Pyoderma gangrenosum and impact on quality of life: A narrative review.

Pyoderma gangrenosum (PG) is an autoinflammatory disorder typically characterized by progressive ulcers with dense neutrophilic infiltrates in the absence of infectious causes. The chronic nature of this disease significantly impacts the patients' quality of life (QoL). Yet there is currently a dearth of information in the literature regarding standardised treatment guidelines and the impact of PG on patients' QoL. We conducted a literature search on PubMed using the terms "pyoderma gangrenosum" AND "quality of life." We identified nine relevant articles that provide insight into which domains are affected and what treatment can improve QoL. The most common domains involved are physical, emotional, and psychological. Patients tend to feel depressed/anxious, isolated, and embarrassed secondary to PG manifestations. Comorbidities such as Crohn's disease, monoclonal gammopathy of dermatologic significance, and ulcerative colitis can worsen the impact on these patients' QoL. Pain is also a significant contributor to decreasing patients' QoL. Treatments such as topical steroids, adalimumab, and canakinumab may help improve QoL scores. We believe this information can help clinicians guide the care of patients with PG and highlight the need for more studies and clinical trials focusing on PG treatments' impact on QoL.

The Cortico-Limbo-Thalamo-Cortical Circuits: An Update to the Original Papez Circuit of the Human Limbic System.

The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex, parahippocampal gyrus, hippocampus, hypothalamus, and thalamus. Pursuant to James Papez, Paul Yakovlev and Paul MacLean incorporated the prefrontal/orbitofrontal cortex, septum, amygdalae, and anterior temporal lobes into the limbic system. Over the past few years, diffusion-weighted tractography techniques revealed additional limbic fiber connectivity, which incorporates multiple circuits to the already known complex limbic network. In the current review, we aimed to comprehensively summarize the anatomy of the limbic system and elaborate on the anatomical connectivity of the limbic circuits based on the published literature as an update to the original Papez circuit.

Quality Assessment of Meta-Analyses on Cervical Cancer.

Meta-analysis (MA) quantitatively summarizes the findings of independent studies and is considered the highest quality of evidence for evidence-based medicine. However, issues in reporting and methodological rigor of MA hamper reproducibility and create the potential for bias. By applying PRISMA reporting guideline and AMSTAR2 execution guidelines on 40 cervical cancer MA samples covering topics such as interventions and risk factors, we determined the extent to which MA execution adhered to best practice guidelines. The results show that the elements with least adherence include "review methods established before MA" and "principal summary measures defined" (each 32.5% per PRISMA) and "characteristics of included studies" (31.3% per AMSTAR2) which undermine reproducibility and increase the risk of bias. This initial work presents common pitfalls in MA and is intended to improve awareness of these issues for clinicians who are interested in conducting MA and to pave the way toward quality improvement via informatics approaches.

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver-Brain Axis for Lipid Homeostasis.

Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a Slc13a5-deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the Slc13a5tm1b/tm1b null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder.

ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants.

BACKGROUND: The success of the clinical use of sequencing based tests (from single gene to genomes) depends on the accuracy and consistency of variant interpretation. Aiming to improve the interpretation process through practice guidelines, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have published standards and guidelines for the interpretation of sequence variants. However, manual application of the guidelines is tedious and prone to human error. Web-based tools and software systems may not only address this problem but also document reasoning and supporting evidence, thus enabling transparency of evidence-based reasoning and resolution of discordant interpretations. RESULTS: In this report, we describe the design, implementation, and initial testing of the Clinical Genome Resource (ClinGen) Pathogenicity Calculator, a configurable system and web service for the assessment of pathogenicity of Mendelian germline sequence variants. The system allows users to enter the applicable ACMG/AMP-style evidence tags for a specific allele with links to supporting data for each tag and generate guideline-based pathogenicity assessment for the allele. Through automation and comprehensive documentation of evidence codes, the system facilitates more accurate application of the ACMG/AMP guidelines, improves standardization in variant classification, and facilitates collaborative resolution of discordances. The rules of reasoning are configurable with gene-specific or disease-specific guideline variations (e.g. cardiomyopathy-specific frequency thresholds and functional assays). The software is modular, equipped with robust application program interfaces (APIs), and available under a free open source license and as a cloud-hosted web service, thus facilitating both stand-alone use and integration with existing variant curation and interpretation systems. The Pathogenicity Calculator is accessible at http://calculator.clinicalgenome.org . CONCLUSIONS: By enabling evidence-based reasoning about the pathogenicity of genetic variants and by documenting supporting evidence, the Calculator contributes toward the creation of a knowledge commons and more accurate interpretation of sequence variants in research and clinical care.