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Cerebral arteriovenous malformations (AVMs) are complex vascular lesions at perpetual risk for rupture, which can lead to significant morbidity and mortality. This study sought to evaluate the dynamic relationship between comorbidities and post-procedure complications to quantify the risk of poor discharge outcomes to create a predictive outcomes model.The National Inpatient Sample (NIS) data from 2012 to 2015 was queried for AVM treatment using International Classification of Diseases, Ninth Revision codes. The Neurovascular Comorbidities Index (NCI) quantified patient comorbidity burden. In-hospital complications included surgical and medical complications or seizures. The primary outcome was the NIS Subarachnoid Hemorrhage Outcome Measure (NIS-SOM).A total of 1363 patients were included. A total of 1330 patients (98%) underwent embolization, 28 (2%) underwent resection, and 9 (0.7%) underwent radiosurgery. A higher NCI was associated with the occurrence of any complication (odds ratio [OR], 1.30 if NCI = 2; P lt; 0.001). Higher NCI was also significantly associated with a poor NIS-SOM outcome (OR, 2.45 if NCI = 2 and no complications; P lt; 0.001). A ruptured AVM with intracranial hemorrhage (ICH) increased the risk of in-hospital complications (OR, 2.16; P = 0.007) and a poor NIS-SOM outcome (OR, 3.18; P lt; 0.001). Various hypothetical patient scenarios and the predicted outcomes are also presented.Neurovascular comorbidities have a significant impact on poor functional outcomes at discharge in patients with and without complications following procedural management of AVMs. At the time of initial patient assessment, risk stratification strategies should take into account neurovascular comorbidities and potential complications. Such an approach would ultimately optimize patient outcomes and increase the value of care provided.

OBJECTIVEOpen and endoscope-assisted repair are surgical options for sagittal craniosynostosis, with limited research evaluating each technique’s immediate and long-term costs. This study investigates the cost-effectiveness of open and endoscope-assisted repair for single, sagittal suture craniosynostosis.METHODSThe authors performed a retrospective cohort study of patients undergoing single, sagittal suture craniosynostosis repair (open in 17 cases, endoscope-assisted in 16) at less than 1 year of age at Monroe Carell Jr. Children’s Hospital at Vanderbilt (MCJCHV) between August 2015 and August 2017. Follow-up data were collected/analyzed for 1 year after discharge. Surgical and follow-up costs were derived by merging MCJCHV financial data with each patient’s electronic medical record (EMR) and were adjusted for inflation using the healthcare Producer Price Index. Proxy helmet costs were derived from third-party out-of-pocket helmet prices. To account for variable costs and probabilities, overall costs were calculated using TreeAge tree diagram software.RESULTSOpen repair occurred in older patients (mean age 5.69 vs 2.96 months, p < 0.001) and required more operating room time (median 203 vs 145 minutes, p < 0.001), more ICU days (median 3 vs 1 day, p < 0.001), more hospital days (median 4 vs 1 day, p < 0.001), and more frequently required transfusion (88% vs 6% of cases). Compared to patients who underwent open surgery, patients who underwent endoscopically assisted surgery more often required postoperative orthotic helmets (100% vs 6%), had a similar number of follow-up clinic visits (median 3 vs 3 visits, p = 0.487) and CT scans (median 3 vs 2 scans), and fewer emergency department visits (median 1 vs 3 visits). The TreeAge diagram showed that, overall, open repair was 73% more expensive than endoscope-assisted repair ($31,314.10 vs $18,081.47). Sensitivity analysis identified surgical/hospital costs for open repair (mean $30,475, SEM $547) versus endoscope-assisted repair (mean $13,746, SEM $833) (p < 0.001) as the most important determinants of overall cost. Two-way sensitivity analysis comparing initial surgical/hospital costs confirmed that open repair remains significantly more expensive under even worst-case initial repair scenarios ($3254.81 minimum difference). No major surgical complications or surgical revisions occurred in either cohort.CONCLUSIONSThe results of this study suggest that endoscope-assisted craniosynostosis repair is significantly more cost-effective than open repair, based on markedly lower costs and similar outcomes, and that the difference in initial surgical/hospital costs far outweighs the difference in subsequent costs associated with helmet therapy and outpatient management, although independent replication in a multicenter study is needed for confirmation due to practice and cost variation across institutions. Longer-term results will also be needed to examine whether cost differences are maintained.

We aim to define the dynamic interplay between neurovascular-specific comorbidities and in-hospital complications on outcomes (functional outcome and mortality), length of stay (LOS), and cost of hospital stay.The 2012-2015 National Inpatient Sample (NIS) was queried for intracranial aneurysm treatment after subarachnoid hemorrhage using International Classification of Diseases, Ninth Revision codes. Neurovascular comorbidity index (NCI) was aggregated. NIS-Subarachnoid Hemorrhage Severity Score (NIS-SSS) was used as a Hunt-Hess grade proxy. In-hospital complications were medical complications, surgical complications, seizures, and cerebral vasospasm. Outcomes were functional outcome (modified Rankin Scale [mRS]-equivalent measure), in-hospital mortality, LOS, and cost. Multivariable logistic regression models were built for mRS equivalent and in-hospital mortality. Multivariable linear regression models in log scale were built for LOS and cost.A total of 5353 patients were included. The median NCI was 4.00 (interquartile range [IQR], 0.00-7.00) and 2882 patients (54%) had in-hospital complication. Higher NCI (odds ratio [OR], 1.13 if NCI = 1; OR, 2.05 if NCI = 7; P0.001) was associated with any complication, seizure (OR, 1.11, NCI = 1; OR, 1.60, NCI = 7; P0.001), medical complication (OR, 1.18, NCI = 1; OR, 2.50, NCI = 7; P0.001), surgical complication (OR, 1.13, NCI = 1; OR, 1.91, NCI = 7; P0.001), and cerebral vasospasm (OR, 1.09, NCI = 1; OR, 1.49, NCI = 7; P0.001). Patients with higher NCI (OR, 1.06, NCI = 1; OR, 1.95, NCI = 7; P0.001) or with in-hospital complication (P0.001) had poorer mRS equivalent outcome. Similar trends were observed for other outcomes including in-hospital mortality, LOS, and cost.Neurovascular comorbidities are the primary driver of poor mRS equivalent outcome, in-hospital mortality, higher LOS, and higher cost after ruptured intracranial aneurysm procedural treatment. The conditional event of complication influences patients with moderate comorbidities more so than those with low or high comorbidities.

This study investigates the relationship between neurovascular comorbidities and in-hospital complications in determining functional outcome, mortality, length of stay (LOS), and cost of stay.Patients were identified from the 2012-2015 National Inpatient Sample (NIS) using International Classification of Diseases, Ninth Revision codes for unruptured intracranial aneurysm (UIA) treatment in patients without subarachnoid hemorrhage. In-hospital complications were divided into medical complications, surgical complications, and seizures. Primary outcomes were functional outcome measured by modified Rankin Scale (mRS)-equivalent measure, in-hospital mortality, LOS, and cost. Multivariable logistic regression models were built for mRS-equivalent and in-hospital mortality. Multivariable linear regression models in log scale were built for LOS and cost.A total of 7398 procedurally managed patients with UIA were included (median age, 58 years; 75% female; 66% white; 43% private insurance). Higher Neurovascular Comorbidities Index (NCI) was associated with seizure (odds ratio [OR], 1.11 if NCI = 1; OR, 2.49 if NCI = 7; P 0.001), medical complication (OR, 1.21, NCI = 1; OR, 3.46, NCI = 7; P0.001), and surgical complication (OR, 1.25, NCI = 1; OR, 3.47, NCI = 7; P0.001). NCI remained significantly predictive of poor mRS-equivalent outcome (OR, 1.20, NCI = 1; OR, 5.79, NCI = 7; P0.001), in-hospital mortality (OR, 1.98, NCI = 1; OR, 10.9, NCI = 7; P0.001), LOS (coefficient dependent on multiple variables, P 0.001), and cost (coefficient dependent on multiple variables, P0.001) after adjustment.Neurovascular comorbidities are the primary driver of poor mRS-equivalent outcome, in-hospital mortality, higher LOS, and higher cost after procedural treatment of UIA. The conditional event of complication influences patients with fewer comorbidities more so than those with no comorbidities or high comorbidities. It is imperative to precisely account for these factors to optimize targeted resource allocation and increase the value of care for patients with UIA.

BackgroundIdentifying drivers of nationwide variation in healthcare costs could help reduce overall cost. Endovascular treatment for unruptured cerebral aneurysms (ETUCR) is an elective neurointerventional procedure that allows for detailed analysis of cost variation. This study aimed to investigate the role of insurance type in cost variation of ETUCR.MethodsA retrospective analysis of patients undergoing ETUCR was done. Demographic and hospital data were obtained from the National Inpatient Sample 2012–2015. Multivariate analysis was done using a generalized linear model. Oaxaca–Blinder decomposition was performed to identify factors driving cost variation.ResultsThere was a significant difference in median cost ($25 331.82 vs $25 825.25, respectively, PConclusionsIn patients aged 65–75 years, private insurance is associated with higher costs compared to Medicare; however, insurance type is not predictive of increased cost in multivariate analysis. Differential treatment of private insurance and Medicare patients at hospitals with greater operative volume seems to influence this difference, likely due to differential reimbursement schemes that lead to weaker cost controls.

Introduction The National Inpatient Sample (NIS) has led to several breakthroughs via large sample size. However, utility of NIS is limited by the lack of admission NIHSS and 90-day modified Rankin score (mRS). This study creates estimates for stroke severity at admission and 90-day mRS using NIS data for acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). Methods Three patient cohorts undergoing MT for AIS were utilized: Cohort 1 (N = 3729) and Cohort 3 (N = 1642) were derived from NIS data. Cohort 2 (N=293) was derived from a prospectively-maintained clinical registry. Using Cohort 1, Administrative Stroke Outcome Variable (ASOV) was created using disposition and mortality. Factors reflective of stroke severity were entered into a stepwise logistic regression predicting poor ASOV. Odds ratios were used to create the Administrative Data Stroke Scale (ADSS). Performances of ADSS and ASOV were tested using Cohort 2 and compared with admission NIHSS and 90-day mRS, respectively. ADSS performance was compared with All Patient Refined-Diagnosis Related Group (APR-DRG) severity score using Cohort 3. Results Agreement of ASOV with 90-day mRS > 2 was fair (κ = 0.473). Agreement with 90-day mRS > 3 was substantial (κ = 0.687). ADSS significantly correlated (p 15. ADSS performed comparably (AUC = 0.749) to admission NIHSS (AUC = 0.697) in predicting 90-day mRS > 2 and mRS > 3 (AUC = 0.767, 0.685, respectively). ADSS outperformed APR-DRG severity score in predicting poor ASOV (AUC = 0.698, 0.682, respectively). Conclusion We developed and validated measures of stroke severity at admission (ADSS) and outcome (ASOV, estimate for 90-day mRS > 3) to increase utility of NIS data in stroke research.

Aims Postural tachycardia syndrome (POTS), a common and debilitating cardiovascular disorder, is characterized by an exaggerated heart rate increase during orthostasis and a wide spectrum of adrenergic-related symptoms. To determine the aetiology of POTS, we examined a possible pathophysiological role for autoantibodies against α1-adrenergic (α1AR) and β1/2-adrenergic receptors (β1/2AR). Methods and results Immunoglobulin G (IgG) derived from 17 POTS patients, 7 with recurrent vasovagal syncope (VVS), and 11 normal controls was analysed for its ability to modulate activity and ligand responsiveness of α1AR and β1/2AR in transfected cells and to alter contractility of isolated rat cremaster arterioles in vitro. Immunoglobulin G activation of α1AR and β1/2AR was significantly higher in POTS compared with VVS and controls in cell-based assays. Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively. Pharmacological blockade suppressed IgG-induced activation of α1AR and β1/2AR. Eight of 17 POTS IgG decreased the α1AR responsiveness to phenylephrine and 13 of 17 POTS IgG increased the β1AR responsiveness to isoproterenol irrespective of their ability to directly activate their receptors. Postural tachycardia syndrome IgG contracted rat cremaster arterioles, which was reversed by α1AR blockade. The upright heart rate correlated with IgG-mediated β1AR and α1AR activity but not with β2AR activity. Conclusion These data confirm a strong relationship between adrenergic autoantibodies and POTS. They support the concept that allosteric-mediated shifts in the α1AR and β1AR responsiveness are important in the pathophysiology of postural tachycardia.

Background Both the adrenergic and renin‐angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome ( POTS ). Activating autoantibodies to the α1‐adrenergic and β1/2‐adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor ( AT 1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT 1R autoantibodies in POTS . Methods and Results Serum immunoglobulin G from 17 patients with POTS , 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT 1R and alter AT 1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT 1R antibody activity in immunoglobulin G purified from their serum. No significant AT 1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT 1R activation by POTS immunoglobulin G was specifically blocked by the AT 1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT 1R and α1‐adrenergic receptor. Conclusions Most patients with POTS harbor AT 1R antibody activity. This supports the concept that AT 1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS .

OBJECTIVEMany studies have aimed to determine the most clinically effective surgical intervention for hydrocephalus. However, the costs associated with each treatment option are poorly understood. In this study, the authors conducted a cost-effectiveness analysis, calculating the incremental cost-effectiveness ratio (ICER) of ventriculoperitoneal shunting (VPS), endoscopic third ventriculostomy (ETV), and ETV with choroid plexus cauterization (ETV/CPC) in an effort to better understand the clinical effectiveness and costs associated with treating hydrocephalus.METHODSThe study cohort includes patients under the age of 18 who were initially treated for hydrocephalus between January 2012 and January 2015 at the authors’ institution. Overall treatment costs were calculated using patient-level hospitalization costs and professional fees reimbursable to the hospital and directly related to the initial and follow-up (postoperative day 1 to 12 months) treatment of hydrocephalus. TreeAge Pro was used to conduct the cost-effectiveness analyses.RESULTSA total of 147 patients were identified. Based on the initial intervention for hydrocephalus, their cases were classified as follows: 113 VPS, 14 ETV, and 20 ETV/CPC. During the initial intervention, VPS patients required a longer length of stay at 5.6 days, compared to ETV/CPC (3.35 days) and ETV (2.36 days) patients. Failure rates for all treatment options ranged from 29% to 45%, leading to recurrent hydrocephalus and additional surgical intervention between postoperative day 1 and 12 months. Cost-effectiveness analyses found ETV to be less costly and more clinically effective, with an ICER of $94,797 compared to VPS ($130,839) and ETV/CPC ($126,394). However, when stratified by etiology, VPS was found to be more clinically effective and cost-effective in both the myelomeningocele and posthemorrhagic hydrocephalus patient groups with an incremental cost per clinical unit of effectiveness (success or failure of intervention) of $76,620 compared to ETV and ETV/CPC. However, when assessing cases categorized as “other etiologies,” ETV was found to be more cost-effective per clinical unit, with an ICER of $60,061 compared to ETV/CPC ($93,350) and VPS ($142,135).CONCLUSIONSThis study is one of the first attempts at quantifying the patient-level hospitalization costs associated with surgical management of hydrocephalus in pediatric patients treated in the United States. The results indicate that the conversation regarding CSF diversion techniques must be patient-specific and consider etiology as well as any previous surgical intervention. Again, these findings are short-run observations, and a long-term follow-up study should be conducted to assess the cost of treating hydrocephalus over the lifetime of a patient.

Activating autoantibodies to the angiotensin type 1 receptor (AT1R) are associated with hypertensive disorders. The angiotensin type 2 receptor (AT2R) is known to counter-regulate the actions of AT1R. We investigated whether AT2R autoantibodies produced in immunized rabbits will activate AT2R and suppress the vasopressor responses to angiotensin II and AT1R-activating autoantibodies. Five rabbits immunized with a peptide corresponding to the second extracellular loop of AT2R developed high AT2R antibody titers. Rabbit anti-AT2R sera failed to directly dilate isolated rat cremaster arterioles; however, when co-perfused with angiotensin II or AT1R-activating autoantibodies, the anti-AT2R sera significantly inhibited their contractile effects. Rabbit anti-AT2R sera recognized a predominant sequence near the N-terminus of the AT2R second extracellular loop. A decoy peptide based on this sequence effectively reversed the opposing effect of the anti-AT2R sera on angiotensin II–induced contraction of rat cremaster arterioles. A similar blockade of the anti-AT2R sera effect was observed with the AT2R antagonist PD 123319 and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Rabbit anti-AT2R sera reacted specifically with AT2R. No cross-reactivity with AT1R was observed. Blood pressure did not change in immunized animals. However, the pressor responses to incremental angiotensin II infusions were blunted in immunized animals. Thirteen subjects with primary aldosteronism demonstrated increased AT2R autoantibody levels compared with normal controls. In conclusion, AT2R autoantibodies produced in immunized rabbits have the ability to activate AT2R and counteract the AT1R-mediated vasoconstriction. These autoantibodies provide useful and selective tools for the study of their roles in blood pressure regulation and possible therapeutic intervention.

Activating autoantibodies to the angiotensin II type 1 receptor (AT1R) have been implicated in hypertensive disorders. We investigated whether AT1R antibodies produced in immunized rabbits will activate AT1R and contribute to hypertension by a direct contractile effect on the vasculature and whether they can be blocked by a novel decoy peptide. A multiple antigenic peptide containing the AT1R epitope AFHYESQ, which is the receptor-binding epitope of AT1R-activating autoantibodies, was used to immunize 6 rabbits. AT1R antibody activity was analyzed in AT1R-transfected cells, and their contractile effects were assayed using isolated perfused rat cremaster resistance arterioles. A retro-inverso d -amino acid epitope-mimetic peptide was tested for AT1R antibody inhibition in vitro and in vivo. All immunized animals produced high AT1R antibody titers and developed elevated blood pressure. No changes in measured blood chemistry values were observed after immunization. Rabbit anti-AT1R sera induced significant AT1R activation in transfected cells and vasoconstriction in the arteriole assay, both of which were blocked by losartan and the retro-inverso d -amino acid peptide. A single intravenous bolus injection of the retro-inverso d -amino acid peptide (1 mg/kg) into immunized rabbits dropped the mean arterial pressure from 122±11 to 82±6 mm Hg. Rabbit anti-AT1R sera partially suppressed angiotensin II–induced contraction of isolated rat cremaster arterioles, and the pressor response to angiotensin II infusion was attenuated in immunized animals. In conclusion, AT1R-activating autoantibodies and the retro-inverso d -amino acid peptide, respectively, have important etiologic and therapeutic implications in hypertensive subjects who harbor these autoantibodies.

We have previously demonstrated that activating autoantibodies to β1-adrenergic receptor (β1AR) and M2 muscarinic receptor (M2R) facilitate atrial fibrillation (AF) in patients with Graves’ disease (GD). The objectives of this expanded study were to examine the prevalence of β1AR, β2AR, and M2R autoantibodies in hyperthyroidism subjects. Sera from 81 patients including 31 with GD and AF, 36 with GD and sinus rhythm, 9 with toxic multinodular goiter, 5 with subacute thyroiditis, and 10 control subjects were examined for these autoantibodies by ELISA. Sera from 20 ELISA-positive GD subjects, 10 with AF and 10 with sinus rhythm, were assayed for autoantibody bioactivity using cell-based bioassays. In patients with GD and AF, 45, 65, and 77 % were ELISA positive for β1AR, M2R, and β2AR autoantibodies, respectively. In patients with GD and sinus rhythm, 17, 39, and 75 % were ELISA positive for β1AR, M2R, and β2AR autoantibodies, respectively. β1AR and M2R autoantibodies were co-present in 39 % of patients with GD and AF compared to 14 % in GD with sinus rhythm (p = 0.026). Patients with toxic multinodular goiter or subacute thyroiditis had a low prevalence of autoantibodies. The mean β1AR and M2R autoantibody activity was elevated in both GD groups but higher in those with AF than those with sinus rhythm. β2AR autoantibody activity was also increased in both groups. In conclusion, β1AR, β2AR, and M2R autoantibodies were elevated in GD. β1AR and M2R autoantibodies appear to be related to concurrent AF, while β2AR autoantibodies were equally prevalent in those with a sinus tachycardia and those with AF.

Background Patients with postural tachycardia syndrome ( POTS ) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS . We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors ( AR ). Methods and Results Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P P cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells. Conclusions POTS patients have elevated α1 AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1 AR for vasoconstriction and concurrent β AR ‐mediated tachycardia. Coexisting β1 AR and β2 AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.

Agonistic autoantibodies to the β-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by ELISA in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 of the patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for β2 receptor activation and β-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of β2 and M3 receptors in the patient group compared with controls. A dose response was observed for both IgG activation of β2 and M3 receptors and inhibition of their activation with the nonselective β blocker propranolol and muscarinic blocker atropine. The antibody effects on β2 and/or M3 (via production of NO) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented β2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the β-blocker propranolol and the NO synthase inhibitor N G -nitro- l -arginine methyl ester partially inhibited IgG-induced vasodilation (percentage of maximal dilatory response: from 57.7±10.4 to 35.3±4.6 and 24.3±5.8, respectively; P