Gamified versus non-gamified online educational modules for teaching clinical laboratory medicine to first-year medical students at a large allopathic medical school in the United States.

BACKGROUND: Medical educators seek innovative ways to engage learners efficiently and effectively. Gamification has been explored as one way to accomplish this feat; however, questions remain about which contexts gamification would be most useful. Time constraints and student interest present major barriers for teaching laboratory medicine to students. This study aims to compare two versions of an interactive online module, one gamified and one not, for teaching laboratory medicine concepts to pre-clinical medical students. METHODS: First-year medical students reviewed either a gamified or non-gamified version of an interactive online module in preparation for an in-person flipped classroom session on Laboratory Medicine. Learning theory guided the design of the modules and both contained identical content, objectives, and structure. The "gamified" module included the additional elements of personalization, progress meters, points, badges, and story/role play. After reviewing the module, students completed an anonymous knowledge check and optional survey. RESULTS: One hundred seventy-one students completed the post module knowledge check as assigned (82 gamified, 89 non-gamified). Knowledge check scores were higher for the students who reviewed the gamified module (p < 0.02), corresponding to an effect size of 0.4 for the gamified module. Eighty-one students completed optional post-module surveys (46 gamified, 35 non-gamified). Instructional efficiency was calculated using task difficulty questions and knowledge check scores, and the resulting instructional efficiency was higher for the gamified module. There was no significant difference in the student-reported time required to complete the modules. Additionally, both versions of the module were well received and led to positive ratings related to motivation and confidence. Finally, examination of open-ended survey results suggested that the addition of game elements added value to the gamified module and enhanced engagement and enjoyment. CONCLUSIONS: In this setting, the addition of gamification to an interactive online module enhanced learning outcome, instructional efficiency, student engagement and enjoyment. These results should inspire further exploration of gamification for teaching Laboratory Medicine concepts to pre-clinical medical students.

Using cognitive load theory to evaluate and improve preparatory materials and study time for the flipped classroom.

BACKGROUND: Preclinical medical education is content-dense and time-constrained. Flipped classroom approaches promote durable learning, but challenges with unsatisfactory student preparation and high workload remain. Cognitive load theory defines instructional design as "efficient" if learners can master the presented concepts without cognitive overload. We created a PReparatory Evaluation Process (PREP) to systematically assess and measure improvement in the cognitive-load efficiency of preparatory materials and impact on study time (time-efficiency). METHODS: We conducted this study in a flipped, multidisciplinary course for ~ 170 first year students at Harvard Medical School using a naturalistic post-test design. For each flipped session (n = 97), we assessed cognitive load and preparatory study time by administering a 3-item PREP survey embedded within a short subject-matter quiz students completed before class. Over three years (2017-2019), we evaluated cognitive load- and time- based efficiency to guide iterative revisions of the materials by content experts. The ability of PREP to detect changes to the instructional design (sensitivity) was validated through a manual audit of the materials. RESULTS: The average survey response rate was ≥ 94%. Content expertise was not required to interpret PREP data. Initially students did not necessarily allocate the most study time to the most difficult content. Over time, the iterative changes in instructional design increased the cognitive load- and time-based efficiency of preparatory materials with large effect sizes (p < .01). Furthermore, this increased the overall alignment of cognitive load with study time: students allocated more time to difficult content away from more familiar, less difficult content without increasing workload overall. CONCLUSIONS: Cognitive load and time constraints are important parameters to consider when designing curricula. The PREP process is learner-centered, grounded in educational theory, and works independently of content knowledge. It can provide rich and actionable insights into instructional design of flipped classes not captured by traditional satisfaction-based evaluations.

The Student-Generated Reasoning Tool (SGRT): Linking medical knowledge and clinical reasoning in preclinical education.

INTRODUCTION: The simultaneous integration of knowledge acquisition and development of clinical reasoning in preclinical medical education remains a challenge. To help address this challenge, the authors developed and implemented the Student-Generated Reasoning Tool (SGRT)-a tool asking students to propose and justify pathophysiological hypotheses, generate findings, and critically appraise information. METHODS: In 2019, students in a first-year preclinical course (n = 171; SGRT group) were assigned to one of 20 teams. Students used the SGRT individually, then in teams, and faculty provided feedback. The control group (n = 168) consisted of students from 2018 who did not use SGRT. Outcomes included academic performance, effectiveness of collaborative environments using the SGRT, and student feedback. RESULTS: Students were five times more likely to get questions correct if they were in the SGRT group versus control group. Accuracy of pathophysiological hypotheses was significantly lower for individuals than teams. Qualitative analysis indicated students benefited from generating their own data, justifying their reasoning, and working individually as well as in teams. CONCLUSIONS: This study introduces the SGRT as a potentially engaging, case-based, and collaborative learning method that may help preclinical medical students become aware of their knowledge gaps and integrate their knowledge in basic and clinical sciences in the context of clinical reasoning.

Assessing the Effectiveness of Using Mechanistic Concept Maps in Case-Based Collaborative Learning.

PROBLEM: Despite the advantages of using mechanistic concept maps (MCMs)-diagrams created individually or collaboratively by a team to foster inductive analysis of a clinical problem-in individual learning, very little is known about their benefits in collaborative learning. APPROACH: First-year medical and dental students (n = 170) were assigned to one of four learning groups in the Homeostasis I course, Harvard Medical School, February-March 2016. One group (n = 43) was randomly assigned to the MCM intervention; students in the remaining groups (n = 127) served as controls. Outcomes included pre- and postcourse surveys on, among other things, reasoning skills, attitudes toward teamwork, and tolerance of ambiguity; final exam scores; and qualitative responses to three open-ended questions on students' perceptions of the effects of MCMs on their learning. OUTCOMES: Response rates for pre- and postcourse surveys were 87/170 (51%) and 91/170 (54%). Compared with students in the control groups, students in the MCM group reported better reasoning skills (P = .01) and attitudes toward teamwork (P = .02). There were no significant differences in final exam scores between the groups. Students in the intervention group found MCMs more helpful in conceptual learning than their own notes and flashcards (P = .0001) or the readiness assessment quizzes (P = .0009). Qualitative analysis indicated MCM students routinely overcame team-learning obstacles through strategies aimed at prioritizing collaborative inductive reasoning. NEXT STEPS: Ongoing studies are evaluating the contextual elements and best practices for optimal employment of MCMs in promoting collaborative inductive reasoning.

Effects on P-Glycoprotein Expression after Blood-Brain Barrier Disruption Using Focused Ultrasound and Microbubbles.

Many blood-borne substances attempting to pass through the luminal membrane of brain endothelial cells are acted upon by a variety of metabolizing enzymes or are actively expelled back into the capillary lumen by embedded efflux transporters, such as Permeability-glycoprotein (Pgp). Overexpression of this protein has also been linked to multidrug resistance in cancer cells. Previous studies have shown that focused ultrasound (FUS), when combined with a microbubble agent, has ability to temporarily disrupt blood-brain barrier (BBBD). In this work, we investigated whether modulation of Pgp expression is part of the FUS-induced effects. We found that ultrasound can temporarily suppress Pgp expression. When BBBD was produced at 0.55 MPa, Pgp was suppressed up to 48 hours and restored by 72 hours. At 0.81 MPa, suppression can last 72 hours or longer. These findings support the idea that microbubble-enhanced FUS disrupts the functional components of the BBB through suppression of drug efflux.

High-resolution renal perfusion mapping using contrast-enhanced ultrasonography in ischemia-reperfusion injury monitors changes in renal microperfusion.

Alterations in renal microperfusion play an important role in the development of acute kidney injury with long-term consequences. Here we used contrast-enhanced ultrasonography as a novel method for depicting intrarenal distribution of blood flow. After infusion of microbubble contrast agent, bubbles were collapsed in the kidney and postbubble destruction refilling was measured in various regions of the kidney. Local perfusion was monitored in vivo at 15, 30, 45, 60 minutes and 24 hours after 28 minutes of bilateral ischemia in 12 mice. High-resolution, pixel-by-pixel analysis was performed on each imaging clip using customized software, yielding parametric perfusion maps of the kidney, representing relative blood volume in each pixel. These perfusion maps revealed that outer medullary perfusion decreased disproportionately to the reduction in the cortical and inner medullary perfusion after ischemia. Outer medullary perfusion was significantly decreased by 69% at 60 minutes postischemia and remained significantly less (40%) than preischemic levels at 24 hours postischemia. Thus, contrast-enhanced ultrasonography with high-resolution parametric perfusion maps can monitor changes in renal microvascular perfusion in space and time in mice. This novel technique can be translated to clinical use in man.

Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep.

Non-invasive brain stimulation using focused ultrasound has largely been carried out in small animals. In the present study, we applied stimulatory focused ultrasound transcranially to the primary sensorimotor (SM1) and visual (V1) brain areas in sheep (Dorset, all female, n = 8), under the guidance of magnetic resonance imaging, and examined the electrophysiologic responses. By use of a 250-kHz focused ultrasound transducer, the area was sonicated in pulsed mode (tone-burst duration of 1 ms, duty cycle of 50%) for 300 ms. The acoustic intensity at the focal target was varied up to a spatial peak pulse-average intensity (Isppa) of 14.3 W/cm(2). Sonication of SM1 elicited electromyographic responses from the contralateral hind leg, whereas stimulation of V1 generated electroencephalographic potentials. These responses were detected only above a certain acoustic intensity, and the threshold intensity, as well as the degree of responses, varied among sheep. Post-sonication animal behavior was normal, but minor microhemorrhages were observed from the V1 areas exposed to highly repetitive sonication (every second for ≥500 times for electroencephalographic measurements, Isppa = 6.6-10.5 W/cm(2), mechanical index = 0.9-1.2). Our results suggest the potential translational utility of focused ultrasound as a new brain stimulation modality, yet also call for caution in the use of an excessive number of sonications.

Potential of minimally invasive procedures in the treatment of uterine fibroids: a focus on magnetic resonance-guided focused ultrasound therapy.

Minimally invasive treatment options are an important part of the uterine fibroid-treatment arsenal, especially among younger patients and in those who plan future pregnancies. This article provides an overview of the currently available minimally invasive therapy options, with a special emphasis on a completely noninvasive option: magnetic resonance-guided focused ultrasound (MRgFUS). In this review, we describe the background of MRgFUS, the patient-selection criteria for MRgFUS, and how the procedure is performed. We summarize the published clinical trial results, and review the literature on pregnancy post-MRgFUS and on the cost-effectiveness of MRgFUS.

Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters.

BACKGROUND: Transcranial focused ultrasound (FUS) has emerged as a new brain stimulation modality. The range of sonication parameters for successful brain stimulation warrants further investigation. OBJECTIVE: The objective of this study was to examine the range of FUS sonication parameters that minimize the acoustic intensity/energy deposition while successfully stimulating the motor brain area in Sprague-Dawley rats. METHODS: We transcranially administered FUS to the somatomotor area of the rat brain and measured the acoustic intensity that caused excitatory effects with respect to different pulsing parameters (tone-burst duration, pulse-repetition frequency, duty cycle, and sonication duration) at 350 and 650 kHz of fundamental frequency. RESULTS: We observed that motor responses were elicited at minimum threshold acoustic intensities (4.9-5.6 W/cm(2) in spatial-peak pulse-average intensity; 2.5-2.8 W/cm(2) in spatial-peak temporal-average intensity) in a limited range of sonication parameters, i.e. 1-5 ms of tone-burst duration, 50% of duty cycle, and 300 ms of sonication duration, at 350 kHz fundamental frequency. We also found that the pulsed sonication elicited motor responses at lower acoustic intensities than its equivalent continuous sonication. CONCLUSION: Our results suggest that the pulsed application of FUS selectively stimulates specific brain areas-of-interest at an acoustic intensity that is compatible with regulatory safety limits on biological tissue, thus allowing for potential applications in neurotherapeutics.

PET∕CT imaging evidence of FUS-mediated (18)F-FDG uptake changes in rat brain.

PURPOSE: Transcranial focused ultrasound (FUS) delivers highly focused acoustic energy to a small region of the brain in a noninvasive manner. Recent studies have revealed that FUS, which is administered either in pulsed or continuous waves, can elicit or suppress neural tissue excitability. This neuromodulatory property of FUS has been demonstrated via direct motion detection, electrophysiological recordings, functional magnetic resonance imaging (fMRI), confocal imaging, and microdialysis sampling of neurotransmitters. This study presents new evidence of local increase in glucose metabolism induced by FUS to the rat brain using FDG (18-fludeoxyglucose) positron emission tomography (PET). METHODS: Sprague-Dawley rats underwent sonication to a unilateral hemispheric area of the brain prior to PET scan. The pulsed sonication (350 kHz, tone burst duration of 0.5 ms, pulse repetition frequency of 1 kHz, and duration of 300 ms) was applied in 2 s intervals for 40 min immediately after the FDG injection via tail vein. Subsequently, the PET was acquired in dynamic list-mode to image FDG activity for an hour, and reconstructed into a single volume representing standardized uptake value (SUV). The raw SUV as well as its asymmetry index (AI) were measured from five different volume-of-interests (VOIs) of the brain for both hemispheres, and compared between sonicated and unsonicated groups. RESULTS: Statistically significant hemispheric changes in SUV were observed only at the center of sonication focus within the FUS group [paired t-test; t(7) = 3.57, p < 0.05]. There were no significant hemispheric differences in SUV within the control group in any of the VOIs. A statistically significant elevation in AI (t-test; t(7) = 3.40, p < 0.05) was observed at the center of sonication focus (7.9 ± 2.5%, the deviations are in standard error) among the FUS group when compared to the control group (-0.8 ± 1.2%). CONCLUSIONS: Spatially distinct increases in the glucose metabolic activity in the rat brain is present only at the center of sonication focus, suggesting localized functional neuromodulation mediated by the sonication.

Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

Nonpharmacologic and nonsurgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36-msec tone burst duration (TBD), 1.5-kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histologic and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB), as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential for diagnostic and therapeutic applications in diseases of the peripheral nervous system.

Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity.

BACKGROUND: Epilepsy is a common neurological disorder, which is attributed to uncontrollable abnormal hyper-excitability of neurons. We investigated the feasibility of using low-intensity, pulsed radiation of focused ultrasound (FUS) to non-invasively suppress epileptic activity in an animal model (rat), which was induced by the intraperitonial injection of pentylenetetrazol (PTZ). RESULTS: After the onset of induced seizures, FUS was transcranially administered to the brain twice for three minutes each while undergoing electroencephalographic (EEG) monitoring. An air-backed, spherical segment ultrasound transducer (diameter: 6 cm; radius-of-curvature: 7 cm) operating at a fundamental frequency of 690 KHz was used to deliver a train of 0.5 msec-long pulses of sonication at a repetitive rate of 100 Hz to the thalamic areas of the brain. The acoustic intensity (130 mW/cm2) used in the experiment was sufficiently within the range of safety guidelines for the clinical ultrasound imaging. The occurrence of epileptic EEG bursts from epilepsy-induced rats significantly decreased after sonication when it was compared to the pre-sonication epileptic state. The PTZ-induced control group that did not receive any sonication showed a sustained number of epileptic EEG signal bursts. The animals that underwent sonication also showed less severe epileptic behavior, as assessed by the Racine score. Histological analysis confirmed that the sonication did not cause any damage to the brain tissue. CONCLUSIONS: These results revealed that low-intensity, pulsed FUS sonication suppressed the number of epileptic signal bursts using acute epilepsy model in animal. Due to its non-invasiveness and spatial selectivity, FUS may offer new perspectives for a possible non-invasive treatment of epilepsy.

Focused ultrasound modulates region-specific brain activity.

We demonstrated the in vivo feasibility of using focused ultrasound (FUS) to transiently modulate (through either stimulation or suppression) the function of regional brain tissue in rabbits. FUS was delivered in a train of pulses at low acoustic energy, far below the cavitation threshold, to the animal's somatomotor and visual areas, as guided by anatomical and functional information from magnetic resonance imaging (MRI). The temporary alterations in the brain function affected by the sonication were characterized by both electrophysiological recordings and functional brain mapping achieved through the use of functional MRI (fMRI). The modulatory effects were bimodal, whereby the brain activity could either be stimulated or selectively suppressed. Histological analysis of the excised brain tissue after the sonication demonstrated that the FUS did not elicit any tissue damages. Unlike transcranial magnetic stimulation, FUS can be applied to deep structures in the brain with greater spatial precision. Transient modulation of brain function using image-guided and anatomically-targeted FUS would enable the investigation of functional connectivity between brain regions and will eventually lead to a better understanding of localized brain functions. It is anticipated that the use of this technology will have an impact on brain research and may offer novel therapeutic interventions in various neurological conditions and psychiatric disorders.

Focused ultrasound as a local therapy for liver cancer.

Conventional surgical treatments of liver cancer are invasive (including minimally invasive) with a high incidence of new metastasis and poor success, even after multiple resections or ablations. These limitations motivated research into new, less invasive solutions for liver cancer treatment.Focused ultrasound surgery (FUS), or high-intensity focused ultrasound, has been recognized as a noninvasive technology for benign and malignant tumor treatment. Previously, FUS was guided with ultrasound that has limited target definition and monitoring capability of the ablation process. Combining magnetic resonance imaging (MRI) with multiple-element phased-array transducers to create MRI-guided focused ultrasound thermal therapy provides more accurate targeting and real-time temperature monitoring. This treatment is hindered by the ribcage that limits the acoustic windows to the liver and the respiratory motion of the liver. New advances in MRI and transducer design will likely resolve these limitations and make MRI-guided FUS a powerful tool in local liver cancer therapy. This article reviews this technology and advances that can expand its use for cancer treatment in general and liver cancer in particular.

On-demand three-dimensional freeform fabrication of multi-layered hydrogel scaffold with fluidic channels.

One of the challenges in tissue engineering is to provide adequate supplies of oxygen and nutrients to cells within the engineered tissue construct. Soft-lithographic techniques have allowed the generation of hydrogel scaffolds containing a network of fluidic channels, but at the cost of complicated and often time-consuming manufacturing steps. We report a three-dimensional (3D) direct printing technique to construct hydrogel scaffolds containing fluidic channels. Cells can also be printed on to and embedded in the scaffold with this technique. Collagen hydrogel precursor was printed and subsequently crosslinked via nebulized sodium bicarbonate solution. A heated gelatin solution, which served as a sacrificial element for the fluidic channels, was printed between the collagen layers. The process was repeated layer-by-layer to form a 3D hydrogel block. The printed hydrogel block was heated to 37 degrees C, which allowed the gelatin to be selectively liquefied and drained, generating a hollow channel within the collagen scaffold. The dermal fibroblasts grown in a scaffold containing fluidic channels showed significantly elevated cell viability compared to the ones without any channels. The on-demand capability to print fluidic channel structures and cells in a 3D hydrogel scaffold offers flexibility in generating perfusable 3D artificial tissue composites.

Renal ultrafiltration changes induced by focused US.

PURPOSE: To determine if focused ultrasonography (US) combined with a diagnostic microbubble-based US contrast agent can be used to modulate glomerular ultrafiltration and size selectivity. MATERIALS AND METHODS: The experiments were approved by the animal care committee. The left kidney of 17 healthy rabbits was sonicated by using a 260-kHz focused US transducer in the presence of a microbubble-based US contrast agent. The right kidney served as the control. Three acoustic power levels were applied: 0.4 W (six rabbits), 0.9 W (six rabbits), and 1.7 W (five rabbits). Three rabbits were not treated with focused US and served as control animals. The authors evaluated changes in glomerular size selectivity by measuring the clearance rates of 3000- and 70,000-Da fluorescence-neutral dextrans. The creatinine clearance was calculated for estimation of the glomerular filtration rate. The urinary protein-creatinine ratio was monitored during the experiments. The authors assessed tubular function by evaluating the fractional sodium excretion, tubular reabsorption of phosphate, and gamma-glutamyltransferase-creatinine ratio. Whole-kidney histologic analysis was performed. For each measurement, the values obtained before and after sonication were compared by using the paired t test. RESULTS: Significant (P < .05) increases in the relative (ratio of treated kidney value/nontreated kidney value) clearance of small- and large-molecule agents and the urine flow rates that resulted from the focused US treatments were observed. Overall, 1.23-, 1.23-, 1.61-, and 1.47-fold enhancement of creatinine clearance, 3000-Da dextran clearance, 70 000-Da dextran clearance, and urine flow rate, respectively, were observed. Focal tubular hemorrhage and transient functional tubular alterations were observed at only the highest (1.7-W) acoustic power level tested. CONCLUSION: Glomerular ultrafiltration and size selectivity can be temporarily modified with simultaneous application of US and microbubbles. This method could offer new opportunities for treatment of renal disease.

Three-dimensional bioprinting of rat embryonic neural cells.

We present a direct cell printing technique to pattern neural cells in a three-dimensional (3D) multilayered collagen gel. A layer of collagen precursor was printed to provide a scaffold for the cells, and the rat embryonic neurons and astrocytes were subsequently printed on the layer. A solution of sodium bicarbonate was applied to the cell containing collagen layer as nebulized aerosols, which allowed the gelation of the collagen. This process was repeated layer-by-layer to construct the 3D cell-hydrogel composites. Upon characterizing the relationship between printing resolutions and the growth of printed neural cells, single/multiple layers of neural cell-hydrogel composites were constructed and cultured. The on-demand capability to print neural cells in a multilayered hydrogel scaffold offers flexibility in generating artificial 3D neural tissue composites.

Multi-layered culture of human skin fibroblasts and keratinocytes through three-dimensional freeform fabrication.

We present a method to create multi-layered engineered tissue composites consisting of human skin fibroblasts and keratinocytes which mimic skin layers. Three-dimensional (3D) freeform fabrication (FF) technique, based on direct cell dispensing, was implemented using a robotic platform that prints collagen hydrogel precursor, fibroblasts and keratinocytes. A printed layer of cell-containing collagen was crosslinked by coating the layer with nebulized aqueous sodium bicarbonate. The process was repeated in layer-by-layer fashion on a planar tissue culture dish, resulting in two distinct cell layers of inner fibroblasts and outer keratinocytes. In order to demonstrate the ability to print and culture multi-layered cell-hydrogel composites on a non-planar surface for potential applications including skin wound repair, the technique was tested on a poly(dimethylsiloxane) (PDMS) mold with 3D surface contours as a target substrate. Highly viable proliferation of each cell layer was observed on both planar and non-planar surfaces. Our results suggest that organotypic skin tissue culture is feasible using on-demand cell printing technique with future potential application in creating skin grafts tailored for wound shape or artificial tissue assay for disease modeling and drug testing.

Composite MR Contrast Agents for Conditional Cell-Labeling.

Gadolinium-chelates (Gd-DTPA) and superparamagnetic particles of iron oxide (SPIO) are two commonly used MR contrast agents that exhibit inherently different relaxation properties. These two agents have been used to label cells ex-vivo to generate signal contrast with respect to background tissue when introduced to a tissue-of-interest. Assuming minimal mutual interaction between these two agents, we were motivated to investigate the creation of composite relaxation properties by mixing the two in aqueous solutions for conditioning cell labeling. Concentration-dependent relaxivity coefficients were first obtained from each contrast agent, independently, in saline solution at 3 Tesla. These coefficients were then used to predict both the R(1) and R(2) relaxation rates of a composite contrast agent using a linear model combining the effects of both contrast media. The predicted relaxation rates were experimentally confirmed from 25 composite solutions (combinations of SPIO-concentration ranging from 0 to 1 mug/mL and Gd-DTPA-concentration ranging from 0 to 0.20 mM). We show that the combination of SPIO and Gd-DTPA in an aqueous solution exhibits unique and predictable relaxivity properties that are unattainable via the individual use of either agent. The method may be applied to create 'user-tunable' contrast conditions for the visualization of magnetically labeled cells in the context of cell replacement therapy.