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Pediatrics in Review Sep 2023Children with intermittent fevers present to pediatricians and other primary care child health providers for evaluation. Most patients will have self-limited, benign... (Review)
Review
Children with intermittent fevers present to pediatricians and other primary care child health providers for evaluation. Most patients will have self-limited, benign infectious illnesses. However, the possibility of a periodic fever syndrome should be considered if febrile episodes become recurrent over an extended period and are associated with particular signs and symptoms during each attack. This review discusses the current conceptualization of autoinflammatory diseases with specific focus and detail on familial Mediterranean fever; tumor necrosis factor receptor-associated periodic syndrome; mevalonate kinase deficiency; NLRP3-associated autoinflammatory disease; and periodic fever, aphthous stomatitis, pharyngitis, and adenitis. The genetic mutations associated with these clinical entities are identified, along with the historical nomenclature that predates the current pathogenetic understanding of these diseases. The episodic signs and symptoms seen across these periodic fever syndromes can be overlapping, but there are some distinguishing features that can be useful, and these are described. The disease course and potential complications, particularly amyloidosis, which is a variable risk in these conditions and a potential source of significant morbidity and mortality, are addressed. Treatment strategies are outlined, highlighting the advances in therapy that have resulted from the advent of proinflammatory cytokine-targeting biological agents.
Topics: Child; Humans; Amyloidosis; Fever; Child Health; Disease Progression; Syndrome; Hereditary Autoinflammatory Diseases
PubMed: 37653132
DOI: 10.1542/pir.2022-005635 -
The Lancet. Neurology Aug 2023Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical... (Review)
Review
Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.
Topics: Humans; Multiple Sclerosis; Diagnosis, Differential; Consensus; Magnetic Resonance Imaging; Syndrome
PubMed: 37479377
DOI: 10.1016/S1474-4422(23)00148-5 -
Bone Marrow Transplantation Jul 2023Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell... (Review)
Review
Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European society for blood and marrow transplantation (EBMT).
Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). A new definition for diagnosis, and a severity grading system for SOS/VOD in adult patients, was reported a few years ago on behalf of the European Society for Blood and Marrow Transplantation (EBMT). The aim of this work is to update knowledge regarding diagnosis and severity assessment of SOS/VOD in adult patients, and also its pathophysiology and treatment. In particular, we now propose to refine the previous classification and distinguish probable, clinical and proven SOS/VOD at diagnosis. We also provide an accurate definition of multiorgan dysfunction (MOD) for SOS/VOD severity grading based on Sequential Organ Failure Assessment (SOFA) score.
Topics: Humans; Adult; Hepatic Veno-Occlusive Disease; Bone Marrow; Vascular Diseases; Syndrome; Hematopoietic Stem Cell Transplantation
PubMed: 37095231
DOI: 10.1038/s41409-023-01992-8 -
Science (New York, N.Y.) Sep 2023The vast majority of missense variants observed in the human genome are of unknown clinical significance. We present AlphaMissense, an adaptation of AlphaFold fine-tuned...
The vast majority of missense variants observed in the human genome are of unknown clinical significance. We present AlphaMissense, an adaptation of AlphaFold fine-tuned on human and primate variant population frequency databases to predict missense variant pathogenicity. By combining structural context and evolutionary conservation, our model achieves state-of-the-art results across a wide range of genetic and experimental benchmarks, all without explicitly training on such data. The average pathogenicity score of genes is also predictive for their cell essentiality, capable of identifying short essential genes that existing statistical approaches are underpowered to detect. As a resource to the community, we provide a database of predictions for all possible human single amino acid substitutions and classify 89% of missense variants as either likely benign or likely pathogenic.
Topics: Humans; Amino Acid Substitution; Benchmarking; Conserved Sequence; Databases, Genetic; Disease; Genome, Human; Mutation, Missense; Protein Conformation; Proteome; Sequence Alignment; Machine Learning
PubMed: 37733863
DOI: 10.1126/science.adg7492 -
Science (New York, N.Y.) May 2023Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown...
Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown effects. Using ancestrally diverse, biobank-scale GWAS data, massively parallel CRISPR screens, and single-cell transcriptomic and proteomic sequencing, we discovered 124 -target genes of 91 noncoding blood trait GWAS loci. Using precise variant insertion through base editing, we connected specific variants with gene expression changes. We also identified -effect networks of noncoding loci when target genes encoded transcription factors or microRNAs. Networks were themselves enriched for GWAS variants and demonstrated polygenic contributions to complex traits. This platform enables massively parallel characterization of the target genes and mechanisms of human noncoding variants in both and .
Topics: Humans; Clustered Regularly Interspaced Short Palindromic Repeats; Genetic Predisposition to Disease; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Proteomics; Quantitative Trait Loci; Single-Cell Analysis; Multifactorial Inheritance; Blood Cells; RNA-Seq; Disease
PubMed: 37141313
DOI: 10.1126/science.adh7699 -
Arthritis & Rheumatology (Hoboken, N.J.) Oct 2023Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic...
OBJECTIVE
Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease.
METHODS
Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort.
RESULTS
Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers).
CONCLUSION
The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.
Topics: Humans; Calcinosis; Calcium Pyrophosphate; Chondrocalcinosis; Rheumatology; Syndrome; United States
PubMed: 37494275
DOI: 10.1002/art.42619 -
Autoimmunity Reviews Jan 2024Fibromyalgia (FM) is a multifactorial syndrome which includes not only widespread pain and stiffness, now recognized as major symptoms, but also numerous other somatic,... (Review)
Review
Fibromyalgia (FM) is a multifactorial syndrome which includes not only widespread pain and stiffness, now recognized as major symptoms, but also numerous other somatic, emotional, and neuropsychic manifestation. The lack of specific validated biological and instrumental biomarkers has made FM a condition of unexplained medical significance, and its pathophysiology remains controversial and subject to debate. The current hypothesis regarding the pathogenesis of FM proposes that its development is influenced by various mechanism, including genetic predisposition, stressful life events, inflammatory processes, and cognitive-emotional factors. However, despite the extensive research conducted to date, the available data do not provide a clear understanding of the pathogenesis of FM. In this article, we report the opposing viewpoints of two leading experts who debate the question of whether FM is an autoimmune disease, based on scientific data regarding this condition. Both perspectives are discussed and the latest evidence on the pathophysiology of FM is reported to provide a comprehensive understanding of this complex syndrome.
Topics: Humans; Fibromyalgia; Syndrome; Biomarkers; Autoimmune Diseases; Genetic Predisposition to Disease
PubMed: 37634681
DOI: 10.1016/j.autrev.2023.103424 -
Journal of Clinical Rheumatology :... Sep 2023VEXAS ( V acuoles, E 1 enzyme, X -linked, A utoinflammatory, S omatic) syndrome is a newly identified disease caused by somatic mutations in the UBA1 gene resulting in... (Review)
Review
VEXAS ( V acuoles, E 1 enzyme, X -linked, A utoinflammatory, S omatic) syndrome is a newly identified disease caused by somatic mutations in the UBA1 gene resulting in refractory autoinflammatory features, frequently accompanied by cytopenias. Although the prevalence of this syndrome is yet unknown, understanding the clinical phenotype can assist clinicians in prompt recognition of cases among patients with glucocorticoid-responsive but immunosuppressive-resistant inflammatory symptoms. The pathophysiology, clinical presentation, diagnostic methods, treatment, and prognosis of VEXAS are herein reviewed.
Topics: Humans; Prognosis; Glucocorticoids; Immunosuppressive Agents; Myelodysplastic Syndromes; Syndrome; Mutation
PubMed: 36251488
DOI: 10.1097/RHU.0000000000001905 -
Annals of the Rheumatic Diseases Oct 2023Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic...
OBJECTIVE
Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease.
METHODS
Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort.
RESULTS
Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers).
CONCLUSION
The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.
Topics: Humans; United States; Chondrocalcinosis; Rheumatology; Calcium Pyrophosphate; Calcinosis; Syndrome
PubMed: 37495237
DOI: 10.1136/ard-2023-224575 -
Frontiers in Immunology 2023Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune... (Review)
Review
Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune responses are dynamically altered at different pathogenic stages. Gasdermins (GSDMs) proteins are pore-forming executors in the membrane, subsequently mediating the release of pro-inflammatory mediators and inflammatory cell death. With the increasing research on GSDMs proteins and sepsis, it is believed that GSDMs protein are one of the most promising therapeutic targets in sepsis in the future. A more comprehensive and in-depth understanding of the functions of GSDMs proteins in sepsis is important to alleviate the multi-organ dysfunction and reduce sepsis-induced mortality. In this review, we focus on the function of GSDMs proteins, the molecular mechanism of GSDMs involved in sepsis, and the regulatory mechanism of GSDMs-mediated signaling pathways, aiming to provide novel ideas and therapeutic strategies for the diagnosis and treatment of sepsis.
Topics: Humans; Gasdermins; Sepsis; Cell Death; Inflammation Mediators; Syndrome
PubMed: 38022612
DOI: 10.3389/fimmu.2023.1203687