Update on Pediatric Mild Traumatic Brain Injury in Rural and Underserved Regions: A Global Perspective.

BACKGROUND: Mild traumatic brain injury (MTBI) causes morbidity and disability worldwide. Pediatric patients are uniquely vulnerable due to developmental and psychosocial factors. Reduced healthcare access in rural/underserved communities impair management and outcome. A knowledge update relevant to current gaps in care is critically needed to develop targeted solutions. METHODS: The National Library of Medicine PubMed database was queried using comprehensive search terms (("mild traumatic brain injury" or "concussion") and ("rural" or "low-income" or "underserved") and ("pediatric" or "child/children")) in the title, abstract, and Medical Subject Headings through December 2022. Fifteen articles on rural/underserved pediatric MTBI/concussion not covered in prior reviews were examined and organized into four topical categories: epidemiology, care practices, socioeconomic factors, and telehealth. RESULTS: Incidences are higher for Individuals in rural regions, minorities, and those aged 0-4 years compared to their counterparts, and are increasing over time. Rural healthcare utilization rates generally exceed urban rates, and favor emergency departments (vs. primary care) for initial injury assessment. Management guidelines require customization to resource-constrained settings for implementation and adoption. Decreased community recognition of the seriousness of injury is a consensus challenge to care provision by clinicians. Low parental education and income were correlated with decreased MTBI knowledge and worse outcome. Telehealth protocols for triage/consultation and rehabilitation were feasible in improving care delivery to rural and remote settings. CONCLUSIONS: Pediatric MTBI/concussion patients in rural/underserved regions experience increased risks of injury, geographic and financial healthcare barriers, and poorer outcomes. Globally, under-reporting of injury has hindered epidemiological understanding. Ongoing MTBI education should be implemented for rural caregivers, schools, and low-income populations to improve community awareness. Telehealth can improve care delivery across acuity settings, and warrants judicious inclusion in triage and treatment protocols.

Predictors of Extreme Hospital Length of Stay After Traumatic Brain Injury.

BACKGROUND: Hospital length of stay (HLOS) after traumatic brain injury (TBI) is an important metric of injury severity, resource utilization, and access to post-acute care services. Risk factors for protracted HLOS after TBI require further characterization. METHODS: Data regarding adult inpatients admitted to a single U.S. level 1 trauma center with a diagnosis of acute TBI between August 1, 2019, and April 1, 2022, were extracted from the electronic health record. Patients with extreme HLOS (XHLOS, >99th percentile of institutional TBI HLOS) were compared with those without XHLOS. Socioeconomic status (SES), clinical/injury factors, and discharge disposition were analyzed. RESULTS: In 1638 patients, the median HLOS was 3 days (interquartile range [IQR]: 2-8 days). XHLOS threshold was >70 days (N = 18; range: 72-146 days). XHLOS was associated with younger age (XHLOS/non-XHLOS: 50.4/59.6 years; P = 0.042) and greater proportions with severe TBI (55.6%/11.4%; P < 0.001), low SES (72.2%/31.4%; P < 0.001), and Medicaid insurance (77.8%/30.1%; P < 0.001). XHLOS patients were more likely to die in hospital (22.2%/8.1%) and discharge to post-acute facility (77.8%/16.3%; P < 0.001). No XHLOS patients were discharged to home. In XHLOS patients alive at discharge, medical stability was documented at median 39 days (IQR: 28-58 days) and were hospitalized for another 56 days (IQR: 26.5-78.5 days). CONCLUSIONS: XHLOS patients were more likely to have severe injuries, low SES, and Medicaid. XHLOS is associated with in-hospital mortality and need for post-acute placement. XHLOS patients often demonstrated medical stability long before placement, underscoring complex relationships between SES, health insurance, and outcome. These findings have important implications for quality improvement and resource utilization at acute care hospitals and await validation from larger trials.

Evacuation of a multi-loculated acute-on-chronic subdural hematoma using tandem bedside subdural evacuation port systems.

Background: Traumatic subdural hematomas (SDH) can have devastating neurologic consequences. Acute-on-chronic SDHs are more frequent in the elderly, who have increased comorbidities and perioperative risks. The subdural evacuation port system (SEPS) procedure consists of a twist drill hole connected to a single drain on suction, which can be performed at bedside to evacuate SDHs without requiring general anesthesia. However, a single SEPS can be limited due to inability to evacuate across septations between SDHs of different ages. Purpose: We present to our knowledge the first case of using tandem SEPS to evacuate a multi-loculated SDH. We discuss the technical nuances of the procedure as a treatment option for complex SDHs. Findings: An 86-year-old man with cognitive impairment and recurrent falls presented acutely after ground-level fall with worsening dysarthria and right hemiparesis. Computed tomography scan showed a 11 mm left holohemispheric mixed-density SDH with loculated acute and subacute/chronic components with 2 mm midline shift. Following two interval stability scans, the patient underwent drainage of a superficial chronic component, and a posterolateral acute/subacute component using two sequential SEPS drains at bedside in the intensive care unit. The patient's symptoms markedly improved, drains were removed, and the patient was discharged home with home health on post-procedure day 6. Conclusions: Judicious patient selection and pre-procedural planning can enable the use of tandem SEPS to evacuate multi-loculated SDHs under moderate sedation. Using multiple subdural ports to evacuate complex SDHs should be an option for proceduralists in settings where general anesthesia is not feasible.

Complications associated with early cranioplasty for patients with traumatic brain injury: a 25-year single-center analysis.

OBJECTIVE: Cranioplasty is a technically simple procedure, although one with potentially high rates of complications. The ideal timing of cranioplasty should minimize the risk of complications, but research investigating cranioplasty timing and risk of complications has generated diverse findings. Previous studies have included mixed populations of patients undergoing cranioplasty following decompression for traumatic, vascular, and other cerebral insults, making results challenging to interpret. The objective of the current study was to examine rates of complications associated with cranioplasty, specifically for patients with traumatic brain injury (TBI) receiving this procedure at the authors' high-volume level 1 trauma center over a 25-year time period. METHODS: A single-institution retrospective review was conducted of patients undergoing cranioplasty after decompression for trauma. Patients were identified and clinical and demographic variables obtained from 2 neurotrauma databases. Patients were categorized into 3 groups based on timing of cranioplasty: early (≤ 90 days after craniectomy), intermediate (91-180 days after craniectomy), and late (> 180 days after craniectomy). In addition, a subgroup analysis of complications in patients with TBI associated with ultra-early cranioplasty (< 42 days, or 6 weeks, after craniectomy) was performed. RESULTS: Of 435 patients identified, 141 patients underwent early cranioplasty, 187 patients received intermediate cranioplasty, and 107 patients underwent late cranioplasty. A total of 54 patients underwent ultra-early cranioplasty. Among the total cohort, the mean rate of postoperative hydrocephalus was 2.8%, the rate of seizure was 4.6%, the rate of postoperative hematoma was 3.4%, and the rate of infection was 6.0%. The total complication rate for the entire population was 16.8%. There was no significant difference in complications between any of the 3 groups. No significant differences in postoperative complications were found comparing the ultra-early cranioplasty group with all other patients combined. CONCLUSIONS: In this cohort of patients with TBI, early cranioplasty, including ultra-early procedures, was not associated with higher rates of complications. Early cranioplasty may confer benefits such as shorter or fewer hospitalizations, decreased financial burden, and overall improved recovery, and should be considered based on patient-specific factors.

Validating Patient-Specific Finite Element Models of Direct Electrocortical Stimulation.

Direct electrocortical stimulation (DECS) with electrocorticography electrodes is an established therapy for epilepsy and an emerging application for stroke rehabilitation and brain-computer interfaces. However, the electrophysiological mechanisms that result in a therapeutic effect remain unclear. Patient-specific computational models are promising tools to predict the voltages in the brain and better understand the neural and clinical response to DECS, but the accuracy of such models has not been directly validated in humans. A key hurdle to modeling DECS is accurately locating the electrodes on the cortical surface due to brain shift after electrode implantation. Despite the inherent uncertainty introduced by brain shift, the effects of electrode localization parameters have not been investigated. The goal of this study was to validate patient-specific computational models of DECS against in vivo voltage recordings obtained during DECS and quantify the effects of electrode localization parameters on simulated voltages on the cortical surface. We measured intracranial voltages in six epilepsy patients during DECS and investigated the following electrode localization parameters: principal axis, Hermes, and Dykstra electrode projection methods combined with 0, 1, and 2 mm of cerebral spinal fluid (CSF) below the electrodes. Greater CSF depth between the electrode and cortical surface increased model errors and decreased predicted voltage accuracy. The electrode localization parameters that best estimated the recorded voltages across six patients with varying amounts of brain shift were the Hermes projection method and a CSF depth of 0 mm (r = 0.92 and linear regression slope = 1.21). These results are the first to quantify the effects of electrode localization parameters with in vivo intracranial recordings and may serve as the basis for future studies investigating the neuronal and clinical effects of DECS for epilepsy, stroke, and other emerging closed-loop applications.

Virtual Interviews in Neurosurgery Resident Selection-A Work in Progress.

INTRODUCTION: Due to the COVID-19 pandemic, the ACGME recommended all interviews for the 2021 residency application cycle be held virtually. Because this is major shift from neurosurgical interviews in past years, this study aims to evaluate both applicant and interviewer satisfaction of conducting interviews virtually. METHODS: For faculty, an 11-question online survey was sent to 116 United States neurosurgery training programs. A 14-question online survey was sent to 255 neurosurgery applicants. The resulting data were analyzed qualitatively and quantitatively. RESULTS: From applicants, 118 responses were received. From faculty, 171 individual responses were received. Thirty-five percent (34.7%) of applicants agreed that they were satisfied with the virtual interview process as a whole. Although 44.5% of faculty disagreed with the statement "I would like to replace in-person interviews with virtual interviews in the future", 57.3% of faculty agreed that they were likely to implement virtual interviews in the future. CONCLUSIONS: Some things might be better assessed through in-person interviews, but there are clear benefits to virtual interviews. Future iterations of the interview process, incorporating virtual interviews, might help determine how and in which situations virtual interviews can be utilized in future residency application cycles.

The Kempe incision for decompressive craniectomy, craniotomy, and cranioplasty in traumatic brain injury and stroke.

OBJECTIVE: Decompressive craniectomy (DC) is an effective, lifesaving option for reducing intracranial pressure (ICP) in traumatic brain injury (TBI), stroke, and other pathologies with elevated ICP. Most DCs are performed via a standard trauma flap shaped like a reverse question mark (RQM), which requires sacrificing the occipital and posterior auricular arteries and can be complicated by wound dehiscence and infections. The Ludwig Kempe hemispherectomy incision (Kempe) entails a T-shaped incision, one limb from the midline behind the hairline to the inion and the other limb from the root of the zygoma to the coronal suture. The authors' objective in this study was to define their implementation of the Kempe incision for DC and craniotomy, report clinical outcomes, and quantify the volume of bone removed compared with the RQM incision. METHODS: A retrospective review of a single-surgeon experience with DC in TBI and stroke was performed. Patient demographics, imaging, and outcomes were collected for all DCs from 2015 to 2020, and the incisions were categorized as either Kempe or RQM. Preoperative and postoperative CT scans were obtained and processed using a combination of automatic segmentation (in Python and SimpleITK) with manual cleanup and further subselection in ITK-SNAP. The volume of bone removed was quantified, and the primary outcome was percentage of hemicranium removed. Postoperative surgical wound infections, estimated blood loss (EBL), and length of surgery were compared between the two groups as secondary outcomes. Cranioplasty data were collected. RESULTS: One hundred thirty-six patients were included in the analysis; there were 57 patients in the craniotomy group (44 patients with RQM incisions and 13 with Kempe incisions) and 79 in the craniectomy group (41 patients with RQM incisions and 38 Kempe incisions). The mean follow-up for the entire cohort was 251 ± 368 days. There was a difference in the amount of decompression between approaches in multivariate modeling (39% ± 11% of the hemicranium was removed via the Kempe incision vs 34% ± 10% via the RQM incision, p = 0.047), although this did not achieve significance in multivariate modeling. Wound infection rates, EBL, and length of surgery were comparable between the two incision types. No wound infections in either cohort were due to wound dehiscence. Cranioplasty outcomes were comparable between the two incision types. CONCLUSIONS: The Kempe incision for craniectomy or craniotomy is a safe, feasible, and effective alternative to the RQM. The authors advocate the Kempe incision in cases in which contralateral operative pathology or subsequent craniofacial/skull base repair is anticipated.

Intraoperative Characterization of Subthalamic Nucleus-to-Cortex Evoked Potentials in Parkinson's Disease Deep Brain Stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a clinically effective tool for treating medically refractory Parkinson's disease (PD), but its neural mechanisms remain debated. Previous work has demonstrated that STN DBS results in evoked potentials (EPs) in the primary motor cortex (M1), suggesting that modulation of cortical physiology may be involved in its therapeutic effects. Due to technical challenges presented by high-amplitude DBS artifacts, these EPs are often measured in response to low-frequency stimulation, which is generally ineffective at PD symptom management. This study aims to characterize STN-to-cortex EPs seen during clinically relevant high-frequency STN DBS for PD. Intraoperatively, we applied STN DBS to 6 PD patients while recording electrocorticography (ECoG) from an electrode strip over the ipsilateral central sulcus. Using recently published techniques, we removed large stimulation artifacts to enable quantification of STN-to-cortex EPs. Two cortical EPs were observed - one synchronized with DBS onset and persisting during ongoing stimulation, and one immediately following DBS offset, here termed the "start" and the "end" EPs respectively. The start EP is, to our knowledge, the first long-latency cortical EP reported during ongoing high-frequency DBS. The start and end EPs differ in magnitude (p < 0.05) and latency (p < 0.001), and the end, but not the start, EP magnitude has a significant relationship (p < 0.001, adjusted for random effects of subject) to ongoing high gamma (80-150 Hz) power during the EP. These contrasts may suggest mechanistic or circuit differences in EP production during the two time periods. This represents a potential framework for relating DBS clinical efficacy to the effects of a variety of stimulation parameters on EPs.

Prevalence of control groups in cardiovascular clinical trials: An analysis of ClinicalTrials.gov from 2009 through 2019.

Clinical trials provide the foundational evidence that guide many patient-facing decisions; however, the therapeutic effect and safety of an intervention is best evaluated when compared to a control group. We used ClinicalTrials.gov to describe the proportion of registered Phase III and IV cardiovascular clinical trials that contain a control group from 2009 through 2019. Of 1,677 registered Phase III and IV cardiovascular clinical trials, 81.2% contain a control group, and the annual prevalence remained unchanged between 2009 and 2019.

Concurrent Deep Brain Stimulation Reduces the Direct Cortical Stimulation Necessary for Motor Output.

BACKGROUND: Converging literatures suggest that deep brain stimulation (DBS) in Parkinson's disease affects multiple circuit mechanisms. One proposed mechanism is the normalization of primary motor cortex (M1) pathophysiology via effects on the hyperdirect pathway. OBJECTIVES: We hypothesized that DBS would reduce the current intensity necessary to modulate motor-evoked potentials from focally applied direct cortical stimulation (DCS). METHODS: Intraoperative subthalamic DBS, DCS, and preoperative diffusion tensor imaging data were acquired in 8 patients with Parkinson's disease. RESULTS: In 7 of 8 patients, DBS significantly reduced the M1 DCS current intensity required to elicit motor-evoked potentials. This neuromodulation was specific to select DBS bipolar configurations. In addition, the volume of activated tissue models of these configurations were significantly associated with overlap of the hyperdirect pathway. CONCLUSIONS: DBS reduces the current necessary to elicit a motor-evoked potential using DCS. This supports a circuit mechanism of DBS effectiveness, potentially involving the hyperdirect pathway that speculatively may underlie reductions in hypokinetic abnormalities in Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society.

Publisher Correction: Direct stimulation of somatosensory cortex results in slower reaction times compared to peripheral touch in humans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Direct Electrical Stimulation in Electrocorticographic Brain-Computer Interfaces: Enabling Technologies for Input to Cortex.

Electrocorticographic brain computer interfaces (ECoG-BCIs) offer tremendous opportunities for restoring function in individuals suffering from neurological damage and for advancing basic neuroscience knowledge. ECoG electrodes are already commonly used clinically for monitoring epilepsy and have greater spatial specificity in recording neuronal activity than techniques such as electroencephalography (EEG). Much work to date in the field has focused on using ECoG signals recorded from cortex as control outputs for driving end effectors. An equally important but less explored application of an ECoG-BCI is directing input into cortex using ECoG electrodes for direct electrical stimulation (DES). Combining DES with ECoG recording enables a truly bidirectional BCI, where information is both read from and written to the brain. We discuss the advantages and opportunities, as well as the barriers and challenges presented by using DES in an ECoG-BCI. In this article, we review ECoG electrodes, the physics and physiology of DES, and the use of electrical stimulation of the brain for the clinical treatment of disorders such as epilepsy and Parkinson's disease. We briefly discuss some of the translational, regulatory, financial, and ethical concerns regarding ECoG-BCIs. Next, we describe the use of ECoG-based DES for providing sensory feedback and for probing and modifying cortical connectivity. We explore future directions, which may draw on invasive animal studies with penetrating and surface electrodes as well as non-invasive stimulation methods such as transcranial magnetic stimulation (TMS). We conclude by describing enabling technologies, such as smaller ECoG electrodes for more precise targeting of cortical areas, signal processing strategies for simultaneous stimulation and recording, and computational modeling and algorithms for tailoring stimulation to each individual brain.

The use of exam wrappers to promote metacognition.

INTRODUCTION: Self-directed learning, self-awareness, and metacognition are becoming more heavily emphasized in healthcare education. Metacognitive activities may be used to promote self-awareness and development of effective self-directed learning strategies. Exam wrappers (wrappers) are a metacognitive tool utilized in other areas of higher education that offer students the ability to learn from exam performance by reviewing missed items in a reflective manner. Wrappers encourage structured reflection and planning for future learning. METHODS: Pharmacy students enrolled in a pathophysiology course were provided structured exam reviews with an opportunity to utilize a wrapper. A baseline questionnaire was given two weeks before the first exam to assess baseline characteristics. Wrappers were provided before Exams 2, 3, 4, and 5, and the effects on exam performance were measured. Mixed effects modeling was utilized for final analysis of effect on student performance. RESULTS: Exam wrapper vs. non-wrapper groups were self-selected, with 53 students participating in at least one wrapper and 35 never utilizing a wrapper. Mixed effects modeling analysis found a non-significant increase in average exam performance (p = 0.142). CONCLUSION: Wrappers have potential as an additional metacognitive tool for exam review. Further studies are needed to evaluate the effectiveness and impact more broadly in pharmacy education.

Differentiation of epileptic regions from voluntary high-gamma activation via interictal cross-frequency windowed power-power correlation.

OBJECTIVEElectrocorticography is an indispensable tool in identifying the epileptogenic zone in the presurgical evaluation of many epilepsy patients. Traditional electrocorticographic features (spikes, ictal onset changes, and recently high-frequency oscillations [HFOs]) rely on the presence of transient features that occur within or near epileptogenic cortex. Here the authors report on a novel corticography feature of epileptogenic cortex-covariation of high-gamma and beta frequency band power profiles. Band-limited power was measured from each recording site based on native physiological signal differences without relying on clinical ictal or interictal epileptogenic features. In this preliminary analysis, frequency windowed power correlation appears to be a specific marker of the epileptogenic zone. The authors' overall aim was to validate this observation with the location of the eventual resection and outcome.METHODSThe authors conducted a retrospective analysis of 13 adult patients who had undergone electrocorticography for surgical planning at their center. They quantified the correlation of high-gamma (70-200 Hz) and beta (12-18 Hz) band frequency power per electrode site during a cognitive task. They used a sliding window method to correlate the power of smoothed, Hilbert-transformed high-gamma and beta bands. They then compared positive and negative correlations between power in the high-gamma and beta bands in the setting of a hand versus a tongue motor task as well as within the resting state. Significant positive correlations were compared to surgically resected areas and outcomes based on reviewed records.RESULTSPositive high-gamma and beta correlations appeared to predict the area of eventual resection and, preliminarily, surgical outcome independent of spike detection. In general, patients with the best outcomes had well-localized positive correlations (high-gamma and beta activities) to areas of eventual resection, while those with poorer outcomes displayed more diffuse patterns.CONCLUSIONSData in this study suggest that positive high-gamma and beta correlations independent of any behavioral metric may have clinical applicability in surgical decision-making. Further studies are needed to evaluate the clinical potential of this methodology. Additional work is also needed to relate these results to other methods, such as HFO detection or connectivity with other cortical areas.

Direct stimulation of somatosensory cortex results in slower reaction times compared to peripheral touch in humans.

Direct cortical stimulation (DCS) of primary somatosensory cortex (S1) could help restore sensation and provide task-relevant feedback in a neuroprosthesis. However, the psychophysics of S1 DCS is poorly studied, including any comparison to cutaneous haptic stimulation. We compare the response times to DCS of human hand somatosensory cortex through electrocorticographic grids with response times to haptic stimuli delivered to the hand in four subjects. We found that subjects respond significantly slower to S1 DCS than to natural, haptic stimuli for a range of DCS train durations. Median response times for haptic stimulation varied from 198 ms to 313 ms, while median responses to reliably perceived DCS ranged from 254 ms for one subject, all the way to 528 ms for another. We discern no significant impact of learning or habituation through the analysis of blocked trials, and find no significant impact of cortical stimulation train duration on response times. Our results provide a realistic set of expectations for latencies with somatosensory DCS feedback for future neuroprosthetic applications and motivate the study of neural mechanisms underlying human perception of somatosensation via DCS.

Design, implementation, and evaluation of an online elective course on current topics in pharmacy.

INTRODUCTION: To describe the design and implementation of the Current Topics in Professional Pharmacy online elective course and evaluate the degree to which the course improved student pharmacists' awareness of and interest in current topics affecting the profession of pharmacy. METHODS: A one-credit hour online summer elective included weekly modules of current topics affecting the profession of pharmacy, along with a longitudinal final project in which students created their own current topic module. Each module consisted of assigned reference materials and online discussion forum posts to answer discussion questions and share professional opinions. Student achievement of curricular outcomes and course-specific objectives was measured utilizing pre- and post-course surveys, assessment of weekly module forum posts, and a final course knowledge and comprehension quiz. RESULTS: Student self-rated awareness and desire to stay updated on current topics in pharmacy increased significantly from pre-survey to post-survey (39.7% to 98.3% agree or strongly agree, p<0.001; 25.9-87.9%, p<0.001, respectively). Student confidence in their ability to formulate and effectively express their professional opinion also significantly improved (67.2% to 93.1%, p<0.001). Seven of the 12 course competencies assessed by the survey significantly improved from pre- to post-course. The majority of students agreed or strongly agreed that the course adequately addressed all 12 pre-selected Accreditation Council for Pharmacy Education (ACPE) Appendix B content areas. CONCLUSIONS: Performance assessment and survey results demonstrated achievement of curricular outcomes and course objectives. Students completing the course showed an increased interest and awareness related to current topics affecting the profession of pharmacy.

Measurement of Grit and Correlation to Student Pharmacist Academic Performance.

Objective. To describe grittiness of students from three pharmacy schools and determine if grit is associated with academic performance measures. Methods. Pharmacy students completed an electronic questionnaire that included the Short Grit Scale (Grit-S). Associations were determined using logistic regression. Results. Grit-S total score was a significant and independent predictor for participants who reported a GPA ≥3.5, and Consistency of Interest (COI) and Perseverance of Effort (POE) domain scores were significantly higher compared to participants with a GPA of 3.0-3.49. Participants reporting a D or F had slightly lower average total Grit-S scores and COI domain scores compared to participants who did not. In addition, the group who reported a GPA <3.0 had lower scores in the POE domain compared to those with a GPA of 3.0-3.4. Conclusion. Grittiness may be associated with student pharmacist academic performance and the Grit-S Scale may have substantive implications for use in pharmacy programs.

Collaborative Examination Item Review Process in a Team-Taught, Self-Care Sequence.

OBJECTIVE: To improve examination item quality by educating and involving course instructors in evidence-based item review and encouraging use of this process in future courses. METHODS: A peer-review process was implemented in a 2-course sequence (intervention) that involved training and review sessions before each examination and was compared to the previous year's courses (control). Instructors completed a presurvey and postsurvey on training, experience, self-confidence, and self-rated success in multiple-choice item writing. Statistics were calculated for all items in the control and intervention sequences and compared using independent t tests. Items also were classified into levels based on difficulty and discrimination, and distribution into these levels was compared between sequences with independent t tests. RESULTS: No significant difference was found between control and intervention sequence items with regard to mean difficulty (86.3% and 84.4%) or discrimination (0.23- and 0.25), respectively, although item classification distribution did appear to change between the control and intervention sequences' subjective feelings of confidence, and success in item writing increased between presurvey and postsurvey. Confidence in ability to peer-review test items and to implement a formal item evaluation process also increased. CONCLUSION: Item statistics did not change significantly, but reviewed and edited items distributed more favorably into item statistic-based categories. This method of review positively affected instructors' perceptions of their item-writing confidence and success and improved self-rated opinions of their ability to edit items and train others to do so.

Dual-phase osteogenic and vasculogenic engineered tissue for bone formation.

Minimally invasive, injectable bone tissue engineering therapies offer the potential to facilitate orthopedic repair procedures, including in indications where enhanced bone regeneration is needed for complete healing. In this study, we developed a dual-phase tissue construct consisting of osteogenic (Osteo) and vasculogenic (Vasculo) components. A modular tissue engineering approach was used to create collagen/fibrin/hydroxyapatite (COL/FIB/HA) hydrogel microbeads containing embedded human bone marrow-derived mesenchymal stem cells (bmMSC). These microbeads were predifferentiated toward the osteogenic lineage in vitro for 14 days, and they were then embedded within a COL/FIB vasculogenic phase containing a coculture of undifferentiated bmMSC and human umbilical vein endothelial cells (HUVEC). In vitro studies demonstrated homogenous dispersion of microbeads within the outer phase, with endothelial network formation around the microbeads over 14 days in the coculture conditions. Subcutaneous injection into immunodeficient mice was used to investigate the ability of dual-phase (Osteo+Vasculo) and control (Osteo, Vasculo, Blank) constructs to form neovasculature and ectopic bone. Laser Doppler imaging demonstrated blood perfusion through all constructs at 1, 4, and 8 weeks postimplantation. Histological quantification of total vessel density showed no significant differences between the conditions. Microcomputed tomography indicated significantly higher ectopic bone volume (BV) in the Osteo condition at 4 weeks. At 8 weeks both the Osteo and Blank groups exhibited higher BV compared to the Vasculo and dual Osteo+Vasculo groups. These data not only show that osteogenic microbeads can be used to induce ectopic bone formation, but also suggest an inhibitory effect on BV when undifferentiated bmMSC and HUVEC were included in dual-phase constructs. This work may lead to improved methods for engineering vascularized bone tissue, and to injectable therapies for the treatment of orthopedic pathologies in which bone regeneration is delayed or prevented.

Noninvasive quantification of in vitro osteoblastic differentiation in 3D engineered tissue constructs using spectral ultrasound imaging.

Non-destructive monitoring of engineered tissues is needed for translation of these products from the lab to the clinic. In this study, non-invasive, high resolution spectral ultrasound imaging (SUSI) was used to monitor the differentiation of MC3T3 pre-osteoblasts seeded within collagen hydrogels. SUSI was used to measure the diameter, concentration and acoustic attenuation of scatterers within such constructs cultured in either control or osteogenic medium over 21 days. Conventional biochemical assays were used on parallel samples to determine DNA content and calcium deposition. Construct volume and morphology were accurately imaged using ultrasound. Cell diameter was estimated to be approximately 12.5-15.5 µm using SUSI, which corresponded well to measurements of fluorescently stained cells. The total number of cells per construct assessed by quantitation of DNA content decreased from 5.6±2.4×10(4) at day 1 to 0.9±0.2×10(4) at day 21. SUSI estimation of the equivalent number of acoustic scatters showed a similar decreasing trend, except at day 21 in the osteogenic samples, which showed a marked increase in both scatterer number and acoustic impedance, suggestive of mineral deposition by the differentiating MC3T3 cells. Estimation of calcium content by SUSI was 41.7±11.4 µg/ml, which agreed well with the biochemical measurement of 38.7±16.7 µg/ml. Color coded maps of parameter values were overlaid on B-mode images to show spatiotemporal changes in cell diameter and calcium deposition. This study demonstrates the use of non-destructive ultrasound imaging to provide quantitative information on the number and differentiated state of cells embedded within 3D engineered constructs, and therefore presents a valuable tool for longitudinal monitoring of engineered tissue development.