Publications by authors named "Carolyn Wu"

45 Publications

Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity.

Br J Ophthalmol 2021 May 12. Epub 2021 May 12.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background/aims: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights.

Methods: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions.

Results: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%.

Conclusions: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318719DOI Listing
May 2021

Retinopathy of prematurity screening and risk mitigation during the COVID-19 pandemic.

J AAPOS 2021 Apr 18. Epub 2021 Apr 18.

Boston Children's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Background: The coronavirus disease 2019 (COVID-19) pandemic has significantly disrupted the delivery of healthcare. Although most nonurgent ophthalmology visits at Boston Children's Hospital were canceled, premature infants at risk for retinopathy of prematurity (ROP) still required timely, in-person care during the initial 3-month period of the infection surge in Massachusetts. The purpose of the current study was to report our protocols for mitigating risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between infants and eye care providers and to compare examination rates and results with the same 3-month period in 2019.

Methods: During the infection surge, we added new infection control measures and strengthened existing ones. Additional personal protective equipment was used, and the number of ophthalmologists rotating in the three high-capacity NICUs we service was limited.

Results: More infants required ROP examinations during the study period in 2020 than in the same period in 2019, but fewer examinations were performed. There were no cases of missed progression to severe ROP during this time and no known transmission of SARS-CoV-2 between ROP patients and ophthalmology staff.

Conclusions: Overall, effective ROP care was safely provided during the COVID-19 pandemic, and contact with this vulnerable population was minimized.
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http://dx.doi.org/10.1016/j.jaapos.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053364PMC
April 2021

Impact of higher oxygen saturation levels on postnatal weight gain to predict retinopathy of prematurity.

Acta Paediatr 2021 Apr 2. Epub 2021 Apr 2.

Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1111/apa.15868DOI Listing
April 2021

Innovations present in the primate interneuron repertoire.

Nature 2020 10 30;586(7828):262-269. Epub 2020 Sep 30.

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Primates and rodents, which descended from a common ancestor around 90 million years ago, exhibit profound differences in behaviour and cognitive capacity; the cellular basis for these differences is unknown. Here we use single-nucleus RNA sequencing to profile RNA expression in 188,776 individual interneurons across homologous brain regions from three primates (human, macaque and marmoset), a rodent (mouse) and a weasel (ferret). Homologous interneuron types-which were readily identified by their RNA-expression patterns-varied in abundance and RNA expression among ferrets, mice and primates, but varied less among primates. Only a modest fraction of the genes identified as 'markers' of specific interneuron subtypes in any one species had this property in another species. In the primate neocortex, dozens of genes showed spatial expression gradients among interneurons of the same type, which suggests that regional variation in cortical contexts shapes the RNA expression patterns of adult neocortical interneurons. We found that an interneuron type that was previously associated with the mouse hippocampus-the 'ivy cell', which has neurogliaform characteristics-has become abundant across the neocortex of humans, macaques and marmosets but not mice or ferrets. We also found a notable subcortical innovation: an abundant striatal interneuron type in primates that had no molecularly homologous counterpart in mice or ferrets. These interneurons expressed a unique combination of genes that encode transcription factors, receptors and neuropeptides and constituted around 30% of striatal interneurons in marmosets and humans.
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http://dx.doi.org/10.1038/s41586-020-2781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957574PMC
October 2020

Systematic Study of Perfluorocarbon Nanoemulsions Stabilized by Polymer Amphiphiles.

ACS Appl Mater Interfaces 2020 Sep 24;12(35):38887-38898. Epub 2020 Aug 24.

Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States.

Perfluorocarbon (PFC) nanoemulsions, droplets of fluorous solvent stabilized by surfactants dispersed in water, are simple yet versatile nanomaterials. The orthogonal nature of the fluorous phase promotes the formation of nanoemulsions through a simple, self-assembly process while simultaneously encapsulating fluorous-tagged payloads for various applications. The size, stability, and surface chemistry of PFC nanoemulsions are controlled by the surfactant. Here, we systematically study the effect of the hydrophilic portion of polymer surfactants on PFC nanoemulsions. We find that the hydrophilic block length and identity, the overall polymer hydrophilic/lipophilic balance, and the polymer architecture are all important factors. The ability to modulate these parameters enables control over initial size, stability, payload retention, cellular internalization, and protein adsorption of PFC nanoemulsions. With the insight obtained from this systematic study of polymer amphiphiles stabilizing PFC nanoemulsions, design features required for the optimal material are obtained.
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http://dx.doi.org/10.1021/acsami.0c07206DOI Listing
September 2020

An Ultra-Sensitive Step-Function Opsin for Minimally Invasive Optogenetic Stimulation in Mice and Macaques.

Neuron 2020 07 29;107(1):38-51.e8. Epub 2020 Apr 29.

McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Optogenetics is among the most widely employed techniques to manipulate neuronal activity. However, a major drawback is the need for invasive implantation of optical fibers. To develop a minimally invasive optogenetic method that overcomes this challenge, we engineered a new step-function opsin with ultra-high light sensitivity (SOUL). We show that SOUL can activate neurons located in deep mouse brain regions via transcranial optical stimulation and elicit behavioral changes in SOUL knock-in mice. Moreover, SOUL can be used to modulate neuronal spiking and induce oscillations reversibly in macaque cortex via optical stimulation from outside the dura. By enabling external light delivery, our new opsin offers a minimally invasive tool for manipulating neuronal activity in rodent and primate models with fewer limitations on the depth and size of target brain regions and may further facilitate the development of minimally invasive optogenetic tools for the treatment of neurological disorders.
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http://dx.doi.org/10.1016/j.neuron.2020.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351618PMC
July 2020

Facilitating the identification of patients hospitalized for acute myocardial infarction and heart failure and the assessment of their readmission risk through the Patient Navigator Program.

Am Heart J 2020 06 26;224:77-84. Epub 2020 Mar 26.

MedStar Heart and Vascular Institute, Washington Hospital Center, Washington, DC. Electronic address:

Background: Optimal transition care mitigates early hospital readmission risk. Given limited resources, hospitals need to identify patients with high readmission risk. This article examines whether a coordinated quality improvement campaign can help achieve this objective.

Methods: The American College of Cardiology Patient Navigator Program, a 2-year quality improvement campaign, sought to assess the impact of transition care interventions on 30-day readmission rates for patients with acute myocardial infarction (AMI) or heart failure (HF) at 35 hospitals. This article examines the change in 2 of the 36 performance metrics the campaign tracked: the number of AMI and HF patients identified predischarge and those whose readmission risk was assessed.

Results: The number of facilities identifying AMI and HF patients predischarge increased from 24 (68.6%) and 28 (80.0%), respectively, at baseline, to 34 (97.1%) (P = .0016) and 34 (97.1%) (P = .014), respectively, at 2 years. The number of facilities assessing the readmission risk of AMI and HF patients risk increased from 9 (25.7%) and 11 (31.4%), respectively, at baseline, to 32 (91.4%) (P < .0001) and 33 (94.5%) (P < .0001), respectively, at 2 years. Importantly, baseline reporting of performance for both metrics was poor, with >25% of the hospitals missing data.

Conclusions: Implementation of a coordinated quality improvement campaign may increase the number of facilities identifying AMI and HF patients predischarge and assessing their readmission risk. Further research is needed to determine if increased identification reduces 30-day readmission or facilitates improvement in other important clinical outcomes.
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http://dx.doi.org/10.1016/j.ahj.2020.03.020DOI Listing
June 2020

Severe reverse amblyopia with atropine penalization.

J AAPOS 2020 04 15;24(2):106-108. Epub 2020 Jan 15.

Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

We report 2 cases of refractory reverse amblyopia that developed after instillation of 1-4 drops of atropine. Risk factors appear to include age <4, large-angle esotropia, and lack of adherence to spectacle wear.
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http://dx.doi.org/10.1016/j.jaapos.2019.12.001DOI Listing
April 2020

Plasticity in brain activity dynamics after task-shifting training in older adults.

Neuropsychologia 2020 01 4;136:107285. Epub 2019 Dec 4.

Saarland University, Saarbrücken, Germany.

Cognitive control is supported by a dynamic interplay of transient (i.e., trial-related) brain activation across fronto-parietal networks and sustained (i.e., block-related) activation across fronto-striatal networks. Older adults show disturbances in this dynamic functional recruitment. There is evidence suggesting that cognitive-control training may enable older adults to redistribute their brain activation across cortical and subcortical networks, which in turn can limit behavioral impairments. However, previous studies have only focused on spatial rather than on temporal aspects of changes in brain activation. In the present study, we examined training-related functional plasticity in old age by applying a hybrid fMRI design that sensitively tracks the spatio-temporal interactions underlying brain-activation changes. Fifty healthy seniors were assigned to a task-shifting training or an active-control group and their pretest/posttest activation-change maps were compared against 25 untrained younger adults. After training, older adults showed the same performance as untrained young adults. Compared to the control group, task-shifting training promoted proactive (i.e., early, cue-related) changes in transient mechanisms supporting the maintenance and top-down biasing of task-set representations in a specific prefrontal circuitry; reactive (i.e., late, probe-related) changes in transient mechanisms supporting response-selection processes in dissociable fronto-parietal networks; overall reductions of sustained activation in striatal circuits. Results highlight the importance of spatio-temporal interactions in training-induced neural changes in age.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.107285DOI Listing
January 2020

Individual Risk Prediction for Sight-Threatening Retinopathy of Prematurity Using Birth Characteristics.

JAMA Ophthalmol 2020 Jan;138(1):21-29

Department of Ophthalmology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Importance: To prevent blindness, repeated infant eye examinations are performed to detect severe retinopathy of prematurity (ROP), yet only a small fraction of those screened need treatment. Early individual risk stratification would improve screening timing and efficiency and potentially reduce the risk of blindness.

Objectives: To create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment.

Design, Setting, And Participants: In this retrospective cohort study, Swedish National Patient Registry data from infants screened for ROP (born between January 1, 2007, and August 7, 2018) were analyzed with Poisson regression for time-varying data (postnatal age, gestational age [GA], sex, birth weight, and important interactions) to develop an individualized predictive model for ROP treatment (called DIGIROP-Birth [Digital ROP]). The model was validated internally and externally (in US and European cohorts) and compared with 4 published prediction models.

Main Outcomes And Measures: The study outcome was ROP treatment. The measures were estimated momentary and cumulative risks, hazard ratios with 95% CIs, area under the receiver operating characteristic curve (hereinafter referred to as AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results: Among 7609 infants (54.6% boys; mean [SD] GA, 28.1 [2.1] weeks; mean [SD] birth weight, 1119 [353] g), 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8 through 12 and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks' GA showed high predictive ability for the model overall (AUC, 0.90 [95% CI, 0.89-0.92] for internal validation, 0.94 [95% CI, 0.90-0.98] for temporal validation, 0.87 [95% CI, 0.84-0.89] for US external validation, and 0.90 [95% CI, 0.85-0.95] for European external validation) by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP (Children's Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulinlike growth factor 1, neonatal, ROP), and CO-ROP (Colorado-ROP), models requiring more complex postnatal data.

Conclusions And Relevance: This study validated an individualized prediction model for infants born at 24 to 30 weeks' GA, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postmenstrual age was a better predictive variable for the temporal risk of ROP treatment. The model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models requiring longitudinal neonatal data not always readily available to ophthalmologists.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.4502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865304PMC
January 2020

Spatio-Temporal Neural Changes After Task-Switching Training in Old Age.

Front Aging Neurosci 2019 15;11:267. Epub 2019 Oct 15.

Department of Psychology, Development of Language, Learning and Action, Saarland University, Saarbrücken, Germany.

In the present study, we aimed at examining selective neural changes after task-switching training in old age by not only considering the spatial location but also the timescale of brain activation changes (i.e., sustained/block-related or transient/trial-related timescales). We assigned a sample of 50 older adults to a task-switching training or an active single-task control group. We administered two task paradigms, either sensitive to transient (i.e., a context-updating task) or sustained (i.e., a delayed-recognition working-memory task) dynamics of cognitive control. These dynamics were captured by utilizing an appropriate event-related or block-related functional magnetic resonance imaging design. We captured selective changes in task activation during the untrained tasks after task-switching training compared to an active control group. Results revealed changes at the neural level that were not evident from only behavioral data. Importantly, neural changes in the transient-sensitive context updating task were found on the same timescale but in a different region (i.e., in the left inferior parietal lobule) than in the task-switching training task (i.e., ventrolateral PFC, inferior frontal junction, superior parietal lobule), only pointing to temporal overlap, while neural changes in the sustained-sensitive delayed-recognition task overlapped in both timescale and region with the task-switching training task (i.e., in the basal ganglia), pointing to spatio-temporal overlap. These results suggest that neural changes after task-switching training seem to be critically supported by the organization of neural processing.
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http://dx.doi.org/10.3389/fnagi.2019.00267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803514PMC
October 2019

Same same but different? Replicating the real surroundings in a virtual trier social stress test (TSST-VR) does not enhance presence or the psychophysiological stress response.

Physiol Behav 2019 12 15;212:112690. Epub 2019 Oct 15.

Department of Biological and Clinical Psychology, University of Trier, D-54290 Trier, Germany. Electronic address:

In recent years, adaptations of the Trier Social Stress Test (TSST) have shown that socially evaluative stress can effectively elicit psychobiological responses in a standardized way in Virtual Reality (VR). While these methods hold many advantages, the underlying mechanisms of stress-induction effects via virtual avatars are still largely unclear. The present study tested whether the similarity of the real and virtual world modulates the stress response during a virtual TSST by intensifying the experience of presence. For this purpose, two groups performed the TSST-VR while their virtual surroundings were either a replication of the real laboratory or a foreign environment. Although a significant stress response with regard to salivary cortisol, salivary alpha amylase, heart rate and subjective feelings of stress was found in both groups, the parallelization of the real and virtual environment did not lead to an increase in physiological or subjective stress. Furthermore, both groups did not differ in self-reported presence. Beyond reproducing previous findings of successful psychobiological stress induction in VR, the results indicate that the paradigm is effective regardless of the context it is employed in and therefore could be a promising tool in multi-center research projects or clinical applications.
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http://dx.doi.org/10.1016/j.physbeh.2019.112690DOI Listing
December 2019

Multimodality Imaging in the Evaluation of Intracardiac Masses.

Curr Treat Options Cardiovasc Med 2019 Sep 5;21(10):55. Epub 2019 Sep 5.

Department of Cardiology, MedStar Georgetown University Hospital, MedStar Washington Hospital Center, MedStar Heart and Vascular Institute, Washington, DC, 20007, USA.

Intracardiac masses are classified as neoplastic or non-neoplastic. Prognosis varies based on the diagnosis of the mass since treatment options differ greatly. As novel imaging techniques emerge, a multimodality approach to the evaluation of intracardiac masses becomes an important part of non-invasive evaluation prior to potential surgical planning or oncological treatment. The purpose of this article is to compare the available imaging modalities-echocardiography, cardiovascular magnetic resonance, cardiac computed tomography, nuclear imaging, and emerging novel hybrid imaging techniques for future clinical applications-and to review the characteristic features seen on those modalities for the most common intracardiac masses.
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http://dx.doi.org/10.1007/s11936-019-0756-xDOI Listing
September 2019

Referral to Cardiac Rehabilitation and Outcomes for Patients With Takotsubo Cardiomyopathy.

J Cardiopulm Rehabil Prev 2019 05;39(3):E8-E11

Division of Cardiology, School of Medicine, Georgetown University, MedStar Washington Hospital Center, Washington, District of Columbia (Dr C. M. Wu); Touro College of Osteopathic Medicine, New York City, New York (Mr McKeon); Division of Cardiology, Warren Alpert Medical School of Brown University, Providence, Rhode Island (Drs Abbott and W.-C. Wu); Veterans Affairs Medical Center, Providence, Rhode Island (Ms Jiang and Dr W.-C. Wu); and Miriam Hospital Center for Cardiac Fitness, Providence, Rhode Island (Dr W.-C. Wu).

Purpose: The aim of this study was to determine participation rates and outcomes for patients with Takotsubo cardiomyopathy (TC) in a cardiac rehabilitation (CR) program.

Methods: Patients at 2 academic medical centers with a discharge diagnosis of TC from January 2008 to March 2015 were retrospectively identified. Patients meeting the Mayo Clinic criteria for TC were cross-matched to the CR center affiliated with the hospitals to determine the referral rate and outcomes after completion of the program.

Results: In total, 380 unique patients were identified who survived the index hospitalization. Eighteen patients (5%) were referred to CR, 15 enrolled, and of those enrolled, 10 patients (67%) completed the program. Patients undergoing percutaneous coronary intervention of a nonculprit vessel at the time of diagnosis was the only predictor for referral to CR (11% vs 1%, P = .01). The 10 patients who completed CR attended 33 ± 6 (range, 20-36) sessions. Weight and body mass index reduction were 2.8 ± 3.5 lb and 0.6 ± 0.7 kg/m (P = .04, both), respectively. Post-CR exercise duration was 37 ± 4 min/session, which improved by 13 ± 6 min/session from baseline (P < .01). Two patients entered the phase III maintenance program. One-year cardiac readmission rates were comparable among patients who completed CR and those who were referred but did not attend or complete CR (0% vs 13%, P = .47).

Conclusions: Referral for the TC population was low; however, enrollment and completion rates were adequate, with percutaneous coronary intervention in nonculprit vessel as the only predictor of CR referral. Limited data showed CR may help with weight reduction and improve exercise duration.
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http://dx.doi.org/10.1097/HCR.0000000000000433DOI Listing
May 2019

Human Sensory LTP Predicts Memory Performance and Is Modulated by the ValMet Polymorphism.

Front Hum Neurosci 2019 15;13:22. Epub 2019 Feb 15.

Faculty of Science, School of Psychology, University of Auckland, Auckland, New Zealand.

: Long-term potentiation (LTP) is recognised as a core neuronal process underlying long-term memory. However, a direct relationship between LTP and human memory performance is yet to be demonstrated. The first aim of the current study was thus to assess the relationship between LTP and human long-term memory performance. With this also comes an opportunity to explore factors thought to mediate the relationship between LTP and long-term memory. The second aim of the current study was to explore the relationship between LTP and memory in groups differing with respect to brain-derived neurotrophic factor ValMet; a single-nucleotide polymorphism (SNP) implicated in memory function. : Participants were split into three genotype groups (Val/Val, Val/Met, Met/Met) and were presented with both an EEG paradigm for inducing LTP- enhancements of the visually-evoked response, and a test of visual memory. : The magnitude of LTP 40 min after induction was predictive of long-term memory performance. Additionally, the Met allele was associated with both reduced LTP and reduced memory performance. : The current study not only presents the first evidence for a relationship between sensory LTP and human memory performance, but also demonstrates how targeting this relationship can provide insight into factors implicated in variation in human memory performance. It is anticipated that this will be of utility to future clinical studies of disrupted memory function.
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http://dx.doi.org/10.3389/fnhum.2019.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384276PMC
February 2019

The Effect of Botulinum Toxin Augmentation on Strabismus Surgery for Large-Angle Infantile Esotropia.

Am J Ophthalmol 2018 05 21;189:160-165. Epub 2018 Feb 21.

Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts. Electronic address:

Purpose: To determine whether botulinum toxin augments the effect of strabismus surgery in pediatric patients with large-angle infantile esotropia.

Design: Retrospective, comparative, case series.

Methods: Setting: Tertiary-care pediatric hospital.

Study Population: Patients with large-angle infantile esotropia.

Intervention: Treatment with botulinum toxin-augmented bilateral medial rectus muscle recessions ("augmented-surgery group") or traditional bilateral medial rectus muscle recessions ("surgery-only group").

Main Outcome Measure: The effect of surgery on ocular alignment at 4 months, measured in prism diopters of change per mm of surgery (PD/mm).

Results: There were 14 patients in the augmented-surgery group and 16 patients in the surgery-only group. The mean effect on alignment was significantly greater in the augmented-surgery group compared to the surgery-only group at 4 months (5.7 ± 1.3 vs 4.0 ± 1.4 PD/mm, P = .002) and at 1 year (5.4 ± 1.2 vs 3.7 ± 1.2 PD/mm, P = .002). There was a partial loss of treatment effect between 4 months and 1 year in both groups, which was similar in magnitude (P = .57). On linear regression, there was a trend toward a positive correlation between botulinum toxin dose and treatment effect, but this was not statistically significant (P = .09).

Conclusions: Botulinum toxin augments the surgical effect of medial rectus muscle recession. Botulinum toxin-augmented surgery may be an alternative to traditional options for large-angle infantile esotropia. A surgical dosing table is proposed for this technique.
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http://dx.doi.org/10.1016/j.ajo.2018.02.010DOI Listing
May 2018

Musical training increases functional connectivity, but does not enhance mu suppression.

Neuropsychologia 2017 Sep 31;104:223-233. Epub 2017 Aug 31.

School of Psychology, The University of Auckland, Auckland, New Zealand.

Musical training provides an ideal platform for investigating action representation for sound. Learning to play an instrument requires integration of sensory and motor perception-action processes. Functional neuroimaging studies have indicated that listening to trained music can result in the activity in premotor areas, even after a short period of training. These studies suggest that action representation systems are heavily dependent on specific sensorimotor experience. However, others suggest that because humans naturally move to music, sensorimotor training is not necessary and there is a more general action representation for music. We previously demonstrated that EEG mu suppression, commonly implemented to demonstrate mirror-neuron-like action representation while observing movements, can also index action representations for sounds in pianists. The current study extends these findings to a group of non-musicians who learned to play randomised sequences on a piano, in order to acquire specific sound-action mappings for the five fingers of their right hand. We investigated training-related changes in neural dynamics as indexed by mu suppression and task-related coherence measures. To test the specificity of training effects, we included sounds similar to those encountered in the training and additionally rhythm sequences. We found no effect of training on mu suppression between pre- and post-training EEG recordings. However, task-related coherence indexing functional connectivity between electrodes over audiomotor areas increased after training. These results suggest that long-term training in musicians and short-term training in novices may be associated with different stages of audiomotor integration that can be reflected in different EEG measures. Furthermore, the changes in functional connectivity were specifically found for piano tones, and were not apparent when participants listened to rhythms, indicating some degree of specificity related to training.
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http://dx.doi.org/10.1016/j.neuropsychologia.2017.08.029DOI Listing
September 2017

Mu rhythm suppression demonstrates action representation in pianists during passive listening of piano melodies.

Exp Brain Res 2016 08 18;234(8):2133-9. Epub 2016 Mar 18.

Cognitive Neuroscience Research Group, School of Psychology, The University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland, 1142, New Zealand.

Musicians undergo extensive training which enhances established neural links between auditory and motor areas of the brain. Long-term training develops, strengthens and enables flexibility in these connections allowing proficiency in performance. Previous research has indicated that passive listening of trained music results in the recruitment of premotor areas. It has been argued that this sound-action representation may rely on activity in mirror neuron systems and that these systems are heavily dependent on actual sensorimotor experience. Action observation studies using electroencephalography have associated changes in mu rhythm activity with the mirror neuron system in the visuomotor domain. We aimed to investigate similar effects in the audiomotor domain. We utilised a mu suppression method in our action-listening study to detect involuntary motor coactivation when pianists passively listened to piano melodies. Wavelet analysis revealed sensorimotor mu rhythm suppression while pianists listened passively to piano melodies. Thus, we show that this spectral analysis method can also be used to demonstrate that auditory stimuli can activate the human mirror neuron system when sounds are linked to actions. Mu suppression could be a useful index for further research on action representation and training-induced plasticity.
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http://dx.doi.org/10.1007/s00221-016-4615-7DOI Listing
August 2016

Intrauterine device infection causing concomitant streptococcal toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus bacteraemia.

BMJ Case Rep 2016 Mar 10;2016. Epub 2016 Mar 10.

Department of Infectious Diseases, The Miriam Hospital and Immunology Center, Providence, Rhode Island, USA Department of Infectious Diseases, Providence VA Medical Center, Providence, Rhode Island, USA.

Intrauterine devices (IUDs) are rarely associated with serious infections. We report an unusual concomitant infection of group A Streptococcus (GAS) causing toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus associated with an IUD in a healthy 50-year-old patient. The IUD was subsequently removed and the patient recovered on the appropriate antibiotics. This case highlights the importance of clinicians' high index of suspicion of an IUD infection and prompt removal of the infected foreign body to obtain source control.
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http://dx.doi.org/10.1136/bcr-2015-213236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800214PMC
March 2016

Medical Therapies of Amblyopia: Translational Research to Expand Our Treatment Armamentarium.

Semin Ophthalmol 2016 ;31(1-2):155-8

a Boston Children's Hospital , Boston , Massachusetts , USA.

Amblyopia is a developmental brain disorder in which vision is lost due to asymmetric or inadequate visual stimulation early in life. Although amblyopia is responsive to treatment if therapy is initiated early, treatment of older children and adults is usually unsuccessful due to closure of a window of cortical brain plasticity. Extensive basic research has been devoted to understanding modulators in shaping the visual cortex during the critical period of plasticity, and to providing potential clinical applications of neurotransmitters in the treatment of amblyopia. Current pharmacological treatments are reviewed from basic science research extending into clinical use, focusing on the acetylcholinesterase inhibitor donezepil, serotonin receptor inhibitor fluoxetine, dopamine precursors carbidopa-levodopa, and catecholamine modulator citicoline.
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http://dx.doi.org/10.3109/08820538.2015.1114851DOI Listing
October 2016

Influence of Physical Activity on Human Sensory Long-Term Potentiation.

J Int Neuropsychol Soc 2015 Nov;21(10):831-40

1School of Psychology,University of Auckland,New Zealand.

A growing body of literature has explored the influence of physical activity on brain structure and function. While the mechanisms of this relationship remain largely speculative, recent research suggests that one of the effects of physical exercise is an increase in synaptic long-term potentiation (LTP). This has not yet been explored directly in humans due to the difficulty of measuring LTP non-invasively. However, we have previously established that LTP-like changes in visual-evoked potentials (VEPs) can be measured in humans. Here, we investigated whether physical fitness status affects the degree of visual sensory LTP. Using a self-report measure of physical activity, participants were split into two groups: a high-activity group, and a low-activity group. LTP was measured and compared between the two groups using the previously established electroencephalography-LTP paradigm, which assesses the degree to which the N1b component of the VEP elicited by a sine grating is potentiated (enhanced) following a rapid "tetanic" presentation of that grating. Both groups demonstrated increased negativity in the amplitude of the N1b component of the VEP immediately after presentation of the visual "tetanus," indicating potentiation. However, after a 30-min rest period, the N1b for the high-activity group remained potentiated while the N1b for the low-activity group returned to baseline. This study presents the first evidence for the impact of self-reported levels of physical activity on LTP in humans, and sheds light on potential neurological mechanisms underlying the relationship between physical fitness and cognition.
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http://dx.doi.org/10.1017/S1355617715001095DOI Listing
November 2015

The Specificity of the WINROP Algorithm Can Be Significantly Increased by Reassessment of the WINROP Alarm.

Neonatology 2015 8;108(2):152-6. Epub 2015 Jul 8.

Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Retinopathy of prematurity (ROP) is a sight-threatening disease affecting extremely preterm infants. The introduction of new ROP screening surveillance systems, with higher sensitivity and specificity than established ROP screening guidelines, has the potential to reduce the number of stressful eye examinations in these infants.

Objectives: To improve the specificity of the WINROP (Weight, Insulin-like growth factor-I, Neonatal, ROP) surveillance system, identifying extremely preterm infants requiring treatment for ROP.

Methods: Two cohorts that had previously been subjected to WINROP analyses were included and reevaluated in this study. The weight at WINROP alarm for extremely preterm infants, born at gestational age <27 weeks, was reevaluated and by establishing 'safe' WINROP alarm weight limits, an intersample reassessment of WINROP alarm was performed. The two cohorts were as follows: (1) the Extremely Preterm Infants in Sweden Study (EXPRESS) cohort, infants born in Sweden during 2004-2007 (n = 407), and (2) extremely preterm infants in a North American cohort, born during 2006-2009 (n = 566).

Results: In the EXPRESS cohort, 12.5% (40/319) of the infants who previously received a WINROP alarm were now reassessed as having no alarm; the specificity of WINROP in EXPRESS increased from 23.9% (86/360) to 35.0% (126/360). In the North American cohort, 15.4% (81/526) were reassessed as having no alarm; the specificity increased from 8.5% (38/447) to 26.6% (119/447). The sensitivity persisted as 97.5% in EXPRESS (45/47) and 98.3% (117/119) in the North American cohort.

Conclusions: The specificity of the WINROP surveillance system for extremely preterm infants can be significantly improved by reassessment using the weight at WINROP alarm.
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http://dx.doi.org/10.1159/000435770DOI Listing
May 2016

Low birth weight is a risk factor for severe retinopathy of prematurity depending on gestational age.

PLoS One 2014 15;9(10):e109460. Epub 2014 Oct 15.

Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Objective: To evaluate the impact of low birth weight as a risk factor for retinopathy of prematurity (ROP) that will require treatment in correlation with gestational age at birth (GA).

Study Design: In total, 2941 infants born <32 weeks GA were eligible from five cohorts of preterm infants previously collected for analysis in WINROP (Weight IGF-I Neonatal ROP) from the following locations: Sweden (EXPRESS) (n = 426), North America (n = 1772), Boston (n = 338), Lund (n = 52), and Gothenburg (n = 353). Data regarding GA at birth, birth weight (BW), gender, and need for ROP treatment were retrieved. Birth weight standard deviation scores (BWSDS) were calculated with Swedish as well as Canadian reference models. Small for gestational age (SGA) was defined as BWSDS less than -2.0 SDS using the Swedish reference and as BW below the 10th percentile using the Canadian reference charts.

Results: Univariate analysis showed that low GA (p<0.001), low BW (p<0.001), male gender (p<0.05), low BWSDSCanada (p<0.001), and SGACanada (p<0.01) were risk factors for ROP that will require treatment. In multivariable logistic regression analysis, low GA (p<0.0001), male gender (p<0.01 and p<0.05), and an interaction term of BWSDS*GA group (p<0.001), regardless of reference chart, were risk factors. Low BWSDS was less important as a risk factor in infants born at GA <26 weeks compared with infants born at GA ≥26 weeks calculated with both reference charts (BWSDSSweden, OR = 0.80 vs 0.56; and BWSDSCanada, OR = 0.72 vs 0.41).

Conclusions: Low BWSDS as a risk factor for vision-threatening ROP is dependent on the infant's degree of immaturity. In more mature infants (GA ≥26 weeks), low BWSDS becomes a major risk factor for developing ROP that will require treatment. These results persist even when calculating BW deficit with different well-established approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198133PMC
June 2015

Importance of early postnatal weight gain for normal retinal angiogenesis in very preterm infants: a multicenter study analyzing weight velocity deviations for the prediction of retinopathy of prematurity.

Arch Ophthalmol 2012 Aug;130(8):992-9

Department of Ophthalmology, Children’s Hospital Boston, 300 Longwood Ave, Fegan 4, Boston, MA 02115, USA.

Objective: To assess WINROP (https://winrop.com), an algorithm using postnatal weight measurements, as a tool for the prediction of retinopathy of prematurity (ROP) in a large geographically and racially diverse study population.

Methods: WINROP analysis was performed retrospectively on conventionally at-risk infants from 10 neonatal intensive careunits.Weight measurements were entered into WINROP, which signals an alarm for an abnormal weight gain rate. Infants were classified into categories of no alarm (unlikely to develop type 1ROP)and alarm (at risk for developing type 1ROP).Use of WINROP requires that an infant has (1) gestational age less than 32 weeks at birth, (2) weekly weight measurements,(3) physiologic weight gain,and(4)absence of other pathologic retinal vascular disease.

Results: A total of 1706 infants with a median gestational age of 28 weeks (range, 22-31 weeks) and median birth weight of 1016 g (range, 378-2240 g) were included in the study analysis. An alarm occurred in 1101 infants (64.5%), with a median time from birth to alarm of 3 weeks (range, 0-12 weeks) and from alarm to treatment of 8 weeks (range, 1 day to 22 weeks). The sensitivity of WINROP was 98.6% and the negative predictive value was 99.7%. Two infants with type 1 ROP requiring treatment after 40 weeks' postmenstrual age did not receive an alarm.

Conclusion: The WINROP system is a useful adjunct for ROP screening that identifies high-risk infants early to optimize care and potentially reduce the overall number of diagnostic ROP examinations.
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http://dx.doi.org/10.1001/archophthalmol.2012.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059056PMC
August 2012

Superior rectus transposition and medial rectus recession for Duane syndrome and sixth nerve palsy.

Arch Ophthalmol 2012 Feb;130(2):195-201

Department of Ophthalmology, Children's Hospital Boston, Boston, MA 02115, USA.

Objective: To describe our results using augmented temporal superior rectus transposition (SRT) with adjustable medial rectus muscle recession (MRc) for treatment of Duane syndrome and sixth nerve palsy.

Methods: Retrospective surgical case review of patients undergoing SRT. Preoperative and postoperative orthoptic measurements were recorded. Minimum follow-up was 6 weeks. Main outcome measures included the angle of esotropia in the primary position and the angle of head turn. Secondary outcomes included duction limitation, stereopsis, and new vertical deviations.

Results: The review identified 17 patients: 10 with Duane syndrome and 7 with sixth nerve palsy. Combining SRT with MRc improved esotropia from 44 to 10 prism diopters (P < .001), reduced abduction limitation from -4.3 to -2.7 (P < .001), and improved compensatory head posture from 28° to 4° (P < .001). Stereopsis was recovered in 8 patients (P = .03). Three patients required a reoperation: 1 for overcorrection and 2 for undercorrection. A new primary position vertical deviation was observed in 2 patients with complex sixth nerve palsy and none with Duane syndrome. No patient described torsional diplopia.

Conclusions: Superior rectus transposition allows for the option of simultaneous MRc in patients with severe abduction imitation who require transposition surgery. Combining SRT and MRc improved esotropia, head position, abduction limitation, and stereopsis without inducing torsional diplopia.
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http://dx.doi.org/10.1001/archophthalmol.2011.384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753366PMC
February 2012

Development of a MR-visible compound for tracing neuroanatomical connections in vivo.

Neuron 2011 Apr;70(2):229-43

Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.

Traditional studies of neuroanatomical connections require injection of tracer compounds into living brains, then histology of the postmortem tissue. Here, we describe and validate a compound that reveals neuronal connections in vivo, using MRI. The classic anatomical tracer CTB (cholera-toxin subunit-B) was conjugated with a gadolinium-chelate to form GdDOTA-CTB. GdDOTA-CTB was injected into the primary somatosensory cortex (S1) or the olfactory pathway of rats. High-resolution MR images were collected at a range of time points at 11.7T and 7T. The transported GdDOTA-CTB was visible for at least 1 month post-injection, clearing within 2 months. Control injections of non-conjugated GdDOTA into S1 were not transported and cleared within 1-2 days. Control injections of Gd-Albumin were not transported either, clearing within 7 days. These MR results were verified by classic immunohistochemical staining for CTB, in the same animals. The GdDOTA-CTB neuronal transport was target specific, monosynaptic, stable for several weeks, and reproducible.
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http://dx.doi.org/10.1016/j.neuron.2011.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419536PMC
April 2011

Mapping cortical representations of the rodent forepaw and hindpaw with BOLD fMRI reveals two spatial boundaries.

Neuroimage 2011 Jul 12;57(2):526-38. Epub 2011 Apr 12.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Electrical stimulation of the rat forepaw and hindpaw was employed to study the spatial distribution of BOLD fMRI. Averaging of multiple fMRI sessions significantly improved the spatial stability of the BOLD signal and enabled quantitative determination of the boundaries of the BOLD fMRI maps. The averaged BOLD fMRI signal was distributed unevenly over the extent of the map and the data at the boundaries could be modeled with major and minor spatial components. Comparison of three-dimensional echo-planar imaging (EPI) fMRI at isotropic 300 μm resolution demonstrated that the border locations of the major spatial component of BOLD signal did not overlap between the forepaw and hindpaw maps. Interestingly, the border positions of the minor BOLD fMRI spatial components extended significantly into neighboring representations. Similar results were found for cerebral blood volume (CBV) weighted fMRI obtained using iron oxide particles, suggesting that the minor spatial components may not be due to vascular mislocalization typically associated with BOLD fMRI. Comparison of the BOLD fMRI maps of the forepaw and hindpaw to histological determination of these representations using cytochrome oxidase (CO) staining demonstrated that the major spatial component of the BOLD fMRI activation maps accurately localizes the borders. Finally, 2-3 weeks following peripheral nerve denervation, cortical reorganization/plasticity at the boundaries of somatosensory limb representations in adult rat brain was studied. Denervation of the hindpaw caused a growth in the major component of forepaw representation into the adjacent border of hindpaw representation, such that fitting to two components no longer led to a better fit as compared to using one major component. The border of the representation after plasticity was the same as the border of its minor component in the absence of any plasticity. It is possible that the minor components represent either vascular effects that extend from the real neuronal representations or the neuronal communication between neighboring regions. Either way the results will be useful for studying mechanisms of plasticity that cause alterations in the boundaries of neuronal representations.
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http://dx.doi.org/10.1016/j.neuroimage.2011.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199081PMC
July 2011

Longitudinal postnatal weight measurements for the prediction of retinopathy of prematurity.

Arch Ophthalmol 2010 Apr;128(4):443-7

Department of Ophthalmology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

Objective: To validate longitudinal postnatal weight gain as a method for predicting severe retinopathy of prematurity (ROP) in a US cohort.

Methods: Both ROP evaluations and weekly weight measurements from birth to postmenstrual week 36 for 318 infants were entered into a computer-based surveillance system, WINROP. This system signaled an alarm when the rate of weight gain decreased compared with control subjects. Infants were classified into 3 groups: (1) no alarm, (2) low-risk alarm, or (3) high-risk alarm. Maximum ROP for each infant was categorized as (1) no ROP (immature or mature vascularization), (2) mild ROP (stage 1 or 2 ROP in zone II or III, without plus disease), or (3) severe ROP (any prethreshold, any stage 3, or threshold ROP). A high-risk alarm identified infants at risk for developing severe ROP.

Results: A high-risk alarm occurred in 81 infants (25.5%) and detected all infants who developed severe ROP a median of 9 weeks before diagnosis. The remaining infants received no alarm or a low-risk alarm. None of these infants developed more than mild ROP.

Conclusions: Longitudinal postnatal weight gain may help predict ROP. In a US cohort, the WINROP system had a sensitivity of 100% and identified infants early who developed severe ROP. With further validation, WINROP has the potential to safely reduce the number of ROP examinations.
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http://dx.doi.org/10.1001/archophthalmol.2010.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393744PMC
April 2010