Jason M. Davies

Improved Structures of Full-Length p97, an AAA ATPase: Implications for Mechanisms of Nucleotide-Dependent Conformational Change.

The ATPases associated with various cellular activities (AAA) protein p97 has been implicated in a variety of cellular processes, including endoplasmic reticulum-associated degradation and homotypic membrane fusion. p97 belongs to a subgroup of AAA proteins that contains two nucleotide binding domains, D1 and D2. We determined the crystal structure of D2 at 3.0 A resolution. This model enabled rerefinement of full-length p97 in different nucleotide states against previously reported low-resolution diffraction data to significantly improved R values and Ramachandran statistics. Although the overall fold remained similar, there are significant improvements, especially around the D2 nucleotide binding site. The rerefinement illustrates the importance of knowledge of high-resolution structures of fragments covering most of the whole molecule. The structures suggest that nucleotide hydrolysis is transformed into larger conformational changes by pushing of one D2 domain by its neighbor in the hexamer, and transmission of nucleotide-state information through the D1-D2 linker to displace the N-terminal, effector binding domain.

Identification of a Novel Rab11/25 Binding Domain Present in Eferin and Rip Proteins

Rab11, a low molecular weight GTP-binding protein, has been shown to play a key role in a variety of cellular processes, including endosomal recycling, phagocytosis, and transport of secretory proteins from the trans-Golgi network. In this study we have described a novel Rab11 effector,EF-hands-containingRab11-interacting protein (Eferin). In addition, we have identified a 20-amino acid domain that is present at the C terminus of Eferin and other Rab11/25-interacting proteins, such as Rip11 and nRip11. Using biochemical techniques we have demonstrated that this domain is necessary and sufficient for Rab11 binding in vitro and that it is required for localization of Rab11 effector proteins in vivo. The data suggest that various Rab effectors compete with each other for binding to Rab11/25 possibly accounting for the diversity of Rab11 functions.

Crystal structure of the CUB1‐EGF‐CUB2 region of mannose‐binding protein associated serine protease‐2

Serum mannose‐binding proteins (MBPs) are C‐type lectins that recognize cell surface carbohydrate structures on pathogens, and trigger killing of these targets by activating the complement pathway. MBPs circulate as a complex with MBP‐associated serine proteases (MASPs), which become activated upon engagement of a target cell surface. The minimal functional unit for complement activation is a MASP homodimer bound to two MBP trimeric subunits. MASPs have a modular structure consisting of an N‐terminal CUB domain, a Ca2+‐binding EGF‐like domain, a second CUB domain, two complement control protein modules and a C‐terminal serine protease domain. The CUB1‐EGF‐CUB2 region mediates homodimerization and binding to MBP. The crystal structure of the MASP‐2 CUB1‐EGF‐CUB2 dimer reveals an elongated structure with a prominent concave surface that is proposed to be the MBP‐binding site. A model of the full six‐domain structure and its interaction with MBPs suggests mechanisms by which binding to a target cell transmits conformational changes from MBP to MASP that allow activation of its protease activity.

The National Neurosurgery Quality and Outcomes Database (N2QOD): a collaborative North American outcomes registry to advance value-based spine care.

Study Design. National Prospective Observational Registry Objective. Describe our preliminary experience with the National Neurosurgery Quality and Outcomes Database (N2QOD), a national collaborative registry of quality and outcomes reporting after low back surgery. Summary of Background Data. All major health care stakeholders are now requiring objective data regarding the value of medical services. Surgical therapies for spinal disorders have faced particular scrutiny in recent value-based discussions, in large part due to the dramatic growth in the cost and application of these procedures. Reliable data are fundamental to understanding the value of delivered health care. Clinical registries are increasingly used to provide such data. Methods. The N2QOD is a prospective observational registry designed to establish risk-adjusted expected morbidity and 1-year outcomes for the most common lumbar surgical procedures performed by spine surgeons; provide practice groups and hospitals immediate infrastructure for analyzing their 30-day morbidity and mortality and 3- and 12-month quality data in real-time; generate surgeon-, practice-, and specialty-specific quality and efficacy data; and generate nationwide quality and effectiveness data on specific surgical treatments. Results. In its first 2 years of operation, the N2QOD has proven to be a robust data collection platform that has helped demonstrate the objective quality of surgical interventions for medically refractory disorders of the lumbar spine. Lumbar spine surgery was found to be safe and effective at the group mean level in routine practice. Subgroups of patients did not report improvement using validated outcome measures. Substantial variation in treatment response was observed among individual patients. Conclusion. The N2QOD is now positioned to determine the combined contribution of patient variables to specific clinical and patient-reported outcomes. These analyses will ultimately facilitate shared decision making and encourage efficient allocation of health care resources, thus significantly advancing the value paradigm in spine care. Level of Evidence: 3

X-ray structure determination at low resolution

Refinement is meaningful even at 4 Å or lower, but with present methodologies it should start from high-resolution crystal structures whenever possible.

Advances in open microsurgery for cerebral aneurysms.

BACKGROUND Endovascular techniques introduced strong extrinsic forces that provoked reactive changes in aneurysm surgery. Microsurgery has become less invasive, more appealing to patients, lower risk, and efficacious for complex aneurysms, particularly those unfavorable for or failing endovascular therapy. OBJECTIVE To review specific advances in open microsurgery for aneurysms. METHODS A university-based, single-surgeon practice was examined for the use of minimally invasive craniotomies, surgical management of recurrence after coiling, the use of intracranial-intracranial bypass techniques, and cerebrovascular volume-outcome relationships. RESULTS The mini-pterional, lateral supraorbital, and orbital-pterional craniotomies are minimally invasive alternatives to standard craniotomies. Mini-pterional and lateral supraorbital craniotomies were used in one-fourth of unruptured patients, increasing from 22% to 28%, whereas 15% of patients underwent orbital-pterional craniotomies and trended upward from 11% to 20%. Seventy-four patients were treated for coil recurrences (2.3% of all aneurysms) with direct clip occlusion (77%), clip occlusion after coil extraction (7%), or parent artery occlusion with bypass (16%). Intracranial-intracranial bypass (in situ bypass, reimplantation, reanastomosis, and intracranial grafts) transformed the management of giant aneurysms and made the surgical treatment of posterior inferior cerebellar artery aneurysms competitive with endovascular therapy. Centralization maximized the volume-outcome relationships observed with clipping. CONCLUSION Aneurysm microsurgery has embraced minimalism, tailoring the exposure to the patients anatomy with the smallest possible craniotomy that provides adequate exposure. The development of intracranial-intracranial bypasses is an important advancement that makes microsurgery a competitive option for complex and recurrent aneurysms. Trends toward centralizing aneurysm surgery in tertiary centers optimize results achievable with open microsurgery.BACKGROUND Endovascular techniques introduced strong extrinsic forces that provoked reactive changes in aneurysm surgery. Microsurgery has become less invasive, more appealing to patients, lower risk, and efficacious for complex aneurysms, particularly those unfavorable for or failing endovascular therapy. OBJECTIVE To review specific advances in open microsurgery for aneurysms. METHODS A university-based, single-surgeon practice was examined for the use of minimally invasive craniotomies, surgical management of recurrence after coiling, the use of intracranial-intracranial bypass techniques, and cerebrovascular volume-outcome relationships. RESULTS The mini-pterional, lateral supraorbital, and orbital-pterional craniotomies are minimally invasive alternatives to standard craniotomies. Mini-pterional and lateral supraorbital craniotomies were used in one-fourth of unruptured patients, increasing from 22% to 28%, whereas 15% of patients underwent orbital-pterional craniotomies and trended upward from 11% to 20%. Seventy-four patients were treated for coil recurrences (2.3% of all aneurysms) with direct clip occlusion (77%), clip occlusion after coil extraction (7%), or parent artery occlusion with bypass (16%). Intracranial-intracranial bypass (in situ bypass, reimplantation, reanastomosis, and intracranial grafts) transformed the management of giant aneurysms and made the surgical treatment of posterior inferior cerebellar artery aneurysms competitive with endovascular therapy. Centralization maximized the volume-outcome relationships observed with clipping. CONCLUSION Aneurysm microsurgery has embraced minimalism, tailoring the exposure to the patients anatomy with the smallest possible craniotomy that provides adequate exposure. The development of intracranial-intracranial bypasses is an important advancement that makes microsurgery a competitive option for complex and recurrent aneurysms. Trends toward centralizing aneurysm surgery in tertiary centers optimize results achievable with open microsurgery.

Comparative effectiveness of treatments for cerebral arteriovenous malformations: trends in nationwide outcomes from 2000 to 2009

OBJECT The development of multimodality approaches for the treatment of cerebral arteriovenous malformations (AVMs), including microsurgery, endovascular therapy, and radiosurgery, has shifted modern treatment paradigms in the last 10 years. This study examines these changes in detail from a nationwide perspective. METHODS The authors examined data from 2001 to 2009 in the Nationwide Inpatient Sample (NIS) database, and they assessed the safety, quality, and cost-effectiveness, including the total number of discharges, discharge proportion, length of stay, and hospital charges. The authors also examined patient demographics (including age, sex, income level, and insurance), hemorrhage status at presentation, and trends in open surgical and endovascular treatment. RESULTS A total of 33,997 inpatient admissions for patients with a primary diagnosis of intracranial AVM were identified, with a mean of 4191 patients admitted annually. The mean hospital charges increased 2-fold over the study period without significant differences in outcomes. There were substantial differences between surgical, endovascular, radiosurgical, and multimodality treatments. The proportion of AVMs treated microsurgically remained stable over this period, while the proportion treated endovascularly dramatically increased in size, and the data demonstrate important patient-level distinctions among groups. Outcomes and complication profiles were significantly different between treatment modalities and were impacted by age and hemorrhage status. CONCLUSIONS Charges associated with treatment of cerebral AVMs to the payer and society have increased dramatically over the first decade of the 21st century without clear improvements in quality parameters. However, analysis of the 3 primary treatment modalities has demonstrated differences and warrants further investigation to understand which patient population would benefit maximally from each. Unfortunately, with only imprecise measurements of quality in health care delivery, it remains imperative to develop national databases in which parameters, such as survival, functional outcomes, quality of life, and complication rates, can be assessed to examine the value of care delivered in a more meaningful way. Demonstrating an ever-increasing value of delivered health care will be imperative in our evolving health care system.

Surgery for primary supratentorial brain tumors in the United States, 2000-2009: effect of provider and hospital caseload on complication rates.

OBJECT The object of this study was to examine how procedural volume and patient demographics impact complication rates and value of care in those who underwent biopsy or craniotomy for supratentorial primary brain tumors. METHODS The authors conducted a retrospective cohort study using data from the Nationwide Inpatient Sample (NIS) on 62,514 admissions for biopsy or resection of supratentorial primary brain tumors for the period from 2000 to 2009. The main outcome measures were in-hospital mortality, routine discharge proportion, length of hospital stay, and perioperative complications. Associations between these outcomes and hospital or surgeon case volumes were examined in logistic regression models stratified across patient characteristics to control for presentation of disease and comorbid risk factors. The authors further computed value of care, defined as the ratio of functional outcome to hospital charges. RESULTS High-case-volume surgeons and hospitals had superior outcomes. After adjusting for patient characteristics, high-volume surgeon correlated with reduced complication rates (OR 0.91, p=0.04) and lower in-hospital mortality (OR 0.43, p<0.0001). High-volume hospitals were associated with reduced in-hospital mortality (OR 0.76, p=0.003), higher routine discharge proportion (OR 1.29, p<0.0001), and lower complication rates (OR 0.93, p=0.04). Patients treated by high-volume surgeons were less likely to experience postoperative hematoma, hydrocephalus, or wound complications. Patients treated at high-volume hospitals were less likely to experience mechanical ventilation, pulmonary complications, or infectious complications. Worse outcomes tended to occur in African American and Hispanic patients and in those without private insurance, and these demographic groups tended to underutilize high-volume providers. CONCLUSIONS A high-volume status for hospitals and surgeons correlates with superior value of care, as well as reduced in-hospital mortality and complications. These findings suggest that regionalization of care may enhance patient outcomes and improve value of care for patients with primary supratentorial brain tumors.

N-gram support vector machines for scalable procedure and diagnosis classification, with applications to clinical free text data from the intensive care unit.

BACKGROUND Existing risk adjustment models for intensive care unit (ICU) outcomes rely on manual abstraction of patient-level predictors from medical charts. Developing an automated method for abstracting these data from free text might reduce cost and data collection times. OBJECTIVE To develop a support vector machine (SVM) classifier capable of identifying a range of procedures and diagnoses in ICU clinical notes for use in risk adjustment. MATERIALS AND METHODS We selected notes from 2001-2008 for 4191 neonatal ICU (NICU) and 2198 adult ICU patients from the MIMIC-II database from the Beth Israel Deaconess Medical Center. Using these notes, we developed an implementation of the SVM classifier to identify procedures (mechanical ventilation and phototherapy in NICU notes) and diagnoses (jaundice in NICU and intracranial hemorrhage (ICH) in adult ICU). On the jaundice classification task, we also compared classifier performance using n-gram features to unigrams with application of a negation algorithm (NegEx). RESULTS Our classifier accurately identified mechanical ventilation (accuracy=0.982, F1=0.954) and phototherapy use (accuracy=0.940, F1=0.912), as well as jaundice (accuracy=0.898, F1=0.884) and ICH diagnoses (accuracy=0.938, F1=0.943). Including bigram features improved performance on the jaundice (accuracy=0.898 vs 0.865) and ICH (0.938 vs 0.927) tasks, and outperformed NegEx-derived unigram features (accuracy=0.898 vs 0.863) on the jaundice task. DISCUSSION Overall, a classifier using n-gram support vectors displayed excellent performance characteristics. The classifier generalizes to diverse patient populations, diagnoses, and procedures. CONCLUSIONS SVM-based classifiers can accurately identify procedure status and diagnoses among ICU patients, and including n-gram features improves performance, compared to existing methods.

Volume-Outcome Relationships in Neurosurgery

For a variety of neurosurgical conditions, increasing surgeon and hospital volumes correlate with improved outcomes, such as mortality, complication rates, length of stay, hospital charges, and discharge disposition. Neurosurgeons can improve patient outcomes at the population level by changing practice and referral patterns to regionalize care for select conditions at high-volume specialty treatment centers. Individual practitioners should be aware of where they fall on the volume spectrum and understand the implications of their practice and referral habits on their patients.