Marker Of Disease Severity Research Articles

Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma.

The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking. We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes. Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype. Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.

Effect of ABO blood group on the severity and clinico-pathological parameters of COVID-19.

The COVID-19 pandemic has highlighted the need to understand the factors affecting disease severity. Prior research has indicated the potential roles of the ABO blood group system in disease susceptibility and progression. Our objective was to investigate the association between ABO Blood groups and the severity of COVID-19 and clinicopathological parameters. An analytical cross-sectional study was conducted across three locations of Ziauddin University Hospital, including COVID-19 outpatient departments (OPDs), wards, and intensive care units (ICUs) from May 2020 to December 2020.The study utilized a non-probability convenient sampling technique with a sample size of 120 PCR-positive adult patients, as calculated by OpenEpi with a 95% confidence interval. Patients were excluded if they were under 14, intellectually impaired, post-chemotherapy or radiotherapy, or had a malignant condition. Disease severity was determined based on clinicopathological parameters and associated with blood group data using ANOVA and Chi-square tests in SPSS version 21. A significant association was found between the ABO blood groups and COVID-19 severity. Blood group-A was notably overrepresented in patients with severe COVID-19 and correlated with higher inflammatory markers and coagulation parameters. ABO blood group, particularly Blood Group-A significantly associates with the severity of COVID-19. This finding suggests the potential utility of ABO blood group typing as a predictive marker for disease severity, which could contribute to personalized patient management strategies. Further research is necessary to understand the mechanisms underlying this association.

Pan-Immune-Inflammation Value Could Be a New Marker to Predict Amyloidosis and Disease Severity in Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever and serositis. Blood-based biomarkers determined in FMF patients during attack-free periods could be used to predict the risk of amyloidosis and the severity of the disease. The recently defined pan-immune-inflammation value (PIV) comprises four distinct subsets of blood cells and serves as an easily accessible and cost-effective marker. The objective of this study was to assess the role of PIV in predicting amyloidosis and moderate-to-severe disease. Clinical characteristics and laboratory values during the attack-free period were retrospectively analyzed in 321 patients over 18 years of age diagnosed with familial Mediterranean fever (FMF). In our tertiary adult rheumatology outpatient clinic, disease severity and laboratory markers were evaluated during the first attack-free interval. At baseline, patients with amyloidosis were excluded. Patients were categorized based on the presence of amyloidosis and the severity of the disease. When focusing on amyloidosis in receiver operating characteristic (ROC) analysis, optimal cut-off values for pan-immune-inflammation value (PIV), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio were determined as ≥518.1, ≥2.3, and ≥127.2, respectively. In multivariate analysis, PIV, C-reactive protein (CRP), and the presence of the M694V homozygous mutation emerged as independent risk factors for both amyloidosis and moderate-to-severe disease. Additionally, NLR was identified as an independent risk factor for amyloidosis, while red blood cell distribution width was associated with moderate-to-severe disease. In patients with FMF, especially in the presence of the M694V homozygous mutation, CRP and PIV may be useful in predicting both amyloidosis and moderate-to-severe disease.

Quantitative T2 Mapping of Acute Pancreatitis.

Quantification of the T2 signal by means of T2 mapping in acute pancreatitis (AP) has the potential to quantify the parenchymal edema. Quantitative T2 mapping may overcome the limitations of previously reported scoring systems for reliable assessment of AP. To evaluate MR-derived pancreatic T2 mapping values in AP and correlate them with markers of disease severity. Prospective single-center study. 76 adults with AP (20-91 years, females/males: 39/37). Fat suppressed multiecho spin-echo prototype sequence to quantify T2 signal at 3T MRI. The severity of AP was assessed clinically, biologically, and by contrast-enhanced CT (CECT) performed 48-72 hours after symptom onset. MRI was then performed ≤24 hours after CT. Two readers blinded to any clinical information independently evaluated the T2 values by placing three regions of interest inside the pancreatic head, body, and tail on the T2 mapping MR sequence. Results were compared with corresponding CECT images as the standard and clinical severity parameters, using the length of hospital stay as our primary endpoint. Continuous variables were compared using the Spearman's rank correlation coefficient, analysis of variance (ANOVA) or Student's t-test. T2 values significantly correlated with the length of hospital stay (rs (74) = 0.29), CT severity index (CTSI) (rs (73) = 0.61; CTSI 0-3: 72 ± 14 msec, CTSI 4-10: 88 ± 15), intensive care unit (ICU) admission (t(2.77) = -3.41) and presence of organ failure (t(6.72) = -3.42), whereas the CTSI and Ranson score were not significantly related with ICU admission (CTSI: P = 0.24; Ranson score: P = 0.24) and organ failure (CTSI: P = 0.11; Ranson score P = 0.11). T2 mapping correlates with AP severity parameters and is useful for assessing the severity of AP with higher sensitivity than the usual clinical and radiological scoring systems. 1 TECHNICAL EFFICACY: Stage 2.

Can complement activation be the missing link in antiphospholipid syndrome?

APS is an autoimmune disorder with life-threatening complications that, despite therapeutic advantages, remains associated with thrombotic recurrences and treatment failure. The role of complement activation in APS pathogenesis is increasingly recognised, specifically in obstetric APS. However, its exact role in thrombotic APS and on the severity of the disease is not yet fully elucidated. Further mechanistic studies are needed to delineate the role of complement activation in the various APS clinical manifestations with aim to identify novel markers of disease severity, together with clinical trials to evaluate the efficacy of complement inhibition in APS. This could ultimately improve risk stratification in APS, patient tailored targeted therapy with complement inhibition identified as an adjunctive treatment. This article reviews current findings and challenges about complement activation in APS, discusses the potential role of platelet mediated complement activation in this setting and provides an overview on clinical implications and current therapeutics.

Plasma from patients undergoing allogeneic hematopoietic stem cell transplantation promotes NETOSIS in vitro and correlates with inflammatory parameters and clinical severity.

NETosis, the mechanism by which neutrophils release extracellular traps (NETs), is closely related to inflammation. During the allogeneic hematopoietic stem cell transplantation (allo-HSCT), different stimuli can induce NETs formation. Inflammation and endothelial injury have been associated with acute graft-versus-host disease (aGVHD) and complications after allo-HSCT. We focus on the study of NETosis and its relation with cytokines, hematological and biochemical parameters and clinical outcomes before, during and after allo-HSCT. We evaluate the capacity of plasma samples from allo-HSCT patients to induce NETosis, in a cell culture model. Plasma samples from patients undergoing allo-HSCT had a stronger higher NETs induction capacity (NETsIC) than plasma from healthy donors throughout the transplantation process. An optimal cut-off value by ROC analysis was established to discriminate between patients whose plasma triggered NETosis (NETs+IC group) and those who did not (NETs-IC group). Prior to conditioning treatment, the capacity of plasma samples to trigger NETosis was significantly correlated with the Endothelial Activation and Stress Index (EASIX) score. At day 5 after transplant, patients with a positive NETsIC had higher interleukin (IL)-6 and C-reactive protein (CRP) levels and also a higher Modified EASIX score (M-EASIX) than patients with a negative NETsIC. EASIX and M-EASIX scores seek to determine inflammation and endothelium damage, therefore it could indicate a heightened immune response and inflammation in the group of patients with a positive NETsIC. Cytokine levels, specifically IL-8 and IL-6, significantly increased after allo-HSCT with peak levels reached on day 10 after graft infusion. Only, IL-10 and IL-6 levels were significantly higher in patients with a positive NETsIC. In our small cohort, higher IL-6 and IL-8 levels were related to early severe complications (before day 15 after transplant). Although early complications were not related to NETosis by itself, NETosis could predict overall non-specific but clinically significant complications during the full patient admission. In summary, NETosis can be directly induced by plasma from allo-HSCT patients and NETsIC was associated with clinical indicators of disease severity, cytokines levels and inflammatory markers.

Mendelian Randomization Study With Clinical Follow-Up Links Metabolites to Risk and Severity of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) exhibits phenotypic heterogeneity and variable response to therapy. The metabolome has been implicated in the pathogenesis of PAH, but previous works have lacked power to implicate specific metabolites. Mendelian randomization (MR) is a method for causal inference between exposures and outcomes. Using genome-wide association study summary statistics, we implemented MR analysis to test for potential causal relationships between serum concentration of 575 metabolites and PAH. Five metabolites were causally associated with the risk of PAH after multiple testing correction. Next, we measured serum concentration of candidate metabolites in an independent clinical cohort of 449 patients with PAH to check whether metabolite concentrations are correlated with markers of disease severity. Of the 5 candidates nominated by our MR work, serine was negatively associated and homostachydrine was positively associated with clinical severity of PAH via direct measurement in this independent clinical cohort. Finally we used conditional and orthogonal approaches to explore the biology underlying our lead metabolites. Rare variant burden testing was carried out using whole exome sequencing data from 578 PAH cases and 361 675 controls. Multivariable MR is an extension of MR that uses a single set of instrumental single-nucleotide polymorphisms to measure multiple exposures; multivariable MR is used to determine interdependence between the effects of different exposures on a single outcome. Rare variant analysis demonstrated that loss-of-function mutations within activating transcription factor 4, a transcription factor responsible for upregulation of serine synthesis under conditions of serine starvation, are associated with higher risk for PAH. Homostachydrine is a xenobiotic metabolite that is structurally related to l-proline betaine, which has previously been linked to modulation of inflammation and tissue remodeling in PAH. Our multivariable MR analysis suggests that the effect of l-proline betaine is actually mediated indirectly via homostachydrine. Our data present a method for study of the metabolome in the context of PAH, and suggests several candidates for further evaluation and translational research.

The coagulation changes associated with acute variceal bleeding in patients with HCV-induced cirrhosis as assessed by rotational thromboelastometry

Background and objectivesAlterations of hemostasis in patients with decompensated cirrhosis are complex. Accordingly, standard coagulation tests are not feasible to evaluate bleeding risk in these patients. The aim of this study was to assess the coagulation kinetics in cirrhotic patients with variceal bleeding using rotational thromboelastometry (ROTEM). ROTEM including EXTEM, INTEM, and FIBTEM which represent extrinsic, intrinsic pathways, and fibrinogen activity, respectively, was measured in 60 cirrhotic patients with variceal bleeding who were compared to 60 patients with stable cirrhosis. APTEM was optionally performed to evaluate fibrinolysis.ResultsOverall, cirrhosis patients displayed features of hypofibrinolysis, whereas the state of hypocoagulability was significantly higher in cirrhotic patients with variceal bleeding (61.7% versus 30%, p = 0.001). Values of clot formation time (CFT) by EXTEM and INTEM correlated positively with those of model for end-stage liver disease score (r = 0.529, p = 0.001, and r = 0.595, p < 0.001, respectively). Furthermore, in a multivariate analysis, values of CFT in both assays were significantly associated with increased risk of 1.9 (95% CI = 1.04–2.45, p = 0.02) and of 1.78 (95% CI = 1.02–2.14, p = 0.01), respectively, for occurrence of variceal bleeding.ConclusionCirrhotic patients with variceal bleeding frequently showed a hypocoagulable state that is triggered by thrombocytopenia and/or hypofibrinogenemia. CFT by EXTEM and INTEM seemed to be an extra marker for disease severity and prognosis in cirrhosis patients, in addition to its valuable role in prediction of variceal bleeding in these patients. However, large multicenter studies have yet been required.

Noninvasive assessment of glymphatic dysfunction in idiopathic normal pressure hydrocephalus with diffusion tensor imaging.

Diffusion tensor imaging (DTI) along the perivascular space (ALPS) (DTI-ALPS)-by calculating the ALPS index, a ratio accentuating water diffusion in the perivascular space-has been proposed as a noninvasive, indirect MRI method for assessing glymphatic function. The main aim of this study was to investigate whether DTI-ALPS would reveal glymphatic dysfunction in idiopathic normal pressure hydrocephalus (iNPH) and whether the ALPS index was associated with disease severity. Thirty iNPH patients (13 men; median age 77 years) and 27 healthy controls (10 men; median age 73 years) underwent MRI and clinical assessment with the Timed Up and Go test (TUG) and Mini-Mental State Examination (MMSE); only the patients were evaluated with the Hellström iNPH scale. MRI data were analyzed with the DTI-ALPS method and Radscale screening tool. iNPH patients showed significantly lower mean ALPS index scores compared with healthy controls (median [interquartile range] 1.09 [1.00-1.15] vs 1.49 [1.36-1.59], p < 0.001). Female healthy controls showed significantly higher ALPS index scores than males in both hemispheres (e.g., right hemisphere 1.62 [1.47-1.67] vs 1.33 [1.14-1.41], p = 0.001). This sex difference was not seen in iNPH patients. The authors found a moderate exponential correlation between mean ALPS index score and motor function as measured with time required to complete TUG (r = -0.644, p < 0.001), number of steps to complete TUG (r = -0.571, p < 0.001), 10-m walk time (r = -0.637, p < 0.001), and 10-m walk steps (r = -0.588, p < 0.001). The authors also found a positive linear correlation between mean ALPS index score and MMSE score (r = 0.416, p = 0.001). Simple linear regression showed a significant effect of diagnosis (B = -0.39, p < 0.001, R2 = 0.459), female sex (B = 0.232, p = 0.002, R2 = 0.157), and Evans index (B = -4.151, p < 0.001, R2 = 0.559) on ALPS index. Multiple linear regression, including diagnosis, sex, and Evans index score, showed a higher predictive value (R2 = 0.626) than analysis of each of these factors alone. The ALPS index, which was significantly decreased in iNPH patients, could serve as a marker of disease severity, both clinically and in terms of neuroimaging. However, it is important to consider the significant influence of biological sex and ventriculomegaly on the ALPS index, which raises the question of whether the ALPS index solely reflects glymphatic function or if it also encompasses other types of injury. Future studies are needed to address potential confounding factors and further validate the ALPS method.

Continuous age- and sex-specific reference ranges of liver enzymes in Chinese children and application in pediatric non-alcoholic fatty liver disease.

Alanine aminotransferase (ALT) is widely used to screen patients with hepatic diseases. However, the current reference ranges (< 50 U/L) were developed by laboratories and have not been validated in populations with a large number of healthy individuals. This study collected venous blood and anthropometric data from a total of 13,287 healthy children aged 3months to 18years who underwent routine physical examinations in the Department of Pediatric Healthcare. We applied the least mean square algorithm to establish age- and sex-related reference percentiles of serum levels of transaminases. For validation, we recruited 4276 children and adolescents with obesity/overweight who underwent evaluation and metabolic tests in the hospital. Using receiver operating characteristic curves, we determined age- and sex-specific upper limit percentiles of liver enzymes for fatty liver diseases. This study revealed a significant correlation between serum transaminase levels and age and sex (P < 0.01). These transaminase levels exhibited age- and sex-specific patterns. Among individuals in the non-alcoholic fatty liver disease (NAFLD) cohort, elevated ALT levels displayed a positive association with clinical markers of disease severity, including homeostatic model assessment of insulin resistance, waist-hip ratio, and serum uric acid levels (P < 0.01). According to the receiver operating characteristic curves, ALT levels at the 92.58th percentile for boys and the 92.07th percentile for girls yielded the highest accuracy and specificity. This study provides age- and sex-specific reference ranges for ALT, aspartate aminotransferase, and γ-glutamyltransferase in Chinese children and adolescents, making it the largest population study to date. Furthermore, the study establishes a precise upper limit for ALT levels, facilitating their use in NAFLD screening. Video Abstract.

Psoriasis: What Is New in Markers of Disease Severity?

Introduction. Psoriasis is a chronic inflammatory skin disease and is the result of the interaction between numerous external and internal factors. Psoriasis presents a wide range of skin manifestations encompassing individual lesions varying from pinpoint to large plaques that can evolve into generalised forms. The lesions mirror the pathophysiological mechanisms involved in psoriasis pathogenesis, such as inflammation, dysregulation of immune response, uncontrolled proliferation of keratinocytes and angiogenesis. In this article, we present the latest advances achieved regarding markers that correlate with psoriasis severity. Material and method. We have performed a narrative review on markers of psoriasis severity, including articles published between March 2018-March 2023. Results. We have identified four categories of markers: inflammation markers, oxidative stress markers, hormonal markers and cancer-related markers. The main focus was on inflammation biomarkers, including immunomodulatory molecules, haematological parameters, inflammatory cells and costimulatory molecules. Conclusions. The analysed data indicate that markers associated with inflammation, oxidative stress and hormones, and cancer-related markers could be useful in assessing the severity of psoriasis. Nevertheless, additional research is required to ascertain the practical importance of these biomarkers in clinical settings.

Cytokeratin-18 as a Non-invasive Biomarker and its Association with Biochemical Parameters in the Diagnosis of Non-alcoholic Fatty Liver Disease

Objective: Nonalcoholic fatty liver disease (NAFLD) is one of the chronic silent diseases in which its therapeutic options and noninvasive markers of disease activity and severity remain limited. We aimed in this study to assess cytokeratin-18 (CK18) as a new non-invasive biomarker to distinguish between NAFLD stages and its correlation with some biochemical parameters.&#x0D; Methods: A case control study was conducted on a sample of 90 subjects aged 12-79 years, categorized into three groups (nonalcoholic steatohepatitis "NASH", steatosis and controls). CK18, fasting blood glucose (FBG), lipid profile parameters, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine were determined. Low destiny lipoprotein-cholesterol (LDL-C), and body mass index (BMI) were calculated in addition to performing complete blood count (CBC).&#x0D; Results: The results indicate that the mean level of serum CK18 in NASH cases was significantly higher than steatosis and control groups. CK18 has a positive correlation with triglycerides (TG) total cholesterol (TC), ALT, AST, FBG, urea, creatinine, age, BMI, and LDL-C, and a negative correlation with high density lipoprotein-cholesterol HDL-C. Finally, ROC curve showed that the sensitivity of CK18 test is 77.1% and specificity is 96.6%. The cut-off value for CK18 test is 161 U/L.&#x0D; Conclusions: In this study, a significant relationship was observed between CK18, hepatic enzymes, and NAFLD degrees. CK18 has good accuracy, sensitivity, and specificity in diagnosing NASH.

Examining the relationship between brain activation and proxies of disease severity using quantile regression in individuals at risk of Alzheimer's disease

Previous studies have reported a pattern of hyperactivation in the pre-dementia phase of Alzheimer's disease (AD), followed by hypoactivation in later stages of the disease. This pattern was modeled as an inverse U-shape function between activation and markers of disease severity. In this study, we used quantile regression to model the association between task-related brain activation in AD signature regions and three markers of disease severity (hippocampal volume, cortical thickness, and associative memory). This approach offers distinct advantages over standard regression models as it analyzes the relationship between brain activation and disease severity across various levels of brain activation. Participants were 54 older adults with subjective cognitive decline+ (SCD+) or mild cognitive impairment (MCI) from the CIMA-Q cohort. The analysis revealed an inverse U-shape quadratic function depicting the relationship between disease severity markers and the activation of the left superior parietal region, while a linear relationship was observed for activation of the hippocampal and temporal regions. Quantile differences were observed for temporal and parietal activation, with more pronounced effects observed in the higher quantiles of activation. When comparing quantiles, we found that higher quantile of activation featured a greater number of individuals with SCD+ compared to mild cognitive impairment (MCI). Results are globally consistent with the presence of an inverse-U shape function of activation in relation to disease severity. They study also underscores the utility of employing quantile regression modeling as the modeling approach revealed the presence of non-homogeneous effects across various quantiles.

Risk factors for mortality in children with hemorrhagic cystitis after hematopoietic transplant

Hemorrhagic cystitis (HC) is a devastating complication of bone marrow (BMT) and stem cell transplant (SCT). Much of the literature has focused on exclusively adult patient populations, with limited evidence regarding risk factors for mortality and morbidity among pediatric HC patients. To examine factors associated with all-cause mortality in children with HC after BMT/SCT. The Pediatric Health Information System database was queried for patients with ICD-9/10 codes for hematopoietic transplant and gross hematuria, hematuria unspecified, or cystitis with hematuria. Multivariable logistic regression examined association of medical and surgical interventions frequently employed for hemorrhagic cystitis with mortality and genitourinary morbidity, defined as having received instillation of any bladder medication or having undergone any genitourinary procedure. A total of 811 patients, mean age of 12.4 years and 62% male, were included. Primary diagnosis included 388 (49%) leukemia/lymphoma, 182 (22%) blood dyscrasia, 99 (12%) solid organ tumor, 27 (3%) metabolic disease, 115 (14%) unknown. Transplant type included 377 (46%) bone marrow, 329 (41%) stem cell, 105, and (13%) unknown. Performing any bladder instillation (p<0.0001) or any type of GU procedure (p<0.0001) was significantly associated with mortality. On multivariate analysis, dialysis (OR=10.7, 95% CI=5.7-20.2), genitourinary morbidity (OR=4, 95% CI=2.2-6.8) and intravenous cidofovir (OR=2.0, 95% CI=1.2-3.3) were significantly associated with all cause mortality. Having an underlying diagnosis of blood dyscrasia was protective against mortality (OR=0.425, CI=0.205-0.88). In this large retrospective study evaluating factors associated with mortality in children with HC, all cause mortality was found to be 11%. This is probably an underrepresentation of true mortality in this population, as many patients discharged from the hospital likely die outside the hospital at home or hospice care. This study supports the current literature that invasive GU procedures are not associated with increased survival in patients with severe HC. This study is limited by retrospective use of a billing database that has the potential for errors in data entry and missing data. Patients who were discharged from the hospital were not captured by the PHIS which only collects data from inpatient stays. Patients with HC who received dialysis, intravenous cidofovir, or underwent GU intervention had significantly higher all-cause mortality. High grade HC is a marker of disease severity and efforts should be made by urologists and oncologists to maximize quality of life and limit futile treatments in this patient population.

A Look Into the Future: Are We Ready for an Approved Therapy in Celiac Disease?

As it appears that we are currently at the cusp of an era in which drugs that are new, re-purposed or as “supplements”, will be introduced to the management of celiac disease, we need to reflect if the framework is set for celiac disease to be increasingly treated by pharmaceuticals as well as diet. This refers to reflecting on the rigor of current diagnostic practices, the limitations of the current standard of care that is gluten-free diet, and that we lack objective markers of disease severity. Interrogating these issues will help us to identify gaps in technology and practices that could be critical for selecting patients with a well-defined need for an improved or alternative treatment. Both aspects, circumscribed limitations of the gluten-free diet and diagnostics helping to define celiac disease target groups, together with the guiding requirements by the responsible regulatory authorities will contribute to defining the subgroups of patients with confirmed celiac disease eligible for distinct pharmacological strategies. Because many celiac disease patients are diagnosed in childhood, these aspects need to be differentially discussed for the pediatric setting.In this perspective, we aim to describe these contextual issues and then look ahead to the future. What might be the major challenges in celiac disease clinics in the coming years once drugs are an option alongside the diet? And what will be future objectives for researchers who further decipher the mucosal immunology of celiac disease? Speculating on the answers to these questions is as stimulating as it is fascinating to be part of this turning point.

Overexpression of VEGFα as a biomarker of endothelial dysfunction in aortic tissue of α-GAL-Tg/KO mice and its upregulation in the serum of patients with Fabry's disease.

Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry's disease and healthy controls. Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness. It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry's disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry's disease. For angiostatin, no significant difference was found between patients with Fabry's disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml). In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry's disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.

Nerve ultrasound in Friedreich’s Ataxia: enlarged nerves as a biomarker of disease severity

ObjectiveIn Friedreich's ataxia research, the focus is on discovering treatments and biomarkers to assess disease severity and treatment effects. Our study examines high-resolution nerve ultrasound in these patients, seeking correlations with established clinical markers of disease severity. MethodTen patients with Friedreich’s Ataxia underwent a comprehensive clinical assessment with established scales (SARA, FARS, mFARS, INCAT, ADL 0-36, IADL). Additionally, they underwent nerve conduction studies and high-resolution nerve ultrasound. Quantitative evaluation of nerve cross-sectional area, conducted at 24 nerve sites using high-resolution nerve ultrasound, was compared with data obtained from 20 healthy volunteers. ResultsAll the patients had a severe sensory axonal neuropathy. High-resolution nerve ultrasound showed significant increase, in cross sectional area, of median and ulnar nerves at the axilla and arm. The cumulative count of affected nerve sites was directly associated with clinical disability, as determined by SARA, FARS, mFARS, ADL 0-36, and INCAT score, while displaying an inverse correlation with IADL. ConclusionsOur study shows that high-resolution ultrasound reveals notable nerve abnormalities, primarily in the upper limbs of patients diagnosed with Friedreich’s Ataxia. The observed correlation between these nerve abnormalities and clinical disability scales indicates the potential use of this technique as a biomarker for evaluating disease severity and treatment effects. SignificanceNerve Ultrasound is a potential biomarker of disease severity in Friedreich’s Ataxia.

Distribution of multi-level B cell subsets in thymoma and thymoma-associated myasthenia gravis

B-cell subsets in peripheral blood (PB) and tumor microenvironment (TME) were evaluated to determine myasthenia gravis (MG) severity in patients with thymoma-associated MG (TMG) and the distribution of B cells in type B TMG. The distribution of mature B cells, including Bm1–Bm5, CD19+ and CD20+ B cells and non-switched (NSMBCs) and switched (SMBCs) memory B cells, were determined in 79 patients with thymoma or TMG. Quantitative relationships between the T and TMG groups and the TMG-low and TMG-high subgroups were determined. NSMBCs and SMBCs were compared in TME and PB. Type B thymoma was more likely to develop into MG, with types B2 and B3 being especially associated with MG worsening. The percentage of CD19+ B cells in PB gradually increased, whereas the percentage of CD20+ B cells and the CD19/CD20 ratio were not altered. The (Bm2 + Bm2′)/(eBm5 + Bm5) index was significantly higher in the TMG-high than in thymoma group. The difference between SMBC/CD19+ and NSMBC/CD19+ B cell ratios was significantly lower in the thymoma than TMG group. NSMBCs assembled around tertiary lymphoid tissue in thymomas of patients with TMG. Few NSMBCs were observed in patients with thymoma alone, with these cells being diffusely distributed. MG severity in patients with TMG can be determined by measuring CD19+ B cells and Bm1-Bm5 in PB. The CD19/CD20 ratio is a marker of disease severity in TMG patients. Differences between NSMBCs and SMBCs in PB and TME of thymomas can synergistically determine MG severity in patients with TMG.

The role of serum asprosin levels in predicting the severity of coronary artery disease in patients with diabetes mellitus.

Asprosin is an emerging biomarker that plays a role in metabolic diseases. This study investigates asprosin as a predictive marker for coronary artery disease (CAD) severity in diabetic patients. Diabetic patients (n = 181) and healthy controls (n = 60) were analyzed. CAD severity was assessed using SYNTAX score. Diabetic patients were divided into 3 groups. Group 1 = patients without CAD, group 2 = patients with low SYNTAX score, and group 3 = patients with moderate-high SYNTAX score. Asprosin levels were measured for all participants using an enzyme-linked immunosorbent assay (ELISA). Asprosin levels were significantly higher in patient group compared to control group (p < 0.001). Asprosin levels were significantly higher in group 3 compared to group 1 and group 2 (p = 0.002). In logistic regression analysis, asprosin levels independently predicted patients with moderate-high SYNTAX scores. According to this analysis, 1ng/mL increase in asprosin level was found to increase the risk of having moderate-high SYNTAX score by 14.1%. When the threshold value of asprosin level was set as 22.17ng/mL, it predicted patients with moderate-high SYNTAX score with 63.6% sensitivity and 62.6% specificity. In multivariate regression analysis, SYNTAX score independently correlated with asprosin level. This is the first study in the literature to demonstrate a positive correlation between asprosin levels and SYNTAX scores in diabetic patients with CAD. More comprehensive studies with larger groups are needed.

Adherence to lung protective mechanical ventilation in patients admitted to a surgical intensive care unit and the associated increased mortality

BackgroundThe adherence rate to the lung protective ventilation (LPV) strategy, which is generally accepted as a standard practice in mechanically ventilated patients, reported in the literature is approximately 40%. This study aimed to determine the adherence rate to the LPV strategy, factors associated with this adherence, and related clinical outcomes in mechanically ventilated patients admitted to the surgical intensive care unit (SICU). MethodsThis prospective observational study was conducted in the SICU of a tertiary university-based hospital between April 2018 and February 2019. Three hundred and six adult patients admitted to the SICU who required mechanical ventilation support for more than 12 h were included. Ventilator parameters at the initiation of mechanical ventilation support in the SICU were recorded. The LPV strategy was defined as ventilation with a tidal volume of equal or less than 8 ml/kg of predicted body weight plus positive end-expiratory pressure of at least 5 cm H2O. Demographic and clinical data were recorded and analyzed. ResultsThere were 306 patients included in this study. The adherence rate to the LPV strategy was 36.9%. Height was the only factor associated with adherence to the LPV strategy (odds ratio for each cm, 1.10; 95% confidence interval (CI), 1.06–1.15). Cox regression analysis showed that the LPV strategy was associated with increased 90-day mortality (hazard ratio, 1.73; 95% CI, 1.02–2.94). ConclusionThe adherence rate to the LPV strategy among patients admitted to the SICU was modest. Further studies are warranted to explore whether the application of the LPV strategy is simply a marker of disease severity or a causative factor for increased mortality.