Stages Of Disease Severity Research Articles

Assessment of Missing Data on Glaucoma Severity among Participants in the NIH All of Us Research Program of the United States.

There were statistically significant differences across multiple socioeconomic characteristics and self-reported barriers to care among primary glaucoma patients with severity staging data versus those missing this data in the NIH All of Us database. To characterize missing data among glaucoma patients within All of Us. We used diagnosis codes to define cohorts of primary glaucoma patients with and without severity staging specified. Descriptive analyses were conducted by presence of disease severity stage. Analysis of missing data was conducted using a set intersection plot and Little's Test of Missing Completely at Random. T-tests were performed to evaluate differences. Of 2982 participants, 1714 (57%) did not have glaucoma severity stage specified, and 11 of 23 analyzed variables had missing data. Little's Test indicated data was not missing completely at random (P<0.001). Significant differences existed between the two cohorts with respect to age, age of first glaucoma diagnosis, gender, ethnicity, education, income, insurance, history of glaucoma surgery and medication use, and answers regarding ability to afford eyeglasses and having seen an eye care provider in the last 12 months (all P values≤0.01). There were significant differences between glaucoma participants with glaucoma severity stage specified versus those with unstaged disease across multiple socioeconomic characteristics and self-reported barriers to care. Glaucoma severity staging data was not missing completely at random. The unstaged cohort included higher rates of multiple underrepresented communities, which may potentially contribute to bias in ophthalmology research as participants from vulnerable populations may be disproportionately excluded from electronic health records or claims data studies where diagnosis codes with severity/staging levels are used to examine risk factors for disease, progression, and treatment efficacy.

Salivary IL-1β, IL-6, and IL-10 Are Key Biomarkers of Periodontitis Severity.

To explore severity and progression biomarkers, we examined the clinical relevance of multiple cytokines and mediators involved in the inflammatory response in periodontitis. A cohort of 68 patients was enrolled in the study and periodontal status assessed by the current classification of periodontal diseases. Immune mediators present in saliva, of both patients and healthy controls, were quantified using a Legendplex-13 panel. Clinic parameters were significantly higher in PD patients compared with HC, with a strong significant association with the disease severity (stage) (p < 0.001), but not with progression (grade). The panel of immune mediators evidenced elevated levels of pro-inflammatory cytokines IL-6 and IL-1β as disease established (p < 0.01). IL-1β/IL-1RA ratio was increased in PD patients, being associated with disease stage. An anti-inflammatory response was spotted by higher IL-10. Lower levels of IL-23 and IP-10 were associated with disease severity. No significant statistical differences were found by grade classification. Moreover, salivary IL-1β and IL-6 exhibited significant positive correlations with several clinical measurements (PI, BOP, PPD, CAL), while IP-10 showed a statistical negative correlation with BOP, PPD, and CAL. These insights highlight the complexity of the periodontitis inflammatory network and the potential of cytokines as biomarkers for refined diagnostic and therapeutic strategies.

Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data

X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson’s Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.

Development and Validation of Paradigms Based on the Global-First Topological Approach for Alzheimer's Disease Severity Staging.

Conventional methods like patient history, neuropsychological testing, cerebrospinal fluid examination, and magnetic resonance imaging are widely used to diagnose cases in the current clinical setting but are limited in classifying Alzheimer's disease (AD) stages. Patients with AD exhibit visual perception deficits, which may be a potential target to assess the severity of the disease according to visual paradigms. However, owing to the inconsistent forms of perceived objects, the defects of current visual processing paradigms often lead to inconsistent results and a lack of sensitivity and specificity. We develop two paradigms based on global-first topological approach of visual perception, which avoids inconsistent results and lack of sensitivity and specificity owing to the inconsistent forms of perceived objects in traditional paradigms, delineate a unique detection strategy from perception organization (Experiment 1) and visual working memory (VWM) (Experiment 2). Except for the significant differences of the reaction times (RTs) between groups, significant differences were found when AD subjects recognize small figures due to the consistency of global and local figures in similarity test. The difference of RTs between recognizing global and local figures can be recognized in AD and mild cognitive impairment (MCI) group compared to healthy elderly (HE) in similarity test (Experiment 1). The memory capacity of AD patients was significantly lower than MCI group. Topological interference effect was observed in MCI and HE group, whereas MCI patients may have a greater difference trend in non-topological and topological changes than HE (Experiment 2). Our paradigms provide a new strategy, which can assist clinical severity staging and linking topological approach of visual perception with pathophysiological processes in AD.

Monitoring cystic fibrosis airway infections with Pseudomonas aeruginosa with anti-OprF serum antibodies

BackgroundThe management of cystic fibrosis (CF) requires knowledge of the patient's microbiological status. The serology of anti-Pseudomonas aeruginosa antibodies against exoenzymes or water-soluble antigens has gained diagnostic value, particularly to detect the onset of colonization with P. aeruginosa. However, the diversity and variable expression of these antigens, which was unknown when the ELISAs became common diagnostic procedures at CF clinics, prohibits the quantitative evaluation of bacterial antigen load during intermittent and chronic infection. MethodsAn ELISA was developed to measure the serum IgG antibody levels against P. aeruginosa porin OprF, a species-specific, conserved, immunogenic and constitutively expressed protein present in the outer membrane and extracellular vesicles. ResultsSerial serum samples were collected from 310 people with CF (pwCF) over a period of up to 15 years. Compared to a reference of P. aeruginosa – negative CF sera set to 1, OprF antibody titers ranged from 0.3 to 13.2 (median: 1.7) in 56 intermittently colonized patients and from 0.5 to 51.2 (median: 11.8) in 176 chronically colonized pwCF showing higher anti-OprF antibody levels during chronic than during intermittent colonization with P. aeruginosa (P = 0, Z = - 21.7, effect size 0.62). Inhalation with twice daily 80 mg tobramycin decreased OprF antibody titers (P = 5 × 10−5), particularly during the third and fourth year of chronic colonization. ConclusionThe OprF ELISA should be an appropriate tool to monitor Pseudomonas serology at all stages of infection and disease severity and to study the impact of short- and long-term therapeutic interventions.

Online dance versus online therapeutic exercise on quality of life - a study protocol for a randomized controlled trial investigating social telerehabilitation efficacy in Parkinson disease

Background Social telerehabilitation delivers rehabilitation services over online video conferencing within a social context. The modality of multimodal therapeutic exercises is the most recommended rehabilitation for individuals with PD, although other modalities, such as dance, have shown potential benefits. The investigation of the feasibility and efficacy of these therapeutic strategies in a remote online format is unknown. Methods This is a prospectively registered two-arm randomised controlled trial investigating the efficacy of online dance compared to online multimodal therapeutic exercise by looking at the biopsychosocial PD aspects. Individuals diagnosed with idiopathic PD between 40 and 90 years old, at any stage of disease severity, and without cognitive impairment will be recruited from the community. Participants will be randomly allocated to one of the two social telerehabilitation groups: (1) dance and music or (2) multimodal therapeutic exercise and music. Interventions will occur twice a week for twelve weeks. Each session will last 60 min. Tele-assessments will be conducted pre-, post-, and one-month follow-up through a videoconference platform. Results For feasibility, primary outcomes will include adherence, attendance, adverse events, and participants’ perceptions of enjoyment and socialisation. For efficacy, primary outcomes will investigate well-being by positive affect (by the Positive Affect and Negative Affect Schedule) and persistent anxiety, episodic anxiety, and avoidance behaviour (by the Parkinson Anxiety Scale). Secondary outcomes will include motor severity (by the UPDRS III), functional lower extremity strength (by the Five Times Sit to Stand Test), memory and attention (by the Attention and Recognition Memory Test), and quality of life (by the Parkinson’s Disease Questionnaire 39). Conclusion We hypothesise that both interventions would effectively ameliorate motor symptoms. However, we expect dance to be more enjoyable and improve well-being by increasing positive affect and reducing anxiety signs.

Retinal Vascular Abnormalities and Clinical Parameters in Systemic Sclerosis.

Background: Systemic sclerosis is a complex autoimmune disease characterized by vasculopathy, fibrosis, and immune dysregulation. Ocular manifestations in these patients are increasingly recognized, suggesting potential correlations between systemic vascular abnormalities and ocular microvascular changes. Advancements in molecular immunology and imaging technology using ocular coherence tomography (OCT) have unveiled intricate pathways underlying possible disease pathogenesis. Understanding the interplay between retinal vascular abnormalities and molecular immunology parameters could provide insights into disease mechanisms and potential biomarkers. Purpose: The aim of this study was to investigate vascular abnormalities, detected with optical coherence tomography angiography (OCT-A), in systemic sclerosis patients and to find correlations between the severity of the disease detected with molecular immunology findings and OCT-A parameters. Methods: A group of 32 systemic sclerosis patients were compared with 9 healthy controls. Ganglion cell complex thickness (GCC), retina thickness of the fovea and parafovea, nerve fiber layer thickness (RNFL) and cup/disc area ratio were investigated using OCT. Vessel density (VD) of the superficial (SCP) and deep capillary plexus (DCP) of the whole macular area and ETDRS grid, size of the foveal avascular zone (FAZ) and vessel density of the radial peripapillary capillary plexus (RPCP) were evaluated using OCT-A. Modified Rodnan skin score (mRSS), capillaroscopy and disease duration were used to stage disease severity. Results: There was a statistically significant reduction in retina thickness of the fovea and parafovea, VD of the whole DCP, VD of the SCP and DCP in ETDRS grid in the patient group compared to controls (p < 0.001). The patients presented a significant enlargement of the FAZ (p 0.005). No significant correlation between OCT and OCT-A parameters and disease severity scores was found. Conclusions: OCT-A could represent a non-invasive tool to detect retinal microvascular damage in systemic sclerosis.

Neurofilament light chain but not glial fibrillary acidic protein is a potential biomarker of overt hepatic encephalopathy in patients with cirrhosis

Introduction and ObjectivesHepatic encephalopathy (HE) is a frequent complication of cirrhosis and may cause cerebral damage. Neurodegenerative diseases can induce the release of neuroproteins like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in body fluids, including blood plasma. We investigated whether NfL and GFAP could serve as potential diagnostic plasma biomarkers for overt HE (oHE). Materials and MethodsWe included 85 patients from three prospective cohorts with different stages of liver disease and HE severity. The following patients were included: 1) 34 patients with primary sclerosing cholangitis (PSC) with compensated disease; 2) 17 patients with advanced liver disease without oHE before elective transjugular intrahepatic portosystemic shunt (TIPS) placement; 3) 17 intensive care unit (ICU) patients with oHE and 17 ICU patients without cirrhosis or oHE. Plasma NfL and GFAP were measured using single molecule assays. ResultsICU oHE patients had higher NfL concentrations compared to pre-TIPS patients or ICU controls (p < 0.05, each). Median GFAP concentrations were equal in the ICU oHE and pre-TIPS patients or ICU controls. Plasma NfL and GFAP concentrations correlated with Model for End-Stage Liver Disease (MELD) scores (R = 0.58 and R = 0.40, p < 0.001, each). ConclusionsPlasma NfL deserves further evaluation as potential diagnostic biomarker for oHE and correlates with the MELD score.

Neuropsychiatric Symptoms in Frontotemporal Dementia: More Than Just Noise?

Neuropsychiatric symptoms cause significant suffering and poor quality of life for patients and their caregivers. They are not considered specific to frontotemporal dementia (FTD); therefore, their clinical role and impact might be underestimated. The aims of the present study are to: 1) describe the prevalence of neuropsychiatric symptoms in FTD starting from the prodromal stage, 2) define their association with disease severity, 3) identify symptoms which are unrelated to FTD-specific symptoms, and 4) assess their association with clinical features and outcomes. In this retrospective study, we analyzed data of 461 FTD patients, including behavioral variant of FTD (bvFTD, n = 318) and primary progressive aphasia (PPA, n = 143). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory, and patients' staging and global disease severity were estimated using the Clinical Dementia Rating plus NACC FTLD. The most common neuropsychiatric symptoms in prodromal FTD were irritability (48%), depression (35%), and anxiety (34%); delusions were reported in 6%of prodromal bvFTD cases. The severity of most neuropsychiatric symptoms increased with global disease severity. Psychosis (delusions and hallucinations) and mood symptoms (depression and anxiety) were mostly independent from FTD-specific symptoms. Psychosis was associated with older age, higher disease severity, shorter survival rate, and was higher in bvFTD than in PPA. Neuropsychiatric symptoms are common in patients with FTD, also in the prodromal phase. Psychosis might be unrelated to FTD pathology, and be associated with worse clinical outcomes. The prompt detection and treatment of these symptoms might improve patient's management and quality of life.

Patient With Parkinson Disease and Care Partner Perceptions of Key Domains Affecting Health-Related Quality of Life: Systematic Review

To effectively customize Parkinson disease (PD) programs, it is important to incorporate the "individual's voice" and have a thorough understanding of the symptom priorities of people with PD (PwP) and care partners (CP). In this convergent integrated mixed-method systematic review, we aimed to analyze qualitative and quantitative evidence of PD motor and nonmotor symptoms affecting health-related quality of life (HRQOL) in PwP and CP, comparing priorities across different levels of disease severity. We searched MEDLINE, PsycINFO, Web of Science, Embase, and Scopus; ProQuest Dissertations and Theses Global; and the Michael J. Fox Foundation Data Resources for studies published up to June 29, 2022. We included qualitative, quantitative, and mixed-method studies investigating PD symptom priorities among PwP and CP. We critically appraised eligible studies for methodological quality using the Mixed-Methods Appraisal Tool. Derived terms were mapped and coded according to thematic attribution. Independent syntheses of qualitative and quantitative evidence and transformation of quantitative data into qualitative formats were performed. Of the 7,716 identified studies, we included 70 that provided qualitative (n = 13), quantitative (n = 53), and mixed (n = 4) evidence. We included 604 mapped terms representing 11 PwP-identified and CP-identified motor and nonmotor symptom categories. Across all PD stages, both PwP and CP considered 5 domains more affecting their HRQOL, namely: "motor functionality," "mood," "cognition," "gait, balance, posture, and falls," and "nighttime sleep disorders." In early disease, PwP and CP considered "mood" the domain that most affected their HRQOL. In advanced PD, PwP considered "pain" the domain that most affects their HRQOL, while CP considered "psychiatric symptoms." The domain "gait, balance, posture, and falls" was equally considered by both PwP and CP as the second domain that most affects their HRQOL in the advanced stage of PD. The ranking of the priority of symptoms is largely shared by PwP and CP, and motor symptom priorities dominate the full disease spectrum. However, the nonmotor symptom priorities shift according to the disease severity stage. Tailored care and research require that providers consider these shifting priorities and incorporate the "individual's voice" into treatment decisions.

Results of laparoscopic Heller-Toupet operation for achalasia

Objectives: This study was carried out to evaluate surgical outcomes of laparoscopic Heller-Toupet surgery for achalasia. Methodology: This is a retrospective case series implemented at the Gastrointestinal Department, Hanoi Medical University Hospital between January 2015 and August 2022, including 71 patients with achalasia who underwent laparoscopic Heller-Toupet. Results: 52.1% of patients in the study are male (more than female 47.9%). The average age of the cohort was 44.9±13.9 years. The incidence of dysphagia was 100%. Most patients report esophageal dilatation grade II (76.1%) and disease severity stage I (57.7%). The mean muscle opening length was 7.4±1.3 cm, the operative time was 135±25 minutes. There was no conversion, no intra-and postoperative adverse events. Long-term outcomes: good (no or very mild dysphagia) was 90.1%, moderate (moderate dysphagia) was 9.9% and clinical incidence of reflux syndrome was 17%. There was no case requiring intervention or re-operation. Conclusions: Laparoscopic Heller-Toupet is a safe, low rate of intra- and postoperative complication, and brings good long-term outcomes in the treatment of achalasia.

TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer’s disease

In Alzheimer’s disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO (NCT03352557), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab—a monoclonal antibody to N-terminal tau—in patients with early Alzheimer’s disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

Urine Albumin/Creatinine Ratio and Serum Uric Acid as Predictors of Severity in Patients with Chronic Obstructive Pulmonary Disease

Background and Objective: As a global healthcare issue, Chronic Obstructive Pulmonary Disease (COPD) is mainly associated with smoking. Nonetheless, environmental and occupational issues are also linked to its development. The present study aimed to assess the urine albumin-to-creatinine ratio (ACR) and serum uric acid (SUA) levels as predictors of disease severity in COPD patients. Materials and Methods: This cross-sectional study was conducted on 67 patients diagnosed with COPD using the Global Initiative for Obstructive Lung Disease diagnostic criteria. The participants were patients who were either referred to the subspecialty clinic of the pulmonology and spirometry unit of Hamadan Shahid Beheshti Hospital or were hospitalized in the pulmonology ward. Blood and urine samples were taken from the COPD patients, and the serum uric acid, urine albumin, and urine creatinine levels were assessed and recorded in a checklist. The data were analyzed in SPSS software (version 23) at a significance level of 0.05. Results: In terms of gender, 5.7% of the participants were male and 34.3% were female. The mean age of patients was 61.77 years. The stages of disease severity in the patients were as follows: 20.89%, 22.38%, 5.73%, and 2.98% of cases had very severe, severe, moderate, and mild COPD, respectively. The regression analysis results demonstrated that SUA levels could significantly predict the FEV1 in COPD patients; nonetheless, urine ACR could not predict the FEV1 scores. Conclusion: As evidenced by the result of the present study, the FEV1 in COPD patients and disease severity could be predicted by the SUA levels. Therefore, it is recommended to consider monitoring and assessing non-pulmonary factors, especially SUA levels, in the treatment of COPD patients.

Health-related quality of life and its associated factors in patients with chronic obstructive pulmonary disease.

The present study aimed to evaluate HRQOL and to explore the factors associated with poor HRQOL among patients with COPD. In the present cross-sectional study, the validated St George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used to evaluate HRQOL among 702 patients with COPD at two major hospitals in Jordan in the period between January and April 2022. Quantile regression analysis was used to explore the factors associated with HRQOL among the study participants. According to SGRQ-C, the HRQOL of the study participants was greatly impaired with a total SGRQ of 55.2 (34-67.8). The highest impairment in the HRQOL was in the impact domain with a median of 58.7 (29-76.3). Increased number of prescribed medications (β = 1.157, P<0.01), older age (β = 0.487, P<0.001), male gender (β = 5.364, P<0.01), low education level (β = 9.313, P<0.001), low and moderate average income (β = 6.440, P<0.05, and β = 6.997, P<0.01, respectively) were associated with poorer HRQOL. On the other hand, being married (β = -17.122, P<0.001), living in rural area (β = -6.994, P<0.01), non-use of steroids inhalers (β = -3.859, P<0.05), not receiving long acting muscarinic antagonists (LAMA) (β = -9.269, P<0.001), not receiving LABA (β = -8.243, P<0.001) and being adherent to the prescribed medications (β = -6.016, P<0.001) were associated with improved HRQOL. Furthermore, lower disease severity (stage A, B, and C) (β = -23.252, -10.389, and -9.696 respectively, P<0.001), and the absence of comorbidities (β = -14.303, P<0.001) were associated with better HRQOL. In order to maximize HRQOL in patients with COPD, future COPD management interventions should adopt a multidisciplinary approach involving different healthcare providers, which aims to provide patient-centered care, implement personalized interventions, and improve medication adherence, particularly for patients who are elderly, males, have low socioeconomic status, receive multiple medications and have multiple comorbid diseases.

Quantitative MRI Analysis of Brachial Plexus and Limb-Girdle Muscles in Upper Extremity Onset Amyotrophic Lateral Sclerosis.

Recent evidence highlights the potential of axonal degeneration as a biomarker for amyotrophic lateral sclerosis (ALS) detection. However, the diagnostic potential of peripheral nerve axon changes in ALS remains unclear. To evaluate the diagnostic performance of quantitative MRI of the brachial plexus and limb-girdle muscles (LGMs) in patients with upper extremity onset of ALS. Retrospective. 47 patients with upper extremity onset of ALS and 20 healthy volunteers. 3-T, three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions with short-tau inversion recovery sequences, T2-weighted turbo spin-echo Dixon sequence. The cross-sectional area (CSA) and nerve-muscle T2 signal intensity ratio (nT2) of the bilateral brachial plexus as well as the CSA and fat fraction (FF) of the bilateral LGMs were assessed by two radiologists. Disease severity and clinical stage of ALS patients were assessed by two neurologists. Student's t-test, Wilcoxon rank-sum test, binary logistic regression, interclass correlation coefficient, receiver operating characteristic analysis, and correlation analysis were performed for MRI quantitative metrics and clinical variables. Significance level: P < 0.05. In the affected limbs of patients with ALS, the CSA of the brachial plexus roots, trunks, and cords and the nT2 values of the brachial plexus trunks were significantly smaller than in the healthy controls. In the LGMs, the affected limbs of ALS showed significantly smaller CSA and higher FF than controls. The model containing parameters such as brachial plexus trunk CSA, subscapularis CSA, infraspinatus CSA, and subscapularis FF had excellent diagnostic efficacy for ALS. Additionally, increased subscapularis FF and supraspinatus FF were correlated with disease severity, and subscapularis CSA was negatively correlated with the clinical stage. Brachial plexus thinning, LGM atrophy, and fatty infiltration might serve as MRI-derived biomarkers for ALS with upper extremity onset. 4 TECHNICAL EFFICACY: Stage 2.

Fluorescence-tagged salivary small extracellular vesicles as a nanotool in early diagnosis of Parkinson’s disease

BackgroundParkinson’s disease is generally asymptomatic at earlier stages. At an early stage, there is an extensive progression in the neuropathological hallmarks, although, at this stage, diagnosis is not possible with currently available diagnostic methods. Therefore, the pressing need is for susceptibility risk biomarkers that can aid in better diagnosis and therapeutics as well can objectively serve to measure the endpoint of disease progression. The role of small extracellular vesicles (sEV) in the progression of neurodegenerative diseases could be potent in playing a revolutionary role in biomarker discovery.MethodsIn our study, the salivary sEV were efficiently isolated by chemical precipitation combined with ultrafiltration from subjects (PD = 70, healthy controls = 26, and prodromal PD = 08), followed by antibody-based validation with CD63, CD9, GAPDH, Flotillin-1, and L1CAM. Morphological characterization of the isolated sEV through transmission electron microscopy. The quantification of sEV was achieved by fluorescence (lipid-binding dye-labeled) nanoparticle tracking analysis and antibody-based (CD63 Alexa fluor 488 tagged sEV) nanoparticle tracking analysis. The total alpha-synuclein (α-synTotal) in salivary sEVs cargo was quantified by ELISA. The disease severity staging confirmation for n = 18 clinically diagnosed Parkinson’s disease patients was done by 99mTc-TRODAT-single-photon emission computed tomography.ResultsWe observed a significant increase in total sEVs concentration in PD patients than in the healthy control (HC), where fluorescence lipid-binding dye-tagged sEV were observed to be higher in PD (p = 0.0001) than in the HC using NTA with a sensitivity of 94.34%. In the prodromal PD cases, the fluorescence lipid-binding dye-tagged sEV concentration was found to be higher (p = 0.008) than in HC. This result was validated through anti-CD63 tagged sEV (p = 0.0006) with similar sensitivity of 94.12%. We further validated our findings with the ELISA based on α-synTotal concentration in sEV, where it was observed to be higher in PD (p = 0.004) with a sensitivity of 88.24%. The caudate binding ratios in 99mTc-TRODAT-SPECT represent a positive correlation with sEV concentration (r = 0.8117 with p = 0.0112).ConclusionsIn this study, for the first time, we have found that the fluorescence-tagged sEV has the potential to screen the progression of disease with clinically acceptable sensitivity and can be a potent early detection method for PD.Graphical

Factors Governing the Erythropoietic Response to Intravenous Iron Infusion in Patients with Chronic Kidney Disease: A Retrospective Cohort Study.

Limited knowledge exists about factors affecting parenteral iron response. A study was conducted to determine the factors influencing the erythropoietic response to parenteral iron in iron-deficient anaemic patients whose kidney function ranged from normal through all stages of chronic kidney disease (CKD) severity. This retrospective cohort study included parenteral iron recipients who did not receive erythropoiesis-stimulating agents (ESA) between 2017 and 2019. The study cohort was derived from two groups of patients: those managed by the CKD team and patients being optimised for surgery in the pre-operative clinic. Patients were categorized based on their kidney function: Patients with normal kidney function [estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2] were compared to those with CKD stages 3-5 (eGFR < 60 mL/min/1.73 m2). Patients were further stratified by the type of iron deficiency [absolute iron deficiency (AID) versus functional iron deficiency (FID)]. The key outcome was change in hemoglobin (∆Hb) between pre- and post-infusion haemoglobin (Hb) values. Parenteral iron response was assessed using propensity-score matching and multivariate linear regression. The impact of kidney impairment versus the nature of iron deficiency (AID vs. FID) in response was explored. 732 subjects (mean age 66 ± 17 years, 56% females and 87% White) were evaluated. No significant differences were observed in the time to repeat Hb among CKD stages and FID/AID patients. The Hb rise was significantly lower with lower kidney function (non-CKD and CKD1-2; 13 g/L, CKD3-5; 7 g/L; p < 0.001). When groups with different degrees of renal impairment were propensity-score matched according to whether iron deficiency was due to AID or FID, the level of CKD was found not to be relevant to Hb responses [unmatched (∆Hb) 12.1 vs. 8.7 g/L; matched (∆Hb) 12.4 vs. 12.1 g/L in non-CKD and CKD1-2 versus CKD3-5, respectively]. However, a comparison of patients with AID and FID, while controlling for the degree of CKD, indicated that patients with FID exhibited a diminished Hb response regardless of their level of kidney impairment. The nature of iron deficiency rather than the severity of CKD has a stronger impact on Hb response to intravenous iron with an attenuated response seen in functional iron deficiency irrespective of the degree of renal impairment.

Association of mannose binding lectin with chronic obstructive pulmonary disease susceptibility and its clinical outcomes.

The physiological interactions of MBL suggest its contribution towards the pathogenesis of COPD. The present case-control study was undertaken to elucidate the role of MBL with COPD risk and clinical outcomes in north Indian cohort. Patients were enrolled as per GOLD criteria. MBL2 variants were selected based on the literature and their putative functional significance. Genotyping of six single nucleotide polymorphisms of MBL2 comprising of two coding (rs1800450, rs1800451) and four non-coding variants (rs11003125, rs7096206, rs11003123 and rs7095891) was done by using PCR-RFLP and ARMS-PCR. Serum MBL levels were analysed by sandwich ELISA. Overall findings of the molecular genetic analysis of MBL2 indicated significant difference in frequency of three of the six studied variants, between patients and controls or among different disease severity stages. Heterozygous genotype of rs7095891 showed significant protective association towards severity of disease. Linkage disequilibrium (LD) analysis indicated a strong LD between rs1800450 and rs7095891 while intermediate LD was observed for rs11003123/rs11003125 and rs7096206/rs11003125. Haplotype analysis revealed 17.14-fold risk of developing exacerbations conferred by GGGTGG haplotype. Significantly low serum MBL levels observed in COPD patients as compared to controls. Significant difference in MBL deficiency levels were also observed for homozygous wild and variant genotypes of rs11003125 and rs7096206 respectively, as well as for all genotypes of rs11003123 than respective controls. The present study reinforces the role played by MBL in the susceptibility, protection and clinical outcomes of COPD. Therefore, including the reported associations at diagnostic, prognostic and therapeutic interventions may prove helpful.

Severity Stage Identification and Pest Detection of Tomato Disease Using Deep Learning

In Bangladesh, most people depend on agriculture for their livelihood. The country's economy and agricultural production are hampered if plants are affected by diseases. Crop pests also disrupt agricultural production. So, this paper proposes leaf disease, disease severity stage, and pest detection strategies with suggestions for prevention strategies using five notable Convolutional Neural Network models (CNN) such as VGG16, Resnet50, AlexNet, EfficientNetB2, and EfficientNetB3. This paper uses a dataset of tomato leaves consisting of 41,763 images which cover 10 classes of tomato disease, and a dataset of pests consisting of 4,271 images which cover 8 classes of pests. Firstly, these models are used for the classification of diseases and pests. Then disease and pest prevention techniques are shown. For disease and pest detection, EfficientNetB3 gives the best accuracy for training (99.85%), (99.80%), and validation (97.85%), (97.45%) respectively. For severity stage identification, AlexNet gives the best accuracy for training (69.02%) and validation (72.49%).

Appl1, Sortilin and Syndecan-1 immunohistochemistry on intraductal carcinoma of the prostate provides evidence of retrograde spread

The presence of intraductal carcinoma of the prostate (IDCP) correlates with late-stage disease and poor outcomes for patients with prostatic adenocarcinoma, but the accurate and reliable staging of disease severity remains challenging. Immunohistochemistry (IHC) has been utilised to overcome problems in assessing IDCP morphology, but the current markers have only demonstrated limited utility in characterising the complex biology of this lesion. In a retrospective study of a cohort of patients who had been diagnosed with IDCP, we utilised IHC on radical prostatectomy sections with a biomarker panel of Appl1, Sortilin and Syndecan-1, to interpret different architectural patterns and to explore the theory that IDCP occurs from retrograde spread of high-grade invasive prostatic adenocarcinoma. Cribriform IDCP displayed strong Appl1, Sortilin and Syndecan-1 labelling patterns, while solid IDCP architecture had high intensity Appl1 and Syndecan-1 labelling, but minimal Sortilin labelling. Notably, the expression pattern of the biomarker panel in regions of IDCP was similar to that of adjacent invasive prostatic adenocarcinoma, and also comparable to prostate cancer showing perineural and vascular invasion. The Appl1, Sortilin, and Syndecan-1 biomarker panel in IDCP provides evidence for the model of retrograde spread of invasive prostatic carcinoma into ducts/acini, and supports the inclusion of IDCP into the five-tier Gleason grading system.