Age-matched Healthy Individuals Research Articles

Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation

ObjectivesThe main goal of this study was to characterise the frequency and phenotype of B, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in peripheral blood and the...

I-Biomarker CaDx: A circulating miRNA-based multi-cancer detection tool with explainable AI for breast cancer.

5 Background: Breast cancer is requires early and accurate detection for effective treatment and improved patient outcomes. Current methods, such as mammography and biopsy, have limitations in accuracy, invasiveness, and accessibility. Circulating microRNAs (miRNAs) are promising non-invasive biomarkers for cancer detection, including breast cancer. i-Biomarker CaDx is a technology-agnostic, multi-cancer early detection and diagnosis test, covering 13 cancer types with 99-100% accuracy. This study evaluates i-Biomarker CaDx performance for breast cancer using a publicly available dataset and assesses explainable artificial intelligence (XAI) interpretations. Methods: The dataset (GEO: GSE73002) contains 1,280 breast cancer patients and an equal number of age-matched healthy individuals. Circulating miRNA profiles were measured using microarray technology. Multiple classification algorithms, including an ensemble of decision trees, neural networks, and support vector machines, were employed for feature selection, classification, and XAI. Hyperparameter optimization was performed, and the best classifiers were integrated with weights proportional to their performance into a final model. The performance of i-Biomarker CaDx was evaluated using cross-validation and independent test sets, while the XAI component provided cohort-level and individual-level explanations of the miRNA alterations associated with the diagnostic outcome. Results: i-Biomarker CaDx demonstrated remarkable diagnostic performance in detecting breast cancer, achieving 100% accuracy in the studied dataset. The sensitivity, specificity, positive predictive value, and negative predictive value of i-Biomarker CaDx surpassed those of traditional diagnostic methods such as mammography and biopsy. The ensemble classifier, consisting of decision trees, neural networks, and support vector machines, effectively captured the complex interactions among miRNAs. The XAI component of i-Biomarker CaDx provided valuable insights into the biological relevance of miRNA alterations in breast cancer diagnosis. Cohort-level and individual-level explanations elucidated the miRNA patterns and their associations with breast cancer, enhancing the understanding of the underlying molecular mechanisms. Conclusions: i-Biomarker CaDx, a technology-agnostic multi-cancer early detection and diagnosis tool, has shown exceptional accuracy in breast cancer detection, outperforming traditional diagnostic methods. The integration of explainable artificial intelligence (XAI) facilitates a deeper understanding of miRNA alterations and their associations with breast cancer, contributing to improved interpretation at both the cohort and individual levels. The results of this study demonstrate the potential of i-Biomarker CaDx as a powerful, non-invasive diagnostic tool for breast cancer.

Femoral head allograft for glenoid bone loss in primary reverse shoulder arthroplasty: functional and radiologic outcomes

Several techniques have been adopted during primary reverse shoulder arthroplasty (RSA) to manage glenoid bone defect. Among bone grafts, humeral head autograft is currently the mainstream option. However, autologous humeral heads may be unavailable or inadequate and allografts may be a viable alternative. The aim of the present study was to evaluate the functional and radiological outcomes of femoral head allografts for glenoid bone defects in primary RSA. We conducted a retrospective study with prospective data collection enrolling 20 consecutive patients who underwent RSA with femoral head allografts for glenoid bone defects. Indications for surgery were eccentric cuff tear arthropathy in 10 (50%) cases, concentric osteoarthritis in 9 (45%) cases, and fracture sequelae in one (5%) case. Each patient was evaluated preoperatively and at follow-up by X-ray and computed tomography (CT) and by assessing the range of motion (ROM) and the Constant-Murley score (CMS). A CT-based software, a patient-specific 3D model of the scapula, and patient specific instrumentation were used to shape the graft and to assess the position of K-wire for central peg. Postoperatively, CT scans were used to identify graft incorporation and resorption. After a median follow-up of 26.5 months (24-38), ROM and CMS showed a statistically significant improvement (all p=0.001). The median measures of the graft were as follows: 28 mm (28-29) for diameter, 22° (10°-31°) for angle, 4 mm (2-8 mm) for minimum thickness, and 15 mm (11-21 mm) for maximum thickness. Before the surgery, the median glenoid version was 21.8° (16.5°-33.5°) for the retroverted glenoids and -13.5° (-23° to -12°) for the anteverted glenoids. At the follow-up, the median postoperative baseplate retroversion was 5.7° (2.2°- 1.5°) (p=0.001), and this value was close to the 4° retroversion planned on the preoperative CT-based software. Postoperative major complications were noted in four patients: two dislocations, one baseplate failure following a high-energy trauma, and one septic baseplate failure. Partial graft resorption without glenoid component failure was observed in three cases that did not require revision surgery. The femoral head allograft for glenoid bone loss in primary RSA restores shoulder function with CMS values comparable to those of sex- and age-matched healthy individuals. A high rate of incorporation of the graft and satisfactory correction of the glenoid version can be expected after surgery. The management of glenoid bone defects remains a challenging procedure, and a 15% risk of major complication must be considered.

Atypical Activation of Laryngeal Somatosensory-Motor Cortex During Vocalization in People With Unexplained Chronic Cough

Unexplained chronic cough is common and has substantial negative quality-of-life implications, yet its causes are not well understood. A better understanding of how peripheral and central neural processes contribute to chronic cough is essential for treatment design. To determine if people with chronic cough exhibit signs of abnormal neural processing over laryngeal sensorimotor cortex during voluntary laryngeal motor activity such as vocalization. This was a cross-sectional study of a convenience sample of participants with chronic cough and healthy participants. Testing was performed in an acoustically and electromagnetically shielded chamber. In a single visit, electroencephalographic (EEG) signals were recorded from participants with chronic cough and healthy participants during voice production. The chronic cough group participants presented with unexplained cough of 8 weeks or longer duration with prior medical evaluation including negative results of chest imaging. None of the participants had a history of any neurologic disease known to impair vocalization or swallowing. Data collection for the healthy control group occurred from February 2 to June 28, 2018, and for the chronic cough group, from November 22, 2021, to June 21, 2022. Data analysis was performed from May 1 to October 30, 2022. Participants with or without chronic cough. Event-related spectral perturbation over the laryngeal area of somatosensory-motor cortex from 0 to 30 Hz (ie, θ, α, and β bands) and event-related coherence as a measure of synchronous activity between somatosensory and motor cortical regions. The chronic cough group comprised 13 participants with chronic cough (mean [SD] age, 63.5 [7.8] years; 9 women and 4 men) and the control group, 10 healthy age-matched individuals (mean [SD] age, 60.3 [13.9] years; 6 women and 4 men). In the chronic cough group, the typical movement-related desynchronization over somatosensory-motor cortex during vocalization was significantly reduced across θ, α, and β frequency bands when compared with the control group. This cross-sectional study found that the typical movement-related suppression of brain oscillatory activity during vocalization is weak or absent in people with chronic cough. Thus, chronic cough affects sensorimotor cortical activity during the asymptomatic voluntary activation of laryngeal muscles.

The Rise Slope of the Compound Sensory Nerve Action Potential in Normal and Pathological Human Nerves

ABSTRACT In spite of the diagnostic importance of the early phase of the sensory nerve action potential (SNAP), reliable electrodiagnostic metrics for this part of the recorded waveform are lacking. The average rise slope of the SNAP appreciates the steepness of the initial negative deflection of the waveform, which might be a useful metric for the first part of the potential. Sural nerve sensory neurography was performed in patients with various axonal neuropathies, and median nerve sensory studies were carried out in patients with carpal tunnel syndrome. Age-matched healthy individuals served as controls. The rise slope was compared to conventional SNAP parameters such as conduction velocity, latency, duration, and rise time. Overall, 537 sensory studies were prospectively analyzed. The rise slope of the sural SNAP demonstrated superior classification performance in terms of sensitivity (92.5%), specificity (97%), and area under the receiver operating characteristic curve (0.986), as compared to conventional SNAP parameters. Its diagnostic power was similarly excellent in median nerve studies, whereas here a slightly better classification performance was obtained by SNAP latency and conduction velocity. The average rise slope appears to do justice to the tight interplay between amplitude and rise time of the initial negative spike deflection, outperforming many conventional measures. This composite metric proved high diagnostic potency in particular with regard to axonal sensory nerve dysfunction.

Association of transcription factor 7-like 2 rs12255372 polymorphism with susceptibility of type 2 diabetes mellitus in Bangladeshi population.

Polymorphism of transcription factor 7-like 2 (TCF7L2) has a link with type 2 diabetes mellitus (T2DM) through β cell dysfunction that causes defect in blood glucose homeostasis. This case-control study recruited 67 T2DM as cases and 65 age-matched healthy individuals as controls to determine whether the polymorphism rs12255372 (G > T) in the TCF7L2 gene have an association with T2DM in Bangladeshi population. Genomic DNA was purified from peripheral whole blood sample and direct Sanger sequencing was done for genotyping of SNP. Bivariate logistic regression was done to find out the association between genetic variant and T2DM. In our study, the minor T allele frequency was significantly more frequent in T2DM group than healthy controls (29.1% vs. 16.9%). After adjusting with confounding factors, heterozygous-genotype GT had higher odds of developing T2DM (OR 2.4; 95% CI: 1.0-5.5; p value = 0.04) and in dominant model, having SNP in TCF7L2 increased the risk of T2DM 2.3 times (95% CI: 1.0-5.2; p value = 0.04). In interaction model, genetic susceptible SNP cases interacted significantly with increasing age and BMI, female gender, and having family history of diabetes mellitus to develop T2DM (pinteraction < 0.001). Having minor T allele either in heterozygous or homozygous variant form of rs12255372 (G > T) TCF7L2 had significant association with T2DM. In conclusion, TCF7L2 gene variant increases risk of developing T2DM among the Bangladeshi population.

Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI): a cohort study.

Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality. In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41. Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations. A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution. The Netherlands Organisation for Health Research and Development and Amsterdam UMC.

Use of a novel indentometer to evaluate skin stiffness in healthy and diseased human skin.

Mechanical behavior of the skin can be evaluated by different non-invasive methods. In this study, we applied a new measurement device based on indentometry to determine the skin mechanical properties in healthy individuals and in patients with systemic sclerosis (SSc). Three studies were performed. Study 1 included 100 healthy individuals (46 male and 54 female) divided into four age groups with mean ages of 21.5, 28.9, 51.2, and 69.3 years, respectively. Test sites were located on the center of the forehead and the middle of both volar forearms. Study 2 included 16 healthy individuals (two males and 14 females). Test sites were on both volar forearms. Measurements were made before and after the application of Vaseline and emulsion with 12% urea. Study 3 included 20 patients (one male and 19 females) with SSc and 60 age-matched healthy individuals (23 males and 37 females). Test sites were on the center of the forehead and the middle of both volar forearms. Skin stiffness was measured with skin Indentometer IDM 800 (Courage + Khazaka, Cologne, Germany) equipped with two probes with pin diameters of 3 and 5mm, respectively. The stiffer the skin, the less deep the displacement by the indenter. The smaller the diameter, the deeper the pin will go into the skin when using the same force. In addition, the Corneometer CM 820 (Courage + Khazaka) was used to determine epidermal water content in study 2. Indentometric (IDM) values of healthy subjects measured with both probes were lower on the forehead compared to volar forearms. There was no significant difference between both forearms. In all age groups, the IDM values on the male forearms were lower than on the female forearms whereas there was no significant difference on the forehead. In both sex and on all test locations a significant positive correlation between age and IDM values measured with both probes was observed. There was a significant positive correlation between IDM values measured with both probes. The application of moisturizers induced significant changes in epidermal water content whereas the IDM values remained unchanged. At both the forehead and volar forearms, the IDM values in patients with SSc were significantly lower compared to the healthy control skin. The non-invasive indentometric method used can successfully distinguish the changes in normal skin mechanical properties related to age, sex, and anatomical location, as well as in patients with SSc. The method is not appropriate to study the changes related to epidermal hydration.

The Relationship between Telomere Length and Nucleoplasmic Bridges and Severity of Disease in Prostate Cancer Patients

Telomeres are repetitive nucleotide (TTAGGG) sequences that stabilize the chromosome ends and play an important role in the prevention of cancer initiation and progression. Nucleoplasmic bridges (NPBs) are formed when chromatids remain joined together during mitotic anaphase either due to mis-repair of DNA breaks or due to chromatid end fusion as a result of telomere loss or telomere dysfunction. We tested the hypotheses that (i) telomere length (TL) is shorter in prostate cancer (PC) patients relative to healthy age-matched individuals, (ii) TL differs in different stages of PC and (iii) shorter TL is significantly correlated with NPBs formation in PC cases. TL was measured in whole blood by well-established quantitative PCR method and the frequency of NPBs was measured in lymphocytes using cytokinesis-block micronucleus cytome (CBMNcyt) assay. Our results indicate that TL is shorter and NPBs are increased in PC patients relative to age-matched healthy controls. Furthermore, TL was significantly shorter (p = 0.03) in patients with a Gleason score more than 7 and there was also a significant trend of decreasing TL across all three stages (p trend = 0.01; Gleason score &lt;7, 7 and &gt;7). Furthermore, TL was significantly inversely correlated with NPB frequency in PC patients (r = −0.316; p = 0.001) but not in controls (r = 0.163; p = 0.06) and their relationships became stronger with higher Gleason scores. More studies are required that can confirm our observations and explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to non-cancer cases.

#3812 ARE KIDNEY CYSTS MORE COMMON IN PEOPLE WITH COL4A3/COL4A4 PATHOGENIC VARIANTS?

Abstract Background and Aims Individuals with pathogenic heterozygous variants in the COL4A3/COL4A4 genes are usually asymptomatic or present only with microhaematuria, although some may develop proteinuria and chronic kidney disease (CKD). Simple renal cysts are common in healthy individuals, with an increasing incidence with age and CKD grade. A possible association between pathogenic variants of collagen type IV and renal cysts has been described. This study investigates the presence of renal cysts in a large cohort of individuals with heterozygous pathogenic variants in COL4A3/COL4A4. Method We evaluated the presence of kidney cysts, kidney size and lithiasis by ultrasound in 162 individuals with pathogenic variants in COL4A3/COL4A4 without kidney replacement therapy. The correlation between kidney cysts and age, proteinuria, eGFR, causing gene and type of variant, was analysed. Genetic testing had been performed in index cases by next generation sequencing (NGS) of a kidney-disease gene panel containing more than 400 genes including COL4A3, COL4A4 and COL4A5 genes. Results 153 patients with a heterozygous disease-causing variant in COL4A3 or COL4A4 and 9 patients with digenic/complex inheritance were included. The mean age at renal ultrasound was 46.19 years (SD 14.93) and the mean eGFR was 75 ml/min/1.73 m2 (SD 35 ml/min/1.73 m2). Renal cysts were present in 50% of patients (81/162) and were bilateral in 30.25%. The mean age of patients with renal cysts was 53.26 years vs. 39.12 years for those without, and the mean eGFR was 60ml/min/1.73 m2 vs. 89ml/min/1.73 m2 for patients with and without renal cysts. Only 2.5% (4/162) of patients had renal lithiasis. The mean kidney size was 104.05 mm (SD 13.86 mm) for the right kidney and 104.98 mm (SD 13.94 mm) for the left kidney. Cystic nephromegaly was observed in 3.7% (6/162). No correlation was found between renal cysts and gender (p = 0.632). Age and CKD stage had a positive correlation with the development of renal cysts (p = &amp;lt;0.001) (Tables 1 and 2). Proteinuria was more common in individuals with renal cysts 61% vs 39% (p = 0.012), but was related to age and CKD stage. The presence of a kidney cyst did not correlate with the mutated gene or the type of variant. Conclusion Individuals with COL4A3/COL4A4 pathogenic variants develop kidney cysts at a higher rate than age-matched healthy individuals, and their presence is also related to ageing, as in the general population. Gender is not relevant for the development of renal cysts, in contrast to the general population cohorts. Proteinuria and CKD grade correlate with the development of renal cysts but nephromegaly is rare. Renal cysts in heterozygous carriers of COL43 or COL4A4 pathogenic variants are common but have no clinical consequences.

Association of Vitamin-D Receptor Gene Single Nucleotide Polymorphism (FokI) with COPD

Background: Vitamin D receptor gene (VDR) polymorphism and its association with various diseases have been previously investigated. But the association of vitamin D receptor gene polymorphism with COPD has not been investigated yet.&#x0D; Objective: To assess the association between vitamin D receptor gene polymorphism (FokI) and COPD.&#x0D; Methods: This cross sectional study was carried out in the Department of Physiology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from March 2019 to February 2020. For this study, 15 (fifteen) pulmonologists diagnosed COPD patients with age 40 to 80 years (post-bronchodilator FEV1/FVC&lt;0.70 and FEV1&lt;80% predicted) and 15 (fifteen) apparently healthy age-matched individuals (for comparison), were selected. The single nucleotide polymorphism of vitamin D receptor gene (FokI) of all subjects was assessed by PCR-RFLPs. Data were expressed as mean ± SD and percentage. Statistical analysis was done by independent sample ‘t’ test and chi-square test. In the interpretation of the results, ≤0.05 level of probability (p) was accepted as significant.&#x0D; Results: The frequency distribution of FokI genotype was 13.33% (FF), 73.34% (Ff), 13.33% (ff) and 13.33% (FF), 80% (Ff), 6.66% (ff) COPD patients and healthy subjects, respectively. Associations of FokI [FF (OR 1,95% CI 0.12-8.21, p=1.00); Ff (OR 0.68,95% CI 0.12-3.78, p=0.66); ff (OR 2.15,95% CI 0.17-26.67, p=0.54)] VDRSNP with COPD was statistically non-significant. Conclusion: The present study reveals that the FokI of VDR SNP is not associated with COPD.&#x0D; Central Medical College Journal Vol 6 No 1 January 2022 Page: 14-21

Stereoptic serious games as a visual rehabilitation tool for individuals with a residual amblyopia (AMBER trial): a protocol for a crossover randomized controlled trial

BackgroundAmblyopia is the most common developmental vision disorder in children. The initial treatment consists of refractive correction. When insufficient, occlusion therapy may further improve visual acuity. However, the challenges and compliance issues associated with occlusion therapy may result in treatment failure and residual amblyopia. Virtual reality (VR) games developed to improve visual function have shown positive preliminary results. The aim of this study is to determine the efficacy of these games to improve vision, attention, and motor skills in patients with residual amblyopia and identify brain-related changes. We hypothesize that a VR-based training with the suggested ingredients (3D cues and rich feedback), combined with increasing the difficulty level and the use of various games in a home-based environment is crucial for treatment efficacy of vision recovery, and may be particularly effective in children.MethodsThe AMBER study is a randomized, cross-over, controlled trial designed to assess the effect of binocular stimulation (VR-based stereoptic serious games) in individuals with residual amblyopia (n = 30, 6–35 years of age), compared to refractive correction on vision, selective attention and motor control skills. Additionally, they will be compared to a control group of age-matched healthy individuals (n = 30) to account for the unique benefit of VR-based serious games. All participants will play serious games 30 min per day, 5 days per week, for 8 weeks. The games are delivered with the Vivid Vision Home software. The amblyopic cohort will receive both treatments in a randomized order according to the type of amblyopia, while the control group will only receive the VR-based stereoscopic serious games. The primary outcome is visual acuity in the amblyopic eye. Secondary outcomes include stereoacuity, functional vision, cortical visual responses, selective attention, and motor control. The outcomes will be measured before and after each treatment with 8-week follow-up.DiscussionThe VR-based games used in this study have been conceived to deliver binocular visual stimulation tailored to the individual visual needs of the patient, which will potentially result in improved basic and functional vision skills as well as visual attention and motor control skills.Trial registrationThis protocol is registered on ClinicalTrials.gov (identifier: NCT05114252) and in the Swiss National Clinical Trials Portal (identifier: SNCTP000005024).

Integrated analysis of the association between methionine cycle and risk of moyamoya disease.

The role of methionine (Met) cycle in the pathogenesis and progression of cardiovascular and cerebrovascular diseases has been established, but its association with moyamoya disease (MMD) has rarely been studied. This study aimed to analyze the levels of Met cycle-related metabolites and constructed a risk model to explore its association with the risk of MMD. In this prospective study, a total of 302 adult MMD patients and 88 age-matched healthy individuals were consecutively recruited. The serum levels of Met cycle-related metabolites were quantified by liquid chromatography-mass spectrometry (LC-MS). Participants were randomly divided into training set and testing set at a ratio of 1:1. The training set was used to construct the risk score model by LASSO regression. The association between Met cycle-related risk score and the risk of MMD was analyzed using logistic regression and assessed by ROC curves. The testing set was used for validation. The levels of methionine sulfoxide and homocysteine were significantly increased, while the levels of betaine and choline were significantly decreased in MMD and its subtypes compared to healthy controls (p < 0.05 for all). The training set was used to construct the risk model and the risk score of each participant has been calculated. After adjusting for potential confounders, the risk score was independently associated with the risk of MMD and its subtypes (p < 0.05 for all). We then divided the participants into low-risk and high-risk groups, the high-risk score was significantly associated with the risk of MMD and its subtypes (p < 0.05 for all). The risk scores were further assessed as tertiles, the highest tertile was significantly associated with a higher risk of MMD and its subtypes compared to the lowest (p < 0.05 for all). The results were validated in the testing set. This study has constructed and validated a risk model based on Met cycle-related metabolites, which was independently associated with the risk of MMD and its subtypes. The findings provided a new perspective on the risk evaluation and prevention of MMD.

Insights Into PROM1-Macular Disease Using Multimodal Imaging.

To describe the features of genetically confirmed PROM1-macular dystrophy in multimodal images. Thirty-six (36) eyes of 18 patients (5-66 years; mean age, 42.4 years) were prospectively studied by clinical examination and multimodal imaging. Short-wavelength autofluorescence (SW-AF) and quantitative fundus autofluorescence (qAF) images were acquired with a scanning laser ophthalmoscope (HRA+OCT, Heidelberg Engineering) modified by insertion of an internal autofluorescent reference. Further clinical testing included near-infrared autofluorescence (NIR-AF; HRA2, Heidelberg Engineering) with semiquantitative analysis, spectral domain-optical coherence tomography (HRA+OCT) and full-field electroretinography. All patients were genetically confirmed by exome sequencing. All 18 patients presented with varying degrees of maculopathy. One family with individuals affected across two generations exhibited granular fleck-like deposits across the posterior pole. Areas of granular deposition in SW-AF and NIR-AF corresponded to intermittent loss of the ellipsoid zone, whereas discrete regions of hypoautofluorescence corresponded with a loss of outer retinal layers in spectral-domain optical coherence tomography scans. For 18 of the 20 eyes, qAF levels within the macula were within the 95% confidence intervals of healthy age-matched individuals; nor was the mean NIR-AF signal increased relative to healthy eyes. Although PROM1-macular dystrophy (Stargardt disease 4) can exhibit phenotypic overlap with recessive Stargardt disease, significantly increased SW-AF levels were not detected. As such, elevated bisretinoid lipofuscin may not be a feature of the pathophysiology of PROM1 disease. The qAF approach could serve as a method of early differential diagnosis and may help to identify appropriate disease targets as therapeutics become available to treat inherited retinal disease.

Gp130 Promotes Inflammation via the STAT3/JAK2 Pathway in Allergic Conjunctivitis.

Allergic conjunctivitis (AC) is a common allergic condition worldwide that requires accurate screening and early diagnosis. We found that gp130 is essential for AC, as gp130 levels are elevated in AC. Therefore, this study aimed to elucidate the functions and the possible underlying mechanisms of gp130 in AC. To compare mRNA expression profiles, the conjunctival tissues of BALB/c mice with ovalbumin (OVA)-induced AC were subjected to RNA-sequencing (RNA-seq) analysis followed by bioinformatic analysis. A nonrandomized study involving 57 patients with AC and 24 sex- and age-matched healthy individuals was conducted. A protein chip was used to detect cytokine levels in patient tears. Differentially expressed proteins in patient serum were detected using label-free quantitative mass spectrometry. Histamine-stimulated conjunctival epithelial cells (HConEpiCs) were used to construct a cell model. LMT-28 which can inhibit gp130 phosphorylation was dropped onto the murine ocular surface, and the resulting symptoms were observed. Gp130 is upregulated in the conjunctival tissues of OVA-induced mice, the serum and tears of patients, and the histamine-stimulated HConEpiCs. Signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2) were upregulated in the conjunctival tissues of mice with OVA-induced AC and in HConEpiCs. Ocular surface inflammation was significantly relieved in LMT-28-treated mice. The expression of IgE, IL-4, IL-5, and IL-13 in serum of LMT-28-treated mice decreased. The number of mast cells in conjunctival tissue was decreased compared with OVA-induced mice. Gp130 may play an important role in AC via the gp130/JAK2/STAT3 pathway. Inhibiting gp130 phosphorylation alleviates ocular surface inflammation in mice, presenting a potential treatment approach for AC.

Abstract 2875: Evidence of immunosuppression in patients with breast ductal carcinoma in situ

Abstract Introduction: Ductal carcinoma in situ (DCIS) is a noninvasive precursor to invasive breast cancer. Although not all DCISlesions progress to cancer, most DCIS are treated as early breast cancer, given the uncertainty of which lesions will progress. The current increase in the incidence of DCIS has sparked interest in the immune contexture of the DCIS lesions as well as the immune status of DCIS patients, as a means to predict which DCIS lesions will progress to cancer. Studies done so far in invasive breast cancer showed that the immune system can mediate both tumor-promoting influence (via T regulatory (Treg) cells, M2 macrophages, myeloid-derived suppressor cells (MDSCs)), as well as tumor-suppressing influences (via CD8+ and CD4+ effector T cells, natural killer cells (NK), M1 macrophages, tissue-resident memory T (Trm) cells, B cell and dendritic (DCs) cells). Similar studies are still lacking in DCIS. Our aim was to start closing the gap in our understanding of the DCIS immune microenvironment, which will pave the way for novel preventative and therapeutic strategy. Methods: We analyzed by flow cytometry peripheral blood mononuclear cells (PBMCs) from newly diagnosed DCIS patients for the presence of various immune cell types expressing specific phenotypic markers of immune effectors or immune suppressors and compared them with PBMC from age-matched healthy individuals. Results: We found a statistically significant increase in the frequency of FoxP3+ regulatory T cells in DCIS PBMC compared with healthy controls. There was also a significant increase in Tim-3+CD8+ T effector memory cells (P= 0.035) and Tim-3+ CD8+ NKT cells (P = 0.033) in the PBMCs of patients with DCIS compared with healthy controls. T cells expressing other exhaustion markers, such as PD-1+ and LAG-3+ were present at very low levels in both groups. Conclusion: Our results suggest that some of the many immunosuppressive mechanisms seen in patients with invasive breast cancer, such as regulatory T cells, are already present in pre-cancer DCIS. Evidence of the beginning of immune suppression is also reflected in the increased frequency of CD4+ and CD8+ T cells expressing the exhaustion marker Tim-3. Citation Format: Sedigheh Taghinezhad-S, Amir Hossein Mohseni, Pamela L. Beatty, Leisha A. Emens, Olivera J. Finn. Evidence of immunosuppression in patients with breast ductal carcinoma in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2875.

Choroidal structure investigated by choroidal vascularity index in patients with inherited retinal diseases

PurposeTo evaluate the choroidal structure in patients with inherited retinal diseases (IRDs) by investigating the choroidal vascularity index (CVI).MethodsThe present study was conducted on 113 IRD patients and 113 sex- and age-matched healthy individuals. Patients’ data was extracted from the Iranian National Registry for IRDs (IRDReg®). Total choroidal area (TCA) was determined between retinal pigment epithelium and choroid-scleral junction,1500 microns on either side of the fovea. Luminal area (LA) was considered as the black area corresponding to the choroidal vascular spaces, following Niblack binarization. CVI was calculated as the ratio of the LA to the TCA. CVI and other parameters were compared among different types of IRD and the control group.ResultsThe IRD diagnosis included retinitis pigmentosa (n = 69), cone-rod dystrophy (n = 15), Usher syndrome (n = 15), Leber congenital amaurosis (n = 9), and Stargardt disease (n = 5). Sixty-one (54.0%) individuals of each of the study and control groups were male. The average CVI was 0.65 ± 0.06 in the IRD patients and 0.70 ± 0.06 in the control group (P < 0.001). Accordingly, the average of TCA and LA were 2.32 ± 0.63 and 1.52 ± 0.44 mm [1] in patients with IRDs, respectively. The measurements for the TCA and the LA were significantly lower in all subtypes of IRD (P-values < 0.05).ConclusionCVI is significantly lower in patients with IRD than in healthy age-matched individuals. Choroidal changes in IRDs may be related to the changes in the lumen of the choroidal vessels rather than the stromal changes.

Состояние хориокапилляров у пациентов с парацентальной острой срединной макулопатией

Purpose. To evaluate with optical coherence tomography angiography the status of the choriocapillaris in the eyes of patients with resolved paracentral acute middle maculopathy (PAMM). Method. Nine patients with unilateral resolved PAMM, 14 age-matched healthy individuals, and 16 age-matched patients with unilateral retinal vein occlusion (RVO) were included. The choriocapillaris flow area, and the number of choriocapillaris flow voids was compared between the eyes of healthy individuals, both eyes of the PAMM patients, and the fellow eyes of unilateral RVO patients. Results. The number of choriocapillaris flow voids in the unaffected eyes of PAMM patients was statistically significantly higher than in the eyes of healthy individuals (p &lt; 0.001) and in the fellow eyes of unilateral RVO patients (p = 0.022). The choriocapillaris flow area in the unaffected eyes of PAMM patients was statistically significantly lower than in the eyes of healthy individuals (p &lt; 0.001) and in the fellow eyes of unilateral RVO patients (p = 0.019). There was no difference in the status of the choriocapillaris between two eyes of PAMM patients. Conclusion. Eyes of patients with resolved PAMM have a substantial decrease of choriocapillaris perfusion. Keywords: paracentral acute middle maculopathy; choriocapillaris; vessel density; optical coherence tomography angiography; retinal vein occlusion

Single-Cell Analysis in Blood Reveals Distinct Immune Cell Profiles in Gouty Arthritis.

Gout is a chronic disease caused by monosodium urate crystal deposition. Previous studies have focused on the resident macrophage, infiltrating monocyte, and neutrophil responses to monosodium urate crystal, yet the mechanisms of the potential involvement of other immune cells remain largely unknown. In this study, we enrolled seven gout patients and five age-matched healthy individuals and applied single-cell mass cytometry to study the distribution of immune cell subsets in peripheral blood. To our knowledge, our study reveals the immune cell profiles of gout at different stages for the first time. We identified many immune cell subsets that are dysregulated in gout and promote gouty inflammation, especially those highly expressing CCR4 and OX40 (TNFR superfamily member 4), including CCR4+OX40+ monocytes, CCR4+OX40+CD56high NK cells, CCR4+OX40+CD4+ NK T cells, and CCR4+CD38+CD4+ naïve T cells. Notably, the plasma levels of CCL17 and CCL22, measured by ELISA, increased in the acute phase of gout and declined in the interval. We also found a clue that Th2-type immune responses may participate in gout pathology. Moreover, the subset of granzyme B+ (GZMB+) CD38+ NK cells is positively correlated with serum urea acid level, and another two γδT subsets, GZMB+CD161+ γδT cells and GZMB+CCR5+ γδT cells, are negatively correlated with erythrocyte sedimentation rate. In sum, gouty arthritis is not a disease simply mediated by macrophages; multiple types of immune cell may be involved in the pathogenesis of the disease. Future research needs to shift attention to other immune cell subsets, such as NK cells and T cells, which will facilitate the identification of novel therapeutic targets.

Evaluation of CD137 and CD137L Transcript Levels and the Serum sCD137 in Immune-mediated Polyneuropathy.

Abnormal humoral and cellular immune responses have been reported in immune-mediated polyneuropathies. CD137, as a costimulatory molecule and a TNF receptor superfamily member, has been demonstrated to have a key role in the pathogenesis of many autoimmune as well as inflammatory disorders. To evaluate the transcripts levels of CD137, its ligand (CD137L), and the serum levels of soluble CD137 (sCD137) in patients with immune-mediated polyneuropathy. A total of 45 patients and 46 sex and age-matched healthy individuals were enrolled in the study. CD137 and CD137L transcript levels were assessed by the Real-Time PCR, and the serum level of sCD137 was measured using the ELISA technique. The Bayesian regression model was used for statistical analysis at the 0.05 significance level in R 4.1.0 statistical environment. Transcript levels of the CD137 and CD137L were higher in polyneuropathy patients in comparison with the healthy subjects (P=0.006 for both). Conversely, the mean level of sCD137 was significantly lower in the sera of patients compared to the controls (P<0.001). Our findings point to the possible role of CD137 and CD137L in immune-mediated polyneuropathy pathogenesis. More investigations are required to clarify the exact contributions of the mentioned molecules to the pathogenesis of immune-mediated polyneuropathies.