Cristina Murray-Krezan

Enhancement of Temporal Resolution and BOLD Sensitivity in Real-Time fMRI using Multi-Slab Echo-Volumar Imaging

In this study, a new approach to high-speed fMRI using multi-slab echo-volumar imaging (EVI) is developed that minimizes geometrical image distortion and spatial blurring, and enables nonaliased sampling of physiological signal fluctuation to increase BOLD sensitivity compared to conventional echo-planar imaging (EPI). Real-time fMRI using whole brain 4-slab EVI with 286 ms temporal resolution (4mm isotropic voxel size) and partial brain 2-slab EVI with 136 ms temporal resolution (4×4×6 mm(3) voxel size) was performed on a clinical 3 Tesla MRI scanner equipped with 12-channel head coil. Four-slab EVI of visual and motor tasks significantly increased mean (visual: 96%, motor: 66%) and maximum t-score (visual: 263%, motor: 124%) and mean (visual: 59%, motor: 131%) and maximum (visual: 29%, motor: 67%) BOLD signal amplitude compared with EPI. Time domain moving average filtering (2s width) to suppress physiological noise from cardiac and respiratory fluctuations further improved mean (visual: 196%, motor: 140%) and maximum (visual: 384%, motor: 200%) t-scores and increased extents of activation (visual: 73%, motor: 70%) compared to EPI. Similar sensitivity enhancement, which is attributed to high sampling rate at only moderately reduced temporal signal-to-noise ratio (mean: -52%) and longer sampling of the BOLD effect in the echo-time domain compared to EPI, was measured in auditory cortex. Two-slab EVI further improved temporal resolution for measuring task-related activation and enabled mapping of five major resting state networks (RSNs) in individual subjects in 5 min scans. The bilateral sensorimotor, the default mode and the occipital RSNs were detectable in time frames as short as 75 s. In conclusion, the high sampling rate of real-time multi-slab EVI significantly improves sensitivity for studying the temporal dynamics of hemodynamic responses and for characterizing functional networks at high field strength in short measurement times.

Utility of routine follow-up head CT scanning after mild traumatic brain injury: a systematic review of the literature

Objective To evaluate the efficacy of routine follow-up CT scans of the head after complicated mild traumatic brain injury (TBI). Methods 74 English language studies published from 1999 to February 2011 were reviewed. The papers were found by searching the PubMed database using a combination of keywords according to Cochrane guidelines. Excluding studies with missing or inappropriate data, 1630 patients in 19 studies met the inclusion criteria: complicated mild TBI, defined as a GCS score 13–15 with abnormal initial CT findings and the presence of follow-up CT scans. For these studies, the progression and type of intracranial haemorrhage, time from trauma to first scan, time between first and second scans, whether second scans were obtained routinely or for neurological decline and the number of patients who had a neurosurgical intervention were recorded. Results Routine follow-up CT scans showed hemorrhagic progression in 324 patients (19.9%). Routine follow-up head CT scans did not predict the need for neurosurgical intervention (p=0.10) but a CT scan of the head performed for decline in status did (p=0.00046). For the 56 patients (3.4%) who declined neurologically, findings on the second CT scan were worse in 38 subjects (67%) and unchanged in the rest. Overall, 39 patients (2.4%) underwent neurosurgical intervention. Conclusion Routine follow-up CT scans rarely alter treatment for patients with complicated mild TBI. Follow-up CT scans based on neurological decline alter treatment five times more often than routine follow-up CT scans.

Low rate of delayed deterioration requiring surgical treatment in patients transferred to a tertiary care center for mild traumatic brain injury

OBJECT Patients with mild traumatic brain injury (mTBI) only rarely need neurosurgical intervention; however, there is a subset of patients whose condition will deteriorate. Given the high resource utilization required for interhospital transfer and the relative infrequency of the need for intervention, this study was undertaken to determine how often patients who were transferred required intervention and if there were factors that could predict that need. METHODS The authors performed a retrospective review of cases involving patients who were transferred to the University of New Mexico Level 1 trauma center for evaluation of mTBI between January 2005 and December 2009. Information including demographic data, lesion type, need for neurosurgical intervention, and short-term outcome was recorded. RESULTS During the 4-year study period, 292 patients (age range newborn to 92 years) were transferred for evaluation of mTBI. Of these 292 patients, 182 (62.3%) had an acute traumatic finding of some kind; 110 (60.4%) of these had a follow-up CT to evaluate progression, whereas 60 (33.0%) did not require a follow-up CT. In 15 cases (5.1% overall), the patients were taken immediately to the operating room (either before or after the first CT). Only 4 patients (1.5% overall) had either clinical or radiographic deterioration requiring delayed surgical intervention after the second CT scan. Epidural hematoma (EDH) and subdural hematoma (SDH) were both found to be significantly associated with the need for surgery (OR 29.5 for EDH, 95% CI 6.6-131.8; OR 9.7 for SDH, 95% CI 2.4-39.1). There were no in-hospital deaths in the series, and 97% of patients were discharged with a Glasgow Coma Scale score of 15. CONCLUSIONS Most patients who are transferred with mTBI who need neurosurgical intervention have a surgical lesion initially. Only a very small percentage will have a delayed deterioration requiring surgery, with EDH and SDH being more concerning lesions. In most cases of mTBI, triage can be performed by a neurosurgeon and the patient can be observed without interhospital transfer.

Distribution of American Congress of Obstetricians and Gynecologists fellows and junior fellows in practice in the United States.

OBJECTIVE: To develop effective policies addressing access to health care for all women in the United States, we report the distribution of the American Congress of Obstetricians and Gynecologists (ACOG) Fellows and Junior Fellows in practice at county and state levels. METHODS: Data were gathered from the 2010 U.S. County Census File for adult women (aged 15 years or older) and reproductive-aged women (15–44 years old) and from the 2010 membership roster of ACOG. The number of postresidency, actively practicing physicians trained in general obstetrics and gynecology per targeted population were recorded at state and district levels and mapped at county levels using uDig GIS software and U.S. Census TIGER/Line Shapefiles. RESULTS: In 2010, the 33,624 general obstetrician–gynecologists (ob-gyns) in the United States, comprised 5.0% of the total 661,400 physicians. There were 2.65 ob-gyns per 10,000 women and 5.39 ob-gyns per 10,000 reproductive-aged women. The density of ob-gyns declined from metropolitan to micropolitan and to rural counties. Approximately half (1,550, 49%) of the 3,143 U.S. counties lacked a single ob-gyn, and 10.1 million women (8.2% of all women) lived in those predominantly rural counties. Such counties, located especially in the central and mountain west regions, were commonly in designated Health Professional Shortage Areas. CONCLUSION: An uneven distribution of ACOG Fellows and Junior Fellows in practice exists throughout the United States and may worsen if resident graduates continue to cluster in metropolitan areas. Meeting the needs of women in underserved areas requires creative innovations in enhancing a more uniform geographic distribution of providers. LEVEL OF EVIDENCE: III

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion, and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high-throughput screening and computational shape homology approaches, we identified R-ketorolac as a Cdc42 and Rac1 inhibitor, distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In the present study, we establish R-ketorolac as an allosteric inhibitor of Cdc42 and Rac1. Cell-based assays validate R-ketorolac activity against Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip) and primary patient-derived ovarian cancer cells show that R-ketorolac is a robust inhibitor of growth factor or serum-dependent Cdc42 and Rac1 activation with a potency and cellular efficacy similar to small-molecule inhibitors of Cdc42 (CID2950007/ML141) and Rac1 (NSC23766). Furthermore, GTPase inhibition by R-ketorolac reduces downstream p21-activated kinases (PAK1/PAK2) effector activation by >80%. Multiple assays of cell behavior using SKOV3ip and primary patient-derived ovarian cancer cells show that R-ketorolac significantly inhibits cell adhesion, migration, and invasion. In summary, we provide evidence for R-ketorolac as a direct inhibitor of Cdc42 and Rac1 that is capable of modulating downstream GTPase-dependent, physiologic responses, which are critical to tumor metastasis. Our findings demonstrate the selective inhibition of Cdc42 and Rac1 GTPases by an FDA-approved drug, racemic ketorolac, that can be used in humans. Mol Cancer Ther; 14(10); 2215–27. ©2015 AACR.

Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults

Malaria results in over 650 000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 108, 109, 1010, or 1011 vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (1010 and 1011 vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 1011 vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (1010 and 1011 vp/mL). Reactogenicity findings were more common after the 1011 vp/mL dose, although most were mild or moderate in nature and resolved without therapy.

The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post-first and post-second hematopoietic stem cell transplant

The reported incidence of post‐allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T‐cell depletion, and chronic GvHD are significantly associated with post‐transplant AIHA. During an 11‐yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post‐first and post‐second transplants. Demographic, transplant, and post‐transplant‐related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post‐first and post‐second HSCT, respectively. Post‐first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post‐second transplant AIHA. The incidence of AIHA post‐first and post‐second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post‐transplant AIHA.

Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases.

Rho family GTPases (including Rac, Rho and Cdc42) collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. Based on high throughput screening of the Prestwick Chemical Library® and cheminformatics we identified the R-enantiomers of two approved drugs (naproxen and ketorolac) as inhibitors of Rac1 and Cdc42. The corresponding S-enantiomers are considered the active component in racemic drug formulations, acting as non-steroidal anti-inflammatory drugs (NSAIDs) with selective activity against cyclooxygenases. Here, we show that the S-enantiomers of naproxen and ketorolac are inactive against the GTPases. Additionally, more than twenty other NSAIDs lacked inhibitory action against the GTPases, establishing the selectivity of the two identified NSAIDs. R-naproxen was first identified as a lead compound and tested in parallel with its S-enantiomer and the non-chiral 6-methoxy-naphthalene acetic acid (active metabolite of nabumetone, another NSAID) as a structural series. Cheminformatics-based substructure analyses—using the rotationally constrained carboxylate in R-naproxen—led to identification of racemic [R/S] ketorolac as a suitable FDA-approved candidate. Cell based measurement of GTPase activity (in animal and human cell lines) demonstrated that the R-enantiomers specifically inhibit epidermal growth factor stimulated Rac1 and Cdc42 activation. The GTPase inhibitory effects of the R-enantiomers in cells largely mimic those of established Rac1 (NSC23766) and Cdc42 (CID2950007/ML141) specific inhibitors. Docking predicts that rotational constraints position the carboxylate moieties of the R-enantiomers to preferentially coordinate the magnesium ion, thereby destabilizing nucleotide binding to Rac1 and Cdc42. The S-enantiomers can be docked but are less favorably positioned in proximity to the magnesium. R-naproxen and R-ketorolac have potential for rapid translation and efficacy in the treatment of several epithelial cancer types on account of established human toxicity profiles and novel activities against Rho-family GTPases.

Cranial radiation exposure during cerebral catheter angiography

Background Radiation exposure to patients and personnel remains a major concern in the practice of interventional radiology, with minimal literature available on exposure to the forehead and cranium. Objective In this study, we measured cranial radiation exposure to the patient, operating interventional neuroradiologist, and circulating nurse during neuroangiographic procedures. We also report the effectiveness of wearing a 0.5 mm lead equivalent cap as protection against radiation scatter. Design 24 consecutive adult interventional neuroradiology procedures (six interventional, 18 diagnostic) were prospectively studied for cranial radiation exposures in the patient and personnel. Data were collected using electronic detectors and thermoluminescent dosimeters. Results Mean fluoroscopy time for diagnostic and interventional procedures was 8.48 (SD 2.79) min and 26.80 (SD 6.57) min, respectively. Mean radiation exposure to the operators head was 0.08 mSv, as measured on the outside of the 0.5 mm lead equivalent protective headgear. This amounts to around 150 mSv/year, far exceeding the current deterministic threshold for the lens of the eye (ie, 20 mSv/year) in high volume centers performing up to five procedures a day. When compared with doses measured on the inside of the protective skullcap, there was a statistically significant reduction in the amount of radiation received by the operators skull. Conclusions Our study suggests that a modern neurointerventional suite is safe when equipped with proper protective shields and personal gear. However, cranial exposure is not completely eliminated with existing protective devices and the addition of a protective skullcap eliminates this exposure to both the operator and support staff.

Titanium mesh as a low-profile alternative for tension-band augmentation in patella fracture fixation: A biomechanical study

OBJECTIVES We performed a simple biomechanical study to compare the fixation strength of titanium mesh with traditional tension-band augmentation, which is a standard treatment for transverse patella fractures. We hypothesised that titanium mesh augmentation is not inferior in fixation strength to the standard treatment. METHODS Twenty-four synthetic patellae were tested. Twelve were fixed with stainless steel wire and parallel cannulated screws. Twelve were fixed with parallel cannulated screws, augmented with anterior titanium mesh and four screws. A custom test fixture was developed to simulate a knee flexed to 90°. A uniaxial force was applied to the simulated extensor mechanism at this angle. A non-inferiority study design was used to evaluate ultimate force required for failure of each construct as a measure of fixation strength. Stiffness of the bone/implant construct, fracture gap immediately prior to failure, and modes of failure are also reported. RESULTS The mean difference in force at failure was -23.0 N (95% CI: -123.6 to 77.6N) between mesh and wire constructs, well within the pre-defined non-inferiority margin of -260 N. Mean stiffness of the mesh and wire constructs were 19.42 N/mm (95% CI: 18.57-20.27 N/mm) and 19.49 N/mm (95% CI: 18.64-20.35 N/mm), respectively. Mean gap distance for the mesh constructs immediately prior to failure was 2.11 mm (95% CI: 1.35-2.88 mm) and 3.87 mm (95% CI: 2.60-5.13 mm) for wire constructs. CONCLUSIONS Titanium mesh augmentation is not inferior to tension-band wire augmentation when comparing ultimate force required for failure in this simplified biomechanical model. Results also indicate that stiffness of the two constructs is similar but that the mesh maintains a smaller fracture gap prior to failure. The results of this study indicate that the use of titanium mesh plating augmentation as a low-profile alternative to tension-band wiring for fixation of transverse patella fractures warrants further investigation.