Circadian ABCG2 Expression Influences the Brain Uptake of Donepezil across the Blood-Cerebrospinal Fluid Barrier.

Donepezil (DNPZ) is a cholinesterase inhibitor used for the management of Alzheimer's disease (AD) and is dependent on membrane transporters such as ABCG2 to actively cross brain barriers and reach its target site of action in the brain. Located in the brain ventricles, the choroid plexus (CP) forms an interface between the cerebrospinal fluid (CSF) and the bloodstream, known as the blood-CSF barrier (BCSFB). Historically, the BCSFB has received little attention as a potential pathway for drug delivery to the central nervous system (CNS). Nonetheless, this barrier is presently viewed as a dynamic transport interface that limits the traffic of molecules into and out of the CNS through the presence of membrane transporters, with parallel activity with the BBB. The localization and expression of drug transporters in brain barriers represent a huge obstacle for drug delivery to the brain and a major challenge for the development of therapeutic approaches to CNS disorders. The widespread interest in understanding how circadian clocks modulate many processes that define drug delivery in order to predict the variability in drug safety and efficacy is the next bridge to improve effective treatment. In this context, this study aims at characterizing the circadian expression of ABCG2 and DNPZ circadian transport profile using an in vitro model of the BCSFB. We found that ABCG2 displays a circadian pattern and DNPZ is transported in a circadian way across this barrier. This study will strongly impact on the capacity to modulate the BCSFB in order to control the penetration of DNPZ into the brain and improve therapeutic strategies for the treatment of AD according to the time of the day.

The impact of biological clock and sex hormones on the risk of disease.

Molecular clocks are responsible for defining 24-h cycles of behaviour and physiology that are called circadian rhythms. Several structures and tissues are responsible for generating these circadian rhythms and are named circadian clocks. The suprachiasmatic nucleus of the hypothalamus is believed to be the master circadian clock receiving light input via the optic nerve and aligning internal rhythms with environmental cues. Studies using both in vivo and in vitro methodologies have reported the relationship between the molecular clock and sex hormones. The circadian system is directly responsible for controlling the synthesis of sex hormones and this synthesis varies according to the time of day and phase of the estrous cycle. Sex hormones also directly interact with the circadian system to regulate circadian gene expression, adjust biological processes, and even adjust their own synthesis. Several diseases have been linked with alterations in either the sex hormone background or the molecular clock. So, in this chapter we aim to summarize the current understanding of the relationship between the circadian system and sex hormones and their combined role in the onset of several related diseases.

Circadian rhythmicity of amyloid-beta-related molecules is disrupted in the choroid plexus of a female Alzheimer's disease mouse model.

The choroid plexus (CP) is part of the blood-cerebrospinal fluid barrier (BCSFB) and was recently described as an important component of the circadian clock system. It is the principal source of cerebrospinal fluid (CSF) and responsible for the synthesis and secretion of various neuroprotective peptides including those involved in amyloid-ß (Aß) transport/degradation, contributing to Aß homeostasis. Inadequate Aß metabolic clearance and transport across the BCSFB have been associated with circadian dysfunctions in Alzheimer's disease (AD) patients. To investigate whether AD pathology influences Aß scavengers circadian expression, we collected CP at different time points from an AD mouse model (APP/PS1) (female and male animals, aged 6- and 12-months-old) and analyzed their mRNA expression by Real-time RT-PCR. Only angiotensin-converting enzyme (Ace) expression in 6-month-old female wild-type mice and transthyretin (Ttr) expression in 12-month-old female wild-type mice presented significant rhythmicity. The circadian rhythmicity of Ace and Ttr, prompt us to analyze the involvement of circadian rhythm in Aß uptake. A human CP papilloma (HIBCPP) cell line was incubated with Aß-488 and uptake was evaluated at different time points using flow cytometry. Aß uptake displayed circadian rhythmicity. Our results suggest that AD might affect Aß scavengers rhythmicity and that Aß clearance is a rhythmic process possibly regulated by the rhythmic expression of Aß scavengers.

In vitro high-content tissue models to address precision medicine challenges.

The field of precision medicine allows for tailor-made treatments specific to a patient and thereby improve the efficiency and accuracy of disease prevention, diagnosis, and treatment and at the same time would reduce the cost, redundant treatment, and side effects of current treatments. Here, the combination of organ-on-a-chip and bioprinting into engineering high-content in vitro tissue models is envisioned to address some precision medicine challenges. This strategy could be employed to tackle the current coronavirus disease 2019 (COVID-19), which has made a significant impact and paradigm shift in our society. Nevertheless, despite that vaccines against COVID-19 have been successfully developed and vaccination programs are already being deployed worldwide, it will likely require some time before it is available to everyone. Furthermore, there are still some uncertainties and lack of a full understanding of the virus as demonstrated in the high number new mutations arising worldwide and reinfections of already vaccinated individuals. To this end, efficient diagnostic tools and treatments are still urgently needed. In this context, the convergence of bioprinting and organ-on-a-chip technologies, either used alone or in combination, could possibly function as a prominent tool in addressing the current pandemic. This could enable facile advances of important tools, diagnostics, and better physiologically representative in vitro models specific to individuals allowing for faster and more accurate screening of therapeutics evaluating their efficacy and toxicity. This review will cover such technological advances and highlight what is needed for the field to mature for tackling the various needs for current and future pandemics as well as their relevancy towards precision medicine.

The Daily Expression of ABCC4 at the BCSFB Affects the Transport of Its Substrate Methotrexate.

The choroid plexuses (CPs), located in the brain ventricles, form an interface between the blood and the cerebrospinal fluid named the blood-cerebrospinal barrier, which, by the presence of tight junctions, detoxification enzymes, and membrane transporters, limits the traffic of molecules into the central nervous system. It has already been shown that sex hormones regulate several CP functions, including the oscillations of its clock genes. However, it is less explored how the circadian rhythm regulates CP functions. This study aimed to evaluate the impact of sex hormones and circadian rhythms on the function of CP membrane transporters. The 24 h transcription profiles of the membrane transporters rAbca1, rAbcb1, rAbcc1, rAbcc4, rAbcg2, rAbcg4, and rOat3 were characterized in the CPs of intact male, intact female, sham-operated female, and gonadectomized rats. We found that rAbcc1 is expressed in a circadian way in the CPs of intact male rats, rAbcg2 in the CPs of intact female rats, and both rAbcc4 and rOat3 mRNA levels were expressed in a circadian way in the CPs of intact male and female rats. Next, using an in vitro model of the human blood-cerebrospinal fluid barrier, we also found that methotrexate (MTX) is transported in a circadian way across this barrier. The circadian pattern of Abcc4 found in the human CP epithelial papilloma cells might be partially responsible for MTX circadian transport across the basal membrane of CP epithelial cells.

Putting Theory to Practice: Applying Cognitive Load Theory to Resident Medical Education.

OBJECTIVE: We built 2 versions of an asynchronous pediatric orthopedic educational intervention for emergency medicine residents and sought to compare the two. We hypothesized that the version incorporating more instructional scaffolding in the form of a cognitive aid (CA) would optimize germane cognitive load for our target novice learners and result in higher test scores. METHODS: Learners were block randomized to either a "CA" or "non-CA" arm, each containing a random set of 18 modules. The CA arm incorporated an orthopedic fracture classification chart embedded within the diagnostic questions to guide the learner in forming a diagnosis. The non-CA arm was designed with more active learning as the classification chart was provided only after each diagnostic answer submission. For both arms, the final 6 modules completed per learner were scored. Learners also completed a perceived cognitive load assessment tool measured on a 10-point Likert scale. RESULTS: Learners in the non-CA arm had a mean total score on the testing modules of 33% correct compared with a mean total score of 44% correct for learners in the CA arm (mean difference, 11; 95% confidence interval, 4%-19%, P = 0.005). There was a trend for the CA arm to have lower perceived overall cognitive load scores; however, this did not reach statistical significance. CONCLUSIONS: Emergency medicine residents performed better after completing the CA version of our educational intervention. Applying cognitive load theory to an educational intervention may increase its success among target learners.

The Crosstalk between Melatonin and Sex Steroid Hormones.

Melatonin, an indolamine mainly released from the pineal gland, is associated with many biological functions, namely, the modulation of circadian and seasonal rhythms, sleep inducer, regulator of energy metabolism, antioxidant, and anticarcinogenic. Although several pieces of evidence also recognize the influence of melatonin in the reproductive physiology, the crosstalk between melatonin and sex hormones is not clear. Here, we review the effects of sex differences in the circulating levels of melatonin and update the current knowledge on the link between sex hormones and melatonin. Furthermore, we explore the effects of melatonin on gonadal steroidogenesis and hormonal control in females. The literature review shows that despite the strong evidence that sex differences impact on the circadian profiles of melatonin, reports are still considerably ambiguous, and these differences may arise from several factors, like the use of contraceptive pills, hormonal status, and sleep deprivation. Furthermore, there has been an inconclusive debate about the characteristics of the reciprocal relationship between melatonin and reproductive hormones. In this regard, there is evidence for the role of melatonin in gonadal steroidogenesis brought about by research that shows that melatonin affects multiple transduction pathways that modulate Sertoli cell physiology and consequently spermatogenesis, and also estrogen and progesterone production. From the outcome of our research, it is possible to conclude that understanding the correlation between melatonin and reproductive hormones is crucial for the correction of several complications occurring during pregnancy, like preeclampsia, and for the control of climacteric symptoms.

Replacing Computed Tomography with "Rapid" Magnetic Resonance Imaging for Ventricular Shunt Imaging.

INTRODUCTION: Children with ventricular shunts undergo frequent neuroimaging, and therefore, radiation exposures, to evaluate shunt malfunctions. The objective of this study was to safely reduce radiation exposure in this population by reducing computed tomography (CT) and increasing "rapid" magnetic resonance imaging (rMRI-shunt) among patients warranting neuroimaging for possible shunt malfunction. METHODS: This was a single-center quality improvement study in a tertiary care pediatric emergency department (ED). We implemented a multidisciplinary guideline for ED shunt evaluation, which promoted the use of rMRI-shunt over CT. We included patients younger than 18 years undergoing an ED shunt evaluation during 11 months of the preintervention and 25 months of the intervention study periods. The primary outcome was the CT rate, and we evaluated the relevant process and balancing measures. RESULTS: There were 266 encounters preintervention and 488 during the intervention periods with similar neuroimaging rates (80.7% versus 81.5%, P = 0.8.) CT decreased from 90.1% to 34.8% (difference -55.3%, 95% confidence interval [CI]: -71.1, -25.8), and rMRI-shunt increased from 9.9% to 65.2% (difference 55.3%, 95% CI: 25.8, 71.1) during the preintervention and intervention periods, respectively. There were increases in the mean time to neuroimaging (53.1 min; [95% CI: 41.6, 64.6]) and ED length of stay (LOS) (52.3 min; [95% CI: 36.8, 67.6]), without changes in total neuroimaging, 72-hour revisits, or follow-up neuroimaging. CONCLUSIONS: Multidisciplinary implementation of a standardized guideline reduced CT and increased rMRI-shunt use in a pediatric ED setting. Clinicians should balance the reduction in radiation exposure with ED rMRI-shunt for patients with ventricular shunts against the increased time of obtaining imaging and LOS.

The role of circadian rhythm in choroid plexus functions.

For several years, a great effort has been devoted to understand how circadian oscillations in physiological processes are determined by the circadian clock system. This system is composed by the master clock at the suprachiasmatic nucleus which sets the pace and tunes peripheral clocks in several organs. It was recently demonstrated that the choroid plexus epithelial cells that compose the blood-cerebrospinal fluid barrier hold a circadian clock which might control their multiple functions with implications for the maintenance of brain homeostasis. However, the choroid plexus activities regulated by its inner clock are still largely unknown. In this review, we propose that several choroid plexus functions might be regulated by the circadian clock, alike in other tissues. We provide evidences that the timing of cerebrospinal fluid secretion, clearance of amyloid-beta peptides and xenobiotics, and the barrier function of the blood-cerebrospinal fluid barrier are regulated by the circadian clock. These data, highlight that the circadian regulation of the blood-cerebrospinal fluid barrier must be taken into consideration for enhancing drug delivery to central nervous system disorders.

Electrospun Poly(butylene-adipate-co-terephthalate)/Nano-hyDroxyapatite/Graphene Nanoribbon Scaffolds Improved the In Vivo Osteogenesis of the Neoformed Bone.

Electrospun ultrathin fibrous scaffold filed with synthetic nanohydroxyapatite (nHAp) and graphene nanoribbons (GNR) has bioactive and osteoconductive properties and is a plausible strategy to improve bone regeneration. Poly(butylene-adipate-co-terephthalate) (PBAT) has been studied as fibrous scaffolds due to its low crystallinity, faster biodegradability, and good mechanical properties; however, its potential for in vivo applications remains underexplored. We proposed the application of electrospun PBAT with high contents of incorporated nHAp and nHAp/GNR nanoparticles as bone grafts. Ultrathin PBAT, PBAT/nHAp, and PBAT/nHAp/GNR fibers were produced using an electrospinning apparatus. The produced fibers were characterized morphologically and structurally using scanning electron (SEM) and high-resolution transmission electron (TEM) microscopies, respectively. Mechanical properties were analyzed using a texturometer. All scaffolds were implanted into critical tibia defects in rats and analyzed after two weeks using radiography, microcomputed tomography, histological, histomorphometric, and biomechanical analyses. The results showed through SEM and high-resolution TEM characterized the average diameters of the fibers (ranged from 0.208 µm ± 0.035 to 0.388 µm ± 0.087) and nHAp (crystallite around 0.28, 0.34, and 0.69 nm) and nHAp/GNR (200-300 nm) nanoparticles distribution into PBAT matrices. Ultrathin fibers were obtained, and the incorporated nHAp and nHAp/GNR nanoparticles were well distributed into PBAT matrices. The addition of nHAp and nHAp/GNR nanoparticles improved the elastic modulus of the ultrathin fibers compared to neat PBAT. High loads of nHAp/GNR (PBATnH5G group) improved the in vivo lamellar bone formation promoting greater radiographic density, trabecular number and stiffness in the defect area 2 weeks after implantation than control and PBAT groups.

Management and Outcome of Pediatric Patients With Transient Small Bowel-Small Bowel Intussusception.

OBJECTIVE: The aim of this study was to assess the management and outcomes of healthy pediatric patients diagnosed radiologically with transient and benign small bowel-small bowel intussusception (SB-SBI). METHODS: Retrospective cohort study of healthy patients 0 to 18 years of age who presented to a children's hospital emergency department from January 1, 2005, to June 30, 2015, and had transient and benign SB-SBI characterized by spontaneous resolution (ie, transient), diameter of less than 2.5 cm, no lead point, normal bowel wall thickness, nondilated proximal small bowel, and no colonic involvement (ie, benign radiographic features). Charts were reviewed for demographics, clinical presentation, radiologic studies obtained, outcomes, and further management. Medical and radiologic records were also reviewed for 1 year after presentation for any subsequent pathologic diagnoses. RESULTS: Sixty-eight patients were included in our study, with a total of 87 episodes of transient and benign SB-SBI on initial or follow-up examination. Overall, 39 patients (57%) were admitted to the hospital, and 38 patients (56%) had a surgical consultation. Twenty-four patients (35%) had further radiologic studies obtained, including computed tomography scans, esophagogastroduodenoscopy, Meckel's scan, barium swallow studies, and magnetic resonance imaging. All studies were negative for concerning pathology including apparent lead points. None of the patients required surgical intervention or had any complications. CONCLUSIONS: Transient and benign SB-SBIs with reassuring radiologic and clinical features diagnosed in healthy pediatric patients are likely incidentally found and are unlikely to be associated with a pathologic lead point.

Management and Outcomes of Spontaneous Pneumomediastinum in Children.

OBJECTIVES: Management of spontaneous pneumomediastinum in the pediatric population is highly variable. There are limited data on the use of diagnostic tests and the need for admission. Our objectives were to characterize the management of pediatric spontaneous pneumomediastinum, determine the diagnostic yield of advanced imaging, and describe the patients' outcomes. METHODS: This is a retrospective cohort study of all patients presenting to a single tertiary pediatric emergency department between January 2008 and February 2015 diagnosed with pneumomediastinum. Patients were identified using 2 complementary strategies: International Classification of Diseases, Ninth Revision billing codes and a keyword search of the hospital radiology database. RESULTS: We identified 183 patients with spontaneous pneumomediastinum. The mean age was 12.8 ± 4.8 years. Diagnosis was established by chest radiograph (CXR) in 165 (90%) patients, chest computed tomography in 15 (8%), neck imaging in 2 (1%), and abdominal imaging in 1. After diagnosis, many patients underwent additional studies: repeat CXR (99, 54%), chest computed tomography (53, 29%), esophagram (45, 25%), and laryngoscopy (15, 8%). Seventy-eight percent of patients (n = 142) were admitted with a median length of stay of 27 hours (18.4-45.6 hours). Six patients returned to the emergency department within 96 hours for persistent chest pain; 2 were admitted, and 1 was found to have worsening pneumomediastinum on CXR. We performed a secondary analysis on 3 key subgroups: primary spontaneous pneumomediastinum (64, 35%), secondary gastrointestinal-associated pneumomediastinum (31, 17%), and secondary respiratory-associated pneumomediastinum (88, 48%). No patients in the study received an invasive intervention for pneumomediastinum. In all patients, further studies did not yield additional diagnostic information. CONCLUSIONS: Our data suggest that patients with spontaneous pneumomediastinum who are clinically well appearing can be managed conservatively with clinical observation, avoiding exposure to radiation and invasive procedures.

Age, Sex Hormones, and Circadian Rhythm Regulate the Expression of Amyloid-Beta Scavengers at the Choroid Plexus.

Accumulation of amyloid-beta (Aß) in the brain is thought to derive from the impairment of Aß clearance mechanisms rather than from its overproduction, which consequently contributes to the development of Alzheimer's disease. The choroid plexus epithelial cells constitute an important clearance route for Aß, either by facilitating its transport from the cerebrospinal fluid to the blood, or by synthesizing and secreting various proteins involved in Aß degradation. Impaired choroid plexus synthesis, secretion, and transport of these Aß-metabolizing enzymes have been therefore associated with the disruption of Aß homeostasis and amyloid load. Factors such as aging, female gender, and circadian rhythm disturbances are related to the decline of choroid plexus functions that may be involved in the modulation of Aß-clearance mechanisms. In this study, we investigated the impact of age, sex hormones, and circadian rhythm on the expression of Aß scavengers such as apolipoprotein J, gelsolin, and transthyretin at the rat choroid plexus. Our results demonstrated that mRNA expression and both intracellular and secreted protein levels of the studied Aß scavengers are age-, sex-, and circadian-dependent. These data suggest that the Aß-degradation and clearance pathways at the choroid plexus, mediated by the presence of Aß scavengers, might be compromised as a consequence of aging and circadian disturbances. These are important findings that enhance the understanding of Aß-clearance-regulating mechanisms at the blood-cerebrospinal fluid barrier.

The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer's Disease.

BACKGROUND: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. OBJECTIVE: The fact that circadian rhythm disruption is closely associated to Alzheimer's disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. METHODS: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-ß stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. RESULTS: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. In addition, a significant circadian pattern of Bmal1 was measured the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. CONCLUSION: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.

Brain MR imaging and spectroscopy for outcome prognostication after pediatric cardiac arrest.

AIM: Children surviving cardiac arrest are at high risk of neurological morbidity and mortality; however, there is a lack of validated prognostic biomarkers. We aimed to evaluate brain magnetic resonance imaging (MRI) and spectroscopy (MRS) as predictors of death and disability. Secondly, we evaluated whether MRI/S by randomized group. METHODS: This single center study analyzed clinically indicated brain MRI/S data from children enrolled in a randomized controlled trial of 24 vs. 72 h of hypothermia following cardiac arrest. Two pediatric radiologists scored conventional MRIs. Lactate and N-acetyl-aspartate (NAA) concentrations (mmol/kg) were determined from spectra acquired from the basal ganglia, thalamus, parietal white matter and parietooccipital gray matter. Mortality and neurological outcomes (favorable = Pediatric Cerebral Performance Category [PCPC] 1, 2, 3 or increase < 2) were assessed at hospital discharge. Non-parametric tests were used to test for associations between MRI/S biomarkers and outcome and randomized group. RESULTS: 23 children with (median [interquartile range]) age of 1.5 (0.3-4.0) years. Ten (44%) had favorable outcome. There were more T2 brain lesions in the lentiform nuclei in children with unfavorable 12 (92%) vs. favorable 3 (33%) outcome, p = 0.007. Increased lactate and decreased NAA concentrations in the parietooccipital gray matter and decreased NAA in the parietal white matter were associated with unfavorable outcome (p's < 0.05). There were no differences for any biomarker by randomized group. CONCLUSION: Regional cerebral and metabolic MRI/S biomarkers are predictive of neurological outcomes at hospital discharge in pediatric cardiac arrest and should undergo validation testing in a large sample.

Unilateral Neuroimaging Findings in Pediatric Craniofacial Scleroderma: Parry-Romberg Syndrome and En Coup de Sabre.

OBJECTIVE: Parry-Romberg syndrome (PRS) and en coup de sabre (ECDS) are subtypes of craniofacial localized scleroderma. Systematic analyses of central nervous system imaging findings and their clinical associations in children are lacking. Here, we aim to characterize neuroimaging findings and associated neurological symptoms in these conditions. METHODS: Neuroimaging and neurological symptoms of children evaluated at our institution with a diagnosis of PRS or ECDS were retrospectively reviewed. Laterality, location, stability, and number of lesion(s) were evaluated, as was the presence of susceptibility lesion(s) and contrast enhancement. History of seizures or headaches was noted. RESULTS: From 2003 to 2019, 80 patients with PRS or ECDS were followed at our institution. Neuroimaging was completed in 73 and found to be abnormal in 25. In 12 (48%) of these 25 cases, headaches and/or seizures were present. In the vast majority of these cases (22/25, 88%), lesions were ipsilateral to skin findings. White matter was involved in 19 (76%) patients. MRI abnormalities preceded a rheumatological diagnosis in 7 (28%). Susceptibility lesions were noted in 11 (44%), and 8 (73%) of these patients endorsed a history of headaches. Most lesions were in the supratentorial compartment, did not enhance, and were stable at 1-year follow up imaging. Of those with progression, susceptibility findings were present at baseline. CONCLUSIONS: Neuroimaging findings in pediatric PRS and ECDS are often supratentorial, stable, unilateral, and ipsilateral to skin findings, and they can precede cutaneous findings.

Printing 3D Hydrogel Structures Employing Low-Cost Stereolithography Technology.

Stereolithography technology associated with the employment of photocrosslinkable, biocompatible, and bioactive hydrogels have been widely used. This method enables 3D microfabrication from images created by computer programs and allows researchers to design various complex models for tissue engineering applications. This study presents a simple and fast home-made stereolithography system developed to print layer-by-layer structures. Polyethylene glycol diacrylate (PEGDA) and gelatin methacryloyl (GelMA) hydrogels were employed as the photocrosslinkable polymers in various concentrations. Three-dimensional (3D) constructions were obtained by using the stereolithography technique assembled from a commercial projector, which emphasizes the low cost and efficiency of the technique. Lithium phenyl-2,4,6-trimethylbenzoyl phosphonate (LAP) was used as a photoinitiator, and a 404 nm laser source was used to promote the crosslinking. Three-dimensional and vascularized structures with more than 5 layers and resolutions between 42 and 83 µm were printed. The 3D printed complex structures highlight the potential of this low-cost stereolithography technique as a great tool in tissue engineering studies, as an alternative to bioprint miniaturized models, simulate vital and pathological functions, and even for analyzing the actions of drugs in the human body.

Rapid brain MRI protocols reduce head computerized tomography use in the pediatric emergency department.

BACKGROUND: Rapid magnetic resonance imaging (MRI) protocols may be effective in the emergency department (ED) to evaluate nontraumatic neurologic complaints. We evaluate neuroimaging (rapid MRI [rMRI]), head computerized tomography [HCT], and full MRI) use following widespread implementation of rMRI protocols in a pediatric emergency department (ED). METHODS: We conducted a retrospective study in a tertiary care pediatric ED of encounters with neuroimaging during two 9-month periods: one prior to (control period) and one after generalized availability of 4 rMRI protocols (rMRI period). The primary outcome was differences in neuroimaging rates between the two periods. Secondary outcomes included ED process measures, unsuccessful imaging, and undetected pathology, with full MRI within 14 days as the reference standard. RESULTS: There were 1052 encounters with neuroimaging during the control and 1308 during the rMRI periods. Differences in neuroimaging between periods were 27.7% for rMRI (95% CI, 24.4, 31.0), - 21.5% for HCT (95% CI, - 25.5, - 17.5), and - 6.2% for full MRI (95% CI, - 9.3, - 3.1%.) Time to imaging (182 [IQR 138-255] versus 86 [IQR 52-137] minutes) as well as ED length of stay (396 [IQR 304-484] versus 257 [IQR 196-334] minutes) was longer for rMRI versus HCT (p < 0.01). Between the control and rMRI periods, there were differences in types of neuroimaging performed for patients with altered mental status, headache, seizure, shunt dysfunction, stroke, syncope, trauma, vomiting, infection, and other neurologic complaints (p < 0.05). rMRI studies were unsuccessful in 3.6% of studies versus 0.0% of HCTs (p < 0.01). The 22 unsuccessful rMRI studies were unsuccessful due to artifacts from dental hardware (n = 2) and patient motion (n = 20). None of the rMRI studies with full MRI follow-up imaging had undetected pathology; the false negative rate for the HCT exams was as high as 25%. CONCLUSIONS: After routine ED use of 4 rMRI protocols, there was a more than 20% decrease in HCT use without missed diagnoses. Time to neuroimaging and length of stay were longer for rMRI than HCT, with higher rates of unsuccessful imaging. Despite these limitations, rMRI may be an alternative to HCT for nontraumatic complaints in the ED.

Implementation of a brain injury screen MRI for infants at risk for abusive head trauma.

BACKGROUND: Head computed tomography (CT) is the current standard of care for evaluating infants at high risk of abusive head trauma. OBJECTIVE: To both assess the feasibility of using a previously developed magnetic resonance imaging (MRI) brain injury screen (MRBRscreen) in the acute care setting in place of head CT to identify intracranial hemorrhage in high-risk infants and to compare the accuracy of a rapid imaging pulse sequence (single-shot T2 fast spin echo [ssT2FSE]) to a conventional pulse sequence (conventional T2 fast spin echo [conT2FSE]). MATERIALS AND METHODS: This was a quality improvement initiative to evaluate infants <12 months of age who were screened for intracranial hemorrhage using an MRBRscreen as part of clinical care. The MRBRscreen included axial conT2FSE, axial gradient recalled echo, coronal T1-weighted inversion recovery, axial diffusion-weighted image and an axial ssT2FSE. A comparison of ssT2FSE to conT2FSE with respect to lesion detection was also performed. RESULTS: Of 158 subjects, the MRBRscreen was able to be completed in 155 (98%); 9% (14/155) were abnormal. Ninety-four percent (137/145) of subjects underwent only an MRBRscreen and avoided both radiation from head CT and sedation from MRI. The axial ssT2FSE and conT2FSE results were congruent 99% of the time. CONCLUSION: An MRBRscreen in place of a head CT is feasible and potentially could decrease head CT use by more than 90% in this population. Using a rapid ssT2FSE in place of a conT2FSE can reduce total scan time without losing lesion detection. If an MRBRscreen is readily available, physicians' threshold to perform neuroimaging may be lowered and lead to earlier detection of abusive head trauma.

Advances in dual functional antimicrobial and osteoinductive biomaterials for orthopaedic applications.

A vast growing problem in orthopaedic medicine is the increase of clinical cases with antibiotic resistant pathogenic microbes, which is predicted to cause higher mortality than all cancers combined by 2050. Bone infectious diseases limit the healing ability of tissues and increase the risk of future injuries due to pathologic tissue remodelling. The traditional treatment for bone infections has several drawbacks and limitations, such as lengthy antibiotic treatment, extensive surgical interventions, and removal of orthopaedic implants and/or prosthesis, all of these resulting in long-term rehabilitation. This is a huge burden to the public health system resulting in increased healthcare costs. Current technologies e.g. co-delivery systems, where antibacterial and osteoinductive agents are delivered encounter challenges such as site-specific delivery, sustained and prolonged release, and biocompatibility. In this review, these aspects are highlighted to promote the invention of the next generation biomaterials to prevent and/or treat bone infections and promote tissue regeneration.