Cervical Total Disc Replacement and Anterior Cervical Discectomy and Fusion: Comparison of 30-Day Population Comorbidities and Perioperative Complications Using 6 Years of American College of Surgeons National Surgical Quality Improvement Program Participant Use File Data.

OBJECTIVE: American College of Surgeons National Surgical Quality Improvement Program Participant Use File data from 2014 through 2019 were used to compare 1- and 2-level anterior cervical discectomy and fusion (ACDF) and cervical total disc replacement (cTDR) with respect to: patient demographics, comorbidities, adverse events, and 30-day morbidity rates. METHODS: One- and 2-level ACDF and cTDR patients were identified by current procedural terminology codes. Demographics, comorbidities, and adverse events were summarized. Unmatched cohorts were compared using Wilcoxon Rank Sum test for continuous variables, Pearson χ2 test for categorical variables, and 30-day morbidity using inverse probability of treatment weighted log-binomial regression. RESULTS: American College of Surgeons National Surgical Quality Improvement Program 2014 through 2019 Participant Use File datasets represent 4,862,497 unique patients, identifying 13,347 1-level, 6933 2-level ACDF, 3114 1-level, and 862 2-level cTDR patient cohorts. Statistically significant differences between cohorts are extensive: age, sex, race, admission status, patient origin, discharge disposition, emergent surgery, surgical specialty, American Society of Anesthesiologists classification, wound class, operative time, hospital LOS, BMI, functional status, smoking, diabetes, dyspnea, chronic obstructive pulmonary disease, congestive heart failure, hypertension, renal failure, dialysis, cancer, steroid use, anemia, bleeding disorders, systemic sepsis, and number of concurrent comorbid conditions. Inverse probability of treatment weighted log-binomial models, demonstrated increased risk of deep venous thrombosis/thrombophlebitis, pulmonary embolism, deep incisional surgical site infection, pneumonia, and unplanned return to operating room associated with ACDF while increased risk of cerebral vascular accident/stroke with neurological deficit and myocardial infarction associated with cTDR. The composite complications outcome favors cTDR over ACDF for 30-day morbidity. No mortalities occurred within the cTDR cohort. CONCLUSIONS: Adjusting for demographics and comorbidities; ACDF has a higher average risk of adverse event. When ACDF and cTDR are equipoise, consideration for cTDR may be indicated in populations with higher rates of comorbid conditions.

Using a Data-Driven Improvement Methodology to Decrease Surgical Site Infections in a Community Neurosurgery Practice: Optimizing Preoperative Screening and Perioperative Antibiotics.

OBJECTIVE: We used a data-driven methodology to decrease the departmental surgical site infection rate to a goal of 1%. METHODS: A prospective interventional study with historical controls comparing preimplementation/intervention (unknown methicillin-sensitive Staphylococcus aureus [MSSA]/methicillin-resistant Staphylococcus aureus [MRSA] status and standard weight and drug allergy-based preoperative antibiotics) with postimplementation/intervention (optimized preoperative chlorhexidine showers, MSSA/MRSA screening, MSSA/MRSA decolonization, and optimized preoperative antibiotic order set implementation). The American College of Surgeons National Surgical Quality Improvement Program was used for case surveillance. The primary outcome was the presence of a surgical site infection with a secondary outcome of cost(s) of implementation. RESULTS: A total of 317 National Surgical Quality Improvement Program abstracted neurosurgical cases were analyzed, 163 cases before implementation and 154 cases after implementation. There were no significant differences between the preimplementation and postimplementation cohorts regarding patient demographics and baseline comorbidities, with the exceptions of inpatient and functional status (P < 0.001). The most common procedures were lumbar decompression (31%), lumbar discectomy (27%), and anterior cervical discectomy and fusion (10.4%). After implementation, 30 patients were MSSA positive (20%) and 4 MRSA positive (2.6%). Thirty patients received preoperative intranasal mupirocin decolonization (88%), and 4 patients received adjusted preoperative antibiotics (12%). After protocol implementation, the surgical site infection rate decreased from 6.7% (odds ratio, 2.82) to 0.96% (odds ratio, 0.91). The cost of implementation was $27,179, or $58 per patient. CONCLUSIONS: The findings highlight the importance of systematically investigating areas of gap in existing clinical practice and quality improvement projects to increase patient safety and enhance the value of care delivered to neurosurgical patients.

Conformation and Domain Movement Analysis of Human Matrix Metalloproteinase-2: Role of Associated Zn2+ and Ca2+ Ions.

Matrix metaloproteinase-2 (MMP-2) is an extracellular Zn2+ protease specific to type I and IV collagens. Its expression is associated with several inflammatory, degenerative, and malignant diseases. Conformational properties, domain movements, and interactions between MMP-2 and its associated metal ions were characterized using a 1.0 µs molecular dynamics simulation. Dihedral principle component analysis revealed ten families of conformations with the greatest degree of variability occurring in the link region connecting the catalytic and hemopexin domains. Dynamic cross-correlation analysis indicated domain movements corresponding to the opening and closing of the hemopexin domain in relation to the fibronectin and catalytic domains facilitated by the link region. Interaction energies were calculated using the molecular mechanics Poisson Boltzman surface area-interaction entropy (MMPBSA-IE) analysis method and revealed strong binding energies for the catalytic Zn2+ ion 1, Ca2+ ion 1, and Ca2+ ion 3 with significant conformational stability at the binding sites of Zn2+ ion 1 and Ca2+ ion 1. Ca2+ ion 2 diffuses freely away from its crystallographically defined binding site. Zn2+ ion 2 plays a minor role in conformational stability of the catalytic domain while Ca2+ ion 3 is strongly attracted to the highly electronegative sidechains of the Asp residues around the central ß-sheet core of the hemopexin domain; however, the interacting residue sidechain carboxyl groups are outside of Ca2+ ion 3's coordination sphere.

Effects of Selective Substitution of Cysteine Residues on the Conformational Properties of Chlorotoxin Explored by Molecular Dynamics Simulations.

Chlorotoxin (CTX) is a 36⁻amino acid peptide with eight Cys residues that forms four disulfide bonds. It has high affinity for the glioma-specific chloride channel and matrix metalloprotease-2. Structural and binding properties of CTX analogs with various Cys residue substitutions with l-α-aminobutyric acid (Abu) have been previously reported. Using 4.2 µs molecular dynamics, we compared the conformational and essential space sampling of CTX and analogs with selective substitution of the Cys residues and associated disulfide bonds with either Abu or Ser. The native and substituted peptides maintained a high degree of α-helix propensity from residues 8 through 21, with the exception of substitution of the Cys5⁻Cys28 residues with Ser and the Cys16⁻Cys33 residues with Abu. In agreement with previous circular dichroism spectropolarimetry results, the C-terminal ß-sheet content varied less from residues 25 through 29 and 32 through 36 and was well conserved in most analogs. The Cys16⁻Cys33 and Cys20⁻Cys35 disulfide-bonded residues appear to be required to maintain the αß motif of CTX. Selective substitution with the hydrophilic Ser, may mitigate the destabilizing effect of Cys16⁻Cys33 substitution through the formation of an inter residue H-bond from Ser16:OγH to Ser33:OγH bridged by a water molecule. All peptides shared considerable sampled conformational space, which explains the retained receptor binding of the non-native analogs.

Diagnosis and Treatment of Isolated Cerebral Mucormycosis: Patient-Level Data Meta-Analysis and Mayo Clinic Experience.

BACKGROUND: Isolated cerebral mucormycosis is a rare and serious infection associated with intravenous drug abuse. METHODS: We performed a comprehensive meta-analysis of cases reported in studies and have included an unreported case from our institution. We searched PubMed/Medline, EMBASE, Scopus, Cochrane Databases, and our institution's electronic medical health records from inception through March 31, 2018. The cases were considered isolated (only affecting the cerebrum, cerebellum, or brainstem) if the absence of other primary sources of infection had been documented. Continuous variables were summarized using the median and interquartile range and categorical variables using frequencies and proportions. The relationships between variables were tested using the Wilcoxon rank sum and Pearson χ2 tests. RESULTS: A total of 130 studies (141 patients) met the eligibility requirements and were screened; 68 patients were included. The median age was 28 years (interquartile range, 24-38); 57% were men. Most patients had a history of intravenous drug abuse (82%), and 20% had positive human immunodeficiency virus findings. The lesion location was mostly supratentorial (91%), especially in the basal ganglia (71.2%). The cultures were positive in 38%, with Rhizopus the most common organism (59%). The mortality rate was 65%. The survivors were significantly more likely to have received amphotericin B (92% vs. 43%; P < 0.001) or to have undergone stereotactic aspiration (58% vs. 25%; P < 0.01). CONCLUSIONS: Isolated cerebral mucormycosis has a pooled mortality rate of 65%. The presence of lesions in the basal ganglia, rapidly progressive symptoms, and a history of intravenous drug abuse should raise suspicion for the early initiation of amphotericin B and stereotactic aspiration.

Effects of force fields on the conformational and dynamic properties of amyloid ß(1-40) dimer explored by replica exchange molecular dynamics simulations.

The conformational space and structural ensembles of amyloid beta (Aß) peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aß(1-40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8 ± 6.4%) and CHARMM36 (2.7 ± 4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3 ± 5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3 ± 12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of ß-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected ß-sheet-turn-ß-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different.

Structural properties of amyloid ß(1-40) dimer explored by replica exchange molecular dynamics simulations.

Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid ß(1-40) (Aß(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37°C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56 ± 6.341 kJ mol-1 . Prevalence of random coil conformations was found for both chains with the exceptions of increased ß-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with ß-turn/ß-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed ß-turn/ß-sheet region from residues 33-38 of both chains. Analysis of intra- and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel ß-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel ß-sheet-loop-ß-sheet conformational motif is favored for many low energy sampled conformations. Our results show that Aß(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected ß-sheet-loop-ß-sheet conformational motif. Proteins 2017; 85:1024-1045. © 2017 Wiley Periodicals, Inc.

Gamma knife stereotactic radiosurgery for renal cell carcinoma and melanoma brain metastases-comparison of dose response.

BACKGROUND: Metastatic melanoma appears to have inferior local control (LC) than renal cell carcinoma (RCC) after stereotactic radiosurgery (SRS) to the brain. OBJECTIVE: To retrospectively examine RCC vs. melanoma LC dose response. METHODS: Follow-up data were available for 88 patients (RCC=38; melanoma=50) with 235 tumors (RCC=92; melanoma=143) treated with Gamma Knife SRS between Dec. 2005 to Aug. 2012. LC was compared among RCC vs. melanoma and then at each margin dose (≤18Gy, 20Gy, 22Gy, and 24Gy). Patient survival and toxicity were analyzed. Median follow-up was 9.8 months (RCC) and 5.4 months (melanoma). RESULTS: Patient characteristics were similar between RCC vs. melanoma with respect to gender, age, KPS, GPA, lesions per patient, and tumor volume. For all margin doses, LC at 6 months was 98.6% (RCC) vs. 79.2% (melanoma). When broken down by margin dose, at ≤18 Gy (P<0.0001) and 20 Gy (P=0.02), RCC had better LC compared to melanoma. At 22 Gy, LC were similar between the two histologies (P=0.19). At 24 Gy, melanoma had better LC than RCC (P=0.02). Tumor volumes were similar between RCC vs. melanoma at each margin dose (P>0.05). Small melanoma tumors (<4ml) exhibited LC dose dependence. Median survival was 16.1 months (RCC) and 9.6 months (melanoma). Toxicity was not significantly different between the two histologies and margin doses. CONCLUSIONS: RCC has significantly better LC than melanoma after SRS. Higher doses could be used for melanoma tumors <4ml to improve melanoma LC.

Aggressive red blood cell transfusion: no association with improved outcomes for victims of isolated traumatic brain injury.

BACKGROUND: Clinical studies have caused blood transfusion practices in critically ill patients to become more conservative in the last decade. However, few studies have focused on trauma patients, particularly those with severe isolated traumatic brain injury. METHODS: We conducted a retrospective study to test the hypothesis that patients with severe brain injury would not benefit from aggressive red blood cell transfusion (RBCT). End points of the study were in-hospital mortality and morbidity (pneumonia, urinary tract infection, deep venous thrombosis, pulmonary embolus, decubitus ulcer, bacteremia, septic shock, myocardial infarction, and seizure). Included in our retrospective study were patients at two urban, level I trauma centers who were admitted with a diagnosis of isolated head injury and with a Glasgow Coma Scale (GCS) score of 8 or less. We recorded demographic, interventional, and outcome variables. RESULTS: In 289 patients, 24 of 25 (96%) were transfused if their lowest recorded intensive care unit (ICU) hemoglobin level was 8.0 g/dl or less. In contrast, only 9/182 (5%) of these 289 patients were transfused if the hemoglobin levels were 10.0 g/dl or greater. In the remaining 82 patients with lowest ICU hemoglobin levels of 8.0-10.0 g/dl, 52% were transfused. These 82 patients (43 underwent RBCT and 39 did not) were included in our analysis. DISCUSSION: The overall in-hospital mortality rate was 32%; rates were similar between the two groups (29%, non-RBCT; 35%, RBCT) (P = 0.64). Likewise, in-hospital morbidity was similar between groups. Logistic and proportional hazard regression analyses identified RBCT as one predictor of mortality. CONCLUSIONS: Our results suggest that a restrictive transfusion practice is safe for severely head-injured patients.