Peripheral T Cell Cytokine Responses for Diagnosis of Active Tuberculosis

BACKGROUND: A test for diagnosis of active Tuberculosis (TB) from peripheral blood could tremendously improve clinical management of patients. METHODS: Of 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB) specific CD4(+) T cells and CD8(+) T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD) or early secretory antigenic target (ESAT)-6, respectively. RESULTS: Among patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4(+) T cell derived interferon (IFN)-γ was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-γ/Interleukin(IL)-2 cytokine ratios discriminated best between active TB and other diseases. CONCLUSION: T cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a "memory type" to an "effector type" cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB

Abnormal cerebral hemodynamics and blood-brain barrier permeability detected with perfusion MRI in systemic lupus erythematosus patients

Objective: Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) has previously shown alterations in cerebral perfusion in patients with systemic lupus erythematosus (SLE). However, the results have been inconsistent, in particular regarding neuropsychiatric (NP) SLE. Thus, we investigated perfusion-based measures in different brain regions in SLE patients with and without NP involvement, and additionally, in white matter hyperintensities (WMHs), the most common MRI pathology in SLE patients. Materials and methods: We included 3 T MRI images (conventional and DSC) from 64 female SLE patients and 19 healthy controls (HC). Three different NPSLE attribution models were used: the Systemic Lupus International Collaborating Clinics (SLICC) A model (13 patients), the SLICC B model (19 patients), and the American College of Rheumatology (ACR) case definitions for NPSLE (38 patients). Normalized cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were calculated in 26 manually drawn regions of interest and compared between SLE patients and HC, and between NPSLE and non-NPSLE patients. Additionally, normalized CBF, CBV and MTT, as well as absolute values of the blood-brain barrier leakage parameter (K2) were investigated in WMHs compared to normal appearing white matter (NAWM) in the SLE patients. Results: After correction for multiple comparisons, the most prevalent finding was a bilateral significant decrease in MTT in SLE patients compared to HC in the hypothalamus, putamen, right posterior thalamus and right anterior insula. Significant decreases in SLE compared to HC were also found for CBF in the pons, and for CBV in the bilateral putamen and posterior thalamus. Significant increases were found for CBF in the posterior corpus callosum and for CBV in the anterior corpus callosum. Similar patterns were found for both NPSLE and non-NPSLE patients for all attributional models compared to HC. However, no significant perfusion differences were revealed between NPSLE and non-NPSLE patients regardless of attribution model. The WMHs in SLE patients showed a significant increase in all perfusion-based metrics (CBF, CBV, MTT and K2) compared to NAWM. Conclusion: Our study revealed perfusion differences in several brain regions in SLE patients compared to HC, independently of NP involvement. Furthermore, increased K2 in WMHs compared to NAWM may indicate blood-brain barrier dysfunction in SLE patients. We conclude that our results show a robust cerebral perfusion, independent from the different NP attribution models, and provide insight into potential BBB dysfunction and altered vascular properties of WMHs in female SLE patients. Despite SLE being most prevalent in females, a generalization of our conclusions should be avoided, and future studies including all sexes are needed

Challenges in diagnosing extrapulmonary tuberculosis in the European Union, 2011

In the European Union (EU) 72,334 tuberculosis (TB) cases were notified in 2011, of which 16,116 (22%) had extrapulmonary tuberculosis (EPTB). The percentage of TB cases with EPTB ranged from 4% to 48% in the reporting countries. This difference might be explained by differences in risk factors for EPTB or challenges in diagnosis. To assess the practices in diagnosis of EPTB we asked European Union/European Economic Area (EU/EEA) countries to participate in a report describing the diagnostic procedures and challenges in diagnosing EPTB. Eleven EU Member States participated and reports showed that in the majority EPTB is diagnosed by a pulmonologist, sometimes in collaboration with the doctor who is specialised in the organ where the symptoms presented. In most countries a medical history and examination is followed by invasive procedures, puncture or biopsy, to collect material for confirmation of the disease (by culture/histology/cytology). Some countries also use the tuberculin skin test or an interferon-gamma-release-assay. A wide variety of radiological tests may be used. Countries that reported challenges in the diagnosis of EPTB reported that EPTB is often not considered because it is a rare disease and most medical professionals will not have experience in diagnosing EPTB. The fact that EPTB can present with a variety of symptoms that may mimic symptoms of other pathologies does pose a further challenge in diagnosis. In addition, obtaining an appropriate sample for confirmation of EPTB was frequently mentioned as a challenge. In summary, diagnosis of EPTB poses challenges due to the diversity of symptoms with which EPTB may present, the low level of suspicion of clinicians, and due to the difficulty in obtaining an adequate sample for confirmation

Artificial neural networks and pathologists recognize basal cell carcinomas based on different histological patterns.

Recent advances in artificial intelligence, particularly in the field of deep learning, have enabled researchers to create compelling algorithms for medical image analysis. Histological slides of basal cell carcinomas (BCCs), the most frequent skin tumor, are accessed by pathologists on a daily basis and are therefore well suited for automated prescreening by neural networks for the identification of cancerous regions and swift tumor classification.In this proof-of-concept study, we implemented an accurate and intuitively interpretable artificial neural network (ANN) for the detection of BCCs in histological whole-slide images (WSIs). Furthermore, we identified and compared differences in the diagnostic histological features and recognition patterns relevant for machine learning algorithms vs. expert pathologists.An attention-ANN was trained with WSIs of BCCs to identify tumor regions (n = 820). The diagnosis-relevant regions used by the ANN were compared to regions of interest for pathologists, detected by eye-tracking techniques.This ANN accurately identified BCC tumor regions on images of histologic slides (area under the ROC curve: 0.993, 95% CI: 0.990-0.995; sensitivity: 0.965, 95% CI: 0.951-0.979; specificity: 0.910, 95% CI: 0.859-0.960). The ANN implicitly calculated a weight matrix, indicating the regions of a histological image that are important for the prediction of the network. Interestingly, compared to pathologists' eye-tracking results, machine learning algorithms rely on significantly different recognition patterns for tumor identification (p < 10 <sup>-4</sup> ).To conclude, we found on the example of BCC WSIs, that histopathological images can be efficiently and interpretably analyzed by state-of-the-art machine learning techniques. Neural networks and machine learning algorithms can potentially enhance diagnostic precision in digital pathology and uncover hitherto unused classification patterns

Tuberculosis Treatment Outcomes in Europe: Based on Treatment Completion, Not Cure

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