4/26 for radiologists. AI detected 22/26 fractures undetected by the radiologists, including 3/4 undetected ISTs. CONCLUSION: Compared to attending radiologists, the artificial intelligence has a lower sensitivity and a higher miss rate of fractures in need of stabilising therapy; however, it detected most fractures undetected by the radiologists, including fractures in need of stabilising therapy. Clinical relevance statement The artificial intelligence algorithm missed more cervical spine fractures on CT than attending radiologists, but detected 84.6% of fractures undetected by radiologists, including fractures in need of stabilising therapy. KEY POINTS: The impact of artificial intelligence for cervical spine fracture detection on CT on fracture management is unknown. The algorithm detected less fractures than attending radiologists, but detected most fractures undetected by the radiologists including almost all in need of stabilising therapy. The artificial intelligence algorithm shows potential as a concurrent reader.

Intraductal fully covered self-expandable metal stent versus multiple plastic stents for treating biliary anastomotic strictures after liver transplantation.

BACKGROUND AND AIMS: Fully covered metal stents (FCSEMSs) are increasingly used for treatment of biliary anastomotic strictures (ASs) after liver transplantation (LT), requiring fewer endoscopic interventions than does treatment with multiple plastic stents (MPSs). Previous studies, however, have reported adverse events such as stent migration and pancreatitis. The intraductal FCSEMS (ID-FCSEMS) potentially avoids these disadvantages. This study aimed to assess the efficacy and safety of ID-FCSEMSs compared with MPSs for AS. METHODS: The cohorts of LT patients treated for AS with endoscopic stenting between 2010 and 2019 from 2 Dutch liver transplantation centers were retrospectively analyzed. Patients treated with ID-FCSEMSs or MPSs were included. RESULTS: 80 patients (44 with ID-FCSEMSs vs 36 with MPSs) were included, with a median follow-up time of 52 versus 64 months (P = .183). Stricture resolution was 93% in the ID-FCSEMS versus 97% in the MPS group (P = 1.000) after a median of 19 and 26 weeks, respectively (P = .031). The median number of ERCPs was 2 in the ID-FCSEMS group versus 4 in the MPS group (P < .001). Stricture recurrence occurred in 33% of ID-FCSEMS versus 29% of MPS patients (P = .653) after a median of 24 and 55 weeks (P = .403). Stent migration occurred in 16% of ID-FCSEMS versus 39% of MPS patients (P = .020). Post-ERCP fever was observed in 34% of ID-FCSEMS patients compared with 14% of MPS patients (P = .038). No significant differences were found in pancreatitis rate between the groups, being 6.8% for ID-FCSEMSs and 5.6% for MPSs (P = .816). CONCLUSION: ID-FCSEMSs for the treatment of AS after LT provides similar stricture resolution and recurrence rates as MPSs, though with a significant reduction of procedures needed.

Improvements in Endovascular Treatment for Acute Ischemic Stroke: A Longitudinal Study in the MR CLEAN Registry.

BACKGROUND: We evaluated data from all patients in the Netherlands who underwent endovascular treatment for acute ischemic stroke in the past 3.5 years, to identify nationwide trends in time to treatment and procedural success, and assess their effect on clinical outcomes. METHODS: We included patients with proximal occlusions of the anterior circulation from the second and first cohorts of the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry (March 2014 to June 2016; June 2016 to November 2017, respectively). We compared workflow times and rates of successful reperfusion (defined as an extended Thrombolysis in Cerebral Infarction score of 2B-3) between cohorts and chronological quartiles (all included patients stratified in chronological quartiles of intervention dates to create equally sized groups over the study period). Multivariable ordinal logistic regression was used to assess differences in the primary outcome (ordinal modified Rankin Scale at 90 days). RESULTS: Baseline characteristics were similar between cohorts (second cohort n=1692, first cohort n=1488) except for higher age, poorer collaterals, and less signs of early ischemia on computed tomography in the second cohort. Time from stroke onset to groin puncture and reperfusion were shorter in the second cohort (median 185 versus 210 minutes; P<0.001 and 236 versus 270 minutes; P<0.001, respectively). Successful reperfusion was achieved more often in the second than in the first cohort (72% versus 66%; P<0.001). Functional outcome significantly improved (adjusted common odds ratio 1.23 [95% CI, 1.07-1.40]). This effect was attenuated by adjustment for time from onset to reperfusion (adjusted common odds ratio, 1.12 [95% CI, 0.98-1.28]) and successful reperfusion (adjusted common odds ratio, 1.13 [95% CI, 0.99-1.30]). Outcomes were consistent in the analysis per chronological quartile. CONCLUSIONS: Clinical outcomes after endovascular treatment for acute ischemic stroke in routine clinical practice have improved over the past years, likely resulting from improved workflow times and higher successful reperfusion rates.

Endovascular Treatment for Acute Ischemic Stroke in Children: Experience From the MR CLEAN Registry.

BACKGROUND AND PURPOSE: Multiple trials have shown the efficacy and safety of endovascular therapy (EVT) of acute ischemic stroke in adults. Trials in children are lacking and only case reports and case series exist. However, the long-term outcome of children with acute ischemic stroke can be devastating with significant mortality and morbidity. In this study, we describe the safety and efficacy of EVT in children with anterior circulation acute ischemic stroke who were included in the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). METHODS: Patients under the age of 18 years who were treated with EVT for acute ischemic stroke between March 2014 and July 2017 were retrospectively reviewed up to 6 months after EVT. Nine children, aged 13 months to 16 years (median 14 years, interquartile range, 3-15 years), underwent EVT. Stroke cause was thromboembolism in children with end-stage heart failure on left ventricular assist device (4 of these 9 cases). Median time from onset to imaging was 133 minutes. Four children received intravenous alteplase before EVT, with median onset to needle time of 165 minutes. In all but one patient, EVT was technically successful. No major periprocedural complications occurred. RESULTS: At 24 hours after EVT, 3 children completely recovered and 4 children showed partial recovery (median National Institutes of Health Stroke Scale, 3.5), whereas 2 patients on left ventricular assist device died within the first week due to the occurrence of multiple strokes. One patient on left ventricular assist device developed a fatal massive intracranial hemorrhage and another child died due to left ventricular assist device-related complications. Among the 5 stroke survivors, all had a favorable outcome (modified Rankin Scale score, 0-2) at 6 months follow-up. CONCLUSIONS: EVT of children with acute ischemic stroke seems safe and feasible. However, these findings should be interpreted with caution as more and larger studies are needed to clarify the trade-off between risks and benefits of this treatment.

Renal nerve stimulation: complete versus incomplete renal sympathetic denervation.

PURPOSE: Blood pressure (BP) reduction after renal sympathetic denervation (RDN) is highly variable. Renal nerve stimulation (RNS) can localize sympathetic nerves. The RNS trial aimed to investigate the medium-term BP-lowering effects of the use of RNS during RDN, and explore if RNS can check the completeness of the denervation. MATERIAL AND METHODS: Forty-four treatment-resistant hypertensive patients were included in the prospective, single-center RNS trial. The primary study endpoint was change in 24-h BP at 6- to 12-month follow-up after RDN. The secondary study endpoints were the acute procedural RNS-induced BP response before and after RDN; number of antihypertensive drugs at follow-up; and the correlation between the RNS-induced BP increase before versus after RDN (delta [Δ] RNS-induced BP). RESULTS: Before RDN, the RNS-induced systolic BP rise was 43(±21) mmHg, and decreased to 9(±12) mmHg after RDN (p < 0.001). Mean 24-h systolic/diastolic BP decreased from 147(±12)/82(±11) mmHg at baseline to 135(±11)/76(±10) mmHg (p < 0.001/<0.001) at follow-up (10 [6-12] months), with 1 antihypertensive drug less compared to baseline. The Δ RNS-induced BP and the 24-h BP decrease at follow-up were correlated for systolic (R = 0.44, p = 0.004) and diastolic (R = 0.48, p = 0.003) BP. Patients with ≤0 mmHg residual RNS-induced BP response after RDN had a significant lower mean 24-h systolic BP at follow-up compared to the patients with >0 mmHg residual RNS-induced BP response (126 ± 4 mmHg versus 135 ± 10 mmHg, p = 0.04). 83% of the patients with ≤0 mmHg residual RNS-induced BP response had normal 24-h BP at follow-up, compared to 33% in the patients with >0 mmHg residual RNS-induced BP response (p = 0.023). CONCLUSION: The use of RNS during RDN leads to clinically significant and sustained lowering of 24-h BP with fewer antihypertensive drugs at follow-up. RNS-induced BP changes were correlated with 24-h BP changes at follow-up. Moreover, patients with complete denervation had significant lower BP compared to the patients with incomplete denervation.

A randomized trial of intraarterial treatment for acute ischemic stroke.

BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking. METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis). RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage. CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).

Renal nerve stimulation identifies aorticorenal innervation and prevents inadvertent ablation of vagal nerves during renal denervation.

PURPOSE: Recently we reported the use of renal nerve stimulation (RNS) during renal denervation (RDN) procedures. RNS induced changes in blood pressure (BP) and heart rate are not fully delineated yet. We hypothesized that electrical stimulation of the sympathetic nerve tissue in the renal artery would lead to an increase in BP and vagal stimulation would cause a decrease in BP. We report the different patterns of BP and heart rate responses elicited by RNS prior to RDN. METHODS: 35 patients with drug-resistant hypertension were included. RNS was performed under general anesthesia at four sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP and heart rate changes were monitored. RESULTS: A total of 289 RNS sites in 35 patients were analyzed. An increase in systolic BP of >10 mmHg was regarded as a positive BP response to RNS. This pattern of response was observed in 180 sites (62%). 86 RNS sites (30%) showed an indifferent response with BP changes ≤10 mmHg. At 13 sites (4.5%) RNS elicited a decrease in BP up to -8 mmHg. However, 10 RNS sites (3.5%) showed a pronounced vagal response with hypotension and sinus cycle lengths ranging between 4224-10272 milliseconds. These sites were distributed among two patients. CONCLUSION: RNS identified sympathetic and parasympathetic nerve tissue in the renal arteries. RNS can be potentially used to map nerve bundles and guide selective ablation of sympathetic nerve fibers and prevent inadvertent ablation of parasympathetic nerve tissue during RDN.

Association between serum brain-derived neurotrophic factor and plasma interleukin-6 in major depressive disorder with melancholic features.

Inflammatory processes as well as attenuation of brain-derived neurotrophic factor (BDNF) availability are involved in the pathophysiology of major depressive disorder (MDD). Although it is generally presumed that these two systems interact negatively in the brain, preclinical and human in vitro studies have shown synergistic rather than antagonistic interactions in the periphery. We therefore examined the association between serum levels of BDNF and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with MDD (n=1070) and non-depressed controls (n=379) from the Netherlands Study of Depression and Anxiety. We used multiple regression analyses with serum BDNF as the dependent variable and we specifically tested the presence of BDNF-cytokine associations in DSM-IV-assigned melancholic MDD patients, identified by the Inventory of Depressive Symptomatology. After adjustment for sociodemographics, sampling variability, lifestyle indicators, somatic diseases and medication use, BDNF levels were predicted by the interaction between MDD diagnosis and IL-6 (p-interaction=.006). Stratified analyses showed that BDNF levels are indeed positively associated with IL-6 levels in MDD patients (ß=.07, p=.02), but not in non-depressed controls (ß=-.07, p=.23). When further stratified for melancholic and non-melancholic MDD (p-interaction=.005), IL-6 emerged as a robust positive predictor of BDNF only in the melancholic sample (ß=.21, p=.01), wherein serum BDNF levels were accordingly enhanced. Post-hoc exploratory analyses verified an accentuated positive association of BDNF levels with leucocyte counts in melancholia. No significant associations emerged between BDNF and TNF-α. Overall, our cross-sectional approach may have disclosed an allostatic, BDNF-inducing component of peripheral immunity and/or an immunotrophic function of peripheral BDNF. Both scenarios may warrant further exploration, as they could inform new research concepts towards immune-based antidepressive treatment strategies.

Atherosclerosis decreases the impact of neuroticism in late-life depression: hypothesis of vascular apathy.

OBJECTIVE: To examine the interplay between subclinical atherosclerotic disease and neuroticism in explaining variance in late-life depressive symptoms. METHODS: This study was part of the Nijmegen Biomedical Study, a population-based survey; 1,517 participants aged 50-70 years were included. Depressive symptoms were measured by the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, representing a cognitive-affective symptom cluster and a somatic-affective symptom cluster. Atherosclerotic disease was measured by the intima media thickness (IMT) of the carotid arteries and neuroticism by the revised Eysenck Personality Questionnaire. RESULTS: Multiple linear regression analyses using different measures of depressive symptoms as the dependent variable showed that neuroticism was strongly and significantly associated with the sum score of the BDI and with the two depressive symptom clusters. IMT, however, was only significantly associated with the somatic-affective symptom cluster but not with the cognitive-affective symptom cluster. Interestingly, we found a significant negative interaction between neuroticism and IMT in explaining the severity of the cognitive-affective symptom cluster but not with respect to the somatic-affective symptom cluster. CONCLUSION: The negative interaction between neuroticism and atherosclerosis indicates that neuroticism is less strongly associated with cognitive-depressive symptoms in the presence of more severe atherosclerosis. This may be explained by apathy due to cerebrovascular disease and fits with a hypothesis of vascular apathy.

Increase in serum brain-derived neurotrophic factor in met allele carriers of the BDNF Val66Met polymorphism is specific to males.

BACKGROUND: Association studies of the Val66Met polymorphism and serum brain-derived neurotrophic factor (BDNF) levels have yielded conflicting results. Recently, sex-specific differences in BDNF levels were demonstrated. As these might explain the reported inconsistencies, we tested sex interactions with the Val66Met genotype on serum BDNF level. METHODS: Participants (n = 548, age range 50-72 years; mean 62.8 ± 5.4 years, 267 males) were tested for rs6265 genotype and serum BDNF levels [Hardy-Weinberg equilibrium (HWE), p = 0.04]. A regression analysis with BDNF level as the dependent variable and BDNF Val66Met genotype as an independent variable was used to test the sex interaction corrected for age, smoking and depressive symptoms. Subsequently, we examined the effect of genotype on BDNF levels stratified for sex. RESULTS: We found a significant interaction between sex and genotype on BDNF levels (p = 0.02). Male Met carriers had significantly higher BDNF levels than Val/Val homozygotes (ß = 0.17, p = 0.013), while in females no effect of Val66Met genotype was found (ß = -0.07, p = 0.28). CONCLUSION: Our findings may partly explain the inconsistent findings of earlier studies where results were influenced by male-female ratios. Replication is warranted, however, as our sample was not in HWE.

A systematic review and meta-analysis on the association between BDNF val(66)met and hippocampal volume--a genuine effect or a winners curse?

Inconsistenties have been reported with regard to an association between val(66)met, a polymorphism on the BDNF gene, and hippocampal volume. We performed a systematic review and a meta-analysis to determine the magnitude and direction of this putative association and estimated the potential influence of demographic, clinical, and methodological characteristics of studies. Tests of publication bias and time-related trends were performed and statistical power of the included studies was calculated. The literature search for MRI studies on differences in total hippocampal volume as a function of BDNF val(66)met returned 25 records that fulfilled our criteria (total N = 3,620). Meta-analysis showed that carriers of a met allele had lower hippocampal volumes relative to val/val homozygotes (d = 0.13, P = 0.02). Between-study heterogeneity in effect size estimates was substantial (Q = 54.47, P < .001) and this could not be explained by demographic, clinical, and methodological differences across studies. Funnel plot inspection and trim-and-fill estimations suggested evidence for publication bias and effect sizes decreased substantially over the years (Pearson's r = -0.54, P < .01). All included studies were underpowered. This meta-analysis shows that carriers of a met allele have lower total hippocampal volumes relative to val/val homozygotes. However, effect sizes converged closer to null with virtually each attempt at replication and were based on underpowered studies. Altogether, this may call into question whether the observed effect is a genuine biological effect of the met allele or whether it is subject to a winners curse, with large effect sizes found in a few early studies and increasingly smaller effect sizes in later studies.

Assessment of cervical spine CT scans by emergency physicians: A comparative diagnostic accuracy study in a non-clinical setting.

OBJECTIVES: To determine and compare the diagnostic accuracy of assessing injuries on cervical spine computed tomography (CT) scans by trained emergency physicians and radiologists, both in a non-clinical setting. METHODS: In this comparative diagnostic accuracy study, 411 cervical spine CT scans, of which 120 contained injuries (fractures and/or dislocations), were divided into 8 subsets. Eight emergency physicians received focused training and assessed 1 subset each before and after training. Four radiologists assessed 2 subsets each. Diagnostic accuracy between both groups was compared. The reference standard used was a multiverified data set, assessed by radiologists, neurosurgeons, and emergency physicians. The neurosurgeons also classified whether an "injury in need of stabilizing therapy" (IST) was present. RESULTS: Posttraining, the emergency physicians demonstrated increased sensitivity and specificity for identifying cervical spine injuries compared to pretraining: sensitivity 88% (95% confidence interval [CI] 80% to 93%) versus 80% (95% CI 72% to 87%) and specificity 89% (95% CI 85% to 93%) versus 86% (95% CI 81% to 89%). When comparing the trained emergency physicians to the group of radiologists, no difference in sensitivity was found, 88% (95% CI 80% to 83%); however, the radiologists showed a significantly higher specificity (P < 0.01): 99% (95% CI 96% to 100%). In the 12% (15 scans) with missed injuries, emergency physicians missed more ISTs than radiologists, 6 versus 4 scans; however, this difference was not significant (P = 0.45). CONCLUSION: After focused training and in a non-clinical setting, no significant difference was found between emergency physicians and radiologists in ruling out cervical spine injuries; however, the radiologists achieved a significantly higher specificity.

Bone visualization of the cervical spine with deep learning-based synthetic CT compared to conventional CT: A single-center noninferiority study on image quality.

PURPOSE: To investigate whether the image quality of a specific deep learning-based synthetic CT (sCT) of the cervical spine is noninferior to conventional CT. METHOD: Paired MRI and CT data were collected from 25 consecutive participants (≥ 50 years) with cervical radiculopathy. The MRI exam included a T1-weighted multiple gradient echo sequence for sCT reconstruction. For qualitative image assessment, four structures at two vertebral levels were evaluated on sCT and compared with CT by three assessors using a four-point scale (range 1-4). The noninferiority margin was set at 0.5 point on this scale. Additionally, acceptable image quality was defined as a score of 3-4 in ≥ 80% of the scans. Quantitative assessment included geometrical analysis and voxelwise comparisons. RESULTS: Qualitative image assessment showed that sCT was noninferior to CT for overall bone image quality, artifacts, imaging of intervertebral joints and neural foramina at levels C3-C4 and C6-C7, and cortical delineation at C6-C7. Noninferiority was weak to absent for cortical delineation at level C3-C4 and trabecular bone at both levels. Acceptable image quality was achieved for all structures in sCT and CT, except for trabecular bone in sCT and level C6-C7 in CT. Geometrical analysis of the sCT showed good to excellent agreement with CT. Voxelwise comparisons showed a mean absolute error of 80.05 (±6.12) HU, dice similarity coefficient (cortical bone) of 0.84 (±0.04) and structural similarity index of 0.86 (±0.02). CONCLUSIONS: This deep learning-based sCT was noninferior to conventional CT for the general visualization of bony structures of the cervical spine, artifacts, and most detailed structure assessments.

Blood Pressure During Endovascular Treatment Under Conscious Sedation or Local Anesthesia.

OBJECTIVE: To evaluate the role of blood pressure (BP) as mediator of the effect of conscious sedation (CS) compared to local anesthesia (LA) on functional outcome after endovascular treatment (EVT). METHODS: Patients treated in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry centers with CS or LA as preferred anesthetic approach during EVT for ischemic stroke were analyzed. First, we evaluated the effect of CS on area under the threshold (AUT), relative difference between baseline and lowest procedural mean arterial pressure (∆LMAP), and procedural BP trend, compared to LA. Second, we assessed the association between BP and functional outcome (modified Rankin Scale [mRS]) with multivariable regression. Lastly, we evaluated whether BP explained the effect of CS on mRS. RESULTS: In 440 patients with available BP data, patients treated under CS (n = 262) had larger AUTs (median 228 vs 23 mm Hg*min), larger ∆LMAP (median 16% vs 6%), and a more negative BP trend (-0.22 vs -0.08 mm Hg/min) compared to LA (n = 178). Larger ∆LMAP and AUTs were associated with worse mRS (adjusted common odds ratio [acOR] per 10% drop 0.87, 95% confidence interval [CI] 0.78-0.97, and acOR per 300 mm Hg*min 0.89, 95% CI 0.82-0.97). Patients treated under CS had worse mRS compared to LA (acOR 0.59, 95% CI 0.40-0.87) and this association remained when adjusting for ∆LMAP and AUT (acOR 0.62, 95% CI 0.42-0.92). CONCLUSIONS: Large BP drops are associated with worse functional outcome. However, BP drops do not explain the worse outcomes in the CS group.

A panel of subunit-selective activity-based proteasome probes.

Mammals express seven different catalytically active proteasome subunits. In order to determine the roles of the different proteolytically active subunits in antigen presentation and other cellular processes, highly specific inhibitors and activity-based probes that selectively target specific active sites are needed. In this work we present the development of fluorescent activity-based probes that selectively target the beta1 and beta5 sites of the constitutive proteasome.

Renal sympathetic denervation induces changes in heart rate variability and is associated with a lower sympathetic tone.

BACKGROUND: Renal nerve stimulation (RNS) is used to localize sympathetic nerve tissue for selective renal nerve sympathetic denervation (RDN). Examination of heart rate variability (HRV) provides a way to assess the state of the autonomic nervous system. The current study aimed to examine the acute changes in HRV caused by RNS before and after RDN. METHODS AND RESULTS: 30 patients with hypertension referred for RDN were included. RNS was performed under general anesthesia before and after RDN. Heart rate (HR) and blood pressure (BP) were continuously monitored. HRV characteristics were assessed 1 min before and after RNS and RDN. RNS before RDN elicited a maximum increase in systolic BP of 45 (± 22) mmHg which was attenuated to 13 (± 12) mmHg (p < 0.001) after RDN. RNS before RDN decreased the sinus cycle length from 1210 (± 201) ms to 1170 (± 203) ms (p = 0.03), after RDN this effect was blunted (p = 0.59). The LF/HF ratio in response to RNS changed from ∆ + 0.448 (± 0.550) before RDN to ∆ - 0.656 (± 0.252) after RDN (p = 0.02). Selecting patients off beta-blockade (n = 11), the RNS-induced changes in HRV components before versus after RDN were more pronounced (LF/HF ratio ∆ + 0.900 ± 1.171 versus ∆ - 0.828 ± 0.519, p = 0.01), whereas changes in HRV parameters in patients on beta-blockade (n = 19) were no longer significant. In patients with diabetes mellitus (n = 7), RNS induced no changes in HRV parameters (LF/HF ratio ∆ - 0.039 ± 0.103 versus ∆ - 0.460 ± 0.491, p = 0.92). CONCLUSION: RNS induces changes in HRV suggesting increased sympathetic activity. Conversely, after RDN, the RNS-induced changes in HRV suggesting a lower sympathetic autonomic balance. These changes were most pronounced in beta-blocker naïve patients and not present in patients with diabetes mellitus. These findings could support RNS-guided RDN to optimize results.

Changes in arterial pressure hemodynamics in response to renal nerve stimulation both before and after renal denervation.

BACKGROUND: Renal nerve denervation (RDN) is developed as a potential treatment for hypertension. Recently, we reported the use of renal nerve stimulation (RNS) to localize sympathetic nerve tissue for subsequent selective RDN. The effects of RNS on arterial pressure dynamics remain unknown. The current study aimed to describe the acute changes in arterial pressure dynamics response to RNS before and after RDN. METHODS AND RESULTS: Twenty six patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia before and after RDN. We continuously monitored heart rate (HR) and invasive femoral blood pressure (BP). Augmentation pressure (AP) and index (Aix), pulse pressure (PP), time to reflected wave, maximum systolic BP and dicrotic notch were calculated. Systolic and diastolic BP at site of maximum response significantly increased in response to RNS (120 ± 16/62 ± 9 to 150 ± 22/75 ± 15 mmHg) (p < 0.001/< 0.001), whereas after RDN no RNS-induced BP change was observed (p > 0.10). RNS increased Aix (29 ± 11 to 32 ± 13%, p = 0.005), PP (59 ± 14 to 75 ± 17 mmHg, p < 0.001), time to reflected wave (63 ± 18 to 71 ± 25 ms, p = 0.004) and time to maximum systolic pressure (167 ± 36 to 181 ± 46 ms, p = 0.004) before RDN, whereas no changes were observed after RDN (p > 0.18). All changes were BP dependent. RNS had no influence on HR or the time to dicrotic notch (p > 0.12).   CONCLUSION: RNS induces temporary rises in Aix, PP, time to maximum systolic pressure and time to reflected wave. These changes are BP dependent and were completely blunted after RDN.

Treatment of atrial fibrillation in patients with enhanced sympathetic tone by pulmonary vein isolation or pulmonary vein isolation and renal artery denervation: clinical background and study design : The ASAF trial: ablation of sympathetic atrial fibrillation.

BACKGROUND: Hypertension is an important, modifiable risk factor for the development of atrial fibrillation (AF). Even after pulmonary vein isolation (PVI), 20-40% experience recurrent AF. Animal studies have shown that renal denervation (RDN) reduces AF inducibility. One clinical study with important limitations suggested that RDN additional to PVI could reduce recurrent AF. OBJECTIVE: The goal of this multicenter randomized controlled study is to investigate whether RDN added to PVI reduces AF recurrence. METHODS: The main end point is the time until first AF recurrence according to EHRA guidelines after a blanking period of 3 months. Assuming a 12-month accrual period and 12 months of follow-up, a power of 0.80, a two-sided alpha of 0.05 and an expected drop-out of 10% per group, 69 patients per group are required. We plan to randomize a total of 138 hypertensive patients with AF and signs of sympathetic overdrive in a 1:1 fashion. Patients should use at least two antihypertensive drugs. Sympathetic overdrive includes obesity, exercise-induced excessive blood pressure (BP) increase, significant white coat hypertension, hospital admission or fever induced AF, tachycardia induced AF and diabetes mellitus. The interventional group will undergo PVI + RDN and the control group will undergo PVI. RESULTS: Patients will have follow-up for 1 year, and continuous loop monitoring is advocated. CONCLUSION: This randomized, controlled study will elucidate if RDN on top of PVI reduces AF recurrence.