Disease Pathology Research Articles

Predicting gestational diabetes mellitus risk at 11–13 weeks’ gestation: the role of extrachromosomal circular DNA

BackgroundGestational diabetes mellitus (GDM) significantly impacts maternal and infant health both immediately and over the long term, yet effective early diagnostic biomarkers are currently lacking. Thus, it is essential to identify early diagnostic biomarkers for GDM risk screening. Extrachromosomal circular DNA (eccDNA), being more stable than linear DNA and involved in disease pathologies, is a viable biomarker candidate for diverse conditions. In this study, eccDNA biomarkers identified for early diagnosis and assessment of GDM risk were explored.MethodsUsing Circle-seq, we identified plasma eccDNA profiles in five pregnant women who later developed GDM and five matched healthy controls at 11–13 weeks of gestation. These profiles were subsequently analyzed through bioinformatics and validated through outward PCR combined with Sanger sequencing. Furthermore, candidate eccDNA was validated by quantitative PCR (qPCR) in a larger cohort of 70 women who developed GDM and 70 normal glucose-tolerant (NGT) subjects. A ROC curve assessed the eccDNA’s diagnostic potential for GDM.Results2217 eccDNAs were differentially detected between future GDM patients and controls, with 1289 increased and 928 decreased in abundance. KEGG analysis linked eccDNA genes mainly to GDM-related pathways such as Rap1, MAPK, and PI3K-Akt, and Insulin resistance, among others. Validation confirmed a significant decrease in eccDNA PRDM16circle in the plasma of 70 women who developed GDM compared to 70 NGT women, consistent with the eccDNA-seq results. PRDM16circle showed significant diagnostic value in 11–13 weeks of gestation (AUC = 0.941, p < 0.001).ConclusionsOur study first demonstrats that eccDNAs are aberrantly produced in women who develop GDM, including PRDM16circle, which can predict GDM at an early stage of pregnancy, indicating its potential as a biomarker.Trial registration ChiCTR2300075971, http://www.chictr.org.cn. Registered 20 September 2023.

Desorption Electrospray Ionization Cyclic Ion Mobility-Mass Spectrometry Imaging for Traumatic Brain Injury Spatial Metabolomics.

Lipidomics focuses on investigating alterations in a wide variety of lipids that harness important information on metabolic processes and disease pathology. However, the vast structural diversity of lipids and the presence of isobaric and isomeric species creates serious challenges in feature identification, particularly in mass spectrometry imaging experiments that lack front-end separations. Ion mobility has emerged as a potential solution to address some of these challenges and is increasingly being utilized as part of mass spectrometry imaging platforms. Here, we present the results of a pilot mass spectrometry imaging study on rat brains subjected to traumatic brain injury (TBI) to evaluate the depth and quality of the information yielded by desorption electrospray ionization cyclic ion mobility mass spectrometry (DESI cIM MSI). Imaging data were collected with one and six passes through the cIM cell. Increasing the number of passes increased the ion mobility resolving power and the resolution of isobaric lipids, enabling the creation of more specific maps. Interestingly, drift time data enabled the recognition of multiply charged phosphoinositide species in the complex data set generated. These species have not been previously reported in TBI MSI studies and were found to decrease in the hippocampus region following injury. These changes were attributed to increased enzymatic activity after TBI, releasing arachidonic acid that is converted to eicosanoids to control inflammation. A substantial reduction in NAD and alterations in other adenine metabolites were also observed, supporting the hypothesis that energy metabolism in the brain is severely disrupted in TBI.

Exploring the Inhibitory Effects of Quinolone Medications on Carbonic Anhydrase Enzyme Activity: In Vitro and In Silico Investigation

AbstractEnzyme inhibition is a frequently employed technique for regulating enzyme activity in several biological systems that are physiologically significant. In this study, it was evaluated the effectiveness of six specific quinolone medicines, namely lomefloxacin, nalidixic acid, gatifloxacin, norfloxacin, sparfloxacin and nitrofurantoin, in inhibiting two human isoforms of the carbonic anhydrase (hCA) that play a role in different physiological and pathological circumstances. In order to achieve this objective, both in vitro and in silico investigations were conducted to get a deeper understanding of the potential binding interactions and affinities for hCA I and II isoforms. The kinetic inhibitory effects (Kis) of hCA I ranged from 1.31 to 13.07 μM, in comparison to the reference medication acetazolamide (AAZ, Ki of 0.12 μM). In addition, hCA II was effectively suppressed by these drugs, with Kis ranging from 1.42 to 11.93 μM, compared to AAZ (Ki of 0.098 μM). Significant interactions between the six medicines and hCAs indicated their potential to support therapeutic targets against pathological diseases. Furthermore, the findings acquired will contribute to the enhancement of therapeutic dose regimens for these medications and the prevention of unforeseen drug‐drug interactions when administered concurrently with other substances.

Analysis of Cytotoxic Granules and Constitutively Produced Extracellular Vesicles from Large Granular Lymphocytic Leukemia Cell Lines

Background: Large granular lymphocyte leukemias (LGLLs) are rare lymphoproliferative malignancies caused by clonal expansion of granular lymphocytes. T-cell LGLL and natural killer (NK) cell LGLL are defined based on their cellular origin. Their clinical manifestation and pathophysiology vary depending on the subtype and include, e.g., neutropenia, anemia, recurrent infections, and autoimmunity. A limited number of available patient-derived cell lines are considered valuable tools to study the biology of these malignancies. They differ in the expression of lineage-specific surface markers, but generally contain cytotoxic effector molecules in characteristic granules. Methods: We investigated the presence and release of lysosome-associated effector proteins in patient-derived LGLL cell lines by flow and imaging cytometry, by Western blotting and by bottom–up proteomics profiling. Results: The tested cell lines did not express FasL (CD178), but did express CD26/DPP4+. Intracellularly, we detected major differences in the abundance and subcellular distribution of granzymes, perforin, and granulysin. Similar differences were seen in enriched lysosome-related effector vesicles (LREVs). The proteomics profiling of enriched EVs from an NK-LGLL line (NKL) and a T-LGLL line (MOTN-1), confirmed individual profiles of effector molecules. Conclusion: Our analyses underscore the individual distribution of effector proteins but also open new routes to define the role of intra- and extracellular granules in the disease manifestation or pathology of LGLLs.

Parkinson’s Disease and Other Alzheimer’s Disease and Related Dementia Pathologies and the Progression of Parkinsonism in Older Adults

Background: The interrelationship of parkinsonism, Parkinson’s disease (PD) and other Alzheimer’s disease (AD) and Alzheimer’s disease and related dementias (ADRD) pathologies is unclear. Objective: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies. Methods: Annual parkinsonian signs were based on a modified Unified Parkinson’s Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined the progression of parkinsonian signs with PD and eight other AD/ADRD pathologies. Results: During average follow-up of 8 years, parkinsonian signs on average increased by 7.3% SD/year (N = 3,807). The progression of parkinsonian signs was slowest in Group1 (never parkinsonism or clinical PD), intermediate in Group2, and fastest in Group3. In decedents (n = 1,717) pathologic PD and cerebrovascular (CVD) pathologies were associated with a faster rate of progressive parkinsonian signs (all p values &lt;0.05). However, pathologic PD was rare in adults without clinical PD (Group1, 5%; Group2, 7% versus Group3, 55%). Yet, 70% of adults in Group2 without pathologic PD showed one or more CVD pathologies. In Group2, adults with pathologic PD showed faster progression of parkinsonian signs compared with those without evidence of pathologic PD and their rate of progression was indistinguishable from adults with clinical PD. Conclusions: Parkinsonism in old age is more commonly related to cerebrovascular pathologies relative to pathologic PD and only a minority manifest prodromal PD.

Enhancing Row-column array (RCA)-based 3D ultrasound vascular imaging with spatial-temporal similarity weighting.

Ultrasound vascular imaging (UVI) is a valuable tool for monitoring the physiological states and evaluating the pathological diseases. Advancing from conventional two-dimensional (2D) to three-dimensional (3D) UVI would enhance the vasculature visualization, thereby improving its reliability. Row-column array (RCA) has emerged as a promising approach for cost-effective ultrafast 3D imaging with a low channel count. However, ultrafast RCA imaging is often hampered by high-level sidelobe artifacts and low signal-to-noise ratio (SNR), which makes RCA-based UVI challenging. In this study, we propose a spatial-temporal similarity weighting (St-SW) method to overcome these challenges by exploiting the incoherence of sidelobe artifacts and noise between datasets acquired using orthogonal transmissions. Simulation, in vitro blood flow phantom, and in vivo experiments were conducted to compare the proposed method with existing orthogonal plane wave imaging (OPW), row-column-specific frame-multiply-and-sum beamforming (RC-FMAS), and XDoppler techniques. Qualitative and quantitative results demonstrate the superior performance of the proposed method. In simulations, the proposed method reduced the sidelobe level by 31.3 dB, 20.8 dB, and 14.0 dB, compared to OPW, XDoppler, and RC-FMAS, respectively. In the blood flow phantom experiment, the proposed method significantly improved the contrast-to-noise ratio (CNR) of the tube by 26.8 dB, 25.5 dB, and 19.7 dB, compared to OPW, XDoppler, and RC-FMAS methods, respectively. In the human submandibular gland experiment, it not only reconstructed a more complete vasculature but also improved the CNR by more than 15 dB, compared to OPW, XDoppler, and RC-FMAS methods. In summary, the proposed method effectively suppresses the side-lobe artifacts and noise in images collected using an RCA under low SNR conditions, leading to improved visualization of 3D vasculatures.

Th17-to-Tfh plasticity during periodontitis limits disease pathology.

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.

PRO: The Goblet Cell: Is It Needed for a Diagnosis of Barrett Esophagus, and Does It Impact Surveillance and Treatment?

Barrett esophagus and esophageal adenocarcinoma are sequential complications of gastroesophageal reflux disease. The diagnosis of Barrett esophagus leads to surveillance, which is aimed at early diagnosis of adenocarcinoma. Surveillance does not prevent adenocarcinoma. The first and universal requirement for diagnosis of Barrett esophagus is the presence of visible columnar lined esophagus at endoscopy. Without endoscopy, Barrett esophagus remains hidden. In the United States, intestinal metaplasia defined by goblet cells, which has a strong association with adenocarcinoma, is a second requirement for the diagnosis of Barrett esophagus. This limits surveillance to patients at highest risk. Patients with only cardiac mucosa have either no or lower risk of carcinoma until they develop goblet cells. Including patients without goblet cells will result in an increase in the surveillance pool with a likely negative cost-benefit. The more fundamental issue is that present guidelines delay pathologic diagnosis of gastroesophageal reflux disease to the point at which Barrett esophagus is detected. 85% of patients who develop adenocarcinoma have never had an endoscopy. To prevent esophageal adenocarcinoma, pathologic diagnosis of reflux disease must occur prior to the development of Barrett esophagus, however it is defined. Recent evidence and consensus indicate that cardiac mucosa distal to the squamocolumnar junction in the endoscopically normal person represents the pre-Barrett esophagus pathology of gastroesophageal reflux disease. Turning our attention to the presence and length of cardiac mucosa may provide a method of reaching the objective of preventing the late stages of gastroesophageal reflux disease manifested by Barrett esophagus and adenocarcinoma.

The role of morphofunctional asymmetries of the female body in the autonomic regulation of heart rate during menopause

The aim of the work was to study the features of autonomic regulation of heart rhythm (HR) in women in the peri- and postmenopausal periods, depending on morphofunctional asymmetries of the female body. A total of 417 women aged 35–60 were examined. According to the lateral behavioral profile of asymmetries of the female body (Annette’s test), the nature of vegetative regulation at rest and orthostasis was determined according to the data of cardiac intervalography using the Varicard 2.51 complex and the Eskim-6 program. As a result, it was found that in the reproductive period in women with the right lateral phenotype, the autonomous circuit of HR variability regulation prevailed, and in ambidextrous women, the central one dominated. Ambidextrous and right-handers were characterized by egalitarian modulation, while left-handers were characterized by a respiratory typology of autonomic regulation of HR. In perimenopause, a moderate tension of regulatory mechanisms was formed in the lateral subgroups, and a high tension was formed in the postmenopausal subgroups. In ambidextrous and left-handers, discoordination of HR regulation prevailed. Thus, women with the polarity of the lateral phenotype in the late reproductive period were distinguished by the stability and economy of the mechanisms of autonomic regulation of HR. Ambidextrous had the most energy-consuming mechanisms in the postmenopausal period, which is a risk of cardiovascular disease pathology.

Time-resolved interactome profiling deconvolutes secretory protein quality control dynamics.

Many cellular processes are governed by protein-protein interactions that require tight spatial and temporal regulation. Accordingly, it is necessary to understand the dynamics of these interactions to fully comprehend and elucidate cellular processes and pathological disease states. To map de novo protein-protein interactions with time resolution at an organelle-wide scale, we developed a quantitative mass spectrometry method, time-resolved interactome profiling (TRIP). We apply TRIP to elucidate aberrant protein interaction dynamics that lead to the protein misfolding disease congenital hypothyroidism. We deconvolute altered temporal interactions of the thyroid hormone precursor thyroglobulin with pathways implicated in hypothyroidism pathophysiology, such as Hsp70-/90-assisted folding, disulfide/redox processing, and N-glycosylation. Functional siRNA screening identified VCP and TEX264 as key protein degradation components whose inhibition selectively rescues mutant prohormone secretion. Ultimately, our results provide novel insight into the temporal coordination of protein homeostasis, and our TRIP method should find broad applications in investigating protein-folding diseases and cellular processes.

Palmatine Ameliorates Motor Deficits and Dopaminergic Neuron Loss by Regulating NLRP3 Inflammasome through Mitophagy in Parkinson's Disease Model Mice.

NLRP3 inflammasomes-mediated proinflammatory response and mitochondrial dysfunction play a critical role in the etiology and pathogenesis of Parkinson's disease. Negative regulation of NLRP3 inflammasome activation through mitophagy may be an important strategy to control NLRP3 inflammasome-mediated proinflammatory responses. Palmatine (PAL), an isoquinoline alkaloid found in various of plants, has potent pharmacological effects such as anti-inflammatory and anti-oxidation. However, the specific role of PAL in the pathology of Parkinson's disease remains unclear. In this study, we found that treatment with PAL improved motor deficits and reduced the loss of dopaminergic neurons in MPTP mice. Further results showed that PAL promoted mitophagy and inhibited the proinflammatory response mediated by NLRP3 inflammasomes. In addition, chloroquine (CQ, mitophagy inhibitor) attenuated the ameliorative effects of PAL on the motor deficits and dopaminergic neuron damage, as well as the inhibitory effect of PAL on NLRP3 inflammasome. Collectively, these results provide strong evidence that PAL ameliorates motor deficits and dopaminergic neuron death in Parkinson's disease, and the mechanism may be related to its inhibition of NLRP3 inflammasome activation via promoting mitophagy.

High Fat Diet-Induced Dysregulation of Tyrosine Kinases Is a Novel Player in Gut–Brain Axis in Alzheimer’s Disease

The gastrointestinal tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent studies have revealed the potential implications of gut–brain and vice-versa communication mediated by gut microbiota and their microbial products in Alzheimer’s disease (AD) pathology. AD is the most common type of dementia where most cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD and classified as non-modifiable (e.g., genetic) and modifiable (e.g., Type-2 diabetes (T2D), diet, etc.). A high fat diet (HFD) was reported to predispose individuals to AD upon the development of metabolic syndrome and systemic inflammation. Mechanistically, HFD induces gut dysbiosis with driven metabolites, which causes the loss of intestinal barrier integrity with concomitant colonic and systemic chronic low-grade inflammation (CLGI), associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation lead to the deposition of Amyloid β (Aβ) and, ultimately, cognitive impairment. So far, on a molecular level, an HFD causes the dysregulation of Janus kinase 3 (JAK3) in both the colon and brain, a non-receptor tyrosine kinase with epithelial functions proposed to regulate microglia’s phagocytic and migratory functions. However, the HFD-dysregulated transcription factors that link JAK3 dysregulation to obesity regarding the gut and brain are still ill-defined. Furthermore, metabolomic studies are required to determine the metabolites involved in HFD-dysregulated JAK3. This review provides a new perspective on the impact of an HFD on brain–gut and microbiota–gut–brain communication in terms of transcription factors as a commonly spoken language between the gut and brain of obese diabetic patients who are at higher risk of developing cognitive impairment and AD. That commonality is in terms of the regulation of JAK3 expression both in the gut and brain, hence maintaining the intestinal barrier integrity and the phagocytic and migratory microglial functions, likely via the regulation of microglial actin remodeling, thereby alleviating systemic CLGI as well as Aβ deposition. Lastly, the characterization of those common transcription factors represents a novel potential pharmacological target to impede AD progression.

Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer’s disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts – including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 – associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.

Defining blood hematology reference values in female pig-tailed macaques (Macaca nemestrina) using the Isolation Forest algorithm.

Pig-tailed macaques (PTMs) are commonly used as preclinical models to assess antiretroviral drugs for HIV prevention research. Drug toxicities and disease pathologies are often preceded by changes in blood hematology. To better assess the safety profile of pharmaceuticals, we defined normal ranges of hematological values in PTMs using an Isolation Forest (iForest) algorithm. Eighteen female PTMs were evaluated. Blood was collected 1-24 times per animal for a total of 159 samples. Complete blood counts were performed, and iForest was used to analyze the hematology data to detect outliers. Median, IQR, and ranges were calculated for 13 hematology parameters. From all samples, 22 outliers were detected. These outliers were excluded from the reference index. Using iForest, we defined a normal range for hematology parameters in female PTMs. This reference index can be a valuable tool for future studies evaluating drug toxicities in PTMs.

Optical Coherence Tomography Angiography Retinal Imaging Associations With Burden of Small Vessel Disease and Amyloid Positivity in the Brain.

Alzheimer disease (AD) and other dementias are associated with vascular changes and amyloid deposition, which may be reflected as density changes in the retinal capillaries. These changes may can be directly visualized and quantified with optical coherence tomography angiography (OCTA), making OCTA a potential noninvasive preclinical biomarker of small vessel disease and amyloid positivity. Our objective was to investigate the feasibility of retinal imaging metrics as noninvasive biomarkers of small vessel disease and amyloid positivity in the brain. We investigated associations between OCTA and neuroimaging and cognitive metrics in 41 participants without dementia from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center. OCTA metrics included superficial, deep, and full retina capillary density of the fovea, parafovea, and macula as well as the area of the foveal avascular zone (FAZ). Neuroimaging metrics included a high burden of white matter hyperintensity (WMH), presence of cerebral microbleeds (CMB), lacunar infarcts, and amyloid positivity as evidenced on positron emission tomography (PET), whereas cognitive metrics included mini-mental status examination (MMSE) score. We performed generalized estimating equations to account for measurements in each eye while controlling for age and sex to estimate associations between OCTA metrics and neuroimaging and cognitive scores. Associations between OCTA and neuroimaging metrics were restricted to the fovea. OCTA showed decreased capillary density with high burden of WMH in both the superficial (P = 0.003), deep (P = 0.004), and full retina (P = 0.01) in the fovea but not the parafovea or whole macula. Similarly, participants with amyloid PET positivity had significantly decreased capillary density in the superficial fovea (P = 0.027) and deep fovea (P = 0.03) but higher density in the superficial parafovea (P = 0.038). Participants with amyloid PET positivity also had a significantly larger FAZ (P = 0.031), whereas in those with high WMH burden the difference did not reach statistical significance (P = 0.075). There was also a positive association between MMSE and capillary density of the full retina within the fovea (P = 0.037) and in the superficial parafovea (P = 0.046). No associations were found between OCTA metrics and presence of CMB or presence of lacunar infarcts. The associations of lower foveal capillary density with cerebral WMH and amyloid positivity suggest that further research is warranted to evaluate for shared mechanisms of disease between small vessel disease and AD pathologies.

Edaravone N-benzyl pyridinium derivatives: BACE-1 inhibition, kinetics and in silico binding pose determination

BACE-1 plays a pivotal role in the production of β-amyloid (Aβ) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC50 = 44.10 µM - 123.70 µM) and obtained IC50 values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC50 = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC50 of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

Spinal endoscopic technique in the surgical treatment of thoracic ossification of the ligamentum flavum

Thoracic ossification of the ligamentum flavum (TOLF) is a pathological heterotopic ossification disease in which the fibrous tissue of the ligamentum flavum of the thoracic spine converts into bony tissue, often leading to thoracic spinal stenosis and compression of the thoracic spinal cord nerve. When TOLF patients present with symptoms of spinal cord nerve compression, surgical treatment is usually required, and traditional open surgery is more invasive and carries a higher risk of spinal cord nerve injury. In recent years, domestic and foreign researchers have tried to apply spinal endoscopic techniques such as microendoscopy, percutaneous foraminoscopy, and unilateral biportal endoscopy for the treatment of TOLF, which can maximize the preservation of normal bone while achieving adequate decompression of the spinal cord nerve, with less damage to spinal stability, and have the advantages of less surgical trauma, less bleeding, and faster postoperative recovery. Due to the special anatomical structure of the thoracic vertebra, spinal endoscopic techniques should focus on safety and it is recommended that they are performed in experienced centers, and surgical indications should be strictly controlled.

Standardizing visual display of gastrointestinal pathology results for improved clinical interpretation.

Pathology is an essential component of disease diagnosis and management in pediatric gastroenterology. Pathology reports have not been standardized in some areas of pediatric gastrointestinal pathology and pathology reporting varies. Development of electronic medical record (EMR) pathology synoptic report templates (PSRT) enables pathology data collection in a specific format and can help standardize pathology reporting. We developed, implemented, and evaluated EMR PSRTs for eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD). PSRTs were developed by a multidisciplinary team of pediatric experts of allergy, gastroenterology, and pathology for both EoE and IBD based on available literature and validated scales. Likert surveys (range 1 low acceptance to 5 high acceptance) based on the Technology Acceptance Model assessed user acceptance of the developed PSRTs. The use of PSRTs was monitored via control charts. Overall, evaluation questionnaires achieved >80% response rates. Clinicians and pathologists reported moderate-to-high levels of Perceived Usefulness (median [interquartile range) for EoE PSRT: clinicians 4.0 (4.0, 5.0) and pathologists 3.5 (3.5, 4.0); and IBD PSRT: clinicians 4.0 (3.0, 4.0) and pathologists 4.0 (4.0, 5.0)) and Perceived Ease of Use (EoE PSRT: clinicians 4.5 (4.0, 5.0) and pathologists 4.0 (4.0, 4.0); and IBD PSRT: clinicians 4.0 (4.0, 5.0) and pathologists 4.0 (4.0, 5.0)) of the developed PSRTs. Control charts demonstrated 100% utilization by 2-5 months from launch. We demonstrate successful implementation of synoptic reporting for both pediatric EoE and IBD pathology. EMR synoptic reporting provides standardization of pathology reporting and improved methods of pathology data presentation, which could potentially optimize provider efficiency, clinician interpretation of pathology results and disease trajectory, patient care, and clinician satisfaction.

Decision making for health-related research outcomes that alter diagnosis: A model from paediatric brain tumours.

The question of how to handle clinically actionable outcomes from retrospective research studies is poorly explored. In neuropathology, this problem is exacerbated by ongoing refinement in tumour classification. We sought to establish a disclosure threshold for potential revised diagnoses as determined by the neuro-oncology speciality. As part of a previous research study, the diagnoses of 73 archival paediatric brain tumour samples were reclassified according to the WHO 2016 guidelines. To determine the disclosure threshold and clinical actionability of pathology-related findings, we conducted a result-evaluation approach within the ethical framework of BRAIN UK using a surrogate clinical multidisciplinary team (MDT) of neuro-oncology specialists. The MDT identified key determinants impacting decision-making, including anticipated changes to patient management, time elapsed since initial diagnosis, likelihood of the patient being alive and absence of additional samples since cohort inception. Ultimately, none of our research findings were considered clinically actionable, largely due to the cohort's historic archival and high-risk nature. From this experience, we developed a decision-making framework to determine if research findings indicating a change in diagnosis require reporting to the relevant clinical teams. Ethical issues relating to the use of archival tissue for research and the potential to identify actionable findings must be carefully considered. We have established a structured framework to assess the actionability of research data relating to patient diagnosis. While our specific findings are most applicable to the pathology of poor prognostic brain tumour groups in children, the model can be adapted to a range of disease settings, for example, other diseases where research is dependent on retrospective tissue cohorts, and research findings may have implications for patients and families, such as other tumour types, epilepsy-related pathology, genetic disorders and degenerative diseases.

DISCREPANCY BETWEEN FUNDUS AUTOFLUORESCENCE ABNORMALITY AND VISUAL FIELD LOSS IN BIETTI CRYSTALLINE DYSTROPHY.

The aim of this study was to explore the potential benefits of retinal pigment epithelium replacement therapy in patients with Bietti crystalline dystrophy (BCD) by assessing the disease pathology with the distinctive relationship between fundus autofluorescence (FAF) abnormality and visual field defect. Sixteen eyes from 16 patients with BCD and 16 eyes from 16 patients with RHO-associated retinitis pigmentosa were included. Fundus autofluorescence, optical coherence tomography, and Goldmann perimetry results were retrospectively reviewed and assessed using image analyses. In patients with BCD, the FAF abnormality area was not correlated with the overall visual field defect area and median overall visual field defect area (57.5%) was smaller than FAF abnormality area (98.5%). By contrast, the ellipsoid zone width was significantly correlated with the central visual field area (r = 0.806, P < 0.001). In patients with RHO-associated retinitis pigmentosa, the FAF abnormality area and ellipsoid zone width were significantly correlated with the overall visual field defect area (r = 0.833, P < 0.001) and central visual field area (r = 0.887, P < 0.001), respectively. The FAF abnormality shown in patients with BCD involves retinal pigment epithelium degeneration without complete loss of photoreceptors or visual function. These results suggest that patients with BCD are good candidates for retinal pigment epithelium replacement therapy for preservation of residual visual function.