Natural Progression Of Disease Research Articles

Long-term HBV infection of engineered cultures of induced pluripotent stem cell-derived hepatocytes.

HBV infects ~257 million people and can cause hepatocellular carcinoma. Since current drugs are not curative, novel therapies are needed. HBV infects chimpanzee and human livers. However, chimpanzee studies are severely restricted and cost-prohibitive, while transgenic/chimeric mouse models that circumvent the species barrier lack natural HBV infection and disease progression. Thus, in vitro human models of HBV infection are useful in addressing the above limitations. Induced pluripotent stem cell-derived hepatocyte-like cells mitigate the supply limitations of primary human hepatocytes and the abnormal proliferation/functions of hepatoma cell lines. However, variable infection across donors, deficient drug metabolism capacity, and/or low throughput limit iHep utility for drug development. We developed an optimal pipeline using combinations of small molecules, Janus kinase inhibitor, and 3',5'-cAMP to infect iHep-containing micropatterned co-cultures (iMPCC) with stromal fibroblasts within 96-well plates with serum-derived HBV and cell culture-derived HBV (cHBV). Polyethylene glycol was necessary for cell-derived HBV but not for serum-derived HBV infection. Unlike iHep monocultures, iMPCCs created from 3 iHep donors could sustain HBV infection for 2+ weeks. Infected iMPCCs maintained high levels of differentiated functions, including drug metabolism capacity. HBV antigen secretion and gene expression patterns in infected iMPCCs in pathways such as fatty acid metabolism and cholesterol biosynthesis were comparable to primary human hepatocyte-MPCCs. Furthermore, iMPCCs could help elucidate the effects of interferons and direct-acting antiviral drugs on the HBV lifecycle and any hepatotoxicity; iMPCC response to compounds was similar to primary human hepatocyte-MPCCs. The iMPCC platform can enable the development of safe and efficacious drugs against HBV and ultimately help elucidate genotype-phenotype relationships in HBV pathogenesis.

New IPECAD open-source model framework for the health technology assessment of early Alzheimer’s disease treatment: development and use cases

Reimbursement decisions for new Alzheimer's disease (AD) treatments are informed by economic evaluations. An open-source model with intuitive structure for model cross-validation can support the transparency and credibility of such evaluations. We describe the new IPECAD open-source model framework (version 2) for the health-economic evaluation of early AD treatment and use it for cross-validation and addressing uncertainty. A cohort state transition model using a categorized composite domain (cognition and function) was developed by replicating an existing reference model and testing it for internal validity. Then, features of existing "ICER" and "AD-ACE" models assessing lecanemab treatment were implemented for model cross-validation. Additional uncertainty scenarios were performed on choice of efficacy outcome from trial, natural disease progression, treatment effect waning and stopping rules, and other methodological choices. The model is available open-source as R code, spreadsheet and web-based version via https://github.com/ronhandels/IPECAD. In the IPECAD model incremental life years, QALY gains and cost savings were 21-31% smaller compared to the ICER model and 36-56% smaller compared to the AD-ACE model. IPECAD model results were particularly sensitive to assumptions on treatment effect waning and stopping rules and choice of efficacy outcome from trial. We demonstrated the ability of a new IPECAD opens-source model framework for researchers and decision-makers to cross-validate other (HTA submission) models and perform additional uncertainty analyses, setting an example for open science in AD decision modeling and supporting important reimbursement decisions.

Overexpression of the receptor for resolvin E1 (ERV1) prevents early alveolar bone loss in leptin receptor deficiency-induced diabetes.

This study was designed to test the hypothesis that the leptin receptor (LepR) regulates changes in periodontal tissues and that the overexpression of the receptor for resolvin E1 (ERV1) prevents age- and diabetes-associated alveolar bone loss. LepR-deficient transgenic (TG) mice were cross-bred with those overexpressing ERV1 (TG) to generate double-TG mice. In total, 95 mice were divided into four experimental groups: wild type (WT), TG, LepR deficient (db/db), and double transgenic (db/db TG). The groups were followed from 4weeks up to 16weeks of age. The natural progression of periodontal disease without any additional method of periodontitis induction was assessed by macroscopic and histomorphometric analyses. Osteoclastic activity was measured by tartrate-resistant acid phosphatase (TRAP) staining. At 4weeks, ERV1 overexpression prevented weight gain. From Week 8 onward, there was a significant increase in the weight of db/db mice with or without ERV1 overexpression compared to the WT mice, accompanied by an increase in glucose levels. By 8weeks of age, the percentage of bone loss in the LepR deficiency groups was significantly greater compared to WT mice. ERV1 overexpression in the db/db TG mice prevented early alveolar bone loss; however, it did not impact the development of diabetic bone loss in aging mice after the onset of weight gain and diabetes. The findings suggest that the overexpression of ERV1 prevents LepR-associated alveolar bone loss during the early phases of periodontal disease by delaying weight gain, diabetes onset, and associated inflammation; however, LepR deficiency increases susceptibility to naturally occurring inflammatory alveolar bone loss as the animal ages, associated with excess weight gain, onset of diabetes, and excess inflammation.

Spatially Resolved Association of Structural Biomarkers on Retinal Function in Non-Exudative Age-Related Macular Degeneration Over 4 Years.

To longitudinally assess the impact of high-risk structural biomarkers for natural disease progression in non-exudative age-related macular degeneration (AMD) on spatially resolved mesopic and scotopic fundus-controlled perimetry testing. Multimodal retinal imaging data and fundus-controlled perimetry stimuli points were semiautomatically registered according to landmark correspondences at each annual visit over a period of up to 4 years. The presence of sub-RPE drusen, subretinal drusenoid deposits, pigment epithelium detachments (PEDs), hyper-reflective foci (HRF), vitelliform lesions, refractile deposits, and incomplete RPE and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) were graded at each stimulus position and visit. Localized retinal layer thicknesses were extracted. Mixed-effect models were used for structure-function correlation. Fifty-four eyes of 49 patients with non-exudative AMD (mean age, 70.7 ± 9.1years) and 27 eyes of 27 healthy controls (mean age, 63.4 ± 8.9years) were included. During study course, presence of PED had the highest functional impact with a mean estimated loss of -1.30 dB (P < 0.001) for mesopic and -1.23 dB (P < 0.001) for scotopic testing, followed by HRF with -0.89 dB (mesopic, P = 0.001) and -0.87 dB (scotopic, P = 0.005). Subretinal drusenoid deposits were associated with a stronger visual impairment (mesopic, -0.38 dB; P = 0.128; scotopic, -0.37 dB; P = 0.172) compared with sub-RPE drusen (-0.22 dB, P = 0.0004; -0.18 dB, P = 0.006). With development of c-RORA, scotopic retinal sensitivity further significantly decreased (-2.15 dB; P = 0.02). Thickening of the RPE-drusen-complex and thinning of the outer nuclear layer negatively impacted spatially resolved retinal sensitivity. The presence of PED and HRF had the greatest prognostic impact on progressive point-wise sensitivity losses. Higher predominant rod than cone-mediated localized retinal sensitivity losses with early signs of retinal atrophy development indicate photoreceptor preservation as a potential therapeutic target for future interventional AMD trials.

Neurological Deterioration in Wilson's Disease-Types, Etiology, Course, and Management.

Wilson's disease (WD) is an inherited disorder of copper metabolism in which pathological copper accumulation, mainly in the liver and the brain, leads to hepatic and/or neuropsychiatric signs and symptoms. Chelators and zinc salts can successfully induce negative copper balance in many patients; however, neurological deterioration may still be observed. This phenomenon can be divided into: (1) early 'paradoxical' neurological deterioration, which usually develops in the first 6 months of anti-copper treatment and may be commonly related to drug type, or (2) late neurological deterioration, which mostly occurs after 6 months of treatment and is often related either to non-compliance with treatment, overtreatment resulting in copper deficiency, or adverse drug reactions. Another explanation, especially for early neurological deterioration, is natural WD progression, which can be difficult to differentiate from drug-related deterioration, but usually leads to a worse outcome. There is still no consensus on how to define neurological deterioration in WD using scales or biomarkers, how to distinguish it from the natural disease progression, its risk factors, and optimal management. This narrative review, based on the current literature, aims to provide definitions, prevalence, pathological mechanisms and factors related to neurological deterioration, and also proposes schemes for diagnosis and treatment.

Cardiometabolic risk comorbidities in exocrine pancreatic insufficiency compared to patients with cancer: A single centered observational retrospective cohort study.

642 Background: Exocrine pancreatic insufficiency (EPI) is characterized by inadequate secretion of digestive enzymes. EPI is associated with increased risk for pancreatic cancer as well as increased risk for diabetes and consequently cardiometabolic (CM) risk equivalents. Emerging data suggest patients with cancer also have increased CM risk equivalents. To explore the cardiovascular risk associated with both EPI and cancer, we sought to describe and compare CM comorbidities and surrogates in patients with EPI vs cancer. Methods: A retrospective observational electronic chart analysis was done at Ochsner Health, Louisiana, spanning records from January 2017-2020 comparing two cohorts: patients with EPI (n=677) and patients with Cancer (n=1432). Results: The Cancer cohort was older (65.1 ± 11.9 yrs) than the EPI cohort (54.2 ± 17.6 yrs) (p &lt; 0.05). The Cancer cohort had higher AST levels (63.2 ± 106.2 U/L [nl 8-33 U/L] at start, 84.9 ± 447.3 U/L at end) vs the EPI cohort (50.2 ± 86.9 U/L at start, 65.4 ± 368.9 U/L at end) (p &lt; 0.05). The Cancer cohort also had higher ALT levels (69 ± 111.4 U/L (nl 7-55 U/L) at start, 58.5 ± 141.2 U/L at end) vs the EPI cohort (48.7 ± 79.5 U/L at start, 41.4 ± 100.3 U/L at end) (p &lt; 0.05). No significant differences were seen in Cancer cohort vs EPI cohort for A1c, TG, amylase, lipase, cholesterol, uric acid, tobacco/alcohol use, or blood pressure levels. Within the Cancer cohort, there was an increase in neuropathy (11% at the start vs 26.9% at end [p &lt; 0.05]), CHF (3.63% at the start vs 11.5% at end [p &lt; 0.05]), and HTN prevalence (29.9% at the start vs 66.1% at end [p &lt; 0.05]). Cancer patients also had decreased weight (175.2 ± 46.5 lbs at start, 163.8 ± 43.4 lbs at end [p &lt; 0.05]) and BMI (27.3 ± 6.5 at start, 25.7 ± 6.4 at end [p &lt; 0.05]). Among the general cancer cohort, no statistically different changes were seen in hypoglycemia, DKA, retinopathy, nephropathy, ESRD, dialysis, HLD, NAFLD, OSA, CAD, CVD, PAD, hyperuricemia, or gout prevalence over the period of observation or in comparison to EPI cohort. Conclusions: Patients in the Cancer cohort in this study have some indices of greater CM risk compared to those with EPI. Though older, they had significantly higher AST and ALT levels compared to EPI cohort. Over the 3 years of observation, cancer patients developed a statistically significant increase in neuropathy, CHF, and HTN prevalence, and decrease in weight and BMI. These changes may reflect consequent morbidity related both to natural disease progression and/or effects of cancer treatments such as chemotherapy.

The experience of using ataluren in Duchenne muscular dystrophy in Moscow: first results

Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder typically manifesting in boys aged 2–5 years, characterized by a progressive course. According to natural disease progression data, individuals with DMD typically lose the ability to walk independently by the age of 13. In most cases, the disease leads to cardiorespiratory complications, resulting in a lethal outcome between the ages of 20–30.In recent years, there have been therapeutic agents developed for the pathogenic treatment of this condition. One such medication is ataluren (Translarna®), used in patients with DMD caused by the formation of a “stop codon” (nonsense mutation) in the DMD gene, responsible for the development of the disease.This article presents the experience of applying ataluren (Translarna®) in boys residing in Moscow who suffer from Duchenne muscular dystrophy.

Chapter 8: Management of Radioiodine Refractory Thyroid Cancer

ABSTRACT A small subset of patients with differentiated thyroid cancers (DTCs), over the course of their natural disease progression, undergo dedifferentiation which leads to altered tumor biology and an inability to concentrate and respond to radioactive iodine (RAI), despite being able to functionally produce and release thyroglobulin. They broadly consist of two groups – (a) thyroglobulin-elevated negative iodine scintigraphy and (b) radioiodine refractory DTC. This review deals with their definitions, presentation, and overall management principles, highlighting the key points of their treatment philosophy. Whole-body 18F positron emission tomography-computed tomography is the investigation of choice since majority of these become fludeoxyglucose avid once they lose their iodine avidity. Asymptomatic patients with low disease burden may be observed. Surgical ablation, for symptomatic patients with accessible disease is the prime treatment modality. For those deemed inoperable with high tumor burden and increasing symptomatology are best treated with multikinase inhibitors. External beam Radiation may be a choice for painful bony metastasis, while those refractory to multikinase inhibitors may be offered newer forms of localized therapy such as radiofrequency ablation, newer isotope therapy, and transarterial chemoembolization.

Reversal and prevention of deregulated autophagy in cutaneous autoimmune disorders—a pilot study on vitiligo with nutrigenomics based approach of “Maximum Nutrition and Minimum Medication”

Abstract Nutritional status of patients, specially prolonged starvations is an important sub-component of the environmental factors, speculated to have indirect impact on the initiation, propagation, resolution, and exacerbation stages of autoimmunity. The study was based on the hypothesis of conscious, selective, and self-destruction, that is, deregulated autophagy of skin and hair in low dietary protein scenario triggered with prolonged starvations. It was aimed to reverse the self-destruction/deregulated autophagy by providing early morning, low carb-high protein nutrition, and correcting underlying micronutrient deficiency and studying its effect on reducing auto-immunity and eventually reducing disease burden and recurrence. Methods: In this retrospective study, patients were divided into two categories based on disease activity and nutrition. Group A: “novice group” of vitiligo patients who presented at an early stage of their disease were managed with basic standard of therapeutics. Group B: “stabilized group” of vitiligo who were given surgical treatment and followed up for 3 years for any recurrences. Personalized diet plan aimed at reversing high carb-low protein diet and avoiding prolonged overnight starvation adhering to early morning breakfast respecting the circadian rhythm and balanced with additional plant based protein was advised. All detectable underlying micronutrient deficiencies were corrected. Results: Thirty patients were enrolled in the study, 20 in group A and 10 in group B. We observed visible signs of improvement in group A, with early vitiligo (90%) with topical therapy and nutritional intervention as early as 3 weeks. Following surgical procedure in group B, 50% patients had near complete pigmentation at the end of 3 months and 30% within next 3 months. At the end of 6 months, all patients had significant improvement in VASI and VIDA score, however two patients in each group had recurrence at end of 1 year who deviated from nutritional protocol and were found to be deficient in protein intake and micronutrients deficiency was detected on blood investigation. The improvement in VASI scores with conventional treatment and nutritional intervention was found to be statistically significant at 6 months and 1-year interval in group A with paired t test (P = 0.013). Similarly, improvement in VASI was statistically very significant at 6 months and 1-year duration in surgically treated vitiligo group B (P = 0.001). These patients were put on immunosuppressive therapies in first group after correction of deficiencies and managed with supportive and conventional therapy in second group in subsequent 3 years follow up. Conclusion: Nutritious diet aimed at correction of underlying protein and micronutrient deficiency with special emphasis on circadian rhythm may arrest the natural progression of disease at an early stages of the disease and prime the body for oral immunosuppressive drugs. This approach may prevent the recurrence in patients already stabilized with standard care of therapeutics and surgery in future.

Quantifying Rift Valley fever virus transmission efficiency in a lamb-mosquito-lamb model.

Rift Valley fever virus (RVFV) is a (re)emerging mosquito-borne pathogen impacting human and animal health. How RVFV spreads through a population depends on population-level and individual-level interactions between vector, host and pathogen. Here, we estimated the probability for RVFV to transmit to naive animals by experimentally exposing lambs to a bite of an infectious mosquito, and assessed if and how RVFV infection subsequently developed in the exposed animal. Aedes aegypti mosquitoes, previously infected via feeding on a viremic lamb, were used to expose naive lambs to the virus. Aedes aegypti colony mosquitoes were used as they are easy to maintain and readily feed in captivity. Other mosquito spp. could be examined with similar methodology. Lambs were exposed to either 1-3 (low exposure) or 7-9 (high exposure) infectious mosquitoes. All lambs in the high exposure group became viremic and showed characteristic signs of Rift Valley fever within 2-4 days post exposure. In contrast, 3 out of 12 lambs in the low exposure group developed viremia and disease, with similar peak-levels of viremia as the high exposure group but with some heterogeneity in the onset of viremia. These results suggest that the likelihood for successful infection of a ruminant host is affected by the number of infectious mosquitoes biting, but also highlights that a single bite of an infectious mosquito can result in disease. The per bite mosquito-to-host transmission efficiency was estimated at 28% (95% confidence interval: 15 - 47%). We subsequently combined this transmission efficiency with estimates for life traits of Aedes aegypti or related mosquitoes into a Ross-McDonald mathematical model to illustrate scenarios under which major RVFV outbreaks could occur in naïve populations (i.e., R0 >1). The model revealed that relatively high vector-to-host ratios as well as mosquitoes feeding preferably on competent hosts are required for R0 to exceed 1. Altogether, this study highlights the importance of experiments that mimic natural exposure to RVFV. The experiments facilitate a better understanding of the natural progression of disease and a direct way to obtain epidemiological parameters for mathematical models.

The potential cost‐effectiveness of roflumilast drug treatment in mild cognitive impairment

AbstractBackgroundEvidence is needed on the value of new (pharmacological) health technologies in their early stage of development, to support stakeholders (industry, regulators, payers, and health care providers) in decision‐making linked to their further development and introduction in routine care. Early health‐technology assessment supports stakeholders by providing insight into the size and uncertainty of the expected benefits new technologies may have. This can facilitate early guidance on positioning in clinical practice and research recommendations. Our objective was to provide a pragmatic example of the potential cost‐effectiveness of roflumilast treatment in addition to usual care versus usual care alone if prevention of progression to dementia is in part realized in a population of patients diagnosed with a mild cognitive impairment (MCI) at a memory clinic.MethodThe IPECAD open‐source decision‐analytic model was used to simulate the natural disease progression of MCI and dementia and estimate the quality‐adjusted life years (QALYs) and care costs, comparing roflumilast treatment added to usual care with usual care alone. In this model roflumilast proof of concept evidence on a visual 30‐word verbal learning test (0.39 z‐score) was translated using a published risk equation model to a relative risk of 0.93 for developing dementia. The treatment was assumed symptomatic with no effect on mortality.ResultMore lifeyears were spent in MCI in the roflumilast strategy compared with usual care, with 0.2 increment lifeyears (95%CI: 0.0 to 0.6) (see figure 1), and 0.04 incremental lifetime QALYs (95%CI: 0.00 to 0.11) and k€1.3 adjusted societal costs (95%CI: ‐6.3 to 5.5) (see figure 2). This resulted in an incremental cost‐effectiveness ratio of k€34 per QALY (see table 1). Roflumilast was estimated to have a 37% probability of being cost‐effective (net health benefit 95% interval ‐0.27 to 0.42), with uncertainty mainly driven by extrapolating the word learning surrogate outcome to the patient‐relevant outcome of dementia onset, and the efficacy estimate (see figure 3).ConclusionThe potential cost‐effectiveness of roflumilast treatment is uncertain, driven by uncertainty in treatment efficacy and extrapolation to postponing dementia onset. We believe the results indicate a potential for roflumilast and provide several recommendations to consider investing in its future research.

Prostaglandin-E1 infusion in persistent pulmonary hypertension of the newborn.

Neonates with persistent pulmonary hypertension of the newborn (PPHN) can present with hypoxia and right ventricular dysfunction with resultant inadequate oxygen delivery and end-organ damage. This study describes the use of prostaglandin-E1 (PGE) for ductal patency to preserve right ventricular systolic function and limit afterload in newborns with PPHN. This is a retrospective cohort study that follows the hemodynamics, markers of end-organ perfusion, length of therapeutics, and echocardiographic variables of 57 newborns who used prostglandin-E1 in the setting of PPHN. Tachycardia, lactic acidosis, and supplemental oxygen use improved following PGE initiation. Fractional area change (FAC), to assess right ventricular systolic function, and pulmonary arterial acceleration time indexed to right ventricular ejection time (PAAT/RVET), to assess right ventricular afterload, also improved over three time points relative to PGE use (before, during, and after). Overall, we described the safety and utility of PGE in newborns with severe PPHN for stabilization while allowing natural disease progression.

Exploring the mechanisms responsible for afterload mismatch in severe aortic stenosis

Abstract Introduction Afterload mismatch (AM) is defined as a reduced ejection fraction (EF) in the setting of severe aortic stenosis (AS) (aortic valve area (AVA) of &amp;lt; 1cm2), but with transaortic pressure gradients in the severe range. The pathomechanism underlying the impaired EF remains unclear, especially with regards to the impact of ventricular hypertrophy and fibrosis, the role of afterload, and the integrity of the intrinsic contractile myocardial strength in AM. This knowledge gap unmasks a lack of understanding into the natural disease progression in AS. Purpose To characterise the morphological and functional contractile mechanics that distinguishes patients with reduced EF from patients with preserved EF in the setting of AS with high transvalvular gradients. Methods A prospective comparative analysis was performed on 21 sequential cases of patients with severe AS, 9 with AM (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;lt; 50%) and 12 with normal flow high gradient (NFHG) AS (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;gt; 50%). Patients with concomitant valve lesions or previously diagnosed myocardial infarction, were excluded. Myocardial morphology, function and tissue characteristics were evaluated using a) transthoracic echocardiography, b) cardiac magnetic resonance imaging, and c) an invasive hemodynamic study with pressure-volume loop derived data. Results Intrinsic load independent contractile muscle function parameters were similar between AM and NFHG AS (p-value non-significant for cardiac index, dP/dT(max), preload recruitable stroke work slope, end systolic pressure volume relationship slope and Starling contractile index slope). Afterload indices as assessed by peak systolic wall stress and valvuloarterial impedance were significantly higher in AM cases compared to NFHG AS (32.5 vs 19.9 N/cm2; p &amp;lt; 0.01 and 4.8 vs 3.4mmHg/ml; P = 0.05). This was driven by disproportionally higher degrees of valvular stenosis in the AM group (valve area 0.46 vs 0.78cm2; p &amp;lt; 0.01). The AM group expressed a more advanced disease phenotype with more symptoms (NYHA 3.3 vs 2.3; p=0.02), more pulmonary hypertension (50 vs 30mmHg; p=0.04), and more extensive myocardial fibrosis (24% vs 13% of left ventricular mass; p=0.03) (see Figure 1). Neither more severe LVH nor higher degrees of fibrosis in the AM group, was associated with a demonstrable impairment in the intrinsic contractile muscle function. Conclusion Our data suggest that the central problem in AM is related to an excessively increased afterload, primarily driven by more severe valvular stenosis, with preserved intrinsic left ventricular contractile function. AM is characterised by more severe myocardial fibrosis, as a marker of a more advanced disease phenotype, but this did not translate into worse intrinsic contractile muscle function. The known time dependence of progressive valvular stenosis and myocardial fibrosis would suggest that AM is an intermediate phase between NFHG AS and so-called low flow low gradient severe AS.A more advanced phenotype

Monoclonal antibodies neutralizing alpha-hemolysin, bicomponent leukocidins, and clumping factor A protected against Staphylococcus aureus-induced acute circulatory failure in a mechanically ventilated rabbit model of hyperdynamic septic shock.

Patients with septic shock caused by Staphylococcus aureus have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of S. aureus septic shock and to determine whether a novel immunotherapy can prevent or halt its natural disease progression. Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after S. aureus intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with S. aureus. Rabbits challenged with S. aureus, but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (P<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury. These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting S. aureus virulence factors for the prevention of staphylococcal septic shock.

P08.10.B COIMBRA: THE IMPACT OF RADIOTHERAPY ON QUALITY OF LIFE AND DISEASE PROGRESSION IN PATIENTS WITH BRAIN METASTASES AND THEIR CAREGIVERS

Abstract INTRODUCTION Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and this incidence is expected to rise due to advancements in primary tumor management. Besides improving survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions. DESIGN/ METHODS The prospective COIMBRA study is designed to monitor a cohort of patients with BMs and their caregivers who are referred to a tertiary academic radiation oncology department (ClinicalTrials.gov Identifier: NCT05267158). The study is designed according to the Trials within Cohorts (TwiCs) framework, an adaptive design that allows for the evaluation of multiple interventions over time. Patients receive state of the art treatment, which includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Clinical data, QoL and cognitive functioning are collected at baseline and at regular intervals post-treatment. Additionally, new MRI techniques can be evaluated for their feasibility and performance in patients with BMs. PRELIMINARY RESULTS Since April 2019, 419 patients have been included of whom 51.2% were men and the majority of the patients had lung cancer (53.6%). SRS was administered in 92.4% and 68.1% received systemic therapy. Median overall survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before treatment (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patients’ diagnosis. CONCLUSION Our study successfully collected in-depth clinical and QoL data from patients with BMs and their caregivers. The results suggest a modest improvement in anxiety and QoL after SRS. These findings highlight the need for ongoing evaluation of interventions in this patient population in order to ultimately guide personalized treatment strategies.

TIPS-16 A PROSPECTIVE COHORT STUDY ON THE IMPACT OF RADIOTHERAPY ON QUALITY OF LIFE AND DISEASE PROGRESSION IN PATIENTS WITH BRAIN METASTASES AND THEIR CAREGIVERS

Abstract INTRODUCTION Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and the incidence is expected to rise due to advancements in primary tumor management. Besides survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions. DESIGN/METHODS COIMBRA is an observational, prospective cohort for patients with brain metastases and their caregivers that are referred to a tertiary academic radiation oncology department. The study is designed according to the Trials within Cohorts (TwiCs) framework. ClinicalTrials.gov Identifier: NCT05267158. PRELIMINARY RESULTS Since April 2019, 419 patients have been included of which 51.2% were men and the majority of the patients had lung cancer (53.6%). Stereotactic radiosurgery (SRS) was administered in 92.4% and 68.1% received any systemic therapy. Median Overall Survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patient’s diagnosis. CONCLUSION Our study successfully collected clinical and QoL data from a large cohort of patients and their caregivers. The results suggest a modest improvement in anxiety and QoL after radiotherapy.

A novel animal model of osteonecrosis of the femoral head based on 3D printing technology

BackgroundOsteonecrosis of the femoral head (ONFH) is a prevalent orthopedic condition characterized by the disruption of blood supply to the femoral head, leading to ischemia of internal tissues, subchondral bone fractures, necrosis, and eventual collapse of the weight-bearing portion of the femoral head. This condition results in severe functional impairment, pain, and even disability of the hip joint. Existing animal models of ONFH have limitations in replicating the natural disease progression accurately. Thus, there is a critical need to develop a novel animal model capable of better simulating localized pressure on the human femoral head to facilitate ONFH-related research.MethodsIn this study, we present a novel approach for modeling ONFH, which involves integrating stress factors into the modeling process through the utilization of 3D printing technology and principles of biomechanics. A total of 36 animals were randomly assigned to six groups, where they received either the novel modeling technique or the traditional hormone induction method. Subsequently, an 8-week treatment period was implemented, followed by conducting micro-CT scans and histological evaluations to assess tissue outcomes.ResultsThe study evaluated the cytotoxicity of the material used in the new model, and it was observed that the material did not exhibit any cytotoxic effects on cells. Additionally, the novel model successfully replicated the pathological features of ONFH, including femoral head collapse, along with a substantial presence of empty bone lacunae, cartilage defects, and subchondral bone fractures in the subchondral bone region.ConclusionIn conclusion, our study provides evidence that the new model shows the ability to simulate the progression of the disease, making it a valuable tool for research in this field and can contribute to the development of better treatment strategies for this debilitating condition. It holds great promise for advancing our understanding of the pathogenesis of ONFH and the potential therapeutic interventions for this challenging clinical problem.

Cytophagic Histiocytic Panniculitis with Undetermined Autoimmune Disease: A Rare Case Report

Cytophagic histiocytic panniculitis is a rare disease, associated with either nonmalignant conditions or subcutaneous panniculitis-like T-cell lymphoma (SPTL), and often also associated with hemophagocytic lymphohistiocytosis (HLH). We report the case of a 63-year-old woman who developed a multiple tender, indurated, erythmatous lesions over the abdomen, back, trunk and limbs. Histopathologic findings from skin biopsy specimens revealed significant lobular panniculitis with benign histiocytes showing hemophagocytosis. ANA by IF was positive. Though it is very rare, to confirm diagnosis of CHP by histopathology is very important as CHP and SPLT may span a clinicopathologic spectrum in which there is a natural disease progression from CHP to fatal SPTL.

LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts.

As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI. LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry. LTBP4 was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed. LTBP4 expression was upregulated in the renal tissues of patients with AKI. Ltbp4-knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells. Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.

The prevalence and changes over time of equine glandular gastric disease in a teaching herd population

SummaryBackgroundThe natural progression of equine glandular gastric disease (EGGD) in the absence of treatment has not yet been described in the literature, nor has the prevalence in a teaching herd population been reported.ObjectivesThe aims of this study were to determine the prevalence of disease in a teaching population over the study period (2019–2021) and to observe the changes over time in disease severity of naturally occurring diseases (not experimentally induced) without medical intervention.MethodsTwenty‐one horses underwent an initial gastroscopy and a repeat gastroscopy between 14 and 731 days later. Gastroscopy data were graded quantitatively and described qualitatively. Prevalence and 95% confidence intervals (CI) were calculated. The changes over time were determined by comparing initial and repeat gastroscopies.ResultsThe prevalence from initial, repeat and total number of gastroscopies was 62% (95% CI: 40.8–79.3), 71% (95% CI: 50.0–86.2) and 67% (95% CI: 51.6–79), respectively. The changes over time included worsening of disease in 29% of horses (95% CI: 13.8–50.0), improvement of disease to a lower grade in 24% (95% CI: 10.6–45.1), no change in grade in 38% (95% CI: 20.8–59.1), and complete resolution of disease to grade 0 in 10% (95% CI: 2.7–28.9).Main limitationsLimitations included a maximum of two gastroscopies per horse given COVID‐19 restrictions on data collection, and highly varied interval times between initial and repeat gastroscopies.ConclusionIn conclusion, there is a high prevalence of disease in this teaching herd. The changes over time in naturally occurring diseases without medical intervention might include worsening, improvement, no change or resolution of disease.