Intensive Therapeutic Intervention Research Articles

Integrative bioinformatics analysis of miRNA and mRNA expression profiles and identification of associated miRNA-mRNA network in intracranial aneurysms

BackgroundIntracranial aneurysms (IAs) represent protrusions in the vascular wall, with their growth and wall thinning influenced by various factors. These processes can culminate in the rupture of the aneurysm, leading to subarachnoid hemorrhage (SAH). Unfortunately, over half of the patients prove unable to withstand SAH, succumbing to adverse outcomes despite intensive therapeutic interventions, even in premier medical facilities. This study seeks to discern the pivotal microRNAs (miRNAs) and genes associated with the formation and progression of IAs. MethodsThe investigation gathered expression data of miRNAs (from GSE66240) and mRNAs (from GSE158558) within human aneurysm tissue and superficial temporal artery (STA) samples, categorizing them into IA and normal groups. This classification was based on the Gene Expression Omnibus (GEO) database. ResultsA total of 70 differentially expressed microRNAs (DEMs) and 815 differentially expressed mRNAs (DEGs) were pinpointed concerning IA. Subsequently, a miRNA-mRNA network was constructed, incorporating 9 significantly upregulated DEMs and 211 significantly downregulated DEGs. Simultaneously, functional enrichment and pathway analyses were conducted on both DEMs and DEGs. Through protein-protein interaction (PPI) network analysis and functional enrichment, 9 significantly upregulated DEMs (hsa-miR-188-5p, hsa-miR-590-5p, hsa-miR-320b, hsa-miR-423-5p, hsa-miR-140-5p, hsa-miR-486-5p, hsa-miR-320a, hsa-miR-342-3p, and hsa-miR-532-5p) and 50 key genes (such as ATP6V1G1, KBTBD6, VIM, PA2G4, DYNLL1, METTL21A, MDH2, etc.) were identified, suggesting their potential significant role in IA. Among these genes, ten were notably negatively regulated by at least two key miRNAs. ConclusionsThe findings of this study provide valuable insights into the potential pathogenic mechanisms underlying IA by elucidating a miRNA-mRNA network. This comprehensive approach sheds light on the intricate interplay between miRNAs and genes, offering a deeper understanding of the molecular dynamics involved in IA development and progression.

Mendelian randomization reveals systemic lupus erythematosus and rheumatoid arthritis and risk of adverse pregnancy outcomes

BackgroundThe effect of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) on adverse pregnancy outcomes is a controversial topic. This study aimed to use Mendelian randomization (MR) analysis to assess the causal relationship between SLE, RA and adverse pregnancy outcomes. MethodsGenetic variants for SLE and RA, as well as adverse pregnancy outcomes, were derived from pooled statistics from large public genome-wide association studies. Several methods, such as inverse variance weighting (IVW), MR-Egger, weighted median and MR-Pleiotropic Residuals Sum and Outliers, were employed to estimate two-sample causality. ResultsGenetic prediction of SLE was associated with higher odds of preterm labour [odds ratio (OR) 1.03, 95 % confidence interval (CI) 1.01–1.05; p = 0.008]. RA was associated with higher odds of preterm labour (OR 1.03, 95 % CI 1.01–1.06; p = 0.009), pre-eclampsia or eclampsia (OR 1.04, 95 % CI 1.01–1.07; p = 0.005), and poor fetal growth (OR 1.08, 95 % CI 1.04–1.12; p = 2.91 × 10−5). The results of bidirectional MR analysis did not indicate that SLE was associated with spontaneous abortion, pre-eclampsia or eclampsia, preterm rupture of membranes, or poor fetal growth (p-value for IVW 0.13–0.97). ConclusionsThis study found a genetic association between SLE and the risk of preterm labour, and highlights the importance of perinatal care and monitoring for patients with SLE. Furthermore, RA was found to be associated with a wide range of adverse outcomes, including preterm labour, pre-eclampsia or eclampsia, and poor fetal growth; as such, there is a need for more intensive therapeutic interventions and prenatal monitoring.

Cause, severity, and efficacy of treatment for hearing loss in children with Trisomy 18: A single institution-based retrospective study.

Trisomy 18 is a common chromosomal aberration syndrome, characterized by variable clinical manifestations, including cardiovascular, pulmonary, genitourinary, and musculoskeletal findings, leading to a shorter survival and severe developmental delay in survivors. However, recently, intensive therapeutic intervention has allowed for prolonging survival. In terms of otological complications, only a limited number of relevant reports have been published. To demonstrate the characteristic of hearing loss (HL) in children with Trisomy 18, we retrospectively evaluated 22 patients (44 ears) by comprehensive auditory evaluation with the auditory steady-state response (ASSR) test and temporal bone computed tomography (CT). ASSR revealed that 20 patients (91%) had bilateral moderate to profound HL, more frequent and severe than that in Trisomy 21; among 42 ears having HL, 12 ears (29%) had conductive HL, and 26 ears (62%) had mixed HL. CT scans of 38 ears revealed that 34 ears (89%) had an external and middle ear malformation. Hearing aids (HA) were fitted in 17 patients (air and bone-conduction HAs). The threshold hearing with HA was improved in all of them. Accurate otological evaluation using ASSR and CT and intervention by HAs could be a feasible choice for children with Trisomy 18.

Multiplex analysis of inflammatory proteins associated with risk of coronary artery disease in type-1 diabetes patients.

Chronic uncontrolled hyperglycemia, a precursor to chronic low-grade inflammation, is a leading cause of coronary artery disease (CAD) due to plaque buildup in type-1 diabetes (T1D) patients. We evaluated levels of 22 inflammatory markers in cross-sectional serum samples from 1222 subjects to evaluate their potential as risk factors for CAD in T1D patients. Circulating levels of markers of inflammation may be the risk factors for incident CAD. The T1D subjects were divided into two groups: those without CAD (n = 1107) and with CAD (n = 115). Serum levels of proteins were assayed using multiplex immunoassays on a Luminex Platform. Differences between the two groups were made by univariate analysis. Multivariate logistic regression was used to ascertain the potential of proteins as risk factors for CAD. Influence of age, duration of diabetes, sex, hypertension, and dyslipidemia was determined in a stepwise manner. Serum levels of 22 proteins were combined into a composite score using Ridge regression for risk-based stratification. Mean levels of CRP, IGFBP1, IGFBP2, insulin-like growth factors binding protein-6 (IGFBP6), MMP1, SAA, sTNFRI, and sTNFRII were elevated in CAD patients (n = 115) compared to T1D patients without CAD (nCAD, n = 1107). After adjusting for age, duration of diabetes, sex, hypertension, and dyslipidemia, higher levels of sTNFRI (odds ratio [OR] = 2.18, 1.1 × 10-3 ), sTNFRII (OR = 1.52, 1 × 10-2 ), and IGFBP6 (OR = 3.62, 1.8 × 10-3 ) were significantly associated with CAD. The composite score based on Ridge regression, was able to stratify CAD patients into low, medium, and high-risk groups. The results show activation of the TNF pathway in CAD patients. Evaluating these markers in serum can be a potential tool for identifying high-risk T1D patients for intensive anti-inflammatory therapeutic interventions.

Non-alcoholic fatty liver disease and cardiovascular risks: A review

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. NAFLD may be associated with concomitant metabolic disorders (obesity, type 2 diabetes mellitus, dyslipidemia) and is often considered a hepatic manifestation of metabolic syndrome. In addition to hepatic morbidity and mortality, NAFLD is closely associated with asymptomatic and overt cardiovascular disease (CVD), leading to increased cardiovascular morbidity and mortality, and the more severe the hepatic disorder, the higher the risk. This review describes the main pathophysiological mechanisms linking NAFLD and CVD, discusses the role of NAFLD as a CVD risk factor, and addresses non-drug and drug therapies for NAFLD in the context of cardiovascular risk reduction. NAFLD makes patients candidates for more intensive therapeutic intervention to reduce hepatic and cardiovascular risks. Lifestyle modifications, including weight loss, increased physical activity, and nutritional adjustment, form the basis of NAFLD treatment. Correction of cardiovascular risk factors includes statins, antihypertensive agents, preferably renin-angiotensin system blockers. Ursodeoxycholic acid has therapeutic potential for beneficial effects on hepatic disorders and reducing cardiovascular risk.

Integrative Plasma Metabolic and Lipidomic Modelling of SARS-CoV-2 Infection in Relation to Clinical Severity and Early Mortality Prediction.

An integrative multi-modal metabolic phenotyping model was developed to assess the systemic plasma sequelae of SARS-CoV-2 (rRT-PCR positive) induced COVID-19 disease in patients with different respiratory severity levels. Plasma samples from 306 unvaccinated COVID-19 patients were collected in 2020 and classified into four levels of severity ranging from mild symptoms to severe ventilated cases. These samples were investigated using a combination of quantitative Nuclear Magnetic Resonance (NMR) spectroscopy and Mass Spectrometry (MS) platforms to give broad lipoprotein, lipidomic and amino acid, tryptophan-kynurenine pathway, and biogenic amine pathway coverage. All platforms revealed highly significant differences in metabolite patterns between patients and controls (n = 89) that had been collected prior to the COVID-19 pandemic. The total number of significant metabolites increased with severity with 344 out of the 1034 quantitative variables being common to all severity classes. Metabolic signatures showed a continuum of changes across the respiratory severity levels with the most significant and extensive changes being in the most severely affected patients. Even mildly affected respiratory patients showed multiple highly significant abnormal biochemical signatures reflecting serious metabolic deficiencies of the type observed in Post-acute COVID-19 syndrome patients. The most severe respiratory patients had a high mortality (56.1%) and we found that we could predict mortality in this patient sub-group with high accuracy in some cases up to 61 days prior to death, based on a separate metabolic model, which highlighted a different set of metabolites to those defining the basic disease. Specifically, hexosylceramides (HCER 16:0, HCER 20:0, HCER 24:1, HCER 26:0, HCER 26:1) were markedly elevated in the non-surviving patient group (Cliff's delta 0.91-0.95) and two phosphoethanolamines (PE.O 18:0/18:1, Cliff's delta = -0.98 and PE.P 16:0/18:1, Cliff's delta = -0.93) were markedly lower in the non-survivors. These results indicate that patient morbidity to mortality trajectories is determined relatively soon after infection, opening the opportunity to select more intensive therapeutic interventions to these "high risk" patients in the early disease stages.

Concept and considerations of a medical device: the active noise cancelling incubator.

An increasingly 24/7 connected and urbanised world has created a silent pandemic of noise-induced hearing loss. Ensuring survival to children born (extremely) preterm is crucial. The incubator is a closed medical device, modifying the internal climate, and thus providing an environment for the child, as safe, warm, and comfortable as possible. While sound outside the incubator is managed and has decreased over the years, managing the noise inside the incubator is still a challenge. Using active noise cancelling in an incubator will eliminate unwanted sounds (i.e., from the respirator and heating) inside the incubator, and by adding sophisticated algorithms, normal human speech, neonatal intensive care unit music-based therapeutic interventions, and natural sounds will be sustained for the child in the pod. Applying different methods such as active noise cancelling, motion capture, sonological engineering. and sophisticated machine learning algorithms will be implemented in the development of the incubator. A controlled and active sound environment in and around the incubator can in turn promote the wellbeing, neural development, and speech development of the child and minimise distress caused by unwanted noises. While developing the hardware and software pose individual challenges, it is about the system design and aspects contributing to it. On the one hand, it is crucial to measure the auditory range and frequencies in the incubator, as well as the predictable sounds that will have to be played back into the environment. On the other, there are many technical issues that have to be addressed when it comes to algorithms, datasets, delay, microphone technology, transducers, convergence, tracking, impulse control and noise rejection, noise mitigation stability, detection, polarity, and performance. Solving a complex problem like this, however, requires a de-disciplinary approach, where each discipline will realise its own shortcomings and boundaries, and in turn will allow for innovations and new avenues. Technical developments used for building the active noise cancellation-incubator have the potential to contribute to improved care solutions for patients, both infants and adults.Code available at: 10.3389/fped.2023.1187815.

Missed meal boluses and poorer glycemic control impact on neurocognitive function may be associated with white matter integrity in adolescents with type 1 diabetes.

The notion that pediatric type 1 diabetes impacts brain function and structure early in life is of great concern. Neurological manifestations, including neurocognitive and behavioral symptoms, may be present from childhood, initially mild and undetectable in daily life. Despite intensive management and technological therapeutic interventions, most pediatric patients do not achieve glycemic control targets for HbA1c. One of the most common causes of such poor control and frequent transient hyperglycemic episodes may be lifestyle factors, including missed meal boluses. The aim of this study was to assess the association between specific neurocognitive accomplishments-learning and memory, inhibition ability learning, and verbal and semantic memory-during meals with and without bolusing, correlated to diffusion tensor imaging measurements of major related tracts, and glycemic control in adolescents with type 1 diabetes compared with their healthy siblings of similar age. This is a case-control study of 12- to 18-year-old patients with type 1 diabetes (N = 17, 8 male patients, diabetes duration of 6.53 ± 4.1 years) and their healthy siblings (N = 13). All were hospitalized for 30 h for continuous glucose monitoring and repeated neurocognitive tests as a function of a missed or appropriate pre-meal bolus. This situation was mimicked by controlled, patient blinded manipulation of lunch pre-meal bolus administration to enable capillary glucose level of <180 mg/dl and to >240 mg/d 2 hours after similar meals, at a similar time. The diabetes team randomly and blindly manipulated post-lunch glucose levels by subcutaneous injection of either rapid-acting insulin or 0.9% NaCl solution before lunch. A specific neurocognitive test battery was performed twice, after each manipulation, and its results were compared, along with additional neurocognitive tasks administered during hospitalization without insulin manipulation. Participants underwent brain imaging, including diffusion tensor imaging and tractography. A significant association was demonstrated between glycemic control and performance in the domains of executive functions, inhibition ability, learning and verbal memory, and semantic memory. Inhibition ability was specifically related to food management. Poorer glycemic control (>8.3%) was associated with a slower reaction time. These findings highlight the potential impairment of brain networks responsible for learning, memory, and controlled reactivity to food in adolescents with type 1 diabetes whose glycemic control is poor.

Hypoglycemia unawareness identified by continuous glucose monitoring system is frequent in outpatients with type 2 diabetes without receiving intensive therapeutic interventions

BackgroundPatients with diabetes are prone to asymptomatic hypoglycemia (AH) due to diminished ability to perceive the onset of hypoglycemia. However, the actual prevalence and influencing factors of AH in outpatients with type 2 diabetes (T2DM) have not been well investigated.MethodsA total of 351 outpatients with T2DM underwent glucose monitoring by continuous glucose monitoring system (CGMS) for consecutive 72 h without changing their lifestyle and treatment regimens. Hypoglycemia is defined as a blood glucose level less than 3.9 mmol/L, which was further divided into Level 1 hypoglycemia (blood glucose 3.0–3.9 mmol/L) and Level 2 hypoglycemia (blood glucose < 3.0 mmol/L). Univariate and multivariate logistic regression analyses were used to determine the possible risk factors of AH.ResultsIn all 351 subjects studied, 137 outpatients (39.0%) were captured AH events, in which Level 1 AH and Level 2 AH accounted for 61.3% and 38.7%, respectively. 85 (62.0%) of the AH patients experienced nocturnal asymptomatic hypoglycemia (NAH) and 25 (18.2%) exclusively NAH. Multivariate logistic regression analysis demonstrated that patients with younger age, lower hemoglobin A1c (HbA1c), and higher systolic blood pressure (SBP) levels were associated with increased risk of AH. While after further grading of AH, male sex and Dipeptidylpeptidase-4 inhibitors (DPP4i) regime were shown to be associated with lower risk of Level 2 AH.ConclusionsHypoglycemia unawareness could be frequently observed at either daytime or nighttime, although NAH was more common, in outpatients with T2DM. Relative relax HbA1c targets should be considered for patients who are prone to AH.

EXTH-93. THE IRAK-4 INHIBITOR EMAVUSERTIB (CA-4948) FOR THE TREATMENT OF PRIMARY CNS LYMPHOMA

Abstract BACKGROUND PCNSL is an aggressive brain tumor accounting for 3% of all CNS malignancies and is associated with poor prognosis. Standard of care treatment includes induction with high-dose methotrexate based chemoimmunotherapy followed by consolidation with autologous stem cell transplant or whole brain radiation. However, more than half of PCNSL patients cannot tolerate this intensive therapeutic intervention. Novel treatments are urgently needed. Toll-like receptor signaling pathway via MyD88/IRAK-4 signalosome is constitutively active in PCNSL secondary to MYD88 L265P mutation and represents an excellent therapeutic target. Emavusertib (CA-4948) is an oral first-in-class small molecule inhibitor of IRAK-4 that demonstrates clinical activity in patients with systemic Non-Hodgkin’s Lymphoma, however it has not been evaluated in the CNS space. HYPOTHESIS: Emavusertib has anti-tumor activity against preclinical PCNSL. METHODS Using multiparameter immunohistochemistry (IHC) and proteomics analysis, IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient PCNSL tissues as compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for emavusertib drug concentration following single oral high dose in a murine model. Survival responses in preclinical PCNSL models were measured in response emavusertib treatment, along with in vivo tumor proliferation and downstream biomarker expression by multi-parameter IHC. RESULTS Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient PCNSL. We show that emavusertib can achieve therapeutically relevant concentrations in the brain and CSF. Emavusertib impairs tumor cell proliferation in vitro and in vivo, and shows dose-dependent single-agent activity in preclinical PCNSL models. We confirm decreased ERK1/2, MAPK and NF-κB activation, indicative of downstream IRAK-4 inhibition. CONCLUSIONS Our data supports that emavusertib demonstrates anti-tumor activity in the CNS space, warranting further preclinical and clinical evaluation of this agent for the treatment of PCNSL.

OA03 “I can't stand this pain anymore. Please chop my leg off.” Is amputation a therapeutic option for Complex Regional Pain Syndrome in children and young people?

Introduction/BackgroundComplex Regional Pain Syndrome (CRPS) is a chronic intensified localised pain condition. Symptoms may include limb pain, allodynia; hyperalgesia; swelling and/or changes in skin colour of the affected limb; dry, mottled skin; hyperhidrosis and trophic changes of the nails and hair. There is no known cure.  Management involves analgesic medication and intensive multidisciplinary pain rehabilitation.  Some cases however seem intractable, with little or no response to therapy.  Some patients feel amputation of the affected limb is the only possible option.  We present four cases of children and young adults requesting amputation for CRPS.Description/MethodCase 1: 13 years, CRPS left leg, with associated gross oedema, ulceration and high risk of sepsis.Case 2: 16 years, CRPS both feet and ankles, ulceration, fixed dystonic posturing bilaterally, Autistic Spectrum DisorderCase 3: 17 years, mild cerebral palsy affecting left side, passionate about sport, development of CRPS following surgery for tendon release right hip flexors, fixed flexion contractures at right hip and knee. Case 4:17 years, high functioning athlete, CRPS initially foot and ankle, contractures ankle, knee and hip; progression to involve other leg.In each of these cases, prolonged intensive therapeutic interventions have not been successful in restoring function or reducing pain. All have requested amputation of the affected limb(s).Discussion/ResultsThe tabloid press has reported the transforming success of amputation for some cases of CRPS, describing individuals who have had CRPS which has not responded to treatment finally having the affected limb amputated, and subsequently achieving great things - including winning medals in the Para-Olympics.  Unsurprisingly such success stories provide hope for some enduring CRPS and becomes part of their ‘evidence’ for requesting amputation.The scientific literature however is sparce, and virtually non-existent in children and young people.  The risks of ongoing pain in the stump; recurrence of CRPS in the amputated limb - or elsewhere; phantom limb pain and inability to tolerate a prosthesis are well documented in the adult literature that is available. Key learning points/ConclusionDespite this, for the child/young person experiencing not only pain, but disgust, shame and body perception disturbance, the argument for amputation can be strong, and has to be considered.  We present the evidence to date and share the complexity of such discussions, focusing on the experience gained from these cases.

Associations between polygenic risk of coronary artery disease and type 2 diabetes, lifestyle, and cardiovascular mortality: A prospective UK Biobank study.

BackgroundPrevious studies primarily targeted the ability of polygenic risk scores (PRSs) to predict a specific disease, and only a few studies have investigated the association between genetic risk scores and cardiovascular (CV) mortality. We assessed PRSs for coronary artery disease (CAD) and type 2 diabetes (T2DM) as the predictive factors for CV mortality, independent of traditional risk factors, and further investigated the additive effect between lifestyle behavior and PRS on CV mortality.MethodsWe used genetic and phenotypic data from UK Biobank participants aged 40–69 years at baseline, collected with standardized procedures. Genome-wide PRSs were constructed using >6 million genetic variants. Cox proportional hazard models were used to analyze the relationship between PRS and CV mortality with stratification by age, sex, disease status, and lifestyle behavior.ResultsOf 377,909 UK Biobank participants having European ancestry, 3,210 (0.8%) died due to CV disease during a median follow-up of 8.9 years. CV mortality risk was significantly associated with CAD PRS [low vs. very high genetic risk groups, CAD PRS hazard ratio (HR) 2.61 (2.02–3.36)] and T2DM PRS [HR 2.08 (1.58–2.73)], respectively. These relationships remained significant even after an adjustment for a comprehensive range of demographic and clinical factors. In the very high genetic risk group, adherence to an unfavorable lifestyle was further associated with a substantially increased risk of CV mortality [favorable vs. unfavorable lifestyle with very high genetic risk for CAD PRS, HR 8.31 (5.12–13.49); T2DM PRS, HR 5.84 (3.39–10.04)]. Across all genetic risk groups, 32.1% of CV mortality was attributable to lifestyle behavior [population attributable fraction (PAF) 32.1% (95% CI 28.8–35.3%)] and 14.1% was attributable to smoking [PAF 14.1% (95% CI 12.4–15.7%)]. There was no evidence of significant interaction between PRSs and age, sex, or lifestyle behavior in predicting the risk of CV mortality.ConclusionPRSs for CAD or T2DM and lifestyle behaviors are the independent predictive factors for future CV mortality in the white, middle-aged population. PRS-based risk assessment could be useful to identify the individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CV mortality.

Sources of Human’s Aggression, Violence, Antisocial and Addictive Behaviors

In the 21st century hunger, starvation and malnutrition is still a scourge of mankind. According to World Bank reports a rise of millions of people lacked year-round access to adequate food in 2020 compared to 2019. Malnutrition, poverty, lack of quality education and insufficient health care are causes and consequences of each other. Preconceptual, prenatal and early postnatal malnutrition have life-long negative consequences on human’s health and behavior via epigenetic processes that regulate gene expression providing short-term survival benefits but predispose to various pathological conditions in adulthood. Based on scientific research there is not any doubt that early epigenetic changes play a major role in the development of excessive aggression, violence, antisocial and addictive behaviors. A body of evidence shows that clinical pictures like oppositional defiant disorders (ODD), conduct disorders (CD) and antisocial personality disorders (APD) have a neurodevelopmental origin based on epigenetic changes of gene expression. It is suggested that only early intensive therapeutic interventions focusing on autonomy, sense of competence and social connectedness in an individualistic, systemic and tightly structured positive and safe environment including healthy lifestyle and nutrition could prevent the progression of ODD into CD and eventually into APD. Quality nutrition, quality education and adequate health care for every human, starting at the very first days of life, are claimed to be unconditional premises to transform humanity into a peaceful species able to deal with the future challenges and dangers of life on planet earth.

P1298: THE IRAK-4 INHIBITOR EMAVUSERTIB (CA-4948) FOR THE TREATMENT OF PRIMARY CNS LYMPHOMA

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive brain tumor accounting for 3% of all CNS malignancies and is usually associated with poor prognosis. 5-year survival is less than 30% with current treatment options. Standard of care treatment includes induction with high-dose methotrexate based chemoimmunotherapy followed by consolidation with autologous stem cell transplant or whole brain radiation. However, more than half of PCNSL patients are not eligible for this type of intensive therapeutic intervention. Novel treatment strategies with better efficacy and toxicity profile are urgently needed. Toll-like receptor signaling pathway via MyD88/IRAK-4 signalosome is constitutively active in PCNSL secondary to MYD88 L265P mutation and represents an excellent therapeutic target. Emavusertib (CA-4948) is an oral first-in-class small molecule inhibitor of IRAK4 that has demonstrated clinical activity in patients with systemic Non-Hodgkin’s Lymphoma, however it has not been evaluated in the CNS space. Aims: In this study we examine translational and clinical therapeutic applicability and efficacy of emavusertib for the treatment of PCNSL. Methods: Using multiparameter immunohistochemistry (IHC) and proteomics analysis, IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient PCNSL tissues as compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for emavusertib drug concentration following single oral high dose in a murine model. Using an aggressive preclinical A20 immunocompetent CNSL model, preclinical therapeutic activity of emavusertib was evaluated with assessment of downstream biomarker response to treatment including phospho-NF-κB, phospho-ERK1/2, and phospho-P38 in control and treated animals by multi-parameter IHC. We also report therapeutic response in a relapsed/refractory PCNSL patient enrolled in a Phase I/II clinical trial (TakeAim) assessing the combination of emavusertib and Ibrutinib. Results: Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient PCNSL. We also demonstrate that emavusertib can achieve therapeutically relevant concentrations in the brain parenchyma and shows single-agent activity in an aggressive preclinical model of PCNSL. We further confirm decreased ERK1/2, MAPK and NF-κB activation in response to preclinical emavusertib treatment, indicative of downstream effect of IRAK-4 inhibition. Finally, one patient who could not tolerate standard therapies and was resistant to Ibrutinib achieved complete response when treated with the combination of emavusertib and Ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib. Summary/Conclusion: Herein we confirm for the first time that targeted inhibition of IRAK-4 with the oral small molecule inhibitor emavusertib demonstrates preclinical and clinical therapeutic activity against CNS lymphoma. Further evaluation of this agent for the treatment of PCNSL is warranted.

Clinical features and risk predictor markers in COVID-19 patients in correlation with disease severity and comorbidities- A data-based retrospective study

Background: COVID-19 infection displays a highly heterogeneous spectrum of severities. Laboratory findings are pivotal cues to assess disease severity and aid in retarding/ reversing disease progression. This study aims to identify the haematological, biochemical, and immunological specifics of COVID-19 patients with varying severity and associated comorbidities. Methods: This retrospective study recruited a total of 192 RT PCR confirmed COVID-19 patients. Data on laboratory findings, clinical characteristics, treatment, and hospital stay were obtained and analysed. Results: The patients were grouped into mild, moderate, and severe categories based on disease severity. 96 patients had mild disease, 31 were classified as having moderate COVID-19, and 67 patients had severe COVID-19. 39.58% of the patients were females. The overall death rate among admitted COVID-19 patients is observed to be 19.02%, sepsis and multi-organ failure as the most common cause. The variation in laboratory variables and comorbidities as CAD, CKD, HTN, DM strongly correlate with the severity and increases with the age factor. Pre-existing chronic liver disease emerged to be a comorbidity of significance for acquiring severe COVID-19. Conclusion: Presence of comorbidities, advanced age and male sex emerged as important risk factors while derangements in thrombo-inflammatory markers and haematological indices might be crucial predictors of disease progression. Thromboembolism or superinfection induced sepsis, and multi-organ failure emerged as leading contributors to mortality. High-risk patterns in thrombo inflammatory and immunohematological markers allow for early detection of the disease progression and aid in the institution of personalized intensive therapeutic interventions and monitoring to avoid further deaths.

Not Control but Conquest: Strategies for the Remission of Type 2 Diabetes Mellitus.

A durable normoglycemic state was observed in several studies that treated type 2 diabetes mellitus (T2DM) patients through metabolic surgery, intensive therapeutic intervention, or significant lifestyle modification, and it was confirmed that the functional β-cell mass was also restored to a normal level. Therefore, expert consensus introduced the concept of remission as a common term to express this phenomenon in 2009. Throughout this article, we introduce the recently updated consensus statement on the remission of T2DM in 2021 and share our perspective on the remission of diabetes. There is a need for more research on remission in Korea as well as in Western countries. Remission appears to be prompted by proactive treatment for hyperglycemia and significant weight loss prior to irreversible β-cell changes. T2DM is not a diagnosis for vulnerable individuals to helplessly accept. We attempt to explain how remission of T2DM can be achieved through a personalized approach. It may be necessary to change the concept of T2DM towards that of an urgent condition that requires rapid intervention rather than a chronic, progressive disease. We must grasp this paradigm shift in our understanding of T2DM for the benefit of our patients as endocrine experts.

Targeted proteomics improves cardiovascular risk prediction in secondary prevention.

AimsCurrent risk scores do not accurately identify patients at highest risk of recurrent atherosclerotic cardiovascular disease (ASCVD) in need of more intensive therapeutic interventions. Advances in high-throughput plasma proteomics, analysed with machine learning techniques, may offer new opportunities to further improve risk stratification in these patients.Methods and resultsTargeted plasma proteomics was performed in two secondary prevention cohorts: the Second Manifestations of ARTerial disease (SMART) cohort (n = 870) and the Athero-Express cohort (n = 700). The primary outcome was recurrent ASCVD (acute myocardial infarction, ischaemic stroke, and cardiovascular death). Machine learning techniques with extreme gradient boosting were used to construct a protein model in the derivation cohort (SMART), which was validated in the Athero-Express cohort and compared with a clinical risk model. Pathway analysis was performed to identify specific pathways in high and low C-reactive protein (CRP) patient subsets. The protein model outperformed the clinical model in both the derivation cohort [area under the curve (AUC): 0.810 vs. 0.750; P < 0.001] and validation cohort (AUC: 0.801 vs. 0.765; P < 0.001), provided significant net reclassification improvement (0.173 in validation cohort) and was well calibrated. In contrast to a clear interleukin-6 signal in high CRP patients, neutrophil-signalling-related proteins were associated with recurrent ASCVD in low CRP patients.ConclusionA proteome-based risk model is superior to a clinical risk model in predicting recurrent ASCVD events. Neutrophil-related pathways were found in low CRP patients, implying the presence of a residual inflammatory risk beyond traditional NLRP3 pathways. The observed net reclassification improvement illustrates the potential of proteomics when incorporated in a tailored therapeutic approach in secondary prevention patients.

An Emerging Role for Epigenetics in Cerebral Palsy.

Cerebral palsy is a set of common, severe, motor disabilities categorized by a static, nondegenerative encephalopathy arising in the developing brain and associated with deficits in movement, posture, and activity. Spastic CP, which is the most common type, involves high muscle tone and is associated with altered muscle function including poor muscle growth and contracture, increased extracellular matrix deposition, microanatomic disruption, musculoskeletal deformities, weakness, and difficult movement control. These muscle-related manifestations of CP are major causes of progressive debilitation and frequently require intensive surgical and therapeutic intervention to control. Current clinical approaches involve sophisticated consideration of biomechanics, radiologic assessments, and movement analyses, but outcomes remain difficult to predict. There is a need for more precise and personalized approaches involving omics technologies, data science, and advanced analytics. An improved understanding of muscle involvement in spastic CP is needed. Unfortunately, the fundamental mechanisms and molecular pathways contributing to altered muscle function in spastic CP are only partially understood. In this review, we outline evidence supporting the emerging hypothesis that epigenetic phenomena play significant roles in musculoskeletal manifestations of CP.

Mortality and heart failure in patients with severe tricuspid regurgitation. Risk stratification based on TR severity by CMR

Abstract Background Tricuspid regurgitation (TR) is related to poor prognosis independently of the etiology. A new scale classification has been proposed to better characterize the grading of more than severe TR. Massive and torrential TR seem to have worse prognosis based on echocardiographic studies. Purpose To stratify patients' risk based on TR severity by CMR Methods Consecutive patients in stable clinical condition evaluated in the Heart Valve Clinic with significant TR (severe, massive or torrential TR) with a contemporaneous echo and CMR were included. TR severity was evaluated by vena contracta (VC) and ERO method, using EPIQ system (Phillip Medical system Andover, Massachusets) and by TR regurgitant fraction (TRF) using a 1.5 Tesla CMR Philips scanner. A combined endpoint of hospital admission due to right heart failure and cardiovascular mortality was defined. Results 75 patients were included in this study (age 75±8 years, 75% female, 91% functional TR). According to echocardiography 75% were severe, 15% were massive and 10% were torrential TR. Patients with massive and torrential TR showed higher RV end-diastolic volume and lower RVEF. A TRF &amp;gt;50% held the best accuracy to define massive / torrential TR. During a median follow-up of 3 years (IQR: 1.4 – 3.9 years), 39% of the patients (n=29) experienced the combined endpoint. After adjusting for age and LVEF in a multivariate Cox proportional model, TRF was independently associated with cardiovascular mortality and heart failure (hazard ratio per 1%=1.05, [1.02–1.08], p&amp;lt;0.001). Patients were stratified in 3 groups according to TR severity. Patients with TRF ≤40% showed the lowest incidence of events and those with TRF ≥50% experienced the worse prognosis (log rank=0.001, figure) Conclusion Patients with massive/torrential TR are populations at higher risk of heart failure and mortality. Risk stratification strategies may identify the patients who benefit the most of intensive therapeutic treatments and intervention on the tricuspid valve. New classification scheme should be included in CMR grading scales. Funding Acknowledgement Type of funding sources: None. Kaplan Meier curve. Risk stratification

1134-P: Polygenic Risk Score of Type 2 Diabetes as a Predictive Factor for Macrovascular Complications: A Prospective Population-Based UK Biobank Study

Background: We aimed to investigate the associations between polygenic risk score (PRS) for T2DM and future risk of cardiovascular disease (CVD) in middle-aged UK Biobank participants of European ancestry. Methods: We used data from UK Biobank participants aged 40-69 years at baseline, registered from 22 assessment centers across the United Kingdom with standardized procedures. Genome-wide PRSs were constructed using &amp;gt;9 million genetic variants, and newly developed myocardial infarction (MI), ischemic stroke, and cardiovascular (CV) mortality were considered as outcomes. Cox proportional hazard models were used to analyze the relationship between PRSs and CV mortality with stratification by age, sex, and lifestyle behavior. Results: Of 362,405 participants having European ancestry, 8,787 (2.4%) experienced cardiovascular events and 2,414 (0.7%) died due to CVD during a median follow-up of 8.9 years. Risk of CV mortality and of myocardial infarction (MI) were both significantly associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.73 [1.23-2.44] and HR of MI 1.55 [1.24-1.96], P &amp;lt;0.001). By contrast, the risk of ischemic stroke was not associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.24 [0.87-1.79], P =0.232). Adherence to an unfavorable lifestyle in the very high genetic risk group was further associated with a substantially increased risk of CV mortality (HR 6.38 [3.46-11.77]) and with risk of MI (HR 3.28 [2.02-5.32]). There was no evidence of significant interaction between PRS and lifestyle behavior in predicting the risk of CVD. Conclusion: PRS for T2DM is an independent predictive factor for future CVD and associated mortality in the white, middle-aged population. PRS-based genetic risk assessment could be useful to identify individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CVD. Disclosure S. Jung: None. D. Kim: None. M. Shivakumar: None. H. Won: None. J. Yun: None.