Feasibility evaluation of novel AI-based deep-learning contouring algorithm for radiotherapy.

PURPOSE: To evaluate the clinical feasibility of the Siemens Healthineers AI-Rad Companion Organs RT VA30A (Organs-RT) auto-contouring algorithm for organs at risk (OARs) of the pelvis, thorax, and head and neck (H&N). METHODS: Computed tomography (CT) datasets from 30 patients (10 pelvis, 10 thorax, and 10 H&N) were collected. Four sets of OARs were generated on each scan, one set by Organs-RT and the others by three experienced users independently. A physician (expert) then evaluated each contour by assigning a score from the following scale: 1-Must Redo, 2-Major Edits, 3-Minor Edits, 4-Clinically usable. Using the highest-scored OAR from the human users as a reference, the contours generated by Organs-RT were evaluated via Dice Similarity Coefficient (DSC), Hausdorff Distance (HDD), Mean Distance to Agreement (mDTA), Volume comparison, and visual inspection. Additionally, each human user recorded the time to delineate each structure set and time-saving efficiency was measured. RESULTS: The average DSC obtained for the pelvic OARs ranged between (0.81 ± 0.06)Rectum and (0.94 ± 0.03)Bladder . (0.75 ± 0.09)Esophagus to ( 0.96 ± 0.02 ) Rt . Lung ${( {0.96 \pm 0.02} )}_{{\mathrm{Rt}}.{\mathrm{\ Lung}}}$ for the thoracic OARs and (0.66 ± 0.07)Lips to (0.83 ± 0.04)Brainstem for the H&N. The average HDD in cm for the pelvis cohort ranged between (0.95 ± 0.35)Bladder to (3.62 ± 2.50)Rectum , (0.42 ± 0.06)SpinalCord to (2.09 ± 2.00)Esophagus for the thoracic set and ( 0.53 ± 0.22 ) Cerv _ SpinalCord ${( {0.53 \pm 0.22} )}_{{\mathrm{Cerv}}\_{\mathrm{SpinalCord}}}$ to (1.50 ± 0.50)Mandible for the H&N region. The time-saving efficiency was 67% for H&N, 83% for pelvis, and 84% for thorax. 72.5%, 82%, and 50% of the pelvis, thorax, and H&N OARs were scored as clinically usable by the expert, respectively. CONCLUSIONS: The highest agreement registered between OARs generated by Organs-RT and their respective references was for the bladder, heart, lungs, and femoral heads, with an overall DSC≥0.92. The poorest agreement was for the rectum, esophagus, and lips, with an overall DSC⩽0.81. Nonetheless, Organs-RT serves as a reliable auto-contouring tool by minimizing overall contouring time and increasing time-saving efficiency in radiotherapy treatment planning.

Early Detection of Alzheimer's Disease-Related Pathology Using a Multi-Disease Diagnostic Platform Employing Autoantibodies as Blood-Based Biomarkers.

BACKGROUND: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. OBJECTIVE: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. METHODS: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. RESULTS: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78-0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93-0.99) and overall accuracy (93.0%). CONCLUSION: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD.

Application of Sysmex XN-Series Automated Haematology Analyser in the Rapid Detection of Malaria.

Malaria, an important parasitic disease worldwide, still has diagnostic challenges in the laboratory. Many studies have been conducted on the detection ability of haematology analysers for malaria. We evaluated the Sysmex XN-series analyser as a tool for detection of malaria by analysing the leukocyte cell population data (LCPD), scattergrams and associated Flow Cytometry Standard (FCS) data from both the WNR (white cell nucleated) and WDF (white cell differential) channels. 1281 clinically suspected cases of malaria were screened for malaria by peripheral blood smear examination and were run in the Sysmex XN-1000 for analysis of haematological parameter data, LCPD, all the scattergrams and FCS data. 1281 clinically suspected cases of malaria were screened for malaria by peripheral blood smear examination and were run in the Sysmex XN-1000 for analysis of haematological parameter data, LCPD, all the scattergrams and FCS data. 48 cases had malarial parasite on microscopy; of which, 41 cases were of Plasmodium vivax, 6 cases of Plasmodium falciparum and 1 case of mixed infection. 46 malaria-positive samples showed certain patterns of clusters in the scattergrams of both WDF and WNR channels. A case with only a few ring forms of P. vivax and another with very low parasite load having only gametocyte of P. falciparum didn't show the distinctive cluster. The most distinctive clusters for all other cases were seen in WNR (SFL-SSC) and WNR (SSC-FSC) scattergrams. FCS data for the same were analysed to gate for those events. The gated events correlated (Spearman ρ = 0.77, p < 0.01) with the parasite load of the patients. By observing the scattergrams and different parameters in the Sysmex XN-series analyser, malaria can be detected from the analyser itself.

Lupus erythematosus cell in body fluids: A case report and review of literature.

The diagnosis of systemic lupus erythematosus (SLE) has undergone radical change after the development of serological techniques. The in vitro demonstration of lupus erythematosus (LE) cell has less significance for the diagnosis of SLE in the present scenario. Although over the years, the spontaneous in vivo occurrence of LE cell in numerous body fluids as an initial presentation of SLE has been documented. The report of the presence of the LE cell can not only aid in the further workup of the patient but also suggest the involvement of a particular organ or body cavities by SLE. The morphology and mimickers of the LE cell should be cogitated and meticulous search of such cells should play an important role in the evaluation of body fluids. In our case, the patient presented at emergency with pericardial tamponade and cytological evaluation of the pericardial fluid demonstrated in vivo presence of LE cells. The serological work-up then confirmed the case to be SLE. This report and review of literature wish to highlight the fact that this cell still plays a significant role even in the era of immunoassays.

Acute encephalopathy in children in Muzaffarpur, India: a review of aetiopathogenesis.

The acute encephalopathy occurring in children in Muzaffarpur, India, also recognised in other litchi-cultivating areas of India, Bangladesh, Vietnam and China, had previously been linked to litchi consumption. Recently, it has been identified as hypoglycaemic encephalopathy of an unusual aetiology with three key factors: undernutrition, prolonged fasting and litchi consumption. A second set of investigators has independently reconfirmed the diagnosis and the three-factor aetiology. Skipping the evening meal with an intake of large amounts of litchi in undernourished children is causative. Early-morning hypoglycaemia with an inadequate glycogen store leads to initiation of gluconeogenesis and fatty acid ß-oxidation, but methylene cyclopropyl alanine and glycine present in the litchi aril block the fatty acid ß-oxidation cycle. The outcomes are uncorrected hypoglycaemia and encephalopathy due to the entry of metabolic intermediates that cross the blood-brain barrier and affect neuronal function. Suggested measures include early 10% dextrose infusion. Awareness about the disease is of prime importance. The diagnosis and aetiopathogenesis are still under question from a part of the scientific community. This review was undertaken to present a comprehensive view of hypoglycaemic encephalopathy and to remove some of the lingering doubts.

Evidence that Brain-Reactive Autoantibodies Contribute to Chronic Neuronal Internalization of Exogenous Amyloid-ß1-42 and Key Cell Surface Proteins During Alzheimer's Disease Pathogenesis.

Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-ß1-42 (Aß42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aß42, IgG, GluR2/3, and α7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble Aß42 peptide and serum from AD and control subjects. The rate and extent of Aß42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for α7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM Aß42. Initial co-localization of IgG, α7nAChR, and Aß42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). Aß42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then rescued by coupling F(ab) fragments with divalent human anti-Fab. Overall, results suggest that cross-linking of neuron-binding autoantibodies targeting cell surface proteins can accelerate intraneuronal Aß42 deposition in AD.

Autoantibodies as diagnostic biomarkers for the detection and subtyping of multiple sclerosis.

The goal of this preliminary proof-of-concept study was to use human protein microarrays to identify blood-based autoantibody biomarkers capable of diagnosing multiple sclerosis (MS). Using sera from 112 subjects, including 51 MS subjects, autoantibody biomarkers effectively differentiated MS subjects from age- and gender-matched normal and breast cancer controls with 95.0% and 100% overall accuracy, but not from subjects with Parkinson's disease. Autoantibody biomarkers were also useful in distinguishing subjects with the relapsing-remitting form of MS from those with the secondary progressive subtype. These results demonstrate that autoantibodies can be used as noninvasive blood-based biomarkers for the detection and subtyping of MS.

Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link Between Diabetes Mellitus and Alzheimer's Disease.

Alzheimer's disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating disorders that afflict people throughout the world. Although typically associated with older demographics, recent epidemiologic studies have reported parallel trends in decreasing age of onset and increasing incidence of these conditions. Promising research continues to implicate the cerebrovasculature and blood-brain barrier (BBB) as playing key roles in AD pathoetiology. Similarly, complications accompanying DM, such as diabetic nephropathy/retinopathy, cardiovascular disease, and stroke, have been rooted in vascular compromise. Not surprisingly, DM is now considered a major risk factor for AD. The purpose of this review is to highlight investigations into the role of the cerebrovasculature in the development and progression of AD. We give particular attention to studies on humans and a variety of animal model systems that have demonstrated a link between BBB dysfunction and pathological changes in the brain consistent with aging and AD. Together, these studies suggest that the vascular complications associated with chronic, poorly managed DM can lead to subclinical BBB breakdown that precedes and drives the pathological changes progressing to symptomatic AD, providing a common mechanistic thread connecting these two disorders. Furthermore, this emphasizes the need to focus on the vasculature as a potential therapeutic target with the intent of limiting BBB breakdown involved in disease initiation and progression. In conclusion, AD may be more than just an associated comorbidity of DM, and instead another manifestation of the underlying vascular pathology that is common to both.

Detection of Alzheimer's disease at mild cognitive impairment and disease progression using autoantibodies as blood-based biomarkers.

INTRODUCTION: There is an urgent need to identify biomarkers that can accurately detect and diagnose Alzheimer's disease (AD). Autoantibodies are abundant and ubiquitous in human sera and have been previously demonstrated as disease-specific biomarkers capable of accurately diagnosing mild-moderate stages of AD and Parkinson's disease. METHODS: Sera from 236 subjects, including 50 mild cognitive impairment (MCI) subjects with confirmed low CSF Aß42 levels, were screened with human protein microarrays to identify potential biomarkers for MCI. Autoantibody biomarker performance was evaluated using Random Forest and Receiver Operating Characteristic curves. RESULTS: Autoantibody biomarkers can differentiate MCI patients from age-matched and gender-matched controls with an overall accuracy, sensitivity, and specificity of 100.0%. They were also capable of differentiating MCI patients from those with mild-moderate AD and other neurologic and non-neurologic controls with high accuracy. DISCUSSION: Autoantibodies can be used as noninvasive and effective blood-based biomarkers for early diagnosis and staging of AD.

Potential utility of autoantibodies as blood-based biomarkers for early detection and diagnosis of Parkinson's disease.

INTRODUCTION: There is a great need to identify readily accessible, blood-based biomarkers for Parkinson's disease (PD) that are useful for accurate early detection and diagnosis. This advancement would allow early patient treatment and enrollment into clinical trials, both of which would greatly facilitate the development of new therapies for PD. METHODS: Sera from a total of 398 subjects, including 103 early-stage PD subjects derived from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, were screened with human protein microarrays containing 9,486 potential antigen targets to identify autoantibodies potentially useful as biomarkers for PD. A panel of selected autoantibodies with a higher prevalence in early-stage PD was identified and tested using Random Forest for its ability to distinguish early-stage PD subjects from controls and from individuals with other neurodegenerative and non-neurodegenerative diseases. RESULTS: Results demonstrate that a panel of selected, blood-borne autoantibody biomarkers can distinguish early-stage PD subjects (90% confidence in diagnosis) from age- and sex-matched controls with an overall accuracy of 87.9%, a sensitivity of 94.1% and specificity of 85.5%. These biomarkers were also capable of differentiating patients with early-stage PD from those with more advanced (mild-moderate) PD with an overall accuracy of 97.5%, and could distinguish subjects with early-stage PD from those with other neurological (e.g., Alzheimer's disease and multiple sclerosis) and non-neurological (e.g., breast cancer) diseases. CONCLUSION: These results demonstrate, for the first time, that a panel of selected autoantibodies may prove to be useful as effective blood-based biomarkers for the diagnosis of early-stage PD.

Utility of autoantibodies as biomarkers for diagnosis and staging of neurodegenerative diseases.

Autoantibodies are self-reactive antibodies that have been widely implicated as causal agents of autoimmune diseases. They are found in the blood of all human sera, regardless of age, gender, or the presence or absence of disease. While the underlying reason for their ubiquity remains unknown, it has been hypothesized that they participate in the clearance of blood-borne cell and tissue debris generated in both healthy and diseased individuals on a daily basis. Although much evidence supports this debris clearance role, recent studies also suggest a causal role for autoantibodies in disease. This chapter first presents well-known examples of autoimmune diseases that emphasize a direct causal role for autoantibodies and then discusses the veritable explosion of evidence now supporting their involvement in a wide variety of other diseases, including cancers and several types of neurological and neurodegenerative diseases. Lastly, translational strategies that take advantage of the "cause and/or effect" role of autoantibodies and recent technological advancements in their detection to exploit autoantibodies as sensitive and specific biomarkers useful for the detection and diagnosis of disease are outlined. Their use in the diagnosis and staging of Alzheimer's and Parkinson's diseases is presented, and future applications in clinical medicine and basic science are highlighted.

Sevoflurane and Isoflurane induce structural changes in brain vascular endothelial cells and increase blood-brain barrier permeability: Possible link to postoperative delirium and cognitive decline.

A large percentage of patients subjected to general anesthesia at 65 years and older exhibit postoperative delirium (POD). Here, we test the hypothesis that inhaled anesthetics (IAs), such as Sevoflurane and Isoflurane, act directly on brain vascular endothelial cells (BVECs) to increase blood-brain barrier (BBB) permeability, thereby contributing to POD. Rats of young (3-5 months), middle (10-12 months) and old (17-19 months) ages were anesthetized with Sevoflurane or Isoflurane for 3h. After exposure, some were euthanized immediately; others were allowed to recover for 24h before sacrifice. Immunohistochemistry was employed to monitor the extent of BBB breach, and scanning electron microscopy (SEM) was used to examine changes in the luminal surfaces of BVECs. Quantitative immunohistochemistry revealed increased BBB permeability in older animals treated with Sevoflurane, but not Isoflurane. Extravasated immunoglobulin G showed selective affinity for pyramidal neurons. SEM demonstrated marked flattening of the luminal surfaces of BVECs in anesthetic-treated rats. Results suggest an aging-linked BBB compromise resulting from exposure to Sevoflurane. Changes in the luminal surface topology of BVECs indicate a direct effect on the plasma membrane, which may weaken or disrupt their BBB-associated tight junctions. Disruption of brain homeostasis due to plasma influx into the brain parenchyma and binding of plasma components (e.g., immunoglobulins) to neurons may contribute to POD. We propose that, in the elderly, exposure to some IAs can cause BBB compromise that disrupts brain homeostasis, perturbs neuronal function and thereby contributes to POD. If unresolved, this may progress to postoperative cognitive decline and later dementia.

Prostate implant dosimetric outcomes and migration patterns between bio-absorbable coated and uncoated brachytherapy seeds.

PURPOSE: To evaluate the lung and pelvic seed migration and intraprostatic dose variability for prostate seed implant (PSI) using bio-absorbable polymer "coated" seeds for intraoperative planning. METHODS AND MATERIALS: A total of 100 PSI patients were initially implanted with uncoated I-125 (STM 1251 or I125-SL, N = 85) or Pd-103 (mod 200, N = 15) seeds, and 105 PSI patients were implanted subsequently with coated seeds using inverse optimization with real-time planning. Implant technique, average number of needles, and dose objectives remained identical among the cohorts. RESULTS: Day 30 postimplant comparison of seed migration demonstrated a significant reduction in overall lung and pelvic seed migration from 25% (uncoated) to 4% (coated) (p < 0.0001). A measurable reduction in intraprostatic dose variability was observed in patients with the coated seeds when comparing 30 days dosimetry results for V100, V150, and D90 for prostate, and V110 for the rectum. A statistically significant reduction in the standard deviation from Day 0 to Day 30 for the above parameters for the prostate as well as for V110 of rectum was also observed. A significant improvement in implant quality at Day 30 was demonstrated using Radiation Therapy Oncology Group (RTOG) evaluation criteria range with the coated seeds cohort. CONCLUSIONS: PSI using coated seeds shows lower lung and pelvic seed migration compared with those using uncoated seeds and compares favorably to pelvic stranded seed migration reports. A higher concordance was observed with less dose variability in dosimetric parameters on Day 30 dosimetry compared with that on Day 0. Improvement in the implant quality was also observed using the RTOG criteria, suggesting reduced intraprostatic migration.

A quality assurance method with submillimeter accuracy for stereotactic linear accelerators.

The Stereotactic Alignment for Linear Accelerator (S. A. Linac) system is developed to conveniently improve the alignment accuracy of a conventional linac equipped with stereotactic cones. From the Winston-Lutz test, the SAlinac system performs three-dimensional (3D) reconstruction of the quality assurance (QA) ball coordinates with respect to the radiation isocenter, and combines this information with digital images of the laser target to determine the absolute position of the room lasers. A handheld device provides near-real-time repositioning advice to enable the user to align the QA ball and room lasers to within 0.25 mm of the centroid of the radiation isocenter. The results of 37 Winston-Lutz tests over 68 days showed that the median 3D QA ball alignment error was 0.09 mm, and 97% of the time the 3D error was ≤ 0.25 mm. All 3D isocentric errors in the study were 0.3 mm or less. The median x and y laser alignment coordinate error was 0.09 mm, and 94% of the time the x and y laser error was ≤ 0.25 mm. A phantom test showed that the system can make submillimeter end-to-end accuracy achievable, making a conventional linac a "Submillimeter Knife".