Virtual Reality for the Management of Pain and Anxiety for IR Procedures: A Prospective, Randomized, Pilot Study on Digital Sedation.

PURPOSE: To assess the analgesic and anxiolytic effects of virtual reality (VR) augmentation in patients undergoing peripherally inserted central catheter (PICC) placement or fine-needle aspiration thyroid biopsy. MATERIALS AND METHODS: This is a prospective, single-center randomized controlled trial with 107 patients enrolled. Patients were randomly assigned to receive standard of care (SOC) or SOC+VR during PICC or thyroid biopsy procedures. Pain and anxiety were individually measured using the visual analog scale (VAS) before and after the procedure. Vital signs including heart rate and systolic and diastolic blood pressure were recorded. One-way analysis of variance test and Games-Howell post hoc analysis were used to assess effect size and statistical significance between SOC and SOC+VR measures. RESULTS: The PICC cohort consisted of 59 patients (33 in SOC+VR and 26 in SOC), with a median age of 53.1 years (interquartile range [IQR], 38.3-62.7 years). The thyroid biopsy cohort consisted of 48 patients (26 in SOC+VR and 22 in SOC), with a median age of 60.1 years (IQR, 49.0-67.2 years). One-way analysis of individuals undergoing thyroid biopsies with adjunctive VR revealed an effect size of -1.74 points (SE ± 0.71; P = .018) on VAS pain scale when compared with SOC. Analysis of individuals undergoing PICC placements revealed an effect size of -1.60 points (SE ± 0.81; P = .053) on VAS anxiety when compared with SOC. CONCLUSIONS: VR as a nonpharmacologic adjunct reduced some procedure-related pain and anxiety without increasing the procedural duration.

Elevated A-to-I RNA editing in COVID-19 infected individuals.

Given the current status of coronavirus disease 2019 (COVID-19) as a global pandemic, it is of high priority to gain a deeper understanding of the disease's development and how the virus impacts its host. Adenosine (A)-to-Inosine (I) RNA editing is a post-transcriptional modification, catalyzed by the ADAR family of enzymes, that can be considered part of the inherent cellular defense mechanism as it affects the innate immune response in a complex manner. It was previously reported that various viruses could interact with the host's ADAR enzymes, resulting in epigenetic changes both to the virus and the host. Here, we analyze RNA-seq of nasopharyngeal swab specimens as well as whole-blood samples of COVID-19 infected individuals and show a significant elevation in the global RNA editing activity in COVID-19 compared to healthy controls. We also detect specific coding sites that exhibit higher editing activity. We further show that the increment in editing activity during the disease is temporary and returns to baseline shortly after the symptomatic period. These significant epigenetic changes may contribute to the immune system response and affect adverse outcomes seen in post-viral cases.

Virtual Reality as a Non-Pharmacological Adjunct to Reduce the Use of Analgesics in Hospitals.

Virtual reality (VR) has become an increasingly viable non-pharmacological adjunct to reduce the use of analgesics in hospitals. Within the context of the ongoing opioid epidemic, VR can serve as an invaluable alternative to traditional pain management techniques. While VR research continues to advance, there is no clear consensus on the terms used to describe critical aspects of VR. This paper presents how immersion, presence, and agency encapsulate the VR experience and investigates the methods by which VR can relieve pain by changing users' cognition and perception of pain. Multiple clinical studies investigating VR efficacy indicate that higher degrees of immersion, presence, and agency are all correlated with greater pain reduction. These studies also demonstrate that VR analgesia is effective for patients with various medical conditions and for those undergoing painful medical procedures. Furthermore, the shared biological mechanisms between pain and anxiety suggest that reducing either through the use of VR will reduce the other. As a nascent field of research, VR analgesia has key obstacles to overcome in order to become a mainstream intervention for pain management in hospital settings.

Bringing prevost's sign into the third dimension: Artificial intelligence estimation of conjugate gaze adjusted length (CGAL) and correlation with acute ischemic stroke.

Conjugate gaze deviation is associated with acute ischemic stroke (AIS), although previously only measured on a 2D plane. The current study evaluates 3D imaging efficacy to assess conjugate gaze deviation and correlate direction and strength of deviation to neuro-clinical findings.A retrospective analysis of 519 patients who had CT scans for suspected AIS at our institution. Direction and angle of eye deviation were calculated based on 2D axial images. Volumetric reconstruction of CT scans allowed for calculation of 3D conjugate gaze adjusted length (CGAL). Angle, direction, and vector strength of both 2D and 3D scans were calculated by an artificial intelligence algorithm and tested for agreement with hemispheric ischemia location. CGAL measurements were correlated to NIHSS scores. Follow up MRI data was used to evaluate the sensitivity and specificity of CGAL in the identification of AIS.The final analysis included 122 patients. A strong agreement was found between 3D gaze direction and hemispheric ischemia location. CGAL measurements were highly correlated with NIHSS score (r = .72, P = .01). A CGAL >0.25, >0.28, and >0.35 exhibited a sensitivity of 91%, 86%, and 82% and specificity of 66%, 89%, and 89%, respectively, in AIS identification. A CGAL >0.28 has the best sensitivity-specificity balance in the identification of AIS. A CGAL >0.25 has the highest sensitivity.Given CED's correlation with NIHSS score a 1/4 deviation in the ipsilateral direction is a sensitive ancillary radiographic sign to assist radiologists in making a correct diagnosis even when not presented with full clinical data.

Incidental COVID-19 in the radiology department: Radiographic findings of COVID-19 in asymptomatic patient undergoing CT staging for breast cancer.

A 59-year-old incarcerated woman who was diagnosed with invasive ductal carcinoma in 2016 was brought in for evaluation of the breast cancer. Upon evaluation of the computed tomography chest for breast cancer restaging, diffuse bilateral ground glass opacities and a reverse halo sign in the right lower lobe concerning for atypical viral pneumonia were discovered. The patient was afebrile, had an oxygen saturation of 100%, and denied chest pain as well as shortness of breath. On physical exam, she exhibited decreased breath sounds bilaterally and expiratory wheezing. She later received a COVID-19 test, which came back positive. Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also known as COVID-19) may remain asymptomatic in the initial phase, leading to under-recognition and incidental detection on procedures for standard clinical indications. Hospitals, in particular diagnostic imaging services, should prepare accordingly in regard to health precautions while keeping in mind the potential discrepancies between clinical presentation and resultant radiologic patterns. This awareness should be heightened in patients at higher risk (ie, prisoners). Furthermore, by acting upon the incidental detection of this virus during its early stages, subsequent steps could help prevent the spread of the virus.

Radically Invasive Projectiles-first reports and imaging features of this new and dangerous bullet.

Recently, civilian patients have begun to present to emergency departments with a new type of bullet injury caused by a frangible bullet designed to splinter and deform in a predictable manner. This bullet "the Radically Invasive Projectile" (RIP) was developed by G2 Research (Winder, GA). In this article, we discuss the fragmentation pattern of this bullet as well present several illustrative cases in an effort to familiarize radiologists, surgeons and emergency medicine physicians with the characteristic wounding patterns and imaging appearances of this new variety of frangible ammunition.

After-hours radiology coverage in children's hospitals: a multi-center survey.

BACKGROUND: Although the provision of pediatric emergency and trauma radiology has become increasingly prevalent in North America over the last few years, many hospitals differ in their models of providing after-hours coverage. OBJECTIVE: To describe the scope of after-hours radiology services provided in children's hospitals in North America, and the means by which different radiology departments deliver this coverage. MATERIALS AND METHODS: The Society for Pediatric Radiology Emergency and Trauma Imaging Committee developed a survey that we electronically distributed to a single representative from each of the 79 hospitals represented in the Society of Chiefs of Radiology at Children's Hospitals (SCORCH). RESULTS: Completed questionnaires were submitted between Aug. 2, 2017, and Sept. 29, 2017, by 44/79 (56%) SCORCH representatives. Contemporaneous after-hours interpretation of radiographs (81%), ultrasounds (81%), body CT (79%) and neurologic CT (75%) with preliminary or final reports was common. Coverage was accomplished most commonly by a combination of evening and overnight shifts 17/44 (39%). Eleven of 44 (25%) hospitals used a model in which radiologists rotate working blocks of overnight service followed by blocks off service. Only 2/44 (5%) hospitals exclusively provided pager coverage after hours. Attending pediatric radiologists were assigned to the majority of after-hours shifts 110/175 (63%), but radiology trainees provided interpretations independently for varying periods of time at 19/44 (43%) surveyed hospitals. Incentives to work after hours included the option to work remotely, as well as additional income, time off, and academic time. CONCLUSION: The model for delivering after-hours pediatric radiology coverage varies. Most hospitals, however, provide contemporaneous interpretations of radiographs, US, body CT and neurologic CT. Most institutions use evening shifts to extend coverage later, with many providing subsequent overnight coverage. Although most shifts are staffed by attending pediatric radiologists, radiology trainees commonly interpret studies independently for varying durations of time after hours.

The association between neck adiposity and long-term outcome.

Anthropometric indices of obesity (e.g. body mass index, waist circumference and neck circumference) are associated with poor long-term cardiovascular outcome. Prior studies have associated neck circumference and central body adiposity. We explored the association between neck fat volume (NFV) and long-term cardiovascular outcome. The study provides a retrospective analysis of all patients undergoing computerized tomography angiography for suspected cerebrovascular accident between January and December 2013. NFV was assessed by three dimensional reconstructions and was adjusted to height to account for differences in body sizes, thus yielding the NFV/height ratio (NHR). Univariate and multivariate analysis were utilized to explore the association between various indices including NHR and all-cause mortality. The analysis included 302 patients. The average age was 61.9±14.3 years, 60.6% of male gender. Diabetes mellitus, hypertension and cardiovascular disease were frequent in 31.5%, 69.9%, and 72.2% of patients, respectively. The median NHR was 492.53cm2 [IQR 393.93-607.82]. Median follow up time was 41.2 months, during which 40 patients (13.2%) died. Multivariate analysis adjusting for age, sex, and diabetes mellitus indicated an independent association between the upper quartile of NHR and all-cause mortality (hazard ratio = 2.279; 95% CI = 1.209-4.299; p = .011). NHR is a readily available anthropometric index which significantly correlated with poor long-term outcome. Following validation in larger scale studies, this index may serve a risk stratifying tool for cardiovascular disease and future outcome.

Continuous positive airway pressure alters brain microstructure and perfusion patterns in patients with obstructive sleep apnea.

OBJECTIVES: To assess the effects of continuous positive airway pressure (CPAP) treatment on brain structure and function in patients with obstructive sleep apnea (OSA). METHODS: A prospective study of seven OSA patients recruited from the sleep center at our institution was carried out. Patients were treated with six weeks of CPAP treatment. Pre-treatment and post-treatment magnetic resonance imaging (MRI) perfusion scans were obtained and compared to assess for treatment-induced changes. Microstructural changes were quantified using functional anistrophy (FA) and mean diffusivity (MD), and brain perfusion was quantified using cerebral blood flow (CBF) and cerebral blood volume (CBV). RESULTS: Of the seven patients included the in study, six (85.7%) were male, and the mean age was 51 years (standard deviation = 13.14). Increased FA and decreased MD were found in the hippocampus, temporal lobes, fusiform gyrus, and occipital lobes. Decreased FA and increased MD were found in frontal regions for all patients (p < 0.05). Increased CBF and CBV were also observed following treatment (p < 0.05). CONCLUSION: In addition to symptom resolution, CPAP treatment may allow for healing of OSA-induced brain damage as seen by restoration of brain structure and perfusion.

Mandibular width as a novel anthropometric measure for assessing obstructive sleep apnea risk.

Craniofacial abnormalities are a known obstructive sleep apnea (OSA) risk factor, but still need to be better characterized. This study investigates the relationship between mandibular width and the risk of developing OSA.We retrospectively analyzed 3D reconstructions of head and neck computed tomography (CT) scans at our institution for mandibular width, neck circumference, neck fat volume (NFV), airway volume (AWV), and NFV:AWV ratio. Age, gender, and BMI were also documented. Patients were contacted to complete a STOP-BANG survey to assess OSA risk. Only patients with reconstructable scans and completed STOP-BANG questionnaires were included in the study. Survey results were analyzed to assess the correlation between mandible width and STOP-BANG. Mandible association was also compared to the associations of the other known risk factors.The final analysis included 427 patients with a mean age of 58.98 years (standard deviation = 16.77), 56% of whom were male. Mandibular width was found to positively correlate with STOP-BANG score (r = .416, P < .001). Statistically significant differences between mandible size for each risk group was seen (P < .001). After controlling for age and sex, mandible size was significantly different only for the low risk vs. high risk groups (odds ratio = 1.11; 95% confidence interval = 1.03-1.20; P = .007). Furthermore, when stratified according to mandible size, the small mandible group (<77.50 mm) predominantly consisted of low risk patients; the medium size mandible group (77.50-84.40 mm) was predominated by intermediate risk patients, and large mandible (>84.40 mm) was predominantly seen in high risk patients. Mandible width expressed a stronger association than NFV:AWV ratio, but neck circumference and NFV had stronger associations than did mandible width.In addition to previously documented OSA risk factors, mandibular width is positively correlated with OSA as an independent risk factor. Observation of a wide mandible (jaw) should raise awareness of OSA risk and increase screening methods when appropriate.

MRI measurements of the normal pediatric optic nerve pathway.

The purpose of this work is to establish a reference scale of optic nerve pathway measurements in pediatric patients according to age using MRI. Optic nerve pathway measurements were retrospectively analyzed using an orbits equivalent sequence on brain MRI scans of 137 pediatric patients (72 male, 65 female, average age = 7.7 years, standard deviation  = 5.3). The examinations were performed on a 1.5-T or 3-T Siemens MR system using routine imaging protocols. Measurements include diameters of the orbital optic nerves (OON), prechiasmatic optic nerves (PON), optic tracts (OT), and optic chiasm (OC). Measurements were performed manually by 2 neuroradiologists, using post-processing software. Patients were stratified into five age groups for measurement analyses: (I) 0-1.49 years, (II) 1.5-2.99 years, (III) 3-5.99 years, (IV) 6-11.99 years, and (V) 12-18 years. The observed value range of OON mean diameter was 2.7 mm (Interquartile range (IQR) = 2.4-2.9), PON was 3.2 mm (IQR  =  3.05-3.5), OT 2.6 mm (IQR = 2-2.9). A strong positive correlation was established between age and mean diameter of OON (r = 0.73, p < .001), PON (r = 0.59, p < .001), and OT (r = 0.72, p < .001). A significant difference in mean OON diameters was found between age groups I-II (d = 0.3, p = .01), II-III (d = 0.5, p < .001), III-IV (d = 0.5, p < .001) followed by a plateau between IV-V (d = 0.l0, p = .19). OON/OT ratio maintained a steady mean value 1 (IQR = 0.93-1.1) regardless of age (p = .7). The diameter of optic pathways was found to increase as a function of age with consistent positive correlation between nerve and tract for all ages.

MRI in detecting facial cosmetic injectable fillers.

BACKGROUND: Despite being considered a non-invasive procedure, injections can cause adverse outcomes including infections, overfilling, asymmetry, foreign body granulomas, and reactions that lead to scarring. Complications may be associated with the procedure itself, the physician's technique, and/or the type of agent injected. In these instances, it is important to be able locate and identify the substance used. This study investigated the viability of using MRI to correctly identify injected substances, their symmetry of distribution, and related complications. METHODS: Fourteen patients with suspected injectable filler complications were identified by our institution's plastic surgery service. All subjects were scanned with MRI, using highly specific face-oriented sequences at high resolution with small field of view and thin slices across the axial and coronal planes by T1 Dixon non-contrast, T2 Dixon, and T1 Dixon after gadolinium injection. Two independent and blinded radiologists evaluated the images and reported (1) the likely injected substance, (2) symmetry, and (3) complications. These radiological results were compared against clinical data provided by the plastic surgery service. RESULTS: Ten patients (83 %) presented objective injectable complications: 4 had abscess, 4 granulomata, and 2 had allergic reactions to the injected substance. The Fleiss Kappa for inter-rater agreement on substances was 0.80. Asymmetry was identified in six patients (50 %) with a Kappa between radiology evaluators of 1. MRI characteristics of these common fillers are summarized in table form. CONCLUSIONS: Given the growing awareness among referring physicians of the value of dedicated facial MRI, utilization of this imaging technique may lead to discovery of the injected substance's true identity, evaluation of symmetry and/or complications.

Anthropometric Assessment of Neck Adipose Tissue and Airway Volume Using Multidetector Computed Tomography: An Imaging Approach and Association With Overall Mortality.

Neck adiposity tissue volume (NATV) accumulation is an indicator for metabolic syndrome and cardiovascular disease (CVD). Neck circumference is a poor measure of NATV, and a quantifier for this entity has not yet been established. To evaluate volumetric quantification by multidetector computed tomography (MDCT) as a reproducible anthropometric tool to measure NATV and airway volume (AWV). A total of 519 patients, including a subset of 70 random patients who underwent head and neck CT scanning in our hospital within 1 year (2013), were studied. Included patients were all those undergoing nonenhanced CT (NECT) or CT angiography (CTA). Neck cross-sectional areas (NCSA) were measured at 2 separate levels of the neck, and 3D postprocessing tissue reconstruction was performed, and NATV and AWVs were quantified volumetrically for all patients within the year. The average NCSA at the level of the soft palate and thyroid cartilage was 22,579 and 14,500 mm, respectively. NATV when compared to the upper and lower levels of NCSA showed correlations of 0.64 and 0.79, respectively (P < 0.001). Interobserver analysis showed mean deviations of 0.46% and 0.32% for NATV and AWV, respectively. A strong correlation between NATV and body mass index (BMI) was found (r = 0.658, P < 0.001), and the top quartile of NATV:AWV patients (out of 519 patients) displayed a statistically significant mortality rate during 670 days of follow-up (d = 7.5%, P = 0.032). After adjustment for age and gender, the association between NATV:AWV and mortality was close to significant (P = 0.072). Volumetric quantification of NATV and AWV is a reproducible and prognostic anthropometric tool, as a high NATV:AWV demonstrated a significant risk factor for mortality; future research may further advance our understanding of this phenomenon.

Cell lineage analysis in human brain using endogenous retroelements.

Somatic mutations occur during brain development and are increasingly implicated as a cause of neurogenetic disease. However, the patterns in which somatic mutations distribute in the human brain are unknown. We used high-coverage whole-genome sequencing of single neurons from a normal individual to identify spontaneous somatic mutations as clonal marks to track cell lineages in human brain. Somatic mutation analyses in >30 locations throughout the nervous system identified multiple lineages and sublineages of cells marked by different LINE-1 (L1) retrotransposition events and subsequent mutation of poly-A microsatellites within L1. One clone contained thousands of cells limited to the left middle frontal gyrus, whereas a second distinct clone contained millions of cells distributed over the entire left hemisphere. These patterns mirror known somatic mutation disorders of brain development and suggest that focally distributed mutations are also prevalent in normal brains. Single-cell analysis of somatic mutation enables tracing of cell lineage clones in human brain.

Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain.

De novo copy-number variants (CNVs) can cause neuropsychiatric disease, but the degree to which they occur somatically, and during development, is unknown. Single-cell whole-genome sequencing (WGS) in >200 single cells, including >160 neurons from three normal and two pathological human brains, sensitively identified germline trisomy of chromosome 18 but found most (≥ 95%) neurons in normal brain tissue to be euploid. Analysis of a patient with hemimegalencephaly (HMG) due to a somatic CNV of chromosome 1q found unexpected tetrasomy 1q in ∼ 20% of neurons, suggesting that CNVs in a minority of cells can cause widespread brain dysfunction. Single-cell analysis identified large (>1 Mb) clonal CNVs in lymphoblasts and in single neurons from normal human brain tissue, suggesting that some CNVs occur during neurogenesis. Many neurons contained one or more large candidate private CNVs, including one at chromosome 15q13.2-13.3, a site of duplication in neuropsychiatric conditions. Large private and clonal somatic CNVs occur in normal and diseased human brains.

Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain.

A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate <0.6 unique somatic insertions per neuron, and most neurons lack detectable somatic insertions, suggesting that L1 is not a major generator of neuronal diversity in cortex and caudate. We then genotyped single cortical cells to characterize the mosaicism of a somatic AKT3 mutation identified in a child with hemimegalencephaly. Single-neuron sequencing allows systematic assessment of genomic diversity in the human brain.

A robotic manipulator for handling TLD badges.

A prototype system for automatic handling of Harshaw/Bicron (now ThermoFisher Scientific) thermoluminescent dosimetry (TLD) badges, which is based on a robotic arm, was designed and built. The robot performs the loading and unloading of the TLD cards in the badges and transports them between the loading/unloading station and magazine stations. For quality assurance, a sticker containing the worker's details printed in barcode format was added to the badge. Automatic on-line identification is performed for checking the correlation between the badge and the TLD card number.

Incidence, possible risk factors, and potential effects of an opaque bubble layer created by a femtosecond laser.

PURPOSE: To describe the incidence, characteristics, risk factors, and sequelae of an opaque bubble layer created by the IntraLase (15 Khz) femtosecond laser (IntraLase, Corp.). SETTING: Private laser center and the Department of Ophthalmology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. METHODS: This study comprised 79 consecutive patients (149 eyes) who had laser in situ keratomileusis for myopic astigmatism. The preoperative visual acuity, refraction, keratometry, pachymetry, and intraoperative data including flap size and thickness were documented. A computerized system was used to calculate the total area of the opaque bubble layer. RESULTS: Eighty-four eyes (56.4%) developed an opaque bubble layer. The layer pattern was diffuse in 32.2% of eyes and hard in 24.2%. The diffuse opaque bubble layer covered a mean of 13.4%+/-10% of the corneal flap and the hard opaque bubble layer, a mean of 21.6%+/-10% (P= .0004). A significant correlation was noted between the corneal steep curvature and central corneal thickness (CCT) and the area of opaque bubble layer. Multivariate logistic regression found that flap diameter (P= .04) and CCT (P = .045) affected the occurrence and area of the opaque bubble layer (P= .04 and P= .05, respectively). Postoperative diffuse lamellar keratitis was not associated with an opaque bubble layer. Three months postoperatively, visual acuity and refraction were not affected by the bubble layer. There was an increase in trefoil aberrations in eyes with a hard opaque bubble layer (P= .01). CONCLUSIONS: Thicker corneas and smaller flaps were associated with a more opaque bubble layer. The presence of an opaque bubble layer did not seem to have detrimental long-term sequelae, although a small harmful effect could not be ruled out.

Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis.

BACKGROUND: Interferon (IFN)-beta therapy represents an important advance in the management of relapsing multiple sclerosis (MS), but information about the relative benefits and risks of available preparations is limited. OBJECTIVE: This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study. METHODS: The EVIDENCE study was a multicenter, randomized, assessor-blinded comparison of 2 IFN-beta dosing regimens. In the study, patients with relapsing MS were randomly assigned to SC IFN-beta1a 44 lag TIW (Rebif, Serono Inc., Geneva, Switzerland) or IM IFN-betala 30 mug QW (Avonex, Biogen Idec, Cambridge, Massachusetts) for 1 to 2 years. The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses; secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, re- spectively. All clinical and magnetic resonance imaging (MRI) evaluations were performed by blinded assessors. In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-dose TIW treatment for an additional 8 months. Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase. RESULTS: A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase. During the comparative phase, a significantly higher proportion of patients in the high-dose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023). The high-dose TIW regimen was also associated with a significant reduction in the annualized relapse rate (-17%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002). MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment. During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant reductions in MRI activity. Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001). Neutralizing antibody formation was more common with high-dose TIW treatment than with low-dose QW treatment (26% vs 3%; P < 0.001). CONCLUSIONS: The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-beta1a 44 microg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-betala 30 microg QW treatment. The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.