The soluble interleukin 2 receptor (sIL-2R) has been proposed as a marker of disease activity in patients with sarcoidosis. However, no studies have evaluated whether serum sIL-2R measurement is of ...use in establishing the diagnosis of sarcoidosis in patients who are suspected of sarcoidosis among other diseases.
A cohort study was conducted, consisting of new patients who visited the immunology outpatient clinic and whose serum sIL-2R levels were available before a definitive diagnosis was established between February 2011 and February 2016. All patients underwent standard diagnostic testing for sarcoidosis (e.g. laboratory tests, radiographic and/or nuclear imaging and/or affected site biopsy). This resulted either in the diagnosis of sarcoidosis or the exclusion of sarcoidosis with the diagnosis of another disease. Results of sIL-2R and angiotensin-converting enzyme (ACE) levels, radiographic and nuclear imaging and histology results were collected and definitive diagnoses were recorded. Sensitivity, specificity, the concordance statistic from the receiver operating characteristic curve and Youden's Index were calculated to assess the performance of sIL-2R in the diagnosis of sarcoidosis and were compared to ACE, currently one of the most used diagnostic biomarkers in the diagnosis of sarcoidosis.
In total 983 patients were screened for inclusion, of which 189 patients met the inclusion criteria. A total of 101 patients were diagnosed with sarcoidosis after diagnostic workup, of whom 79 were biopsy-proven. In 88 patients a diagnosis other than sarcoidosis was made. The sensitivity and specificity of serum soluble interleukin 2 receptor levels to detect sarcoidosis were 88% and 85%. The sensitivity and specificity of ACE were 62% and 76%. Receiver operating characteristic curve analysis revealed that sIL-2R receptor is superior to ACE (p<0.0001).
Serum sIL-2R is a sensitive biomarker and superior to ACE in establishing the diagnosis of sarcoidosis and can be used to rule out sarcoidosis in patients suspected of sarcoidosis.
Industry 4.0 has revolutionized the use of physical and digital systems while playing a vital role in the digitalization of maintenance plans for physical assets in an optimal way. Road network ...conditions and timely maintenance plans are essential in the predictive maintenance (PdM) of a road. We developed a PdM-based approach that uses pre-trained deep learning models to recognize and detect the road crack types effectively and efficiently. We, in this work, explore the use of deep neural networks to classify roads based on the amount of deterioration. This is done by training the network to identify various types of cracks, corrugation, upheaval, potholes, and other types of road damage. Based on the amount and severity of the damage, we can determine the degradation percentage and have a PdM framework where we can identify the intensity of damage occurrence and, thus, prioritize the maintenance decisions. The inspection authorities and stakeholders can make maintenance decisions for certain types of damages using our deep learning-based road predictive maintenance framework. We evaluated our approach using precision, recall, F1-score, intersection-over-union, structural similarity index, and mean average precision measures, and found that our proposed framework achieved significant performance.
The etiology of Behçet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies ...(GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts.
We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published.
We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3.
We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases.
A novel object-based quality measure, which contains three distinct components that consider aspects of the structure (S), amplitude (A), and location (L) of the precipitation field in a prespecified ...domain (e.g., a river catchment) is introduced for the verification of quantitative precipitation forecasts (QPF). This quality measure is referred to as SAL. The amplitude component A measures the relative deviation of the domain-averaged QPF from observations. Positive values of A indicate an overestimation of total precipitation; negative values indicate an underestimation. For the components S and L, coherent precipitation objects are separately identified in the forecast and observations; however, no matching is performed of the objects in the two datasets. The location component L combines information about the displacement of the predicted (compared to the observed) precipitation field's center of mass and about the error in the weighted-average distance of the precipitation objects from the total field's center of mass. The structure component S is constructed in such a way that positive values occur if precipitation objects are too large and/or too flat, and negative values if the objects are too small and/or too peaked. Perfect QPFs are characterized by zero values for all components of SAL. Examples with both synthetic precipitation fields and real data are shown to illustrate the concept and characteristics of SAL. SAL is applied to 4 yr of daily accumulated QPFs from a global and finer-scale regional model for a German river catchment, and the SAL diagram is introduced as a compact means of visualizing the results. SAL reveals meaningful information about the systematic differences in the performance of the two models. While the median of the S component is close to zero for the regional model, it is strongly positive for the coarser-scale global model. Consideration is given to the strengths and limitations of the novel quality measure and to possible future applications, in particular, for the verification of QPFs from convection-resolving weather prediction models on short time scales. PUBLICATION ABSTRACT
Background
Mastocytosis is characterized by the accumulation of aberrant mast cells (MC). Patients suffering from mastocytosis suffer from a wide range of symptoms due to increased levels of MC ...mediators. It would therefore be of great benefit to inhibit MC mediator release. However, to date there are few drugs available that are known to effectively lower MC mediator levels. The evidence for the involvement of the janus kinase 2 (JAK2)—signal transducer and activation of transcription 5 (STAT5) signalling pathway in MC activation is slowly accumulating. Interference with the JAK2‐STAT5 pathway might inhibit MC mediator release. Ruxolitinib, a JAK1/JAK2 inhibitor, indeed decreases symptoms like pruritus and fatigue in patients with myeloproliferative neoplasms. Yet, detailed studies on how ruxolitinib affects human mast cell activity are lacking.
Objective
To investigate the effect of JAK1/2‐inhibition with ruxolitinib in the human mast cell lines LAD2 and HMC1.
Methods
LAD2 and HMC1 were stimulated with substance P, codeine or the calcium ionophore A23817. The effect of ruxolitinib on mast cell degranulation (via measurement of β‐hexosaminidase, histamine release and CD63 membrane expression) and IL‐6, IL‐13, MCP‐1 and TNF‐α production was investigated. The involvement of STAT5 activation was explored using the selective STAT5 inhibitor pimozide.
Results
Ruxolitinib effectively inhibited codeine‐ and substance P‐induced degranulation in a concentration‐dependent manner. Ruxolitinib also significantly inhibited the production of IL‐6, TNF‐α and MCP‐1 as induced by A23817 and substance P. Selective STAT5 inhibition with pimozide resulted in diminished degranulation and inhibition of cytokine production as induced by A23817 and substance P.
Conclusions & clinical relevance
This study demonstrates that the JAK1/JAK2 inhibitor ruxolitinib can inhibit MCactivity, possibly through prevention of STAT5 activation. This renders the JAK‐STAT pathway as an interesting target for therapy to release symptom burden in mastocytosis and many other MC mediator‐related diseases.
The 2017 International Union of Immunological Societies (IUIS) classification recognizes 3 hyper‐IgE syndromes (HIES), including the prototypic Job's syndrome (autosomal dominant STAT3‐loss of ...function) and autosomal recessive PGM3 and SPINK5 syndromes. Early diagnosis of PID can direct life‐saving or transformational interventions; however, it remains challenging owing to the rarity of these conditions. This can result in diagnostic delay and worsen prognosis. Within increasing access to “clinical‐exome” testing, clinicians need to be aware of the implication and rationale for genetic testing, including the benefits and limitations of current therapies. Extreme elevation of serum IgE has been associated with a growing number of PID syndromes including the novel CARD11 and ZNF341 deficiencies. Variable elevations in IgE are associated with defects in innate, humoral, cellular and combined immunodeficiency syndromes. Barrier compromise can closely phenocopy these conditions. The aim of this article was to update readers on recent developments at this important interface between allergy and immunodeficiency, highlighting key clinical scenarios which should draw attention to possible immunodeficiency associated with extreme elevation of IgE, and outline initial laboratory assessment and management.
Purpose
The vitreous proteome might provide an attractive gateway to discriminate between various uveitis aetiologies and gain novel insights into the underlying pathophysiological processes. Here, ...we investigated 180 vitreous proteins to discover novel biomarkers and broaden disease insights by comparing (1). primary vitreoretinal lymphoma ((P)VRL) versus other aetiologies, (2). sarcoid uveitis versus tuberculosis (TB)‐associated uveitis and (3). granulomatous (sarcoid and TB) uveitis versus other aetiologies.
Methods
Vitreous protein levels were determined by proximity extension assay in 47 patients with intraocular inflammation and a prestudy diagnosis (cohort 1; training) and 22 patients with a blinded diagnosis (cohort 2; validation). Differentially expressed proteins identified by t‐tests on cohort 1 were used to calculate Youden’s indices. Pathway and network analysis was performed by ingenuity pathway analysis. A random forest classifier was trained to predict the diagnosis of blinded patients.
Results
For (P)VRL stratification, the previously reported combined diagnostic value of IL‐10 and IL‐6 was confirmed. Additionally, CD70 was identified as potential novel marker for (P)VRL. However, the classifier trained on the entire cohort (cohort 1 and 2) relied primarily on the interleukin score for intraocular lymphoma diagnosis (ISOLD) or IL‐10/IL‐6 ratio and only showed a supportive role for CD70. Furthermore, sarcoid uveitis displayed increased levels of vitreous CCL17 as compared to TB‐associated uveitis.
Conclusion
We underline the previously reported value of the ISOLD and the IL‐10/IL‐6 ratio for (P)VRL identification and present CD70 as a potentially valuable target for (P)VRL stratification. Finally, we also show that increased CCL17 levels might help to distinguish sarcoid uveitis from TB‐associated uveitis.
Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the ...interleukin-1-receptor antagonist, with prominent involvement of skin and bone.
We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.
We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.
We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 ...gain-of-function variants leading to allergies in humans.
We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members.
Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines.
We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient’s father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood TH2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules.
A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions.
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