Quality indicators in cranial neurosurgery: current insights and critical evaluation - a systematic review.

In recent decades, there has been increasing interest in measuring the quality of care across all medical fields, including neurosurgery. This interest aims not only to optimize care but also to reduce healthcare costs. For this purpose, different quality indicators (QIs) have been developed. We performed a systematic review according to the PRISMA guidelines aiming at identifying studies that critically evaluate QIs applied in cranial neurosurgery. A total of 34 studies, suggesting 22 indicators, were identified. The most discussed indicator was the 30-day readmission rate, followed by the 30-day reoperation rate. The majority of QIs are influenced by baseline and underlying patient characteristics, reflecting the severity of the patient`s underlying disease, rather than adherence to best available evidence of treatment. Therefore, it is crucial to implement adequate risk adjustment strategies when applying QIs to compensate for differences in patient complexity and to ensure that departments that are treating high-risk patients do not have worse results. The review revealed several limitations of the currently used quality indicators. Most suggested indicators are attractive from a payer point of view, easy to measure and therefore convenient for reimbursement purposes. However, from a clinician's point of view, most indicators were considered poor performance markers as they do not correlate with meaningful outcome and do not reflect treatment quality. In addition, there is a lack of disease- and neurosurgery specific indicators. This highlights the need for clinicians to actively participate in developing more clinically relevant QIs tailored to neurosurgical practice.

Does Early Mobilization Following Resection of Spinal Intra-Dural Pathology Increase the Risk of Cerebrospinal Fluid Leaks?-A Dual-Center Comparative Effectiveness Research.

Background and Objectives: Prolonged bed rest after the resection of spinal intradural tumors is postulated to mitigate the development of cerebrospinal fluid leaks (CSFLs), which is one of the feared postoperative complications. Nonetheless, the empirical evidence supporting this conjecture remains limited and requires further investigation. The goal of the study was to investigate whether prolonged bed rest lowers the risk of CSFL after the resection of spinal intradural tumors. The primary outcome was the rate of CSFL in each cohort. Materials and Methods: To validate this hypothesis, we conducted a comparative effectiveness research (CER) study at two distinct academic neurosurgical centers, wherein diverse postoperative treatment protocols were employed. Specifically, one center adopted a prolonged bed rest regimen lasting for three days, while the other implemented early postoperative mobilization. For statistical analysis, case-control matching was performed. Results: Out of an overall 451 cases, we matched 101 patients from each center. We analyzed clinical records and images from each case. In the bed rest center, two patients developed a CSFL (n = 2, 1.98%) compared to four patients (n = 4, 3.96%) in the early mobilization center (p = 0.683). Accordingly, CSFL development was not associated with early mobilization (OR 2.041, 95% CI 0.365-11.403; p = 0.416). Univariate and multivariate analysis identified expansion duraplasty as an independent risk factor for CSFL (OR 60.33, 95% CI: 0.015-0.447; p < 0.001). Conclusions: In this CER, we demonstrate that early mobilization following the resection of spinal intradural tumors does not confer an increased risk of the development of CSFL.

Prognosis and histology of sporadic synchronous and metachronous meningiomas and comparative analyses with singular lesions.

Synchronous or metachronous growth of multiple tumors (≥ 2) is found in up to 20% of meningioma patients. However, biological as well as histological features and prognosis are largely unexplored. Clinical and histological characteristics were retrospectively investigated in 95 patients harboring 226 multiple meningiomas (MMs) and compared with 135 cases of singular meningiomas (SM) using uni- and multivariate analyses. In MM, tumors occurred synchronously and metachronously in 62% and 38%, respectively. WHO grade was intra-individually constant in all but two MMs, and histological subtype varied in 13% of grade 1 tumors. MM occurred more commonly in convexity/parasagittal locations, while SM were more frequent at the skull base (p < .001). In univariate analyses, gross total resection (p = .014) and high-grade histology in MM were associated with a prolonged time to progression (p < .001). Most clinical characteristics and rates of high-grade histology were similar in both groups (p ≥ .05, each). Multivariate analyses showed synchronous/metachronous meningioma growth (HR 4.50, 95% CI 2.26-8.96; p < .001) as an independent predictor for progression. Compared to SM, risk of progression was similar in cases with two (HR 1.56, 95% CI .76-3.19; p = .224), but exponentially raised in patients with 3-4 (HR 3.25, 1.22-1.62; p = .018) and ≥ 5 tumors (HR 13.80, 4.06-46.96; p < .001). Clinical and histological characteristics and risk factors for progression do not relevantly differ between SM and MM. Although largely constant, histology and WHO grade occasionally intra-individually vary in MM. A distinctly higher risk of disease progression in MM as compared to SM might reflect different underlying molecular alterations.

Resection of Intramedullary Hemangioblastoma: Timing of Surgery and Its Impact on Neurological Outcome and Quality of Life.

Background and Objectives: Spinal intramedullary hemangioblastomas (SIMH) are benign vascular lesions that are pathological hallmarks of von Hippel-Lindau disease (vHL) and constitute the third most common intramedullary neoplasm in adults. So far, maximal and safe resection is the first choice of treatment. However, as SIMH show no malignant transformation, it remains unclear whether surgical resection is beneficial for all patients. Materials and Methods: We retrospectively analyzed the surgical outcomes of 27 patients who were treated between 2014 and 2022 at our neurosurgical department and investigated potential risk factors that influence the surgical outcome. Pre- and postoperative neurological status were classified according to the McCormick scale. Furthermore, surgical quality indicators, such as length of hospital stay (LOS; days), 90-day readmissions, nosocomial infections, and potential risk factors that might influence the surgical outcome, such as tumor size and surgical approach, have been analyzed. In addition to that, patients were asked to fill out the EQ-5D-3L questionnaire to assess their quality of life after surgery. Results: Surgery on SIMH patients that display no or minor neurological deficits (McCormick scale I or II) is associated with a favorable postoperative outcome and overall higher quality of life compared to those patients that already suffer from severe neurological deficits (McCormick scale III or IV). Conclusion: Early surgical intervention prior to the development of severe neurological deficits may offer a better neurological outcome and quality of life.

Applicability of contemporary quality indicators in vestibular surgery-do they accurately measure tumor inherent postoperative complications of vestibular schwannomas?

BACKGROUND: Due to rising costs in health care delivery, reimbursement decisions have progressively been based on quality measures. Such quality indicators have been developed for neurosurgical procedures, collectively. We aimed to evaluate their applicability in patients that underwent surgery for vestibular schwannoma and to identify potential new disease-specific quality indicators. METHODS: One hundred and three patients operated due to vestibular schwannoma were subject to analysis. The primary outcomes of interest were 30-day and 90-day reoperation, readmission, mortality, nosocomial infection and surgical site infection (SSI) rates, postoperative cerebral spinal fluid (CSF) leak, facial, and hearing function. The secondary aim was the identification of prognostic factors for the mentioned primary outcomes. RESULTS: Thirty-day (90-days) outcomes in terms of reoperation were 10.7% (14.6%), readmission 9.7% (13.6%), mortality 1% (1%), nosocomial infection 5.8%, and SSI 1% (1%). A 30- versus 90-day outcome in terms of CSF leak were 6.8% vs. 10.7%, new facial nerve palsy 16.5% vs. 6.1%. Hearing impairment from serviceable to non-serviceable hearing was 6.8% at both 30- and 90-day outcome. The degree of tumor extension has a significant impact on reoperation (p < 0.001), infection (p = 0.015), postoperative hemorrhage (p < 0.001), and postoperative hearing loss (p = 0.026). CONCLUSIONS: Our data demonstrate the importance of entity-specific quality measurements being applied even after 30 days. We identified the occurrence of a CSF leak within 90 days postoperatively, new persistent facial nerve palsy still present 90 days postoperatively, and persisting postoperative hearing impairment to non-serviceable hearing as potential new quality measurement variables for patients undergoing surgery for vestibular schwannoma.

Minimally Invasive Facetectomy and Fusion for Resection of Extensive Dumbbell Tumors in the Lumbar Spine.

Background and Objectives: Resection of dumbbell tumors can be challenging, and facet joint sparing approaches carry the risk of incomplete resection. In contrast, additional facetectomy may allow better surgical exposure at the cost of spinal stability. The aim of this study is to compare facet-sparing and facetectomy approaches for the treatment of lumbar spine dumbbell tumors. Materials and Methods: In a cohort study setting, we analyzed Eden type 2 and 3 tumors operated in our department. Conventional facet-sparing microsurgical or facetectomy approaches with minimally invasive fusions were performed according to individual surgeons' preference. Primary outcomes were extent of resection and tumor progression over time. Secondary outcomes were perioperative adverse events. Results: Nineteen patients were included. Nine patients were operated on using a facet-sparing technique. Ten patients underwent facetectomy and fusion. While only one patient (11%) in the facet-sparing group experienced gross total resection (GTR), this was achieved for all patients in the facetectomy group (100%). The relative risk (RR) for incomplete resection in the facet-sparing cohort was 18.7 (95% CI 1.23-284.047; p = 0.035). In addition, time to progression was shorter in the facet-sparing cohort (p = 0.022) and all patients with a residual tumor underwent a second resection after a median follow-up time of 42 months (IQR 25-66). Conclusions: Minimally invasive resection of lumbar Eden type 2 and 3 dumbbell tumors including facetectomy in combination with instrumentation appears to be safe and superior to the facet-sparing approach in terms of local tumor control.

Evaluation of 311 contemporary cases of stereotactic biopsies in patients with neoplastic and non-neoplastic lesions-diagnostic yield and management of non-diagnostic cases.

Stereotactic biopsies are an established tool for obtaining diagnosis of unclear brain lesions. However, non-diagnostic biopsies still occur. We aimed to analyze the contemporary diagnostic yield of stereotactic biopsies, predictors for non-diagnostic biopsies, outcome, and follow-up strategy after non-diagnostic biopsy. We conducted a single-center retrospective study of 311 adult patients undergoing stereotactic biopsies due to a newly diagnosed lesion at our department between 2012 and 2018. Patient data regarding comorbidities, presenting symptoms, imaging features, and non-invasive diagnostic procedures were obtained. The overall diagnostic yield was 86.2% and differed significantly between the various suspected diagnosis groups and was the highest when suspecting primary brain tumor compared with non-neoplastic lesions (91.2% vs. 73.3%, p > 0.001). Predicators for non-diagnostic biopsies were small lesion size, lack of contrast-enhancement, presence of sepsis, or underlying hemato-oncological disease. In case of non-diagnostic biopsy, a re-biopsy was performed in 12 cases, revealing a final diagnosis in 75%. In 16 cases, empiric therapy was started based on the suspected underlying disease. Close follow-up was performed in the remaining 15 cases. We showed that stereotactic biopsy is a safe procedure with reasonable diagnostic yield even for non-neoplastic lesions, when non-invasive diagnostic was inconclusive. In addition, we developed treatment recommendations for cases of non-diagnostic biopsies.

Repetitive percutaneous radiofrequency thermocoagulation for persistent idiopathic facial pain and central neuropathic pain attributed to multiple sclerosis-a retrospective monocentric analysis.

BACKGROUND: Persistent idiopathic facial pain (PIFP) is a debilitating chronic pain condition with pain radiating to trigeminal dermatomes. Typically, there are no pathological findings that can be identified during workup and therapy is symptomatic. Facial pain is common in patients with multiple sclerosis (central neuropathic pain attributed to MS). Our aim was to evaluate the effectiveness of percutaneous radiofrequency thermocoagulation (PRTC) of the gasserian ganglion and the duration of pain relief, as well as the identification of factors associated with its outcome. METHODS: Data on all the above-mentioned patients that have been treated with PRTC between 2009 and 2019 were included into the study. The outcome was assessed with a six-tiered score from 1 (complete remission) to 6 (no benefit). Univariate and multivariate analyses were performed in order to obtain factors associated with the outcome. RESULTS: A total of 52 patients were included. The total number of procedures performed was 114. 61.5% of patients who experienced temporary pain relief that lasted for a median of 60 days (range 3-1490 days). In patients with recurrence, the fraction of successful interventions was higher, and also transient, with successful pain amelioration in over 80% of patients. Successful responses to PRTC were observed in 27.9% after 1 year, 19.4% after 2 years, and 8.3% after 3 years. The only independent variable predicting pain relief was a repeat intervention with a history of ≥ 2 interventions (OR: 4.36, 95%-CI: 1.34-14.34, p = 0.015). No severe complications occurred. CONCLUSIONS: Our data showed good and immediate pain relief after PRTC in the majority of our patients. PRTC is a low-risk procedure that can be discussed as an option in case of failure of medical treatment even in critically ill patients and can be repeated with good results when necessary. Long-term pain amelioration, even with repeated procedures, was not possible and no patient was permanently cured.

The 30-day readmission rate in neurosurgery-a useful indicator for quality assessment?

BACKGROUND: A shift in how we evaluate healthcare outcomes has driven the introduction of quality indicators as potential parameters to evaluate value-based healthcare delivery. So far, only few studies have been performed evaluating quality indicators in the context of neurosurgery, especially in the European region. The purpose of this study was to evaluate the 30-day readmission rate, identify reasons for readmission regarding the various neurosurgical diagnoses, and discuss the usefulness of this rate as a potential quality indicator. METHODS: During a 6-year period, a total of 8878 hospitalized patients in our neurosurgical department were retrospectively analyzed and included in this study. Reasons for readmission were identified. Patients' diagnoses and baseline characteristics were obtained in order to identify possible risk factors for readmission. RESULTS: The 30-day readmission rate was 2.9%. The most common reason for unplanned readmissions were surgical site infections. The reasons for readmissions varied significantly between the different underlying neurosurgical diseases (p < 0.001). Multivariate logistic regression revealed hydrocephalus (OR, 4) and shorter length of stay during index admission (OR, 0.9) as risk factors for readmission. CONCLUSIONS: We provided an analysis of reasons for readmission for various neurosurgical diseases in a large patient spectrum in Germany. Although readmission rates are easy to track and an attractive tool for quality assessment, the rate alone cannot be seen as an adequate measure for quality in neurosurgery as it lacks a homogenous definition and depends on the underlying health care system. In addition, strategies for risk adjustment are required.

Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients.

Frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders characterized by cognitive and behavioral impairments. Heterozygous mutations in progranulin (PGRN) cause familial FTD and result in decreased PGRN expression, while homozygous mutations result in complete loss of PGRN expression and lead to the neurodegenerative lysosomal storage disorder neuronal ceroid lipofuscinosis (NCL). However, how dose-dependent PGRN mutations contribute to these two different diseases is not well understood. Using iPSC-derived human cortical neurons from FTD patients harboring PGRN mutations, we demonstrate that PGRN mutant neurons exhibit decreased nuclear TDP-43 and increased insoluble TDP-43, as well as enlarged electron-dense vesicles, lipofuscin accumulation, fingerprint-like profiles and granular osmiophilic deposits, suggesting that both FTD and NCL-like pathology are present in PGRN patient neurons as compared to isogenic controls. PGRN mutant neurons also show impaired lysosomal proteolysis and decreased activity of the lysosomal enzyme cathepsin D. Furthermore, we find that PGRN interacts with cathepsin D, and that PGRN increases the activity of cathepsin D but not cathepsins B or L. Finally, we show that granulin E, a cleavage product of PGRN, is sufficient to increase cathepsin D activity. This functional relationship between PGRN and cathepsin D provides a possible explanation for overlapping NCL-like pathology observed in patients with mutations in PGRN or CTSD, the gene encoding cathepsin D. Together, our work identifies PGRN as an activator of lysosomal cathepsin D activity, and suggests that decreased cathepsin D activity due to loss of PGRN contributes to both FTD and NCL pathology in a dose-dependent manner.

Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36.

Members of the CD36 superfamily of scavenger receptor proteins are important regulators of lipid metabolism and innate immunity. They recognize normal and modified lipoproteins, as well as pathogen-associated molecular patterns. The family consists of three members: SR-BI (which delivers cholesterol to the liver and steroidogenic organs and is a co-receptor for hepatitis C virus), LIMP-2/LGP85 (which mediates lysosomal delivery of ß-glucocerebrosidase and serves as a receptor for enterovirus 71 and coxsackieviruses) and CD36 (a fatty-acid transporter and receptor for phagocytosis of effete cells and Plasmodium-infected erythrocytes). Notably, CD36 is also a receptor for modified lipoproteins and ß-amyloid, and has been implicated in the pathogenesis of atherosclerosis and of Alzheimer's disease. Despite their prominent roles in health and disease, understanding the function and abnormalities of the CD36 family members has been hampered by the paucity of information about their structure. Here we determine the crystal structure of LIMP-2 and infer, by homology modelling, the structure of SR-BI and CD36. LIMP-2 shows a helical bundle where ß-glucocerebrosidase binds, and where ligands are most likely to bind to SR-BI and CD36. Remarkably, the crystal structure also shows the existence of a large cavity that traverses the entire length of the molecule. Mutagenesis of SR-BI indicates that the cavity serves as a tunnel through which cholesterol(esters) are delivered from the bound lipoprotein to the outer leaflet of the plasma membrane. We provide evidence supporting a model whereby lipidic constituents of the ligands attached to the receptor surface are handed off to the membrane through the tunnel, accounting for the selective lipid transfer characteristic of SR-BI and CD36.

Characterization of the complex formed by ß-glucocerebrosidase and the lysosomal integral membrane protein type-2.

The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of ß-glucocerebrosidase (GC) to lysosomes. Mutations in GC result in Gaucher's disease (GD) and are the major genetic risk factor for the development of Parkinson's disease (PD). Variants in the LIMP-2 gene cause action myoclonus-renal failure syndrome and also have been linked to PD. Given the importance of GC and LIMP-2 in disease pathogenesis, we studied their interaction sites in more detail. Our previous data demonstrated that the crystal structure of LIMP-2 displays a hydrophobic three-helix bundle composed of helices 4, 5, and 7, of which helix 5 and 7 are important for ligand binding. Here, we identified a similar helical motif in GC through surface potential analysis. Coimmunoprecipitation and immunofluorescence studies revealed a triple-helical interface region within GC as critical for LIMP-2 binding and lysosomal transport. Based on these findings, we generated a LIMP-2 helix 5-derived peptide that precipitated and activated recombinant wild-type and GD-associated N370S mutant GC in vitro. The helix 5 peptide fused to a cell-penetrating peptide also activated endogenous lysosomal GC and reduced α-synuclein levels, suggesting that LIMP-2-derived peptides can be used to activate endogenous as well as recombinant wild-type or mutant GC efficiently. Our data also provide a structural model of the LIMP-2/GC complex that will facilitate the development of GC chaperones and activators as potential therapeutics for GD, PD, and related synucleinopathies.

5-ALA fluorescence-guided surgery in pediatric brain tumors-a systematic review.

BACKGROUND: 5-Aminolevulinic acid (5-ALA)-guided resection of gliomas in adults enables better differentiation between tumor and normal brain tissue, allowing a higher degree of resection, and improves patient outcomes. In recent years, several reports have emerged regarding the use of 5-ALA in other brain tumor entities, including pediatric brains tumors. Since gross total resection (GTR) of many brain tumors in children is crucial and the role of 5-ALA-guided resection of these tumors is not clear, we sought to perform a comprehensive literature review on this topic. METHODS: A systematic literature review of EMBASE and MEDLINE/PubMed databases revealed 19 eligible publications encompassing 175 5-ALA-guided operations on pediatric brain tumors. To prevent bias, publications were revised independently by two authors. RESULTS: We found that 5-ALA-guided resection enabled the surgeons to identify the tumor more easily and was considered helpful mainly in cases of glioblastoma (GBM, 21/27, 78%), anaplastic ependymoma WHO grade III (10/14, 71%), and anaplastic astrocytoma (4/6, 67%). In contrast, cases of pilocytic astrocytomas (PAs) and medulloblastomas 5-ALA-guided surgery did not show consistent fluorescent signals and 5-ALA was considered helpful only in 12% and 22% of cases, respectively. Accumulation of fluorescent porphyrins seems to depend on WHO tumor grading. One important finding is that when 5-ALA-guided resections were considered helpful, the degree of resection was higher than is cases where it was not helpful. The rate of adverse events related to 5-ALA was negligible, especially new postoperative sequelae. CONCLUSION: 5-ALA could play a role in resection of pediatric brain tumors. However, further prospective clinical trials are needed.

Adverse events in brain tumor surgery: incidence, type, and impact on current quality metrics.

BACKGROUND: The aim of the study was to determine pre-operative factors associated with adverse events occurring within 30 days after neurosurgical tumor treatment in a German center, adjusting for their incidence in order to prospectively compare different centers. METHODS: Adult patients that were hospitalized due to a benign or malignant brain were retrospectively assessed for quality indicators and adverse events. Analyses were performed in order to determine risk factors for adverse events and reasons for readmission and reoperation. RESULTS: A total of 2511 cases were enrolled. The 30 days unplanned readmission rate to the same hospital was 5.7%. The main reason for readmission was tumor progression. Every 10th patient had an unplanned reoperation. The incidence of surgical revisions due to infections was 2.3%. Taking together all monitored adverse events, male patients had a higher risk for any of these complications (OR 1.236, 95%CI 1.025-1.490, p = 0.027). Age, sex, and histological diagnosis were predictors of experiencing any complication. Adjusted by incidence, the increased risk ratios greater than 10.0% were found for male sex, age, metastatic tumor, and hemiplegia for various quality indicators. CONCLUSIONS: We found that most predictors of outcome rates are based on preoperative underlying medical conditions and are not modifiable by the surgeon. Comparing our results to the literature, we conclude that differences in readmission and reoperation rates are strongly influenced by standards in decision making and that comparison of outcome rates between different health-care providers on an international basis is challenging. Each health-care system has to develop own metrics for risk adjustment that require regular reassessment.

Spectroscopic measurement of 5-ALA-induced intracellular protoporphyrin IX in pediatric brain tumors.

OBJECTIVE: 5-Aminolevulinic acid (5-ALA)-guided resection of gliomas in adults enables better delineation between tumor and normal brain, allowing improved resection and improved patients' outcome. Recently, several reports were published regarding 5-ALA for resection of pediatric brain tumors. The aim of the study was to determine the intracellular fluorescence of protoporphyrin IX (PPIX) in pediatric brain tumors by hyperspectral imaging and to compare it with visually observed intraoperative fluorescence. METHODS: 5-ALA was administered orally 4 h prior to surgery. During tumor resection, the surgeon assessed the fluorescence signal to be strong, weak, or absent. Subsequently, fluorescence intensity of tumor samples was measured via spectroscopy. In addition, clinical data, imaging, and laboratory data were analyzed. RESULTS: Eleven children (1-16 years) were operated. Tumor entities included three (n = 3) medulloblastomas, two (n = 2) pilocytic astrocytomas (PA), two (n = 2) anaplastic ependymomas and one (n = 1) diffuse astrocytoma, anaplastic astrocytoma (n = 1), pilomyxoid astrocytoma (n = 1) and anaplastic pleomorphic xanthoastrocytoma (n = 1). Strong fluorescence was visible in all anaplastic tumors and one PA; one PA demonstrated weak fluorescence. Visible fluorescence was strongly associated with intracellular fluorescence intensity and PPIX concentration (P < 0.05). Within all tumors with visible fluorescence, the intracellular PPIX concentration was greater than 4 µg/ml. Except for moderate and transient elevation of liver enzymes, no 5-ALA related adverse events were reported. CONCLUSION: We demonstrate a strong association between intraoperative observations and spectrometric measurements of PPIX fluorescence in tumor tissue. As in former studies, fluorescence signal was more commonly observed in malignant glial tumors. Further prospective controlled trials should be conducted to investigate the feasibility of 5-ALA-guided resection of pediatric brain tumors.

Establishing risk-adjusted quality indicators in surgery using administrative data-an example from neurosurgery.

BACKGROUND: The current draft of the German Hospital Structure Law requires remuneration to incorporate quality indicators. For neurosurgery, several quality indicators have been discussed, such as 30-day readmission, reoperation, or mortality rates; the rates of infections; or the length of stay. When comparing neurosurgical departments regarding these indicators, very heterogeneous patient spectrums complicate benchmarking due to the lack of risk adjustment. OBJECTIVE: In this study, we performed an analysis of quality indicators and possible risk adjustment, based only on administrative data. METHODS: All adult patients that were treated as inpatients for a brain or spinal tumour at our neurosurgical department between 2013 and 2017 were assessed for the abovementioned quality indicators. DRG-related data such as relative weight, PCCL (patient clinical complexity level), ICD-10 major diagnosis category, secondary diagnoses, age and sex were obtained. The age-adjusted Charlson Comorbidity Index (CCI) was calculated. Logistic regression analyses were performed in order to correlate quality indicators with administrative data. RESULTS: Overall, 2623 cases were enrolled into the study. Most patients were treated for glioma (n = 1055, 40.2%). The CCI did not correlate with the quality indicators, whereas PCCL showed a positive correlation with 30-day readmission and reoperation, SSI and nosocomial infection rates. CONCLUSION: All previously discussed quality indicators are easily derived from administrative data. Administrative data alone might not be sufficient for adequate risk adjustment as they do not reflect the endogenous risk of the patient and are influenced by certain complications during inpatient stay. Appropriate concepts for risk adjustment should be compiled on the basis of prospectively designed registry studies.

Triage of 5 Noncontrast Computed Tomography Markers and Spot Sign for Outcome Prediction After Intracerebral Hemorrhage.

Background and Purpose- Besides the established spot sign (SS) in computed tomography angiography (CTA), there is growing evidence that different imaging markers in noncontrast CT offer great value for outcome prediction in patients with intracerebral hemorrhage (ICH). However, it is unclear how the concurrent presence of each sign independently contributes to the predictive power of poor outcome. We, therefore, aimed to clarify the predictive value of 5 recently published noncontrast CT parameters (blend sign, black hole sign, island sign, hematoma heterogeneity, and hypodensities) and the established SS in 1 consecutive series of patients with ICH. Methods- Retrospective study of patients with ICH at 2 German tertiary stroke centers; inclusion criteria were (1) spontaneous ICH and (2) noncontrast CT and CTA performed on admission within 6 hours after onset of symptoms. We defined a binary outcome (good outcome [modified Rankin Scale score of ≤3] versus poor outcome [modified Rankin Scale score of >3]) at discharge. The predictive value of each sign was assessed in univariate and multivariable logistic regression models. Results- Of 201 patients with spontaneous ICH, 28 (13.9%) presented with black hole sign, 38 (18.9%) with blend sign, 120 (59.7%) with hypodensities, 97 (48.3%) with heterogeneous densities, 53 with island sign (26.4%), and 45 (22.4%) with SS. In univariable logistic regression, higher hematoma volume ( P<0.001), intraventricular hemorrhage ( P=0.002), and the presence of black hole sign/blend sign/hypodensities/island sign/SS/heterogeneous density (all P<0.001) on admission CT were associated with poor outcome. Multivariable analysis confirmed intraventricular hemorrhage (odds ratio, 2.20; P=0.025), higher hematoma volume (odds ratio, 1.02 per mL; P<0.019), the presence of hypodensities (odds ratio, 2.47; P=0.018), and SS (odds ratio, 12.22; P<0.001) as independent predictors of poor outcome. Conclusions- This study demonstrates the degree of interaction between 5 recent noncontrast CT imaging markers and SS and their individual contribution for outcome prediction in patients with ICH. Of the CT variables indicating poor outcome SS on CTA and hypodensities were the most reliable outcome predictors.

ß-Glucocerebrosidase Modulators Promote Dimerization of ß-Glucocerebrosidase and Reveal an Allosteric Binding Site.

ß-Glucocerebrosidase (GCase) mutations cause Gaucher's disease and are a high risk factor in Parkinson's disease. The implementation of a small molecule modulator is a strategy to restore proper folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, JZ-4109, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (JZ-5029) for in vitro mechanistic studies. By using native top-down mass spectrometry, we located two potentially covalently modified lysines. We obtained the first crystal structure, at 2.2 Å resolution, of a GCase with a noniminosugar modulator covalently bound, and were able to identify the exact lysine residue modified (Lys346) and reveal an allosteric binding site. GCase dimerization was induced by our modulator binding, which was observed by native mass spectrometry, its crystal structure, and size exclusion chromatography with a multiangle light scattering detector. Finally, the dimer form was confirmed by negative staining transmission electron microscopy studies. Our newly discovered allosteric site and observed GCase dimerization provide a new mechanistic insight into GCase and its noniminosugar modulators and facilitate the rational design of novel GCase modulators for Gaucher's disease and Parkinson's disease.

Mannose 6-phosphate-independent Lysosomal Sorting of LIMP-2.

The lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) has been described as a mannose 6-phosphate (M6P)-independent trafficking receptor for ß-glucocerebrosidase (GC). Recently, a putative M6P residue in a crystal structure of a recombinantly expressed LIMP-2 ectodomain has been reported. Based on surface plasmon resonance and fluorescence lifetime imaging analyses, it was suggested that the interaction of soluble LIMP-2 with the cation-independent M6P receptor (MPR) results in M6P-dependent targeting of LIMP-2 to lysosomes. As the physiological relevance of this observation was not addressed, we investigated M6P-dependent delivery of LIMP-2 to lysosomes in murine liver and mouse embryonic fibroblasts. We demonstrate that LIMP-2 and GC reach lysosomes independent of the M6P pathway. In fibroblasts lacking either MPRs or the M6P-forming N-acetylglucosamine (GlcNAc)-1-phosphotransferase, LIMP-2 still localizes to lysosomes. Immunoblot analyses also revealed comparable LIMP-2 levels within lysosomes purified from liver of wild-type (wt) and GlcNAc-1-phosphotransferase-defective mice. Heterologous expression of the luminal domain of LIMP-2 in wild-type, LIMP-2-deficient and GlcNAc-1-phosphotransferase-defective cells further established that the M6P modification is dispensable for lysosomal sorting of LIMP-2. Finally, cathepsin Z, a known GlcNAc-1-phosphotransferase substrate, but not LIMP-2, could be precipitated with M6P-specific antibodies. These data prove M6P-independent lysosomal sorting of LIMP-2 and subsequently GC in vivo.

Impaired Lysosomal Integral Membrane Protein 2-dependent Peroxiredoxin 6 Delivery to Lamellar Bodies Accounts for Altered Alveolar Phospholipid Content in Adaptor Protein-3-deficient pearl Mice.

The Hermansky Pudlak syndromes (HPS) constitute a family of disorders characterized by oculocutaneous albinism and bleeding diathesis, often associated with lethal lung fibrosis. HPS results from mutations in genes of membrane trafficking complexes that facilitate delivery of cargo to lysosome-related organelles. Among the affected lysosome-related organelles are lamellar bodies (LB) within alveolar type 2 cells (AT2) in which surfactant components are assembled, modified, and stored. AT2 from HPS patients and mouse models of HPS exhibit enlarged LB with increased phospholipid content, but the mechanism underlying these defects is unknown. We now show that AT2 in the pearl mouse model of HPS type 2 lacking the adaptor protein 3 complex (AP-3) fails to accumulate the soluble enzyme peroxiredoxin 6 (PRDX6) in LB. This defect reflects impaired AP-3-dependent trafficking of PRDX6 to LB, because pearl mouse AT2 cells harbor a normal total PRDX6 content. AP-3-dependent targeting of PRDX6 to LB requires the transmembrane protein LIMP-2/SCARB2, a known AP-3-dependent cargo protein that functions as a carrier for lysosomal proteins in other cell types. Depletion of LB PRDX6 in AP-3- or LIMP-2/SCARB2-deficient mice correlates with phospholipid accumulation in lamellar bodies and with defective intraluminal degradation of LB disaturated phosphatidylcholine. Furthermore, AP-3-dependent LB targeting is facilitated by protein/protein interaction between LIMP-2/SCARB2 and PRDX6 in vitro and in vivo Our data provide the first evidence for an AP-3-dependent cargo protein required for the maturation of LB in AT2 and suggest that the loss of PRDX6 activity contributes to the pathogenic changes in LB phospholipid homeostasis found HPS2 patients.