To examine the validity of the timed Up and Go (TUG) test as a measure of functional mobility in persons with multiple sclerosis (MS) by using a comprehensive framework based on construct validity ...(ie, convergent and divergent validity).
Cross-sectional study.
Hospital setting.
Community-residing persons with MS (N=47).
Not applicable.
Main outcome measures included the TUG test, timed 25-foot walk test, 6-minute walk test, Multiple Sclerosis Walking Scale-12, Late-Life Function and Disability Instrument, posturography evaluation, Activities-specific Balance Confidence scale, Symbol Digits Modalities Test, Expanded Disability Status Scale, and the number of steps taken per day.
The TUG test was strongly associated with other valid outcome measures of ambulatory mobility (Spearman rank correlation, rs=.71-.90) and disability status (rs=.80), moderately to strongly associated with balance confidence (rs=.66), and weakly associated with postural control (ie, balance) (rs=.31). The TUG test was moderately associated with cognitive processing speed (rs=.59), but not associated with other nonambulatory measures (ie, Late-Life Function and Disability Instrument-upper extremity function).
Our findings support the validity of the TUG test as a measure of functional mobility. This warrants its inclusion in patients' assessment alongside other valid measures of functional mobility in both clinical and research practice in persons with MS.
Asymmetry in the form of left-hemisphere lateralization is a striking characteristic of the cerebral regions involved in the adult language network. In this study, we leverage a large sample of ...typically developing human infants with longitudinal resting-state functional magnetic resonance imaging scans to delineate the trajectory of interhemispheric functional asymmetry in language-related regions during the first 2 years of life. We derived the trajectory of interhemispheric functional symmetry of the inferior frontal gyrus (IFG) and superior temporal gyrus (STG), the sensory and visual cortices, and two higher-order regions within the intraparietal sulcus and dorsolateral prefrontal cortex. Longitudinal models revealed a best fit with quadratic age terms and showed significant estimated coefficients of determination for both the IFG (r
= 0.261, p < 0.001) and the STG (r
= 0.142, p < 0.001) regions while all other regions were best modeled by log-linear increases. These inverse-U-shaped functions of the language regions peaked at ∼11.5 months of age, indicating that a transition toward asymmetry began in the second year. This shift was accompanied by an increase in the functional connectivity of these regions within the left hemisphere. Finally, we detected an association between the trajectory of the IFG and language outcomes at 4 years of age (χ
= 10.986, p = 0.011). Our results capture the developmental timeline of the transition toward interhemispheric functional asymmetry during the first 2 years of life. More generally, our findings suggest that increasing interhemispheric functional symmetry in the first year might be a general principle of the developing brain, governing different functional systems, including those that will eventually become lateralized in adulthood.
Cross-sectional studies of the language system in early infancy suggest that the basic neural mechanisms are in place even before birth. This study represents the first of its kind, using a large longitudinal sample of infants, to delineate the early language-related transition toward interhemispheric functional asymmetry in the brain using resting-state functional MRI. More generally, our findings suggest that increasing interhemispheric functional symmetry in the first year might be a general principle of the developing brain governing multiple functional systems, including those that will eventually become lateralized in adulthood. Although resting-state functional MRI cannot provide direct insights into the developmental mechanisms of language lateralization, this study reveals language-related functional connectivity changes during infancy, marking critical points in the development of the brain's functional architecture.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early ...interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% 95% confidence interval (CI), 62.9 to 100, correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3). These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.
Human children possess the ability to approximate numerical quantity nonverbally from a young age. Over the course of early childhood, children develop increasingly precise representations of ...numerical values, including a symbolic number system that allows them to conceive of numerical information as Arabic numerals or number words. Functional brain imaging studies of adults report that activity in bilateral regions of the intraparietal sulcus (IPS) represents a key neural correlate of numerical cognition. Developmental neuroimaging studies indicate that the right IPS develops its number‐related neural response profile more rapidly than the left IPS during early childhood. One prediction that can be derived from previous findings is that there is longitudinal continuity in the number‐related neural responses of the right IPS over development while the development of the left IPS depends on the acquisition of numerical skills. We tested this hypothesis using fMRI in a longitudinal design with children ages 4 to 9. We found that neural responses in the right IPS are correlated over a 1–2‐year period in young children whereas left IPS responses change systematically as a function of children's numerical discrimination acuity. The data are consistent with the hypothesis that functional properties of the right IPS in numerical processing are stable over early childhood whereas the functions of the left IPS are dynamically modulated by the development of numerical skills.
Children's neural responses during numerical discrimination show different longitudinal profiles in the right versus left intraparietal sulcus (IPS). The right IPS shows correlated number‐related neural responses over development. The left IPS shows developmental changes in number‐related neural responses that correlate with children's numerical acuity.
Radiotherapy is a highly effective anticancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. ...Radiotherapy is known to enhance tumor immunogenicity; however, the contribution and mechanisms of radiotherapy-induced immune responses are unknown.
The impact of low-dose fractionated radiotherapy (5 × 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing of the T-cell receptor (TCR) repertoire. A dual-tumor model was used, with fractionated radiotherapy delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field.
We show that fractionated radiotherapy leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of preexisting T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anticancer immunity following radiotherapy, which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T cells resident in the tumor at the time of radiotherapy and infiltrating T cells.
These data provide evidence that radiotherapy can enhance T-cell trafficking to locally treated tumor sites and augment preexisting anticancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.
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Purpose:
To analyze a case series of retinal vasculitis reported to the American Society of Retina Specialists (ASRS) following Food and Drug Administration approval of brolucizumab for treatment of ...neovascular age-related macular degeneration.
Methods:
The ASRS Research and Safety in Therapeutics Committee analyzed clinical and imaging characteristics from submitted reports of retinal vasculitis after brolucizumab.
Results:
Retinal vasculitis was reported in 26 eyes of 25 patients (22 88% female) after treatment with brolucizumab. Imaging studies were available for 24 of 26 eyes. Most cases (92%) were associated with intraocular inflammation, which presented at a mean of 25 days (range, 3-63 days) after the most recent brolucizumab injection. Mean visual acuity (VA) was 20/52 (range, 20/25-4/200) before the adverse event, 20/151 (range, 20/25-hand motion) at presentation of the adverse event, and 20/243 (range, 20/30-light perception) at last follow-up. Twelve eyes (46%) had a greater than 3-line decrease in VA at final follow-up, and 12 eyes (46%) had a final VA of 20/200 or worse. Analysis of retinal imaging identified vasculopathy that involved retinal arteries (91%), retinal veins (79%), and choroidal vessels (48%). Occlusive disease was apparent on imaging in 83% of eyes. Treatment approaches were varied.
Conclusions:
Retinal vasculitis has been identified in a series of eyes following brolucizumab. Although a few eyes in this series were asymptomatic or minimally symptomatic, some eyes had significant vision loss. A careful examination for signs of active inflammation prior to brolucizumab injection is recommended. Once vasculopathy is suspected, angiographic imaging may help define the spectrum of involvement. Optimal treatment strategies remain unknown.
Resting state functional magnetic resonance imaging (rs-fMRI) in infants enables important studies of functional brain organization early in human development. However, rs-fMRI in infants has ...universally been obtained during sleep to reduce participant motion artifact, raising the question of whether differences in functional organization between awake adults and sleeping infants that are commonly attributed to development may instead derive, at least in part, from sleep. This question is especially important as rs-fMRI differences in adult wake vs. sleep are well documented. To investigate this question, we compared functional connectivity and BOLD signal propagation patterns in 6, 12, and 24 month old sleeping infants with patterns in adult wakefulness and non-REM sleep. We find that important functional connectivity features seen during infant sleep closely resemble those seen during adult sleep, including reduced default mode network functional connectivity. However, we also find differences between infant and adult sleep, especially in thalamic BOLD signal propagation patterns. These findings highlight the importance of considering sleep state when drawing developmental inferences in infant rs-fMRI.
IMPORTANCE: Use of laser vitreolysis for symptomatic floaters has increased in recent years, but prospective studies are not available and the complication profile is poorly understood. OBJECTIVE: To ...analyze cases of complications following laser vitreolysis as voluntarily reported to the American Society of Retina Specialists Research and Safety in Therapeutics (ASRS ReST) Committee, an independent task force formed to monitor device-related and drug-related safety events. DESIGN, SETTING, AND PARTICIPANTS: A retrospective assessment was performed of all cases of complications following laser vitreolysis that were voluntarily reported by practitioners throughout the United States to the ASRS ReST Committee from the first report on September 19, 2016, through March 16, 2017, the date of data analysis and manuscript writing. MAIN OUTCOMES AND MEASURES: Complications reported to the ASRS ReST Committee following laser vitreolysis were analyzed by type to gain an understanding of the spectrum of potential complications. RESULTS: A total of 16 complications following laser vitreolysis were reported in 15 patients by 7 US vitreoretinal specialists during the study period. Complications included elevated intraocular pressure leading to glaucoma; cataracts, including posterior capsule defects requiring cataract surgery; retinal tear; retinal detachment; retinal hemorrhages; scotomas; and an increased number of floaters. CONCLUSIONS AND RELEVANCE: This report presents a spectrum of complications reported to the ASRS ReST Committee across 6 months. The rate of complications cannot be determined because the denominator of total cases is unknown. Also, these findings cannot determine whether there is a causal association between these complications and laser vitreolysis. Prospective studies are warranted to better understand the efficacy of this procedure and the frequency of attendant complications. Until then, practitioners should be aware of the profile of potential complications to properly inform patients during the consent process. The ASRS ReST Committee will continue to monitor device-related and drug-related adverse events and encourages active surveillance and reporting by all physicians.
Abstract Background We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 ...to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. Methods A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. Results Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen’s d = 0.54). Extra-axial CSF volume remained elevated through 24 months ( d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. Conclusions This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.
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