Marker Of Progression Research Articles

Immune regulation and blood–brain barrier permeability in cerebral small vessel disease: study protocol of the INflammation and Small Vessel Disease (INSVD) study – a multicentre prospective cohort study

IntroductionThe INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood–brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease...

GAS6/TAM Axis as Therapeutic Target in Liver Diseases.

TAM (TYRO3, AXL, and MERTK) protein tyrosine kinase membrane receptors and their vitamin K-dependent ligands GAS6 and protein S (PROS) are well-known players in tumor biology and autoimmune diseases. In contrast, TAM regulation of fibrogenesis and the inflammation mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and, ultimately, liver cancer has recently been revealed. GAS6 and PROS binding to phosphatidylserine exposed in outer membranes of apoptotic cells links TAMs, particularly MERTK, with hepatocellular damage. In addition, AXL and MERTK regulate the development of liver fibrosis and inflammation in chronic liver diseases. Acute hepatic injury is also mediated by the TAM system, as recent data regarding acetaminophen toxicity and acute-on-chronic liver failure have uncovered. Soluble TAM-related proteins, mainly released from activated macrophages and hepatic stellate cells after hepatic deterioration, are proposed as early serum markers for disease progression. In conclusion, the TAM system is becoming an interesting pharmacological target in liver pathology and a focus of future biomedical research in this field.

Comparative evaluation of serum and gingival crevicular fluid levels of interleukin 21 in periodontally diseased and healthy patients.

Periodontitis is an inflammatory reaction to subgingival pathogenic microorganisms that causes gradual deterioration of the gingiva, periodontal ligament,and alveolar bone. Interleukin (IL)-21 is the most recently found member of type I cytokine family that is upregulated during inflammation. The current study aims to investigate the biological plausibility of IL-21 as a biomarker for chronic periodontitis. This cross-sectional clinico-biochemical investigation included 15 systemically healthy, 15 periodontally healthy, 15 chronic gingivitis, and 15 chronic periodontitis subjects aged 25 to 60 years. Following subject enrollment, gingival crevicular fluid (GCF) and blood samples were then taken from each subject. The concentration of IL-21 in all samples was determined using enzyme-linked immunosorbent assay (ELISA) kit. The data was examined using the Kruskal-Wallis test and the Spearman correlation test. Serum IL-21 levels in chronic periodontitis patients were substantially greater than in periodontally healthy individuals. GCF IL-21 levels were substantially greater in gingivitis and chronic periodontitis patients compared to periodontally healthy individuals. In terms of clinical indicators, serum IL-21 levels correlated significantly with bleeding index (BI) in the chronic periodontitis group. In chronic periodontitis group, disease severity as evaluated by probing pocket depth (PPD) and clinical attachment loss (CAL) did not correlate with serum or GCF IL-21 levels. According to the current study's findings, periodontally involved patients had higher IL-21 levels than periodontally healthy patients, suggesting it can be used as biomarker. Further studies with larger sample size can shed more light on the clinical advantage of IL-21 as a possible marker for disease activity and progression.

Research progress on the correlation between platelet aggregation and tumor progression.

Platelets are generally considered as the main functional unit of the coagulation system. However, more and more studies have confirmed that platelets also have an important relationship with tumor progression. Tumor cells can utilize platelets to promote their own infiltration and hematogenous metastasis, and platelets are activated and aggregated in this process. Therefore, platelet aggregation may be a concomitant marker of tumor progression. This is of great significance for predicting tumor metastasis before timely treatments.

Distribution and Clinical Significance of Hepatitis B virus A1762T/G1764A Double Mutation in Chronic Hepatitis B Patients: A Cross-Sectional Study.

Chronic hepatitis B (CHB) is well-known as a major risk for liver cirrhosis and hepatocellular carcinoma (HCC). The A1762T/G1764A double mutation in the hepatitis B virus genome affects the production of HBe antigen and is established as a predictive marker for progression to HCC. Thus, this study aimed to investigate the prevalence and clinical significance of the mutation in Thai CHB patients. A cross-sectional study was conducted in 78 Thai CHB patients who were assessed for hepatitis B profiles, HBsAg, HBeAg and anti-HBeAg, transaminitis, liver fibrosis defined by FIB-4 (FIB-4) score and AST to platelet ratio index (APRI), alpha-fetoprotein (AFP) and active hepatitis B status. HBV A1762T/G1764A mutation was examined by SYBR Green I Real-time PCR. Chi-square and Mann-Whiney U tests were performed to determine the association between the mutation and variables. The prevalence of patients infected with the A1762T/G1764A mutation was 44.9%. The mutation was associated with HBeAg status (p=0.027) and HBsAg levels (p=0.008), transaminitis (p=0.011), and active hepatitis B (p=0.037), but not liver fibrosis markers, FIB-4 score and APRI, and AFP. Binary logistic regression identified the mutation as a predictive factor of active hepatitis B (OR 3.5, 95%CI, 1.1-11.3, p=0.037). Patients infected with the mutant exhibited significantly higher levels of HBsAg (p=0.011) and HBV viral load (p=0.047), but lower levels of HBeAg (p=0.12) than those infected with the wild-type HBV. The data indicate the high prevalence of the A1762T/G1764A mutation and its significant association with the severity of Thai CHB patients and the HBV mutation is proposed as a predictive marker of active hepatitis B status in CHB patients.

Association of Family History and Polygenic Risk Score With Longitudinal Prognosis in Parkinson Disease.

Evidence suggests that either family history or polygenic risk score (PRS) is associated with developing Parkinson disease (PD). However, little is known about the longitudinal prognosis of PD according to family history and higher PRS. From the Parkinson's Progression Markers Initiative database, 395 patients with PD who followed up for more than 2 years were grouped into those with family history within first-degree, second-degree, and third-degree relatives (N = 127 [32.2%]) vs those without (N = 268 [67.8%]). The PRS of 386 patients was computed using whole-genome sequencing data. Longitudinal assessment of motor, cognition, and imaging based on dopaminergic degeneration was conducted during the regular follow-up period. Effects of family history, PRS, or both on longitudinal changes of cognition, motor severity, and nigrostriatal degeneration were tested using a linear mixed model. The risk of freezing of gait (FOG) according to family history was assessed using the Kaplan-Meier analysis and Cox regression models. During a median follow-up of 9.1 years, PD with positive family history showed a slower decline of caudate dopamine transporter uptake (β estimate of family history × time = 0.02, 95% CI = 0.002-0.036, p = 0.027). Family history of PD and higher PRS were independently associated with a slower decline of Montreal Cognitive Assessment (β estimate of family history × time = 0.12, 95% CI = 0.02-0.22, p = 0.017; β estimate of PRS × time = 0.09, 95% CI = 0.03-0.16, p = 0.006). In those 364 patients without FOG at baseline, PD with positive family history had a lower risk of FOG (hazard ratio of family history = 0.57, 95% CI = 0.38-0.84, p = 0.005). Having a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS. Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD. The study was registered at clinicaltrials.gov (NCT01141023), and the enrollment began June 1, 2010.

Longitudinal brain structure changes in Parkinson's disease: A replication study.

An existing major challenge in Parkinson's disease (PD) research is the identification of biomarkers of disease progression. While magnetic resonance imaging is a potential source of PD biomarkers, none of the magnetic resonance imaging measures of PD are robust enough to warrant their adoption in clinical research. This study is part of a project that aims to replicate 11 PD studies reviewed in a recent survey (JAMA neurology, 78(10) 2021) to investigate the robustness of PD neuroimaging findings to data and analytical variations. This study attempts to replicate the results in Hanganu et al. (Brain, 137(4) 2014) using data from the Parkinson's Progression Markers Initiative (PPMI). Using 25 PD subjects and 18 healthy controls, we analyzed the rate of change of cortical thickness and of the volume of subcortical structures, and we measured the relationship between structural changes and cognitive decline. We compared our findings to the results in the original study. (1) Similarly to the original study, PD patients with mild cognitive impairment (MCI) exhibited increased cortical thinning over time compared to patients without MCI in the right middle temporal gyrus, insula, and precuneus. (2) The rate of cortical thinning in the left inferior temporal and precentral gyri in PD patients correlated with the change in cognitive performance. (3) There were no group differences in the change of subcortical volumes. (4) We did not find a relationship between the change in subcortical volumes and the change in cognitive performance. Despite important differences in the dataset used in this replication study, and despite differences in sample size, we were able to partially replicate the original results. We produced a publicly available reproducible notebook allowing researchers to further investigate the reproducibility of the results in Hanganu et al. (2014) when more data is added to PPMI.

INTERVENTIONS AFFECTING PROGNOSIS AND QUALITY OF LIFE IN PEDIATRIC MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW

Introduction: Multiple sclerosis, autoimmune disease of the central nervous system primarily affecting young adults. The number of individuals suffering from multiple sclerosis under the age of 18 is gradually increasing. Early interventions in the form of pharmacotherapy have proven to be beneficial in reducing the severity of disease and thereby preventing disability. Furthermore, cognitive impairment affecting working memory, attention, and other domains is concerning in children. Methodology: We identified papers by searching various electronic databases (PubMed, Google Scholar, Europe PMC, Scopus, Web of Science). Search terms included: Pediatric multiple sclerosis OR pediatric MS AND interventions AND prognosis OR disease progression OR disability OR quality of life OR QoL. Papers were included in this review if they were published in English, referenced interventions and their effects on quality of life of the patients, and included pediatric-onset multiple sclerosis as a primary population. Results: Seventeen papers were identified via the literature search that addressed interventions made in the field of pediatric multiple sclerosis and their effects on the quality of life of the patients. The current study extracted data from a diverse range of articles focusing on various aspects of pediatric-onset multiple sclerosis (POMS) treatment, outcomes, and associated factors. The data provided valuable insights into the clinical characteristics, treatment approaches, and quality of life considerations for POMS patients. Discussion: Interventions include first line drugs (interferon beta-1a and glatiramer acetate) and disease modifying therapies like fingolimod, teriflunomide, natalizumab and rituximab. Potential modifiable factors like breastfeeding, vitamin D levels, exercise and diet were identified. CSF Neurofilament levels and various inflammatory genes are helpful in diagnosis. Conclusion: The data extraction from diverse studies on POMS shed light on various treatment approaches, disease progression markers and psychosocial factors. The findings underscore the importance of early intervention, tailored treatment strategies, and multidisciplinary care to enhance outcomes for pediatric MS patients.

Olfactory and cognitive decrements in 1991 Gulf War veterans with gulf war illness/chronic multisymptom illness

BackgroundGulf War illness (GWI)/Chronic Multisymptom Illness (CMI) is a disorder related to military service in the 1991 Gulf War (GW). Prominent symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. Although anosmia is not a typical GWI/CMI symptom, anecdotally some GW veterans have reported losing their sense smell shortly after the war. Because olfactory deficit is a prodromal symptom of neurodegenerative diseases like Parkinson’s and Alzheimer’s disease, and because we previously reported suggestive evidence that deployed GW veterans may be at increased risk for Mild Cognitive Impairment (MCI) and dementia, the current study examined the relationship between olfactory and cognitive function in deployed GW veterans.MethodsEighty deployed GW veterans (mean age: 59.9 ±7.0; 4 female) were tested remotely with the University of Pennsylvania Smell Identification Test (UPSIT) and the Montreal Cognitive Assessment (MoCA). Veterans also completed self-report questionnaires about their health and deployment-related exposures and experiences. UPSIT and MoCA data from healthy control (HC) participants from the Parkinson’s Progression Markers Initiative (PPMI) study were downloaded for comparison.ResultsGW veterans had a mean UPSIT score of 27.8 ± 6.3 (range 9–37) and a mean MoCA score of 25.3 ± 2.8 (range 19–30). According to age- and sex-specific normative data, 31% of GW veterans (vs. 8% PPMI HCs) had UPSIT scores below the 10th percentile. Nearly half (45%) of GW veterans (vs. 8% PPMI HCs) had MoCA scores below the cut-off for identifying MCI. Among GW veterans, but not PPMI HCs, there was a positive correlation between UPSIT and MoCA scores (Spearman’s ρ = 0.39, p < 0.001). There were no significant differences in UPSIT or MoCA scores between GW veterans with and without history of COVID or between those with and without Kansas GWI exclusionary conditions.ConclusionsWe found evidence of olfactory and cognitive deficits and a significant correlation between UPSIT and MoCA scores in a cohort of 80 deployed GW veterans, 99% of whom had CMI. Because impaired olfactory function has been associated with increased risk for MCI and dementia, it may be prudent to screen aging, deployed GW veterans with smell identification tests so that hypo- and anosmic veterans can be followed longitudinally and offered targeted neuroprotective therapies as they become available.

The effectiveness of early administration of antifibrotic therapy as a reflection of properly organized medical care for patients with progressive pulmonary fibrosis

The issues of organization of medical care and early administration of antifibrotic therapy in patients with progressive fibrotic phenotype require in-depth study and implementation in real clinical practice.The aim of this paper is to provide a rationale for the early administration of antifibrotic drugs in patients with various forms of interstitial lung disease.Results. The article addresses organizational issues in the medical care for interstitial lung disease with a progressive fibrotic phenotype. Topical epidemiological problems are also addressed, in particular the high mortality rate in this disease. The main risk factors of the disease are considered. Diagnostic markers for the fibrosis progression are analyzed. Data from large-scale studies on the early initiation of antifibrotic therapy and its effect on disease outcomes are presented.Conclusion. The main reasons for early initiation of therapy in a progressive fibrotic phenotype are presented: an unfavorable prognosis, an unpredictable course, a progressive decrease in forced vital capacity, and the association of changes in FVC with an increase in mortality. Using the Chelyabinsk region as an example, a model of care for patients with interstitial lung diseases is considered, with a brief analysis of the effectiveness of antifibrotic therapy, its early initiation and the impact on mortality in patients with this disease.

Associations of drusen location with risk factors and incidence of late age-related macular degeneration in the Alienor study.

To test the hypothesis that central drusen location is strongly linked with known Age-related Macular Degeneration (AMD) risk factors and risk of incident late AMD. The Alienor study is a prospective population-based cohort study of residents of Bordeaux, France, followed from 2009 to 2017. On retinal photographs, we defined central drusen as at least one soft drusen (>63 μm) within 500 μm from fovea and pericentral drusen as at least one drusen 500-3000 μm from fovea, in the absence of any central drusen. Late AMD (atrophic and/or neovascular) was diagnosed using multimodal imaging. In total, 481 eyes were included in the analysis: 160 central and 321 pericentral. We investigated associations with systemic (age, sex, smoking, medical prescriptions, plasma concentrations of lipids and nutrients, UV exposure, blood pressure), ocular (retinal thickness, cataract extraction) and genetic risk scores (GRS). In multivariate logistic regression central drusen were associated with smoking (OR, 2.95 for smoking more than 20 pack-years, p = 0.02), HDL-cholesterol (OR, 1.57 for 1 standard deviation (SD) increase, p = 0.0048), pulse pressure (OR, 0.77 for 1 SD increase, p = 0.04), Age-Related Maculopathy Susceptibility 2 (ARMS2) GRS (OR, 1.42; 95% CI, 1.11-1.83) and complement GRS (OR, 1.55; 95% CI, 1.15-2.10). In Cox modelling, the central location of drusen (at baseline or during the follow-up) was associated with a 4.41-fold increased risk (95% CI,1.98-9.81) for an incident late AMD. Central drusen were strongly associated with AMD risk factors and incident late AMD, suggesting that it represents a key marker for AMD progression.

Comparison of Two Methods for Determining Item Characteristic Functions and Latent Variable Time-Course for Pharmacometric Item Response Models

There are examples in the literature demonstrating different approaches to defining the item characteristic functions (ICF) and characterizing the latent variable time-course within a pharmacometrics item response theory (IRT) framework. One such method estimates both the ICF and latent variable time-course simultaneously, and another method establishes the ICF first then models the latent variable directly. To date, a direct comparison of the “simultaneous” and “sequential” methodologies described in this work has not yet been systematically investigated. Item parameters from a graded response IRT model developed from Parkinson’s Progression Marker Initiative (PPMI) study data were used as simulation parameters. Each method was evaluated under the following conditions: (i) with and without drug effect and (ii) slow progression rate with smaller sample size and rapid progression rate with larger sample size. Overall, the methods performed similarly, with low bias and good precision for key parameters and hypothesis testing for drug effect. The ICF parameters were well determined when the model was correctly specified, with an increase in precision in the scenario with rapid progression. In terms of drug effect, both methods had large estimation bias for the slow progression rate; however, this bias can be considered small relative to overall progression rate. Both methods demonstrated type 1 error control and similar discrimination between model with and without drug effect. The simultaneous method was slightly more precise than the sequential method while the sequential method was more robust towards longitudinal model misspecification and offers practical advantages in model building.

Personalized Prediction of Parkinson's Disease Progression Based on Deep Gaussian Processes.

Parkinson's disease is a chronic progressive neurodegenerative disease with highly heterogeneous symptoms and progression. It is helpful for patient management to establish a personalized model that integrates heterogeneous interpretation methods to predict disease progression. In the study, we propose a novel approach based on a multi-task learning framework to divide Parkinson's disease progression modeling into an unsupervised clustering task and a disease progression prediction task. On the one hand, the method can cluster patients with different progression trajectories and discover new progression patterns of Parkinson's disease. On the other hand, the discovery of new progression patterns helps to predict the future progression of Parkinson's disease markers more accurately through parameter sharing among multiple tasks. We discovered three different Parkinson's disease progression patterns and achieved better prediction performance (MAE=5.015, RMSE=7.284, r2=0.727) than previously proposed methods on Parkinson's Progression Markers Initiative datasets, which is a longitudinal cohort study with newly diagnosed Parkinson's disease.

Digital assessment of speech in Huntington disease.

Speech changes are an early symptom of Huntington disease (HD) and may occur prior to other motor and cognitive symptoms. Assessment of HD commonly uses clinician-rated outcome measures, which can be limited by observer variability and episodic administration. Speech symptoms are well suited for evaluation by digital measures which can enable sensitive, frequent, passive, and remote administration. We collected audio recordings using an external microphone of 36 (18 HD, 7 prodromal HD, and 11 control) participants completing passage reading, counting forward, and counting backwards speech tasks. Motor and cognitive assessments were also administered. Features including pausing, pitch, and accuracy were automatically extracted from recordings using the BioDigit Speech software and compared between the three groups. Speech features were also analyzed by the Unified Huntington Disease Rating Scale (UHDRS) dysarthria score. Random forest machine learning models were implemented to predict clinical status and clinical scores from speech features. Significant differences in pausing, intelligibility, and accuracy features were observed between HD, prodromal HD, and control groups for the passage reading task (e.g., p < 0.001 with Cohen'd = -2 between HD and control groups for pause ratio). A few parameters were significantly different between the HD and control groups for the counting forward and backwards speech tasks. A random forest classifier predicted clinical status from speech tasks with a balanced accuracy of 73% and an AUC of 0.92. Random forest regressors predicted clinical outcomes from speech features with mean absolute error ranging from 2.43-9.64 for UHDRS total functional capacity, motor and dysarthria scores, and explained variance ranging from 14 to 65%. Montreal Cognitive Assessment scores were predicted with mean absolute error of 2.3 and explained variance of 30%. Speech data have the potential to be a valuable digital measure of HD progression, and can also enable remote, frequent disease assessment in prodromal HD and HD. Clinical status and disease severity were predicted from extracted speech features using random forest machine learning models. Speech measurements could be leveraged as sensitive marker of clinical onset and disease progression in future clinical trials.

Increased cAMP-PKA signaling pathway activation is involved in up-regulation of CTLA-4 expression in CD4+ T cells in acute SIVmac239-infected Chinese rhesus macaques

Human immunodeficiency virus-1 (HIV-1) infection can cause chronic activation, exhaustion, and anergy of the immune system. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint molecule, which plays an important role in immune homeostasis and disease. CTLA-4 expression is elevated in HIV-1-infected patients and is associated with disease progression. However, the mechanism controlling expression of CTLA-4 in HIV-1 infection is poorly characterized. In this study, we used a SIV-infected Chinese rhesus macaque (ChRM) model to explore CTLA-4 expression in SIV infection. Results showed that SIV infection significantly increased CTLA-4 expression in all T cell subsets, especially central memory T cells. CTLA-4+CD4+ T cell frequency was significantly associated with disease progression markers. Activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway regulated CTLA-4 expression in CD4+T cells, as confirmed by stimulation with dibutyryl cyclic adenosine monophosphate, forskolin, and 3-isobutyl-1-methylxanthine, and inhibition with H-89 ex vivo. Simultaneously, cAMP concentration in PBMCs and PKA activity in both PBMCs and CD4+ T cells were increased in acute SIV-infected ChRMs, accompanied by an increase in adenylate cyclase 6 expression and a decrease in cAMP-phosphodiesterase 3A (PDE3A), PDE4B, and PDE5A expression in PBMCs. In addition, selective inhibition of PDE4B and PDE5A activity enhanced CTLA-4 expression in CD4+ T cells. These results suggest that SIV infection alters cAMP metabolism and increases cAMP-PKA signaling pathway activation, which up-regulates the expression of CTLA-4 in acute SIVmac239-infected ChRMs. Thus, regulation of the cAMP-PKA signaling pathway may be a potential strategy for the restoration of T cell function and therapy for AIDS.

Plasma MCP-1 and TGF-β1 Levels are Associated with Kidney Injury in Children with Congenital Anomalies of the Kidney and Urinary Tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are primarily causal for end-stage renal disease and have significant implications for long-term survival. A total of 39 healthy controls and 94 children with chronic kidney disease (CKD) were enrolled (3-12 years old as children, 13-18 years old as adolescents), who were divided into CAKUT and Non-CAKUT according to the etiology of CKD. CKD group was further classified according to estimating glomerular filtration rate (eGFR). Circulating levels of inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemokine-1 (MCP-1), and transforming growth factor-β1 (TGF-β1) were analyzed. The relationship between these inflammatory markers with eGFR and the kidney injury parameter (urine protein) was investigated to assess their potential as early markers of disease progression. All circulating levels of these inflammatory cytokines were increased in CKD patients (including CAKUT and Non-CAKUT) compared with healthy subjects. The circulating levels of MCP-1 and TGF-β1 were increased in CAKUT adolescents compared with CAKUT children. In CAKUT children, levels of MCP-1 and TGF-β1 increased as CKD progressed, and MCP-1 and TGF-β1 were negatively and significantly correlated with eGFR and positively with urine protein. MCP-1 and TGF-β1 may contribute to the early detection of CKD and disease stage/progression in CAKUT children.

3D-Nanostructured microfluidic device arranged in a herringbone pattern for the highly effective capture of HER2-Positive cancer-derived exosomes in urine

Exosomes in body fluids are important in liquid biopsy as they reflect the information of their originating cells. Thus, exosome analysis can provide valuable insights into diseases such as cancer. However, the low concentration of exosomes in body fluids is accompanied by background noise, making exosome analysis challenging. Here, a microfluidic chip in which three-dimensional nanostructures were arranged in a herringbone pattern (nanochip) that could efficiently capture specific exosomes was developed. Nanostructures were prepared by stacking silica nanoparticles to enhance the contact and interaction between the exosomes and structures, which were then arranged in a herringbone pattern to improve mass transfer through micromixing. To analyze exosomes derived from human epidermal growth factor receptor 2 (HER2, an important marker for cancer progression and patient survival)-positive cancer, anti-HER2 antibody was introduced into the nanostructures in the nanochip and approximately 97.7% of exosome capture efficiency was confirmed. The nanochip performed better than chips with a solid herringbone structure or without a structure (solid and flat chips). The feasibility of capturing multiple exosomes was demonstrated using both in vitro and in vivo samples by employing a dual nanochip configuration in which nanochips with different antibodies were interconnected in a series. This nanochip can effectively capture HER2-positive exosomes and has potential for multiple exosome isolations. Additionally, this chip can capture and detect various disease-related exosomes because various antibodies can be applied; this nanochip will be useful for exosome-based disease diagnosis and monitoring in liquid biopsies.

New marker for chronic kidney disease progression and mortality in medical-word virtual space

A new marker reflecting the pathophysiology of chronic kidney disease (CKD) has been desired for its therapy. In this study, we developed a virtual space where data in medical words and those of actual CKD patients were unified by natural language processing and category theory. A virtual space of medical words was constructed from the CKD-related literature (n = 165,271) using Word2Vec, in which 106,612 words composed a network. The network satisfied vector calculations, and retained the meanings of medical words. The data of CKD patients of a cohort study for 3 years (n = 26,433) were transformed into the network as medical-word vectors. We let the relationship between vectors of patient data and the outcome (dialysis or death) be a marker (inner product). Then, the inner product accurately predicted the outcomes: C-statistics of 0.911 (95% CI 0.897, 0.924). Cox proportional hazards models showed that the risk of the outcomes in the high-inner-product group was 21.92 (95% CI 14.77, 32.51) times higher than that in the low-inner-product group. This study showed that CKD patients can be treated as a network of medical words that reflect the pathophysiological condition of CKD and the risks of CKD progression and mortality.

3-Year test-retest reliability in Parkinson’s disease and healthy older adults: The Parkinson’s progression markers initiative study

Repeated neuropsychological assessments are often conducted in clinical and research settings to track cognitive changes over single or multiple intervals in patients with Parkinson’s disease (PD). Yet few studies have documented test-retest reliability in PD. To address this gap, we used data from the Parkinson’s Progression Markers Initiative (PPMI) to investigate the reliability of five well-known neuropsychological tests over a 3-year follow-up assessment in early-stage PD with either normal (PD-NC; N = 158) or abnormal (PD-AC; N = 39) cognitive screening, categorized based on recommended cutoffs for the Montreal Cognitive Assessment (MoCA), and healthy older adults (HOA; N = 102). All participants analyzed maintained the same cognitive status category across the assessment points. Intraclass correlation coefficients (ICCs) estimated reliability. The overall ICCs calculated across time points were as follows: Judgment of Line Orientation (PD-NC = .47, PD-AC = .50, HOA = .59); Letter-Number Sequencing (PD-NC = .64, PD-AC = .64, HOA = .65); Semantic Fluency (PD-NC = .69, PD-AC = .89, HOA = .77); Symbol Digit Modalities Test (PD-NC = .67, PD-AC = .83, HOA = .71). For the two primary components of the Hopkins Verbal Learning Test-Revised, we found the following ICCs: immediate recall (PD-NC = .46, PD-AC = .57, HOA = .58); delayed recall (PD-NC = .42, PD-AC = .57, HOA = .54). Findings from this study provide useful information for clinicians and researchers toward selecting suitable neuropsychological tests to monitor cognition at two or more time points among newly diagnosed individuals with PD and HOA.

A Delphi panel to build consensus on assessing disease severity and disease progression in adult patients with hypophosphatasia in the United States

BackgroundHypophosphatasia (HPP) is an inborn error of metabolism with a variable presentation. We conducted a modified Delphi panel to obtain expert consensus on knowledge gaps regarding disease severity and progression in adult patients with HPP.MethodsHealthcare professionals (HCPs) with experience managing adult patients with HPP were recruited to participate in a 3-round Delphi panel (round 1: paper survey and 1:1 interview; rounds 2–3: email survey). Panelists rated the extent of their agreement with statements about disease severity and progression in adult patients with HPP. Consensus was defined as ≥ 80% agreement.ResultsTen HCPs completed round 1; nine completed rounds 2 and 3. Consensus was reached on 46/120 statements derived from steering committee input. Disease severity markers in adult patients with HPP can be bone-related (recurrent/poorly healing fractures, pseudo-fractures, metatarsal fractures, osteomalacia) or involve dentition or physiologic/functional manifestations (use of mobility devices/home modifications, abnormal gait, pain). Disease progression markers can include recurrent/poorly healing low-trauma fractures, development of ectopic calcifications, and/or impairment of functional activity. Panelists supported the development of a tool to help assess disease severity in the clinic and track changes in severity over time. Panelists also highlighted the role of a multidisciplinary team, centers with expertise, and the need to refer patients when disease severity is not clear.ConclusionsThese statements regarding disease severity, progression, and assessment methods address some knowledge gaps in adult patients with HPP and may be helpful for treating HCPs, although the small sample size affects the ability to generalize the healthcare provider experience.