Predicting Acute Brain Injury in Venoarterial Extracorporeal Membrane Oxygenation Patients with Tree-Based Machine Learning: Analysis of the Extracorporeal Life Support Organization Registry.

Objective: To determine if machine learning (ML) can predict acute brain injury (ABI) and identify modifiable risk factors for ABI in venoarterial extracorporeal membrane oxygenation (VA-ECMO) patients. Design: Retrospective cohort study of the Extracorporeal Life Support Organization (ELSO) Registry (2009-2021). Setting: International, multicenter registry study of 676 ECMO centers. Patients: Adults (≥18 years) supported with VA-ECMO or extracorporeal cardiopulmonary resuscitation (ECPR). Interventions: None. Measurements and Main Results: Our primary outcome was ABI: central nervous system (CNS) ischemia, intracranial hemorrhage (ICH), brain death, and seizures. We utilized Random Forest, CatBoost, LightGBM and XGBoost ML algorithms (10-fold leave-one-out cross-validation) to predict and identify features most important for ABI. We extracted 65 total features: demographics, pre-ECMO/on-ECMO laboratory values, and pre-ECMO/on-ECMO settings.Of 35,855 VA-ECMO (non-ECPR) patients (median age=57.8 years, 66% male), 7.7% (n=2,769) experienced ABI. In VA-ECMO (non-ECPR), the area under the receiver-operator characteristics curves (AUC-ROC) to predict ABI, CNS ischemia, and ICH was 0.67, 0.67, and 0.62, respectively. The true positive, true negative, false positive, false negative, positive, and negative predictive values were 33%, 88%, 12%, 67%, 18%, and 94%, respectively for ABI. Longer ECMO duration, higher 24h ECMO pump flow, and higher on-ECMO PaO2 were associated with ABI.Of 10,775 ECPR patients (median age=57.1 years, 68% male), 16.5% (n=1,787) experienced ABI. The AUC-ROC for ABI, CNS ischemia, and ICH was 0.72, 0.73, and 0.69, respectively. The true positive, true negative, false positive, false negative, positive, and negative predictive values were 61%, 70%, 30%, 39%, 29% and 90%, respectively, for ABI. Longer ECMO duration, younger age, and higher 24h ECMO pump flow were associated with ABI. Conclusions: This is the largest study predicting neurological complications on sufficiently powered international ECMO cohorts. Longer ECMO duration and higher 24h pump flow were associated with ABI in both non-ECPR and ECPR VA-ECMO.

Epidemiology of ischemic stroke and hemorrhagic stroke in venoarterial extracorporeal membrane oxygenation.

BACKGROUND: While venoarterial extracorporeal membrane oxygenation (V-A ECMO) provides lifesaving support for cardiopulmonary failure, complications may increase mortality, with few studies focusing on ischemic/hemorrhagic stroke. We aimed to determine the trends and associations of stroke incidence and mortality, and their risk factors, including the effects of annual case volumes of ECMO centers. METHODS: Retrospective analysis was performed on the Extracorporeal Life Support Organization (ELSO) registry, including adult V-A ECMO patients from 534 international centers between 2012 and 2021, excluding extracorporeal cardiopulmonary resuscitation. Temporal trend analyses were performed for stroke incidence and mortality. Univariate testing, multivariable regression, and survival analysis were used to evaluate the associations of stroke, 90-day mortality, and impact of annual center volume. RESULTS: Of 33,041 patients, 20,297 had mortality data, and 12,327 were included in the logistic regression. Between 2012 and 2021, ischemic stroke incidence increased (p < 0.0001), hemorrhagic stroke incidence remained stable, and overall 90-day mortality declined (p < 0.0001). Higher 24-h PaO2 and greater decrease between pre-ECMO PaCO2 and post-cannulation 24-h PaCO2 were associated with greater ischemic stroke incidence, while annual case volume was not. Ischemic/hemorrhagic strokes were associated with increased 90-day mortality (both p < 0.0001), while higher annual case volume was associated with lower 90-day mortality (p = 0.001). Hazard of death was highest in the first several days of V-A ECMO. CONCLUSION: In V-A ECMO patients between 2012 and 2021, 90-day mortality decreased, while ischemic stroke incidence increased. ELSO centers with higher annual case volumes had lower mortality, but were not associated with ischemic/hemorrhagic stroke incidence. Both ischemic/hemorrhagic strokes were associated with increased mortality.

Epidemiology of Ischemic Stroke and Hemorrhagic Stroke in Venoarterial Extracorporeal Membrane Oxygenation.

Background: While venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides lifesaving support for cardiopulmonary failure, complications may arise that increase mortality, with few studies focusing on ischemic/hemorrhagic stroke. We aimed to determine the trends of stroke incidence and mortality, associations with each other, and associations with total case volume at each Extracorporeal Life Support Organization (ELSO) center. Methods: Retrospective analysis of ELSO registry, including adult VA-ECMO patients from 534 international centers between 2012-2021, excluding extracorporeal cardiopulmonary resuscitation. Cochran-Armitage test and Poisson regression were used for trend analysis of stroke incidence and mortality. Kaplan-Meier curves, hazard functions, and multivariable logistic regression were used to study the impact of stroke on 90-day mortality. Results: Of 33,041 patients (median age = 58 years, female = 32%), 4% developed ischemic stroke, and 2% developed hemorrhagic stroke. Ischemic stroke incidence increased (×1.21/year, p < 0.0001), while hemorrhagic stroke incidence remained stable, and overall 90-day mortality declined (1.78%/year, p < 0.0001). Ischemic/hemorrhagic strokes were associated with increased overall 90-day mortality (OR = 3.29, 3.99 respectively, both p < 0.0001) after controlling for pre-selected covariates, including age, pre/post-cannulation lab values, ECMO duration, center volume, and on-ECMO complications. Total center volume was associated positively with ischemic/hemorrhagic stroke incidences (OR = 1.039, 1.053 per-additional-100-cases respectively, both p = 0.022), but inversely with 90-day mortality (OR = 0.909 per-additional-100-cases, p < 0.0001). Hazard of death was highest in the first several days of VA-ECMO. Conclusion: In VA-ECMO patients, while the reported ischemic stroke incidence steadily increased over time, 90-day mortality decreased. ELSO centers with higher case volumes reported greater stroke incidence, but lower mortality. Both ischemic/hemorrhagic strokes were associated with increased mortality.

Utilizing Machine Learning to Predict Neurological Injury in Venovenous Extracorporeal Membrane Oxygenation Patients: An Extracorporeal Life Support Organization Registry Analysis.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is associated with acute brain injury (ABI), including central nervous system (CNS) ischemia (defined as ischemic stroke or hypoxic-ischemic brain injury) and intracranial hemorrhage (ICH). There is limited data on prediction models for ABI and neurological outcomes in VV-ECMO. Research Question: Can machine learning (ML) accurately predict ABI and identify modifiable factors of ABI in VV-ECMO? Study Design and Methods: We analyzed adult (≥18 years) VV-ECMO patients in the Extracorporeal Life Support Organization Registry (2009-2021) from 676 centers. ABI was defined as CNS ischemia, ICH, brain death, and seizures. Overall, 65 total variables were extracted including clinical characteristics and pre-ECMO and on-ECMO variables. Random Forest, CatBoost, LightGBM, and XGBoost ML algorithms (10-fold leave-one-out cross-validation) were used to predict ABI. Feature Importance Scores were used to pinpoint variables most important for predicting ABI. Results: Of 37,473 VV-ECMO patients (median age=48.1 years, 63% male), 2,644 (7.1%) experienced ABI: 610 (2%) and 1,591 (4%) experienced CNS ischemia and ICH, respectively. The median ECMO duration was 10 days (interquartile range=5-20 days). The area under the receiver-operating characteristics curves to predict ABI, CNS ischemia, and ICH were 0.67, 0.63, and 0.70, respectively. The accuracy, positive predictive, and negative predictive values for ABI were 79%, 15%, and 95%, respectively. ML identified pre-ECMO cardiac arrest as the most important risk factor for ABI while ECMO duration and bridge to transplantation as an indication for ECMO were associated with lower risk of ABI. Interpretation: This is the first study to use machine learning to predict ABI in a large cohort of VV-ECMO patients. Performance was sub-optimal due to the low reported prevalence of ABI with lack of standardization of neuromonitoring/imaging protocols and data granularity in the ELSO Registry. Standardized neurological monitoring and imaging protocols may improve machine learning performance to predict ABI.

Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma.

How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.

Recent applications of quantitative electroencephalography in adult intensive care units: a comprehensive review.

Quantitative electroencephalography (qEEG) refers to the numerical analysis and/or visual transformations of raw electroencephalography (EEG) signals. Evaluation of qEEG in intensive care units (ICU) faces unique challenges that warrant investigation separate from those conducted in other settings. Additionally, the pathophysiology, management, and EEG patterns of critically ill conditions often significantly differ between adults and children. Thus, it is important to distinguish the literature on qEEGs specifically performed in adult ICUs. The aim of this review is to summarize the studies using qEEG for clinical evaluation of patients in adult ICUs performed over the past decade (since 2010), and to present the state of the art of these techniques. Overall, these studies have reported that qEEG can reveal important information faster than typically possible with traditional methods of reviewing the raw EEG only, with reasonable accuracy. However, it is crucial to emphasize that qEEG must be reviewed in conjunction with raw EEG and in context of understanding the patients' clinical status. Because each qEEG panel only focuses on a few aspects of the entire EEG, different combinations of qEEG panels may be required for optimal analyses of each medical condition and individual patient. Currently in practical terms, qEEG can serve as a complementary, valuable tool for portions of the EEG that require more detailed review. Further multi-center collaborative studies are needed to ultimately develop standardized methods of employing qEEG that are generalizable across institutions. As qEEG techniques continue to advance, including those involving machine learning, qEEG will further benefit from algorithms specifically suited for ICUs.

The effect of tranexamic acid in open reduction and internal fixation of pelvic and acetabular fracture: A systematic review and meta-analysis.

BACKGROUND: Pelvic bone fractures may cause extensive bleeding; however, the efficacy of tranexamic acid (TXA) usage in pelvic fracture surgery remains unclear. In this systematic review and meta-analysis, we aimed to evaluate the efficacy of TXA in open reduction and internal fixation surgery for pelvic and acetabular fracture. METHODS: MEDLINE, Embase, and Cochrane Library databases were systematically searched for studies published before April 22, 2020, that investigated the effect of TXA in the treatment of pelvic and acetabular fracture with open reduction and internal fixation. A pooled analysis was used to identify the differences between a TXA usage group and a control group in terms of estimated blood loss (EBL), transfusion rates, and postoperative complications. RESULTS: We included 6 studies involving 764 patients, comprising 293 patients who received TXA (TXA group) and 471 patients who did not (control group). The pooled analysis showed no differences in EBL between the groups (mean difference -64.67, 95% confidence interval [CI] -185.27 to -55.93, P = .29). The study period transfusion rate showed no significant difference between the groups (odds ratio [OR] 0.77, 95% CI 0.19-3.14, P = .71, I2 = 82%), nor in venous thromboembolism incidence (OR 1.53, 95% CI 0.44-5.25, P = .50, I2 = 0%) or postoperative infection rates (OR 1.15, 95% CI 0.13-9.98, P = .90, I2 = 48%). CONCLUSIONS: Despite several studies having recommended TXA administration in orthopedic surgery, our study did not find TXA usage to be more effective than not using TXA in pelvic and acetabular fracture surgery, especially in terms of EBL reduction, transfusion rates, and the risk of postoperative complications.

Continuous Electroencephalography Markers of Prognostication in Comatose Patients on Extracorporeal Membrane Oxygenation.

BACKGROUND: We aimed to identify continuous electroencephalogram (cEEG) markers associated with survival and death in patients with extracorporeal membrane oxygenation (ECMO) support under standardized sedation cessation protocol. METHODS: Prospectively collected records of adult patients (age ≥ 18 years) who were started on ECMO support in July 2016 to December 2020 at a single tertiary center were analyzed. cEEGs were performed on patients on the basis of inclusion and exclusion criteria. Patients receiving sedation that affect cEEG reactivity at the start of cEEG recording, including propofol, ketamine, or benzodiazepines, were excluded. We allowed fentanyl and dexmedetomidine during cEEG monitoring. cEEGs were evaluated for frequency, amplitude, variability, reactivity, and state changes. RESULTS: Of 290 patients, 40 underwent cEEG in the absence of confounding sedation (median age 60 years, 85% venoarterial-ECMO, 15% venovenous-ECMO). The median length of ECMO support and analyzable cEEG were 143 h and 24 h, respectively. A total of 27 patients underwent withdrawal of life-sustaining therapies (WOLST) during ECMO support. Of the 13 who weaned off ECMO, 9 underwent WOLST later in the hospitalization and 4 survived at hospital discharge. Decisions of WOLST were not influenced by cEEG features' results. Proportions of present EEG reactivity, present state changes, and fair/good variability were significantly higher in patients who survived compared with those who died (odds ratios infinity, infinity, and 13.57, respectively; p values < 0.001, < 0.001, and 0.0299, respectively). Sensitivity and specificity for survival at discharge were 100% and 91.67% for intact reactivity, 100% and 97.20% for present state changes, and 75% and 83.3% for fair/good variability. CONCLUSIONS: Although future multicenter studies with larger patient cohorts are certainly warranted, we were able to validate the feasibility of protocolized sedation cessation and cEEG analyses in the absence of a confounding effect from sedating medications. Moreover, we demonstrate some evidence that cEEG features of intact reactivity, present state changes, and fair/good variability in comatose patients on ECMO may be associated with survival at hospital discharge.

Cerebral Microbleeds and Intracranial Hemorrhages in Adult Patients on Extracorporeal Membrane Oxygenation-Autopsy Study.

Current studies lack robust information on the prevalence and associated factors of cerebral microbleeds in patients who underwent extracorporeal membrane oxygenation. DESIGN: Retrospective analysis. SETTING: We reviewed patients who underwent (extracorporeal membrane oxygenation) and subsequent brain autopsy with gross and microscopic examinations from January 2009 to December 2018 from a single tertiary center. PATIENTS: Twenty-five extracorporeal membrane oxygenation patients (median age, 53 yr; interquartile range, 36-61 yr; 17 women and 8 men) underwent brain autopsy. INTERVENTIONS: Descriptive analysis of neuropathologic findings. Cerebral microbleed was defined as a small focus (< 10 mm diameter) of accumulation of blood product in the brain tissue. Macrohemorrhage was defined as any of the grossly identifiable epidural, subdural, subarachnoid, or intraparenchymal hemorrhages larger than 10 mm. MEASUREMENT AND MAIN RESULTS: Of 25 (22 venoarterial extracorporeal membrane oxygenation; three venovenous extracorporeal membrane oxygenation), 15 patients (60%) were found to have cerebral microbleeds, whereas 13 (52%) had macrohemorrhages, of whom five (20%) had both. Overall, 92% of brains demonstrated the presence of either cerebral microbleeds or macrohemorrhages after extracorporeal membrane oxygenation support. Of the patients with cerebral microbleeds, lobar cerebral microbleeds (80%) occurred more frequently than deep cerebral microbleeds (60%), with 40% of patients having both types. The cases of macrohemorrhages consisted of one epidural (8%), two subdural (15%), and 10 subarachnoid hemorrhages (77%). In univariate analyses, the presence of macrohemorrhages was significantly associated with the presence of cerebral microbleeds (p = 0.03) with odds ratio of 0.13 (CI, 0.02-0.82). Age, sex, extracorporeal membrane oxygenation duration, extracorporeal membrane oxygenation type, use of aspirin or dialysis during extracorporeal membrane oxygenation support, bloodstream infections, hemoglobin, platelets, and coagulopathy profiles were not associated with cerebral microbleeds. CONCLUSIONS: In patients with postmortem neuropathologic evaluation, 92% sustained acute cerebral microbleeds or macrohemorrhages after extracorporeal membrane oxygenation support. Cerebral microbleeds were commonly present in the majority of extracorporeal membrane oxygenation nonsurvivors. Further research is necessary to study the long-term sequelae, such as cognitive outcome of extracorporeal membrane oxygenation-associated cerebral microbleeds in extracorporeal membrane oxygenation survivors.

DNA-Engineerable Ultraflat-Faceted Core-Shell Nanocuboids with Strong, Quantitative Plasmon-Enhanced Fluorescence Signals for Sensitive, Reliable MicroRNA Detection.

There has been enormous interest in understanding and utilizing plasmon-enhanced fluorescence (PEF) with metal nanostructures, but maximizing the enhancement in a reproducible, quantitative manner while reliably controlling the distance between dyes and metal particle surface for practical applications is highly challenging. Here, we designed and synthesized fluorescence-amplified nanocuboids (FANCs) with highly enhanced and controlled PEF signals, and fluorescent silica shell-coated FANCs (FS-FANCs) were then formed to fixate the dye position and increase particle stability and fluorescence signal intensity for biosensing applications. By uniformly modifying fluorescently labeled DNA on Au nanorods and forming ultraflat Ag shells on them, we were able to reliably control the distance between fluorophores and Ag surface and obtained an ∼186 fluorescence enhancement factor with these FANCs. Importantly, FS-FANCs were utilized as fluorescent nanoparticle tags for microarray-based miRNA detection, and we achieved >103-fold higher sensitivity than commercially available chemical fluorophores with 100 aM to 1 pM dynamic range.

Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies.

Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which results in an internally truncated, partially functional protein. In antisense-mediated exon-skipping synthetic antisense oligonucleotide binds to pre-mRNA to induce exon skipping. Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A. Novel methods that induce exon skipping utilizing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are also being developed where splice site mutations are created within the genome to induce exon skipping. Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.

Spinal cord α-synuclein deposition associated with myoclonus in patients with MSA-C.

OBJECTIVE: To test the hypothesis that myoclonus in patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) is associated with a heavier burden of α-synuclein deposition in the motor regions of the spinal cord, we compared the degree of α-synuclein deposition in spinal cords of 3 patients with MSA-C with myoclonus and 3 without myoclonus. METHODS: All human tissue was obtained by the Massachusetts General Hospital Department of Pathology with support from and according to neuropathology guidelines of the Massachusetts Alzheimer's Disease Research Center. Tissue was stained with Luxol fast blue and hematoxylin & eosin for morphologic evaluation, and with a mouse monoclonal antibody to α-synuclein and Vectastain DAB kit. Images of the spinal cord sections were digitized using a 10× objective lens. Grayscale versions of these images were transferred to ImageJ software for quantitative analysis of 8 different regions of interest (ROIs) in the spinal cord: dorsal column, anterior white column, left and right dorsal horns, left and right anterior horns, and left and right lateral corticospinal tracts. A mixed-effect, multiple linear regression model was constructed to determine if patients with and without myoclonus had significantly different distributions of α-synuclein deposition across the various ROIs. RESULTS: Patients with myoclonus had more α-synuclein in the anterior horns (p < 0.001) and lateral corticospinal tracts (p = 0.02) than those without myoclonus. CONCLUSIONS: In MSA-C, myoclonus appears to be associated with a higher burden of α-synuclein deposition within spinal cord motor regions. Future studies with more patients will be needed to confirm these findings.

Improvement of the osteogenic potential of ErhBMP-2-/EGCG-coated biphasic calcium phosphate bone substitute: in vitro and in vivo activity.

PURPOSE: The aim of this study was to evaluate the enhancement of osteogenic potential of biphasic calcium phosphate (BCP) bone substitute coated with Escherichia coli-derived recombinant human bone morphogenetic protein-2 (ErhBMP-2) and epigallocatechin-3-gallate (EGCG). METHODS: The cell viability, differentiation, and mineralization of osteoblasts was tested with ErhBMP-2-/EGCG solution. Coated BCP surfaces were also investigated. Standardized, 6-mm diameter defects were created bilaterally on the maxillary sinus of 10 male New Zealand white rabbits. After removal of the bony windows and elevation of sinus membranes, ErhBMP-2-/EGCG-coated BCP was applied on one defect in the test group. BCP was applied on the other defect to form the control group. The animals were sacrificed at 4 or 8 weeks after surgery. Histologic and histometric analyses of the augmented graft and surrounding tissue were performed. RESULTS: The 4-week and 8-week test groups showed more new bone (%) than the corresponding control groups (P<0.05). The 8-week test group showed more new bone (%) than the 4-week test group (P<0.05). CONCLUSIONS: ErhBMP-2-/EGCG-coated BCP was effective as a bone graft material, showing enhanced osteogenic potential and minimal side effects in a rabbit sinus augmentation model.

Surgeon Variability and Factors Predicting for Reoperation Following Breast-Conserving Surgery.

BACKGROUND: Reoperation after breast-conserving surgery (BCS) is common and has been partially associated with the lack of consensus on margin definition. We sought to investigate factors associated with reoperations and variation in reoperation rates across breast surgeons at our cancer center. METHODS: Retrospective analyses of patients with clinical stage I-II breast cancer who underwent BCS between January and December 2014 were conducted prior to the recommendation of 'no ink on tumor' margin. Patient demographics and tumor and surgical data were extracted from medical records. A multivariate regression model was used to identify factors associated with reoperation. RESULTS: Overall, 490 patients with stage I (n  = 408) and stage II (n  = 89) breast cancer underwent BCS; seven patients had bilateral breast cancer and underwent bilateral BCS procedures. Median invasive tumor size was 1.1 cm, reoperation rate was 22.9% (n  = 114) and varied among surgeons (range 15-40%), and, in 100 (88%) patients, the second procedure was re-excision, followed by unilateral mastectomy (n  = 7, 6%) and bilateral mastectomy (n  = 7, 6%). Intraoperative margin techniques (global cavity or targeted shaves) were utilized in 50.1% of cases, while no specific margin technique was utilized in 49.9% of cases. Median total specimen size was 65.8 cm3 (range 24.5-156.0). In the adjusted model, patients with multifocal disease were more likely to undergo reoperation [odds ratio (OR) 5.78, 95% confidence interval (CI) 2.17-15.42]. In addition, two surgeons were found to have significantly higher reoperation rates (OR 6.41, 95% CI 1.94-21.22; OR 3.41, 95% CI 1.07-10.85). CONCLUSIONS: Examination of BCS demonstrated variability in reoperation rates and margin practices among our breast surgeons. Future trials should look at surgeon-specific factors that may predict for reoperations.

Gender and Ethnic Diversity in Academic PM&R Faculty: National Trend Analysis of Two Decades.

Over the years, a number of studies have demonstrated an increase in gender and ethnic diversity among US physicians. Despite substantial progress in eliminating gender and racial inequities in the field of medicine, women and ethnic minorities are still underrepresented among medical faculty at academic institutions. This study aims to describe the trends in gender and ethnic diversity among Physical Medicine and Rehabilitation (PM&R) faculty through statistical analysis of data describing gender and ethnicity of full-time academic faculty gathered from the Association of American Medical Colleges Faculty Roster from 1994 to 2014. Proportions representing the percentages of females and ethnic minorities of a given faculty position in medical schools were compared across each of the other faculty ranks. Results showed that the average yearly percent increases in the proportion of female PM&R faculty in associate professor (0.68%) and full professor (0.54%) positions were greater than those in instructor (0.30%) and assistant professor (0.35%) positions. In contrast, the average yearly percent increase in the proportion of non-Caucasian PM&R faculty in full professor positions (0.19%) was less than those in instructor (0.84%), assistant (0.93%), and associate professor (0.89%) positions. Overall, trends among faculty exhibit a steady increase in gender and ethnic diversity, although promotion disparity continues to exist among specific academic positions for some groups. This study provides a current perspective on recent changes in diversity among faculty in PM&R and may prove useful when defining strategies to improve workforce diversity.

Optokinetically Encoded Nanoprobe-Based Multiplexing Strategy for MicroRNA Profiling.

Multiplexed real-time analysis on multiple interacting molecules and particles is needed to obtain information on binding patterns between multiple ligands and receptors, specificity of bond formations, and interacting pairs in a complex medium, often found in chemical and biological systems, and difference in binding affinity and kinetics for different binding pairs in one solution. In particular, multiplexed profiling of microRNA (miRNA) in a reliable, quantitative manner is of great demand for the use of miRNA in cell biology, biosensing, and clinical diagnostic applications, and accurate diagnosis of cancers with miRNA is not possible without detecting multiple miRNA sequences in a highly specific manner. Here, we report a multiplexed molecular detection strategy with optokinetically (OK) coded nanoprobes (NPs) that show high photostability, distinct optical signals, and dynamic behaviors on a supported lipid bilayer (SLB) (OK-NLB assay). Metal NPs with three distinct dark-field light scattering signals [red (R), green (G), and blue (B)] and three different target miRNA half-complements were tethered to a two dimensionally fluidic SLB with mobile (M) or immobile (I) state. In situ single-particle monitoring and normalized RGB analysis of the optokinetically combinatorial assemblies among three M-NPs and three I-NPs with dark-field microscopy (DFM) allow for differentiating and quantifying 9 different miRNA targets in one sample. The OK-NP-based assay enables simultaneous detection of multiple miRNA targets in a highly quantitative, specific manner within 1 h and can be potentially used for diagnosis of different cancer types. We validated the OK-NLB assay with single-base mismatched experiments and HeLa cell-extracted total RNA samples by comparing the assay results to the quantitative reverse transcription polymerase chain reaction (qRT-PCR) results.

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors.

BACKGROUND: Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. METHODS: Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. RESULTS: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. CONCLUSION: The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

Interaction of stem cells with nano hydroxyapatite-fucoidan bionanocomposites for bone tissue regeneration.

The combination of bioceramics with biopolymers are playing major role in the construction of artificial bone. Hydroxyapatite (HA) has been extensively studied as a material in bone repair and replacement in last two decades. In the present study, we have prepared the hydroxyapatite-fucoidan (HA-Fucoidan) nanocomposites by in situ chemical method and biologically characterized them for bone graft substitute. Biological results inferred that mineralization effect of HA-F nanocomposites shows significant enhancement compared to HA in adipose derived stem cell (ADSC). It may be due to the addition of fucoidan in the nanocomposites. The important gene expression such as osteocalcin, osteopontin, collagen and runx-2 were checked using ADSC with HA and HA-fucoidan nanocomposites and the results show that the enhancements were found at 7th day. Furthermore, we have performed in vivo study of HA-fucoidan nanocomposites with rabbit model and a slight amount of bone formation was observed in HA-fucoidan nanocomposites. Herewith, we suggest that HA-fucoidan nanocomposites will be good biomaterials for bone repair/replacement in future.

Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation.

Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2-14 years) were identified from the Dana-Farber/Boston Children's Hospital and the Royal Children's Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.