Head and Neck Squamous Cell Carcinoma Biopsies Maintained Ex Vivo on a Perfusion Device Show Gene Changes with Time and Clinically Relevant Doses of Irradiation.

Advancements in 3-Dimensional (3D) culture models for studying disease have increased significantly over the last two decades, but fully understanding how these models represent in vivo still requires further investigation. The current study investigated differences in gene expression between a baseline sample and that maintained on a tissue-on-chip perfusion device for up to 96 h, with and without clinically-relevant doses of irradiation, to allow differentiation of model and treatment effects. Tumour tissue samples from 7 Head and Neck Squamous Cell Carcinomas (HNSCC) patients were sub-divided and either fixed immediately upon excision or maintained in a tissue-on-chip device for 48 and 96 h, with or without 2 Gray (Gy) or 10 Gy irradiation. Gene expression was measured using an nCounter® PanCancer Progression Panel. Differentially expressed genes between pre- and post-ex vivo culture, and control and irradiated samples were identified using nSolver software (version 4.0). The secretome from the tumour-on-chip was analysed for the presence of cytokines using a Proteome Profiler™ platform. Significant numbers of genes both increased (n = 6 and 64) and decreased (n = 18 and 58) in expression in the tissue maintained on-chip for 48 and 96 h, respectively, compared to fresh tissue; however, the irradiation schedule chosen did not induce significant changes in gene expression or cytokine secretion. Although HNSCC tissue maintained ex vivo shows a decrease in a large proportion of altered genes, 25% and 53% (48 and 96 h) do show increased expression, suggesting that the tissue remains functional. Irradiation of tumour tissue-on-chip needs to be conducted for longer time periods for specific gene changes to be observed, but we have shown, for the first time, the feasibility of using this perfusion platform for studying the genomic response of HNSCC tissue biopsies.

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases.

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.

A comparison of physical image quality of two hologic digital mammography systems that utilise linear and 2D anti-scatter grids.

Objective. Full-field digital mammography (FFDM) systems manufactured by Hologic that utilise either a 2D or linear anti-scatter grid have recently been installed in our clinic. The manufacturer advise that for matched dose, both grids deliver comparable image quality. The aim of this study was to test the manufacturer's claim using advanced physical image quality metrics and to inform whether the different grids are indeed dose neutral.Approach. Effective detective quantum efficiency (eDQE), effective noise equivalent quanta (eNEQ) and effective dose efficiency (eDE) were measured on a Hologic Dimensions (2D grid) and a Hologic 3Dimensions (linear grid) FFDM system, both calibrated at installation to provide matched threshold contrast, according to the EUREF protocol. eDQE, eNEQ and eDE were calculated and compared using 2, 4, 6 and 7 cm thicknesses of poly (methyl methacrylate) (PMMA) to simulate a clinically appropriate range of breast thicknesses. The beam qualities (target/filter and kilovoltage) chosen were identical between the two systems.Main results. All image quality metrics investigated show that the 2D grid outperforms the linear grid across all spatial frequencies. Furthermore, mean glandular dose (MGD) must be increased by up to 38% on those units that utilise the linear grid if eNEQ is to be matched, although MGD to the standard breast remains within NHSBSP tolerance and below the UK diagnostic reference level. The gradient and shape of each curve was the same irrespective of which grid was used, suggesting that subtle lesions (low frequency information) and micro-calcifications (high frequency information) will be imaged just as efficiently with a linear or 2D grid.Significance. If image quality is to be matched between those units utilising 2D and linear grids, dose must be increased on the latter. This information will be useful to the medical physicist tasked with the optimisation and standardisation of Hologic FFDM units.

Evaluation of the dataset quality in gamma passing rate predictions using machine learning methods.

OBJECTIVE: Gamma passing rate (GPR) predictions using machine learning methods have been explored for treatment verification of radiotherapy plans. However, these methods presented datasets with unbalanced number of plans having different treatment conditions (heterogeneous datasets), such as anatomical sites or dose per fractions, leading to lower model interpretability and prediction performance. METHODS: We investigated the impact of the dataset composition on GPR binary classification (pass/fail) using random forest (RF), XG-boost, and neural network (NN) models. 945 plans were used to create one reference dataset (randomly assembled) and 24 customized datasets that considered four heterogeneity factors independently (anatomical region, number of arcs, dose per fraction, and treatment unit). 309 predictor features were extracted and calculated from plan parameters, modulation complexity metrics, and radiomic analysis (leave-trajectory maps, 3D dose distributions, and portal dosimetry images). The models' performances were measured using the area under the curve from the receiver operating characteristic (ROC-AUC). RESULTS: Radiomics features for reference models increased ROC-AUC values up to 13%, 15%, and 5% for RF, XG-Boost, and NN, respectively. The datasets with higher heterogeneous conditions presented the lower ROC-AUC values (RF: 0.72 ± 0.11, XG-Boost: 0.67 ± 0.1, NN: 0.89 ± 0.05) compared to models with less heterogeneous treatment conditions (RF: 0.88 ± 0.06, XG-Boost: 0.89 ± 0.07, NN: 0.98 ± 0.01). The ten most important features for each heterogeneity dataset group demonstrated their correlation with the treatments' physical aspects and GPR prediction. CONCLUSION: Improvements in data generalization and model performances can be associated with datasets having similar treatment conditions. This analysis might be implemented to evaluate the dataset quality and model consistency of further ML applications in radiotherapy. ADVANCES IN KNOWLEDGE: Dataset heterogeneities decrease ML model performance and reliability.

TAAR1 Regulates Purinergic-induced TNF Secretion from Peripheral, But Not CNS-resident, Macrophages.

Trace amine-associated receptor 1 (TAAR1) is an established neuroregulatory G protein-coupled receptor with recent studies suggesting additional functions related to immunomodulation. Our lab has previously investigated TAAR1 expression within cells of the innate immune system and herein we aim to further elucidate TAAR1 function in both peripherally-derived and CNS-resident macrophages. The selective TAAR1 agonist RO5256390 was used in combination with common damage associated molecular patterns (ATP and ADP) to observe the effect of TAAR1 agonism on modulating cytokine secretion and metabolic profiles. In mouse bone-marrow derived macrophages, TAAR1 agonism inhibited TNF secretion following ATP stimulation, which appeared to be downstream of an associated pro-inflammatory shift in metabolic profile and transcriptional regulation of TNF synthesis. In contrast, TAAR1 agonism had no effect on ADP-induced TNF and IL-6 secretion in mouse microglia in either the presence or absence of astrocytes. In summary, we report a novel interaction between TAAR1 and purinergic signaling in peripherally-derived, but not CNS-resident, macrophages. These findings provide the first evidence of trace aminergic and purinergic crosstalk, and support the potential for TAAR1 as a novel therapeutic target in inflammatory disorders.

Machine learning-based predictions of gamma passing rates for virtual specific-plan verification based on modulation maps, monitor unit profiles, and composite dose images.

Machine learning (ML) methods have been implemented in radiotherapy to aid virtual specific-plan verification protocols, predicting gamma passing rates (GPR) based on calculated modulation complexity metrics because of their direct relation to dose deliverability. Nevertheless, these metrics might not comprehensively represent the modulation complexity, and automatically extracted features from alternative predictors associated with modulation complexity are needed. For this reason, three convolutional neural networks (CNN) based models were trained to predict GPR values (regression and classification), using respectively three predictors: (1) the modulation maps (MM) from the multi-leaf collimator, (2) the relative monitor units per control point profile (MUcp), and (3) the composite dose image (CDI) used for portal dosimetry, from 1024 anonymized prostate plans. The models' performance was assessed for classification and regression by the area under the receiver operator characteristic curve (AUC_ROC) and Spearman's correlation coefficient (r). Finally, four hybrid models were designed using all possible combinations of the three predictors. The prediction performance for the CNN-models using single predictors (MM, MUcp, and CDI) were AUC_ROC = 0.84 ± 0.03, 0.77 ± 0.07, 0.75 ± 0.04, andr= 0.6, 0.5, 0.7. Contrastingly, the hybrid models (MM + MUcp, MM + CDI, MUcp+CDI, MM + MUcp+CDI) performance were AUC_ROC = 0.94 ± 0.03, 0.85 ± 0.06, 0.89 ± 0.06, 0.91 ± 0.03, andr= 0.7, 0.5, 0.6, 0.7. The MP, MUcp, and CDI are suitable predictors for dose deliverability models implementing ML methods. Additionally, hybrid models are susceptible to improving their prediction performance, including two or more input predictors.

Predicting personalised and progressive adaptive dose escalation to gross tumour volume using knowledge-based planning models for inoperable advanced-stage non-small cell lung cancer patients treated with volumetric modulated arc therapy.

Objectives. Increased radiation doses could improve local control and overall survival of lung cancer patients, however, this could be challenging without exceeding organs at risk (OAR) dose constraints, especially for patients with advanced-stage disease. Increasing OAR doses could reduce the therapeutic ratio and quality of life. It is therefore important to investigate methods to increase the dose to target volume without exceeding OAR dose constraints.Methods. Gross tumour volume (GTV) was contoured on synthetic computerised tomography (sCT) datasets produced using the Velocity adaptive radiotherapy software for eleven patients. The fractions where GTV volume decreased compared to that prior to radiotherapy (reference plan) were considered for personalised progressive dose escalation. The dose to the adapted GTV (GTVAdaptive) was increased until OAR doses were affected (as compared to the original clinical plan). Planning target volume (PTV) coverage was maintained for all plans. Doses were also escalated to the reference plan (GTVClinical) using the same method. Adapted, dose-escalated, plans were combined to estimate accumulated dose, D99(dose to 99%) of GTVAdapted, PTV D99and OAR doses and compared with those in the original clinical plans. Knowledge-based planning (KBP) model was developed to predict D99of the adapted GTV with OAR doses and PTV coverage kept similar to the original clinical plans; prediction accuracy and model verification were performed using further data sets.Results. Compared to the original clinical plan, the dose to GTV was significantly increased without exceeding OAR doses. Adaptive dose-escalation increased the average D99to GTVAdaptiveby 15.1Gy and 8.7Gy compared to the clinical plans. The KBP models were verified and demonstrated prediction accuracy of 0.4% and 0.7% respectively.Conclusion. Progressive adaptive dose escalation can significantly increase the dose to GTV without increasing OAR doses or compromising the dose to microscopic disease. This may increase overall survival without increasing toxicities.

TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation.

TAAR1 is a neuroregulator with emerging evidence suggesting a role in immunomodulation. Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Here, we investigate TAAR1 expression in human primary monocytes, peripherally-derived macrophages, and MS brain tissue. RT-qPCR was used to assess TAAR1 levels in MS monocytes. Using a previously validated anti-human TAAR1 antibody and fluorescence microscopy, TAAR1 protein was visualized in lipopolysaccharide-stimulated or basal human macrophages, as well as macrophage/microglia populations surrounding, bordering, and within a mixed active/inactive MS lesion. In vivo, TAAR1 mRNA expression was significantly lower in MS monocytes compared to age- and sex-matched healthy controls. In vitro, TAAR1 protein showed a predominant nuclear localization in quiescent/control macrophages with a shift to a diffuse intracellular distribution following lipopolysaccharide-induced activation. In brain tissue, TAAR1 protein was predominantly expressed in macrophages/microglia within the border region of mixed active/inactive MS lesions. Considering that TAAR1-mediated anti-inflammatory effects have been previously reported, decreased mRNA in MS patients suggests possible pathophysiologic relevance. A shift in TAAR1 localization following pro-inflammatory activation suggests its function is altered in pro-inflammatory states, while TAAR1-expressing macrophages/microglia bordering an MS lesion supports TAAR1 as a novel pharmacological target in cells directly implicated in MS neuroinflammation.

Predicting personalised optimal arc parameter using knowledge-based planning model for inoperable locally advanced lung cancer patients to reduce organ at risk doses.

Objectives. Volumetric modulated arc therapy (VMAT) allows for reduction of organs at risk (OAR) volumes receiving higher doses, but increases OAR volumes receiving lower radiation doses and can subsequently increasing associated toxicity. Therefore, reduction of this low-dose-bath is crucial. This study investigates personalizing the optimization of VMAT arc parameters (gantry start and stop angles) to decrease OAR doses.Materials and Methods. Twenty previously treated locally advanced non-small cell lung cancer (NSCLC) patients treated with half-arcs were randomly selected from our database. These plans were re-optimized with seven different arcs parameters; optimization objectives were kept constant for all plans. All resulting plans were reviewed by two clinicians and the optimal plan (lowest OAR doses and adequate target coverage) was selected. Furthermore, knowledge-based planning (KBP) model was developed using these plans as 'training data' to predict optimal arc parameters for individual patients based on their anatomy. Treatment plan complexity scores and deliverability measurements were performed for both optimal and original clinical plans.Results.The results show that different arc geometries resulted in different dose distributions to the OAR but target coverage was mostly similar. Different arc geometries were required for different patients to minimize OAR doses. Comparison of the personalized against the standard (2 half-arcs) plans showed a significant reduction in lung V5(lung volume receiving 5 Gy), mean lung dose and mean heart doses. Reduction in lung V20and heart V30were statistically insignificant. Plan complexity and deliverability measurements show the test plans can be delivered as planned.Conclusions.Our study demonstrated that personalizing arc parameters based on an individual patient's anatomy significantly reduces both lung and heart doses. Dose reduction is expected to reduce toxicity and improve the quality of life for these patients.

Validation of in-house knowledge-based planning model for predicting change in target coverage during VMAT radiotherapy to in-operable advanced-stage NSCLC patients.

Objectives. anatomical changes are inevitable during the course of radiotherapy treatments and, if significant, can severely alter expected dose distributions and affect treatment outcome. Adaptive radiotherapy (ART) is employed to maintain the planned distribution and minimise detriment to predicted treatment outcome. Typically, patients who may benefit from adaptive planning are identified via a re-planning process, i.e., re-simulation, re-contouring, re-planning and treatment plan quality assurance (QA). This time-intensive process significantly increases workload, can introduce delays and increases unnecessary stress to those patients who will not actually gain benefit. We consider it crucial to develop efficient models to predict changes to target coverage and trigger ART, without the need for re-planning.Methods.knowledge-based planning (KBP) models were developed using data for 20 patients' (400 fractions) to predict changes in PTV V95coverageΔV95PTV.Initially, this change in coverage was calculated on the synthetic computerised tomography (sCT) images produced using the Velocity adaptive radiotherapy software. Models were developed using patient (cell death bio-marker) and treatment fraction (PTV characteristic) specific parameters to predictΔV95PTVand verified using five patients (100 fractions) data.Results. three models were developed using combinations of patient and fraction specific terms. The prediction accuracy of the model developed using biomarker (PD-L1 expression) and the difference in 'planning' and 'fraction' PTV centre of the mass (characterised by mean square difference, MSD) had the higher prediction accuracy, predicting theΔV95PTVwithin ± 1.0% for 77% of the total fractions; with 59% for the model developed using, PTV size, PD-L1 and MSD and 48% PTV size and MSD respectively.Conclusion. the KBP models can predictΔV95PTVvery effectively and efficiently for advanced-stage NSCLC patients treated using volumetric modulated arc therapy and to identify patients who may benefit from adaption for a specific fraction.

Fitness Shifts the Balance of BDNF and IL-6 from Inflammation to Repair among People with Progressive Multiple Sclerosis.

Physical sedentarism is linked to elevated levels of circulating cytokines, whereas exercise upregulates growth-promoting proteins such as brain-derived neurotrophic factor (BDNF). The shift towards a 'repair' phenotype could protect against neurodegeneration, especially in diseases such as multiple sclerosis (MS). We investigated whether having higher fitness or participating in an acute bout of maximal exercise would shift the balance of BDNF and interleukin-6 (IL-6) in serum samples of people with progressive MS (n = 14), compared to matched controls (n = 8). Participants performed a maximal graded exercise test on a recumbent stepper, and blood samples were collected at rest and after the test. We assessed walking speed, fatigue, and maximal oxygen consumption (V·O2max). People with MS achieved about 50% lower V·O2max (p = 0.003) than controls. At rest, there were no differences in BDNF between MS and controls; however, IL-6 was significantly higher in MS. Higher V·O2max was associated with a shift in BDNF/IL-6 ratio from inflammation to repair (R = 0.7, p = 0.001) when considering both groups together. In the MS group, greater ability to upregulate BDNF was associated with faster walking speed and lower vitality. We present evidence that higher fitness indicates a shift in the balance of blood biomarkers towards a repair phenotype in progressive MS.

Effect of treatment planning system parameters on beam modulation complexity for treatment plans with single-layer multi-leaf collimator and dual-layer stacked multi-leaf collimator.

OBJECTIVE: High levels of beam modulation complexity (MC) and monitor units (MU) can compromise the plan deliverability of intensity-modulated radiotherapy treatments. Our study evaluates the effect of three treatment planning system (TPS) parameters on MC and MU using different multi-leaf collimator (MLC) architectures. METHODS: 192 volumetric modulated arc therapy plans were calculated using one virtual prostate phantom considering three main settings: (1) three TPS-parameters (Convergence; Aperture Shape Controller, ASC; and Dose Calculation Resolution, DCR) selected from Eclipse v15.6, (2) four levels of dose-sparing priority for organs at risk (OAR), and (3) two treatment units with same nominal conformity resolution and different MLC architectures (Halcyon-v2 dual-layer MLC, DL-MLC & TrueBeam single-layer MLC, SL-MLC). We use seven complexity metrics to evaluate the MC, including two new metrics for DL-MLC, assessed by their correlation with γ passing rate (GPR) analysis. RESULTS: DL-MLC plans demonstrated lower dose-sparing values than SL-MLC plans (p<0.05). TPS-parameters did not change significantly the complexity metrics for either MLC architectures. However, for SL-MLC, significant variations of MU, target volume dose-homogeneity, and dose spillage were associated with ASC and DCR (p<0.05). MU were found to be correlated (highly or moderately) with all complexity metrics (p<0.05) for both MLC plans. Additionally, our new complexity metrics presented a moderate correlation with GPR (r<0.65). An important correlation was demonstrated between MC (plan deliverability) and dose-sparing priority level for DL-MLC. CONCLUSIONS: TPS-parameters selected do not change MC for DL-MLC architecture, but they might have a potential use to control the MU, PTV homogeneity or dose spillage for SL-MLC. Our new DL-MLC complexity metrics presented important information to be considered in future pre-treatment quality assurance programs. Finally, the prominent dependence between plan deliverability and priority applied to OAR dose sparing for DL-MLC needs to be analyzed and considered as an additional predictor of GPRs in further studies. ADVANCES IN KNOWLEDGE: Dose-sparing priority might influence in modulation complexity of DL-MLC.

Validation of in-house knowledge-based planning model for advance-stage lung cancer patients treated using VMAT radiotherapy.

OBJECTIVES: Radiotherapy plan quality may vary considerably depending on planner's experience and time constraints. The variability in treatment plans can be assessed by calculating the difference between achieved and the optimal dose distribution. The achieved treatment plans may still be suboptimal if there is further scope to reduce organs-at-risk doses without compromising target coverage and deliverability. This study aims to develop a knowledge-based planning (KBP) model to reduce variability of volumetric modulated arc therapy (VMAT) lung plans by predicting minimum achievable lung volume-dose metrics. METHODS: Dosimetric and geometric data collected from 40 retrospective plans were used to develop KBP models aiming to predict the minimum achievable lung dose metrics via calculating the ratio of the residual lung volume to the total lung volume. Model accuracy was verified by replanning 40 plans. Plan complexity metrics were calculated using locally developed script and their effect on treatment delivery was assessed via measurement. RESULTS: The use of KBP resulted in significant reduction in plan variability in all three studied dosimetric parameters V5, V20 and mean lung dose by 4.9% (p = 0.007, 10.8 to 5.9%), 1.3% (p = 0.038, 4.0 to 2.7%) and 0.9 Gy (p = 0.012, 2.5 to 1.6Gy), respectively. It also increased lung sparing without compromising the overall plan quality. The accuracy of the model was proven as clinically acceptable. Plan complexity increased compared to original plans; however, the implication on delivery errors was clinically insignificant as demonstrated by plan verification measurements. CONCLUSION: Our in-house model for VMAT lung plans led to a significant reduction in plan variability with concurrent decrease in lung dose. Our study also demonstrated that treatment delivery verifications are important prior to clinical implementation of KBP models. ADVANCES IN KNOWLEDGE: In-house KBP models can predict minimum achievable lung dose-volume constraints for advance-stage lung cancer patients treated with VMAT. The study demonstrates that plan complexity could increase and should be assessed prior to clinical implementation.

The prevalence and determinants of physical activity promotion by Australian chiropractors: A cross sectional study.

BACKGROUND: Approximately one in four adults do not meet the World Health Organisation physical activity recommendations. While health promotion (i.e., physical activity) is common within chiropractic settings, little is known about chiropractors discussing this public health issue with their patients. The aim of our study is to examine the prevalence and characteristics of Australian chiropractors who frequently discuss patient physical activity. METHODS: A national cross-sectional survey of chiropractors focusing upon practitioner characteristics, practice settings and clinical management characteristics. Regression analyses were conducted on 1924 survey respondents to identify factors associated with practitioners who frequently discuss physical activity with patients. RESULTS: Eighty-five percent of Australian chiropractors reported 'often' discussing physical activity as part of their patient management. The strongest factors associated with chiropractors who frequently discuss physical activity obtained from the multivariate analysis include: often discussing occupational health and safety (odds ratio [OR] = 6.10; 95%CI: 3.88, 9.59), often discussing diet/nutrition (OR = 4.56; 95%CI: 3.12, 6.66), often discussing smoking/drugs/alcohol (OR = 4.41; 95%CI: 2.06, 9.40), often use of specific exercise therapy/rehabilitation/injury taping (OR = 3.76; 95%CI: 2.62, 5.39) and often caring for athletes or sports people (OR = 2.18; 95%CI: 1.56, 3.06) within their practice setting. CONCLUSION: Discussing physical activity is a frequent feature of patient management among most chiropractors in Australia. The association between these practitioners and discussion of other costly public health burdens could suggest chiropractors have a valuable role to play in chronic disease prevention. Given the growing need for practitioner-led promotion of patient physical activity further research examination of the role and contribution of chiropractors in promoting this important public health topic among patients and communities is needed.

Two rare cases of pancreatic adenosquamous carcinoma: A review of the literature with focus on radiologic findings.

Pancreatic adenosquamous carcinoma (PASC) is a rare, aggressive subtype of pancreatic tumor with a poor prognostic outlook compared to the much more common pancreatic adenocarcinoma. Here we present two cases of the rare PASC and analyze the radiologic findings on computed tomography (CT) and 18F- fluorodeoxyglucose positron emission tomography (FDG-PET). Both cases involve 62-year-old women presenting with abdominal pain, nausea, and vomiting who on imaging were found to have infiltrating lobular pancreatic masses with ring enhancement on CT and peripheral hypermetabolism with central necrosis on FDG-PET. Location in the pancreas and involvement of adjacent structures differed in the two cases, resulting in varying progressive clinical manifestations. PASC is a rare subtype of pancreatic cancer with nonspecific imaging findings. Here we presented two cases of PASC supporting previously reported imaging findings suggestive of PASC with additional FDG-PET manifestations and SUV levels, which only few reports have previously described.

Phagocytosis in the Brain: Homeostasis and Disease.

Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, and diseased states. Phagocytosis is a highly complex process that is specialized for the uptake and removal of opsonized and non-opsonized targets, such as pathogens, apoptotic cells, and cellular debris. While the role of phagocytosis in mediating classical innate and adaptive immune responses has been known for decades, it is now appreciated that phagocytosis is also critical throughout early neural development, homeostasis, and initiating repair mechanisms. As such, modulating phagocytic processes has provided unexplored avenues with the intent of developing novel therapeutics that promote repair and regeneration in the CNS. Here, we review the functional consequences that phagocytosis plays in both the healthy and diseased CNS, and summarize how phagocytosis contributes to overall pathophysiological mechanisms involved in brain injury and repair.

Prolonged cortical silent period is related to poor fitness and fatigue, but not tumor necrosis factor, in Multiple Sclerosis.

OBJECTIVE: Poor fitness among people with Multiple Sclerosis (MS) aggravates disease symptoms. Whether low fitness levels accompany brain functioning changes is unknown. METHODS: MS patients (n = 82) completed a graded maximal exercise test, blood was drawn, and transcranial magnetic stimulation determined resting and active motor thresholds, motor evoked potential latency, and cortical silent period (CSP). RESULTS: Sixty-two percent of participants had fitness levels ranked below 10th percentile. Fitness was not associated with disability measured using the Expanded Disability Status Scale (EDSS). Regression analyses revealed that, cardiorespiratory fitness, when controlling for disease demographics, contributed 23.7% (p < 0.001) to the model explaining variance in CSP. Regression analysis using cardiorespiratory fitness and CSP as predictors showed that CSP alone explained 19.9% of variance in subjective fatigue (p = 0.002). Tumor necrosis factor was not associated with any variable. CONCLUSION: Low fitness was associated with longer CSP in MS. Longer CSP was, in turn, related to greater MS fatigue. SIGNIFICANCE: MS patients had extremely low levels of cardiorespiratory fitness. Poor fitness predicted longer CSP, a marker of greater intracortical inhibition, which was linked to MS fatigue. Future research should examine whether aerobic training could shorten CSP and potentially lessen inhibition of cortical networks.

Current evidence for spinal X-ray use in the chiropractic profession: a narrative review.

The use of routine spinal X-rays within chiropractic has a contentious history. Elements of the profession advocate for the need for routine spinal X-rays to improve patient management, whereas other chiropractors advocate using spinal X-rays only when endorsed by current imaging guidelines. This review aims to summarise the current evidence for the use of spinal X-ray in chiropractic practice, with consideration of the related risks and benefits. Current evidence supports the use of spinal X-rays only in the diagnosis of trauma and spondyloarthropathy, and in the assessment of progressive spinal structural deformities such as adolescent idiopathic scoliosis. MRI is indicated to diagnose serious pathology such as cancer or infection, and to assess the need for surgical management in radiculopathy and spinal stenosis. Strong evidence demonstrates risks of imaging such as excessive radiation exposure, overdiagnosis, subsequent low-value investigation and treatment procedures, and increased costs. In most cases the potential benefits from routine imaging, including spinal X-rays, do not outweigh the potential harms. The use of spinal X-rays should not be routinely performed in chiropractic practice, and should be guided by clinical guidelines and clinician judgement.

Differential transcriptional response profiles in human myeloid cell populations.

This study examines the transcriptional profiles of human adult brain-derived microglia in response to in vitro activating conditions previously used to polarize systemic myeloid cells into M1 and M2 phenotypes. A comparative study is done with monocyte-derived macrophages (MDMs), a myeloid cell type that also participates in disease relevant tissue injury and repair processes in the CNS. Current markers used to distinguish microglia and MDMs have been defined under homeostatic conditions. We observe that gene expression profiles of M1 microglia and MDMs overlap with an overrepresentation of immune-related pathways. M2 microglia and MDMs have distinct transcriptional signatures. Upregulated genes in M2 microglia favor neural-related pathways whereas upregulated genes in M2 MDMs are mostly involved in antigen presentation. Our microarray screen identifies candidate molecules that can potentially distinguish microglia and MDMs under all activation conditions. To be determined is how our observations made using conventional in vitro polarization translate into cellular responses to the complex combination of signals encountered in neurologic disease states.