Marker Of Disease Research Articles

Intracerebral haemorrhage - mechanisms, diagnosis and prospects for treatment and prevention.

Intracerebral haemorrhage (ICH) is a devastating condition associated with high mortality and substantial residual disability among survivors. Effective treatments for the acute stages of ICH are limited. However, promising findings from randomized trials of therapeutic strategies, including acute care bundles that target anticoagulation therapies, blood pressure control and other physiological parameters, and trials of minimally invasive neurosurgical procedures have led to renewed optimism that patient outcomes can be improved. Currently ongoing areas of research for acute treatment include anti-inflammatory and haemostatic treatments. The implementation of effective secondary prevention strategies requires an understanding of the aetiology of ICH, which involves vascular and brain parenchymal imaging; the use of neuroimaging markers of cerebral small vessel disease improves classification with prognostic relevance. Other data underline the importance of preventing not only recurrent ICH but also ischaemic stroke and cardiovascular events in survivors of ICH. Ongoing and planned randomized controlled trials will assess the efficacy of prevention strategies, including antiplatelet agents, oral anticoagulants or left atrial appendage occlusion (in patients with concomitant atrial fibrillation), and optimal management of long-term blood pressure and statin use. Together, these advances herald a new era of improved understanding and effective interventions to reduce the burden of ICH.

Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test

The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al ’s work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.

Reactive arthritis in children

One of the common childhood illnesses is reactive arthritis, which develops during or soon after an infection.Purpose. The aim of the study was to study the etiology, clinical and laboratory manifestations of arthritis in children.Material and methods. The study included 37 children with arthritis aged 1 year 10 months to 15 years who were hospitalized at Kazan City Children’s Hospital № 1.Results. Reactive arthritis was diagnosed in 26 children, and juvenile idiopathic arthritis in 11. In 20 patients, reactive arthritis manifested itself as monoarthritis with predominant damage to the hip or knee joints – in 11 and 9 cases, respectively. Two children had ankle arthritis. In 4 cases there was oligoarthritis. Markers of infectious diseases were identified in 10 out of 26 children with reactive arthritis (38%). In 5 children (19%) IgM to Mycoplasma pneumonia was detected, in two (8%) – IgM to capsid antigen of Epstein–Barr virus, in one child (4%) – IgM to Chlamydia pneumonia. Two children had elevated ASLO values (more than 400 IU/ml). Inflammatory in the blood in 33 cases (89%) were characterized by increased erythrocyte sedimentation rate, the median of which was 22 mm/hour. Increased level of C-reactive protein and leukocytes in the blood were observed only in 9 (24%) and 7 (19%) children, respectively.Conclusion. Reactive arthritis in children mainly manifests as monoarthritis, with predominant damage to the hip or knee joints and in most cases was associated with Mycoplasma pneumonia.

Additive effects of cerebrovascular disease functional connectome phenotype and plasma p-tau181 on longitudinal neurodegeneration and cognitive outcomes.

We investigated the effects of multiple cerebrovascular disease (CeVD) neuroimaging markers on brain functional connectivity (FC), and how such CeVD-related FC changes interact with plasma phosphorylated tau (p-tau)181 (an Alzheimer's disease [AD] marker) to influence downstream neurodegeneration and cognitive changes. Multivariate associations among four CeVD markers and whole-brain FC in 529 participants across the dementia spectrum were examined using partial least squares correlation. Interactive effects of CeVD-related FC patterns and p-tau181 on longitudinal gray matter volume (GMV) and cognitive changes were investigated using linear mixed-effects models. We identified a brain FC phenotype associated with high CeVD burden across all markers. Further, expression of this general CeVD-related FC phenotype and p-tau181 contributed additively, but not synergistically, to baseline and longitudinal GMV and cognitive changes. Our findings suggest that CeVD exerts global effects on the brain connectome and highlight the additive nature of AD and CeVD on neurodegeneration and cognition. Effects of multiple cerebrovascular disease (CeVD) markers on functional connectivity were studied. A global network phenotype linked to high burden across CeVD markers was identified. CeVD phenotype and plasma phosphorylated tau 181 contributed additively to downstream outcomes.

Abstract 4138647: Opportunistic Screening for Cardiovascular Risk Using Chest X-Rays and Deep Learning: Associations with Coronary Artery Disease in the Project Baseline Health Study and Mass General Brigham Biobank

Introduction/Background: We previously demonstrated that an open-source deep learning model (CXR-CVD Risk) can predict 10-year major adverse cardiovascular events (myocardial infarction&stroke), based on a chest radiograph image (CXR). As deep learning models are black boxes, establishing the biological processes the model captures to predict risk may help build understanding and trust in the model. Research Questions/Hypothesis: To test associations between deep-learning derived CXR-CVD Risk and markers of cardiovascular disease including coronary artery calcium (CAC) and stenosis ≥50% on CT, systolic blood pressure (SBP), ankle brachial index (ABI), and prevalent myocardial infarction and stroke. Methods/Approach: We conducted external validation of CXR-CVD-Risk in two cohorts: 1) 2,097 volunteers in the Project Baseline Health Study (PBHS) and 2) 1,644 Mass General Brigham Biobank (MGBB) patients. The CXR-CVD-Risk model estimated 10-year cardiovascular event risk (probability between 0 and 1) from a CXR image. We calculated linear associations with SBP, ABI, and the logarithm of coronary artery calcium and odds ratios for prevalent hypertension, myocardial infarction, stroke, and, in the MGBB, coronary artery stenosis ≥50%. Analyses were adjusted for age, BMI, sex, smoking status, and enrolling site. Results/Data: CXR-CVD-Risk was associated with CAC in both populations (PBHS: 1.11-fold increase, 95% CI: [1.07-1.16]; MGBB: 1.03-fold increase [1.01-1.05] in CAC per 1% increase in CXR-CV-Risk). CXR-CVD-Risk was also associated with SBP (0.59 mmHg increase [0.24-0.93] in SBP per 1% increase in CXR-CV-Risk), history of hypertension, history of myocardial infarction, and stroke. There was an inverse association with ABI (0.010 decrease [0.005-0.014] in ABI) in the PBHS. In the MGBB, CXR-CVD-Risk was associated with coronary artery stenosis ≥50% (OR = 1.004 [1.002-1.007]). All estimates are after covariate adjustment. Conclusion: This deep learning CXR risk score was associated with coronary artery disease (calcium score and stenosis ≥50%), CVD risk factors, and prevalent CVD. Opportunistic screening using CXRs in the electronic record can identify patients at high risk of CVD who may benefit from prevention.

Occupational and Hobby Exposures Associated with Myositis Phenotypes in a National Myositis Patient Registry.

To investigate occupational and hobby exposures to silica, solvents, and heavy metals and odds of idiopathic inflammatory myositis (IIM) phenotypes, dermatomyositis (DM) and polymyositis (PM) versus inclusion body myositis (IBM), lung disease plus fever or arthritis (LD+), and systemic autoimmune rheumatic disease-overlap myositis (OM). The sample included 1390 patients (598 DM, 409 PM, and 383 IBM) ages ≥18 years from a national registry. Of these, 218 (16%) were identified with LD+, i.e., self-reported lung disease with fever and/or arthritis, and 166 (12%) with OM. Questionnaire data on jobs, hobbies, and exposures before diagnosis were evaluated using a rules-based protocol and expert assessment of silica dust, solvents, and heavy metals exposure. We calculated adjusted odds ratios (OR) and 95% confidence intervals (CI) and explored joint effects with smoking. High silica exposure was associated with an increased odds of having DM (OR=2.02; 95%CI 1.18-3.46, compared to no exposure; p-trend=0.004), LD+ (1.75; 1.10-2.78; p-trend=0.005, versus no LD), and OM (2.07; 1.19-3.61; p-trend=0.020). Moderate to high heavy metals exposure was associated with greater odds of having LD+ (1.49; 1.00-2.14; p-trend=0.026) and OM (1.59; 0.99-2.55, p-trend=0.051). Greater odds of LD+ were seen among smokers with moderate to high silica exposure versus non-smokers with low or no exposure (high-certainty assessment, 2.53; 1.31-4.90; p-interaction=0.061). These findings, based on a systematic exposure assessment, suggest that occupational and hobby exposures to silica and heavy metals contribute to adult IIM phenotypes, including DM, OM, and LD+, a possible marker for anti-synthetase or other autoantibody-associated lung disease.

Exploring Haptoglobin as a Promising Marker for Severe Liver Diseases: A Comprehensive Review

Liver damage is a common symptom of many diseases, including metabolic disorders and cancers. Such patient condition requires effective examinations aimed at prompt diagnosis and implementation of the most appropriate treatment for a specific disease. Haptoglobin, the subject of many studies, has proven to be a protein that can be used as a biomarker of liver damage, thereby aiding not only in the diagnosis but also in the treatment, resulting in more favorable prognoses regarding patient longevity and quality of life.The aim of this study is to elucidate the role of haptoglobin as a diagnostic and prognostic biomarker in cases of liver damage.This is a review of scientific literature and analysis of clinical data regarding haptoglobin levels in liver damage were conducted to assess the reliability of haptoglobin as a biomarker.This paper primarily utilized the latest publications produced after 2015. PubMed and Google Scholar were used to find relevant publications. All cited works provided useful information to achieve the aim of our article.Analysis of the literature suggests that haptoglobin levels may be significantly associated with the development and severity of liver damage. It may serve as a suitable biomarker for diagnosing diseases that coincide with hepatocyte damage, thus improving the diagnosis of these diseases and increasing the chance of appropriate treatment, which may contribute to prolonging and improving the patient's quality of life.Haptoglobin appears to be a promising biomarker in liver damage; however, further research is necessary to confirm its diagnostic and prognostic accuracy. Haptoglobin exists in various genotypic forms, each characteristic of different disease entities. Understanding the mechanisms regulating haptoglobin levels may lead to a better understanding of liver damage pathogenesis and the development of more effective therapies, increasing the chance of patient recovery and improving their quality of life.

Enhanced Molecular Imaging through a Versatile Peptide Nanofiber for Self-assembly and Precise Recognition.

Designing molecules for multivalent targeting of specific disease markers can enhance binding stability which is critical in molecular imaging and targeted therapy. Through rational molecular design, the nanostructures formed by self-assembly of targeting peptides are expected to achieve multivalent targeting by increasing the density of recognition ligands. However, the balance between targeting peptide self-assembly and molecular recognition remains elusive. In this study, we designed a targeting-peptide-based imaging probe system TAP which consist of the signal unit, the recognition motif, the assembly motif and a Pro-leverage. It is verified that TAP could specifically binds to PD-L1-positive tumor cells in a multivalent manner to produce biological effects, and could also be combined with imaging probes through unique self-assembly strategies. By the balance between the peptide self-assembly and targeting recognition, the specificity and stability can be improved while the accumulation capacity of the probes at the tumor site can be greatly enhanced compared with the conventional strategy, thus reducing side effects, providing an effective tool for diagnostic and therapeutic integration of tumors.

Structural and Functional Insights into Dishevelled-Mediated Wnt Signaling

Dishevelled (DVL) proteins precisely control Wnt signaling pathways with many effectors. While substantial research has advanced our understanding of DVL’s role in Wnt pathways, key questions regarding its regulatory mechanisms and interactions remain unresolved. Herein, we present the recent advances and perspectives on how DVL regulates signaling. The experimentally determined conserved domain structures of DVL in conjunction with AlphaFold-predicted structures are used to understand the DVL’s role in Wnt signaling regulation. We also summarize the role of DVL in various diseases and provide insights into further directions for research on the DVL-mediated signaling mechanisms. These findings underscore the importance of DVL as a pharmaceutical target or biological marker in diseases, offering exciting potential for future biomedical applications.

Bevacizumab as a mitigating factor for the impact of high systemic immune-inflammation index on chemorefractory in advanced epithelial ovarian cancer.

Predicting chemorefractory disease in advanced epithelial ovarian cancer (EOC) remains challenging. This study aimed to identify clinicopathological factors and hemogram data as predictive markers for chemorefractory EOC and to explore potential therapeutic approaches that may mitigate these unfavorable conditions. We conducted a retrospective analysis of patients with advanced EOC treated with chemotherapy. Hemogram data and clinicopathological variables were collected. We employed logistic regression to assess factors associated with chemorefractory EOC and used the Kaplan-Meier method for survival analysis. Among the 191 patients analyzed, suboptimal surgery, lymphocyte count < 1440/mm3, systemic immune-inflammation index (SII) ≥ 2350, and lack of bevacizumab therapy were independently associated with chemorefractory EOC (OR 19.30, 95% CI 7.01-53.12; OR 9.07, 95% CI 2.76-29.82; OR 12.45, 95% CI 3.87-40.07; OR 6.61, 95% CI 2.01-21.78, respectively). Elevated SII was also identified as a risk factor for poor progression-free (PFS) and overall survival (OS). Specifically, patients with high SII who did not receive bevacizumab had a significantly higher probability of chemorefractory EOC and poorer survival outcomes compared to those who received bevacizumab. Our findings suggest that hemogram parameters and clinicopathological factors such as suboptimal surgery, lymphocyte count, SII, and bevacizumab therapy status are predictive markers for chemorefractory disease in advanced EOC. Elevated SII emerged as a predictor for poorer PFS and OS outcomes, particularly in the absence of bevacizumab therapy.

Analyzing immune cell infiltrates in skeletal muscle of infantile-onset Pompe disease using bioinformatics and machine learning

Pompe disease, a severe lysosomal storage disorder, is marked by heart problems, muscle weakness, and respiratory difficulties. This study aimed to identify novel markers for infantile-onset Pompe disease by analyzing key genes and immune cells infiltrating affected skeletal muscles, building on existing research linking its progression to the immune cell infiltration. The datasets GSE38680 and GSE159062 were downloaded and differential expression genes (DEGs) were identified. Potential markers were screened using support vector machine recursive feature elimination (SVM-RFE) analysis and least absolute shrinkage and selection operator (LASSO) regression models. To analyze DEGs and immune processes, 22 immune cell types in affected tissues were examined using CIBERSORT. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant enrichment in the calcium signaling pathway, phosphatidylinositol signaling system, ubiquitin-mediated proteolysis and JAK-STAT signaling pathway. Machine learning identified GPNMB, CALML6 and TRIM7 as key genes. Immune cell infiltration analysis showed that the expression levels of the above three genes were closely related to immune cells in our target population under study, including T cells regulatory (Tregs), monocytes, macrophages M0, resting and activated dendritic cells, naive and memory B cells. Overall, our study results may provide new clues for exploring markers related to Pompe disease by highlighting key genes and their relationship with immune infiltration, offering insights into the disease’s development. However, previous studies have shown limited evidence of significant immune cell infiltration in muscle biopsies from Pompe patients, and this lack of direct evidence necessitates further investigation and experimental validation in laboratory settings to confirm these associations.

BIOM-04. SINGLE-CELL RNA SEQUENCING PROTOCOL OF THE HUMAN METASTATIC PROSTATE SPINE TUMOR MICROENVIRONMENT

Abstract INTRODUCTION 90% of spine tumor patients can develop metastases with debilitating complications, such as sensorimotor dysfunction, paralysis, and spinal instability. As spine tumor patients have limited eligibility to participate in clinical trials and have heterogenous tumor pathology, there is a distinct lack of therapeutic targets and prognostication markers of disease. Thus, there is a distinct need for molecular profiling of spine tumors. OBJECTIVE We describe an OR-to-bench-top processing of spine tumors for single-cell omic studies, with samples from a metastatic prostate cancer patient to demonstrate the ability to compare molecular markers and microenvironments of difficult-to-process spine tumors and adjacent normal tissue. METHODS Under IRB protocol #Pro00101198, patients undergoing spine surgery with the Department of Neurosurgery at Duke University were consented for tissue collection. Vertebral osseous metastases and adjacent normal tissue were confirmed histologically (H&amp;E, immunohistochemistry) and radiologically (MRI, PET, CT, and x-ray). Tissues were manually and enzymatically homogenized in serum-free media with collagenase A and DNAse I to obtain a single cell suspension. Cells were then filter sterilized, erythrolyzed, counted to determine live-death ratio, resuspended to 10-20 million cells per mL, then cryopreserved for downstream standard library preparation for single-cell sequencing using the 10X genomics platform. Downstream analysis was performed using Seurat pipeline, InferCNV analysis, and SingleR. RESULTS P404S and PSA expression confirmed tumor was prostate in origin. Radiological imaging and H&amp;E staining confirmed the presence of T7 osseous metastasis. Uniform manifold approximation and project (UMAP) plots identified 12 unique clusters of immune cell subpopulations between normal and tumorous vertebrae, with their own subsets of differentially expressed genes. CONCLUSION We have developed a protocol to generate granular single cell molecular profiling for spine tumors and metastases. Applications of this protocol can aid in identifying therapeutic targets, molecular predictors of disease, and potentiate increased eligibility of patients for clinical trials.

INNV-33. ADVANCING PRECISION TREATMENT FOR DIFFUSE MIDLINE GLIOMA: THE DMG LEARNING HUB INITIATIVE

Abstract Diffuse Midline Glioma (DMG) poses a significant challenge in neuro-oncology due to its heterogeneous presentation and limited therapeutic options. Clinical trials often serve as the primary avenue for treatment, yet families encounter numerous barriers in navigating and selecting appropriate trials. Health disparities, including disparities in medical literacy and access to specialized medical centers, further complicate decision-making processes. Existing registries lack comprehensive data integration, focusing on isolated perspectives of either research or clinical data, neglecting the holistic patient profile. Evaluation of treatment endpoints beyond Progression-Free Survival (PFS) and Overall Survival (OS) remain inconsistent, despite being a priority for families. The DMG Learning Hub emerges as a transformative platform designed to empower families by offering informed options and guidance while fostering a collaborative environment where patient families actively contribute to shaping the landscape of clinical trials. Leveraging AI-assisted matching, the platform assists families in navigating the complex decision-making process surrounding clinical trial participation. The inclusion of a patient-reported outcome journal feature enables families to track vital information such as symptom changes and supplement usage, with autonomy over the timing of shared data. Using real-time data sharing facilitates invaluable insights for researchers, bridging gaps that would otherwise be overlooked and enriching the collective understanding of DMG. Harmonizing molecular, imaging, and clinical data within the platform equips care teams with comprehensive, near-real-time information crucial for personalized treatment strategies. This integrated approach not only supports the inclusion of n-of-1 arms in current trials but also extends therapeutic opportunities to patients previously ineligible for studies due to specific disease markers or progression patterns. The DMG Learning Hub represents a significant stride towards precision oncology by synergizing patient-centric priorities with cutting-edge technology, integrating harmonized data, and fostering collaborative efforts, the initiative heralds a promising era of personalized treatment for DMG and beyond the neuro-oncology community.

The triglyceride-glucose index as an indicator of latent atherogenicity of the plasma lipid profile in healthy men with normolipidaemia

ABSTRACT Objectives The triglyceride-glucose (TyG) index is a novel diagnostic marker for various metabolic and cardiovascular diseases. However, little is known about the association of the TyG index with plasma atherogenicity, especially with its latent forms. The aim of this study was to assess the potential of the use of the TyG index as a marker of atherogenic risk. Methods A total of 202 men with normolipidaemia, aged 20–60 years, were enrolled in this study. Fasting biochemical parameters were measured. The TyG index was calculated as ln[triglyceride(mg/dL)×glucose(mg/dL)]/2. The diagnostic ability of the TyG index for detecting atherogenic risk was tested by receiver operating characteristic (ROC) curve analysis. Results A substantial portion of normolipidaemic men had deviations from the reference values for the indices calculated using apolipoproteins. Unfavorable values for the apolipoprotein (apo) B/apoA-I ratio, low-density lipoprotein cholesterol/apoB (LDL-C/apoB) ratio, and the atherogenic index (ATH index) were observed in 32.7%, 31.7%, and 14.4% of men, respectively. The results of ROC curve analysis showed that the TyG index had good diagnostic ability for identifying unfavorable apolipoprotein indices in normolipidaemic men. Conclusions Thus, the TyG index can be a valuable additional marker for assessing latent atherogenic risk; it can provide useful information for the diagnosis and treatment of early atherosclerosis.

“Early Mortality and Health Care Costs in Patients Recently Diagnosed with Kaposi Sarcoma at the National Cancer Institute, Mexico City”

Abstract Background Kaposi Sarcoma (KS) is a marker of advanced HIV disease; it is still the most frequent AIDS-associated malignancy in Mexico despite universal access to antiretroviral therapy, reflecting a gap in early HIV diagnosis. Objectives To describe people with HIV (PWH) with KS who died within 30 days of admission at INCan and quantify resources and years of life lost (YLL). Methodology We collected demographic data, HIV-related variables, all diagnostic and therapeutic procedures, hospitalizations, and estimated YLL and Disability-Adjusted Life Years (DALYs). Results Eighteen (6.7 %) PWH with KS from 270 patients admitted at INCan from 2014-2021 were included. The median age was 31 years (IQR 27-36), and the median days from admission to death were 15 (IQR 6-24), and from HIV diagnosis to death, 73 days (IQR 30-857). Upon admission, the median HIV viral load was 314,476 copies/mL (IQR 140,709-695,613), CD4+ T cells count was 93 cells/mL (IQR 35-124), and CD4/CD8 ratio was 0.08 (IQR 0.06-0.12), coinfections were diagnosed in 14 (77.7 %) patients, The average expenditure per patient was 7685.99 USD, and the total YLL was 737.4, a median of 42 years (IQR 37.7-47) per patient. The total care cost was 183,947.48 USD, equivalent to a screening program in key populations, which would have allowed the early detection of 1227 cases and saved 8,410 DALYs. Conclusions Reinforcement of early HIV infection detection in key population programs should be prioritized to reduce KS-associated deaths and YLL and for rational use of health budgets.

The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.MethodsWe used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.ResultsAPG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.ConclusionsOur results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.Graphical

Expediting treatments in the 21st century: orphan drugs and accelerated approvals

BackgroundIn response to activated patient communities’ catalyzation, two significant efforts by the FDA to expedite treatments have now been in place for multiple decades. In 1983, the United States Congress passed the Orphan Drug Act to provide financial incentives for development of drugs for rare diseases. In 1992, partly in response to the HIV epidemic, the FDA implemented Accelerated Approval (AA) to expedite access to promising new therapies to treat serious conditions with unmet medical need based on surrogate marker efficacy while additional clinical data is confirmed.The uses of these regulatory approaches over time are assessed in this study.MethodsThe following U.S. FDA CDER published lists were used in this analysis: 1. all orphan designations and approvals; 2. all AA and their details updated through December 31, 2022; new molecular entities (NMEs).ResultsOrphan drug designations and approvals have increased several-fold over the past four decades. The largest increase recently has been in therapies targeting oncological diseases (comprised of both oncology and malignant hematology).Although orphan drug approvals based on NMEs are the minority of orphan drug designations, the count of approved orphan drug NMEs has increased in recent years.The characteristics of orphan drug approvals show notable differences by disease area with rare diseases and medical genetics (49%) having a relatively large fraction of orphan drug approvals with NMEs compared to the oncological diseases (32%).Similar to the use of orphan drug designation, oncological disease therapies have been the largest utilizers of AA. Many therapies targeting these diseases address unmet medical need and can leverage surrogate markers that have previously been used in similar trials.The timings of conversion of AA (confirmed or withdrawn) were assessed and found to be consistent across decades and to have some dependency upon the broad disease area (when assessed by three large groups: HIV conversions were fastest; followed by oncology; followed by all others). By the end of 2022, 98% of the first 105 (approved in 2010 or earlier) AA had been converted to confirmed or withdrawn.ConclusionsAlthough the typical timings for AA to be confirmed or withdrawn has not changed significantly over the decades, the disease areas utilizing orphan drug designation and AA have changed significantly over time. Both programs have had increases in their use for therapies targeting oncological diseases.The re-use of surrogate markers for oncological diseases has been an advantage in a way that may not be scientifically feasible in many other disease areas that have greater differentiation across disease etiology. For non-oncological diseases, applicability of AA is, in part, dependent upon greater focus on characterization and acceptance of novel surrogate markers.

Agreement between Cerebrospinal Fluid Biomarkers, Brain 18-Fluorodeoxyglucose PET, and Clinical Diagnosis in Older Adults with Cognitive Impairment.

Background: Clinical practice has advanced toward a combined diagnostic approach that involves clinical criteria and biological markers for Alzheimer's disease (AD) and other dementias. Objective: To establish the level of diagnostic agreement between an initial clinical diagnosis and cerebrospinal fluid (CSF) and [18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) biomarkers in a cohort of patients from a memory clinic. Methods: This is a observational, retrospective, cohort study conducted at an outpatient memory clinic. Between July 2018 and September 2023, data from adults' ≥ 55 years with a mild cognitive impairment or dementia diagnosis without etiological diagnosis were obtained, complemented with the evaluation of biomarkers in CSF and [18F] FDG-PET biomarker assessment were included. Kappa coefficients (κ) were used to establish the level of agreement between CSF and [18F] FDG-PET results. Results: Seventy-seven patients had an available [18F] FDG-PET scan, and 25 (32.5%) had both biomarkers. We observed a fair-to-moderate diagnostic agreement between patients' initial and their final diagnosis in the presence of CSF (κ = 0.233, 95% confidence interval [CI]: -0.099-0.566) and [18F] FDG-PET (κ = 0.451, 95% CI: 0.277-0.625, p < 0.001) results. The Kappa value for diagnostic concordance between [18F] FDG-PET and CSF to differentiate between AD and other dementias was 0.733 (95% CI: 0.425-1.000, p < 0.005). Conclusion: This study demonstrates good agreement between the CSF and FDG-PET biomarkers to differentiate AD from other dementias. (Rev Invest Clin. 2024;76(5):230-7).

Diagnostic and prognostic value of plasma lipocalin-2 levels in patients with metabolic dysfunction–associated steatotic liver disease

Abstract Background Non-Alcoholic Fatty Liver Disease, recently better recognised as Metabolic Dysfunction–Associated Steatotic Liver Disease, is the most prevalent form of chronic liver disease at present time. It is estimated to impact 32% of the world's population, hence representing a significant health burden. Aim of the work To assess the significance of plasma Lipocalin-2 (LCN2) levels in the diagnosis and prognosis of NAFLD patients. Patients and methods In this retrospective case–control study we recruited 102 subjects aged between 18 and 70 years. The included participants were split into two study groups. Group I: 51 NAFLD patients (61% men, 39% females) and Group II: 51 healthy controls (51% men and 49% females), for whom plasma LCN2 levels were assessed and correlated with NAFLD fibrosis score, FIB4 and fatty liver index. Results In this study, LCN2 levels in NAFLD patients were significantly greater compared to individuals in the control group (p &lt; 0.001), with a mean of 1893.214 ± 1002.852 ng/dL in the cases and a mean of 466.020 ± 397.699 ng/dL in the controls. This suggests the use of LCN2 as a possible diagnostic marker of NAFLD. The mean LCN2 levels in this study also significantly increased as the grade of fatty liver increased from I to III (p &lt; 0.001). This in turn proposes the use of LCN2 as a prognostic marker for NAFLD progression. LCN2 also significantly correlated with the fatty liver index and NAFLD Fibrosis scoring systems, but not with Fib-4. With an area under the ROC of 0.906, it demonstrated excellent diagnostic performance with 84% sensitivity, 90% specificity, 89.6% PPV and 85.2% NPV for the prediction of NAFLD patients. Conclusion Lipocalin-2 performs as a diagnostic and a possible prognostic marker for metabolic dysfunction-associated steatotic liver disease.

Early Diagnosis of Subclinical Atherosclerosis in Asymptomatic Type 2 Diabetic Normotensive Menopausal Women: A Global Pulse Wave Velocity Study

AbstractArterial stiffness serves as a cardiovascular disease marker, aiding in the early identification of high-risk patients. We aimed to evaluate the prevalence of arterial stiffness, measured by global pulse wave velocity (gPWV), among diabetic normotensive menopausal women (DPMW) and its correlation with levels of glycosylated hemoglobin (HbA1c). We recruited 641 consecutive DPMW diagnosed with type 2 diabetes over 5 years. The control group (CG) consisted of 300 normotensive, normoglycemic menopausal women. Normal gPWV was defined as a velocity ≤7.1 m/s. We enrolled 641 DPMW with a mean age of 57 ± 12 years. The CG comprised 300 normotensive, normoglycemic postmenopausal women with a mean age of 56 ± 4 years. Among DPMW, 29 (4.5%) exhibited increased gPWV compared with 4 (1.3%) in the CG (p &lt; 0.01). Of the 225 (35.1%) DPMW with HbA1c &gt; 7.5%, 23 (10.2%) had increased gPWV. In contrast, among the 416 (64.9%) DPMW with HbA1c &lt; 7.5%, only 6 (1.4%) had increased gPWV (p &lt; 0.0001). Electrocardiographic (ECG) abnormalities were detected in 208 (32.4%) DPMW, with 11 (5.3%) of them exhibiting increased gPWV (p = 0.6). There was a higher prevalence of increased gPWV in asymptomatic normotensive DPMW, with a significant association between increased gPWV and elevated HbA1c levels. However, there was no correlation between increased gPWV and abnormal ECG findings, despite ECG being the sole test recommended by current guidelines for all diabetic patients. Early detection of elevated HbA1c levels and increased gPWV may identify asymptomatic DPMW at higher cardiovascular risk, highlighting the inadequacy of a simple ECG in assessing cardiovascular risk in this population.