Course Of Disease Progression Research Articles

Leukemia circulation kinetics revealed through blood exchange method

Leukemias and their bone marrow microenvironments undergo dynamic changes over the course of disease. However, little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of CLC dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1–2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: (i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and (ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells.

Reticulon 2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to scarcity of supporting evidence. In our study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite Reticulon-2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with Reticulon-2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN, and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Methylome-wide and meQTL analysis helps to distinguish treatment response from non-response and pathogenesis markers in schizophrenia.

Schizophrenia is a complex condition with entwined genetic and epigenetic risk factors, posing a challenge to disentangle the intermixed pathological and therapeutic epigenetic signatures. To resolve this, we performed 850K methylome-wide and 700K genome-wide studies on the same set of schizophrenia patients by stratifying them into responders, non-responders, and drug-naïve patients. The key genes that signified the response were followed up using real-time gene expression studies to understand the effect of antipsychotics at the gene transcription level. The study primarily implicates hypermethylation in therapeutic response and hypomethylation in the drug-non-responsive state. Several differentially methylated sites and regions colocalized with the schizophrenia genome-wide association study (GWAS) risk genes and variants, supporting the convoluted gene-environment association. Gene ontology and protein-protein interaction (PPI) network analyses revealed distinct patterns that differentiated the treatment response from drug resistance. The study highlights the strong involvement of several processes related to nervous system development, cell adhesion, and signaling in the antipsychotic response. The ability of antipsychotic medications to alter the pathology by modulating gene expression or methylation patterns is evident from the general increase in the gene expression of response markers and histone modifiers and the decrease in class II human leukocyte antigen (HLA) genes following treatment with varying concentrations of medications like clozapine, olanzapine, risperidone, and haloperidol. The study indicates a directional overlap of methylation markers between pathogenesis and therapeutic response, thereby suggesting a careful distinction of methylation markers of pathogenesis from treatment response. In addition, there is a need to understand the trade-off between genetic and epigenetic observations. It is suggested that methylomic changes brought about by drugs need careful evaluation for their positive effects on pathogenesis, course of disease progression, symptom severity, side effects, and refractoriness.

Acute Post-streptococcal Glomerulonephritis in a Pediatric Population: A Five-Year Retrospective Study.

Post-streptococcal glomerulonephritis is a kidney disease that occurs after infection with a certain strain of streptococcal bacteria. It has a high hospitalization rate, especially in developing countries. It is characterized by the sudden appearance of edema, hematuria, proteinuria, and hypertension. The objective of this retrospective descriptive study conducted at James L. Gordon Memorial Hospital in Olongapo, Zambales, Philippines, is to analyze the demographic distribution, clinical presentation, complication, and outcome of acute post-streptococcal glomerulonephritis (APSGN) in a pediatric population. Methods: A retrospective descriptive study was done in patients (below 18 years of age) admitted with the diagnosis of post-streptococcal glomerulonephritis during a five-year period in the pediatric ward of a tertiary hospital in the Philippines. All patients underwent detailed clinical history and examination and were closely monitored during treatment. The course of disease progression was closely monitored and recorded. Seventy-seven children were treated for APSGN with a mean age of 7.8 years and with standard deviation of 3.85. Edema and gross hematuria were noted in 53 (68.8%) and 24 (31.1%) cases, respectively. Hypertension was present in 54 patients (70.1%). Among those 54 patients, 49 (63.6%) patients developed acute renal injury (based on normal creatinine for age), three cases (3.8%) had pleural effusion, and two patients (2.5%) developed hypertensive encephalopathy. All patients underwent KUB (kidneys, ureters, and bladder) ultrasound, among which 13 (16.88%) had diffuse parenchymal swelling which improved and eventually were discharged. Increased blood urea nitrogen (BUN) was noted in 60-65% of patients. Hypoalbuminemia and lower hemoglobin were also quite common. There was no mortality during treatment and hospital stay. APSGN remains one of the most common causes of glomerulonephritis in the region. Edema, hypertension, and hematuria were the most common presenting features. Early identification and comprehensive monitoring and management are required to prevent morbidity and mortality. The prognosis is generally good if early treatment is done.

Small fibre integrity and axonal pathology in the rat model of experimental autoimmune neuritis.

Experimental autoimmune neuritis is a common animal model for acute human immune-mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms remain unknown. In this study, we extensively characterize experimental autoimmune neuritis progression in Lewis rats, including new insights into the integrity of small nerve fibres, neuropathic pain and macrophage activation. Acute experimental autoimmune neuritis was induced with P253-78 peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative polymerase chain reaction (PCR), dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves tests. For the longitudinal setup, rats were sacrificed at Day (d) 10 (onset), d15 (peak), d26 (recovery) and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the experimental autoimmune neuritis. The dual role of macrophages in experimental autoimmune neuritis is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on Cx3-motif chemokine receptor 1 (Cx3cr1), platelet factor 4 (Pf4) and macrophage galactose-type lectin-1 (Mgl1) expressions were identified. In addition, modulation of the sensory system in experimental autoimmune neuritis was detected. An outgrowth of small fibres in the plantar skin at the onset and peak of the experimental autoimmune neuritis was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict experimental autoimmune neuritis as a primary demyelinating disease with implicated axonal damage, a small unmyelinated fibre impairment throughout the disease progression course, and underline the pivotal role of macrophages in the effector and during the recovery stage.

Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFβ/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

Autoimmune Autonomic Neuropathy: From Pathogenesis to Diagnosis.

Autoimmune autonomic ganglionopathy (AAG) is a disease of autonomic failure caused by ganglionic acetylcholine receptor (gAChR) autoantibodies. Although the detection of autoantibodies is important for distinguishing the disease from other neuropathies that present with autonomic dysfunction, other factors are important for accurate diagnosis. Here, we provide a comprehensive review of the clinical features of AAG, highlighting differences in clinical course, clinical presentation, and laboratory findings from other neuropathies presenting with autonomic symptoms. The first step in diagnosing AAG is careful history taking, which should reveal whether the mode of onset is acute or chronic, followed by an examination of the time course of disease progression, including the presentation of autonomic and extra-autonomic symptoms. AAG is a neuropathy that should be differentiated from other neuropathies when the patient presents with autonomic dysfunction. Immune-mediated neuropathies, such as acute autonomic sensory neuropathy, are sometimes difficult to differentiate, and therefore, differences in clinical and laboratory findings should be well understood. Other non-neuropathic conditions, such as postural orthostatic tachycardia syndrome, chronic fatigue syndrome, and long COVID, also present with symptoms similar to those of AAG. Although often challenging, efforts should be made to differentiate among the disease candidates.

High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study.

Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones. In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024.

The role of genetic factors in pediatric myelodysplastic syndromes with different outcomes

BackgroundPediatric myelodysplastic syndromes (MDS) are rare disorders with an unrevealed pathogenesis. Our aim is to explore the role of genetic factors in the pathogenesis of MDS in children with different outcomes and to discover the correlation between genetic features and clinical outcomes as well as disease characteristics.MethodsWe conducted an analysis of archived genetic data from 26 patients diagnosed with pediatric MDS at our institution between 2015 and 2021, examining the association between different genetic characteristics and clinical manifestations as well as prognosis. Additionally, We presented three cases with distinct genetic background and outcomes as examples to elaborate the role of genetic factors in pediatric MDS with different prognoses.ResultsGenetic variations were detected in 13 out of the 26 patients, including 8 patients with co-occurrence of somatic and germline mutations (CSGMs) and 5 patients with somatic mutations alone. Our analysis revealed that advanced MDS (4/8, 50% vs. 1/5, 20% and 4/11, 36.4%), PD (3/8, 37.5% vs. 1/5, 20% and 1/11 9.1%), and TD (6/8, 75% vs. 2/5, 40% and 2/11, 18.2%) were more common in patients with CSGMs than those with somatic mutations alone or without any mutations. We also found out in our study that 8 patients with CSGMs had evidently different clinical outcomes, and we presented 3 of them as examples for elaboration. Case 1 with germline and somatic mutations of unknown significance had a relatively slow disease course and a good prognosis. Case 2 with compound heterozygous germline SBDS variants and somatic mutations like del20q had a stable disease course and a reversed outcome. Case 3 with a germline GATA2 variant and somatic mutations including − 7 had a rapidly progressive disease course and a worst prognosis.ConclusionOur findings indicate that genetic background of pediatric MDS is closely linked with disease characteristics as well as outcomes and that CSGMs may lead to disease progression. It should be emphasized that the interaction between certain germline variants and somatic mutations, such as SBDS and del20q, may result in hematopoietic stem cell adaptation (improved hematopoiesis) and reversed clinical outcomes, which can facilitate the development of targeted therapy.

An Intelligent Search & Retrieval System (IRIS) and Clinical and Research Repository for Decision Support Based on Machine Learning and Joint Kernel-based Supervised Hashing.

Large-scale, multi-site collaboration is becoming indispensable for a wide range of research and clinical activities in oncology. To facilitate the next generation of advances in cancer biology, precision oncology and the population sciences it will be necessary to develop and implement data management and analytic tools that empower investigators to reliably and objectively detect, characterize and chronicle the phenotypic and genomic changes that occur during the transformation from the benign to cancerous state and throughout the course of disease progression. To facilitate these efforts it is incumbent upon the informatics community to establish the workflows and architectures that automate the aggregation and organization of a growing range and number of clinical data types and modalities ranging from new molecular and laboratory tests to sophisticated diagnostic imaging studies. In an attempt to meet those challenges, leading health care centers across the country are making steep investments to establish enterprise-wide, data warehouses. A significant limitation of many data warehouses, however, is that they are designed to support only alphanumeric information. In contrast to those traditional designs, the system that we have developed supports automated collection and mining of multimodal data including genomics, digital pathology and radiology images. In this paper, our team describes the design, development and implementation of a multi-modal, Clinical & Research Data Warehouse (CRDW) that is tightly integrated with a suite of computational and machine-learning tools to provide actionable insight into the underlying characteristics of the tumor environment that would not be revealed using standard methods and tools. The System features a flexible Extract, Transform and Load (ETL) interface that enables it to adapt to aggregate data originating from different clinical and research sources depending on the specific EHR and other data sources utilized at a given deployment site.

A Causal Network-Based Markov Decision Process Model for Intervention Planning

Patients suffering from chronic diseases often receive interventions after they are discharged from hospitals for their health management. The intervention decisions can be made sequentially during the course of disease progression and treatment process, and timely and proper interventions can lead to better health condition and quality of life and reduce the rate of re-hospitalization. Moreover, to determine effective intervention plans, personalized care should be considered. However, in many cases, intervention plans are not tailored to patients’ health conditions or dynamically adjusted based on their status changes due to the lack of adequate analytical methods. To address this issue, we introduce a causal Bayesian network-based Markov decision process (CNMDP) model to dynamically evaluate the health status and effectiveness of interventions for each patient and update the corresponding intervention strategy. In such a model, a causal Bayesian network is integrated in order to predict the effect of interventions in each patient’s health status. The resulting risk at each decision point is considered in a Markov decision process model by examining diverse factors of a patient to make a personalized optimal decision on intervention planning to minimize the risk of health deterioration or readmission. To illustrate the applicability of the model and develop a specific formulation, an intervention decision model for chronic obstructive pulmonary disease (COPD) patients is presented using the proposed method. Such a model can be applied to other diseases as well to design personalized, prompt, and effective intervention plans. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —Substantial efforts have been devoted to treatment and care management of chronic diseases. Particularly, there has been an initiative to design appropriate follow-up plans and interventions for postdischarge care to reduce hospital readmissions. However, many intervention plans are not patient specific and do not change with patient conditions. To mitigate such an limitation, based on identified risk factors and causal relationships, a causal Bayesian network model is introduced to predict readmission risk and evaluate intervention effectiveness. The results are then embedded into a Markov decision process to derive optimal intervention plan to minimize readmission risk. Such a process is repeated dynamically to evaluate health status and update intervention strategies. Using chronic obstructive pulmonary disease (COPD) as an example of chronic disease, a case study at a community hospital is presented to illustrate the applicability of the model.

German Parkinson’s network as a scalable approach for integrated care in daily medical routine

Due to the sectoral boundaries of the German healthcare system, a lack of interdisciplinary cooperation is evident. As a result, patients are either under-supplied or incorrectly treated. Mainly initiated by regional players, health care networks help to overcome local deficits in care. The core element of health care networks is the inclusion of all health care providers in the patient-centered treatment as well as a strengthened exchange of experiences and knowledge.&#x0D; Parkinson's disease (PD) is a neurodegenerative disorder, with a chronic progressive disease course divided into different stages. It is the second most common neurodegenerative disease with the fastest increase in the number of people affected of all neurological disorders worldwide. PD is considered as a model condition for the implementation of innovative healthcare concepts in chronic neurological diseases. For adequate healthcare and an optimized support, a multidisciplinary approach is necessary, considering the individual needs as well as the complexity of PD with its various motor and non-motor symptoms.&#x0D; Based on the findings of recent research projects, especially from the Dutch ParkinsonNET, several regional network structures for PD have been established in Germany in the past five years. Meanwhile, the German care landscape includes more than ten regional PD health care networks. In 2022, the “German PD network” has been founded as an umbrella organization.&#x0D; The overall goal of the umbrella organization is to provide PD patients in Germany with nationwide access to the networked structures described above. To ensure such universal access, data from international experiences as well as from Germany demonstrate that a coordinating institution  is indispensable. The coordinating institution (networking centre) is responsible for the daily and practical integration of the PD patients into the network as well as for the maintenance and further development of the networks. Scientific evidence for the effects of PD networks is widely available , therefore the goal of the German PD network is to reach the financial support of network structures by statutory health insurance, while evaluation the structures on an ongoing basis. Therefore, the German PD network designs structures, such as a digital care path, to create an integrated and coordinated care concept for PD patients which then can be transmitted to further neurological diseases.&#x0D; Challenges in PD healthcare routines are targeted using multidisciplinary care networks. Scientific evidence shows clear effects of PD network structures evolving in a strengthened intra- and interdisciplinary communication as well as greater and improved treatment coordination. Simultaneously, increased coordination leads to a reduction in the use of resources and mortality, a higher health-related quality of life as well as self-management for PD patients. Support and active participation in the development process of PD networks by the statutory health insurance is sought as a next step.

The politics of disease.

The COVID-19 pandemic highlights a long-known but often neglected aspect of international relations: the ability of disease to challenge and change all aspects of security, as well as the ability of public policies to change the course of disease progression. Diseases, especially mass epidemics like COVID-19, clearly affect political, economic, and social structures, but they can also be ameliorated or exacerbated by political policies, including public health policies. The threat of pandemic disease poses a widespread and increasing threat to international stability. Indeed, the political implications of pandemic disease have become increasingly evident as COVID-19 has precipitated death, economic collapse, and political instability around the globe. Any pandemic disease can precipitate catastrophes, from increasing health care costs to decreased productivity. This theoretical discussion highlights the intertwined interactions between social, political, and economic forces and the emergence and evolution of pandemic disease, with widespread implications for governance and international security.

Translational investigation of apathy and affective symptom hub genes in Alzheimer’s disease

AbstractBackgroundApproximately 90% of Alzheimer’s disease (AD) patients experience at least one neuropsychiatric symptom (NPS) over the course of disease progression. However, little is known about the neural mechanisms underlying NPS in AD, leaving treatment options for these symptoms underdeveloped. Here we use a translational approach to refine hub gene candidacy for the two most common NPS domains in AD (i.e., apathy, affective) and identify targets for investigation of causal relationships between genes and behavior.MethodWeighted gene co‐expression network analysis (WGCNA) was performed on RNA‐sequencing data from human postmortem anterior cingulate cortex of 60 individuals with AD and antemortem clinical evaluations of NPS. Human and mouse protein‐protein interaction networks (PPIs) were constructed from WGCNA modules that significantly correlated with NPS domains. Expression levels of potential hub genes discovered in humans were measured in the prefrontal cortex (PFC) of 16‐month‐old wild type (WT) and 5xFAD mice by RT‐qPCR and correlated with composite z‐scores for representative apathy‐ and affective‐like behaviors.ResultWGCNA revealed that a microglial phagocytic pathway and complement cascade module was uniquely correlated with apathy. PPI analyses refined the list of 43 WGCNA potential apathy hub genes to 21 candidate hub genes suitable for translational investigation. Further, human and mouse PPI analyses identified TYROBP as the highest‐ranking apathy hub gene. Expression levels of Tyrobp were significantly higher in the PFC of 5xFAD mice than in WT controls and positively correlated with apathy z‐scores. Only two genes retained affective domain hub gene candidacy (Tgfb1 and Nfkbia) in mice. Whereas Tgfb1 expression was elevated in the 5xFAD PFC, Nfkbia was not differentially expressed. Z‐scores for affective‐like behavior did not significantly correlate with either Tgfb1 or Nfkbia expression levels.ConclusionOur results suggest that the complement system is uniquely implicated in cases of AD with apathy; Tyrobp is a strong candidate gene for the regulation of that relationship. 5xFAD mice are an appropriate model for future investigation of Tyrobp‐complement‐apathy mechanisms in AD. Further study is needed to evaluate Tgfb1 and Nfkbia as possible regulators of affective behavior in models that exhibit other AD pathology(s) (e.g., tau) alone or in conjunction with pathologic amyloid‐beta.

Lymphopenia and high Ki-67 expression in peripheral blood CD4+ and CD8+ T cells associate with progressive sarcoidosis

BackgroundEarly identification of patients at risk for progressive sarcoidosis may improve intervention. High bronchoalveolar lavage fluid (BALF) lymphocytes and peripheral blood (PB) lymphopenia are associated with worse prognosis. The mechanisms...

Pathogenesis of Rift Valley Fever Virus in a BALB/c Mouse Model Is Affected by Virus Culture Conditions and Sex of the Animals.

Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing disease in livestock and humans. Whilst initially restricted to the African continent, recent spread to the Arabian Peninsula has highlighted the likelihood of entry into new regions. Due to the absence of a regulatory-approved human vaccine, work is ongoing to develop and assess countermeasures. As such, small animal models play a pivotal role in providing information on disease pathogenesis and elucidating which intervention strategies confer protection. To develop and establish the BALB/c mouse model, we challenged mice with RVFV grown from two separate cell lines: one derived from mosquitoes (C6/36) and the other mammalian derived (Vero E6). Following infection, we assessed the clinical course of disease progression at days 1 and 3 post-challenge and evaluated viral tropism and immune analytes. The results demonstrated that RVFV infection was affected by the cell line used to propagate the challenge virus, with those grown in insect cells resulting in a more rapid disease progression. The lowest dose that caused uniform severe disease remained the same across both virus preparations. In addition, to demonstrate reproducibility, the lowest dose was used for a subsequent infection study using male and female animals. The results further demonstrated that male mice succumbed to infection more rapidly than their female counterparts. Our results establish an RVFV mouse model and key parameters that affect the course of disease progression in BALB/c mice.

Accelerating the Adoption of New and Emerging Therapies for DLBCL: A Community-Based Quality Improvement Initiative

Background Remarkable progress has been made in the treatment and management of DLBCL. With a rapidly evolving landscape and novel treatment options, support is needed for community oncologists to guide integration of the latest safety and efficacy data into existing treatment planning. In this quality improvement (QI) initiative, we undertook an innovative practice transformation model bringing together providers from 4 community-based oncology clinics to assess current practice patterns and develop strategies to overcome barriers to optimal care for patients with relapsed/refractory DLBCL. Methods Between 8/2022-11/2022, 75 hematology/oncology clinicians completed surveys designed to evaluate practice patterns, challenges, and barriers to patient-centered care (Table 1). HCP cohorts within each oncology clinic participated in 1-hour live small-group audit-feedback (AF) sessions in which the teams reviewed the survey data, reflected on their own practice patterns and developed action plans to close identified DLBCL care gaps. Additional surveys conducted before and after the AF sessions evaluated changes in participants' knowledge and confidence in delivering quality care. Results Baseline Provider Surveys: HCPs reported identifying when patients have shifted to a more progressive disease course (31%) and selecting optimal therapies for individual patients (20%) as the biggest challenges in selecting therapies for DLBCL patients. The most challenging issues in managing DLBCL patients were supportive care counseling (28%) and recognizing and managing adverse events (20%). In addition to clinical guidelines, the other factors HCPs identified as most important for treatment decision-making for patients with DLBCL were the effects on quality of life (53%) and treatment effectiveness (48%). In terms of confidence, 23% reported very high confidence in the team's ability to stay up-to-date with new data on DLBCL treatment advances, and 29% reported very high confidence in aligning their clinical practices with evidence-based DLBCL guidelines. When asked about discussing novel treatment options with patients, 8% do not discuss, while 36% briefly discussed, and 56% discussed in detail. Moreover, 36% of HCPs reported low/very low confidence in identifying patients eligible for treatment with novel therapies, and 43% had low/very low confidence in navigating access to incorporate novel therapies into individual DLBCL treatment plans. To improve DLBCL care, only 3% of HCPs felt completely educated on the management of DLBCL, with 44% wanting to improve efficiency and ease of obtaining insurance approval for novel therapies and 44% seeking education on identifying patients eligible for newer therapies. Small-Group AF Sessions: In assessing HCPs' knowledge impact, only 35% correctly selected T-cell as the other targeted cell, in addition to tumor cells, for the mechanism of bispecific antibodies in DLBCL (Figure 1). Although this was improved compared to the 26% correct prior to the activity, more education is needed to close this knowledge gap. HCPs plan to address the following challenges: employing strategies to better identify and manage adverse events of novel therapies for DLBCL (79%), enhancing knowledge of clinical evidence for new and emerging therapies for DLBCL (71%), and developing personalized treatment plans incorporating patient-specific factors and preferences (68%). To achieve these goals, HCPs committed to improve patient communication and education, expand treatment access, engage patients by working to understand patient-specific considerations related to cellular therapies, and to educate and train staff in managing adverse events. Conclusions Barriers to providing patient-centered care in DLBCL identified in this QI initiative include staying up-to-date with novel therapies, recognizing and managing adverse events, and identifying patients eligible for novel therapies. After participating in this QI initiative, HCPs developed action plans to address the identified gaps and reported meaningful confidence gains in delivering DLBCL care. Practice gaps uncovered in this initiative can inform future QI programs. Study Sponsor Statement The study reported in this abstract was funded by an independent educational grant from Genmab US, Inc. and Kite Pharma, Inc. The grantors had no role in the study design, execution, analysis, or reporting.

NIMG-28. DIFFUSION DIFFERENCES IN LOW TO HIGH GRADE GLIOMA TRANSFORMATION

Abstract PURPOSE Apparent diffusion coefficient (ADC) maps offer tremendous insight into cellularity and local tissue environment. Proliferation of tumor cells results in increased local cellularity and cell density, thus impairing the free diffusion of water molecules. Therefore, hypointense ADC signals are thought to reflect regions of increased cellularity, and are useful imaging markers for distinguishing neoplastic cellular processes. In this study, we tested the hypothesis that changes in ADC intensity over the course of disease progression differ in progressing gliomas within the tumor-delineated region. METHODS Sixty-three glioma patients from our brain bank were separated into two groups. Group 1 included patients with Grade 1-3 gliomas at surgical diagnosis and progressed to a Grade 4 glioma at autopsy. The second group of patients were those with an initial and final Grade 4 glioma diagnosis. Contrast-enhancing tumor regions on MRI sequences were annotated with an established machine-learning algorithm for each patient on their initial and final MRIs. Average ADC intensity within the contrast enhancing regions was extracted and change in signal intensity between the first and last MRI was calculated for each patient. Finally, the mean intensity difference between Group 2 and Group 1 were evaluated using a linear mixed model. RESULTS We report a negative mean difference between the Group 2 and Group 1s change in ADC intensity over time (p=0.03). CONCLUSIONS These findings suggest changes in cellularity, identified by ADC, are greater in patients who progress from low-to-high grade gliomas. With these results, it may be concluded that change in ADC hypointensity, as a proxy for cellularity, may be a defining imaging characteristic to identify progressing gliomas.

Inflammasome-triggered IL-18 controls skin inflammation in the progression of Buruli ulcer

Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence factor so far, but the functions of this toxin and the mechanisms of disease progression remain unclear. By interfering Sec61 translocon, mycolactone inhibits the Sec61-dependent co-translational translocation of newly synthesized proteins, such as induced cytokines and immune cell receptors, into the endoplasmic reticulum. However, in regard to IL-1β, which is secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1β secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1β, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the inflammasome activation triggered in a manner independent of mycolactone. Intriguingly, mycolactone suppressed the expression of proIL-1β as well as TNF-α at the transcriptional level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional inhibitory effect on proIL-1β expression. Remarkably, constitutively produced IL-18 was cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans exhibited exacerbated skin inflammation during the course of disease progression. On the other hand, IL-1β controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of Buruli ulcer.

Targeting the central nervous system: The future of therapeutic strategies for MS

Targeting the central nervous system: The future of therapeutic strategies for MS Tara M. DeSilva from the Department of Neurosciences, Cleveland Clinic, looks at the future of therapeutic strategies for MS, focusing on targeting the central nervous system. Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease initially characterized by white matter lesions in the central nervous system (i.e., brain, spinal cord, and optic nerve) detected by magnetic resonance imaging (MRI). Lesions are caused by the infiltration of immune cells, resulting in loss of the insulation (myelin) around nerve fibers (neuronal axons). Early in the MS disease course, myelin regenerates; however, over time, sustained demyelination results in axonal injury and permanent disability. (1) The location of a lesion in the brain, spinal cord, or optic nerve determines the type of deficit a patient with MS will experience. Most patients with MS initially present with a relapsing-remitting disease course. During this phase, manifestations of clinical deficits indicate a relapse followed by a recovery or remittance of symptoms. Eventually, MS patients enter into a progressive disease course. During the progressive phase, there is no remittance, and symptoms gradually worsen, leading to permanent disability (Fig. 1).