-
Thrombosis Research Oct 2022Endotheliopathy and coagulopathy appear to be the main causes for critical illness and death in patients with coronavirus disease 2019 (COVID-19). The adhesive ligand... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endotheliopathy and coagulopathy appear to be the main causes for critical illness and death in patients with coronavirus disease 2019 (COVID-19). The adhesive ligand von Willebrand factor (VWF) has been involved in immunothrombosis responding to endothelial injury. Here, we reviewed the current literature and performed meta-analyses on the relationship between both VWF and its cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) with the prognosis of COVID-19.
METHODS
We searched MEDLINE, Cochrane Library, Web of Science, and EMBASE databases from inception to 4 March 2022 for studies analyzing the relationship between VWF-related variables and composite clinical outcomes of patients with COVID-19. The VWF-related variables analyzed included VWF antigen (VWF:Ag), VWF ristocetin cofactor (VWF:Rco), ADAMTS13 activity (ADAMTS13:Ac), the ratio of VWF:Ag to ADAMTS13:Ac, and coagulation factor VIII (FVIII). The unfavorable outcomes were defined as mortality, intensive care unit (ICU) admission, and severe disease course. We used random or fixed effects models to create summary estimates of risk. Risk of bias was assessed based on the principle of the Newcastle-Ottawa Scale.
RESULTS
A total of 3764 patients from 40 studies were included. The estimated pooled means indicated increased plasma levels of VWF:Ag, VWF:Rco, and VWF:Ag/ADAMTS13:Ac ratio, and decreased plasma levels of ADAMTS13:Ac in COVID-19 patients with unfavorable outcomes when compared to those with favorable outcomes (composite outcomes or subgroup analyses of non-survivor versus survivor, ICU versus non-ICU, and severe versus non-severe). In addition, FVIII were higher in COVID-19 patients with unfavorable outcomes. Subgroup analyses indicated that FVIII was higher in patients admitting to ICU, while there was no significant difference between non-survivors and survivors.
CONCLUSIONS
The imbalance of the VWF-ADAMTS13 axis (massive quantitative and qualitative increases of VWF with relative deficiency of ADAMTS13) is associated with poor prognosis of patients with COVID-19.
Topics: ADAMTS13 Protein; COVID-19; Disintegrins; Factor VIII; Humans; Ligands; Prognosis; Thrombospondins; von Willebrand Factor
PubMed: 36027630
DOI: 10.1016/j.thromres.2022.08.017 -
Frontiers in Immunology 2022The complement system is a field of growing interest for pharmacological intervention. Complement protein C1q, the pattern recognition molecule at the start of the...
The complement system is a field of growing interest for pharmacological intervention. Complement protein C1q, the pattern recognition molecule at the start of the classical pathway of the complement cascade, is a versatile molecule with additional non-canonical actions affecting numerous cellular processes. Based on observations made in patients with hereditary C1q deficiency, C1q is protective against systemic autoimmunity and bacterial infections. Accordingly, C1q deficient mice reproduce this phenotype with susceptibility to autoimmunity and infections. At the same time, beneficial effects of C1q deficiency on disease entities such as neurodegenerative diseases have also been described in murine disease models. This systematic review provides an overview of all currently available literature on the C1q knockout mouse in disease models to identify potential target diseases for treatment strategies focusing on C1q, and discusses potential side-effects when depleting and/or inhibiting C1q.
Topics: Animals; Autoimmunity; Complement Activation; Complement C1q; Complement Pathway, Classical; Humans; Mice; Mice, Knockout
PubMed: 35990646
DOI: 10.3389/fimmu.2022.958273 -
Hormone Research in Paediatrics 2023Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of cortisol, aldosterone, or both. The most common type is the 21-hydroxylase enzyme deficiency in approximately 95% of cases resulting from CYP21A2 gene mutations or deletions.
OBJECTIVES
This study aimed to systematically review the national differences in CAH incidence and analyze the pooled results to determine disparities and whether ethnicity can predispose people to develop CAH.
METHODS
PubMed, Scopus, and LILACS were used to achieve results until June 22, 2018. Study eligibility criteria included availability of full-text; English, Spanish, or Portuguese languages; incidence or number of new cases; and number of live births or sample population. Only the classic CAH type (salt-wasting and simple-virilizing) was considered, and no distinction was made between the enzyme deficiency types.
RESULTS
This study summarizes the findings of 58 studies and 31 countries (from 1969 to 2017), in which the overall CAH incidence was 1:9,498 (95% confidence interval: 1:9,089, 1:9,945). Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. The lowest incidence was reported in countries of the Western Pacific of Asia. No remarkable difference was observed in the Hispanics/Latino and White groups. However, they manifested a higher incidence of CAH than people identified as Black or of African descent. Published studies on CAH incidence in the sub-Saharan African region and parts of Europe were insufficient.
CONCLUSIONS
This study highlights the at-risk population for CAH and regions that need monitoring for CAH. The highest CAH incidence could be attributed to higher consanguinity, less genetic diversity, or other genetic causes since CAH is an inherited genetic disorder. Cultural practices in some places regarding consanguineous unions or geographic isolation may directly affect the incidence. Newborn screening for CAH may be unavailable in many developing countries, thereby affecting the actual CAH incidence. Therefore, healthcare workers should be trained to recognize CAH at an early stage to reduce its complications and mortality.
Topics: Infant, Newborn; Humans; Adrenal Hyperplasia, Congenital; Neonatal Screening; Adrenal Cortex; Mutation; Steroid 21-Hydroxylase
PubMed: 35973409
DOI: 10.1159/000526401 -
Reproductive Sciences (Thousand Oaks,... Apr 2023Uterine fibroids are the most common tumor of reproductive-age women worldwide and cause significant morbidity in affected women. Vitamin D has emerged as a potential... (Review)
Review
Uterine fibroids are the most common tumor of reproductive-age women worldwide and cause significant morbidity in affected women. Vitamin D has emerged as a potential therapy for uterine fibroids based on experimental and epidemiologic evidence. The objective of this systematic review was to evaluate the role of vitamin D in the pathophysiology of uterine fibroids and its efficacy for prevention and treatment of fibroids. A comprehensive search was conducted of Cochrane Library, Embase, PubMed, Scopus, and Web of Science from inception to March 2022. English-language publications that evaluated vitamin D and uterine fibroids in humans, whether experimental or clinical, were considered. The search yielded 960 publications, and 89 publications met inclusion criteria: 23 preclinical studies, 25 clinical studies, and 41 review articles. Preclinical studies indicated that the vitamin D receptor was decreased in fibroid cells. Vitamin D treatment of fibroid cells decreased proliferation, extracellular matrix protein expression, and Wnt/β-catenin signaling. Fourteen clinical studies (n = 3535 participants) assessed serum vitamin D level in women with ultrasound-proven fibroids, and all found an inverse correlation between serum vitamin D level and presence of fibroids. Five clinical studies (n = 472 patients) evaluated treatment of fibroids with vitamin D. Four of five studies showed vitamin D significantly inhibited fibroid growth. One pilot study (n = 109 patients) of vitamin D for secondary prevention of fibroids demonstrated smaller recurrent fibroids in the treated group. These studies provide evidence for vitamin D as a therapy for uterine fibroids and underscore the need for well-designed, randomized, placebo-controlled clinical trials.
Topics: Humans; Female; Vitamin D; Uterine Neoplasms; Pilot Projects; Leiomyoma
PubMed: 35960442
DOI: 10.1007/s43032-022-01011-z -
Journal of Nephrology Nov 2022This systematic review provides an up-to-date synthesis on the effects of extended hemodialysis on nutritional outcomes. (Review)
Review
OBJECTIVE
This systematic review provides an up-to-date synthesis on the effects of extended hemodialysis on nutritional outcomes.
DESIGN AND METHODS
Ten databases were searched. Inclusion criteria were: randomised and non-randomised studies of extended hemodialysis (defined by > 15 h/week) with a comparator group which received conventional in-centre hemodialysis (usually ≤ 12 h per week). Outcomes of interest included lean body mass, protein and carbohydrate intake, body mass index, dry lean mass, water-soluble vitamin levels, serum levels of appetite hormones, and nutritional status as assessed by the PEW and SGA scoring tools.
RESULTS
Five studies were eligible. All investigated extended nocturnal hemodialysis (one with the addition of short daily), three were in-centre and two were at home. Range of duration for the included studies was 2-18 months. These studies reported data on lean body mass, protein and carbohydrate intake, body mass index, dry lean mass and water-soluble vitamin levels. There was insufficient homogeneity between the studies to meta-analyse the data. Extended hemodialysis had no significant effects on any of the reported outcomes except for lean body mass, where a significant increase was found, and water-soluble vitamin levels, where deficiency was identified in one of the included studies.
CONCLUSION
There is currently no evidence to suggest that extended hemodialysis modalities impact nutritional parameters, although the quality of the available evidence is low.
Topics: Humans; Renal Dialysis; Nutritional Status; Body Mass Index; Vitamins; Hormones; Carbohydrates; Water
PubMed: 35960430
DOI: 10.1007/s40620-022-01395-w -
Critical Reviews in Food Science and... 2024Despite enormous research efforts, a sufficiently sensitive and reliable biomarker for the assessment of zinc (Zn) status has not been identified to date. Zn affects... (Meta-Analysis)
Meta-Analysis
Despite enormous research efforts, a sufficiently sensitive and reliable biomarker for the assessment of zinc (Zn) status has not been identified to date. Zn affects fatty acid metabolism and alters the activity of certain desaturases; thus, desaturase activity has been proposed as a potential new biomarker of Zn status. This systematic review complied and assessed studies that examined changes in fatty acid desaturase 1 (FADS1) and fatty acid desaturase 2 (FADS2) activities in relation to modifications in dietary Zn intake. A systematic search was performed in PubMed, Web of Science, Scopus, Web of Knowledge, and Central with strictly defined search, inclusion, and exclusion criteria. Twenty-one studies were included, 8 animal and 13 human trials (5 randomized controlled trials, two non-randomized controlled trials, and 6 cross-sectional studies). This systematic review was performed using PRISMA guidelines and where feasible a random-effects meta-analysis was conducted. No significant correlation was seen between the delta 6 desaturase and Zn status (-0.0958, 95% CIs (-0.2912; 0.1074), p = 0.2928). Delta 6 desaturase seems to respond in a greater magnitude than Zn status to Zn-containing interventions (the standardized mean difference for delta 6 desaturase was -0.6052, 95% CIs (-2.7162; 1.5058), p = 0.4289, while for plasma/serum Zn it was 0.0319, 95% CIs (-0.9133; 0.9770), p = 0.9213). Finally, two separate meta-analyses on same studies that assessed the correlations between LA:DGLA and Zn intake and Zn status and Zn intake revealed that the magnitude of correlations was only slightly different (the pooled correlation coefficient between the LA:DGLA ratio and Zn intake had a value of -0.1050, 95% CIs (-0.5356; 0.3690), p = 0.454, while between plasma Zn and Zn intake had a value of -0.0647, 95% CIs (-0.4224; 0.3106), p = 0.5453). According to the descriptive analysis, the magnitude of variation in desaturase activities in response to Zn intake was not consistent among studies, FADS1 and FADS2 activity corresponded to dietary Zn manipulations, both in animals and humans. A plausible explanation for this observation might be the difference between the studies in study populations, types of dietary interventions, study durations, etc. In addition, several potential confounders and covariates are identified from the qualitative synthesis, such as gender, age, the type of fat provided within the dietary intervention, the size of Zn particles, among others. Further high-quality studies are needed to additionally clarify the suggested associations and applicability of utilizing fatty acid desaturase activities as Zn status biomarkers.
Topics: Animals; Humans; Fatty Acid Desaturases; Linoleoyl-CoA Desaturase; Zinc; Cross-Sectional Studies; Biomarkers; Polymorphism, Single Nucleotide
PubMed: 35880429
DOI: 10.1080/10408398.2022.2103790 -
JIMD Reports Jul 2022Arginase 1 deficiency (ARG1-D) is a rare, progressive and debilitating urea cycle disorder characterized by clinical manifestations including spasticity, seizures,...
BACKGROUND
Arginase 1 deficiency (ARG1-D) is a rare, progressive and debilitating urea cycle disorder characterized by clinical manifestations including spasticity, seizures, developmental delay, and intellectual disability. The aim of this systematic review was to identify and summarize the natural history of ARG1-D and the unmet needs of patients.
METHODS
A comprehensive search of published case reports was undertaken to identify patients with ARG1-D regardless of interventions, comparisons, or outcomes. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and other evidence-based medicine literature databases were searched on 20 April 2020. Quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. (PROSPERO registration: CRD42020212142.).
RESULTS
One hundred and fifty seven ARG1-D patients were included from 111 publications (good overall quality based on JBI's Checklist); 84 (53.5%) were males. Motor deficits (including spasticity), intellectual disability, and seizures were reported in >50% of the cases. Mean age (SD) at diagnosis was 6.4 years and the laboratory findings most commonly reported to support diagnosis included elevated plasma arginine (81.5%), mutation in gene through genetic testing (60%), and absence/reduction of red blood cell arginase activity (51%). Reported management approaches mainly included dietary protein restriction (68%), nitrogen scavengers (45%), and essential amino acid supplements (21%). Author-reported clinical improvement was documented for 26% of patients, 15% deteriorated, and 19% had limited or no change; notably, no indication of clinical outcome was reported for 40% cases.
CONCLUSION
This review illustrates a significant burden of disease and highlights a considerable unmet need for clinically effective treatment options for patients with ARG1-D.
PubMed: 35822089
DOI: 10.1002/jmd2.12283 -
Journal of Clinical Laboratory Analysis Jul 2022The incidence of premature atherosclerotic cardiovascular disease in familial hypercholesterolemia (FH) is high. In recent years, novel therapeutic modalities have shown... (Review)
Review
BACKGROUND
The incidence of premature atherosclerotic cardiovascular disease in familial hypercholesterolemia (FH) is high. In recent years, novel therapeutic modalities have shown significant lipid-lowering ability. In this paper, we summarize the recent developments in novel therapies for FH via the treatment of different targets and discuss the characteristics of each targeted therapy. Based on the process of protein synthesis, we attempt to summarize the direct-effect targets including protein, RNA, and DNA.
METHODS
For this systematic review, relevant studies are assessed by searching in several databases including PubMed, Web of Science, Scopus, and Google Scholar. The publications of original researches are considered for screening.
RESULTS
Most drugs are protein-targeted such as molecule-based and monoclonal antibodies, including statins, ezetimibe, alirocumab, evolocumab, and evinacumab. Both antisense oligonucleotide (ASO) and small interfering RNA (siRNA) approaches, such as mipomersen, vupanorsen, inclisiran, and ARO-ANG3, are designed to reduce the number of mRNA transcripts and then degrade proteins. DNA-targeted therapies such as adeno-associated virus or CRISPR-Cas9 modification could be used to deliver or edit genes to address a genetic deficiency and improve the related phenotype.
CONCLUSION
While the therapies based on different targets including protein, RNA, and DNA are on different stages of development, the mechanisms of these novel therapies may provide new ideas for precision medicine.
Topics: Anticholesteremic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Oligonucleotides, Antisense; RNA
PubMed: 35712827
DOI: 10.1002/jcla.24552 -
Journal of Clinical Immunology Aug 2022Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3...
BACKGROUND
Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans.
OBJECTIVES
To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human.
METHODS
We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24 2022.
RESULTS
We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients.
CONCLUSIONS
DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).
Topics: Antibodies, Antineutrophil Cytoplasmic; Chromatin; DNA; Endodeoxyribonucleases; Humans; Inflammatory Bowel Diseases; Interferon Type I; Interferons; Lupus Erythematosus, Systemic; Lupus Nephritis; Phenotype; Vasculitis
PubMed: 35670985
DOI: 10.1007/s10875-022-01287-5 -
Arthritis & Rheumatology (Hoboken, N.J.) Jul 2022The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin- associated periodic syndromes (CAPS), tumour necrosis factor...
The 2021 EULAR/American College of Rheumatology Points to Consider for Diagnosis, Management and Monitoring of the Interleukin-1 Mediated Autoinflammatory Diseases: Cryopyrin-Associated Periodic Syndromes, Tumour Necrosis Factor Receptor-Associated Periodic Syndrome, Mevalonate Kinase Deficiency,...
BACKGROUND
The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin- associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes.
OBJECTIVE
To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management.
METHODS
A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.
RESULTS
The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.
CONCLUSION
The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.
Topics: Child, Preschool; Cryopyrin-Associated Periodic Syndromes; Fever; Hereditary Autoinflammatory Diseases; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Mevalonate Kinase Deficiency; Quality of Life; Receptors, Interleukin-1; Rheumatology; United States
PubMed: 35621220
DOI: 10.1002/art.42139