Persistent Elevation Research Articles

2958. Investigating the mechanisms of persistent inflammation and the association with non-communicable diseases (NCDs), Tuberculosis (TB) recurrence, and other infections

Abstract Background TB continues to be a major cause of morbidity and mortality worldwide. Despite successful completion of anti-tuberculosis therapy (ATT), studies indicate that TB survivors (post-TB) have a significantly higher risk of mortality compared to the general population, primarily due to increased incidence of non-communicable diseases (NCDs; cardiovascular disease, cancer, lung disease) and recurrent infections. Furthermore, a considerable proportion of TB patients exhibit persistent inflammation even after ATT. Methods We enrolled 325 individuals with microbiologically confirmed pulmonary TB, diagnosed between 2014 and 2020. Blood samples were obtained at baseline and 12- months (6-months after completing antimicrobial therapy) to evaluate persistent inflammation. Plasma C-reactive protein (CRP) was used to measure inflammation. Lipid peroxidation (LP) was measured by oxidized (HNE) LDL. Redox capacity was measured via the Trolox assay. Immune activation was measured by the Indoleamine 2,3 dioxygenases (IDO) enzyme by measuring the Kynurenine-Tryptophan ratio. Results After successful TB treatment, 62% of participants exhibited persistent elevation of CRP (P< 0.001) (Figure 1a). Univariate analysis of the first 186 participants revealed no association between elevated post-TB inflammation and HIV status (Fig. 1B), gender, or age. Individuals with increased CRP levels had a lower redox capacity compared to those whose CRP normalized at the end of ATT (P< 0.001) (Figure 2). Analysis of Oxidized LDL in successfully treated TB patients demonstrated that low antioxidant capacity also had persistent LP (Figure 2b). IDO activity was increased among TB participants with high CRP, which persisted even after successful therapy in participants with high and low CRP levels (Figure 3). Fig 1a: CRP was evaluated on TB participants and their asymptomatic, healthy household contacts. The median CRP of the healthy contacts was <2 mg/L, whereas the median CRP for TB participants at baseline was 21 and decreased to 8 at the end of successful therapy (EOT). Previous studies have demonstrated that CRP levels >3 mg/L are associated with increased CVD risk . 62% (111/186) of TB participants have CRP levels >3 mg//L at the end of TB therapy. Fig 1b: All TB participants living with HIV (PLWH) are started on ART, with >90% having a viral load <1000 at end of therapy (EOT). At EOT, TB participants without HIV do not have lower CRP levels compared to PLWHIV, preliminarily suggesting HIV is not driving the persistent inflammation. Fig2a: The Trolox antioxidant capacity was evaluated on TB Participants with High CRP >3mg/L (n:36) vs Low CRP <3mg/L (n:32) and Healthy Controls (n:32). Conclusion This study shows that a substantial proportion of TB participants exhibit persistent inflammation and IDO activity even after ATT. Among TB participants who do not normalize inflammation at the end of successful therapy, there is also persistent LP and decreased redox capacity. This suggests that there is a bidirectional malignant relationship between LP and redox capacity. Potentially, this suggests that mitigating lipid peroxidation may help decrease post-TB inflammation. Fig2b: Oxidized LDL was measured in TB individuals with High levels of CRP High CRP >3mg/L (n:16) vs Low CRP <3mg/L (n:16) and Healthy Controls (n:4) Fig3 Plasma Kynurenine to Tryptophan ratio was evaluated in TB individuals with persistent augmented levels of CRP (n:19) at baseline and Heathy Controls. At the end of Therapy the KYN:TRYP was evaluated in TB individuals with high (n:22) and Low CRP levels (n:17) Disclosures All Authors: No reported disclosures

Bayesian longitudinal modeling of blood pressure measurements of hypertensive patients at Wachemo University Nigist Elleni Mohamed Memorial Teaching and Referral Hospital Hosanna, Southern Ethiopia

Hypertension is characterized by the persistent elevation of blood pressure (BP) above the normal range or the use of antihypertensive medication. It represents a major global health issue and serves as a significant risk factor for conditions such as stroke, myocardial infarction, vascular disease, and chronic kidney disease. This study aimed to model the longitudinal measurements of diastolic blood pressure and systolic blood pressure in hypertensive patients using a Bayesian approach. The data were obtained from the records of Wachemo University Nigist Elleni Mohamed Memorial Teaching and Referral Hospital. It encompassed the basic demographic and clinical characteristics of 200 hypertensive patients who commenced antihypertensive treatment between September 2015 and March 2020. Descriptive analysis and a Linear mixed-effects model were employed to analyze the data, utilizing the Bayesian approach with the JMbayes package in R software. The results of this study revealed significant associations between age, time, family history, related diseases, and the mean change of systolic blood pressure (SBP) measurements within the bivariate linear mixed model. Likewise, time, residence, related diseases, and the interaction of time with sex and diabetes demonstrated a significant effect on the mean change of diastolic blood pressure (DBP) measurements in antihypertensive patients. By employing a bivariate linear mixed model, an association of 0.8565 was observed between the evolution (AE) of SBP and DBP. Based on the study findings, we can summarize that age, time, family history, and related diseases have a significant impact on the mean change of SBP, while time, residence, related diseases, and the interaction of time with sex and diabetes affect the mean change of DBP. Furthermore, a strong association exists between the evolution of SBP and DBP.

Unexplained increases in serum carcinoembryonic antigen levels in colorectal cancer patients during the postoperative follow-up period: an analysis of its incidence and longitudinal pattern

Background Carcinoembryonic antigen (CEA) monitoring facilitates the detection of recurrence in patients with colorectal cancer (CRC) after resection. False-positive CEA has been reported in CRC patients with certain comorbidities or smokers. However, limited information is currently available on the frequency of and changes in falsely elevated CEA levels in patients without these conditions. Materials and methods We retrospectively examined CRC patients who underwent surgical resection at our hospital between 2001 and 2017, had no recurrence for at least five years, and were free of known factors that may increase CEA. Postoperative CEA levels were retrieved until 2 years before the last contact. For comparison, we similarly selected patients who developed recurrence after resection of CRC during the same period, and CEA levels at initial presentation, at nadir, and at the time of recurrence were reviewed. The patterns of elevated CEA (>5 ng/ml) were classified as transient, repeated, or persistent based on longitudinal changes. The relationships between CEA and carbohydrate antigen 19-9, transaminases, creatinine, and C-reactive protein were examined. Results CEA elevation occurred in 90 (20%) out of 446 eligible patients without recurrence at least once during the mean postoperative period of 50.5 months, whereas CEA was >5 ng/ml in 117 (53%) of 221 patients when they developed recurrence. Twenty-seven patients without recurrence showed a transient elevation in CEA, 45 repeated elevations, and 18 a persistent elevation; the frequency of a high preoperative CEA level increased in this order. The majority (98%) of false elevations ranged between 5 and 15 ng/ml. CEA was not associated with other laboratory data. Conclusions Unexplained CEA elevations were observed in 20% of recurrence-free CRC patients after surgery, and were classified into three patterns based on longitudinal changes. A more detailed understanding of patient-specific fluctuations in CEA will prevent unnecessary imaging studies and reduce medical costs.

Abstract 14106: Predicting Persistently Elevated Pulmonary Artery Diastolic Pressure Despite Adequate Diuresis

Introduction: Patients with chronic HF can be challenging to manage via ambulatory hemodynamic monitoring due to persistent elevations in pulmonary artery diastolic pressure (PADP) despite appropriate diuresis. Knowing what factors predict persistently elevated PADP on CardioMEMS can help guide patient selection and management. Hypothesis: We propose that underlying heart failure phenotypes exist that are less likely to respond to hemodynamic guided management. Methods: This was a single-center, retrospective analysis of Scripps Clinic patients who underwent CardioMEMS implantation from June 2015 to September 2022. A total of 115 patients were included and divided into two cohorts based off their average PADP calculated using their last 4 transmissions. The normal PADP cohort included patients with an average PADP ≤ 20 mmHg while the persistently elevated PADP cohort included patients with a PADP > 20 mmHg. Results: Of the 115 patients analyzed, 62 patients were in the normal PADP cohort while 53 patients were in the persistently elevated PADP cohort. There was no significant difference between baseline demographic data, except for renal function, as shown in Table 1. There was a significant difference between the two groups when comparing pulmonary pressures and PVR via right heart catheterization prior to CardioMEMS implantation, but not when comparing pulmonary artery pressure obtained via echocardiogram (Table 1). The persistently elevated PADP cohort had a significantly lower GFR and were on higher doses of loop diuretics than the normal PADP cohort. Conclusions: Our analysis shows that renal function, baseline invasive hemodynamic data consistent with pulmonary vascular remodeling and decreased cardiac index can help predict patients with persistent elevations in their PADP on ambulatory hemodynamic monitoring and highlights the importance of early HF management before vascular remodeling complicates hemodynamic guided management.

Instantaneous and Persistent Elevation of Serum Potassium and Progression of CKD

Instantaneous and Persistent Elevation of Serum Potassium and Progression of CKD

Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFRwt and mutant EGFRT790M receptor tyrosine kinases

Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFRwt inhibition and QU351, for EGFRmt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations. Communicated by Ramaswamy H. Sarma

Proinflammatory Cytokine Profiles in Both Mild Symptomatic and Asymptomatic SARS-CoV-2-Infected Egyptian Individuals and a Proposed Relationship to Post-COVID-19 Sequela.

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with proinflammatory cytokine release as mediators of host antiviral response to the infection. Cytokine persistent elevation leads to post-Coronavirus disease-2019 (COVID-19) post-COVID-19 sequela (PCS) reported in about 60% of patients affecting individual's normal life after recovery. This study evaluates relationship of cytokines and chemokines pattern during and postinfection to PCS events. Serum samples collected from 82 individuals with symptomatic, asymptomatic, or no SARS-CoV-2 infection were classified as recently or formerly infected groups according to levels of anti-2019nCoV Immunoglobulin G/Immunoglobulin M. Levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, interferon alpha (IFN-α), tumor necrosis factor alpha (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein-1 were assessed via ELISA for each individual. All asymptomatic groups showed nonsignificant differences in cytokines' levels than control group. Significant elevation of IFN-α, TNF-α, and GM-CSF levels were observed in recent symptomatic, while IFN-α and TNF-α levels were significant in former symptomatic groups. We observed an association between fever with IL-1α and IFN-α levels, fatigue with TNF-α and GM-CSF, dyspnea with IFN-α, TNF-α, and GM-CSF, and chest-wheezing with GM-CSF. Individuals were surveyed 12 months postsampling for PCS events. Among 35 responders to survey, 8 (22.8%) reported PCS events, 6 of which were females. Upon studying PCS events, IL-8, IFN-α, TNF-α, and GM-CSF levels showed significant elevation in active infection, that was not seen in a resolved state of infection. Cytokines patterns suggest that either a persistent elevation in levels or damage caused during infection contributes to PCS. Although with the limited sample size, our study emphasizes the importance to conduct medical approaches targeting the associated cytokines to improve the PCS symptoms.

Characterisation of Patients with Acute Coronary Syndrome: A 10-Year Experience

Introduction: Coronary intervention is a therapeutic method for acute coronary syndrome. Objectives: Characterise patients with acute coronary syndrome treated by percutaneous coronary intervention. Method: Analytical, observational, retrospective, and cross-sectional study of 1,469 patients with the diagnosis of acute coronary syndrome, treated with percutaneous coronary intervention at the Hermanos Ameijeiras Hospital, Havana, Cuba, between 2010–2019. Results: The mean age of the patients was 61.1±10.6 years, 72% were male, and 68.3% had acute coronary syndrome without persistent ST-segment elevation. The commonest risk factor was hypertension (69%). Radial access was used in 75.0% of procedures, and 82.0% had a single occluded epicardial coronary artery (42.4% anterior descending artery, 29.7% right coronary artery). One (63.3%) bare metal stent was implanted in 70.7% of patients, with a 96.0% angiographic success rate. There were complications in 1.1% of cases. Diabetes was significantly associated with the failure of the procedure. Conclusions: Most of the patients were middle-aged, with hypertension and a diagnosis of non-ST-segment elevation acute coronary syndrome, where the most frequently treated artery is the left anterior descending artery, and the radial artery is the most commonly used vascular access route with an elevated number of successful procedures. The presence of diabetes is significantly associated with the failure of the procedure.

FRI228 Primary Adrenal T-cell Lymphoma: A Case Report

Abstract Disclosure: H. Tabassum: None. S. Xu: None. A. Manavalan: None. Introduction: Primary T-cell adrenal lymphoma (PAL) is exceedingly rare. Adrenal insufficiency (AI) is common in these cases. Here we describe a patient with bilateral, large, T-cell PAL with rapid progression, without adrenal insufficiency. Clinical Case: A 62-year-old male, with coronary artery disease and recent coronary intervention, hyperlipidemia and hypertension presented to the hospital with abdominal pain, fever, night sweats and weight loss for a month. Work up revealed a 5.8 cm left adrenal mass with 14% absolute washout, measuring 34 Hounsfield Units (HU) pre-contrast, 68 HU postcontrast, and 63 HU on delayed images, and a 5.2 cm right adrenal mass with 42% absolute washout, measuring 35 HU pre-contrast, 81 HU postcontrast, and 62 HU on the delayed images with no other suspicious lesions or lymphadenopathy. The patient demonstrated no clinical symptoms or signs of adrenal hormone excess or deficiency. Levels of renin, aldosterone, serum cortisol, ACTH, 24-hour urine free cortisol, serum metanephrines, and thyroid function were normal. Additional tests to rule out adrenal cortical carcinoma (ACC) revealed normal levels of androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and estradiol. Persistent non-significant elevation of 11-deoxycortisol was observed at 51 ng/dL and 63ng/dL (Ref < 42 ng/dL). Adrenal biopsy was suggested but deferred due to the increased risk of hemorrhage given recent coronary revascularization and use of dual antiplatelet therapy. Follow up imaging in a few weeks revealed diffuse, retroperitoneal lymphadenopathy with unchanged adrenal masses. A lymph node biopsy confirmed a diagnosis of peripheral T-cell lymphoma. The left adrenal gland demonstrated an uptake SUV of 22.7 and the right, 19.17 on FDG PET. The patient was initiated on chemotherapy with etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin. Imaging three months later revealed a marked decrease in FDG activity SUV 6.98 g/mL on the left and SUV up to 3.32 g/mL on the right. Adrenal function remained intact on follow up. Conclusion: Peripheral T-cell lymphoma with adrenal involvement is an extremely rare and aggressive disease with rapid progression. Mostly seen in males over the age of 50, it may present with abdominal pain, B symptoms or both. While ACC is usually unilateral, lymphoma and metastatic disease may present bilaterally, however, other imaging features can be similar. AI is expected when 90% of the adrenal glands are destroyed by tumor infiltration, however, this does not always correlate with tumor size. In our patient, AI was not observed on presentation or follow up. As adrenal insufficiency can occur at any time in the disease course and may mimic symptoms of cancer or chemotherapy, the clinician should always be vigilant for its development in these cases. Presentation: Friday, June 16, 2023

FRI532 Thyroid Hormone Resistance: A Possible New Variant In The THRB Gene

Abstract Disclosure: A. Siddiqui: None. Z. Khan: None. T. Ahmed: None. K. Selk: None. Background: Resistance to the Thyroid Hormone (RTH) is caused by reduced target tissue response to thyroid hormone, resulting in the loss of the normal feedback mechanism that suppresses secretion of thyrotropin (TSH). Most cases of RTH are familial, usually inherited in an autosomal dominant manner, with over 100 different pathogenic variants having been described. Clinical Case: A 45-year-old male with history of attention deficit disorder presented for management of hypothyroidism. The patient was Anti-TPO positive, consistent with Hashimoto's thyroiditis and he was treated with varying doses of levothyroxine. Labs on 100 mcg levothyroxine showed a TSH of 7.07 (0.35-4.94 uIU/mL), free t4 1.86 (0.7-1.48 ng/dL), and free t3 4.41 (2.3-4.2 pg/mL). This initially prompted concern for a TSHoma. An alpha subunit level was found to be 0.3 ng/dL and pituitary MRI was within normal limits. Given continued persistent thyroid hormone elevations, further testing for human anti-mouse antibody interference was performed and also unrevealing. The patient continued to report feeling tired and fatigued, with multiple joint pains and inability to focus or concentrate. His levothyroxine was increased to 125 mcg per day. However, even after the adjustment, he still did not notice any change in his symptoms. A trial of addition of liothyronine 5mcg daily was also performed but he self-discontinued this as he did note any improvement. Overall, his findings were highly suspicious for thyroid hormone resistance. Genetic testing for a thyroid hormone resistance beta (THRB) mutation was performed. Direct sequence analysis of the coding region and splice-sites of the THRB gene identified one copy of the c.1368G>T (p.Leu456Phe) variant of uncertain significance. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. However, the THRB c.1368G>T (p.Leu456Phe) variant has not been described in online databases or published literature. It also has not been reported in large, multi-ethnic general populations. Conclusion: This is the first case to our knowledge demonstrating the THRB c.1368G>T (p.Leu456Phe) variant gene as likely giving rise to RTH. Further testing of family members has been recommended to help clarify the clinical significance of this finding. Presentation: Friday, June 16, 2023

THU320 Uncontrolled Diabetes May Increase The Risk Of COVID-19-related Cytokine Storm

Abstract Disclosure: S. Sadiq: None. K.E. Criner: None. A.D. Rao: Other; Self; Advisory Board Member for Horizon Pharmaceuticals, but no conflict of interest. S. Zheng: None. A. Vargas: None. A. Amalfitano: None. Introduction: COVID-19 infection can lead to a hyperinflammatory state resulting in cytokine storm and in turn, mortality [1]. Furthermore, persistent glucose elevations in the setting of cytokine storms have been associated with increased mortality [2]. We hypothesize that among patients with diabetes hospitalized with COVID-19 infection, those with higher baseline HbA1c are more predisposed to cytokine storm and mortality. Methods: A retrospective chart review was performed of 477 patients with COVID-19 infection hospitalized between March 1, 2020, to May 31, 2020, at a large urban center. Patients > 18 years of age were included. Baseline characteristics obtained included age, gender, BMI, race, comorbidities, diagnosis of diabetes, type of diabetes, admission HbA1c, length of stay (LOS), and endocrinology consult. Cytokine storm was identified by rheumatology consult based on clinical condition, inflammatory markers, and fibrinogen level or by the use of immunosuppressants (tocilizumab, anakinra or sarilumab). Results: Baseline characteristics showed that 191 (41%) were women, 286 were men (59%). Majority of patients were African American 38% (n=183); 23% were Hispanic (n=110), 12% White (n=61), 2.5% (n=12) Asian/ Pacific Islander, 24.5% (n=111) were mixed/other race. 34% of these patients had diabetes. Out of 477 patients, 152 had an admission HbA1c, and of those 34% had an HbA1c > 8%. 16% of patients with diabetes had cytokine storm (n=67) compared to 12% of patients without diabetes (n=267). Mean pre-admission HbA1c in patients with diabetes with cytokine storm was significantly higher at 10.2% compared to 7.8% in patients with diabetes without cytokine storm (p=0.01), indicating a possible link between diabetes control and cytokine storm. Patients with cytokine storm had a higher rate of endocrinology consults (31%) compared to those without (10%) (p<0.01). Patients with endocrine consults had a longer LOS (median of 11.2 days vs 4.25 days), which may indicate a higher severity of the illness. Additionally, there was a higher use of steroids, with a mean dose of methylprednisolone (1625 +/−1205 mg) in all patients with cytokine storm compared to (433 +/−514 mg) in those without cytokine storm over the course of hospitalization. Conclusion: Patients with diabetes hospitalized with COVID-19 infection having higher baseline HbA1c had a greater incidence of cytokine storm, which is well known to effect COVID-19-related mortality. Our study showed the importance of admission baseline HbA1c to identify those patients at risk and early interventions to decrease morbidity.

FRI093 Severe Hypertriglyceridemia Post Liver Transplant- A Multifactorial Disorder

Abstract Disclosure: A.R. Saand: None. A.R. Drinnon: None. F. Mubeen: None. J. Shakil: None. Introduction: Hypertriglyceridemia (HTG) is a known complication in solid organ transplant patients. In addition to increasing cardiovascular complications and mortality risk, these metabolic abnormalities also increase the risk of allograft atherosclerosis and vasculopathy. Although medications used in post-transplant management have a well-documented effect of worsening lipid profile, multiple factors may be contributing in the development of severe HTG. Case Description: We describe a 68-year-old male with elevated triglycerides (TG) of 3957 mg/dL on hospital admission for pneumomediastinum. He received liver transplant 2 years prior due to alcohol-related liver cirrhosis. He had normal TGs prior to the transplant. Immunosuppressant regimen included tacrolimus (TAC) and methylprednisone. Lipoprotein electrophoresis was normal. Intravenous insulin infusion was initiated with moderate improvement however, upon transition to oral medications: fenofibrate, omega-3 fatty acids, niacin and rosuvastatin, TGs continued to increase. Reinitiating insulin infusion showed no improvement. TAC was switched to cyclosporin with transient decrease in TGs. Upon discharge amylase and lipase levels remained normal despite TG elevation. When readmitted for an unrelated reason, his TGs were elevated at 2218 mg/dl. Plasmapheresis was initiated but was complicated by anaphylaxis with angioedema requiring intubation. After partial plasmapheresis, TGs significantly decreased and soon returned to normal. Post-discharge, the patient was changed back to previous TAC dosage due to cyclosporin related renal injury. His steroid dose was reduced and icosapent was added, resulting in no further recurrence of HTG. Discussion: Following liver transplant, about 15-40% recipients have increased cholesterol levels and about 40% have HTG. Although, immunosuppressant-induced dyslipidemia is seen frequently, additional risk factors have been identified. A retrospective study of 85 patients post liver transplant showed HTG developed early within the first month in about 67% patients and persisted throughout the first year. Some common factors predictive of HTG post liver transplant include pre-liver transplant hepatocellular disease and post-transplant renal dysfunction. A study in pediatric patients post liver transplant observed that changes in lipoprotein and HDL subfraction post-transplant may lead to hypertriglyceridemia. Our case suggests that HTG may be multifactorial given the persistent elevation of TGs despite the change in immunosuppressant regimen. Patient factors as well as genetic characteristics of the donor liver may be potential causes. Recognizing this variation in patient populations may be extremely important due to high risk for pancreatitis and cardiovascular events. Early identification and management may prevent complications. Presentation: Friday, June 16, 2023

SAT327 A Curious Case of Immune Checkpoint Inhibitor Induced Hypophysitis with Transient ACTH-dependent Hypercortisolism

Abstract Disclosure: M. Shi: None. F. AlRubaish: None. N. Gupta: None. V. Larouche: None. S. Christopoulos: None. The use of immune checkpoint inhibitors (ICI) has increased exponentially over the last decade as these agents have shown to substantially improve the prognosis in multiple advanced malignancies. Despite these important clinical benefits, ICI are associated with many immune-related adverse events (irAE). Endocrinopathies are the most frequent irAE and include autoimmune thyroid disorders, hypophysitis and primary adrenal insufficiency. These endocrinopathies often require long-term surveillance and hormone supplementation. We report a relatively novel irAE case of transient central hypercortisolism that progressed to hypopituitarism. A 72-year-old woman with metastatic melanoma on combined ICI therapy of nivolumab-ipilimumab developed subclinical hyperthyroidism (TSH <0.02 mU/L [reference range (RR) 0.40-4.50 mU/L]; FT4 20.2 pmol/L [RR 9.0-26.0 pmol/L]) eight weeks following initiation of her immunotherapy. At week 11, she was found to have refractory hypokalemia (initial potassium at presentation 2.3 mmol/L RR 3.5-5.5 mmol/L) and metabolic alkalosis (pH 7.57 [RR 7.35-7.45]; bicarbonate 39 mmol/L [RR 22-31 mmol/L]). Physical exam was unremarkable for Cushingoid features. Subsequent investigations revealed central hypothyroidism (TSH 0.02 mU/L [RR 0.40-4.50 mU/L]; FT4 8.1 pmol/L [RR 9.0-26.0 pmol/L]) and levothyroxine replacement was started. She also had evidence of hypogonadotropic hypogonadism (FSH 4.2 U/L [postmenopausal RR 25.8-143.9 U/L]; LH 1.5 U/L [postmenopausal RR 13.2-45.7U/L]) and central hypercortisolism with a morning cortisol of 1082 nmol/L [RR 172-497 nmol/L] and an ACTH level of 18.3 pmol/L [RR 1.6-13.9 pmol/L]. The low dose dexamethasone suppression test was not suppressed (morning cortisol at 983 nmol/L). She underwent imaging studies of her abdomen and brain which revealed normal adrenal and pituitary glands, respectively. Close pituitary function monitoring during endocrinology follow-up revealed persistent elevation of cortisol and ACTH levels until week 15, then a subsequent decline in both cortisol and ACTH levels for which she started hydrocortisone replacement. Further follow-up blood work revealed morning cortisol levels below 50 nmol/L [RR 172-497 nmol/L] with undetectable ACTH levels from week 16 onwards. The hydrocortisone and levothyroxine replacement were continued, and the patient remained asymptomatic throughout her follow-ups. This case highlights that a transient episode of ACTH dependent hypercortisolism may be an early marker prior to the development of central adrenal insufficiency from ICI-related destructive immune hypophysitis. Furthermore, our report highlights that physicians and other healthcare professionals should remain vigilant in monitoring laboratory progression in these patients, as early recognition facilitated timely management in our patient and prevented complications. Presentation: Saturday, June 17, 2023

A Novel Technique Using Paretic Superior Rectus as a Globe Suspender for Monocular Elevation Deficiency.

Surgical innovations in strabismus provide opportunities to improve visual function, eye alignment, and cosmesis in rare pediatric ophthalmological conditions. Monocular elevation deficiency is a rare and multifactorial disease in which the affected eye is equally limited in terms of elevation during adduction and abduction. We aimed to present a novel procedure for the treatment of acquired monocular elevation deficiency using the paretic superior rectus muscle as a globe suspender to resolve hypotropia. We report the case of an eight-year-old girl with left eyelid ptosis and hypotropia two months after draining a left orbital abscess. Left inferior rectus muscle recession was performed at five years, with residual left hypotropia. Ophthalmological examination revealed a best-corrected visual acuity of 20/20 OD and 20/100 OS. Severe left eyelid ptosis and poor levator function were also observed. Extraocular motility showed left hypotropia of 40 prism diopters with the left superior rectus muscle under action (-4) in the adduction and abduction positions. A force duction test negative for restrictions on the inferior rectus muscle was performed intraoperatively. To reduce the risks of the Knapp procedure, the left superior rectus muscle was split into medial and temporal halves. Double-armed sutures were secured in half, and the halves were detached from the sclera. The medial and temporal halves were reattached anteriorly to the medial and lateral rectus insertions, respectively. Eight weeks after surgery, the patient had nine prism diopters of hypotropia in the primary gaze. Ten weeks after surgery, there was no change in visual acuity. In the cover test, the patient exhibited residual left hypotropia of nine prism diopters with a restriction (-4) of elevation in adduction and abduction. The parents were pleased with the satisfactory cosmetic outcomes, and postoperative clinical photographs of the patient showed improved hypotropia and persistent minimal elevation of the left eye during adduction and abduction. Superior rectus muscle splitting and vertical transposition to the medial and lateral rectus could be safer and simpler alternatives to the Knapp procedure and may offer a lower risk of anterior segment ischemia. Further studies are required to confirm these findings.

PB0051 Persistent Elevation of ɣ’ Fibrinogen in Acute and Convalescent COVID-19

PB0051 Persistent Elevation of ɣ’ Fibrinogen in Acute and Convalescent COVID-19

Acute Coronary Syndrome in Women at the CHU le Luxembourg of Bamako

Introduction: Acute coronary syndromes have been very little studied in the female population in black Africa. Our series showed an increase in the prevalence of acute coronary syndromes in the female population compared to previous studies. Through this retrospective study, we evaluated the epidemiological, clinical, paraclinical, therapeutic and evolutionary specifications of acute coronary syndromes in women. Methodology: This was a retro and prospective study, concerning patients admitted for an acute coronary syndrome over a period of 3 years from September 1, 2019, to August 30, 2022, in the interventional cardiology unit at the CHU le Luxembourg of Bamako. Results: During the study period, 74 patients’ files were collected out of 251 patients, i.e., a frequency of ACS in women of 29.5%. The average age of the patients was 59.31 ± 10.89 years (37 and 83 years) and the age group 45-65 years was the most affected. The risk factors were essentially high blood pressure 66.2% (n=49), physical inactivity 66.2% (n=49) and diabetes 59.5% (n=44). The predominant functional signs were atypical chest pain in 56.8% of cases (n=42). The electrical aspect was mainly persistent ST-segment elevation in 61% (n=45). Seventy-six percent (n=56) of patients were treated 12 hours after the first medical contact. The approach for coronary angiography was radical in 93%. Coronary angiography was pathological in 92% (n=68). Lesions were single vessel in 29.7% of cases and multi-vessel in 62.2% of cases. Conclusion: Acute coronary syndrome in women is characterized by atypical of symptoms with a delay in diagnosis and management. Coronary lesions are characterized by multi-vessel involvement in the majority of cases.

Comparative Effectiveness of Intracranial Pressure Monitoring on 6-Month Outcomes of Critically Ill Patients With Traumatic Brain Injury

While the relationship between persistent elevations in intracranial pressure (ICP) and poorer outcomes is well established for patients with traumatic brain injury (TBI), there is no consensus on how ICP measurements should drive treatment choices, and the effectiveness of ICP monitoring remains unknown. To evaluate the effectiveness of ICP monitoring on short- and mid-term outcomes of patients with TBI. CREACTIVE was a prospective cohort study that started in March 2014 and lasted 5 years. More than 8000 patients with TBI were enrolled at 83 intensive care units (ICUs) from 7 countries who joined the CREACTIVE Consortium. Patients with TBI who met the Brain Trauma Foundation guidelines for ICP monitoring were selected for the current analyses, which were performed from January to November 2022. Patients who underwent ICP monitoring within 2 days of injury (exposure group) were propensity score-matched to patients who were not monitored or who underwent monitoring 2 days after the injury (control group). Functional disability at 6 months as indicated by Glasgow Outcome Scale-Extended (GOS-E) score. A total of 1448 patients from 43 ICUs in Italy and Hungary were eligible for analysis. Of the patients satisfying the ICP-monitoring guidelines, 503 (34.7%) underwent ICP monitoring (median [IQR] age: 45 years [29-61 years]; 392 males [77.9%], 111 females [22.1%]) and 945 were not monitored (median [IQR] age: 66 years [48-78 years]; 656 males [69.4%], 289 females [30.6%]). After matching to balance the variables, worse 6-month recovery was observed for monitored patients compared with nonmonitored patients (death/vegetative state: 39.2% vs 40.6%; severe disability: 33.2% vs 25.4%; moderate disability: 15.7% vs 14.9%; good recovery: 11.9% vs 19.1%, respectively; P = .005). Monitored patients received medical therapies significantly more frequently. In this cohort study, ICP monitoring was associated with poorer recovery and more frequent medical interventions with their relevant adverse effects. Optimizing the value of ICP monitoring for TBI requires further investigation on monitoring indications, clinical interventions, and management protocols.

Cardiac AC8 Over-Expression Increases Locomotion by Altering Heart-Brain Communication

BackgroundThe central nervous system’s influence on cardiac function is well described; however, direct evidence for signaling from heart to brain remains sparse. Mice with cardiac-selective overexpression of adenylyl cyclase type 8 (TGAC8) display elevated heart rate/contractility and altered neuroautonomic surveillance. ObjectivesIn this study the authors tested whether elevated adenylyl cyclase type 8–dependent signaling at the cardiac cell level affects brain activity and behavior. MethodsA telemetry system was used to record electrocardiogram (ECG) and electroencephalogram (EEG) in TGAC8 and wild-type mice simultaneously. The Granger causality statistical approach evaluated variations in the ECG/EEG relationship. Mouse behavior was assessed via elevated plus maze, open field, light-dark box, and fear conditioning tests. Transcriptomic and proteomic analyses were performed on brain tissue lysates. ResultsBehavioral testing revealed increased locomotor activity in TGAC8 that included a greater total distance traveled (+43%; P < 0.01), a higher average speed (+38%; P < 0.01), and a reduced freezing time (–45%; P < 0.01). Dual-lead telemetry recording confirmed a persistent heart rate elevation with a corresponding reduction in ECG-R-waves interval variability and revealed increased EEG-gamma activity in TGAC8 vs wild-type. Bioinformatic assessment of hippocampal tissue indicated upregulation of dopamine 5, gamma-aminobutyric acid A, and metabotropic glutamate 1/5 receptors, major players in gamma activity generation. Granger causality analyses of ECG and EEG recordings showed a marked increase in informational flow between the TGAC8 heart and brain. ConclusionsPerturbed signals arising from the heart cause changes in brain activity, altering mouse behavior. More specifically, the brain interprets augmented myocardial humoral/functional output as a “sustained exercise-like” situation and responds by activating central nervous system output controlling locomotion.

Évaluation post-transplantation précoce de la dysfonction aiguë du greffon rénal

AbstractKidney transplantation is the best option in the treatment of end-stage kidney disease. Early acute kidney transplant dysfunction is a common complication that corresponds to acute renal failure (AKI) postoperatively after renal transplantation. When it occurs, it favors acute rejection and chronic dysfunction of kidney transplant. Incidence of this complication is constantly rising due to the increased use of grafts from extended criteria donors and from donors after circulatory death. This acute renal failure clinically results in a persistent elevation of serum creatinine and possibly a decrease in diuresis and the need for dialysis during the first postoperative week. However, these signs of renal damage are mostly inefficient and lead to a late diagnosis, limiting treatment efficiency. Therefore, it is essential to develop and use new methods for evaluating acute renal damage early after kidney transplantation. This review explores the various established or developing diagnostic modalities for early AKI after kidney transplantation, whether glomerular filtration rate (GFR) assessment methods or other approaches.

Evaluation of antioxidant activity in without persistent ST-segment elevation

Aims: Coronary artery disease is the most common cause of mortality and morbidity worldwide. Oxidative stress is involved in the pathogenesis of many diseases, including atherosclerosis. Thiols are important antioxidants for the elimination of reactive oxygen radicals and oxidative stress. In this study, we aimed to compare patients suffering from without persistent ST-segment elevation (NSTMI) and volunteers with normal coronary arteries in terms of antioxidants. Methods: The study included 105 patients diagnosed with NSTMI and 51 controls. Plasma total thiol, native thiol, and disulfide levels were measured. Results: Baseline demographic characteristics were similar between the groups. The ejection fraction was lower in the patient group. In terms of biochemical and hematologic parameters, glucose, AST, ALT, white blood cell count, and troponin were higher in the patient group, while other parameters were similar. Plasma native thiol (344.32 ± 81.28 µmol/L versus 403.62 ± 62.36 µmol/L, p &lt; 0.0001) and total thiol (382.90 ± 91.13 µmol/L versus 444.17 ± 65.53 µmol/L, p &lt; 0. 0001) levels were lower in NSTMI patients compared to control patients, while disulfide (19.29± 3.19 versus 20.27± 8.10, p = 0.77) levels were similar between the groups. Conclusion: In this study, we found that native thiol and total thiol levels, which are antioxidant markers, were lower in patients with NSTMI compared with the control group. Our study shows that antioxidant activity is affected in NSTMI, and antioxidant levels are decreased.