Tej D. Azad

All Publications

• Inflammatory macrophage-associated 3-gene signature predicts subclinical allograft injury and graft survival. JCI insight Azad, T. D., Donato, M., Heylen, L., Liu, A. B., Shen-Orr, S. S., Sweeney, T. E., Maltzman, J. S., Naesens, M., Khatri, P. 2018; 3 (2)

  Abstract

  Late allograft failure is characterized by cumulative subclinical insults manifesting over many years. Although immunomodulatory therapies targeting host T cells have improved short-term survival rates, rates of chronic allograft loss remain high. We hypothesized that other immune cell types may drive subclinical injury, ultimately leading to graft failure. We collected whole-genome transcriptome profiles from 15 independent cohorts composed of 1,697 biopsy samples to assess the association of an inflammatory macrophage polarization-specific gene signature with subclinical injury. We applied penalized regression to a subset of the data sets and identified a 3-gene inflammatory macrophage-derived signature. We validated discriminatory power of the 3-gene signature in 3 independent renal transplant data sets with mean AUC of 0.91. In a longitudinal cohort, the 3-gene signature strongly correlated with extent of injury and accurately predicted progression of subclinical injury 18 months before clinical manifestation. The 3-gene signature also stratified patients at high risk of graft failure as soon as 15 days after biopsy. We found that the 3-gene signature also distinguished acute rejection (AR) accurately in 3 heart transplant data sets but not in lung transplant. Overall, we identified a parsimonious signature capable of diagnosing AR, recognizing subclinical injury, and risk-stratifying renal transplant patients. Our results strongly suggest that inflammatory macrophages may be a viable therapeutic target to improve long-term outcomes for organ transplantation patients.

  View details for DOI 10.1172/jci.insight.95659

  View details for PubMedID 29367465

• Geographic variation in the surgical management of lumbar spondylolisthesis: characterizing practice patterns and outcomes. The spine journal : official journal of the North American Spine Society Azad, T. D., Vail, D., O'Connell, C., Han, S. S., Veeravagu, A., Ratliff, J. K. 2018

  Abstract

  The role of arthrodesis in the surgical management of lumbar spondylolisthesis remains controversial. We hypothesized that practice patterns and outcomes for this patient population may vary widely.To characterize geographic variation in surgical practices and outcomes for patients with lumbar spondylolisthesis.Retrospective analysis on a national longitudinal database between 2007 and 2014.We calculated arthrodesis rates, inpatient and long term costs, and key quality indicators (e.g. reoperation rates). Using linear and logistic regression models, we then calculated expected quality indicator values, adjusting for patient-level demographic factors, and compared these values to the observed values, to assess quality variation apart from differences in patient populations.We identified a cohort of 67,077 patients (60.7% female, mean age of 59.8 years (SD, 12.0) with lumbar spondylolisthesis who received either laminectomy or laminectomy with arthrodesis. The majority of patients received arthrodesis (91.8%). Actual rates of arthrodesis varied from 97.5% in South Dakota to 81.5% in Oregon. Geography remained a significant predictor of arthrodesis even after adjusting for demographic factors (p<0.001). Marked geographic variation was also observed in initial costs ($32,485 in Alabama to $78,433 in Colorado), two-year post-operative costs ($15,612 in Arkansas to $34,096 in New Jersey), length of hospital stay (2.6 days in Arkansas to 4.5 in Washington, D.C.), 30-day complication rates (9.5% in South Dakota to 22.4% in Maryland), 30-day readmission rates (2.5% in South Dakota to 13.6% in Connecticut), and reoperation rates (1.8% in Maine to 12.7% in Alabama).There is marked geographic variation in the rates of arthrodesis in treatment of spondylolisthesis within the United States. This variation remains pronounced after accounting for patient-level demographic differences. Costs of surgery and quality outcomes also vary widely. Further study is necessary to understand the drivers of this variation.

  View details for DOI 10.1016/j.spinee.2018.05.008

  View details for PubMedID 29746964

• Long-Term Effectiveness of Gross-Total Resection for Symptomatic Spinal Cord Cavernous Malformations. Neurosurgery Azad, T. D., Veeravagu, A., Li, A., Zhang, M., Madhugiri, V., Steinberg, G. K. 2018

  Abstract

  Intramedullary spinal cord cavernous malformations (CMs) account for 5% of all CMs in the central nervous system and 5% to 12% of all spinal cord vascular lesions, yet their optimal management is controversial.To identify factors associated with the clinical progression of spinal cord CMs and quantify the range of surgical outcomes.Retrospective observational cohort study of 32 patients who underwent open surgical resection for spinal CMs, the majority of which presented to a dorsal or lateral pial surface, from 1996 to 2017 at a single institution. We evaluated outcomes as clinically improved, worsened, or unchanged against preoperative baseline; Frankel and Aminoff-Logue disability grades were also calculated.Mean age at presentation was 44.2 (range, 0.5-77 yr). Symptoms included sensory deficits (n = 26, 81%), loss of strength/coordination (n = 16, 50%), pain (n = 16, 50%), and bladder/bowel dysfunction (n = 6, 19%). Thoracic (n = 16, 50%) and cervical CMs (n = 16, 50%) were equally common, with overall mean size of 7.1 mm (range, 1-20 mm). Functional outcomes at last follow-up, compared to preoperative status for patients with >6 mo of follow-up, were improved in 6 (23%), unchanged in 19 (73%), and worsened in 1 (4%) patients. Preoperative Frankel grade and improved Frankel grade immediately following resection were strongly associated with improvement from baseline at long-term followup (P < .01).Gross total resection of symptomatic spinal cord CMs can prevent further neurological decline. Our experience suggests excellent long-term outcomes and minimal surgical morbidity following resection.

  View details for DOI 10.1093/neuros/nyx610

  View details for PubMedID 29425323

• Neurosurgical Randomized Controlled Trials-Distance Travelled. Neurosurgery Azad, T. D., Veeravagu, A., Mittal, V., Esparza, R., Johnson, E., Ioannidis, J. P., Grant, G. A. 2017

  Abstract

  The evidence base for many neurosurgical procedures has been limited. We performed a comprehensive and systematic analysis of study design, quality of reporting, and trial results of neurosurgical randomized controlled trials (RCTs).To systematically assess the design and quality characteristics of neurosurgical RCTs.From January 1961 to June 2016, RCTs with >5 patients assessing any 1 neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINE, Scopus, and Cochrane Library.The median sample size in the 401 eligible RCTs was 73 patients with a mean patient age of 49.6. Only 111 trials (27.1%) described allocation concealment, 140 (34.6%) provided power calculations, and 117 (28.9%) were adequately powered. Significant efficacy or trend for efficacy was claimed in 226 reports (56.4%), no difference between the procedures was found in 166 trials (41.4%), and significant harm was reported in 9 trials (2.2%). Trials with a larger sample size were more likely to report randomization mode, specify allocation concealment, and power calculations (all P < .001). Government funding was associated with better specification of power calculations ( P = .008) and of allocation concealment ( P = .026), while industry funding was associated with reporting significant efficacy ( P = .02). Reporting of funding, specification of randomization mode and primary outcomes, and mention of power calculations improved significantly (all, P < .05) over time.Several aspects of the design and reporting of RCTs on neurosurgical procedures have improved over time. Better powered and accurately reported trials are needed in neurosurgery to deliver evidence-based care and achieve optimal outcomes.

  View details for DOI 10.1093/neuros/nyx319

  View details for PubMedID 28645203

• Preoperative depression, lumbar fusion, and opioid use: an assessment of postoperative prescription, quality, and economic outcomes. Neurosurgical focus O'Connell, C., Azad, T. D., Mittal, V., Vail, D., Johnson, E., Desai, A., Sun, E., Ratliff, J. K., Veeravagu, A. 2018; 44 (1): E5

  Abstract

  OBJECTIVE Preoperative depression has been linked to a variety of adverse outcomes following lumbar fusion, including increased pain, disability, and 30-day readmission rates. The goal of the present study was to determine whether preoperative depression is associated with increased narcotic use following lumbar fusion. Moreover, the authors examined the association between preoperative depression and a variety of secondary quality indicator and economic outcomes, including complications, 30-day readmissions, revision surgeries, likelihood of discharge home, and 1- and 2-year costs. METHODS A retrospective analysis was conducted using a national longitudinal administrative database (MarketScan) containing diagnostic and reimbursement data on patients with a variety of private insurance providers and Medicare for the period from 2007 to 2014. Multivariable logistic and negative binomial regressions were performed to assess the relationship between preoperative depression and the primary postoperative opioid use outcomes while controlling for demographic, comorbidity, and preoperative prescription drug-use variables. Logistic and log-linear regressions were also used to evaluate the association between depression and the secondary outcomes of complications, 30-day readmissions, revisions, likelihood of discharge home, and 1- and 2-year costs. RESULTS The authors identified 60,597 patients who had undergone lumbar fusion and met the study inclusion criteria, 4985 of whom also had a preoperative diagnosis of depression and 21,905 of whom had a diagnosis of spondylolisthesis at the time of surgery. A preoperative depression diagnosis was associated with increased cumulative opioid use (β = 0.25, p < 0.001), an increased risk of chronic use (OR 1.28, 95% CI 1.17-1.40), and a decreased probability of opioid cessation (OR 0.96, 95% CI 0.95-0.98) following lumbar fusion. In terms of secondary outcomes, preoperative depression was also associated with a slightly increased risk of complications (OR 1.14, 95% CI 1.03-1.25), revision fusions (OR 1.15, 95% CI 1.05-1.26), and 30-day readmissions (OR 1.19, 95% CI 1.04-1.36), although it was not significantly associated with the probability of discharge to home (OR 0.92, 95% CI 0.84-1.01). Preoperative depression also resulted in increased costs at 1 (β = 0.06, p < 0.001) and 2 (β = 0.09, p < 0.001) years postoperatively. CONCLUSIONS Although these findings must be interpreted in the context of the limitations inherent to retrospective studies utilizing administrative data, they provide additional evidence for the link between a preoperative diagnosis of depression and adverse outcomes, particularly increased opioid use, following lumbar fusion.

  View details for DOI 10.3171/2017.10.FOCUS17563

  View details for PubMedID 29290135

• Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters. Critical care medicine Sweeney, T. E., Azad, T. D., Donato, M., Haynes, W. A., Perumal, T. M., Henao, R., Bermejo-Martin, J. F., Almansa, R., Tamayo, E., Howrylak, J. A., Choi, A., Parnell, G. P., Tang, B., Nichols, M., Woods, C. W., Ginsburg, G. S., Kingsmore, S. F., Omberg, L., Mangravite, L. M., Wong, H. R., Tsalik, E. L., Langley, R. J., Khatri, P. 2018

  Abstract

  To find and validate generalizable sepsis subtypes using data-driven clustering.We used advanced informatics techniques to pool data from 14 bacterial sepsis transcriptomic datasets from eight different countries (n = 700).Retrospective analysis.Persons admitted to the hospital with bacterial sepsis.None.A unified clustering analysis across 14 discovery datasets revealed three subtypes, which, based on functional analysis, we termed "Inflammopathic, Adaptive, and Coagulopathic." We then validated these subtypes in nine independent datasets from five different countries (n = 600). In both discovery and validation data, the Adaptive subtype is associated with a lower clinical severity and lower mortality rate, and the Coagulopathic subtype is associated with higher mortality and clinical coagulopathy. Further, these clusters are statistically associated with clusters derived by others in independent single sepsis cohorts.The three sepsis subtypes may represent a unifying framework for understanding the molecular heterogeneity of the sepsis syndrome. Further study could potentially enable a precision medicine approach of matching novel immunomodulatory therapies with septic patients most likely to benefit.

  View details for DOI 10.1097/CCM.0000000000003084

  View details for PubMedID 29537985

• Cranioplasty Complications and Costs: A National Population-Level Analysis Using the MarketScan Longitudinal Database. World neurosurgery Li, A., Azad, T. D., Veeravagu, A., Bhatti, I., Long, C., Ratliff, J. K., Li, G. 2017; 102: 209-220

  Abstract

  To characterize cranioplasty complications and costs at a population level using a longitudinal national claims database.We identified cranioplasty patients between 2007-2014 in the MarketScan national database. We evaluated age, autograft usage, cranioplasty size, and cranioplasty timing on postoperative outcomes. We further analyzed associated costs. A subset analysis of adult cranioplasty patients with emergent indications, including stroke and trauma, was also performed.We identified 8,275 patients (mean 44.0±20.0 years, 45.2% male) consisting of 13.8% pediatric (<18 years), 76.0% adults (18-64 years), and 10.2% elderly adults (>65 years). Overall complication rate was 36.6%, mortality rate 0.5%, and 30-day readmission rate 12.0%. Elderly patients had the highest complication rate (p<0.0001). Overall, large cranioplasties (>5 cm) saw higher complication rates than small cranioplasties (≤5 cm, p=0.047). In those with emergent indications only(N=1,282), size did not influence complications-though large cranioplasties showed higher infection risk (p=0.02). Overall, autograft use did not affect outcomes, but was associated with higher complication risk-including infections-in the subset with only emergent indications (p<0.001, p=0.001). Late (>90 days) cranioplasty timing had higher complication rates in both the overall cohort and subset with emergent indications (p<0.001, p<0.001). Index costs of care were mainly driven by hospital payments in both the overall cohort and those with emergent indications.We found a high complication rate associated with cranioplasty in the U.S.A. Older age, large cranioplasties, and delayed cranioplasties increased complication risk overall. Among those with only emergent indications, complications were associated with a delayed time to cranioplasty and autograft usage.

  View details for DOI 10.1016/j.wneu.2017.03.022

  View details for PubMedID 28315803

• Predicting complication risk in spine surgery: a prospective analysis of a novel risk assessment tool. Journal of neurosurgery. Spine Veeravagu, A., Li, A., Swinney, C., Tian, L., Moraff, A., Azad, T. D., Cheng, I., Alamin, T., Hu, S. S., Anderson, R. L., Shuer, L., Desai, A., Park, J., Olshen, R. A., Ratliff, J. K. 2017: 1-11

  Abstract

  OBJECTIVE The ability to assess the risk of adverse events based on known patient factors and comorbidities would provide more effective preoperative risk stratification. Present risk assessment in spine surgery is limited. An adverse event prediction tool was developed to predict the risk of complications after spine surgery and tested on a prospective patient cohort. METHODS The spinal Risk Assessment Tool (RAT), a novel instrument for the assessment of risk for patients undergoing spine surgery that was developed based on an administrative claims database, was prospectively applied to 246 patients undergoing 257 spinal procedures over a 3-month period. Prospectively collected data were used to compare the RAT to the Charlson Comorbidity Index (CCI) and the American College of Surgeons National Surgery Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator. Study end point was occurrence and type of complication after spine surgery. RESULTS The authors identified 69 patients (73 procedures) who experienced a complication over the prospective study period. Cardiac complications were most common (10.2%). Receiver operating characteristic (ROC) curves were calculated to compare complication outcomes using the different assessment tools. Area under the curve (AUC) analysis showed comparable predictive accuracy between the RAT and the ACS NSQIP calculator (0.670 [95% CI 0.60-0.74] in RAT, 0.669 [95% CI 0.60-0.74] in NSQIP). The CCI was not accurate in predicting complication occurrence (0.55 [95% CI 0.48-0.62]). The RAT produced mean probabilities of 34.6% for patients who had a complication and 24% for patients who did not (p = 0.0003). The generated predicted values were stratified into low, medium, and high rates. For the RAT, the predicted complication rate was 10.1% in the low-risk group (observed rate 12.8%), 21.9% in the medium-risk group (observed 31.8%), and 49.7% in the high-risk group (observed 41.2%). The ACS NSQIP calculator consistently produced complication predictions that underestimated complication occurrence: 3.4% in the low-risk group (observed 12.6%), 5.9% in the medium-risk group (observed 34.5%), and 12.5% in the high-risk group (observed 38.8%). The RAT was more accurate than the ACS NSQIP calculator (p = 0.0018). CONCLUSIONS While the RAT and ACS NSQIP calculator were both able to identify patients more likely to experience complications following spine surgery, both have substantial room for improvement. Risk stratification is feasible in spine surgery procedures; currently used measures have low accuracy.

  View details for DOI 10.3171/2016.12.SPINE16969

  View details for PubMedID 28430052

• Reverse phase protein arrays enable glioblastoma molecular subtyping JOURNAL OF NEURO-ONCOLOGY Hutter, G., Sailer, M., Azad, T. D., von Bueren, A. O., Nollau, P., Frank, S., Tostado, C., Sarvepalli, D., Ghosh, A., Ritz, M., Boulay, J., Mariani, L. 2017; 131 (3): 437-448

  View details for DOI 10.1007/s11060-016-2316-5

  View details for Web of Science ID 000397329100002

• Endoscopic vs. Microscopic Resection of Sellar Lesions-A Matched Analysis of Clinical and Socioeconomic Outcomes. Frontiers in surgery Azad, T. D., Lee, Y. J., Vail, D., Veeravagu, A., Hwang, P. H., Ratliff, J. K., Li, G. 2017; 4: 33

  Abstract

  Direct comparisons of microscopic and endoscopic resection of sellar lesions are scarce, with conflicting reports of cost and clinical outcome advantages.To determine if the proposed benefits of endoscopic resection are realized on a population level.We performed a matched cohort study of 9,670 adult patients in the MarketScan database who underwent either endoscopic or microscopic surgery for sellar lesions. Coarsened matching was applied to estimate the effects of surgical approach on complication rates, length of stay (LOS), costs, and likelihood of postoperative radiation.We found that LOS, readmission, and revision rates did not differ significantly between approaches. The overall complication rate was higher for endoscopy (47% compared to 39%, OR 1.37, 95% CI 1.22-1.53). Endoscopic approach was associated with greater risk of neurological complications (OR 1.32, 95% CI 1.11-1.55), diabetes insipidus (OR 1.65, 95% CI 1.37-2.00), and cerebrospinal fluid rhinorrhea (OR 1.83, 95% CI 1.07-3.13) compared to the microscopic approach. Although the total index payment was higher for patients receiving endoscopic resection ($32,959 compared to $29,977 for microscopic resection), there was no difference in long-term payments. Endoscopic surgery was associated with decreased likelihood of receiving post-resection stereotactic radiosurgery (OR 0.67, 95% CI 0.49-0.90) and intensity-modulated radiation therapy (OR 0.78, 95% CI 0.65-0.93).Our results suggest that the transition from a microscopic to endoscopic approach to sellar lesions must be subject to careful evaluation. Although there are evident advantages to transsphenoidal endoscopy, our analysis suggests that the benefits of the endoscopic approach are yet to be materialized.

  View details for DOI 10.3389/fsurg.2017.00033

  View details for PubMedID 28691009

  View details for PubMedCentralID PMC5479879

• Diagnostic Utility of Intraoperative Neurophysiological Monitoring for Intramedullary Spinal Cord Tumors: Systematic Review and Meta-Analysis. Clinical spine surgery Azad, T. D., Pendharkar, A. V., Nguyen, V., Pan, J., Connolly, I. D., Veeravagu, A., Popat, R., Ratliff, J. K., Grant, G. A. 2017

  Abstract

  Systematic review and meta-analysis.The aim of this study was to systematically evaluate the diagnostic utility of intraoperative neurophysiological monitoring (IONM) for detecting postoperative injury in resection of intramedullary spinal cord tumors (IMSCT).Surgical management of IMSCT can involve key neurological and vascular structures. IONM aims to assess the functional integrity of susceptible elements in real time. The diagnostic value of IONM for ISMCT has not been systematically evaluated.We performed a systematic review of the PubMed and MEDLINE databases for studies investigating the use of IONM for IMSCT and conducted a meta-analysis of diagnostic capability.Our search produced 257 citations. After application of exclusion criteria, 21 studies remained, 10 American Academy of Neurology grade III and 11 American Academy of Neurology grade IV. We found that a strong pooled mean sensitivity of 90% [95% confidence interval (CI), 84-94] and a weaker pooled mean specificity of 82% (95% CI, 70-90) for motor-evoked potential (MEP) recording changes. Somatosensory-evoked potential (SSEP) recording changes yielded pooled sensitivity of 85% (95% CI, 75-91) and pooled specificity of 72% (95% CI, 57-83). The pooled diagnostic odds ratio for MEP was 55.7 (95% CI, 26.3-119.1) and 14.3 (95% CI, 5.47-37.3) for SSEP. Bivariate analysis yielded summary receiver operative characteristic curves with area under the curve of 91.8% for MEPs and 86.3% for SSEPs.MEPs and SSEPs appear to be more sensitive than specific for detection of postoperative injury. Patients with perioperative neurological deficits are 56 times more likely to have had changes in MEPs during the procedure. We observed considerable variability in alarm criteria and interventions in response to IONM changes, indicating the need for prospective studies capable of defining standardized alarm criteria and responses.

  View details for DOI 10.1097/BSD.0000000000000558

  View details for PubMedID 28650882

• Outcomes of cervical laminoplasty-Population-level analysis of a national longitudinal database. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Veeravagu, A., Azad, T. D., Zhang, M., Li, A., Pendharkar, A. V., Ratliff, J. K., Shuer, L. M. 2017

  Abstract

  Cervical laminoplasty is an important alternative to laminectomy in decompressing of the cervical spine. Further evidence to assess the utility of laminoplasty is required. We examine outcomes of cervical laminoplasty via a population level analysis in the United States.We performed a population-level analysis using the national MarketScan longitudinal database to analyze outcomes and costs of cervical laminoplasty between 2007 and 2014. Outcomes included postoperative complications, revision rates, and functional outcomes.Using a national administrative database, we identified 2613 patients (65.6% male, mean 58.5 years) who underwent cervical laminoplasty. Mean length of stay was 3.1 ± 2.8 days and mean follow-up was 795.5 ± 670.6 days. The overall complication rate was 22.5% (N = 587), 30-day readmission rate was 7.5% (N = 195), and mortality rate was 0.08% (N = 2, elderly patients only). The complication rate was significantly increased in elderly patients (age >65 years) compared to non-elderly patients (OR 0.751, p < .01). The use of intraoperative neuromonitoring (IONM) during the cervical laminoplasty procedure did not significantly impact outcomes. The overall re-operation rate after the initial procedure was 10.9%. Total costs of cervical laminoplasty were mainly driven by hospital charges with physician-related payments comprising a small amount.Our national analysis of cervical laminoplasty found the procedure to be clinically effective with low complication rates and postoperative symptomatic improvement.

  View details for DOI 10.1016/j.jocn.2017.10.089

  View details for PubMedID 29153782

• Postoperative Opioid Use, Complications, and Costs in Surgical Management of Lumbar Spondylolisthesis. Spine Vail, D., Azad, T. D., O'Connell, C., Han, S. S., Veeravagu, A., Ratliff, J. K. 2017

  Abstract

  Retrospective analysis on a national longitudinal database (2007-2014).To determine the association between arthrodesis and complication rates, costs, surgical revision, and postoperative opioid prescription.Arthrodesis in patients receiving laminectomy for lumbar spondylolisthesis remains controversial. However, population-level evidence to support the use of arthrodesis remains limited.We identified 73,176 patient records and used coarsened exact matching to create comparable populations of patients who received laminectomy or laminectomy with arthrodesis. We use linear and logistic regression models to analyze the relationship between arthrodesis and postoperative complications, length of stay, costs, readmissions, surgical revisions, and postoperative opioid prescribing.Patients who underwent arthrodesis spent one more day in the hospital on average (p < 0.01), and had higher costs of care at their index visit ($24,126, p < 0.01), which were partially offset by lower costs of care over the two years following their procedure ($14,667 less in arthrodesis patients, p = 0.01). Patients with arthrodesis were less likely to have a surgical revision (OR = 0.66, p < 0.01). Patients with arthrodesis used more opioids in the first two months following their procedure, but had comparable opioid use to patients undergoing laminectomy without arthrodesis in all other post-operative months over the next two years, and were not more or less likely to convert to chronic opioid use. Postoperative opioid prescription varied dramatically across states (p < 0.01); geographic variation in opioid use is substantially greater than differences in opioid use based on procedure performed.Arthrodesis is associated with reduced likelihood of surgical revision and increased use of opioids in the first two months following surgery, but not associated with greater or lesser opioid use beyond the initial two postoperative months. Geographic variation in opioid use is substantial even after accounting for patient characteristics and for whether patients underwent arthrodesis.3.

  View details for DOI 10.1097/BRS.0000000000002509

  View details for PubMedID 29215492

• Spontaneous Intrauterine Depressed Skull Fractures: Report of Two Cases Requiring Neurosurgical Intervention and Literature Review. World neurosurgery Veeravagu, A., Azad, T. D., Jiang, B., Edwards, M. S. 2017

  Abstract

  Spontaneous intrauterine depressed skull fractures (IDSF) are rare fractures that often require neurosurgical evaluation and therapy. The majority of reported congenital depressions are secondary to maternal abdominal trauma or instrumentation during delivery. Spontaneous IDSF occur in the setting of uneventful normal spontaneous vaginal delivery (NSVD) or cesarean section, without obvious predisposing risk factors. The etiology and optimal management of spontaneous IDSF remain controversial.We describe 2 cases of spontaneous IDSF that underwent cranioplasty at our institution using an absorbable mesh, as well as review the current state of knowledge regarding the diagnosis and management of spontaneous IDSF. The 2 neonates, 1 male and 1 female, presented at Lucile Packard Children's Hospital with spontaneous IDSF after uneventful NSVDs. The fractures were located in the left frontal and right parieto-temporal calvarium, respectively. Both patients underwent open craniotomy and elevation of their IDSF with mesh cranioplasty. At last follow-up, both patients were normocephalic and neurologically intact.Neurosurgery consultation is necessary for initial evaluation of spontaneous IDSF. Surgical intervention is indicated for larger defects and/or intracranial involvement. Expectant management and negative-pressure elevation have also been shown to be effective.

  View details for DOI 10.1016/j.wneu.2017.10.029

  View details for PubMedID 29051109

• Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L., Scherer, F., Kurtz, D. M., Say, C., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. 2017

  Abstract

  Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

  View details for DOI 10.1158/2159-8290.CD-17-0716

  View details for PubMedID 28899864

• Precision annotation of digital samples in NCBI's gene expression omnibus. Scientific data Hadley, D., Pan, J., El-Sayed, O., Aljabban, J., Aljabban, I., Azad, T. D., Hadied, M. O., Raza, S., Rayikanti, B. A., Chen, B., Paik, H., Aran, D., Spatz, J., Himmelstein, D., Panahiazar, M., Bhattacharya, S., Sirota, M., Musen, M. A., Butte, A. J. 2017; 4: 170125

  Abstract

  The Gene Expression Omnibus (GEO) contains more than two million digital samples from functional genomics experiments amassed over almost two decades. However, individual sample meta-data remains poorly described by unstructured free text attributes preventing its largescale reanalysis. We introduce the Search Tag Analyze Resource for GEO as a web application (http://STARGEO.org) to curate better annotations of sample phenotypes uniformly across different studies, and to use these sample annotations to define robust genomic signatures of disease pathology by meta-analysis. In this paper, we target a small group of biomedical graduate students to show rapid crowd-curation of precise sample annotations across all phenotypes, and we demonstrate the biological validity of these crowd-curated annotations for breast cancer. STARGEO.org makes GEO data findable, accessible, interoperable and reusable (i.e., FAIR) to ultimately facilitate knowledge discovery. Our work demonstrates the utility of crowd-curation and interpretation of open 'big data' under FAIR principles as a first step towards realizing an ideal paradigm of precision medicine.

  View details for DOI 10.1038/sdata.2017.125

  View details for PubMedID 28925997

  View details for PubMedCentralID PMC5604135

• Cervical Spondylotic Myelopathy CLINICAL SPINE SURGERY Iyer, A., Azad, T. D., Tharin, S. 2016; 29 (10): 408-414

  Abstract

  Cervical spondylotic myelopathy (CSM) is a degenerative disease that represents the most common spinal cord disorder in adults. The natural history of the disease can be insidious, and patients often develop debilitating spasticity and weakness. Diagnosis includes a combination of physical examination and various imaging modalities. There are various surgical options for CSM, consisting of anterior and posterior procedures. This article summarizes the literature regarding the pathophysiology, natural history, and diagnosis of CSM, as well as the various treatment options and their associated risks and indications.

  View details for Web of Science ID 000388489300010

  View details for PubMedID 27352369

• Impact of Inpatient Venous Thromboembolism Continues After Discharge: Retrospective Propensity Scored Analysis in a Longitudinal Database. Clinical spine surgery Li, A. Y., Azad, T. D., Veeravagu, A., Bhatti, I., Li, A., Cole, T., Desai, A., Ratliff, J. K. 2016: -?

  Abstract

  Propensity score matched retrospective study using a nationwide longitudinal database.To quantify the longitudinal economic impact of venous thromboembolism (VTE) complications in spinal fusion patients.VTE is a rare and serious complication that may occur after spine surgery. The long-term socioeconomic impact understanding of these events has been limited by small sample sizes and a lack of longitudinal follow-up. We provide a comparative economic outcomes analysis of these complications.We identified 204,308 patients undergoing spinal fusion procedures in a national billing claims database (MarketScan) between 2006 and 2010. Cohorts were balanced using 50:1 propensity score matching and outcome measures compared at 6, 12, and 18 months postoperation.A total of 1196 (0.6%) patients developed postoperative VTE, predominantly occurring following lumbar fusion (69.7%). Postoperative VTE patients demonstrated an increase in hospital length of stay (7.8 vs. 3.3 d, P<0.001) and a decreased likelihood of being discharged home (71% vs. 85%, P<0.001). A $26,306 increase in total hospital payments (P<0.001) was observed, with a disproportionate increase seen in hospital payments ($22,103, P<0.001), relative to physician payments ($1766, P=0.001).At 6, 12, and 18 months postfusion, increased rates of readmission and follow-up clinic visits were observed. Delayed readmissions were associated with decreased length of stay (3.6 vs. 4.6 d, P<0.001), but increased total payments, averaging at $21,270 per readmission. VTE patients generated greater cumulative outpatient service payments, costing $8075, $11,134, and $13,202 more at 6, 12, and 18 months (P<0.001).VTEs are associated with longer hospitalizations, a decreased likelihood of being discharged home, and overall increases of hospital resource utilization and cost in inpatient and outpatient settings. VTE patients generate greater charges in the outpatient setting and are more likely to become readmitted at 6, 12, and 18 months after surgery, demonstrating a significant socioeconomic impact long after occurrence.Level III-therapeutic.

  View details for PubMedID 27750270

• Delayed Presentation of Sciatic Nerve Injury after Total Hip Arthroplasty: Neurosurgical Considerations, Diagnosis, and Management. Journal of neurological surgery reports Xu, L. W., Veeravagu, A., Azad, T. D., Harraher, C., Ratliff, J. K. 2016; 77 (3): e134-8

  Abstract

  Total hip arthroplasty (THA) is an established treatment for end-stage arthritis, congenital deformity, and trauma with good long-term clinical and functional outcomes. Delayed sciatic nerve injury is a rare complication after THA that requires prompt diagnosis and management.We present a case of sciatic nerve motor and sensory deficit in a 52-year-old patient 2 years after index left THA. Electromyography (EMG) results and imaging with radiographs and CT of the affected hip demonstrated an aberrant acetabular cup screw in the posterior-inferior quadrant adjacent to the sciatic nerve.The patient underwent surgical exploration that revealed injury to the peroneal division of the sciatic nerve due to direct injury from screw impingement. A literature review identified 11 patients with late-onset neuropathy after THA. Ten patients underwent surgical exploration and pain often resolved after surgery with 56% of patients recovering sensory function and 25% experiencing full recovery of motor function.Delayed neuropathy of the sciatic nerve is a rare complication after THA that is most often due to hardware irritation, component failure, or wear-related pseudotumor formation. Operative intervention is often pursued to explore and directly visualize the nerve with limited results in the literature showing modest relief of pain and sensory symptoms and poor restoration of motor function.

  View details for DOI 10.1055/s-0035-1568134

  View details for PubMedID 27602309

  View details for PubMedCentralID PMC5011454

• Surgical outcomes of cervical spondylotic myelopathy: an analysis of a national, administrative, longitudinal database. Neurosurgical focus Veeravagu, A., Connolly, I. D., Lamsam, L., Li, A., Swinney, C., Azad, T. D., Desai, A., Ratliff, J. K. 2016; 40 (6): E11-?

  Abstract

  OBJECTIVE The authors performed a population-based analysis of national trends, costs, and outcomes associated with cervical spondylotic myelopathy (CSM) in the United States. They assessed postoperative complications, resource utilization, and predictors of costs, in this surgically treated CSM population. METHODS MarketScan data (2006-2010) were used to retrospectively analyze the complications and costs of different spine surgeries for CSM. The authors determined outcomes following anterior cervical discectomy and fusion (ACDF), posterior fusion, combined anterior/posterior fusion, and laminoplasty procedures. RESULTS The authors identified 35,962 CSM patients, comprising 5154 elderly (age ≥ 65 years) patients (mean 72.2 years, 54.9% male) and 30,808 nonelderly patients (mean 51.1 years, 49.3% male). They found an overall complication rate of 15.6% after ACDF, 29.2% after posterior fusion, 41.1% after combined anterior and posterior fusion, and 22.4% after laminoplasty. Following ACDF and posterior fusion, a significantly higher risk of complication was seen in the elderly compared with the nonelderly (reference group). The fusion level and comorbidity-adjusted ORs with 95% CIs for these groups were 1.54 (1.40-1.68) and 1.25 (1.06-1.46), respectively. In contrast, the elderly population had lower 30-day readmission rates in all 4 surgical cohorts (ACDF, 2.6%; posterior fusion, 5.3%; anterior/posterior fusion, 3.4%; and laminoplasty, 3.6%). The fusion level and comorbidity-adjusted odds ratios for 30-day readmissions for ACDF, posterior fusion, combined anterior and posterior fusion, and laminoplasty were 0.54 (0.44-0.68), 0.32 (0.24-0.44), 0.17 (0.08-0.38), and 0.39 (0.18-0.85), respectively. CONCLUSIONS The authors' analysis of the MarketScan database suggests a higher complication rate in the surgical treatment of CSM than previous national estimates. They found that elderly age (≥ 65 years) significantly increased complication risk following ACDF and posterior fusion. Elderly patients were less likely to experience a readmission within 30 days of surgery. Postoperative complication occurrence, and 30-day readmission were significant drivers of total cost within 90 days of the index surgical procedure.

  View details for DOI 10.3171/2016.3.FOCUS1669

  View details for PubMedID 27246481

• Neurorestoration after stroke NEUROSURGICAL FOCUS Azad, T. D., Veeravagu, A., Steinberg, G. K. 2016; 40 (5)

  Abstract

  Recent advancements in stem cell biology and neuromodulation have ushered in a battery of new neurorestorative therapies for ischemic stroke. While the understanding of stroke pathophysiology has matured, the ability to restore patients' quality of life remains inadequate. New therapeutic approaches, including cell transplantation and neurostimulation, focus on reestablishing the circuits disrupted by ischemia through multidimensional mechanisms to improve neuroplasticity and remodeling. The authors provide a broad overview of stroke pathophysiology and existing therapies to highlight the scientific and clinical implications of neurorestorative therapies for stroke.

  View details for DOI 10.3171/2016.2.FOCUS15637

  View details for Web of Science ID 000375119300001

  View details for PubMedID 27132523

  View details for PubMedCentralID PMC4916840

• Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo PLOS ONE Zhang, M., Hutter, G., Kahn, S. A., Azad, T. D., Gholamin, S., Xu, C. Y., Liu, J., Achrol, A. S., Richard, C., Sommerkamp, P., Schoen, M. K., McCracken, M. N., Majeti, R., Weissman, I., Mitra, S. S., Cheshier, S. H. 2016; 11 (4)

  Abstract

  Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

  View details for DOI 10.1371/journal.pone.0153550

  View details for Web of Science ID 000374541200027

  View details for PubMedID 27092773

  View details for PubMedCentralID PMC4836698

• Abducens Nerve Avulsion and Facial Nerve Palsy After Temporal Bone Fracture: A Rare Concomitance of Injuries. World neurosurgery Azad, T. D., Veeravagu, A., Corrales, C. E., Chow, K. K., Fischbein, N. J., Harris, O. A. 2016; 88: 689 e5-8

  Abstract

  Avulsion of the abducens nerve in the setting of geniculate ganglion injury after temporal bone fracture is unreported previously. We discuss clinical assessment and management of a patient with traumatic avulsion of cranial nerve (CN) VI in the setting of an ipsilateral CN VII injury after temporal bone fracture and call attention to this unusual injury.A 26-year-old man suffered a temporal bone fracture after a motor vehicle accident and developed diplopia and right-sided facial droop. Six weeks after the accident, the patient was readmitted with worsening diplopia and ipsilateral facial weakness. He demonstrated absent lateral gaze on the right suggestive of either restrictive movement or right.In addition, he had right-sided facial palsy graded as 6/6 House-Brackmann. High-resolution computed tomography demonstrated a right-sided longitudinal otic capsule-sparing temporal bone fracture that propagated into the facial nerve canal and geniculate fossa. Magnetic resonance imaging revealed discontinuity of the right CN VI between the pons and the Dorello canal, as well as injury to the ipsilateral geniculate ganglion. CN VII was intact proximally, from the pons through the internal auditory canal. Consensus was reached to proceed with conservative management. At 13 months after injury, the patient reported 1/6 House-Brackmann with no improvement in CN VI function.This case illustrates 2 subtle findings on imaging with potential therapeutic implications, notably the role of surgical intervention for facial nerve palsy.

  View details for DOI 10.1016/j.wneu.2015.11.076

  View details for PubMedID 26723286

• Trigeminal and sphenopalatine ganglion stimulation for intractable craniofacial pain-case series and literature review ACTA NEUROCHIRURGICA William, A., Azad, T. D., Brecher, E., Cherry, T., Bernstein, I., Bruce, D. M., Rohrer, S., Smith, Z., William, M., Sabelman, E., Heit, G., Pezeshkian, P., Sedrak, M. 2016; 158 (3): 513-520

  Abstract

  Facial pain is often debilitating and can be characterized by a sharp, stabbing, burning, aching, and dysesthetic sensation. Specifically, trigeminal neuropathic pain (TNP), anesthesia dolorosa, and persistent idiopathic facial pain (PIFP) are difficult diseases to treat, can be quite debilitating and an effective, enduring treatment remains elusive.We retrospectively reviewed our early experience with stimulation involving the trigeminal and sphenopalatine ganglion stimulation for TNP, anesthesia dolorosa, and PIFP between 2010-2014 to assess the feasibility of implanting at these ganglionic sites. Seven patients received either trigeminal and/or sphenopalatine ganglion stimulation with or without peripheral nerve stimulation, having failed multiple alternative modalities of treatment. The treatments were tailored on the physical location of pain to ensure regional coverage with the stimulation.Fluoroscopy or frameless stereotaxy was utilized to place the sphenopalatine and/or trigeminal ganglion stimulator. All patients were initially trialed before implantation. Trial leads implanted in the pterygopalatine fossa near the sphenopalatine ganglion were implanted via transpterygoid (lateral-medial, infrazygomatic) approach. Trial leads were implanted in the trigeminal ganglion via percutaneous Hartel approach, all of which resulted in masseter contraction. Patients who developed clinically significant pain improvement underwent implantation. The trigeminal ganglion stimulation permanent implants involved placing a grid electrode over Meckel's cave via subtemporal craniotomy, which offered a greater ability to stimulate subdivisions of the trigeminal nerve, without muscular (V3) side effects. Two of the seven overall patients did not respond well to the trial and were not implanted. Five patients reported pain relief with up to 24-month follow-up. Several of the sphenopalatine ganglion stimulation patients had pain relief without any paresthesias. There were no electrode migrations or post-surgical complications.Refractory facial pain may respond positively to ganglionic forms of stimulation. It appears safe and durable to implant electrodes in the pterygopalatine fossa via a lateral transpterygoid approach. Also, implantation of an electrode grid overlying Meckel's cave appears to be a feasible alternative to the Hartel approach. Further investigation is needed to evaluate the usefulness of these approaches for various facial pain conditions.

  View details for DOI 10.1007/s00701-015-2695-y

  View details for Web of Science ID 000370074500020

  View details for PubMedID 26743912

• Size and distribution of the global volume of surgery in 2012. Bulletin of the World Health Organization Weiser, T. G., Haynes, A. B., Molina, G., Lipsitz, S. R., Esquivel, M. M., Uribe-Leitz, T., Fu, R., Azad, T., Chao, T. E., Berry, W. R., Gawande, A. A. 2016; 94 (3): 201-209F

  Abstract

  To estimate global surgical volume in 2012 and compare it with estimates from 2004.For the 194 Member States of the World Health Organization, we searched PubMed for studies and contacted key informants for reports on surgical volumes between 2005 and 2012. We obtained data on population and total health expenditure per capita for 2012 and categorized Member States as very-low, low, middle and high expenditure. Data on caesarean delivery were obtained from validated statistical reports. For Member States without recorded surgical data, we estimated volumes by multiple imputation using data on total health expenditure. We estimated caesarean deliveries as a proportion of all surgery.We identified 66 Member States reporting surgical data. We estimated that 312.9 million operations (95% confidence interval, CI: 266.2-359.5) took place in 2012, an increase from the 2004 estimate of 226.4 million operations. Only 6.3% (95% CI: 1.7-22.9) and 23.1% (95% CI: 14.8-36.7) of operations took place in very-low- and low-expenditure Member States representing 36.8% (2573 million people) and 34.2% (2393 million people) of the global population of 7001 million people, respectively. Caesarean deliveries comprised 29.6% (5.8/19.6 million operations; 95% CI: 9.7-91.7) of the total surgical volume in very-low-expenditure Member States, but only 2.7% (5.1/187.0 million operations; 95% CI: 2.2-3.4) in high-expenditure Member States.Surgical volume is large and growing, with caesarean delivery comprising nearly a third of operations in most resource-poor settings. Nonetheless, there remains disparity in the provision of surgical services globally.

  View details for DOI 10.2471/BLT.15.159293

  View details for PubMedID 26966331

  View details for PubMedCentralID PMC4773932

• Stereotactic radiosurgery for metastasis to the craniovertebral junction preserves spine stability and offers symptomatic relief JOURNAL OF NEUROSURGERY-SPINE Azad, T. D., Esparza, R., Chaudhary, N., Chang, S. D. 2016; 24 (2): 241-247

  View details for DOI 10.3171/2015.6.SPINE15190

  View details for Web of Science ID 000368866000006

• Building an electronic health record integrated quality of life outcomes registry for spine surgery. Journal of neurosurgery. Spine Azad, T. D., Kalani, M., Wolf, T., Kearney, A., Lee, Y., Flannery, L., Chen, D., Berroya, R., Eisenberg, M., Park, J., Shuer, L., Kerr, A., Ratliff, J. K. 2016; 24 (1): 176-185

  Abstract

  Demonstrating the value of spine care requires adequate outcomes assessment. Long-term outcomes are best measured as overall improvement in quality of life (QOL) after surgical intervention. Present registries often require parallel data entry, introducing inefficiencies and limiting compliance. The authors detail the methodology of constructing an integrated electronic health record (EHR) system to collect QOL metrics and demonstrate the effect of data collection on routine clinical workflow. A streamlined approach to collecting QOL data can capture patient data without requiring dual data entry and without increasing clinic visit times.Through extensive literature review, a combination of QOL assessments was selected, consisting of the Patient Health Questionnaire-2 and -9, Oswestry Disability Index, Neck Disability Index, and visual analog scale for pain. These metrics were used to provide assessment of QOL following spine surgery and were incorporated into standard clinic workflow by a multidisciplinary team of surgeons, advanced practice providers, and health care information technology specialists. A clinical dashboard tracking more than 25 patient variables was developed. Clinic flow was assessed and opportunities for improvement reviewed. Duration of clinic visits before and after initiation of QOL measure capture was recorded, with assessment of mean clinic visit times for the 12 months before and the 12 months after implementation.The integrated QOL capture was instituted for 3 spine surgeons in a tertiary care academic center. In the 12-month period prior to initiating collection of QOL data, 806 new patient visits were completed with an average visit time of 127.9 ± 51.5 minutes. In the 12 months after implementation, 1013 new patient visits were recorded, with 791 providing QOL measures with an average visit time of 117.0 ± 45.7 minutes. Initially the primary means of collecting patient outcome data was via paper form, with gradual transition to collection via entry into the electronic medical records system. To improve electronic data capture, paper forms were eliminated and an online portal used as part of the patient rooming process. This improved electronic capture to nearly 98% without decreasing the number of patients enrolled in the process.A systematic approach to collecting spine-related QOL data within an EHR system is feasible and offers distinct advantages over registries that require dual data entry. The process of data collection does not impact patients' clinical visit or providers' clinical workflow. This approach is scalable, and may form the foundation for a decentralized outcomes registry network.

  View details for DOI 10.3171/2015.3.SPINE141127

  View details for PubMedID 26431073

• Telemedical Education: Training Digital Natives in Telemedicine. Journal of medical Internet research Pathipati, A. S., Azad, T. D., Jethwani, K. 2016; 18 (7)

  Abstract

  Telemedicine plays an important role in the delivery of medical care, and will become increasingly prominent going forward. Current medical students are among the first generation of "digital natives" who are well versed in the incorporation of technology into social interaction. These students are well positioned to apply advances in communications to patient care. Even so, providers require training to effectively leverage these opportunities. Therefore, we recommend introducing telemedicine training into medical school curricula and propose a model for incorporation.

  View details for DOI 10.2196/jmir.5534

  View details for PubMedID 27405323

  View details for PubMedCentralID PMC4961876

• Heparan sulfate proteoglycans mediate Aβ-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells. Molecular neurodegeneration Reynolds, M. R., Singh, I., Azad, T. D., Holmes, B. B., Verghese, P. B., Dietrich, H. H., Diamond, M., Bu, G., Han, B. H., Zipfel, G. J. 2016; 11: 9

  Abstract

  Substantial evidence suggests that amyloid-β (Aβ) species induce oxidative stress and cerebrovascular (CV) dysfunction in Alzheimer's disease (AD), potentially contributing to the progressive dementia of this disease. The upstream molecular pathways governing this process, however, are poorly understood. In this report, we examine the role of heparan sulfate proteoglycans (HSPG) in Aβ-induced vascular smooth muscle cell (VSMC) dysfunction in vitro.Our results demonstrate that pharmacological depletion of HSPG (by enzymatic degradation with active, but not heat-inactivated, heparinase) in primary human cerebral and transformed rat VSMC mitigates Aβ(1-40⁻) and Aβ(1-42⁻)induced oxidative stress. This inhibitory effect is specific for HSPG depletion and does not occur with pharmacological depletion of other glycosaminoglycan (GAG) family members. We also found that Aβ(1-40) (but not Aβ(1-42)) causes a hypercontractile phenotype in transformed rat cerebral VSMC that likely results from a HSPG-mediated augmentation in intracellular Ca(2+) activity, as both Aβ(1-40⁻)induced VSMC hypercontractility and increased Ca(2+) influx are inhibited by pharmacological HSPG depletion. Moreover, chelation of extracellular Ca(2+) with ethylene glycol tetraacetic acid (EGTA) does not prevent the production of Aβ(1-40⁻) or Aβ(1-42⁻)mediated reactive oxygen species (ROS), suggesting that Aβ-induced ROS and VSMC hypercontractility occur through different molecular pathways.Taken together, our data indicate that HSPG are critical mediators of Aβ-induced oxidative stress and Aβ(1-40⁻)induced VSMC dysfunction.

  View details for DOI 10.1186/s13024-016-0073-8

  View details for PubMedID 26801396

  View details for PubMedCentralID PMC4722750

• Pediatric Central Nervous System Tumors in Nepal: Retrospective Analysis and Literature Review of Low- and Middle-Income Countries WORLD NEUROSURGERY Azad, T. D., Shrestha, R. K., Vaca, S., Niyaf, A., Pradhananga, A., Sedain, G., Sharma, M. R., Shilpakar, S. K., Grant, G. A. 2015; 84 (6): 1832-1837

  Abstract

  Central nervous system (CNS) tumors are the most common cause of cancer-related death in children. Little is known about the demographics and treatment of pediatric brain tumors in low- and middle-income countries (LMICs).We performed a retrospective chart review of all pediatric patients who presented to the neurosurgical service at Tribhuvan University Teaching Hospital in Kathmandu, Nepal from 2009-2014 and collected information on patients <18 years old who received a diagnosis of a CNS tumor. We analyzed age, gender, clinical presentation, extent of surgical resection, histopathology, and length of hospital stay. We also conducted a literature review using specific terminology to capture studies of pediatric neuro-oncologic epidemiology conducted in LMICs. Study location, length of study, sample size, study type, and occurrence of 4 common pediatric brain tumors were extracted.We identified 39 cases of pediatric CNS tumors, with 62.5% observed in male children. We found that male children (median = 13 years) presented later than female children (median = 8 years). The most frequently observed pediatric brain tumor type was ependymoma (17.5%), followed by astrocytoma (15%) and medulloblastoma (15%). Surgical resection was performed for 80% of cases, and gross total resection reported in 62.9% of all surgeries. More than half (54.1%) of patients had symptoms for more than 28 days before seeking treatment. Symptomatic hydrocephalus was noted in 57.1% of children who presented with CNS tumors. The literature review yielded studies from 18 countries. Study length ranged from 2-20 years, and sample sizes varied from 35-1948. Overall, we found more pronounced variation in the relative frequencies of the most common pediatric brain tumors, compared with high-income countries.We present the first operative series of childhood CNS tumors in Nepal. Children often had delayed diagnosis and treatment of a tumor, despite symptoms. More comprehensive data are required to develop improved treatment and management algorithms in the context of a given country's demographics and medical capabilities for childhood CNS tumors.

  View details for DOI 10.1016/j.wneu.2015.07.074

  View details for Web of Science ID 000366286300060

  View details for PubMedID 26283488

• Relationship Between Cesarean Delivery Rate and Maternal and Neonatal Mortality. JAMA Molina, G., Weiser, T. G., Lipsitz, S. R., Esquivel, M. M., Uribe-Leitz, T., Azad, T., Shah, N., Semrau, K., Berry, W. R., Gawande, A. A., Haynes, A. B. 2015; 314 (21): 2263-2270

  Abstract

  Based on older analyses, the World Health Organization (WHO) recommends that cesarean delivery rates should not exceed 10 to 15 per 100 live births to optimize maternal and neonatal outcomes.To estimate the contemporary relationship between national levels of cesarean delivery and maternal and neonatal mortality.Cross-sectional, ecological study estimating annual cesarean delivery rates from data collected during 2005 to 2012 for all 194 WHO member states. The year of analysis was 2012. Cesarean delivery rates were available for 54 countries for 2012. For the 118 countries for which 2012 data were not available, the 2012 cesarean delivery rate was imputed from other years. For the 22 countries for which no cesarean rate data were available, the rate was imputed from total health expenditure per capita, fertility rate, life expectancy, percent of urban population, and geographic region.Cesarean delivery rate.The relationship between population-level cesarean delivery rate and maternal mortality ratios (maternal death from pregnancy related causes during pregnancy or up to 42 days postpartum per 100,000 live births) or neonatal mortality rates (neonatal mortality before age 28 days per 1000 live births).The estimated number of cesarean deliveries in 2012 was 22.9 million (95% CI, 22.5 million to 23.2 million). At a country-level, cesarean delivery rate estimates up to 19.1 per 100 live births (95% CI, 16.3 to 21.9) and 19.4 per 100 live births (95% CI, 18.6 to 20.3) were inversely correlated with maternal mortality ratio (adjusted slope coefficient, -10.1; 95% CI, -16.8 to -3.4; P = .003) and neonatal mortality rate (adjusted slope coefficient, -0.8; 95% CI, -1.1 to -0.5; P < .001), respectively (adjusted for total health expenditure per capita, population, percent of urban population, fertility rate, and region). Higher cesarean delivery rates were not correlated with maternal or neonatal mortality at a country level. A sensitivity analysis including only 76 countries with the highest-quality cesarean delivery rate information had a similar result: cesarean delivery rates greater than 6.9 to 20.1 per 100 live births were inversely correlated with the maternal mortality ratio (slope coefficient, -21.3; 95% CI, -32.2 to -10.5, P < .001). Cesarean delivery rates of 12.6 to 24.0 per 100 live births were inversely correlated with neonatal mortality (slope coefficient, -1.4; 95% CI, -2.3 to -0.4; P = .004).National cesarean delivery rates of up to approximately 19 per 100 live births were associated with lower maternal or neonatal mortality among WHO member states. Previously recommended national target rates for cesarean deliveries may be too low.

  View details for DOI 10.1001/jama.2015.15553

  View details for PubMedID 26624825

• Neural Placode Tissue Derived From Myelomeningocele Repair Serves as a Viable Source of Oligodendrocyte Progenitor Cells. Neurosurgery Mitra, S. S., Feroze, A. H., Gholamin, S., Richard, C., Esparza, R., Zhang, M., Azad, T. D., Alrfaei, B., Kahn, S. A., Hutter, G., Guzman, R., Creasey, G. H., Plant, G. W., Weissman, I. L., Edwards, M. S., Cheshier, S. 2015; 77 (5): 794-802

  Abstract

  The presence, characteristics, and potential clinical relevance of neural progenitor populations within the neural placodes of myelomeningocele patients remain to be studied. Neural stem cells are known to reside adjacent to ependyma-lined surfaces along the central nervous system axis.Given such neuroanatomic correlation and regenerative capacity in fetal development, we assessed myelomeningocele-derived neural placode tissue as a potentially novel source of neural stem and progenitor cells.Nonfunctional neural placode tissue was harvested from infants during the surgical repair of myelomeningocele and subsequently further analyzed by in vitro studies, flow cytometry, and immunofluorescence. To assess lineage potential, neural placode-derived neurospheres were subjected to differential media conditions. Through assessment of platelet-derived growth factor receptor α (PDGFRα) and CD15 cell marker expression, Sox2+Olig2+ putative oligodendrocyte progenitor cells were successfully isolated.PDGFRαCD15 cell populations demonstrated the highest rate of self-renewal capacity and multipotency of cell progeny. Immunofluorescence of neural placode-derived neurospheres demonstrated preferential expression of the oligodendrocyte progenitor marker, CNPase, whereas differentiation to neurons and astrocytes was also noted, albeit to a limited degree.Neural placode tissue contains multipotent progenitors that are preferentially biased toward oligodendrocyte progenitor cell differentiation and presents a novel source of such cells for use in the treatment of a variety of pediatric and adult neurological disease, including spinal cord injury, multiple sclerosis, and metabolic leukoencephalopathies.

  View details for DOI 10.1227/NEU.0000000000000918

  View details for PubMedID 26225855

• Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities. Science translational medicine Itakura, H., Achrol, A. S., Mitchell, L. A., Loya, J. J., Liu, T., Westbroek, E. M., Feroze, A. H., Rodriguez, S., Echegaray, S., Azad, T. D., Yeom, K. W., Napel, S., Rubin, D. L., Chang, S. D., Harsh, G. R., Gevaert, O. 2015; 7 (303): 303ra138-?

  Abstract

  Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic "clusters" emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters--pre-multifocal, spherical, and rim-enhancing, names reflecting their image features--were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.

  View details for DOI 10.1126/scitranslmed.aaa7582

  View details for PubMedID 26333934

  View details for PubMedCentralID PMC4666025

• Improved capture of adverse events after spinal surgery procedures with a longitudinal administrative database JOURNAL OF NEUROSURGERY-SPINE Veeravagu, A., Cole, T. S., Azad, T. D., Ratliff, J. K. 2015; 23 (3): 374-382

  View details for DOI 10.3171/2014.12.SPINE14659

  View details for Web of Science ID 000360027300017

• Glioblastoma stem cells and stem cell-targeting immunotherapies. Journal of neuro-oncology Esparza, R., Azad, T. D., Feroze, A. H., Mitra, S. S., Cheshier, S. H. 2015; 123 (3): 449-457

  Abstract

  Advancements in immunotherapeutics promise new possibilities for the creation of glioblastoma (GBM) treatment options. Ongoing work in cancer stem cell biology has progressively elucidated the role of this tumor sub-population in oncogenesis and has distinguished them as prime therapeutic targets. Current clinical trials take a multifaceted approach with the intention of harnessing the intrinsic cytotoxic capabilities of the immune system to directly target glioblastoma cancer stem cells (gCSC) or indirectly disrupt their stromal microenvironment. Monoclonal antibodies (mAbs), dendritic cell (DC) vaccines, and chimeric antigen receptor (CAR) T cell therapies have emerged as the most common approaches, with particular iterations incorporating cancer stem cell antigenic markers in their treatment designs. Ongoing work to determine the comprehensive antigenic profile of the gCSC in conjunction with efforts to counter the immunosuppressive tumor microenvironment holds much promise in future immunotherapeutic strategies against GBM. Given recent advancements in these fields, we believe there is tremendous potential to improve outcomes of GBM patients in the continuing evolution of immunotherapies targeted to cancer stem cell populations in GBM.

  View details for DOI 10.1007/s11060-015-1729-x

  View details for PubMedID 25682090

• Glioblastoma antigen discovery--foundations for immunotherapy. Journal of neuro-oncology Azad, T. D., Razavi, S., Jin, B., Lee, K., Li, G. 2015; 123 (3): 347-358

  Abstract

  Prognosis for patients with glioblastoma (GBM), the most common high-grade primary central nervous system (CNS) tumor, remains discouraging despite multiple discoveries and clinical advances. Immunotherapy has emerged as a promising approach to GBM therapy as the idea the human CNS is immunoprivileged is being challenged. Early clinical studies of vaccine-based approaches have been encouraging, but further investigation is required before these therapies become clinically meaningful. A key challenge in immunotherapy involves identification of target antigens that are specific and sensitive for GBM. Here we discuss tumor-associated antigens that have been targeted for GBM therapy, strategies for discovery of novel antigens, and the theory of epitope spreading as it applies to GBM immunotherapy.

  View details for DOI 10.1007/s11060-015-1836-8

  View details for PubMedID 26045361

• Anterior Versus Posterior Approach for Multilevel Degenerative Cervical Disease: A Retrospective Propensity Score-Matched Study of the MarketScan Database. Spine Cole, T., Veeravagu, A., Zhang, M., Azad, T. D., Desai, A., Ratliff, J. K. 2015; 40 (13): 1033-1038

  Abstract

  Retrospective 2:1 propensity score-matched analysis on a national longitudinal database between 2006 and 2010.To compare rates of adverse events, revisions procedure rates, and payment differences in anterior cervical fusion procedures compared with posterior laminectomy and fusion procedures with at least 3 levels of instrumentation.The comparative benefits of anterior versus posterior approach to multilevel degenerative cervical disease remain controversial. Recent systematic reviews have reached conflicting conclusions. We demonstrate the comparative economic and clinical outcomes of anterior and posterior approaches for multilevel cervical degenerative disk disease.We identified 13,662 patients in a national billing claims database who underwent anterior or posterior cervical fusion procedures with 3 or more levels of instrumentation. Cohorts were balanced using 2:1 propensity score matching and outcomes were compared using bivariate analysis.With the exception of dysphagia (6.4% in anterior and 1.4% in posterior), overall 30-day complication rates were lower in the anterior approach group. The rate of any complication excluding dysphagia with anterior approaches was 12.3%, significantly lower (P < 0.0001) than that of posterior approaches, 17.8%. Anterior approaches resulted in lower hospital ($18,346 vs. $23,638) and total payments ($28,963 vs. $33,526). Patients receiving an anterior surgical approach demonstrated significantly lower rate of 30-day readmission (5.1% vs. 9.9%, P < 0.0001), were less likely to require revision surgery (12.8% vs. 18.1%, P < 0.0001), and had a shorter length of stay by 1.5 nights (P < 0.0001).Anterior approaches in the surgical management of multilevel degenerative cervical disease provide clinical advantages over posterior approaches, including lower overall complication rates, revision procedure rates, and decreased length of stay. Anterior approach procedures are also associated with decreased overall payments. These findings must be interpreted in light of limitations inherent to retrospective longitudinal studies including absence of subjective and radiographical outcomes.3.

  View details for DOI 10.1097/BRS.0000000000000872

  View details for PubMedID 25768690

• Nelson Syndrome: Update on Therapeutic Approaches WORLD NEUROSURGERY Azad, T. D., Veeravagu, A., Kumar, S., Katznelson, L. 2015; 83 (6): 1135-1140

  View details for DOI 10.1016/j.wneu.2015.01.038

  View details for Web of Science ID 000356138800052

• Perspective on "the role of adjuvant radiotherapy after gross total resection of atypical meningiomas". World neurosurgery Veeravagu, A., Azad, T. D., Chang, S. D. 2015; 83 (5): 737-738

  View details for DOI 10.1016/j.wneu.2015.01.047

  View details for PubMedID 25681598

• Avoidable maternal and neonatal deaths associated with improving access to caesarean delivery in countries with low caesarean delivery rates: an ecological modelling analysis. Lancet Molina, G., Esquivel, M. M., Uribe-Leitz, T., Lipsitz, S. R., Azad, T., Shah, N., Semrau, K., Berry, W. R., Gwande, A. A., Weiser, T. G., Haynes, A. B. 2015; 385: S33-?

  Abstract

  Reducing maternal and neonatal deaths are important global health priorities. We have previously shown that up to a country-level caesarean delivery rate (CDRs) of roughly 19·0%, cesarean delivery rates and maternal mortality ratio (MMR) and neonatal mortality rate (NMR) were inversely correlated. We investigated the absolute reductions in maternal and neonatal deaths if countries with low CDR increased their rates to a range of greater than 7·2% but less than or equal to 19·1%.We calculated maternal and neonatal deaths in 2013 and 2012, respectively, for countries with CDR 7·2% or less (N=45) with available data from the World Bank Development Indicators. We modelled the expected reduction in deaths in these countries if they had the 25th and 75th MMR and NMR percentiles observed for countries (N=48) with CDRs ranging from greater than 7·2% but less than or equal to 19·1%. This model assumes that if countries with low CDRs increased their rates of caesarean delivery to greater than 7·2% but less than or equal to 19·1%, they would achieve levels of MMR and NMR observed in countries with those CDRs.We estimate 176 078 (95% CI 163 258-188 898) maternal and 1 117 257 (95% CI 1 033 611-1 200 902) neonatal deaths occurred in 45 countries with low CDRs in 2013 and 2012, respectively. If these countries had the 25th and 75th MMR and NMR percentiles (MMR, IQR 36-190; NMR, 9-24) observed in countries (N=48) with a CDR ranging from greater than 7·2% but less than or equal to 19·1%, there would be a potential reduction of 109 762-163 513 and 279 584-803 129 maternal and neonatal deaths, respectively.Increasing caesarean delivery in countries with low CDRs could avert as many as 163 513 maternal deaths and 803 129 neonatal deaths annually. These findings assume that as health systems develop the capacity to deliver surgical care, there is a concurrent improvement in the quality of care and in the ability to rescue women and neonates who would otherwise die. Improving access to safe caesarean delivery should be a central focus in surgical care globally.None.

  View details for DOI 10.1016/S0140-6736(15)60828-5

  View details for PubMedID 26313081

• Estimate of the global volume of surgery in 2012: an assessment supporting improved health outcomes. Lancet Weiser, T. G., Haynes, A. B., Molina, G., Lipsitz, S. R., Esquivel, M. M., Uribe-Leitz, T., Fu, R., Azad, T., Chao, T. E., Berry, W. R., Gawande, A. A. 2015; 385: S11-?

  Abstract

  It was previously estimated that 234·2 million operations were performed worldwide in 2004. The association between surgical rates and population health outcomes is not clear. We re-estimated global surgical volume to track changes over time and assess rates associated with healthy populations.We gathered demographic, health, and economic data for 194 WHO member states. Surgical volumes were obtained from published studies and other reports from 2005 onwards. We estimated rates of surgery for all countries without available data based on health expenditure in 2012 and assessed the proportion of surgery comprised by caesarean delivery. The rate of surgery was plotted against life expectancy to describe the association between surgical care and this health indicator.We identified 66 countries reporting surgical data between 2005 and 2013. We estimate that 312·9 million operations (95% CI 266·2-359·5) took place in 2012-a 33·6% increase over 8 years; the largest proportional increase occurred in countries spending US$400 or less per capita on health care. Caesarean delivery comprised 29·8% (5·8 million operations) of the total surgical volume in poor health expenditure countries compared with 10·8% (7·8 million operations) in low health expenditure countries and 2·7% (5·1 million operations) in high health expenditure countries. We noted a correlation between increased life expectancy and increased surgical rates up to 1533 operations per 100 000 people, with significant but less dramatic improvement above this rate.Surgical volume is large and continues to grow in all economic environments. A single procedure-caesarean delivery-comprised almost a third of surgical volume in the most resource-limited settings. Surgical care is an essential part of health care and is associated with increased life expectancy, yet many low-income countries fail to achieve basic levels of service. Improvements in capacity and delivery of surgical services must be a major component of health system strengthening.None.

  View details for DOI 10.1016/S0140-6736(15)60806-6

  View details for PubMedID 26313057

• Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurgical focus Azad, T. D., Pan, J., Connolly, I. D., Remington, A., Wilson, C. M., Grant, G. A. 2015; 38 (3): E9-?

  Abstract

  Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.

  View details for DOI 10.3171/2014.12.FOCUS14758

  View details for PubMedID 25727231

  View details for PubMedCentralID PMC4493051

• Retrosigmoid Versus Translabyrinthine Approach for Acoustic Neuroma Resection: An Assessment of Complications and Payments in a Longitudinal Administrative Database. Cure¯us Cole, T., Veeravagu, A., Zhang, M., Azad, T., Swinney, C., Li, G. H., Ratliff, J. K., Giannotta, S. L. 2015; 7 (10)

  Abstract

  Object Retrosigmoid (RS) and translabyrinthine (TL) surgery remain essential treatment approaches for symptomatic or enlarging acoustic neuromas (ANs). We compared nationwide complication rates and payments, independent of tumor characteristics, for these two strategies. Methods We identified 346 and 130 patients who underwent RS and TL approaches, respectively, for AN resection in the 2010-2012 MarketScan database, which characterizes primarily privately-insured patients from multiple institutions nationwide. Results Although we found no difference in 30-day general neurological or neurosurgical complication rates, in TL procedures there was a decreased risk for postoperative cranial nerve (CN) VII injury (20.2% vs 10.0%, CI 0.23-0.82), dysphagia (10.4% vs 3.1%, CI 0.10-0.78), and dysrhythmia (8.4% vs 2.3%, CI 0.08-0.86). Overall, there was no difference in surgical repair rates of CSF leak; however, intraoperative fat grafting was significantly higher in TL approaches (19.8% vs 60.2%, CI 3.95-9.43). In patients receiving grafts, there was a trend towards a higher repair rate after RS approach, while in those without grafts, there was a trend towards a higher repair rate after TL approach. Median total payments were $16,856 higher after RS approaches ($67,774 vs $50,918, p < 0.0001), without differences in physician or 90-day postoperative payments. Conclusions  Using a nationwide longitudinal database, we observed that the TL, compared to RS, approach for AN resection experienced lower risks of CN VII injury, dysphagia, and dysrhythmia. There was no significant difference in CSF leak repair rates. The payments for RS procedures exceed payments for TL procedures by approximately $17,000. Data from additional years and non-private sources will further clarify these trends.

  View details for DOI 10.7759/cureus.369

  View details for PubMedID 26623224

  View details for PubMedCentralID PMC4659577

• The Alzheimer's disease-8 and Montreal Cognitive Assessment as screening tools for neurocognitive impairment in HIV-infected persons. Journal of neurovirology Overton, E. T., Azad, T. D., Parker, N., Demarco Shaw, D., Frain, J., Spitz, T., Westerhaus, E., Paul, R., Clifford, D. B., Ances, B. M. 2013; 19 (1): 109-116

  Abstract

  The diagnosis of human immunodeficiency virus (HIV)-associated neurocognitive impairment is time-intensive and often omitted in busy outpatient settings. Brief screening tools are needed. The Montreal Cognitive Assessment (MoCA) and the Alzheimer's disease (AD)-8 have been used in neurodegenerative disorders. We evaluated the sensitivity and specificity of these brief screening tools in HIV-infected persons. The AD-8, MoCA, and formal neuropsychological testing were administered to 200 HIV-infected patients who were followed at a single institution. Normalized scores on formal neuropsychological testing were used to define neurocognitive impairment. The sensitivity and specificity of the MoCA and AD-8 were assessed to diagnose the impairment. Neurocognitive impairment was highly prevalent in this cohort: 127 persons (64 %) were diagnosed with neurocognitive impairment based on formal testing. Using the AD-8 and MoCA, 113 (57 %) and 101 (51 %) persons were identified with neurocognitive impairment, respectively. The sensitivity and specificity of MoCA were 63 % and 71 %, respectively. The sensitivity and specificity of AD-8 were 61 % and 51 %, respectively. Our findings highlight that brief screening tools correlate with formal neuropsychological testing. However, the sensitivities of these screening tools are lower than desired. Nevertheless, given their ease in administration, these tools could assist as a first line for identifying individuals who may subsequently require formal neuropsychological testing.

  View details for DOI 10.1007/s13365-012-0147-5

  View details for PubMedID 23345074

  View details for PubMedCentralID PMC3655767

• Learning Chronobiology by Improving Wikipedia JOURNAL OF BIOLOGICAL RHYTHMS Chiang, C. D., Lewis, C. L., Wright, M. D., Agapova, S., AKERS, B., Azad, T. D., Banerjee, K., Carrera, P., Chen, A., Chen, J., Chi, X., Chiou, J., Cooper, J., Czurylo, M., Downs, C., Ebstein, S. Y., Fahey, P. G., Goldman, J. W., Grieff, A., Hsiung, S., Hu, R., Huang, Y., Kapuria, A., Li, K., Marcu, I., Moore, S. H., Moseley, A. C., Nauman, N., Ness, K. M., Ngai, D. M., Panzer, A., Peters, P., Qin, E. Y., Sadhu, S., Sariol, A., Schellhase, A., Schoer, M. B., Steinberg, M., Surick, G., Tsai, C. A., Underwood, K., Wang, A., Wang, M. H., Wang, V. M., WESTRICH, D., Yockey, L. J., Zhang, L., Herzog, E. D. 2012; 27 (4): 333-336

  Abstract

  Although chronobiology is of growing interest to scientists, physicians, and the general public, access to recent discoveries and historical perspectives is limited. Wikipedia is an online, user-written encyclopedia that could enhance public access to current understanding in chronobiology. However, Wikipedia is lacking important information and is not universally trusted. Here, 46 students in a university course edited Wikipedia to enhance public access to important discoveries in chronobiology. Students worked for an average of 9 h each to evaluate the primary literature and available Wikipedia information, nominated sites for editing, and, after voting, edited the 15 Wikipedia pages they determined to be highest priorities. This assignment (http://www.nslc.wustl.edu/courses/Bio4030/wikipedia_project.html) was easy to implement, required relatively short time commitments from the professor and students, and had measurable impacts on Wikipedia and the students. Students created 3 new Wikipedia sites, edited 12 additional sites, and cited 347 peer-reviewed articles. The targeted sites all became top hits in online search engines. Because their writing was and will be read by a worldwide audience, students found the experience rewarding. Students reported significantly increased comfort with reading, critiquing, and summarizing primary literature and benefited from seeing their work edited by other scientists and editors of Wikipedia. We conclude that, in a short project, students can assist in making chronobiology widely accessible and learn from the editorial process.

  View details for DOI 10.1177/0748730412449578

  View details for Web of Science ID 000307021800008

  View details for PubMedID 22855578

• Endothelial Nitric Oxide Synthase Mediates Endogenous Protection Against Subarachnoid Hemorrhage-Induced Cerebral Vasospasm STROKE Vellimana, A. K., Milner, E., Azad, T. D., Harries, M. D., Zhou, M., Gidday, J. M., Han, B. H., Zipfel, G. J. 2011; 42 (3): 776-782

  Abstract

  Vasospasm-induced delayed cerebral ischemia remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS).Wild-type mice were subjected to hypoxic PC or normoxia followed 24 hours later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery Day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild-type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits.PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and in eNOS-null mice.Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of PC-induced neurovascular protection. These data provide strong "proof-of-principle" evidence that PC represents a promising new strategy to reduce vasospasm and delayed cerebral ischemia after SAH.

  View details for DOI 10.1161/STROKEAHA.110.607200

  View details for Web of Science ID 000287479402016

  View details for PubMedID 21317271

  View details for PubMedCentralID PMC3042520