An integrated molecular risk score early in life for subsequent childhood asthma risk.

BACKGROUND: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.

CXCR4 - a possible serum marker for risk stratification of abdominal aortic aneurysms.

Background: Abdominal aortic aneurysm (AAA) rupture is still associated with a mortality rate of 80-90%. Imaging techniques or molecular fingerprinting for patient-specific risk stratification to identify pending rupture are still lacking. The chemokine (C-X-C motif) receptor (CXCR4) activation by CXCL12 ligand has been identified as a marker of inflammation and atherosclerosis, associated with AAA. Both are highly expressed in the aortic aneurysm wall. However, it is still unclear whether different expression levels of CXCR4 and CXCL12 can distinguish ruptured AAAs (rAAA) from intact AAAs (iAAA). Patients and methods: Abdominal aortic tissue samples (rAAA: n=29; iAAA: n=54) were excised during open aortic repair. Corresponding serum samples from these patients (n=9 from rAAAs; n=47 from iAAA) were drawn pre-surgery. Healthy aortic tissue samples (n=8) obtained from adult kidney donors during transplantation and serum samples from healthy adult volunteers were used as controls (n=5 each). Results: CXCR4 was mainly expressed in the media of the aneurysmatic tissue. Focal positive staining was also observed in areas of inflammatory infiltrates within the adventitia. In tissue lysates, no significant differences between iAAA, rAAA, and healthy controls were observed upon ELISA analysis. In serum samples, the level of CXCR4 was significantly increased in rAAA by 4-fold compared to healthy controls (p=0.011) and 3.0-fold for rAAA compared to iAAA (p<0.001). Furthermore a significant positive correlation between aortic diameter and serum CXCR4 concentration was found for both, iAAA and rAAA (p=0.042). Univariate logistic regression analysis showed that increased CXCR4 serum concentrations were associated with AAA rupture (OR: 4.28, 95% CI: 1.95-12.1, p=0.001). Conclusions: CXCR4 concentration was significantly increased in serum of rAAA patients and showed a significant correlation with an increased aortic diameter. The level of CXCR4 in serum was associated with a more than 4-fold risk increase for rAAA and thus could possibly serve as a biomarker in the future. However, further validation in larger studies is required.

Mitogen-activated protein kinase signaling in childhood asthma development and environment-mediated protection.

BACKGROUND: While childhood asthma prevalence is rising in Westernized countries, farm children are protected. The mitogen-activated protein kinase (MAPK) pathway with its negative regulator dual-specificity phosphatase-1 (DUSP1) is presumably associated with asthma development. OBJECTIVES: We aimed to investigate the role of MAPK signaling in childhood asthma and its environment-mediated protection, including a representative selection of 232 out of 1062 children from two cross-sectional cohorts and one birth cohort study. METHODS: Peripheral blood mononuclear cells (PBMC) from asthmatic and healthy children were cultured upon stimulation with farm-dust extracts or lipopolysaccharide. In subgroups, gene expression was analyzed by qPCR (PBMCs, cord blood) and NanoString technology (dendritic cells). Protein expression of phosphorylated MAPKs was measured by mass cytometry. Histone acetylation was investigated by chromatin immunoprecipitation. RESULTS: Asthmatic children expressed significantly less DUSP1 (p = .006) with reduced acetylation at histone H4 (p = .012) compared with healthy controls. Farm-dust stimulation upregulated DUSP1 expression reaching healthy levels and downregulated inflammatory MAPKs on gene and protein levels (PBMCs; p ≤ .01). Single-cell protein analysis revealed downregulated pMAPKs upon farm-dust stimulation in B cells, NK cells, monocytes, and T-cell subpopulations. CONCLUSION: Lower DUSP1 baseline levels in asthmatic children and anti-inflammatory regulation of MAPK in several immune cell types by farm-dust stimulation indicate a regulatory function for DUSP1 for future therapy contributing to anti-inflammatory characteristics of farming environments.

Acute abdominal aortic occlusion: A 16-year single-center experience.

BACKGROUND: Acute abdominal aortic occlusion (AAO) is a rare vascular emergency associated with high morbidity and mortality. In the present study, we analyzed the clinical management and outcomes for a consecutive patient series during a 16-year period. METHODS: We included all patients with an acute AAO and bilateral acute limb ischemia who had been treated between 2004 and 2019. Patients with dissection, aneurysm rupture, or chronic occlusive disease were excluded. The patient characteristics, surgical procedures, and outcomes were extracted retrospectively from a prospective aortic database, electronic patient files, and outpatient examination records. The extent of ischemia was classified according to the TASC II (Inter-Society Consensus for the Management of Peripheral Arterial Disease) section on acute limb ischemia. The primary endpoints were 30-day mortality (safety endpoint) and the combined 6-month amputation and/or death rate (efficacy endpoint). The follow-up outcomes, amputation rates, and 30-day complications were evaluated as secondary endpoints. The patient cohort was divided into four 4-year groups (2004-2007, 2008-2011, 2012-2015, 2016-2019) to assess the outcome changes over time. Statistical analysis included χ2 tests and univariate and linear regression analyses. RESULTS: A total of 74 patients (57% male; median age, 64.5 years) with an acute AAO were identified. Arterial thrombosis was the most common etiology (66%). The extent of ischemia was TASC I, IIa, IIb, and III in 7%, 39%, 40%, and 14%, respectively. The patient numbers had increased significantly over time (P = .016). Of the patients, 42% had undergone open transfemoral recanalization (including hybrid procedures), 35% open aortic surgery, 15% extra-anatomic bypass surgery, and 5% (four patients) endovascular therapy alone. The overall 30-day mortality rate was 23%, and the 6-month amputation and/or death rate was 43%. The 30-day mortality rate had declined significantly from 54% for 2004 to 2007 to 10% for 2011 to 2015 (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.001-0.52) and 20% for 2016 to 2019 (OR, 0.21; 95% CI, 0.05-0.90), a statistically nonsignificant trend showing that the relative decline in the use of open aortic procedures was associated with decreased 30-day mortality (P = .06). Univariate analysis indicated that elevated serum lactate on admission (OR, 3.33; 95% CI, 1.06-10.48) and an advanced stage of limb ischemia (OR, 4.33), were strongly associated with an increased 30-day mortality rate. The incidence of severe postoperative systemic complications also indicated a greater incidence of both primary endpoints. The 6-month amputation and/or mortality rates were also affected by the presence of atrial fibrillation (OR, 3.63; 95% CI, 1.34-9.79) and increased patient age (OR, 3.96; 95% CI, 1.49-10.53). CONCLUSIONS: Acute AAO remains a life-threatening emergency. Immediate transfemoral open or endovascular techniques should be preferred, if technically possible and proper intraoperative imaging is available.

Editor's Choice - Distribution of Care and Hospital Incidence of Carotid Endarterectomy and Carotid Artery Stenting: A Secondary Analysis of German Hospital Episode Data.

OBJECTIVE: This is a description of the German healthcare landscape regarding carotid artery disease, assessment of hospital incidence time courses for carotid endarterectomy (CEA) and carotid artery stenting (CAS), and simulation of potential effects of minimum hospital caseload requirements for CEA and CAS. METHODS: The study is a secondary data analysis of diagnosis related group statistics data (2005-2016), provided by the German Federal Statistical Office. Cases encoded by German operation procedure codes for CEA or CAS and by International Classification of Diseases (ICD-10) codes for carotid artery disease were included. Hospitals were categorised into quartiles according to annual caseloads. Linear distances to the closest hospital fulfilling hypothetical caseload requirements were calculated. RESULTS: A total of 132 411 and 33 709 patients treated with CEA and CAS from 2012 to 2016 were included. CEA patients had lower rates of myocardial infarction (1.4% vs. 1.8%) and death (1.2% vs. 4.0%), and CAS patients were more often treated after emergency admission (38.1% vs. 27.1%). Age standardised annual hospital incidences were 67.2 per 100 000 inhabitants for CEA and 16.3 per 100 000 inhabitants for CAS. The incidence for CEA declined from 2005 to 2016, with CAS rising again until 2016 after having declined from 2010 to 2013. Regarding distance from home to hospital, centres offering CEA are distributed more homogeneously across Germany, compared with those performing CAS. Hypothetical introduction of minimum annual caseloads (> 20 for CEA; > 10 for CAS) imply that 75% of the population would reach their hospital after travelling 45 km for CEA and 70 km for CAS. CONCLUSION: Differences in spatial distribution mean that statutory minimum annual caseloads would have a greater impact on CAS accessibility than CEA in Germany. Presumably because of a decline in carotid artery disease and a transition towards individualised therapy for asymptomatic patients, hospital incidence for CEA has been declining.

[Relationship between regional settlement structure and hospital incidence, type of therapy and mortality of non-ruptured abdominal aortic aneurysms]. / Zusammenhang zwischen der regionalen Siedlungsstruktur und der Krankenhausinzidenz, Therapieform und Mortalität von nicht-rupturierten abdominalen Aortenaneurysmen. Sekundärdatenanalyse der deutschen DRG-Statistik von 2005­2014.

INTRODUCTION: In Germany, the regional settlement structure is heterogenous, ranging from densely populated cities with a tight network of vascular health care to large regions in which access to health care is limited in terms of space and time. Therefore, the aim of this secondary data analysis was to investigate the association between the settlement structure of the patient's home district (KT), and the hospital incidence, type of therapy, and mortality of non-ruptured abdominal aortic aneurysms (nrAAA). METHODS: The microdata of the DRG statistics of the Federal Statistical Office for the years 2005-2014 were evaluated. All patients with nrAAA (ICD-10 Code I71.4) who were admitted to a German hospital and treated by open surgery and endovascular repair were included. Classification of treatment was based on the German Operation and Procedure Code. Patients were grouped according to the settlement structure of their home district defined by the Federal Institute for Research on Building, Urban Affairs and Spatial Development (KT1 independent city, KT2 urban district, KT3 rural district, KT4 sparsely populated region). The age-, sex- and risk-adjusted association between the type of settlement structure and in-hospital mortality was analysed using a multivariable multi-level regression model. The Elixhauser co-morbidity score validated for administrative data was used for risk adjustment. RESULTS: Of 95,452 cases included, 88 % were men. Mean age was 72 years. There were 28,970 (30 %) patients in KT1, 37,759 (40 %) in KT2, 14,442 (15 %) in KT3 and 14,281 (15 %) in KT4. The hospital incidence was 12.4 per 100,000 inhabitants in KT1, 11.8 in KT2, 10.8 in KT3 and 11.2 in KT4 (p <0.001, falling trend). The proportion of EVAR treatment was 56 % in KT1, 54 % in KT2, 57 % KT3, and 59 % in KT4 (p <0.001, increasing trend). The raw hospital mortality of patients from KT1 to KT4 was 3.4 %, 3.4 %, 3.2 % and 3.6 %, respectively (p=0.553 for trend). The multivariable regression analysis revealed no statistically significant association between the KT and hospital mortality (KT1=reference, RR KT2=0.97 [95% CI 0.79-1.15], RR KT3=0.98 [0.81-1.14], RR KT4=0.98 [0.86-1.11]). CONCLUSIONS: The study shows that both the hospital incidence and the type of therapy (endovascular vs. open) differed between the settlement structural district types, but there is no urban-rural gap regarding in-hospital mortality of treated nrAAA.

Childhood asthma: Novel endotyping by cytokines, validated through sensitization profiles and clinical characteristics.

BACKGROUND: Specific allergy sensitization pattern, using "component-resolved diagnosis" (CRD), is a central component of allergy and asthma in childhood. Besides this, allergic asthma has been characterized by a Th2-shifted endotype with elevation of classical Th2 cytokines. Recently, other endotypes with distinct mechanisms focusing on cytokine regulation evolved, yet those pathways are still not well understood. OBJECTIVE: (a) To define reproducible immunological endotypes using cytokine expression in an asthma cohort and (b) to characterize their sensitization profile and clinical phenotype. METHODS: Supernatants from PBMCs of 234 children (median age 10 years) of an asthma cohort were analysed for cytokine expressions. The children were split into a training (n = 49) and validation (n = 185) group. The training group was used to identify immunological endotypes by clustering cytokine expressions, which were then assessed regarding clinical characteristics and specific IgE of recombinant allergen components. Next, our findings were validated in the validation group. RESULTS: We identified novel endotypes based on primarily unstimulated cytokine expression. One endotype showed an IFN-γ/Interleukin (IL)-17/IL-5 predominance, a different sensitization pattern (high in birch/apple; p < .01), and inferior lung function (p < .01). A second endotype grouped young children with food allergy and reduced lung function. Our findings were reproducible in the validation group. CONCLUSION AND CLINICAL RELEVANCE: We identified two novel clinical asthma endotypes via cytokine expression pattern with distinct sensitization patterns. These novel findings are critical for clinical guidance and open avenues for identifying underlying mechanisms and more patient-specific therapies.

Screening cardiovascular patients for aortic aneurysms (SCAN) - high prevalence of abdominal aortic aneurysms in coronary heart disease patients requiring intervention.

Background: Since the prevalence of abdominal aortic aneurysms (AAA) in Europe has declined to about 2.5%, general screening programs of elderly men are being called into question. On the other hand, other vascular diseases (e.g. coronary heart disease, CHD) are associated with a higher prevalence of AAA. This might have an impact on future targeted AAA screening programs. This study aimed to reevaluate the current prevalence of AAA in male patients with CHD, in order to assess whether CHD patients should be offered a targeted AAA ultrasound screening program. Patients and methods: The SCAN (Screening Cardiovascular Patients for Aortic Aneurysms) study prospectively evaluated the AAA prevalence in 1000 consecutive male CHD patients (70.1 ± 11.2 years) requiring any coronary intervention at an university hospital. All patients received transverse and longitudinal ultrasound scans of the abdominal aorta. Aortic diameter was assessed using the outer-to-outer measurement-technique. Primary endpoint was the prevalence of AAA. Secondary outcomes included stratification in 1-, 2-, or 3-vessel CHD. Results: AAA was detected in 85 patients (median diameter 38 mm, range 30-80 mm), corresponding to an overall prevalence of 8.5%. AAA prevalence was significantly associated with CHD severity: 5.6% in 1-vessel, 7.1% in 2-vessel, and 10.8% in 3-vessel CHD (P = 0.037). The multivariable analysis showed, that age per 10 years increase (OR 1.5, 95% CI 1.2-1.9, P = 0.001) and hyperlipidemia (OR 2.2, 95% CI 1.3-3.8, P = 0.003) were significantly associated with an AAA. The likelihood to be diagnosed with an AAA was significantly lower in non-smokers (OR 0.24, 95% CI, P < 0.001). Conclusions: This study confirms that CHD requiring any type of coronary intervention is strongly associated with AAA in male patients. AAA prevalence increases with CHD severity. Since the AAA prevalence is still significantly higher than in the general population, targeted ultrasound screening should be considered for all CHD patients.

Early and Midterm Outcomes of Open and Endovascular Revascularization of Chronic Mesenteric Ischemia.

BACKGROUND: Revascularization strategies for chronic mesenteric ischemia (CMI) include open (OR) and endovascular (ER) modalities. The primary objective of this study was to analyze the safety and effectiveness of OR and ER and the impact of clinical and morphological variables on early and midterm outcomes in a consecutive series of CMI patients in a tertiary referral center. PATIENTS AND METHODS: From 2004 to 2017, all CMI patients treated with OR and ER were retrospectively identified. Patient records, preoperative imaging, as well as peri- and postoperative outcomes were analyzed. Univariable and multivariable analysis was performed to identify clinical or morphological variables affecting reintervention rates within 2 years. RESULTS: In total, 63 patients (33% male; mean age 71, range 60-76 years) were treated by ER (41 patients) or OR (22 patients) for CMI. Mean follow-up was 26 (10-71) months. 30-day mortality was 0.0% after ER and 4.5% after OR (p = 0.069); 30-day morbidity was 9.8% vs. 31.8%, respectively (p = 0.030). Length of stay was significantly longer after OR (14 vs. 4 days; p < 0.001). Freedom from reintervention rate after 2 years was 82% after OR and 73% after ER (p = 0.14). Overall survival did not differ after 2 years (OR 85% vs. ER 86%; p = 0.35). Multivariable analysis revealed that smoking was associated with higher risk of reintervention (hazard ratio, HR: 4.14; 95% confidence interval, CI 1.11-15.53; p = 0.03). Additionally, a nonsignificant trend of lower reintervention rates after OR was detected (HR 0.23 95% CI 0.05-1.08; p = 0.06). CONCLUSION: Due to a lower invasiveness, despite the higher reintervention rate, an "endovascular first" strategy is justified and recommended.

Prospective Comparison of Duplex Ultrasound and Angiography for Intra-operative Completion Studies after Carotid Endarterectomy.

OBJECTIVE: The application of intra-operative completion studies may have contributed to the ongoing improvement of peri-operative outcomes in carotid surgery. METHODS: This prospective study aimed to compare angiography and duplex ultrasound (IDUS) as intra-operative completion studies after carotid endarterectomy (CEA) with respect to differences in the rating of vessel wall defects and interobserver reliability. Patients undergoing CEA for symptomatic or asymptomatic carotid stenosis were included. After CEA, angiography and IDUS were performed. Intra-operatively obtained video footage was evaluated at a later date by three independent and blinded raters with different levels of clinical experience. Rating was done according to a four step rating scale, with higher grades representing more severe defects. Standard statistical methods (Pearson's chi square test; permutation test; Wilcoxon signed rank test; Kendall's coefficient of concordance, Wt) were applied. RESULTS: In total, 150 patients (mean ± standard deviation age 72 ± 7 years, 68.7% male, 33.3% symptomatic) were enrolled between March 2016 and September 2017. Significantly more defects requiring intra-operative revision (grades 3 and 4 on rating scale) were detected by IDUS, which, in part, remained undetected by angiography: 22 (14.7%) vs. 10 (6.7%) (p = .040). Defects were also judged to be more severe with IDUS than with angiography: median rating grade 1: 74 (49.3%) vs. 102 (68.0%); grade 2: 54 (36.0%) vs. 38 (25.3%); grade 3: 21 (14.0%) vs. 9 (6.0%); grade 4: 1 (0.7%) vs.1 (0.7%) (p < .001). Furthermore, Wt was significantly higher for IDUS compared with angiography (0.70 vs. 0.57; p = .003). CONCLUSION: IDUS revealed more defects after CEA than angiography. Despite both techniques only showing moderate interobserver reliability, IDUS is less dependent on the surgeon's subjectivity than angiography. Taking into account the absence of procedure associated risks (i.e., adverse effects of iodinated contrast media and Xray), IDUS could be considered as an alternative intra-operative morphological assessment tool in carotid surgery.

Effect Modification of Sex and Age for the Hospital Volume-Outcome Relationship in Abdominal Aortic Aneurysm Treatment: Secondary Data Analysis of the Nationwide German Diagnosis Related Groups Statistics From 2005 to 2014.

Background Trials and registries associated female sex and high age with unfavorable outcomes in abdominal aortic aneurysm treatment. Many studies showed an inverse correlation between annual hospital volume and in-hospital mortality. The volume-outcome relationship has not been investigated separately for women and men or across the age range. The aim was to analyze whether sex and age are effect modifiers or confounders of the volume-outcome association. Methods and Results In a nationwide setting, all in-hospital cases from 2005 to 2014 with a diagnosis of intact abdominal aortic aneurysm and procedure codes for endovascular or open aortic repair were included. Primary outcome was in-hospital mortality. Using a multilevel multivariable regression model, hospital volume was modeled as a continuous variable. Separate analyses were performed for women and men and for predefined age groups. A total of 94 966 cases were included (12% women; median age, 72 years). Mortality was 4.9% in women and 3.0% in men (3.2% overall). Mortality increased with age. Although there was no significant volume-outcome association in women (P=0.57), there was in men (P=0.02). The strongest volume-outcome association was found in younger men. The younger female subpopulation was found to show a trend for an inverse volume-outcome relationship, whereas an opposite association was found for the women aged >79 years. Conclusions Women have a higher mortality risk after elective abdominal aortic aneurysm treatment. Sex and age are modifiers of the volume-outcome relationship. Unlike in male patients, in women there is no consistent effect of hospital volume on outcome.

The Effects of Minimum Caseload Requirements on Management and Outcome in Abdominal Aortic Aneurysm Repair.

BACKGROUND: The German quality assurance guideline on abdominal aortic aneurysm (AAA) was implemented by the Joint Federal Committee (Gemeinsamer Bundesausschuss, G-BA) in 2008. The aims of this study were to verify the association between hospital case volume and outcome and to assess the hypothetical effect of minimum caseload requirements. METHODS: The German diagnosis-related groups statistics for the years 2012 to 2016 were scrutinized for AAA (ICD-10 GM I71.3/4) with procedure codes for endo - vascular or open surgical treatment. The primary endpoint was in-hospital mortality. Logistic regression models were used for risk adjustment, and odds ratios (OR) were calculated as a function of the annual hospital-level case volume of AAA. In a hypo - thetical approach, the linear distances for various minimum caseloads (MC) were evaluated to assess accessibility. RESULTS: The mortality of intact AAA (iAAA) was 2.7% (men [M] 2.4%, women [W] 4.2%); ruptured AAA (rAAA), 36.9% (M 36.9%, F 37.5%). An inverse relationship between annual hospital case volume of AAA and mortality was confirmed (iAAA/rAAA: from 3.9%/51% [<10 cases/year] through 3.3%/37% [30-39 cases/year] to 1.9%/28% [≥ 75 cases/year]). For a reference category of 30 AAA procedures/year, the following significant OR were found: 10 AAA cases/year, OR 1.21 (95% confidence interval [1.20; 1.21]); 20 cases, OR 1.09 [1.09; 1.09]; 50 cases, OR 0.89 [0.89; 0.89]; 75 cases, OR 0.82 [0.82; 0.82]. In a hypothetical centralization scenario with assumed MC of 30/year, 86% of the population would have to travel less than 100 km to the nearest hospital; with an MC of 40, this would apply to only 50% (without redistribution effects). CONCLUSION: In the observed period, a significant correlation was confirmed between high annual case volume and low in-hospital mortality. A minimum caseload requirement of 30 AAA operations/year seems reasonable in view of the accessibility of hospitals. Cite this.

Regional variation in endovascular treatment rate and in-hospital mortality of abdominal aortic aneurysms in Germany.

Background: Abdominal aortic aneurysms (AAA) can be treated by either open surgery (OAR) or endovascular aortic repair (EVAR). The aim of this study was to analyze regional variations in application of (EVAR) and in-hospital mortality after intact AAA (iAAA) repair. Methods: Using data provided by the German Federal Statistical Office, a nationwide analysis for 2012 to 2014 was conducted. Patients with a diagnosis of iAAA (I71.4) and corresponding procedure codes for OAR (5-384.5/7) or EVAR (5-38a.1) were included. Odds ratios (ORs) for use of EVAR (proportion of EVAR among total EVAR + OAR cases) and mortality were calculated for all regions in Germany. ORs for EVAR use were adjusted for age, sex, and risk (Elixhauser score). ORs for mortality were additionally adjusted for type of procedure (OAR/EVAR). Results: Finally, 31,757 procedures for iAAA were included. Median age of all patients was 73 years (interquartile range 67-78 years) and 87.1 % were male. The mean proportion of EVAR procedures was 72.6 %; however, the application of EVAR for repair of iAAA varied widely depending on region. The lowest unadjusted regional rate of EVAR use was 48.8 %, while the highest was 92.5 %. After adjustment, the lowest regional OR for EVAR use (compared to the nationwide mean) was 0.23 (95 % confidence interval [0.15-0.36]), the highest 5.93 [1.79-19.65]. Overall in-hospital mortality was 2.9 % (OAR 6.2 %; EVAR 1.7 %). The adjusted regional OR for mortality ranged from 0.31 [0.07-1.42] to 4.98 [2.08-11.93]. Conclusions: This study reveals variations in use of EVAR and in-hospital mortality for iAAA treatment in Germany. This may imply that selection of treatment might not only be influenced by patient characteristics, but also by regional location. These results need to be taken into account when discussing centralization of AAA treatment in Germany.

Associations of Perioperative Variables With the 30-Day Risk of Stroke or Death in Carotid Endarterectomy for Symptomatic Carotid Stenosis.

Background and Purpose- This analysis was performed to assess the association between perioperative and clinical variables and the 30-day risk of stroke or death after carotid endarterectomy for symptomatic carotid stenosis. Methods- Individual patient-level data from the 5 largest randomized controlled carotid trials were pooled in the Carotid Stenosis Trialists' Collaboration database. A total of 4181 patients who received carotid endarterectomy for symptomatic stenosis per protocol were included. Determinants of outcome included carotid endarterectomy technique, type of anesthesia, intraoperative neurophysiological monitoring, shunting, antiplatelet medication, and clinical variables. Stroke or death within 30 days after carotid endarterectomy was the primary outcome. Adjusted risk ratios (aRRs) were estimated in multilevel multivariable analyses using a Poisson regression model. Results- Mean age was 69.5±9.2 years (70.7% men). The 30-day stroke or death rate was 4.3%. In the multivariable regression analysis, local anesthesia was associated with a lower primary outcome rate (versus general anesthesia; aRR, 0.70 [95% CI, 0.50-0.99]). Shunting (aRR, 1.43 [95% CI, 1.05-1.95]), a contralateral high-grade carotid stenosis or occlusion (aRR, 1.58 [95% CI, 1.02-2.47]), and a more severe neurological deficit (mRS, 3-5 versus 0-2: aRR, 2.51 [95% CI, 1.30-4.83]) were associated with higher primary outcome rates. None of the other characteristics were significantly associated with the perioperative stroke or death risk. Conclusions- The current results indicate lower perioperative stroke or death rates in patients operated upon under local anesthesia, whereas a more severe neurological deficit and a contralateral high-grade carotid stenosis or occlusion were identified as potential risk factors. Despite a possible selection bias and patients not having been randomized, these findings might be useful to guide surgeons and anesthetists when treating patients with symptomatic carotid disease.

Hospital Incidence and In-Hospital Mortality of Surgically and Interventionally Treated Aortic Dissections: Secondary Data Analysis of the Nationwide German Diagnosis-Related Group Statistics From 2006 to 2014.

Background Population-based data about the incidence and mortality of patients with aortic dissections ( ADs ) are sparse. Therefore, the hospital incidence and in-hospital mortality of patients undergoing open or endovascular surgery for type A ADs ( TAADs ) and type B ADs ( TBADs ) in Germany were analyzed on a nationwide basis between 2006 and 2014. Methods and Results A secondary data analysis of the nationwide diagnosis-related group statistics, compiled by the German Federal Statistical Office, was performed for patients who were surgically/interventionally treated for AD ( International Classification of Diseases, Tenth Revision, German Modification [ ICD -10- GM] codes I71.00-I71.07; n=20 533). By using specific procedure codes, a distinction between TAAD (n=14 911/72.6%) and TBAD (n=5622/27.4%) could be made. The standardized hospital incidence of surgically/interventionally treated AD was 2.7/100 000 per year, comprising 2.0/100 000 per year for TAAD and 0.7/100 000 per year for TBAD . The in-hospital mortality of TAAD was 19.5%; and of TBAD, 9.3%. Both the incidence and in-hospital mortality increased over the 9-year period. The share of endovascularly treated TBAD increased steadily during the same time interval. A multilevel multivariable analysis revealed that, for TAAD , age and comorbidity were significantly associated with a higher mortality risk. The latter was also true for TBAD . Sex was not significantly associated with mortality. A significant association between higher annual center volume and mortality was found for TAAD , but not for TBAD . Conclusions This is the first report on hospital incidence and mortality for surgically/interventionally treated AD on a nationwide basis. Overall, in Germany, hospital incidence and mortality of TAAD and TBAD increased over time. In addition, TAAD is performed more safely in high-volume centers.

Quality appraisal of systematic reviews, and meta-analysis of the hospital/surgeon-linked volume-outcome relationship of carotid revascularization procedures.

INTRODUCTION: Several systematic reviews and meta-analyses of primary studies have been published on the relationship between annual case load of carotid endarterectomy (CEA) and carotid artery stenting (CAS) performed at hospital level or by individual surgeons, and perioperative outcomes. Many studies on volume-outcome relationship have already been published and high-quality systematic reviews are crucial for further guideline development. EVIDENCE ACQUISITION: Systematic reviews and meta-analyses on the relationship between hospital or surgeon CEA/CAS volume and periprocedural outcomes were identified through a systematic literature search of Medline, Web of Science, and the Cochrane Database of Systematic Reviews. Methodological quality of the systematic reviews was appraised using the AMSTAR2 tool independently by two authors. Systematic reviews were aggregated in their volume-outcome findings. Quantitative data from primary studies included in the systematic reviews were synthesized. Additionally, volume definitions and the time point of outcome assessment used in primary studies were analyzed. EVIDENCE SYNTHESIS: In total, five systematic reviews published between 2000 and 2018 were identified, each comprising 11-25 primary studies. Methodological quality appraisal of these reviews revealed high quality for only the most recent review, low quality for three reviews, and critically low quality in one review. Aggregation of the systematic reviews revealed a significant inverse relationship between hospital/operator volume and the periprocedural risk of death or stroke following CEA. For CAS, high operator volume was associated with lower outcome rates. Regarding hospital volume, an inverse but non-significant relationship between CAS hospital volume and outcome rate was found. In our synthesis of primary studies from these systematic reviews an inverse CEA hospital and operator volume relationship was present for stroke or death and for CAS for hospital volume, respectively. A high heterogeneity regarding the definitions of volume categories, and of time points assessing outcomes was apparent. CONCLUSIONS: For CEA, high quality aggregated evidence revealed an inverse relationship between hospital/surgeon CEA volume and periprocedural rate of stroke or death. The same was true for operator linked CAS volume. Regarding hospital linked CAS volume, no unequivocal evidence was found. Additionally, heterogeneity was found regarding volume definition, and time of outcome assessment. Thus, future studies should aim to harmonize volume definitions and outcome time points.

Editor's Choice - Hospital Incidence, Treatment, and In Hospital Mortality Following Open and Endovascular Surgery for Thoraco-abdominal Aortic Aneurysms in Germany from 2005 to 2014: Secondary Data Analysis of the Nationwide German DRG Microdata.

OBJECTIVE: Hospital incidence, treatment modality, and in hospital mortality after surgery are reported for thoraco-abdominal aortic aneurysms (TAAAs) treated by endovascular or open means in Germany from 2005 to 2014. METHODS: Data were extracted from diagnosis related group statistics from the German Federal Statistical Office. All inpatient cases with a diagnosis of ruptured and non-ruptured TAAA (ICD-10 I71.5 and I71.6) and procedure codes for fenestrated or branched endovascular aortic repair (f/bEVAR 5-38a.7x and 5-38a.8x), open aortic repair (OAR 5-384.4), or hybrid procedure (5-384.b/c, 5-38a.a/b/8/80) were included. To adjust for sex, age, medical risk (Elixhauser comorbidity score), type of procedure, and type of admission, a multilevel multivariable regression model with robust error variance was applied. The primary outcome was in hospital mortality; secondary outcomes were organ complications. The relationship between annual hospital volume and outcome was analysed. RESULTS: A total of 2607 cases (406 rTAAA, 2201 nrTAAA) were included. f/bEVAR was performed in 856 cases (32.8%), OAR in 1422 cases (54.5%), and hybrid repair in 354 cases (13.6%). Endovascular repair became more frequent over time (6% in 2005 vs. 76% in 2014 for nrTAAA). Hypertension (75.2%), peripheral artery disease (including abdominal aortic aneurysm, 49.5%), other heart diseases (44.6%), coronary heart disease (30.6%), and renal failure (28.7%) were the most frequently coded comorbidities. The number of hospitals treating TAAAs almost tripled within 9 years. The in hospital mortality was 46.1% for rTAAA and 15.9% for nrTAAA. f/bEVAR (RR 0.35, 0.24-0.51) and high hospital volume (p < .001) were significantly associated with decreased in hospital mortality. Aortic rupture, increasing age, and comorbidity were significantly associated with higher mortality (RR 3.17, 2.45-4.09; 1.52, 1.32-1.76, and 1.05, 1.04-1.06). CONCLUSIONS: Seventy-six percent of all TAAAs were treated endovascularly in 2014 with increasing frequency over a decade. In hospital mortality is lower with endovascular repair and in high volume centres. Aortic rupture, age, and severe comorbidities are associated with worse outcomes.

Increasing Incidence of Thoracic Aortic Aneurysm Repair in Germany in the Endovascular Era: Secondary Data Analysis of the Nationwide German DRG Microdata.

OBJECTIVES: Nationwide population based data on epidemiology and surgical treatment of descending thoracic aortic (DTA) aneurysms are not available for Germany. The aim was to assess the in hospital incidence, and to report outcomes of patients who received surgical treatment. METHODS: Data were acquired by analysing the diagnosis related group (DRG) statistics of the German Federal Statistical Office. All inpatient cases of ruptured (rDTA aneurysm, ICD Code I71.1) or non-ruptured DTA aneurysm (nrDTA aneurysm; I71.2) who received thoracic endovascular (TEVAR; OPS procedure code 5-38a.7/70/8/80) or open aortic repair (OAR; OPS 5-384.3) between 2005 and 2014 were included. To adjust for sex, age, medical risk (Elixhauser comorbidity score), type of procedure, and type of admission, a multilevel multivariable regression model with robust error variance was applied. The primary outcome was in hospital mortality; secondary outcomes were organ complications. A volume outcome analysis was performed. RESULTS: A total of 48,098 cases of DTA aneurysm (5,848, 12.2% rDTA aneurysm) were identified. The average age was 69 ± 12 years. 65.2% were male. Frequent comorbidities were hypertension (74.9%), peripheral artery disease (including abdominal aortic aneurysm, 42.6%), other heart diseases (41.6%), coronary heart disease (26.2%), and renal failure (22.5%). Surgical treatment was received by 4969 patients (10.3%): 4057 TEVAR (81.6%) and 912 OAR (18.4%) procedures. Mortality for rDTA aneurysm was 42.9% (OAR) and 22.3% (TEVAR). It was 10.5% and 3.7% for DTA aneurysm, respectively. Rupture, increasing age, and higher comorbidity score were significantly associated with higher mortality (RR 6.66, 5.33-8.25; 1.28, 1.17-1.40; and 1.06, 1.05-1.08, respectively). Endovascular treatment was associated with lower mortality (RR 0.31, 0.23-0.41). Hospital volume was not significantly associated with in hospital mortality. CONCLUSIONS: Eighty per cent of patients treated surgically for a DTA aneurysm receive endovascular therapy, with low peri-operative mortality in non-ruptured cases. Elective endovascular repair should be considered for individuals at a high risk of rupture who are fit for surgery. Open repair, increased age, and a high comorbidity score are associated with higher mortality.

Open Versus Endovascular Repair of Isolated Iliac Artery Aneurysms.

PURPOSE:: Outcomes of open iliac artery repair (OIR) and endovascular iliac artery repair (EVIR) were compared at a tertiary referral vascular center. METHODS:: From 2004 to 2015, all patients treated for isolated iliac artery aneurysms (IAAs) were retrospectively identified, and patient records and computed tomography (CT) scans were analyzed. The primary end point was overall survival; secondary end points were 30-day mortality and morbidity and freedom from reintervention. For follow-up, data from outpatient visits and CT scans following a standard surveillance protocol were used. RESULTS:: A total of 106 IAAs in 94 patients were treated (mean follow-up: 35.7 months; 66 OIR; 40 EVIR). Six (15%) aneurysms from the EVIR group and 4 (6.1%) from open-operated IAA presented in the state of rupture. There was no difference in overall survival between EVIR and OIR ( P = .14). In multivariable analysis, higher risk of death was associated with ruptured IAA (rIAA; hazard ratio [HR]: 40.44, 95% confidence interval [CI]: 2.05-796.18; P = .02) and coronary heart disease (HR: 11.07, 95% CI: 1.94-63.36; P < .01). The 30-day mortality was 1.9% overall (0% OIR, 5.0% EVIR, P = .27), but there were no differences between OIR and EVIR in 30-day morbidity ( P = .11). Freedom from reintervention was higher for OIR than for EVIR ( P < .01). In multivariable analysis, a higher reintervention rate was seen in EVIR (HR: 10.80, 95% CI: 2.20-53.01; P < .01) and in rIAA (HR: 12.02, 95% CI: 1.31-111.11; P = .03). CONCLUSION:: Iliac artery aneurysmss can be safely and effectively treated by EVIR or OIR regarding 30-day morbidity, mortality, and long-term survival, although freedom from reintervention is significantly lower after EVIR.

Spatial Analysis of Hospital Incidence and in Hospital Mortality of Abdominal Aortic Aneurysms in Germany: Secondary Data Analysis of Nationwide Hospital Episode (DRG) Data.

OBJECTIVE: This study aimed to analyze the spatial distribution and regional variation of the hospital incidence and in hospital mortality of abdominal aortic aneurysms (AAA) in Germany. METHODS: German DRG statistics (2011-2014) were analysed. Patients with ruptured AAA (rAAA, I71.3, treated or not) and patients with non-ruptured AAA (nrAAA, I71.4, treated by open or endovascular aneurysm repair) were included. Age, sex, and risk standardisation was done using standard statistical procedures. Regional variation was quantified using systematic component of variation. To analyse spatial auto-correlation and spatial pattern, global Moran's I and Getis-Ord Gi* were calculated. RESULTS: A total of 50,702 cases were included. Raw hospital incidence of AAA was 15.7 per 100,000 inhabitants (nrAAA 13.1; all rAAA 2.7; treated rAAA 1.6). The standardised hospital incidence of AAA ranged from 6.3 to 30.3 per 100,000. Systematic component of variation proportion was 96% in nrAAA and 55% in treated rAAA. Incidence rates of all AAA were significantly clustered with above average values in the northwestern parts of Germany and below average values in the south and eastern regions. Standardised mortality of nrAAA ranged from 1.7% to 4.3%, with that of treated rAAA ranging from 28% to 52%. Regional variation and spatial distribution of standardised mortality was not different from random. CONCLUSIONS: There was significant regional variation and clustering of the hospital incidence of AAA in Germany, with higher rates in the northwest and lower rates in the southeast. There was no significant variation in standardised (age/sex/risk) mortality between counties.