Treatment of Depression After Traumatic Brain Injury: A Systematic Review Focused on Pharmacological and Neuromodulatory Interventions.

BACKGROUND: Depression is the most common psychiatric sequela after traumatic brain injury (TBI) and poses a variety of treatment challenges. There is a lack of clinical trials focused on biological interventions used to manage TBI depression. OBJECTIVE: The aim of this systematic review is to summarize the current evidence of psychotropic and neuromodulatory interventions used to treat TBI depression and to provide directions for future research. METHODS: Key words were used to describe the following search terms: "traumatic brain injury", "depression", "pharmacological/drug therapy", and "neuromodulation". Studies focused on pharmacotherapy or neuromodulation in TBI depression were identified in 5 databases: Medline (PubMed), EMBASE (Embase.com), the Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), PsycINFO (EbscoHost), and Web of Science. Article inclusion/exclusion using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based systematic protocol of extraction and evaluation was applied. Level of evidence for each study was determined using the American Academy of Neurology criteria. RESULTS: The initial search provided 1473 citations. Twenty-two studies met inclusion criteria. Sixteen studies explored pharmacological interventions with emphasis on serotonergic agents. Results between studies were conflicting, and interventions did not always outperform placebos, although sertraline provided the highest level of evidence for treatment of TBI depression. Six studies examining neuromodulatory interventions show preliminary evidence of efficacy with a range of interventions and modes of delivery used. CONCLUSIONS: Additional research including large-sample randomized-controlled trials using pharmacological, neuromodulation, or combination treatment is needed. These studies should incorporate premorbid psychosocial functioning, preinjury psychiatric disease, cognitive deficits, and functional recovery when examining outcomes.

Deep-Learning-Based Semantic Labeling for 2D Mammography and Comparison of Complexity for Machine Learning Tasks.

Machine learning has several potential uses in medical imaging for semantic labeling of images to improve radiologist workflow and to triage studies for review. The purpose of this study was to (1) develop deep convolutional neural networks (DCNNs) for automated classification of 2D mammography views, determination of breast laterality, and assessment and of breast tissue density; and (2) compare the performance of DCNNs on these tasks of varying complexity to each other. We obtained 3034 2D-mammographic images from the Digital Database for Screening Mammography, annotated with mammographic view, image laterality, and breast tissue density. These images were used to train a DCNN to classify images for these three tasks. The DCNN trained to classify mammographic view achieved receiver-operating-characteristic (ROC) area under the curve (AUC) of 1. The DCNN trained to classify breast image laterality initially misclassified right and left breasts (AUC 0.75); however, after discontinuing horizontal flips during data augmentation, AUC improved to 0.93 (p < 0.0001). Breast density classification proved more difficult, with the DCNN achieving 68% accuracy. Automated semantic labeling of 2D mammography is feasible using DCNNs and can be performed with small datasets. However, automated classification of differences in breast density is more difficult, likely requiring larger datasets.

Ultra-high dose-rate proton FLASH improves tumor control.

BACKGROUND AND PURPOSE: Proton radiotherapy (PRT) offers potential benefits over other radiation modalities, including photon and electron radiotherapy. Increasing the rate at which proton radiation is delivered may provide a therapeutic advantage. Here, we compared the efficacy of conventional proton therapy (CONVpr) to ultrahigh dose-rate proton therapy, FLASHpr, in a mouse model of non-small cell lung cancers (NSCLC). MATERIALS AND METHODS: Mice bearing orthotopic lung tumors received thoracic radiation therapy using CONVpr (<0.05 Gy/s) and FLASHpr (>60 Gy/s) dose rates. RESULTS: Compared to CONVpr, FLASHpr was more effective in reducing tumor burden and decreasing tumor cell proliferation. Furthermore, FLASHpr was more efficient in increasing the infiltration of cytotoxic CD8+ T-lymphocytes inside the tumor while simultaneously reducing the percentage of immunosuppressive regulatory T-cells (Tregs) among T-lymphocytes. Also, compared to CONVpr, FLASHpr was more effective in decreasing pro-tumorigenic M2-like macrophages in lung tumors, while increasing infiltration of anti-tumor M1-like macrophages. Finally, FLASHpr treatment reduced expression of checkpoint inhibitors in lung tumors, indicating reduced immune tolerance. CONCLUSIONS: Our results suggest that FLASH dose-rate proton delivery modulates the immune system to improve tumor control and might thus be a promising new alternative to conventional dose rates for NSCLC treatment.

Complications During Ketogenic Diet Initiation: Prevalence, Treatment, and Influence on Seizure Outcomes.

BACKGROUND: Many centers still admit children for several days to start the ketogenic diet. The exact incidence of adverse effects during the admission and their potential later impact on seizure reduction has not been widely studied. METHODS: We performed a retrospective study of children with intractable epilepsy electively admitted for ketogenic diet initiation at our institution from 2011 to 2016. Charts were reviewed for adverse effects during the admission period and then examined for seizure reduction and compliance at three months. A rating scale (1 to 4) was created for severity of any adverse events. RESULTS: A total of 158 children were included, with the mean age 4.6 years. Potentially attributable adverse effects occurred in 126 (80%) children, most commonly emesis, food refusal, and hypoglycemia. Seventy-three (46%) children received some form of intervention by the medical team, most commonly the administration of juice (24%). Younger age was correlated with an increased likelihood of moderate to severe adverse effects during admission, often repeated hypoglycemia (3.6 versus 4.9 years, P = 0.04). Fasting was more likely to result in lethargy and a single blood glucose in the 30 to 40 mg/dL range, but it was not correlated with emesis, repeated hypoglycemia, or higher adverse effect scores. There was no statistically significant correlation between the severity of adverse effects and the three-month seizure reduction. CONCLUSIONS: Mild easily treated adverse effects occurred in most children admitted for the ketogenic diet. Younger children were at greater risk for significant difficulties and should be monitored closely. Because fasting led to more lethargy and hypoglycemia, it may be prudent to avoid this in younger children.

Computational simulation of the predicted dosimetric impact of adjuvant yttrium-90 PET/CT-guided percutaneous ablation following radioembolization.

BACKGROUND: 90Y PET/CT post-radioembolization imaging has demonstrated that the distribution of 90Y in a tumor can be non-uniform. Using computational modeling, we predicted the dosimetric impact of post-treatment 90Y PET/CT-guided percutaneous ablation of the portions of a tumor receiving the lowest absorbed dose. A cohort of fourteen patients with non-resectable liver cancer previously treated using 90Y radioembolization were included in this retrospective study. Each patient exhibited potentially under-treated areas of tumor following treatment based on quantitative 90Y PET/CT. 90Y PET/CT was used to guide electrode placement for simulated adjuvant radiofrequency ablation in areas of tumor receiving the lowest dose. The finite element method was used to solve Penne's bioheat transport equation, coupled with the Arrhenius thermal cell-death model to determine 3D thermal ablation zones. Tumor and unablated tumor absorbed-dose metrics (average dose, D50, D70, D90, V100) following ablation were compared, where D70 is the minimum dose to 70% of tumor and V100 is the fractional tumor volume receiving more than 100 Gy. RESULTS: Compared to radioembolization alone, 90Y radioembolization with adjuvant ablation was associated with predicted increases in all tumor dose metrics evaluated. The mean average absorbed dose increased by 11.2 ± 6.9 Gy. Increases in D50, D70, and D90 were 11.0 ± 6.9 Gy, 13.3 ± 10.9 Gy, and 11.8 ± 10.8 Gy, respectively. The mean increase in V100 was 7.2 ± 4.2%. All changes were statistically significant (P < 0.01). A negative correlation between pre-ablation tumor volume and D50, average dose, and V100 was identified (ρ < - 0.5, P < 0.05) suggesting that adjuvant radiofrequency ablation may be less beneficial to patients with large tumor burdens. CONCLUSIONS: This study has demonstrated that adjuvant 90Y PET/CT-guided radiofrequency ablation may improve tumor absorbed-dose metrics. These data may justify a prospective clinical trial to further evaluate this hybrid approach.

The missense of smell: functional variability in the human odorant receptor repertoire.

Humans have ~400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variation in olfactory perception. We used a heterologous assay to determine how often genetic polymorphisms in odorant receptors alter receptor function. We identified agonists for 18 odorant receptors and found that 63% of the odorant receptors we examined had polymorphisms that altered in vitro function. On average, two individuals have functional differences at over 30% of their odorant receptor alleles. To show that these in vitro results are relevant to olfactory perception, we verified that variations in OR10G4 genotype explain over 15% of the observed variation in perceived intensity and over 10% of the observed variation in perceived valence for the high-affinity in vitro agonist guaiacol but do not explain phenotype variation for the lower-affinity agonists vanillin and ethyl vanillin.