Diagnostics — Open Access Journal

Most non-small-cell lung cancer (NSCLC) patients are likely to develop brain metastases during the course of their illness. Currently, no consensus on NSCLC patients’ treatment with brain metastasis has been established. Although whole brain radiotherapy prolongs the median survival time of approximately 4 months, a cisplatin-pemetrexed combination may also represent a potential option in the treatment of asymptomatic NSCLC patients with brain metastases. Herein, we report the case of a non-smoker male patient with multiple, large and diffuse brain metastases from an “epidermal growth factor receptor(EGFR)wild-type” lung adenocarcinoma who underwent an overly aggressive chemo/radiation therapy. This approach led to a complete and durable remission of the disease and to a long survival of up to 58 months from diagnosis of primary tumor. The uncommon course of this metastatic disease induced us to describe its oncological management and to investigate the molecular features of the tumor. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses. In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity. We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB). After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L). The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case = 0.05 (95% confidence interval (CI) = 0.02–0.15) compared to controls, and OR = 0.16 (95% CI = 0.07–0.40), compared to mild cases). This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS. Full article

This study investigated correlations between fluorodeoxyglucose (FDG) uptake in tumors as assessed by modified dual-time-point (mDTP) FDG positron emission tomography/computed tomography (PET/CT) in invasive breast cancer (iBC) and several prognostic parameters. Thirty-two women who underwent mastectomies for iBC were retrospectively evaluated. mDTP scanning was performed using standard FDG PET/CT (PET1), followed by early delayed acquisition (PET2) without repositioning and additional CT scanning. Using maximal standardized uptake values on PET1 (SUV1) and PET2 (SUV2) in the primary breast tumor, the percentage changes between SUV1 and SUV2 (retention index, (RI)) were calculated. Prognostic parameters (e.g., tumor size and stage; number of metastatic lymph nodes; histologic grade; expression of estrogen receptor (ER), progesterone, epidermal growth factor receptor (HER-2), and p53; and the Ki-67 labeling index (LI)) were evaluated from the surgical specimens. PET2 scans were conducted 17.7 ± 1.5 min after PET1. RI values gradually increased as the histologic grade increased (p = 0.016), and were significantly higher when ER expression was absent (p = 0.023) and Ki-67 LI was high (p < 0.001). RI values also showed a moderately positive correlation with Ki-67 LI (r = 0.629; p < 0.001). RI correlated with well-known biologic prognostic factors of iBC and mDTP scanning, which could be used as a substitute for conventional DTP PET. Full article

: Epithelial ovarian cancer (EOC) is the18th most common cancer worldwide and the 8th most common in women. The aim of this study was to diagnose the potential importance of, as well as novel genes linked with, EOC and to provide valid biological information for further research. The gene expression profiles of E-MTAB-3706 which contained four high-grade ovarian epithelial cancer samples, four normal fallopian tube samples and four normal ovarian epithelium samples were downloaded from the ArrayExpress database. Pathway enrichment and Gene Ontology (GO) enrichment analysis of differentially expressed genes (DEGs) were performed, and protein-protein interaction (PPI) network, microRNA-target gene regulatory network and TFs (transcription factors ) -target gene regulatory network for up- and down-regulated were analyzed using Cytoscape. In total, 552 DEGs were found, including 276 up-regulated and 276 down-regulated DEGs. Pathway enrichment analysis demonstrated that most DEGs were significantly enriched in chemical carcinogenesis, urea cycle, cell adhesion molecules and creatine biosynthesis. GO enrichment analysis showed that most DEGs were significantly enriched in translation, nucleosome, extracellular matrix organization and extracellular matrix. From protein-protein interaction network (PPI) analysis, modules, microRNA-target gene regulatory network and TFs-target gene regulatory network for up- and down-regulated, and the top hub genes such as E2F4, SRPK2, A2M, CDH1, MAP1LC3A, UCHL1, HLA-C (major histocompatibility complex, class I, C) , VAT1, ECM1 and SNRPN (small nuclear ribonucleoprotein polypeptide N) were associated in pathogenesis of EOC. The high expression levels of the hub genes such as CEBPD (CCAAT enhancer binding protein delta) and MID2 in stages 3 and 4 were validated in the TCGA (The Cancer Genome Atlas) database. CEBPD andMID2 were associated with the worst overall survival rates in EOC. In conclusion, the current study diagnosed DEGs between normal and EOC samples, which could improve our understanding of the molecular mechanisms in the progression of EOC. These new key biomarkers might be used as therapeutic targets for EOC. Full article

Deep learning (DL) methods are increasingly being applied for developing reliable computer-aided detection (CADe), diagnosis (CADx), and information retrieval algorithms. However, challenges in interpreting and explaining the learned behavior of the DL models hinders their adoption and use in real-world systems. In this study, we propose a novel method called “Class-selective Relevance Mapping” (CRM) for localizing and visualizing discriminative regions of interest (ROI) within a medical image. Such visualizations offer improved explanation of the convolutional neural network (CNN)-based DL model predictions. We demonstrate CRM effectiveness in classifying medical imaging modalities toward automatically labeling them for visual information retrieval applications. The CRM is based on linear sum of incremental mean squared errors (MSE) calculated at the output layer of the CNN model. It measures both positive and negative contributions of each spatial element in the feature maps produced from the last convolution layer leading to correct classification of an input image. A series of experiments on a “multi-modality” CNN model designed for classifying seven different types of image modalities shows that the proposed method is significantly better in detecting and localizing the discriminative ROIs than other state of the art class-activation methods. Further, to visualize its effectiveness we generate “class-specific” ROI maps by averaging the CRM scores of images in each modality class, and characterize the visual explanation through their different size, shape, and location for our multi-modality CNN model that achieved over 98% performance on a dataset constructed from publicly available images. Full article

Lower respiratory tract infections (LRTIs) are the leading infectious cause of death and the sixth-leading cause of death overall worldwide. Streptococcus pneumoniae, with more than 90 serotypes, remains the most common identified cause of community-acquired acute bacterial pneumonia. Antibiotics treat LRTIs with a bacterial etiology. With the potential for antibiotic-resistant bacteria, defining the etiology of the LRTI is imperative for appropriate patient treatment. C-reactive protein and procalcitonin are point-of-care tests that may differentiate bacterial versus viral etiologies of LRTIs. Major advancements are currently advancing the ability to make rapid diagnoses and identification of the bacterial etiology of LRTIs, which will continue to support antimicrobial stewardship, and is the focus of this review. Full article

The rapid identification of Mycobacteriumavium subspecies paratuberculosis (MAP) infected animals within the herd is essential for preventing the spread of the disease as well as avoiding human exposure. Although culture is seen as the gold standard, there are various molecular assays available i.e., polymerase chain reaction (PCR) or isothermal amplification technique (recombinase polymerase amplification (RPA)) for the detection of MAP. The accuracy of the molecular assays is highly dependent on the DNA extraction method. In order to establish a rapid point of need system for the detection of MAP DNA from stool samples, we developed a rapid DNA extraction protocol (MAP DNA SpeedXtract) specified for use in combination with the RPA. The whole procedure from “sample in” to “result out” was conducted in a mobile suitcase laboratory. The DNA extraction is based on reverse purification by magnetic beads, which reduces the required technical demand. The MAP DNA SpeedXtract was performed within 25 min and only three pipetting steps were needed. The amplification and detection time were 20 min in RPA. The sensitivity and specificity of the developed protocol in comparison with the lab-based silica membrane column extraction and real-time PCR were 90.9% (n = 22) and 100% (n = 23), respectively. In conclusion, we established a rapid and reliable protocol for the extraction and detection of MAP DNA. All reagents are cold chain independent. The entire setup is ideal for point of need identification of MAP infected cases. Full article

Purpose: With the increasing number of therapy options available for patients with lung cancer, early response evaluation is needed. We performed this pilot study to assess the feasibility of early, repeated Positron emission tomography-magnetic resonance (PET/MR), the impact of timing and the capability for response prediction in lung tumors during chemotherapy. Methods: Patients with stage IV non-small cell lung cancer referred for chemotherapy were prospectively recruited. Fluorine-18-Fluorodeoxyglucose(¹⁸F-FDG)-PET/MR scans were performed prior to, during and after the first or second cycle of chemotherapy. Primary tumors were defined on all scans and size, FDG-uptake and apparent diffusion coefficient (ADC) were measured. Early response was described over time and a Standard Linear Mixed Model was applied to analyze changes over time. Results: 45 FDG-PET/MR scans were performed in 11 patients. Whereas the overall changes measured by ADC did not change significantly, there was an overall significant decrease in FDG-uptake from pre to post treatment scans. There was no difference in the FDG-uptake measured 1 or 3 weeks after therapy, but uptake measured 2 weeks after therapy differed from measurements at week 3. Changes measured in patients scanned during the first treatment cycle appeared more pronounced than during the second cycle. Conclusions: This pilot study indicates that response evaluation shortly after initiation of chemotherapy appears concordant with later evaluation and probably more reliable than evaluation midway between cycles. Responses during or after the first cycle of chemotherapy rather than during subsequent cycles are likely to be more readily measured. Full article

This cross-sectional study compares the effectiveness of an active MMP-8 (aMMP-8) point-of-care (PoC)/chairside mouthrinse test to the conventional bleeding on probing (BOP) (cutoff 20%) test in detecting subclinical periodontitis/pre-periodontitis in Finnish adolescents. The study was carried out at the Kotka Health Center, Finland. A total of 47 adolescents (30 boys/17 girls) aged 15–17 were first tested with the aMMP-8 PoC test, followed by a full-mouth evaluation of clinical parameters of oral health including periodontal, oral mucosal, and caries assessment. A periodontist performed these clinical examinations. The aMMP-8 PoC test result had much stronger association with subclinical periodontitis than the BOP 20% test (2.8–5.3 times stronger in terms of odds ratio). The aMMP-8 PoC test had ≥2 times higher sensitivity than the BOP 20% test with, generally, the same specificity. Further, the aMMP-8 PoC test had generally better accuracy and lower false negative percentages. The aMMP-8 PoC test seemed to be more effective than the conventional BOP test in detecting subclinical periodontitis/pre-periodontitis in adolescents reducing the risk of their undertreatment. However, the sample size may be a limiting factor, and more studies are needed to confirm our results for both adolescents and adults. Full article

Introduction: Quantitative computed tomography (qCT) is an emergent technique for diagnostics and research in patients with chronic obstructive pulmonary disease (COPD). qCT parameters demonstrate a correlation with pulmonary function tests and symptoms. However, qCT only provides anatomical, not functional, information. We evaluated five distinct, partial-machine learning-based mathematical models to predict lung function parameters from qCT values in comparison with pulmonary function tests. Methods: 75 patients with diagnosed COPD underwent body plethysmography and a dose-optimized qCT examination on a third-generation, dual-source CT with inspiration and expiration. Delta values (inspiration—expiration) were calculated afterwards. Four parameters were quantified: mean lung density, lung volume low-attenuated volume, and full width at half maximum. Five models were evaluated for best prediction: average prediction, median prediction, k-nearest neighbours (kNN), gradient boosting, and multilayer perceptron. Results: The lowest mean relative error (MRE) was calculated for the kNN model with 16%. Similar low MREs were found for polynomial regression as well as gradient boosting-based prediction. Other models led to higher MREs and thereby worse predictive performance. Beyond the sole MRE, distinct differences in prediction performance, dependent on the initial dataset (expiration, inspiration, delta), were found. Conclusion: Different, partially machine learning-based models allow the prediction of lung function values from static qCT parameters within a reasonable margin of error. Therefore, qCT parameters may contain more information than we currently utilize and can potentially augment standard functional lung testing. Full article

Autism spectrum disorder (ASD) is a neurological and developmental disorder whose late diagnosis is based on subjective tests. In seeking for earlier diagnosis, we aimed to find objective biomarkers via analysis of resting-state functional MRI (rs-fMRI) images obtained from the Autism Brain Image Data Exchange (ABIDE) database. Thus, we estimated brain functional connectivity (FC) between pairs of regions as the statistical dependence between their neural-related blood-oxygen-level-dependent (BOLD) signals. We compared FC of individuals with ASD and healthy controls, matched by age and intelligence quotient (IQ), and split into three age groups (50 children, 98 adolescents, and 32 adults), from a developmental perspective. After estimating the correlation, we observed hypoconnectivities in children and adolescents with ASD between regions belonging to the default mode network (DMN). Concretely, in children, FC decreased between the left middle temporal gyrus and right frontal pole (p = 0.0080), and between the left orbitofrontal cortex and right superior frontal gyrus (p = 0.0144). In adolescents, this decrease was observed between bilateral postcentral gyri (p = 0.0012), and between the right precuneus and right middle temporal gyrus (p = 0.0236). These results help to gain a better understanding of the involved regions on autism and its connection with the affected superior cognitive brain functions. Full article

Diabetes technology has continually evolved over the years to improve quality of life and ease of care for affected patients. Frequent blood glucose (BG) checks and multiple daily insulin injections have become standard of care in Type 1 diabetes (T1DM) management. Continuous glucose monitors (CGM) allow patients to observe and discern trends in their glycemic control. These devices improve quality of life for parents and caregivers with preset alerts for hypoglycemia. Insulin pumps have continued to improve and innovate since their emergence into the market. Hybrid closed-loop systems have harnessed the data gathered with CGM use to aid in basal insulin dosing and hypoglycemia prevention. As technology continues to progress, patients will likely have to enter less and less information into their pump system manually. In the future, we will likely see a system that requires no manual patient input and allows users to eat throughout the day without counting carbohydrates or entering in any blood sugars. As technology continues to advance, endocrinologists and diabetes providers need to stay current to better guide their patients in optimal use of emerging management tools. Full article

It has been reported that endoscopic retrograde cholangiopancreatography (ERCP) is of value in evaluating precise pancreatograms of the pancreatic duct (PD). Recently, institutions have tended to perform magnetic resonance cholangiopancreatography (MRCP) for the diagnosis of PD due to post-ERCP pancreatitis (PEP). In small pancreatic cancer (PC), including PC in situ (PCIS) which is undetectable on cross sectional images, endoscopic ultrasonography (EUS) and MRCP serve important roles in detecting local irregular stenosis of the PD or small cystic lesions. Subsequently, ERCP and associated serial pancreatic juice aspiration cytologic examination (SPACE) obtained by endoscopic nasopancreatic drainage (ENPD) may be useful in the diagnosis of very early-stage PC. Further prospective multicenter studies are required to establish a standard method of SPACE for the early diagnosis of PC. Full article

The aim of this study was to provide an overview of the literature available on machine learning (ML) algorithms applied to the Lung Image Database Consortium Image Collection (LIDC-IDRI) database as a tool for the optimization of detecting lung nodules in thoracic CT scans. This systematic review was compiled according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only original research articles concerning algorithms applied to the LIDC-IDRI database were included. The initial search yielded 1972 publications after removing duplicates, and 41 of these articles were included in this study. The articles were divided into two subcategories describing their overall architecture. The majority of feature-based algorithms achieved an accuracy >90% compared to the deep learning (DL) algorithms that achieved an accuracy in the range of 82.2%–97.6%. In conclusion, ML and DL algorithms are able to detect lung nodules with a high level of accuracy, sensitivity, and specificity using ML, when applied to an annotated archive of CT scans of the lung. However, there is no consensus on the method applied to determine the efficiency of ML algorithms. Full article

Background: Vascular diseases are multifactorial and several risk factors may have synergetic effect on the global vascular risk. Among patients with diabetes, we investigated whether vitamin B6 species differ according to global cardiovascular risk. Methods: The present observational study included 122 patients with type 2 diabetes (mean (SD) age = 69.9 (9.1) years; 50% men). Concentrations of vitamin B6 vitamers were measured. Classical blood biomarkers and risk factors were used to compute a multivariate risk score. Results: Plasma concentrations of 4-pyridoxic acid were higher in patients with high risk versus those with low risk scores (48.2 (63.7) vs. 31.9 (15.0) nmol/L; p = 0.031). Plasma pyridoxine was significantly lowered in patients at high risk (2.8 (28.4) vs. 38.1 (127.8) nmol/L; p = 0.003). PAr index (4-pyridoxic acid/pyridoxal + pyridoxal 5′-phosphate) (1.05 (0.07) vs. 0.84 (0.06); p = 0.017) and the ratio of 4-pyridoxic acid/pyridoxine (7.0 (4.8) vs. 3.9 (3.2); p < 0.001) were higher in patients at high risk. After adjustment for cystatin C and C-reactive protein, only pyridoxine and 4-pyridoxic acid/pyridoxine ratio remained significantly different according to vascular risk scores. 4-Pyridoxic acid/pyridoxine ratio was the best marker to discriminate between patients according to their risk scores—area under the curve (AUC) (95% confidence intervals (CI)) = 0.72 (0.62–0.81). 4-Pyridoxic acid/pyridoxine ratio was directly related to plasma levels of soluble vascular cell adhesion molecule 1. Conclusion: Vitamin B6 metabolism was shifted in patients with multiple vascular risk factors. The catabolism to 4-pyridoxic acid was enhanced, whereas the catabolism to pyridoxine was lowered. High 4-Pyridoxic acid/pyridoxine ratio is independently associated with global cardiovascular risk. Full article

In regenerative medicine, evaluation of bone mineral density using a microfocus X-ray generator could eventually be used to determine the degree of bone tissue regeneration. To evaluate bone mineral density against regenerated bone material, two low-energy X-rays are necessary. Herein, the acquisition of quasi-monochromatic, dual-energy soft X-ray and the subsequent medical application were examined using the K-absorption edges of two types of metal filters (i.e., zirconium and tin) in a microfocus X-ray generator. Investigation of the optimal tube voltage and filter thickness to form a quasi-monochromatic energy spectrum with a single filter revealed that a filter thickness of 0.3 mm results in an optimal monochromatization state. When a dual filter was used, the required filter thickness was 0.3 mm for tin and 0.2 mm for zirconium at a tube voltage of 35 kV. For the medical application, we measured quasi-monochromatic, dual-energy X-rays to evaluate the measurement accuracy of bone mineral density. Using aluminum as a simulated bone sample, a relative error of ≤5% was consistent within the aluminum thickness range of 1–3 mm. These data suggest that a bone mineral density indicator of recycled bone material can be easily obtained with the quasi-monochromatic X-ray technique using a microfocus X-ray generator. Full article

Considerable controversy has existed with efforts to assess post-exertional malaise (PEM), which is one of the defining features of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). While a number of self-report questionnaires have been developed to assess this symptom, none have been comprehensive, and a recent federal government report has recommended the development of a new PEM measure. The current study involved a community-based participatory research process in an effort to develop a comprehensive PEM instrument, with critical patient input shaping the item selection and overall design of the tool. A survey was ultimately developed and was subsequently completed by 1534 members of the patient community. The findings of this survey suggest that there are key domains of this symptom, including triggers, symptom onset, and duration, which have often not been comprehensively assessed in a previous PEM instrument. This study indicates that there are unique benefits that can be derived from patients collaborating with researchers in the measurement of key symptoms defining ME and CFS. Full article

We describe the clinical course of a 24-year old male with Crohn’s disease in immunosuppressive therapy admitted with a 6-week history of fever, weight loss, night sweat, and general malaise. The patient received extensive workup for a fever of unknown origin and received empiric antibiotics. Workup with Fluorine-18 fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) positron-emission tomography (PET/CT), and magnetic resonance imaging (MRI) with intravenous contrast showed multifocal ostitis of the columna and os sacrum, as well as abscesses in m. iliopsoas and m. iliacus and affection of the retroperitoneum, liver, and spleen. Initially, malignancy was suspected, but a subsequent liver biopsy showed necrotizing granulomatous inflammation and a later polymerase chain reaction (PCR) showed Bartonella henselae. The patient had relevant exposure from housecats. He was treated with Doxycycline and Rifampicin for 12 weeks resulting in complete recovery. This case is, to our knowledge, a rare example of disseminated infection with Bartonella henselae visualized on both [¹⁸F]FDG-PET/CT and MRI. Full article

Bilirubin encephalopathy/kernicterus is relatively rare, but continues to occur despite universal newborn screening. What is more interesting is the spectrum of clinical and even neuropathological findings that have been reported in the literature to be associated with bilirubin encephalopathy and kernicterus. In this review, the authors discuss the array of clinicopathological findings reported in the context of bilirubin encephalopathy and kernicterus, as well as the types of diagnostic testing used in patients suspected of having bilirubin encephalopathy or kernicterus. The authors aim to raise the awareness of these features among both pediatric neurologists and neuropathologists. Full article