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Application of Cerebrospinal Fluid Host Protein Biosignatures in the Diagnosis of Tuberculous Meningitis in Children from a High Burden Setting
Background. The diagnosis of tuberculous meningitis (TBM) especially in children is challenging. New tests are urgently needed for the diagnosis of the disease, especially in resource-limited settings. Methods. We collected cerebrospinal fluid (CSF) samples from children presenting with symptoms requiring investigation for meningitis at a tertiary hospital in Cape Town, South Africa. Children were later classified as TBM or no TBM using published case definitions. Using a multiplex platform, we investigated the concentrations of biomarkers comprising a previously established 3-marker biosignature (VEGF, IL-13, and LL-37) and other potentially useful host biomarkers as diagnostic candidates for TBM. Findings. Out of 47 children, age, 3 months to 13 years, 23 were diagnosed with TBM and six (16%) were HIV-infected. We validated the previously identified CSF biosignature (sensitivity of 95.7% (95% CI, 79.0-99.2%) and specificity of 37.5% (95% CI, 21.2-57.3%)). However, substitution of IL-13 and LL-37 with IFN-γ and MPO, respectively, resulted in improved accuracy (area under the ROC curve , 95% CI, 0.92-1.00, up to 91.3% (21/23) sensitivity and up to 100% (24/24) specificity). An alternative four-marker biosignature (sICAM-1, MPO, CXCL8, and IFN-γ) also showed potential, with an AUC of 0.97. Conclusion. We validated a previously identified CSF biosignature and showed that refinement of this biosignature by incorporation of other biomarkers diagnosed TBM with high accuracy. Incorporation of these biomarkers into a point-of-care or bedside diagnostic test platform may result in the improved management of TBM in children.
1. Introduction
Tuberculosis (TB) remains a global health problem and was responsible for the deaths of estimated 1.6 million people in 2017 [1]. Although it is difficult to accurately estimate the burden of childhood TB, one million children were estimated to have become ill with the disease in 2017 [1].
Tuberculous meningitis (TBM) is the most severe form of extra pulmonary TB as it affects the central nervous system (CNS). It mostly occurs during early childhood and has high morbidity and mortality, mainly due to delayed diagnosis [2]. It is well established that diagnosing pulmonary TB disease in children is challenging, especially in resource-constrained settings [3]. It is even more challenging to diagnose extrapulmonary TB in this patient group, including TBM. As a consequence, TBM frequently results in a poor outcome due to nonspecific symptoms and signs [4]. The limitations of both the most widely used diagnostic test for TB (smear microscopy) [5] and the culture gold standard test are well publicised [3, 5]. These tests have been shown to be suboptimal in the diagnosis of TBM [6, 7]. The GeneXpert MTB/RIF test®, the most important recent advancement in the field of TB diagnostics, is limited by the large CSF volumes required and low negative predictive value [8]. However, the use of the GeneXpert Ultra resulted in an improved negative predictive value in a more recent study on HIV-positive adults [9]. The diagnosis of TBM is mostly based on a combination of clinical findings, multiple laboratory tests on the CSF, imaging findings, and the exclusion of common differential diagnoses in routine clinical practice [10]. Diagnosing the disease in most high-burden, but resource-constrained settings is difficult due to the unavailability of most of these techniques, with children seen at primary and secondary healthcare facilities often having multiple missed opportunities; up to six visits before the eventual diagnosis of TBM are made [11]. New tests are urgently needed for the diagnosis of TBM.
Host biomarker-based tests may be valuable in the diagnosis of TBM as they have previously been shown to be potentially useful in other extrapulmonary forms of TB [12] and may be easily converted into point-of-care or bedside tests [13, 14]. In a previous study, we identified a 3-marker CSF host protein biosignature comprising VEGF, IL-13, and cathelicidin LL-37, which showed potential in the diagnosis of TBM in children [15]. As there have been multiple recent studies in which new, potentially useful TB diagnostic biomarkers were identified [16, 17], we hypothesized that at least some of these biomarkers, which were identified in mostly adult pulmonary TB studies, will be useful in the diagnosis of TBM in children. We therefore aimed to evaluate the usefulness of our previously established 3-marker CSF biosignature in a new cohort of children with suspected meningitis and to also evaluate the potential of other host biomarkers that have shown potential in adult pulmonary TB studies, as candidate markers for the diagnosis of TBM in children. We further hypothesized that the accuracy of the previously identified 3-marker CSF signature [15] may be improved if refined through the incorporation of some of these new biomarkers.
2. Materials and Methods
Children suspected of having meningitis and requiring CSF examination for routine diagnostic purposes were recruited from the Tygerberg Academic Hospital in Cape Town, South Africa. Study participants were recruited between November 2016 and November 2017. Children were eligible for participation in the study if they were between the ages 3 months and 13 years, provided that written informed consent was obtained from the parents or legal guardians. Assent was obtained from children older than 7 years if they had a normal level of consciousness, i.e., a Glasgow Coma Score (GCS) of 15/15. The study was approved by the Health Research Ethics Committee of the University of Stellenbosch, Tygerberg Academic Hospital, and the Western Cape Provincial Government.
After the collection of CSF and blood samples for routine diagnostic purposes, an additional 1 ml of CSF was collected into a sterile tube (BD Biosciences). Samples were then taken to the immunology research laboratory for further processing for research purposes, within an average of 2 hours from collection. CSF samples were centrifuged in a biosafety level 3 laboratory at 4000 xg for 15 minutes, followed by aliquoting and storage at -80°C until analysed.
2.1. Diagnostic Work-Up of Study Participants
All patients underwent a comprehensive clinical evaluation by a specialist paediatric neurologist. After routine clinical investigations, computed tomography (CT) of the brain, air encephalography, and magnetic resonance (MR) imaging were performed as clinically indicated. Following lumbar puncture, investigations including appearance and colour determination, differential cell counts, protein, glucose, and other routinely investigated markers (Supplementary Table 1) were assessed, followed by centrifugation of the CSF, Gram staining, India ink examination, culture of the centrifuged sediment on blood agar plates (for pyogenic bacteria), auramine "O" staining and fluorescence microscopy, culture using the mycobacterium growth indicator tubes (MGIT)™ method (Becton and Dickinson), and examination for M.tb DNA using the HAIN Genotype MTBDRplus kit (Hain Lifescience GmbH, Germany). All data generated from the study were recorded in a study-specific RedCap web-based database.
Patients were classified as possible, probable, or definite TBM according to a uniform research case definition based on a scoring system consisting of clinical, CSF, and neuroimaging findings [18]. TBM was classified as "probable" when patients scored ≥12 when neuroimaging was available and ≥10 when neuroimaging was unavailable. A diagnosis of definite TBM was made if acid-fast bacilli were present in the CSF, M.tb was isolated from the CSF by cultured, a nucleic acid amplification test of CSF yielded positive results, or there was histopathological evidence of M.tb from another CNS sites.
2.2. Immunoassays
In addition to the three biomarkers that comprised our previous 3-marker model [15] (IL-13, VEGF, and cathelicidin LL-37), we evaluated the concentrations of 66 other candidate biomarkers including markers that were previously investigated in adult TB studies [16, 17, 19, 20] and other proteins which have not been previously investigated in the TB field, including complement factors and other proteins, as possible diagnostic biomarkers for TBM by ELISA (cathelicidin LL-37) or the Luminex platform (all other host biomarkers).
Cathelicidin LL-37 levels in CSF samples were evaluated using an ELISA kit purchased from Elabscience Biotechnology Inc. (catalog #E-EL-H2438). Experiments were done according to the procedure recommended by the manufacturer after which optical densities (OD) were read at 450 nm by an automated microplate reader (iMark™ Microplate Reader, Bio-Rad Laboratories). The mean OD of the blank wells was subtracted from the OD of the sample wells and the background-corrected ODs used for statistical analysis.
The concentrations of CCL1 (I-309), CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CD40 ligand (CD40L), CXCL8 (IL-8), CXCL9 (MIG), CXCL10 (IP-10), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), interleukin- (IL-) 1β, IL-10, IL-12/23 (p40), IL-17A, IL-21, IL-4, IL-6, IL-7, matrix metalloproteinase- (MMP-) 1, MMP-8, transforming growth factor- (TGF-) α, tumour necrosis factor- (TNF-) α, soluble neural cell adhesion molecule (sNCAM-1/CD56), MMP-7, ferritin, and MMP-9 were evaluated in patient samples using Luminex kits purchased from R&D Systems Inc. (Bio-Techne), Minneapolis, USA. The levels of apolipoprotein- (Apo-) AI, Apo-CIII, complement C3, complement factor H, BDNF, cathepsin D, soluble intracellular adhesion molecule- (sICAM-) 1, myeloperoxidase (MPO), platelet-derived growth factor- (PDGF-) AA, CCL5 (RANTES), PDGF-AB/BB, soluble vascular adhesion molecule (sVCAM-1), plasminogen activator inhibitor-1 (PAI-1) (total), S100 calcium-binding protein B (S100B), amyloid beta 1-40 (Ab40), Ab42, soluble receptor for advanced glycation end products (sRAGE), Glial cell-derived neurotrophic factor (GDNF), C-reactive protein (CRP), alpha-2-antitrypsin (A1AT), pigment epithelium-derived factor (PEDF), serum amyloid P (SAP), CCL18 (MIP-4/PARC), complement C4 (CC4), CC2, CC4b, CC5, CC5a, CC9, complement factor D (CFD/adipsin), mannose-binding lectin (MBL), complement factor 1 (CF1), sP-selectin, von Willebrand factor-cleaving protease (ADAMTS13), D-DIMER, growth differentiation factor- (GDF-) 15, myoglobin, lipocalin 2 (NGAL), and serum amyloid A (SAA) were evaluated using kits purchased from Merck Millipore, Billerica, MA, USA. All biomarkers were evaluated in CSF samples collected from all study participants following the instructions of the respective kit manufacturers (R&D Systems and Merck Millipore), respectively. All experiments were performed on the Bio Plex platform (Bio Rad Laboratories, Hercules, USA) in an ISO 15189 accredited laboratory. Data acquisition and analysis of median fluorescent intensity were done using the Bio Plex Manager version 6.1 software (Bio Rad Laboratories). The laboratory staff performing the Luminex experiments were blinded to the clinical classification of the study participants. The values of analytes in the quality control reagents evaluated with the samples were within their expected ranges.
2.3. Statistical Analysis
Differences in the concentrations of host biomarkers between the TBM and the no TBM groups were assessed using the Mann–Whitney test. The receiver operator characteristic (ROC) curve analysis procedure was used to assess the diagnostic accuracy of individual host biomarkers for TBM. Optimal cut-off values and associated sensitivities and specificities were selected based on Youden's index [21]. The utility of combinations of biomarkers in the diagnosis of TBM was ascertained by general discriminant analysis (GDA), followed by leave-one-out cross-validation. The data was analysed using Statistica (TIBCO Software Inc., CA, USA), and GraphPad Prism version 6 (GraphPad software, CA, USA).
3. Results
A total of 47 children in whom meningitis was strongly suspected, 30 (63.8%) of whom were males, were included in the study (Figure 1). The median age of all the children was 22 months (interquartile range: 10.5 to 57 months), and six out of 37 with known HIV status (16.2%) were HIV-infected. Using a composite reference standard based on a uniform research case definition of TBM [18], 23 of the children were diagnosed with definite or probable TBM (; ). The 24 children without TBM included children with bacterial meningitis () and viral meningitis () and children with other diagnoses (Table 1).
3.1. Usefulness of the Previously Identified 3-Marker CSF Biosignature in the Diagnosis of TBM
As we were interested in validating the diagnostic accuracy of the previously established 3-marker CSF biosignature (VEGF, IL-13, and cathelicidin LL-37), we first looked at the utility of individual analytes comprising this signature, followed by the evaluation of combinations between different biomarkers comprising the signature.
As observed in our previous study [15], VEGF was the most useful individual biomarker in this signature as none of the other two markers showed significant differences between groups with the Mann–Whitney test. The median levels of all the three analytes were higher in children with TBM (Table 2). As reagent kits from different manufacturers were used in this study, in comparison with what was employed in the previous study, we performed receiver operator characteristic (ROC) curve analysis to ascertain the optimal threshold values for the analytes using these new reagent kits. Using these new cut-off values, we observed that combining all three biomarkers (that is, a patient yielding positive results with all three), or positivity with any two out of the three analytes, was inferior to the accuracy obtained with VEGF A alone. However, when considering values above the threshold for any one of the three markers taken as a positive result, the accuracy of the 3-biomarker signature improved, with positive and negative predictive values of 59.5% (95% CI, 51.5-66.9%) and 90.0% (95% CI, 55.3-98.5%), respectively (Table 2).
3.2. Utility of Alternative Host Biomarkers in the Diagnosis of TBM
When the concentrations of the other 66 host markers investigated in our study were compared between children with and those without TBM using the Mann–Whitney test, the levels of multiple host biomarkers were significantly different () between the two groups (Supplementary Table 2). When the data for individual host markers were assessed by ROC curve analysis, the area under the ROC (AUC) was above 0.70 for 45 of the 66 proteins. Of note, the AUCs for 28 of these proteins including IFN-γ, MIP-4, CXCL9, CCL1, RANTES, IL-6, TNF-α, MPO, MMP-9, MMP-8, CC2, IL-10, PAI-1, CXCL8, IL-1b, A1AT, CXCL10, G-CSF, CC4, CC4b, GM-CSF, PDGF AB/BB, Apo-AI, MBL, ferritin, CC5a, SAP, and CC5 were ≥0.80 (Figure 2, Supplementary Table 2).
As all the six known HIV-infected children were in the no TBM group, we excluded these children and reanalysed the data for individual host biomarkers, to assess the possible influence of HIV infection on the accuracy of the biomarkers. After excluding the HIV-infected children, the median levels of PEDF, IL-12/23p40, MMP-1, CD40L, and GDF-15 were no longer significantly different between the children with TBM vs. no TBM. CD40L and GDF-15 showed trends for significant differences (0.05 < -value ≤ 0.09), whereas the observations for all other host markers were unchanged (data not shown).
3.3. Utility of Combinations between Other Host Biomarkers in the Diagnosis of TBM
When the data obtained for all host markers (including VEGF A, IL-13, and LL-37) were fitted into general discriminant analysis (GDA) models irrespective of HIV status, optimal prediction of TBM was shown to be achieved with a combination of four markers. The most accurate four-marker biosignature is comprised of sICAM-1, MPO, CXCL8, and IFN-γ diagnosed TBM with an AUC of 0.97 (95% CI, 0.92-1.00), corresponding to a sensitivity of 87.0% (20/23) (95% CI, 66.4-97.2%) and specificity of 95.8% (23/24) (95% CI, 78.9-99.9%). After leave-one-out cross validation, there was no change in the sensitivity (87.0%) and specificity (95.8%) of the four-marker biosignature. The positive and negative predictive values of the biosignature were 95.2% (95% CI, 74.5-99.3%) and 88.5% (95% CI, 72.7-95.7%), respectively. Further optimization of the four-marker biosignature resulted in both sensitivity and specificity (96%) (Figure 3).
Given that VEGF has consistently shown promise as a biomarker for TBM [15, 22–24] and that we identified other candidate biomarkers with strong potential in the present study, we wondered whether the previous 3-marker VEGF-based biosignature could be further optimized using other analytes. A GDA model in which IL-13 and cathelicidin LL-37 were replaced with IFN-γ and MPO, respectively, resulted in an improved AUC of 0.97 (95% CI, 0.92-1.00), corresponding to a sensitivity of 82.6% (19/23) (95% CI, 61.2-95.1%) and specificity of 95.8% (23/24) (95% CI, 78.9-99.9%). After leave-one-out cross validation, the sensitivity and specificity of the biosignature were 78.3% (18/23) (95% CI, 56.3-92.5%) and 91.7% (22/24) (95% CI, 73.0-99.0%), respectively. The positive and negative predictive values of the refined VEGF-based biosignature after leave-one-out cross validation were 90.0% (95% CI, 70.1-97.2%) and 81.5% (95% CI, 66.8-90.6%), respectively. Further optimization of the biosignature through the selection of better cut-off values resulted in improved sensitivity and specificity of 92% and 100%, respectively (Figure 4).
4. Discussion
We assessed the utility of a previously identified 3-marker CSF biosignature (IL-13, VEGF, and cathelicidin LL-37) [15] as well as host biomarkers that have shown potential as pulmonary TB diagnostic candidates in recent adult studies, as tools for the diagnosis of TBM in children with suspected meningitis. Although we validated the diagnostic accuracy of the previously identified 3-marker biosignature, other major findings from our study included the identification of a novel four-marker CSF biosignature comprising sICAM-1, MPO, CXCL8, and IFN-γ and a modified 3-marker signature (VEGF, IFN-γ, and MPO) which diagnosed TBM with promising accuracy. We also identified multiple host biomarkers that are detectable in CSF and which showed strong potential as diagnostic candidates for TBM in children.
It is well known that the diagnosis of TB disease in children remains a major challenge worldwide. This is mainly due to several well-publicised limitations in the currently available diagnostic tools [3, 5]. It is even more challenging to diagnose extrapulmonary TB including TBM in this patient group, with unstandardized and cumbersome approaches without reliable diagnostic criteria currently being used in routine clinical practice [25, 26]. In order to improve standardization of clinical diagnosis of TBM for research purposes, a uniform research case definition for both adults and children was proposed, categorizing patients as definite, probable, or possible TBM according to a composite score based on clinical, CSF, and neuroimaging findings [18]. None of the tests that are used in the diagnosis of TBM in children performs with high accuracy individually [6, 7, 27, 28]. The disease consequently results in high morbidity and mortality, due mainly to diagnostic delay [2, 29].
Host inflammatory biomarker-based biosignatures have been shown to have potential in the diagnosis of TB disease in both adults and children in previous studies [16, 20, 30]. Furthermore, these immunological biomarker-based tests have the potential to be readily converted into user-friendly, point-of-care diagnostic tests [13, 14] with the development of such tools for the management of TBM especially in children promising to be a major breakthrough in the future. In the present study, we validated the diagnostic accuracy of a previously identified CSF inflammatory biomarker-based biosignature [15]. Although a diagnostic test with positive and negative predictive values of 59.5% and 90.0%, respectively, will be imperfect, such a test may indeed contribute significantly to the management of children with suspected TBM if it is a rapid, point-of-care or bedside test, considering that it currently takes up to six hospital visits before TBM is diagnosed in children with the current diagnostic approaches in a country such as South Africa, which is relatively well resourced, compared to other lower- and middle-income countries [11]. Our data indicates that replacement of two of the proteins in this previously identified signature (IL-13 and cathelicidin LL-37) with new biomarkers (MPO and IFN-γ, respectively) has the potential to yield a test with both sensitivity and specificity (>95%). Furthermore, host markers comprising the alternative four-marker biosignature (sICAM-1, MPO, CXCL8, and IFN-γ) and other analytes that showed potential individually may be backup host markers that might be employed during the development of such a test. Our findings may therefore pave the way for the development of a prototype CSF biomarker-based test for the diagnosis of TBM in children.
During the development of such a test, the biosignature could be optimized further for use as a rule-in or rule-out test and the newly developed tests used as a screening test for TBM. If the test is based on a point-of-care diagnostic platform, such as the lateral flow technology, successful implementation of the test at the point-of-care or bedside would lead to a significant reduction in the costs and delays that are currently incurred in the diagnosis of TBM in children [11], with a consequent reduction in morbidity and mortality. Although a CSF-based point-of-care or bedside test will be useful in the management of TBM in children, the expertise required for lumbar punctures, opposed to that needed for the collection of other samples such as blood, saliva, or urine, may be a challenge in resource-limited settings, making the implementation of such a diagnostic tool difficult. That notwithstanding, such a test will also contribute to the management of the disease in children where sample collection is possible.
The fact that host inflammatory biomarkers detectable in CSF show potential in the diagnosis of TBM is not surprising, given that previous studies identified VEGF and other candidate biomarkers [15, 22–24] as potential tools for the diagnosis of the disease. Such candidate biomarkers that are detectable in biological fluids including blood [16, 17, 31–33], saliva [19, 20, 34], urine [35], and other specimens [12, 14, 36, 37] have been identified as TB diagnostic candidates in several previous studies. It is well established that individual host biomarkers might not suffice as diagnostic tools for TB disease [16, 31, 33] owing to the fact that these inflammatory biomarkers will be raised in other diseases, including cancers. However, these specificity concerns may be addressed through the use of a panel of biomarkers as done in the present study.
The main limitation of the current study was the relatively small sample size, especially the few children with confirmed TBM and alternative diagnoses including children with other forms of meningitis. However, as this was a TBM-suspect study, the design of the study was relatively strong and the number of participants enrolled into the study is consistent with the patient numbers described in multiple previous studies. Validation of the previously established 3-marker CSF signature in the current study indicates that the novel biosignatures identified in the study have strong potential. Further studies should include larger numbers of study participants with suspected meningitis, including those who are HIV-infected, and individuals with confirmed alternative meningitides. HIV-infected children included in such studies should be appropriately staged with CD4 counts and viral loads, to assess the possible influence of severe HIV infection on the accuracy of the diagnostic biosignatures. For the biosignatures described in the current study to be useful in the management of children with suspected TBM, the biosignatures would require incorporation into a point-of-care or bedside diagnostic test platform, for example, based on the lateral flow technology. Such prototype blood-based TB tests have been developed and successfully investigated in multiple African countries [13, 14], with multibiomarker finger prick-based formats currently under the development for the diagnosis of adult pulmonary TB disease (http://www.screen-tb.eu). Incorporation of host inflammatory biomarkers into such a platform may be relatively easier and faster as lessons learned during the development of adult pulmonary TB tests will be beneficial.
In conclusion, we validated a previously established 3-marker CSF biosignature as a tool for the adjunctive diagnosis of TBM in children and furthermore showed that modification of this signature through the substitution of two of the proteins with new protein biomarkers results in a strong biosignature for the diagnosis of the disease. These biosignatures will only be beneficial for people who would benefit from the urgently required new tools (children with suspected TBM, parents) if these signatures are further validated in other geographical areas and are developed in point-of-care or bedside diagnostic tests. Our study therefore paves the way for the development of such a prototype test.
|Cerebrospinal fluid
|Chemokine (C-C motif) ligand 1, also abbreviated as I-309
|Chemokine (C-C motif) ligand 2, also known as monocyte chemoattractant protein- (MCP-) 1
|Chemokine (C-C motif) ligand 3, also known as macrophage inflammatory protein- (MIP-) 1α
|Chemokine (C-C motif) ligand 4, also known as macrophage inflammatory protein- (MIP-) 1β
|Chemokine (C-C motif) ligand 5, also known as regulated upon activation, normally T-expressed, and presumably secreted (RANTES)
|Chemokine (C-C motif) ligand 18, also known as macrophage inflammatory protein- (MIP-) 4
|Cluster of differentiation 40 ligand
|C-X-C motif chemokine ligand 8, also known as interleukin-8
|C-X-C motif chemokine ligand 9, also known as monokine induced by interferon gamma (MIG)
|C-X-C motif chemokine ligand 10, also known as interferon gamma inducible protein 10 (IP-10)
|Granulocyte colony-stimulating factor
|Granulocyte-macrophage colony-stimulating factor
|Interferon gamma
|Matrix metalloproteinase
|Transforming growth factor
|Tumour necrosis factor
|Soluble neural cell adhesion molecule-1, also known as cluster of differentiation 56 (CD56)
|Apolipoprotein, e.g., Apo-CIII (apolipoprotein CIII)
|Complement component C3
|Complement factor H
|Brain-derived neurotrophic factor
|Soluble intracellular adhesion molecule
|Platelet-derived growth factor
|Soluble vascular adhesion molecule
|Plasminogen activator inhibitor-1
|S100 calcium-binding protein B
|Amyloid beta 1-40
|Soluble receptor for advanced glycation end products
|Glial cell-derived neurotrophic factor
|C-reactive protein
|Pigment epithelium-derived factor
|Serum amyloid P
|Complement factor D, also known as adipsin
|Mannose-binding lectin
|Complement factor 1
|von Willebrand factor-cleaving protease
|Growth differentiation factor
|Neutrophil gelatinase-associated lipocalin, also known as lipocalin 2
|Serum amyloid A
|General discriminant analysis
|Area under the curve.
Data Availability
The Luminex and ELISA data used to support the findings of this study are available from the corresponding author upon request.
The funders played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. An earlier version of this work was presented at the Ninth EDCTP forum, 2018, and at the 49th Union World Conference on Lung Health, 2018.
Conflicts of Interest
NNC, CMM, GW, and RSS are listed as inventors on a South African Provisional Patent Application No. 2018/03410, entitled "Cerebrospinal fluid (CSF) and blood based biomarkers for diagnosing tuberculous meningitis." NNC and GW are listed as inventors on another patent application (PCT/IB2015/052751) entitled "Method for diagnosing tuberculous meningitis." These applications are pending.
Authors' Contributions
Charles M. Manyelo and Regan S. Solomons contributed equally to this work.
This study was funded by the South African Government through the Technology Innovation Agency (TIA, to NNC), the South African Research Chairs Initiative (SARChi) in TB Biomarkers (#86535, to GW), the National Research Foundation (#109437 to RSS), and also the International Collaborations in Infectious Disease Research (ICIDR): Biology and Biosignatures of Anti-TB Treatment Response (#5U01IA115619, to GW). We are grateful to all our study participants and support staff for their contribution to this study.
Supplementary Materials
Supplementary Table 1: detailed clinical and demographic characteristics, CSF laboratory measurements, and neurological findings in children with and without TBM. TBM = tuberculous meningitis, CSF = cerebrospinal fluid, TB = tuberculosis, BCG = Bacille Calmette-Guerin, PCR = polymerase chain reaction, IQR = interquartile range. Three of the children in the no TBM group yielded TB-positive culture results from gastric washings. This is a common finding in children with pulmonary TB but without TB meningitis in our high burden setting. Supplementary Table 2: utility of host biomarkers detectable in CSF samples from children with suspected meningitis in the diagnosis of TB meningitis. Median levels (interquartile ranges in parentheses) of all host markers and accuracies in the diagnosis of TBM as determined by ROC curve analysis are shown. Cut-off values and associated sensitivities and specificities were selected based on Youden's index. #Values shown are in ng/ml, and all other analytes are in pg/ml. Values shown are absorbance and not concentration values. (Supplementary Materials)
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Sometimes a musical blast from the past is so exhilarating, I feel moved to share my enthusiasm; such has been the case, in the last few years, with releases or re-releases of works by major jazz figures like John Coltrane, Charlie Haden, Paul Bley, Graham Collier and Mike Westbrook. So I've been delighted by the … Continue reading Just in Time for Christmas: Some Great Jazz Revisited
Behind the Beautiful Mask: Paul Newman on Paul Newman
I've never been very interested in reading autobiographies by movie stars; wrongly or rightly, I've had the impression that they often have a tendency towards mythomania. But recently I was asked if I'd like a review copy of Paul Newman: The Extraordinary Life of an Ordinary Man – A Memoir, and since I'd seen a fellow … Continue reading Behind the Beautiful Mask: Paul Newman on Paul Newman
Maidan: A Musical Prayer for Ukraine
In mid-March of this year, I attended a concert by the pianist Boris Giltburg. Came the time to announce his encore: a lovely Bagatelle by the great if sadly too-little known Ukrainian composer Valentin Silvestrov, who at the age of 84 had just a week earlier been whisked out of his homeland and taken, via … Continue reading Maidan: A Musical Prayer for Ukraine
Giving Voice: Heiner Goebbels' 'A House of Call'
There have been quite a few extremely rewarding 'classical' releases on CD in recent weeks, ranging from Robert Levin's seven-disc set of the complete Mozart piano sonatas performed on the composer's very own fortepiano (ECM), through Igor Levit's selection of pieces by Liszt, Wagner, Mahler and Henze on Tristan (Sony) and Christian Immler and Andreas … Continue reading Giving Voice: Heiner Goebbels' 'A House of Call'
Here comes some sun: the music of Enrico Rava
Last month saw the 83rd birthday of the great Italian trumpeter Enrco Rava. You'd think that he might have slowed down a little, but apparently not. Checking the ECM website, I just saw that he has nine gigs in Italy coming up over the next couple of months; what's more, this week he has a … Continue reading Here comes some sun: the music of Enrico Rava
Ripe for (re)discovery: marvellous artist Milton Avery
It's not often that I write about the visual arts, mainly, I suppose, because I suspect that most of you reading my posts know at least as much as I do about the subject, maybe more. But just occasionally, as happened with the Swiss painter Félix Vallotton or the Malian photographer Malick Sidibé, I come … Continue reading Ripe for (re)discovery: marvellous artist Milton Avery
Back to Bach, Beethoven and others: recent classical releases
There is, of course, no such thing as a greatest piece of music, any more than there might be a greatest movie, novel, painting or whatever. But we all have our favourites – though mine, it must be said, are constantly changing – and as far as classical music goes, one of my most frequent … Continue reading Back to Bach, Beethoven and others: recent classical releases
But Is It Jazz? (Five recent examples of suite sounds.)
I haven't written much recently about jazz, for many reasons, one of which was the illness and passing of David Fraser, a music publicist – also, in time, a friend – who introduced me to a great deal of marvellous music (and not just jazz). David's speciality, as far as I was concerned, was ECM … Continue reading But Is It Jazz? (Five recent examples of suite sounds.)
Revisiting Hollywood's last golden age: my part in a new publication
Over the decades the two questions I've been asked most, as critic and programmer, have been what my favourite film is and what made me want to work in film. To the first, after explaining that I don't have a single favourite film, I used to reply L'Atalante, but that often met with blank looks, … Continue reading Revisiting Hollywood's last golden age: my part in a new publication
Best of another bad year: movies, music and other highlights of 2021.
For the list of my best (ie favourite) films, music, books, etc two years ago, I noted the importance of taking solace from the arts at a time when Brexit, Johnson, Trump, climate change and others were cause for such anxiety, anger and despondency. Last year, of course, with Covid having taken its toll, we'd … Continue reading Best of another bad year: movies, music and other highlights of 2021.

subset: commoncrawl


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We are facing a climate emergency. As the world wakes up to the catastrophic implications of climate change, it falls to national, state and especially municipal governments to take practical steps to prepare for the impacts.
But even the greenest cities are facing a grim reality. No matter what national governments and businesses do to reduce carbon emissions, massive climate disruption is unavoidable in the short to medium term. While firmly committed to decarbonizing, growing numbers of city leaders recognize some climate change is inevitable and they must be prepared to manage it. Some are actively exploring ways to design-in resilience, including redesigning, repurposing and retrofitting the built environment. While some cities are taking heroic steps to curb emissions and adapt their cities, it's time they also start preparing for Plan B.
Preparing for Plan B is about adapting a mindset focused on smart, achievable and future-looking adjustments at the local level. We call this the cellular city. A cellular mindset involves hyper-localizing resilience and investing in self-sufficiency and adaptive regeneration. Cellular thinking requires every law, tax, zoning act, procurement policy, new building or purchasing decision to be embedded with local self-sufficiency, adaptability and resilience top of mind.
Building the cellular city means investing in, but moving beyond, mitigation and adaptation. It means acknowledging the "climate emergency" is a global reality, not a remote possibility. It requires seeing climate change as an opportunity for upgrading, retrofitting and re-purposing the urban landscape for a sustainable future. It will involve making investments in public and private buildings, so they are not only green and efficient, but also autonomous and self-sufficient.
The smartest cities are who invest in and subsidizing smarter public transport, electric vehicles, renewable energy plants and industrial symbiosis to promote a more circular economy, offering ideas on how to localize resilience and regenerative capacities at a granular scale.
While we must do everything we can to prevent climate change from spinning out of control, the cities that will weather the coming storm – will be cellular.


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P200 CRO HEART 2022 autumn and winter new! The official website is on sale simultaneously. The brand's classic LOGO casual pants, customized fabric, excellent comfort, strong hand touch. Highly recognizable, perfect appearance and craftsmanship. Size: M-3XL
Where to buy fakes Chrome Hearts Clothing Pants? Topreplicaluxury.ru Shop the Best High Authentic Quality Replica.Free worldwide shipping.


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Water, water all the time even in fall and winter
Water is critical to plant survival all year long. This week Hank Musso has investigated the methods for getting moisture to plants through the fall and winter.
Dry air and low soil moisture are characteristic of many areas of Colorado in fall and winter. During extended periods of dry weather, particularly October through February when the snow cover is sparse, trees, shrubs, and lawn grasses can be damaged if they do not receive supplemental water.
These dry periods can contribute to the injury and death of plant root systems. The affected plants may appear perfectly normal and resume growth in the spring by using stored energy, only to weaken and die in late spring or early summer when all the energy is consumed. The weakened plants are also susceptible to insect and disease problems.
Most woody plants with shallow root systems are affected by these dry periods. Included are shade trees such as European white birch, Norway or soft (or silver) maples and linden (basswood), and such evergreens as Colorado blue spruce.
Evergreen shn bs, particularly those growing near buildings, will be affected. Included are pfitzer and "Tammy" junipers, Manhattan euonymus and Oregon grape holly.
Lawn grasses are also prone to winter damage. Newly established lawns, whether seeded or sodded, are especially vulnerable; vulnerability increases with lawns which have southern or western exposure.
In most years, one or two waterings in late fall and early winter will suffice to protectsyegetation. The most important time to water is in the fall before sub-zero weather begins. Lawns should be watered when air temperatures are above freezing and the soil is not frozen. Apply water early in the day so it will have time to soak in before freezing occurs at night. If water freezes around the base of a tree or shrub it can cause physical damage to the bark. Heavy coatings of ice on turf grass can cause it to mat and suffocate.
A soil needle (root feeder) attachment for the garden hose is recommended for applying water to newly planted trees and all shrubs. These attachments are available in garden supply stores.
The depth at which the water is applied will depend on the type of plant. For most junipers, about 24 inches is adequate. On shallow rooted trees such as linden, maple, and birch, 12 to 18 inches will suffice. If a portion of the root system is beneath a sidewalk or other ground cover the soil needle can be slanted to reach these areas. If the soil needle is used in a zigzag pattern around the plant all parts should receive adequate moisture. In heavy clay soils it is important that the soil needle not be left in the ground over a minute or so in any one spot. The needle should be inserted frequently in spots 6 to 8 inches apart. Slant the needle away from the plant.
This procedure will help avoid overwatering and also increase the aeration of the root system. In sandy soil the needle should also be moved frequently or the water will be wasted and valuable minerals and nutrients may be leached below the root zone. When watering newly planted trees and shrubs the most important area to water is the area from a point halfway between the trunk and the outer stretch of the branches to approximately 1 foot beyond the "drip line" or branch extension; the majority of moisture absorbing roots are in this area.
Established trees (two or more years) should be watered with a lawn sprinkler to insure coverage of all the root areas. Tree roots extend radially as far as the tree is tall. For shallow rooted trees a sufficient amount of water can be applied with sprinklers.
More information on fall and winter watering can be obtained by contacting the Colorado State University Cooperative Extension Service and asking for Service in Action Sheet No. 7.211.
Frank Sobolik is the Pueblo County Extension director.


text: Division I Men's Basketball Coaches A total of up to 1,600 prospective student-athletes including seniors (2021) and juniors (2022), as well as sophomores (2023), will be chosen for the academy. Up to 400 participants will be assigned to each region with up to 200 attending Session I on July 20-23 (Monday-Thursday) and up to 200 attending Session II on July 23-26 (Thursday-Sunday). This is the only other event DI coaches can attend during this week. Division I men's college basketball coaches will not be required to purchase coaching packets. All information about prospective student-athletes will be distributed electronically for free. Every prospective student-athlete who would like to attend the invitation-only academy MUST be registered with the NCAA Eligibility Center and MUST nominate himself for consideration, so please remind your prospective student-athletes to register AND nominate themselves. Division I men's college basketball coaches who are members of the National Association of Basketball Coaches will receive an email to send prospective student-athletes with instructions on how to nominate themselves for academy consideration. Division I men's basketball head coaches and select scouting agencies will vote for NCAA College Basketball Academy players beginning Monday, May 11. Voting will conclude at 5:00 p.m. Eastern time Friday, May 15. Coaches will only be able to vote for players in the class of 2021, 2022 and 2023 who are registered with the NCAA Eligibility Center and who have already nominated themselves for consideration to attend the NCAA College Basketball Academy. Division I men's basketball head coaches will designate automatic qualifiers and at-large players. Automatic qualifiers will receive an invitation to the academy while at-large players will receive consideration, but are not guaranteed an invitation to participate. After the voting window has concluded, selected players will be notified no later than 11:59 p.m. Eastern time Friday, May 22. All votes are confidential and will not be released to the public or prospective student-athletes. Coaches working the academy may be: Division II and Division III men's college basketball coaches. Boys basketball high school coaches. Former NBA players and coaches. Shop official NCAA team and championship gear Latest Video Features and Highlights


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Excerpt from Chojun—A Novel
December 31, 2012
Set in Okinawa during World War II, it's a story of reverence, the coming of age, love, tragedy, war, and honor. A retired Okinawa karate instructor, Ota Kenichi Ota, writes memoirs of training with world-famous master, Chojun Miyagi.
Tai Chi for Relaxation: Dealing with Stress
December 10, 2012
We are faced with many kinds of stress every single day. Modern life is fast-paced. The images we see in advertising and on TV are flashy and rapid-fire. The media and Internet blast millions of images before our eyes and minds every day. Prime-time television is cynical and obsessed with action, murder, and mayhem.
Yang Tai Chi for Beginners
January 29, 2012
Yang-style Tai Chi is the most popular form in the world, with millions of practitioners. Since the Yang family popularized Tai Chi during the 1800s, the form has been passed down from teacher to student in an oral tradition, resulting in a wide variety in the way the form is practiced.


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Amniotic Band Sequence
This full-term baby was born with malformations of the upper and lower extremities. The mother, a 21-year-old primigravida, had a normal spontaneous vaginal delivery and no prenatal or perinatal complications. A prenatal ultrasound examination at 32 weeks' gestation was reported as unremarkable.
The newborn physical examination findings included a stubbed left fifth finger with no distal interphalangeal joint, a right clubfoot with missing toes (except for a vestigial third toe), and a soft tissue nodule in place of the right ankle. The left lower leg appeared as if a rubber band had been tightly wrapped around it. The infant also had a large umbilical granuloma, an unrelated finding.
The deformities were attributed to amniotic band sequence, also known as amniotic band syndrome. This comprises a broad clinicalspectrum of congenital defects caused by amniotic bands that include disruptions, deformations, and malformations of developing structures.1 The estimated incidence ranges from 1:1234 to 1:15,000 live births. The condition affects both sexes equally. The pathogenesis, although not completely established, may be linked to early amniotic rupture and the release of loose strands that adhere to the fetus. This results in mechanical or vascular constriction of a limb or digits (eg, clubfoot), the body wall
(eg, thoracoschisis, gastroschisis), or the head (eg, facial cleft, encephalocele).2
The condition may be detected by prenatal ultrasonography. In most cases, the bands are not visualized by this method; however, the fetal abnormality is often evident.3 In utero treatment with fetoscopic laser transection of amniotic bands performed between 20 and 28 weeks' gestation has been attempted.3
This infant was referred to a pediatric orthopedic surgeon for evaluation and future surgical correction and treatment, if required for cosmetic reasons or
ambulation. A genetic evaluation for associated underlying disorders, including genetic diseases that may mimic amniotic band sequence (eg, Adams-Oliver syndrome, which has an autosomal dominant pattern of inheritance), was also recommended.


text: Hawaii News Rail funding, technology split mayoral candidates By Gordon Y.K. Pang email@example.com July 27, 2016 Mahalo for supporting Honolulu Star-Advertiser. Enjoy this free story! STAR-ADVERTISER Kirk Caldwell, left, Peter Carlisle and Charles Djou Mayor Kirk Caldwell, former U.S. Rep. Charles Djou and former Mayor Peter Carlisle criticized one another for their respective positions on rail but failed to provide specific plans of their own during a forum Tuesday sponsored by the Rotary Club of Honolulu. Read more Mahalo for reading the Honolulu Star-Advertiser! You're reading a premium story. Read the full story with our Print & Digital Subscription. Subscribe Now Read this story for free: Watch an ad or complete a survey Log In Already a subscriber? Log in now to continue reading this story. Activate Digital Account Print subscriber but without online access? Activate your Digital Account now. Mayor Kirk Caldwell, former U.S. Rep. Charles Djou and former Mayor Peter Carlisle criticized one another for their respective positions on rail but failed to provide specific plans of their own during a forum Tuesday sponsored by the Rotary Club of Honolulu. The major takeaways from the forum, held at the Japanese Cultural Center of Honolulu's Manoa Grand Ballroom: >> All three candidates want the rail project to span the entire 20-mile route to Ala Moana, and are willing to try to tap federal transit dollars and the private sector for necessary funding. >> While experts now say the $6.8 billion in projected revenues will not be enough cash under current funding mechanisms to get the rail project past Middle Street, all three agree they do not want to raise property taxes to pay for construction to Ala Moana, but offered no real plans to pay for it. >> Djou differs from Caldwell and Carlisle in that he vowed not to seek an extension of Oahu's existing 0.5 percent surcharge on the general excise tax to pay for rail to get to Ala Moana, and appears more willing to go back to the drawing board for the Middle Street-to-Ala Moana segment. The other two candidates would prefer to see the steel-on-steel technology continue. Carlisle said, "It would be absolutely nonsensical under any circumstances to stop what was promised, which was from Ala Moana back to Kapolei, and Kapolei to Ala Moana." The former mayor said he would seek federal dollars to cover the shortfall. Djou maintains that the project should be modified to match financial realities. "We have to be open to any alternative here to change our mass-transit objectives to get people from the west side all the way not to Ala Moana, but to (the University of Hawaii)," Djou said. "But we have to do it within reason and with a budget we can afford." The city should "stay the course" with the current technology, which has been proven reliable elsewhere, Caldwell said. Changing the technology now, he said, would require a new environmental impact statement and a new route, and could pose legal challenges — changes that could set back the project another 10 years and cost an unknown amount of money. "We have the trains, we have the rail line in place," Caldwell said. Djou said he supports the idea of having the project run at ground level from Middle Street to Ala Moana. "We need to look at changing the route and the system. If we don't, this system will consume us. I am fully supportive of looking at any reasonable alternative here that can achieve our transit objectives without breaking the bank." Carlisle said an at-ground line would "invite … suicides, interactions with cars, and splits downtown Honolulu right in half with an impenetrable barrier." He added, "Putting this thing on the ground is a disaster." While above the ground is expensive, "we have a way to pay for it," Caldwell said. "If it's on the ground, it can't go any faster than the fastest car or bus." Djou said Caldwell's plan to take Middle Street "and then figure out the rest after the election isn't accountable. It's not working." The mayor said Djou has yet to pinpoint a plan to extend the project to Ala Moana. "That is not being honest with all of you," Caldwell said, nodding to the audience. "How is he going to fix it, and where is the money coming from to do so?" After the forum Carlisle said, "We need to look at every possible (funding) source" to get rail to Ala Moana except raising property taxes. He said he would support an extension of the excise tax surcharge because "we've already got it going." Caldwell said he is the only one who has a solution for additional funding. "There are multiple sources, and one is talking to the federal government," he said. "They've said, 'No, not right now.' They said, 'Until the election is finished, we can't make that commitment because there will be a new administration (in the White House).'" Caldwell is also hoping that developers and landowners along the rail line will either build rail stations or provide financing to the city. Djou said it's Caldwell who "has no clue … and has no plan whatsoever" to fund the rail to Ala Moana. "I think the realistic solution to do that is to look at putting the system on the ground, including looking at perhaps … light rail or … bus rapid transit." The mayor's race has drawn eight other candidates, none of whom have held elected office or have as high a profile as Caldwell, Carlisle or Djou. The primary election is Aug. 13, although absentee mail-in ballots have started being delivered to Oahu voters. A candidate from the field of 10 getting 50 percent of the votes cast plus one vote would be declared the winner. Otherwise, the top two candidates will face off in conjunction with the Nov. 8 general election. Previous Story Casting director put local extras on the screen Next Story City's 2-month arts festival will be held every other year


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The design of world-class libraries
Scandinavian architect Morten Schmidt discusses how contemporary design can transform modern libraries into social hubs.
History & politics52Collection insights43Exhibitions36Australian history32Artists & writers30art26Family History Feast25Popular culture18art & design18Culture17world of the book16printmaking15literature14WWI14illustration13Family history13war13architecture13military13Big ideas under the dome12world of the book12State Library Victoria12performance12children's books11family history feast11Rome: Piranesi's vision11Australian history11Giovanni Battista Piranesi11books11rare books9History of the book8creative fellows8Writing the war7human rights7creative fellows7Victorian history7family history7music7literature6cultural history6Library collections6digital technology6library fellowships6fellowships6Poetry Slam6artists' books6Foxcroft Lecture6library6education6social justice5Stephen Murray-Smith Memorial Lecture5poetry5Exhibition talks & tours5Melbourne5WWII5performance4poetry slam4library fellowships4one object many stories4indigenous people4culture4author in conversation4foxcroft lecture4Library collections4history4Redmond Barry lecture4author in conversation4journalism4Redmond Barry Lecture4artists and writers4Multicultural history4youth literature3White Night3culinary history3persian manuscripts3Don Grant Lecture3collections3gender issues3Gusto!3history of the book3Ned Kelly3Environment3genealogy3victorian history3Artists' books3food3velvet iron ashes3storytelling3Making Public Histories3exhibitions3literacy3Collection insights3music2library fellows2web2velvet iron ashes2pop culture2State Library of Victoria2Indigenous people2foreign policy2interior design2health2victoria gallery2books2family history records2diaries and manuscripts2social justice2national security2graphic design2sport2Journalism2popular culture2australian literature2India2Gallipoli2Exhibitions & tours2fellowship2world war one2victoria gallery2Fromelles2rare books2spoken word2Indigenous Australians2food2design2art2Law2book printing2Ned Kelly2
Scandinavian architect Morten Schmidt discusses how contemporary design can transform modern libraries into social hubs.
Colin Holden describes the aristocrats and Grand Tourists in Piranesi's print from Vedute di Roma.
Colin Holden reveals why Piranesi included ground staff amongst the well-to-do visitors in this print.
Colin Holden highlights details from everyday life in this print from Piranesi's Vedute di Roma.
Colin Holden discusses how the ruined villa in this print by Piranesi represents the folly of unrestrained power.
Colin Holden provides insights into the activities of the people portrayed in this Piranesi print.
Colin Holden points out the visitors Piranesi brings to life in his print of this pilgrimage church.
Colin Holden contrasts the Grand Tourists and beggars seen in this print by Piranesi.
Colin Holden explains how Piranesi's exaggerated scale celebrates the ancient Romans' engineering work.


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Day's Until 'We do' Valentine's Card
Personalised Valentine's Card, personalised with the number of days until you say 'I do!'!
Add your wedding date in the box and we will do the calculation for you and add it to the card. The date will be calculated from Valentine's Day, please email us if you'd require a different calculation on firstname.lastname@example.com.
Blank inside.
Supplied with complimenting envelope and presented in a clear cellophane bag.
Please note the colours you see on your monitor may vary slightly to the printed card.
Design copyright Emma Maddocks all rights reserved.
made from:
300gsm uncoated, textured card stock.
Luxury brown kraft envelope.
Hand-cut and folded.
A6 (10.5cm x 14.8cm)
Customer Reviews
Would recommend anyone to order
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Was really quick to arrive and great quality design - perfect!
Beautiful card, great quality.
I bought this for my fiancé for valentines and I was very pleased with it! Beautifully made, the quality of the card is really good too and the card arrived in plenty of time! Thank you very much!
'Day's Until 'We do' Valentine's Card


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WORK: "Don't Forget About Me (Keri)." 2009
Working with paintings, photography and collage, Thomas explores notions of Black beauty and female representation in popular culture. The New York Times called her work "a mix of rhinestones, acrylic and attitude." "Her brash, larger-than-life paintings of great-looking black women in florid 1970s-style interiors rough up the history of painting while pushing buttons regarding class, taste, race and gender," said one reviewer.
Find out more about Mickalene Thomas, here.
WORK: "Riffs on Real Time."
Hewitt, 33, is a photographer and sculptor born in New York City. Her dense still life arrangements combine personal family artifacts and place them within a historical context. New York Magazine declared her one it's "influentials."
Find out more about Leslie Hewitt, here.
WORK: "Untitled." 2003
Kenyan-born artist Wangechi Mutu often uses painting and collage to explore female sexuality and the myths surrounding African women as "wild and exotic." "Divine and decadent" is how Time Out New York describes the new mom's luscious work.
Find out more about Wangechi Mutu, here.
WORK: "Untitled." 2009
Former Ford assembly worker, Abney, 28, often pairs politics with celebrity news and scandal in her bold paintings. "I'm fascinated by how celebrity news has become not more interesting, but more important than politics," she told W Magazine.
Find out more about Nina Chanel Abney, here.
WORK: "Slavery, Slavery." 1997
Artist Kara Walker creates silhouettes dealing with America's dirtiest history: slavery. Renowned art critic Jerry Saltz described Walker's larger-than-life depictions of antebellum slavery—some towering as high as 50-feet—as "bitterly beautiful."
Find out more about Kara Walker, here.
WORK: "One Day and Back Then (Standing)." 2007
Multimedia artist Xaviera Simmons often combines performance, video and photography to examine assumed notions surrounding African American identities. "Xaviera Simmons' work challenges existing ideas regarding history, community and art by allowing viewers and artists to participate in the environments she creates," Micheal E. Shapiro, director of the High Museum in Atlanta, said of the artist's work.
WORK: "Black Leather Lace-Up." 2001
Jamaican-born mixed-media artist Renee Cox examines Black female sexuality and politics, often using her own body as subject. Her interpretation of the Last Supper—in which she appeared naked, standing in for Jesus Christ with only Black disciples—caused an uproar among Catholics. "The hoopla and the fury are because I'm a Black female," she responded. "It's about me having nothing to hide."
Find out more about Renee Cox, here.
WORK: "Queen Bee." 2008
Brooklyn-based artist Simone Leigh works with ceramics to create oversized installations that examine issues surrounding race, gender and culture. Here she uses terra cotta, porcelain and graphite to create a stunning chandelier-like object.
Find out more about Simone Leigh, here.
Multi-media artist Kenya Robinson's recent exhibition "HAIRPOLITIC: The Pursuit of Nappiness" addressed the unwritten rules and politics of culture and how they affect what we consider beautiful.
Read Kenya's musings on her blog, Workspace.
WORK: "Crone-Huntress." 2007
Baltimore native Shinique Smith uses second-hand clothing and other found materials to create towering sculptures, for which she is best known for. Her work has been exhibited at the New Museum and the Studio Museum in Harlem, among others.
Find out more about Shinique Smith, here.


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"Life's Good" is the famous slogan of global innovator LG Electronics, and creating a better life for its customers is the foundation for LG's activities in the U.S. and around the world.
Maintaining an efficient supply chain is a huge part of delivering on their promise of customer value. This means creating and designing products that make people's lives easier, but it also means ensuring that those products—everything from home appliances and consumer electronics to solar panels and automotive components for electric vehicles—are delivered quickly and correctly.
"Making sure that our freight is moving correctly, on time, and at the right price is getting more complex everyday," said Paul Heffernan, LG's U.S. Vice President of Supply Chain, who was looking for ways to continue innovating, this time within their logistics processes.
LG partnered with Uber Freight to help streamline their operations, and now, Uber Freight is a top carrier for LG. Specifically, Powerloop, an Uber Freight affiliate, has enabled LG to increase driver favorability in a tight market and keep up with consumer demand during busy seasons.
"One of the biggest pain points over the past few years in the transportation market has been tight capacity," said Jeung Choi, LG's U.S. Logistics and Transportation Manager. Because the market wasn't favorable to shippers, LG searched for ways to transform operations to prioritize carriers and their drivers and make LG a shipper of choice. The first place ripe for change: facilities.
With Powerloop, a scaled-trailer pool system, LG could pre-load trailers at night. In the morning, drivers could show up, hook up, and get right back on the road, cutting loading and waiting times dramatically, and streamlining the process for facility managers, and the carriers and drivers they depended on.
LG also leveraged Uber Freight's shipper platform to book and manage loads seamlessly and gain valuable insight into their fragmented and complex supply chains. Facility insights allows LG to see ratings and reviews of their facilities from drivers who have just picked up or dropped off a load. This actionable feedback gives LG the information they need to make meaningful improvements to facilities around the country.
Like most consumer companies, the holidays are a busy time for LG. Denis Marion, LG's U.S. Director of Logistics Operations, reflected on the surging demand during last year's Black Friday. "We were asking ourselves: How do we make our logistics smoother? Better? Uber Freight and Powerloop were the perfect introductions."
Uber Freight worked with LG to optimize their entire freight operations process in a way that was both tailored to meet their current needs, and scalable to meet holiday demands. Uber Freight offers 24/7 capacity, unprecedented visibility into their supply chain, and the guarantee that each shipment will be managed effectively.
"As a result, we were able to plan ahead, optimize our annual spend, and improve our relationships with our customers," said Choi.
To see how you can bring innovation to your supply chain, learn more about shipping with Uber Freight.
Trailer rentals are provided by Powerloop LLC, which is an equipment rental company. Powerloop LLC is an affiliate of Uber Freight LLC.
With instant quotes, real-time tracking, and 24/7 access to trusted carriers, Uber helps streamline your operations.
With upfront pricing, instant booking, free Quickpay, and facility ratings, Uber Freight puts you in the driver's seat.


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Girl's Cowgirl Hardware Daisy w/ Cacti Pink w/ Black 3/4 Sleeve Raglan Tee
The contrast sleeves with the body is a perfect combination for this mixed daisy with cacti tee. The material is flowy and comfortable for all day wear. Tagless back for an even more comfortable fit.
Fabric Content: 95% rayon 5% spandex
Style: 455119-010-K


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Leaking roof, damaged walls, and updating electrical and plumbing can add up to tens of thousands of dollars and months of repairs not including if you are trying to sell a mobile home on property as big as an acre or more, the property clean up can be very time consuming, just to sell the home with a realtor, still take many months to find a buyer that is ready to commit to the purchase.
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We not only buy houses, We buy mobile home parks and looking to pay cash for mobile homes on land in Bridgeport TX, Decatur TX, Lake Bridgeport TX, New Fairview TX, Newark TX, Paradise TX, Rhome TX, Runaway Bay TX, Alvoid TX, Boyd TX, Chico TX, Briar TX, Pecan Acres TX.Get A No-Obligation Offer
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Houses can be even harder to sell the older they are because they usually need the most repairs and updating, if you are looking for someone that is able to buy your house now, we buy houses of any age and do the repairs needed to bring new life to the older homes.


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Jim Haynes' not-so-famous Aussie characters
This week Jim shines the spotlight on Mei Quong Tart – Mandarin Of The Fifth Degree With A Scottish accent.
Mei Quong Tart (1850–26 July 1903) was a prominent nineteenth century Sydney merchant from China and one of Sydney's most famous and well-loved personalities.
He made a significant impact on the social and political scene of Sydney at a time of strong anti-Chinese sentiment in Australia.
Download this podcast here


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Richters Herbs German Chamomile Natural Seeds Packet
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This variety is the most prolific producer of flowers; the flowers can be harvested and mixed into a sedating and soothing tea. Chamomile is known to ease insomnia, depression, headaches, and anxiety. A strong, cooled, chamomile tea can be washed through your hair to lighten and highlight blonde locks. If left to seed, this annual will re-seed itself into the soil, and you will have abundant growth again the following year. Blooms mid-summer; harvest young flowers the day they open. Sow in full sun. Ht 6-12in; spacing 6-9in.


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Luke Hemmings said that he wouldn't have previously come out to reveal things about his personal life, but after being in the industry for so long he has learnt a few things. He credited Arzaylea for bringing in a positive change in him. This might not be something that the fans would readily agree with.
Arzaylea had been responsible for reducing the followers of the band on social media and she earnestly apologized to them all. She said that she had no intention of hurting any of them and had been sharing photos and posts because is genuinely happy.
She said that she doesn't want to ever come in between the fans and 5 Seconds of Summer and hoped that the fans would be able to forgive her.
There were rumors that Luke Hemmings and Arzaylea had broken up in the middle when she shared a Snapchat with another guy with tattoos and Luke Hemmings was spotted having dinner with Hailey Baldwin. However, they all proved to be rumors and the couple is still very much together.
Leave a comment and share your thoughts on Arzaylea.


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- Internet Basics
- Home
- Internet Overview
- Intranet Overview
- Extranet Overview
- Internet reference Models
- Internet Domain Name System
- Internet Services
- Internet Connectivity
- Internet Protocols
- Electronic Mail Basics
- E-Mail Overview
- E-Mail Protocols
- E-Mail Working
- E-Mail Operations
- E-mail Features
- E-Mail Etiquettes
- E-mail Security
- E-mail Providers
- Website Development
- Websites Overview
- Websites Types
- Website Designing
- Websites Development
- Website Publishing
- Website URL Registration
- Website Hosting
- Website Security
- Search Engine Optimization
- Website Monetization
- World Wide Web
- WWW Overview
- Web Pages
- Web Browsers
- Web Servers
- Proxy Servers
- Search Engines
- Internet Collaboration
- Collaboration Overview
- Mailing List
- Usenet Newsgroup
- Online Education
- Social Networking
- Internet Security and Privacy
- Internet Security Overview
- Data Encryption
- Digital Signature
- Firewall Security
- Internet Web Programming
- JavaScript
- Internet Useful Resources
- Internet Quick Guide
- Internet Useful Resources
- Internet Discussion
- Selected Reading
- UPSC IAS Exams Notes
- Developer's Best Practices
- Questions and Answers
- Effective Resume Writing
- HR Interview Questions
- Computer Glossary
- Who is Who
Social Networking
Beginners Masterclass into Internet of Things
61 Lectures 8 hours
Digital Citizenship and Internet Maturity - Basics
13 Lectures 2.5 hours
Internet and Web Development Fundamentals
62 Lectures 3.5 hours
Social Networking refers to grouping of individuals and organizations together via some medium, in order to share thoughts, interests, and activities.
There are several web based social network services are available such as facebook, twitter, linkedin, Google+ etc. which offer easy to use and interactive interface to connect with people with in the country an overseas as well. There are also several mobile based social networking services in for of apps such as Whatsapp, hike, Line etc.
Available Social networking Services
The following table describes some of the famous social networking services provided over web and mobile:
|Service Description
Allows to share text, photos, video etc. It also offers interesting online games.
It is pronounced as Google Plus. It is owned and operated by Google.
Twitter allows the user to send and reply messages in form of tweets. These tweets are the small messages, generally include 140+ characters.
Faceparty is a UK based social networking site. It allows the users to create profiles and interact with each other using forums messages.
Linkedin is a business and professional networking site.
Flickr offers image hosting and video hosting.
Ibibo is a talent based social networking site. It allows the users to promote one's self and also discover new talent.
It is a mobile based messaging app. It allows to send text, video, and audio messages
It is same as whatsapp. Allows to make free calls and messages.
It is also mobile based messager allows to send messages and exciting emoticons.
Where Social Networking Helps
Following are the areas where social networking has become most popular:
Online Marketing
Website like facebook allows us to create a page for specific product, community or firm and promiting over the web.
Online Jobs
Website like linkedin allows us to create connection with professionals and helps to find the suitable job based on one's specific skills set.
Online News
On social networking sites, people also post daily news which helps us to keep us updated.
Social networking allows us to keep in contact with friends and family. We can communicate with them via messages.
Share Picture, Audio and video
One can share picture, audio and video using social networking sites.


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Salam. I've concern over kid buddies? Can it be fine to have buddies that are guys and also you understand with you or take your guys friendship over the line that they won't do anything? Or should we Muslim girls do not have close buddies that are guys?
Alaikumassalam wa rahmatullah,
There are not any texts into the Quran as well as the Sunnah that apply precisely to presenting "friends" of the sex that is opposite. Theoretically getting together with and speaking with folks of the alternative sex just isn't forbidden, and there's absolutely absolutely nothing wrong with having expert relationships with individuals associated with the opposite gender, or having acquaintances associated with sex that is opposite.
When befriending an individual regarding the sex that is opposite you will find always two facets in play.
We should connect as fellow humans and to enjoy their companionship with them soul-to-soul, to know them. But we likewise have our brains' hereditary instincts then will get inside our fight and way against us. Its impractical to just take away the brain's awareness that people are coping with an individual regarding the opposite gender, somebody who could possibly be our partner. Even when we make an effort to keep all things expert and platonic, even though we succeed in having an excellent relationship for months or years, our minds can invariably slip up making sure that we start to get romantically involved in them.
Whether a friendship using the sex that is opposite appropriate or perhaps not depends entirely from the amount of psychological reference to them. The more powerful the psychological connection, the greater improper the relationship becomes. The greater we are emotionally involved in a person associated with opposite gender, the greater amount of this may interfere with your lives. An extreme instance is a husband whose "best friend" is a female apart from their spouse. This relationship will without doubt interfere along with his relationship together with his spouse, making her feel left out, and making her feel there is certainly an other woman contending along with her on her husband's attention and sympathy.
It really is similarly improper for just two unmarried individuals of the sex that is opposite be close friends. The much much deeper their emotional connection, the greater amount of it will probably affect any partnership they gets associated with.
For a person, it's often super easy to slip up and simply take a conversation within an direction that is inappropriate. It really is really easy to joke with and complement the girl and ultimately the man's brain may turn to get into full "courtship" mode making sure that he starts to deal with the girl as being a intimate interest. A pious and self-aware guy may have good control over himself making sure that he constantly attempts to treat females as though they truly are their siblings (and also this is really what i usually attempt to do), but constantly there is the undeniable fact that their own brain's instincts are their enemy. It prompts him to take care of the ladies much more than simply friends, and this is one thing which he will will have to battle.
Another problem with befriending females for a person is he cannot get a handle on what exactly is into the minds of his female friends and exactly how they react to his relationship. They might maybe not have since much self-control as he does so they could become romantically attached with him.
Whenever coping with folks of the contrary intercourse, our minds are always completely conscious that this person is a spouse that is potential. Our brains may constantly prompt us to just take the discussion in a direction that is romantic to ensure we must utilize our souls to overcome our minds to help keep things appropriate.
Befriending an individual associated with sex that is opposite consequently dangerous.
It isn't forbidden in Islam, but then we are taking a risk if we engage in it. Often a person meets a lady whom like him has extremely good self-control and has zero curiosity about becoming romantically attached with him. They are able to develop a great and friendship that is beneficial. Nevertheless the more they connect to one another, as well as the closer they get emotionally, the greater amount of they chance letting things develop a lot of between them. So each of these need certainly to hopefully remain self-aware and ensure it is a training to read the Quran day-to-day or do other things that ensure they will have Jesus at heart.
The fatwas we have actually checked at either express platonic friendships are forbidden or strongly discouraged, as a result of the risks included. The truth is we don't have any such thing explicit in Islam to forbid such friendships. You can find endless colors of relationship between women and men. From the one end of this range you will find people who know one another expertly and share their work and passions with one another several times per year. Regarding the other end there are buddies of this sex that is opposite chat day-to-day and consider each other close friends. While absolutely nothing about this range is strictly forbidden, the potential risks get greater since the relationship gets to be more intimate. The camster. com 2 friends are doing something dangerous, as well as should truthfully and sincerely look within their hearts and determine if they're in a position to manage risk that is such. In the event that two buddies are mature and intelligent, if they keep an extremely close relationship with Jesus through things such as day-to-day Quran reading, they is going to be in a position to manage the danger.
Observe that spending some time in personal within the exact same space as a person of this contrary intercourse is forbidden in Islam. Above, i will be let's assume that the relationship is mainly maintained through such things as e-mail and social media marketing. It's best that friends regarding the opposite gender work to keep up some distance, such as for example by avoiding giving each other pictures, and avoiding speaking from the phone or doing video clip chats.
Just Jesus knows just exactly what amount of danger we're able to manage. The essential pious and thing that is admirable do would be to always strive to help keep friendships with individuals for the contrary intercourse under good control, such as for instance by avoiding interacting a lot of, and also by imagining our daddy, mom or partner is viewing the relationship.
In a world that is perfect could have had the opportunity to savor close friendships with individuals associated with the opposing intercourse and never have to bother about any such thing (as well as perhaps it's by doing this in Paradise, inshaAllah). However in this world that is imperfect we need to stay conscious of our limitations therefore we need certainly to work correctly.
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