Modest Elevation Research Articles

SAT568 A Case Of Medullary Thyroid Cancer Associated With Cutaneous Metastasis: A Rare And Aggressive Presentation

Abstract Disclosure: N. Vaghasia: None. F. Hasan: None. M. Grimes: None. Introduction: Cutaneous metastasis (CM) is an extremely rare site of metastasis in medullary thyroid cancer (MTC). It suggests aggressive malignancy and poor prognosis in most cases. Case: A 26 year old male with no PMH presented to ER with neck discomfort and lump noted few weeks prior to presentation. Neck examination revealed a tender left uninodular goiter. Thyroid US revealed a 7.1 cm solid, hypoechoic, lobular, taller than wide left thyroid nodule with macrocalcification and two abnormal appearing level 2 and 3 left cervical lymph nodes. FNA of all three lesions were positive for MTC. CT neck and PET scan suggested locally advanced tumor surrounding carotid artery and esophagus plus metastatic lesion in the pelvis. Interestingly, serum calcitonin was only modestly elevated at 28.9 pg/ml (0.0-8.4), while serum CEA was high at 8.7 ng/mL (0-3.0). Genetic testing for germline RET mutation was negative. Patient underwent a total thyroidectomy with central and left lateral neck dissection and pelvic mass resection with pathology revealing MTC, stage T4b N1b M1. Molecular testing was negative for RET mutation. Patient underwent EBRT of the neck for residual disease after surgery. Patient was started on Cabozantinib therapy. Seven months after initial presentation, he had new skin lesions, one on scalp and two on left lateral chest wall described as 1-2 cm cystic papular lesion, reddish-yellow in color and tender to palpation. Excision of all three lesions were positive for MTC confirming CM. Patient’s most recent PET scan suggested residual disease in the neck and new metastatic lesion in the right humerus. Patient’s serum calcitonin level remained within the reference range after surgery despite residual disease. Discussion: MTC with CM is extremely rare with fewer than 10 reported cases. Most of them are associated with high mortality with death within one year from diagnosis. Most of the cases had skin lesions in upper body with scalp being the most common site. Not much is known about the molecular profiling of MTC with CM. Our case is similar to previously reported cases in terms of disease aggressiveness and skin lesions involving the scalp and upper chest. Two unique features about our case are: first, the modest elevation of calcitonin preoperatively despite large tumor burden and normal calcitonin after surgery despite having residual disease and new distant metastasis. Second, molecular profiling of our patient was negative for germline mutations in association with MTC. This may suggest the presence of an unknown mutation or pathway leading to this unusual manifestation in MTC. Conclusion: In a patient with known MTC, skin lesions especially on scalp should raise suspicion for metastatic and aggressive MTC. With minimally elevated calcitonin and negative RET mutation our case raise one important question - Is a normal calcitonin and negative RET oncogene associated with an aggressive form of MTC? Presentation: Saturday, June 17, 2023

Tectonic-Thermal Evolution of the Wadi El-Dahal Area, North Eastern Desert, Egypt: Constraints on the Suez Rift Development

The Suez Rift developed as a northern extension of the Red Sea rift during the Oligocene-Miocene, whose flanks were constructed from the Neoproterozoic basement rocks of the Arabian–Nubian Shield. These basement rocks are comprised of the whole tectonic history since their formation. The Suez Rift initiation model and proposed thermal overprint role in the rifting process and flank development remain uncertain. Additionally, the amplitude of different regional tectonic events’ effects on the region is still debatable. Integration of fission-track thermochronology data with modeling of the time-temperature history has demonstrated efficiency in addressing such issues. In the context of this study, eleven representative samples were collected from the different rock units in the Wadi El-Dahal area at the northern tip of the western flank of the Suez Rift. These samples revealed Carboniferous zircon fission-track cooling ages of 353 ± 9 Ma and 344 ± 11 Ma. Meanwhile, the apatite fission-track analysis provided two spatially separated age groups: Permian-Triassic and Late Cretaceous, with average ages of 249 ± 11 Ma and ca. 86 ± 10 Ma, respectively. The time-temperature modeling revealed four possible cooling pulses representing exhumation events, which were initiated as a response to four tectonic activities: the accretion-subsequent event of erosion during the Neoproterozoic, the Hercynian (Variscan) tectonic event during the Devonian-Carboniferous, the Mid-Atlantic opening during the Cretaceous, and the Suez Rift opening during the Oligocene-Miocene. The western flank of the Suez Rift suggests a passive mechanical type with no extra thermal overprint, as indicated by the dominance of older thermochronological ages, modest rift flank elevations, and a reduction in the heat flow.

Trmun (north-eastern Italy): Multi-scale remote and ground-based sensing of a Bronze Age and post-Roman fortification

We have used multi-scale remote sensing to investigate a little known archaeological site in northern Istria (north-eastern Italy). Airborne Laser Scanning (ALS) and archaeological field surveys have allowed us to identify the position and extension of a large Protohistoric hillfort. Its highest and best-preserved sector, corresponding to a modest elevation at the eastern margin of the settlement, has been further investigated through thermal imaging, high-resolution ALS, drone Structure from Motion (SfM) photogrammetry and 3D Ground Penetrating Radar (GPR), leading to a detailed identification of unexpected buried features. An excavation campaign conducted in 2022 has confirmed the remote and ground-based sensing results. This excavation has led to the discovery of a Bronze Age fortification, partially reused and modified with the construction of 2 or 3 square towers during the post-Roman period. Our results demonstrate that the combined analysis of multi-scale remote and ground-based sensing is crucial to planning archaeological exploration in the field. Digital methods provide high-resolution topography and detect buried features that assist in monitoring and managing cultural heritage.

Association between glycated hemoglobin (HbA1c) level and cardiac perfusion and function on gated myocardial perfusion SPECT

BackgroundGlycated hemoglobin (HbA1c) is a recognized biomarker that keeps track of long-term blood sugar levels. Some studies revealed that even a modest elevation of blood glucose levels was linked to a higher chance of developing CAD. In this study we aim to test the impact of HbA1c level on perfusion and function metrics derived from myocardial perfusion gated SPECT (MPGS) imaging.ResultsTwo hundred patients were recruited in this study (mean age 58.21 ± 11.53 years; 51% males), of whom 132 patients (66%) were diabetic. Diabetic patients had a higher mean HbA1c of 7.92 ± 1.99 versus 6.05 ± 0.99 in non-diabetics (p < 0.001). HbA1c% was negatively correlated to LVEF% (r = − 0.262; p < 0.001) and HDL (r = − 0.316; p < 0.001), though, it was positively correlated to ESV (r = 0.221; p = 0.002) and EDV (r = 0.291; p < 0.001). Patients with HbA1c% > 6.5 compared to ≤ 6.5%, had lower LVEF% of 53.17 ± 14.55 vs. 57.8 ± 12.61 (p = 0.017), lower HDL of 1.046 ± 0.262 vs. 1.196 ± 0.295 (p < 0.001), more LVEF < 50% (30% vs. 15.6%; p = 0.017), ESV > 44 ml (38.2% vs. 20%; p = 0.005), and WMA (24.5% vs. 12.2%; p = 0.027), hypertension (77.3% vs. 54.4%; p = 0.001) and dyspnea (27.3% vs. 15.6%; p = 0.047), however, with less chest pain (70.9% vs. 83.3%; p = 0.039). Diabetic patients with HbA1c% > 7.5 had lower LVEF% (52.0 ± 14.59 vs. 57.6 ± 11.55; p = 0.018) and HDL (1.005 ± 0.239 vs 1.148 ± 0.273; p < 0.002), more LVEF < 50% (33.3% vs. 14.5%; p = 0.011), ESV > 44 ml (41.3% vs. 20.3%; p = 0.009), WMA (30.2% vs. 11.6%; p = 0.008), and EDV > 100 ml (34.9% vs. 18.8%; p = 0.037). No significant relation was found between HbA1c% and perfusion variables.ConclusionsElevated HbA1c% was associated with multiple abnormal MPGS function parameters including lower LVEF, greater ESV, and more WMA. The same was observed in the diabetic group, together with greater EDV. No significant relation was detected between HbA1c% and perfusion parameters. The effect of impaired glycemic control on cardiac function parameters, even in absence of significant effect on perfusion, could be an alarming sign, while interpreting MPGS studies, both in known diabetic patients and in those with probably insulin resistance but not known to be diabetic. Such findings may be calling for further investigations, to uncover the true mechanisms behind cardiac dysfunction and the possibility of associated microvascular disease.

Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice

BackgroundFrontotemporal dementia (FTD) is a heterogeneous group of early onset and progressive neurodegenerative disorders, characterized by degeneration in the frontal and temporal lobes, which causes deterioration in cognition, personality, social behavior and language. Around 45% of the cases are characterized by the presence of aggregates of the RNA-binding protein TDP-43.MethodsIn this study, we have used a murine model of FTD that overexpresses this protein exclusively in the forebrain (under the control of the CaMKIIα promoter) for several biochemical, histological and pharmacological studies focused on the endocannabinoid system.ResultsThese mice exhibited at postnatal day 90 (PND90) important cognitive deficits, signs of emotional impairment and disinhibited social behaviour, which were, in most of cases, maintained during the first year of life of these animals. Motor activity was apparently normal, but FTD mice exhibited higher mortality. Their MRI imaging analysis and their ex-vivo histopathological evaluation proved changes compatible with atrophy (loss of specific groups of pyramidal neurons: Ctip2- and NeuN-positive cells) and inflammatory events (astroglial and microglial reactivities) in both cortical (medial prefrontal cortex) and subcortical (hippocampus) structures at PND90 and also at PND365. The analysis of the endocannabinoid system in these mice proved a decrease in the hydrolysing enzyme FAAH in the prefrontal cortex and the hippocampus, with an increase in the synthesizing enzyme NAPE-PLD only in the hippocampus, responses that were accompanied by modest elevations in anandamide and related N-acylethanolamines. The potentiation of these elevated levels of anandamide after the pharmacological inactivation of FAAH with URB597 resulted in a general improvement in behaviour, in particular in cognitive deterioration, associated with the preservation of pyramidal neurons of the medial prefrontal cortex and the CA1 layer of the hippocampus, and with the reduction of gliosis in both structures.ConclusionsOur data confirmed the potential of elevating the endocannabinoid tone as a therapy against TDP-43-induced neuropathology in FTD, limiting glial reactivity, preserving neuronal integrity and improving cognitive, emotional and social deficits.

Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants.

To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.

Drought, armed conflict and population mortality in Somalia, 2014-2018: A statistical analysis.

During 2010-2012, extreme food insecurity and famine in Somalia were estimated to account for 256,000 deaths. Since 2014 Somalia has experienced recurrent below-average rainfall, with consecutive failed rains in late 2016 and 2017 leading to large-scale drought, displacement and epidemics. We wished to estimate mortality across Somalia from 2014 to 2018, and measure the excess death toll attributable to the 2017-2018 drought-triggered crisis. We used a statistical approach akin to small-area estimation, and relying solely on existing data. We identified and re-analysed 91 household surveys conducted at the district level and estimating the crude (CDR) and under 5 years death rate (U5DR) over retrospective periods of 3-4 months. We captured datasets of candidate predictors of mortality with availability by district and month. We also reconstructed population denominators by district-month combining alternative census estimates and displacement data. We combined these data inputs into predictive models to estimate CDR and U5DR and combined the predictions with population estimates to project death tolls. Excess mortality was estimated by constructing counterfactual no-crisis scenarios. Between 2013 and 2018, Somalia's population increased from 12.0 to 13.5 million, and internally displaced people or returnees reached 20% of the population. We estimated an excess death toll of 44,700 in the most likely counterfactual scenario, and as high as 163,800 in a pessimistic scenario. By contrast to 2010-2012, excess deaths were widespread across Somalia, including central and northern regions. This analysis suggests that the 2017-2018 crisis had a lower, albeit still very substantial, mortality impact than its 2010-2012 predecessor. Despite modest elevations in death rate, crisis conditions were widespread and affected a population of millions. Humanitarian response to drought-related crises in Somalia needs to be strengthened, target the most vulnerable and emphasise very early interventions.

Dramatic elevation of LDL cholesterol from ketogenic-dieting: A Case Series

High-fat, low carb dieting, also known as the "ketogenic diet," has increased in popularity as a rapid weight-loss tool. Previous studies describe a modest elevation in cholesterol in the average keto-diet participant without specific cardiovascular impact. We hypothesize that patients with a genetic predisposition to cholesterol metabolism dysregulation may have a disproportionate elevation in cholesterol in response to ketogenic dieting.

Abstract 846: Utilizing quantitative systems pharmacology (QSP) model to understand cytokine release syndrome (CRS) following administration of epcoritamab in DLBCL patients

Abstract Background: Epcoritamab is a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells (1). Epcoritamab’s pharmacokinetics (PK), pharmacodynamics, and safety profiles were investigated in GCT3013-01 escalation study across a wide range of doses. CRS is an adverse event of special interest for T cell engagers such as Epcoritamab. As such, step-up dosing (SUD) has been investigated in study GCT3013-01 escalation to minimize release of cytokines and mitigate severe CRS symptoms. Seventeen permutations of SUD were tested, with doses ranging from 0.004 to 60 mg. Based on observed CRS data, a SUD regimen of 0.16/0.8/48 mg was selected. The aim of the analysis was to develop a QSP model capable of predicting cytokine release which can be used to identify potential optimal SUD regimen. Method: Leveraging Epcoritamab preclinical and clinical data, we have developed a QSP platform that captures the observed tumor responses and allows for systemic predictions of biomarkers with the selected SUD regimen. A minimal physiologically based PK model was linked to submodels of T cell activation, proliferation, and cytotoxicity of target-bearing cells, to create an integrated QSP model of the DLBCL system. Epcoritamab-mediated cross-linking of target(s) and CD3 receptor to form trimer complexes drives cell trafficking and cytokine production as well as inducing death of target-bearing cells. The model described the PK, cellular effects, and observed cytokine profiles within the plasma, and simulated similar effects in lymph node(s), tumor, and other peripheral body tissue. Result: After SC administration of Epcoritamab, transient and modest elevation of selected cytokines was observed. Patients’ cytokine profiles were categorized into three different trends based on Cycle 1 data. By accounting for the interaction of receptors and ligands at the nano-scale level (time and physical size) we characterized the dose response and dynamics of T cells, B cells, IL6, and IL10 in patients enrolled in the study by using the QSP model. Conclusions: This analysis integrated underlying mechanisms to predict various systemic biomarkers dynamics including T cells, B cells, IL6 and IL10 following administration of Epcoritamab. The well-studied pathways and mechanisms allow implementation of the model in disease indications other than DLBCL.

In this Issue.

HomeCirculation ResearchVol. 132, No. 7In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Originally published30 Mar 2023https://doi.org/10.1161/RES.0000000000000608Circulation Research. 2023;132:791is related toDiscovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell PhenotypeDestabilization of Atherosclerotic Plaque by Bilirubin DeficiencyIntegrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte HypertrophyDiscovery of Trans-Acting Long Non-Coding RNAs that Regulate Smooth Muscle Cell Phenotype (p 795)Download figureDownload PowerPointShi et al identify long non-coding RNAs that regulate a phenotype switch in smooth muscle cells.Vascular smooth muscle cells (VSMCs) are a major contributing cell type in the progression of coronary artery disease (CAD) and become pathological by transitioning into a highly proliferative and migratory state. In searching for factors that regulate this transition—which could thus reveal ways to stop it—Shi and colleagues focused on the potential role of long non-coding RNAs (lncRNAs), many of which are regulatory in nature. Human coronary artery SMCs (HCASMCs) were subjected to various CAD stimuli and the expression changes of lncRNAs were analyzed. From the many differentially expressed lncRNAs, the team focused on two—ZIPPOR and TNS1-AS2, which were down- and up-regulated respectively relative to unstimulated cells. Interestingly, functional analysis of these two revealed that, despite being differently affected by CAD stimuli, repression of either led to similar effects in HCASMCs—increased migration and proliferation and increased expression of ZEB2, a master regulator of SMC phenotype transition. Both ZIPPOR and TNS1-AS2 were also found to interact directly with the ZEB2 protein to suppress its expression.While it is not known if these lncRNAs influence CAD progression, their suppression of SMC transition suggests such investigations are warranted.Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency (p 812)Download figureDownload PowerPointLow bilirubin aggravates atherosclerosis in mice, report Chen et al.Bilirubin is a yellowish pigment formed during the breakdown of red blood cells and is ordinarily processed by the liver and excreted. Liver dysfunction can cause a severe build-up of bilirubin resulting in jaundice, but a more modest elevation is associated with lower levels of cardiovascular disease (CVD). Indeed, people with higher levels of the pigment have a lower incidence of CVD, while coronary artery disease patients with especially low levels of bilirubin have less stable plaques and worse outcomes. To investigate how bilirubin might protect against CVD, Chen and colleagues engineered atherosclerosis-prone mice to produce less of the pigment, and compared them with control mice whose bilirubin levels were normal. A lack of bilirubin worsened atherosclerosis in multiple ways. For example, the test animals had increased levels of blood lipids, increased systemic inflammation and oxidative stress, evidence of endothelial dysfunction, and increased plaque instability. While the latter appeared to result from infiltration of inflammatory cells and increased expression of the pro-inflammatory enzyme, MPO, the molecular details behind bilirubin’s other effects are yet to be determined. Nonetheless, the findings lead the way for further research into whether modifying levels of bilirubin might help lower CVD risk.Integrated Proteomics Unveils Regulation of Cardiac Myocyte Hypertrophic Growth by a Nuclear cAMP Nanodomain Under the Control of PDE3A2 (p 828)Download figureDownload PowerPointA PDE3A2-controlled cAMP nanodomain regulates cardiomyocyte hypertrophy, say Subramaniam et al.Within cardiomyocytes, cAMP conveys beta-adrenergic receptor (βAR) signals to boost the strength and frequency of the heart’s contractions. But cAMP has other jobs within cells and its interactions with specific factors at specific subcellular nanodomains are thought to regulate task execution. One such factor is the enzyme PDE, which degrades cAMP. There are many different isoforms of PDE and they are thought to occupy and specify different nanodomains. Subramaniam and colleagues investigated the proteins associating with individual PDE isoforms when cardiomyocytes were stimulated with isoproterenol—a βAR agonist—and in this way discovered that βAR-activated PDE3A2 nanodomains associate with the transcription regulators SMAD4 and HDAC1, are located in the nucleus, and normally repress the expression of genes involved in hypertrophy. Sure enough, inhibition of PDE3 enabled cAMP-induced activation of hypertrophy genes and resulted in cardiomyocyte growth. PDE3 inhibitors are inotropic drugs that provide short term benefits to heart failure patients, but can worsen the condition if used long term. The finding that PDE3 inhibition led to cAMP-induced hypertrophy may thus partly explain the detrimental effects of such drugs on the heart, say the authors. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesDiscovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell PhenotypeHuitong Shi, et al. Circulation Research. 2023;132:795-811Destabilization of Atherosclerotic Plaque by Bilirubin DeficiencyWeiyu Chen, et al. Circulation Research. 2023;132:812-827Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte HypertrophyGunasekaran Subramaniam, et al. Circulation Research. 2023;132:828-848 March 31, 2023Vol 132, Issue 7 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000608PMID: 36996178 Originally publishedMarch 30, 2023 PDF download Advertisement

Association of qacA/B and smr Carriage with Staphylococcus aureus Survival following Exposure to Antiseptics in an Ex Vivo Venous Catheter Disinfection Model.

Many health care centers have reported an association between Staphylococcus aureus isolates bearing efflux pump genes and an elevated MIC/minimal bactericidal concentration (MBC) to chlorhexidine gluconate (CHG) and other antiseptics. The significance of these organisms is uncertain, given that their MIC/MBC is typically far lower than the CHG concentration in most commercial preparations. We sought to evaluate the relationship between carriage of the efflux pump genes qacA/B and smr in S. aureus and the efficacy of CHG-based antisepsis in a venous catheter disinfection model. S. aureus isolates with and without smr and/or qacA/B were utilized. The CHG MICs were determined. Venous catheter hubs were inoculated and exposed to CHG, isopropanol, and CHG-isopropanol combinations. The microbiocidal effect was calculated as the percent reduction in CFU following exposure to the antiseptic relative to the control. The qacA/B- and smr-positive isolates had modest elevations in the CHG MIC90 compared to the qacA/B- and smr-negative isolates (0.125 mcg/ml vs. 0.06 mcg/ml, respectively). However, the CHG microbiocidal effect was significantly lower for qacA/B- and/or smr-positive strains than for susceptible isolates, even when the isolates were exposed to CHG concentrations up to 400 μg/mL (0.04%); this finding was most notable for isolates bearing both qacA/B and smr (89.3% versus 99.9% for the qacA/B- and smr-negative isolates; P = 0.04). Reductions in the median microbiocidal effect were also observed when these qacA/B- and smr-positive isolates were exposed to a solution of 400 μg/mL (0.04%) CHG and 70% isopropanol (89.5% versus 100% for the qacA/B- and smr-negative isolates; P = 0.002). qacA/B- and smr-positive S. aureus isolates have a survival advantage in the presence of CHG concentrations exceeding the MIC. These data suggest that traditional MIC/MBC testing may underestimate the ability of these organisms to resist the effects of CHG. IMPORTANCE Antiseptic agents, including chlorhexidine gluconate (CHG), are commonly utilized in the health care environment to reduce rates of health care-associated infections. A number of efflux pump genes, including smr and qacA/B, have been reported in Staphylococcus aureus isolates that are associated with higher MICs and minimum bactericidal concentrations (MBCs) to CHG. Several health care centers have reported an increase in the prevalence of these S. aureus strains following an escalation of CHG use in the hospital environment. The clinical significance of these organisms, however, is uncertain, given that the CHG MIC/MBC is far below the concentration in commercial preparations. We present the results of a novel surface disinfection assay utilizing venous catheter hubs. We found that qacA/B-positive and smr-positive S. aureus isolates resist killing by CHG at concentrations far exceeding the MIC/MBC in our model. These findings highlight that traditional MIC/MBC testing is insufficient to evaluate susceptibility to antimicrobials acting on medical devices.

Evaluation of Over-the-Counter Portable Oxygen Concentrators Utilizing a Metabolic Simulator.

Supplemental oxygen is designed to raise alveolar PO2 to facilitate diffusion into arterial blood. Oxygen is generally delivered by nasal cannula either by continuous or pulsatile flow. Battery-powered portable oxygen concentrators (POCs) facilitate ambulation in patients experiencing exertional hypoxemia. In the United States, the Food and Drug Administration (FDA) clears these devices to be sold by physician prescription. Recently, however, lower-cost devices described as POCs have been advertised by online retailers. These devices lack FDA clearance and are obtained over the counter (OTC) without prescription. This study determined whether a selected group of OTC POCs have oxygen delivery characteristics suitable for use by hypoxemic patients. A metabolic simulator, capable of simulating a range of metabolic rates and minute ventilations, determined effects of oxygen supplementation delivered by a variety of devices on alveolar PO2 . Devices tested included 3 OTC POCs, an FDA-cleared POC, and continuous-flow oxygen from a compressed oxygen cylinder. End-tidal PETO2 , a surrogate of alveolar PO2 , was determined at each of each device's flow settings at 3 metabolic rates. Continuous-flow tank oxygen yielded a linear PETO2 increase as flow increased, with progressively lower slope of increase for higher metabolic rate. The prescription POC device yielded similar PETO2 elevations, though with somewhat smaller elevations in pulse-dose operation. One OTC POC was only technically portable (no on-board battery); it provided only modest PETO2 elevation that failed to increase as flow setting was incremented. A second OTC POC produced only minimal PETO2 elevation. A third OTC POC, a pulsed-dose device, produced meaningful PETO2 increases, though not as great as the prescription device. Only one of 3 OTC POCs tested was potentially of use by patients requiring ambulatory oxygen. Physicians and respiratory therapists should inform patients requiring portable oxygen that OTC devices may not meet their oxygenation requirements.

Native T1 Mapping for the Diagnosis of Myocardial Fibrosis in Patients With Chronic Myocardial Infarction

BackgroundMyocardial fibrosis is a fundamental process in cardiac injury. Cardiac magnetic resonance native T1 mapping has been proposed for diagnosing myocardial fibrosis without the need for gadolinium contrast. However, recent studies suggest that T1 measurements can be erroneous in the presence of intramyocardial fat. ObjectivesThe purpose of this study was to investigate whether the presence of fatty metaplasia affects the accuracy of native T1 maps for the diagnosis of myocardial replacement fibrosis in patients with chronic myocardial infarction (MI). MethodsConsecutive patients (n = 312) with documented chronic MI (>6 months old) and controls without MI (n = 50) were prospectively enrolled. Presence and size of regions with elevated native T1 and infarction were quantitatively determined (mean + 5SD) on modified look-locker inversion-recovery and delayed-enhancement images, respectively, at 3.0-T. The presence of fatty metaplasia was determined using an out-of-phase steady-state free-precession cine technique and further verified with standard fat-water Dixon methods. ResultsNative T1 mapping detected chronic MI with markedly higher sensitivity in patients with fatty metaplasia than those without fatty metaplasia (85.6% vs 13.3%) with similar specificity (100% vs 98.9%). In patients with fatty metaplasia, the size of regions with elevated T1 significantly underestimated infarct size and there was a better correlation with fatty metaplasia size than infarct size (r = 0.76 vs r = 0.49). In patients without fatty metaplasia, most of the modest elevation in T1 appeared to be secondary to subchronic infarcts that were 6 to 12 months old; the T1 of infarcts >12 months old was not different from noninfarcted myocardium. ConclusionsNative T1 mapping is poor at detecting replacement fibrosis but may indirectly detect chronic MI if there is associated fatty metaplasia. Native T1 mapping for the diagnosis and characterization of myocardial fibrosis is unreliable.

Amplified Thrombo-Inflammatory Biomarkers in Pulmonary Embolism with Augmented Responses in Von-Willebrand Factor, Microparticles and Interleukin-6 in Patients with Cancer

Introduction: The multifactorial and complex pathophysiology of pulmonary embolism (PE) involves dysregulation of hemostatic system including fibrinolytic imbalance, endothelial compromise, and generation of thrombotic mediators, along with cellular defects and hemodynamic derangement. These pathophysiologic processes results in the generation of thrombo-inflammatory biomarkers reflecting the endogenous hemostatic imbalance. Cancer is prevalent in PE patients and is considered as an added risk factor for the adverse outcomes. Thrombo-inflammatory biomarker profiling provide means to risk stratify PE patients. This study aimed to profile several of these biomarkers in normal individuals and PE patients and further demonstrate their additional amplification in patients with cancer as a co-morbidity. Materials & Method: Four hundred male and female patients of 18 years or older age, were included through enrolment in conjunction with an IRB approved project by the pulmonary embolism response team (PERT) registry. Diagnosis of PE was confirmed by computed tomography (CT), angiography or ventilation perfusion imaging. Blood samples were drawn with in 24-72 hours of confirmed diagnosis of acute PE. Normal human plasma (NHP) samples were obtained from 50 healthy individuals including 25 male and 25 female and used for referencing purposes. All of the plasma samples were analyzed for D-Dimer, plasminogen activator inhibitor-1 (PAI-1) antigen, tissue-type plasminogen activator (tPA), activated thrombin-activatable fibrinolysis inhibitor (TAFI-a), von Willebrand factor (vWF), c-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured by commercially available ELISA methods. Microparticles were measured by using a chromogenic functional method. Individual biomarkers were compared to normal plasma and further stratified on cancer status and PE severity. Results are presented as mean±SD and fold increase. For the degree of association, GraphPad Prism Software was used. Results: PE patients exhibited varying levels of upregulation of all of the individual biomarkers compared to normal's, D-Dimer (37.05-fold), PAI-1 antigen (3.95-fold), tPA (4.69-fold), TAFI (1.21-fold), vWF (1.89-fold), CRP (35.34-fold), IL-6 (21.62-fold), and microparticles (3.04-fold) increase in PE patients with reference to NHP. When the PE group stratified into cancer and non-cancer patients, most of the biomarkers except D-Dimer and microparticles showed varying degree of modest elevation in the cancer group (figure 1). vWF, IL6 and microparticles levels were found to be further amplified in PE group with cancer. Of these three biomarkers, only vWF remained amplified when stratified by PE severity in patients with cancer, however this change was only observed in the low-grade PE patients (table 1). The IL-6 levels showed increased trend in the low-grade and sub-massive patient group, however because of the wide scatter, it was not significant. Conclusion: These studies demonstrate that thrombo-inflammatory biomarkers are upregulated in PE patients. Furthermore, PE patients with cancer exhibit amplified responses for vWF, IL-6 and microparticles levels suggesting their role in mediating the pathogenesis involving endothelial, inflammatory and thrombogenic mechanisms. Among the biomarkers studied, vWF is central to thrombo-inflammatory process and is distinct in PE cohort with cancer, despite taking into account the lower PE severity. These studies suggest that selective biomarker profiling of thrombo-inflammatory biomarkers may be valuable in the risk stratification and therapeutic management of PE patients at large. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 10876: Thrombo-Inflammatory Biomarkers in Pulmonary Embolism as Stratified in Cancer and Non-Cancer Patient Groups

Introduction: The multifactorial and complex pathophysiology of pulmonary embolism (PE) involves dysregulation of hemostatic system including fibrinolytic imbalance, endothelial compromise, and generation of thrombotic mediators, along with cellular defects and hemodynamic derangement. Cancer is prevalent in PE patients and is considered an added risk factor for the adverse outcomes. Thrombo-inflammatory biomarkers profiling provide means to risk stratify PE patients. Hypothesis: This study aimed to profile several of these biomarkers in normal and PE patients and to further demonstrate any potential difference between cancer and non-cancer patients. Methods: Four hundred patients of 18 years or older age, were included through enrolment in conjunction with IRB approved project by the pulmonary embolism response team (PERT) registry. Diagnosis of PE was confirmed by computed tomography (CT), angiography or ventilation perfusion imaging. Blood samples were drawn with in 24 hours of confirmed diagnosis of acute PE. Control plasma samples were obtained from 50 healthy individuals. All plasma samples were analyzed for D-Dimer, PAI-1 antigen, tPA, TAFI-a, vWF, CRP, troponin and IL-6 were measured by ELISA methods. Microparticles were measured using a chromogenic functional method. Individual biomarkers were compared to normal plasma and further stratified into cancer and non-cancer. Results: All the individual biomarkers exhibited up to 50-fold elevation in PE patients compared to normal groups. D-Dimer and CRP showed the most pronounced increase. When the PE group stratified into cancer and non-cancer patients, most of the biomarkers except D-Dimer and microparticles showed varying degree of modest elevation in the cancer group. vWF, IL6 and microparticles levels were found to be significantly different in the cancer group (p&lt;0.050). Conclusions: These studies demonstrate that thrombo-inflammatory biomarkers are upregulated in PE patients. Furthermore, PE patients with cancer exhibit amplified levels of some of the markers suggesting the increased severity of pathogenesis involving thrombo-inflammatory mechanisms.

Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease.

Mutations in β-amyloid (Aβ) precursor protein (APP) cause familial Alzheimer's disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish-mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations.

Bacillus Calmette-Guérin (BCG) osteomyelitis among children: Experience in a single tertiary center in central Taiwan

The insidious nature of BCG-osteomyelitis makes it challenging for clinicians to detect it early on. This 12-year retrospective analysis was conducted at a single tertiary hospital in central Taiwan. Electronic medical records of pediatric patients treated for BCG-osteomyelitis were reviewed. Demographics, clinical features, and laboratory findings were compared with patients diagnosed with culture-proven pyogenic osteomyelitis. In total, eight patients fulfilled our inclusion criteria. Their median age was 16 months, and no obvious gender prevalence was found. Six of the eight patients had lesions involving the lower extremities. When compared with the pyogenic osteomyelitis group, age of disease onset was found to be significantly younger in the BCG osteomyelitis group (p=0.038). Absence of fever and pain in the BCG osteomyelitis group was found to be statistically significant when compared with the pyogenic group (p=0.002 and p=0.026 respectively). CRP and ESR were found to be significantly higher in the pyogenic osteomyelitis group (p=0.000 and p=0.004 respectively). BCG-related osteomyelitis must be considered when evaluating an afebrile child presenting with an unexplainable swelling or limp, and especially when the lesion is located on a lower limb. Laboratory studies may reveal normal WBC and CRP, with a normal to modest elevation of ESR. Imaging studies, including plain radiographs, magnetic resonance imaging (MRI), or computed tomography (CT) should be employed to rule out BCG-related osteomyelitis. Early diagnosis help minimize inappropriate antibiotics use, and may lead to a better outcome.

Association of Chest Pain Protocol–Discordant Discharge With Outcomes Among Emergency Department Patients With Modest Elevations of High-Sensitivity Troponin

Accelerated diagnostic protocols (ADPs) for chest pain using high-sensitivity troponin (hsTn) levels have excellent sensitivity and negative predictive value for rapid risk stratification of patients with chest pain. However, little is known about the outcomes of patients who are discharged despite abnormal ADP results, ie, after "ruling-in" with a modest elevation of hsTn. To determine outcomes of patients discharged following ADP, including those who were ruled in with modestly elevated levels of hsTnT but discharged nonetheless. This retrospective cohort study included patients with chest pain who presented to the emergency departments (EDs) of a large multisite health system ED between January 2017 to September 2019. Patients were assessed using an ADP, had a peak hsTnT level measured between the limit of quantitation and 52 ng/L, were discharged, and had follow-up in the electronic medical record. Data analysis was conducted from January 2017 to September 2019. Application of an hsTnT ADP. Thirty-day major adverse cardiac events (MACE), including myocardial infarction, urgent coronary revascularization, and all-cause death, comparing patients who were discharged following ADP-concordant vs ADP-discordant results. Of 10 342 patients with chest pain (mean [SD] age 51 [17] years; 5902 [57%] women) discharged following ADP, 29 (0.28%) had MACE. Patients with MACE were older (median [IQR] age, 66 [53-75] years vs 50 [38-62] years; P < .001) and more likely to have prior CAD (12 [41.4%] vs 1805 [17.5%]; P = .002) and hyperlipidemia (13 [44.8%] vs 2248 [21.8%]; P = .006). Additionally, patients with MACE were 5-fold more likely to have been discharged despite ADP discordance (16 [55.2%] vs 1145 [11.1%]; P < .001). A multivariable logistic regression analysis revealed only ADP discordance was independently associated with MACE (odds ratio, 6.42 [95% CI, 2.94-14.0]; P < .001). When stratified by peak hsTnT level, there were no differences in MACE between ADP-concordant and -discordant discharges provided the peak hsTnT measured was less than 12 ng/L. In contrast, patients with peak hsTnT level between 12 and 51 ng/L were significantly more likely to have MACE if they were discharged after ADP-discordant vs -concordant hsTnT series (14 of 609 [2.30%] vs 5 of 1047 [0.48%]; P < .002). Notably, a HEART (history, electrocardiogram, age, risk factors, troponin) score of 4 or greater retrospectively identified the most ADP-discordant discharges (13 of 16 [81.3%]) who had MACE. In this cohort study, an hsTnT ADP identified patients who could be discharged from the ED with low 30-day risk of MACE, provided the discharge was based on ADP-concordant "rule-out." Conversely, the rate of MACE was significantly higher among patients discharged despite ADP discordance. Most patients with ADP-discordant discharges who experienced MACE had a HEART score of 4 or greater, suggesting that application of this score may augment discharge decisions of patients despite ADP-discordant troponin series.

The role of urinary N-acetyl-β-D-glucosaminidase in early detection of acute kidney injury among pediatric patients with neoplastic disorders in a retrospective study

BackgroundThe 1-year cumulative incidence of AKI reportedly is high (52%) in pediatric neoplastic disorders. About half of these events occur within 2 weeks. However, subclinical AKI episodes may remain unrecognized by the conventional creatinine-based approaches. We investigated the diagnostic value of urinary N-acetyl-β-D-glucosaminidase (uNAG) as an early marker of acute kidney injury (AKI).MethodsIn our retrospective study, 33 children with neoplastic disorders were inculded who had serial uNAG tests (at least 5 samples/patient) with a total of 367 uNAG measurements. Renal function was determined by cystatin-C and creatinine based GFR, and relative increase of uNAG index (uNAGRI). We focused on detecting both clinical and subclinical AKI episodes (according to Biomarker-Guided Risk Assessment using pRIFLE criteria and /or elevated uNAG levels) and the incidence of chronic kidney damage.ResultsSixty episodes in 26 patients, with positivity at least in one parameter of kidney panel, were identified during the observation period. We detected 18/60 clinical and 12/60 subclinical renal episodes. In 27/60 episodes only uNAG values was elevated with no therapeutic consequence at presentation. Two patients were detected with decreased initial creatinine levels with 3 „silent” AKI.In 13 patients, modest elevation of uNAG persisted suggesting mild, reversible tubular damage, while chronic tubuloglomerular injury occurred in 5 patients.Based on ROC analysis for the occurence of AKI, uNAGRI significantly indicated the presence of AKI, the sensitivity and specificity are higher than the changes of GFRCreat. Serial uNAG measurements are recommended for the reduction of the great amount of false positive uNAG results, often due to overhydratation.ConclusionUse of Biomarker-guided Risk Assessment for AKI identified 1.5 × more clinical and subclinical AKI episodes than with creatinine alone in our pediatric cancer patients. Based on the ROC curve for the occurence of AKI, uNAGRI has relatively high sensitivity and specificity comparable to changes of GFRCysC. The advantage of serial uNAG measurements is to decrease the number of false positive results.Trial registrationThe consent to participate is not applicable because it was not reqired for ethical approval and it is a retrospectiv study.

Abstract 334: Convection enhanced delivery of EGFR-targeting antibody drug conjugates ABBV-321 and Depatux-M

Abstract Introduction: EGFR targeted antibody-drug conjugates (ADCs) show promise as a novel treatment in a subset of glioblastoma (GBM). Two EGFR targeting ADCs include first generation Depatux-M, with an antimitotic toxin monomethyl auristatin F (MMAF), and ABBV-321, with a DNA crosslinking agent pyrrolobenzodiazepine dimer (PBD) toxin. Due to the large molecular weight, poor drug distribution across the blood-brain barrier significantly limits the efficacy in EGFR-amplified GBM. We studied whether convection enhanced delivery (CED) can be used to safely infuse these two EGFR-targeted ADCs in patient-derived xenograft (PDX) models of EGFR-amplified GBM. Methods: The efficacy of Depatux-M and ABBV-321 was evaluated in vitro and in vivo in two EGFRviii-amplified PDXs (GBM6 and GBM108). Immunofluorescence staining was used to evaluate drug distribution along with pharmacodynamics of the ADCs. CED was performed by stereotactic placement of an infusion catheter in the same location as the original tumor implantation. Immunohistochemistry was used to explore mechanisms of normal cell toxicity. Results: Despite potent activity in vitro (high ng/ml IC50), systemic administration of either ADC conferred minimal extension in survival for either GBM6 or GBM108. In contrast, CED significantly enhanced ADC delivery to tumor and peri-tumoral regions and extended survival. In a pilot study in GBM6 with n=3 mice per group, a single CED infusion of 0.002mg ABBV-321 resulted in extended survival beyond 365 days for two mice, while other doses and placebo were associated with shorter median survival (0 mg - 39 days; 0.03 mg - 105 days; 0.3 mg - 49 days). In a subsequent trial evaluating serial infusions performed every 21 days, four infusions at 0.002 mg ABBV-321 resulted in lethal toxicity. In contrast, limiting ABBV-321 to only two serial CED infusions in GBM108 was associated with extended survival of more than 300 days vs. 53 days for AB095 antibody control infusion. In contrast, serial infusion with Depatux-M was much better tolerated. In a single infusion in GBM6, a 0.06 mg dose was well tolerated and associated with a 49-day extension in median survival. Further, four serial infusions at 0.06 mg given every 21 days in GBM6 and GBM108 was associated with 100 day and more than 250-day extension in survival as compared to AB095 antibody control infusion. To investigate the mechanism of toxicity, infusion of non-tumor bearing C57Bl6 mice with ABBV-321 resulted in a marked loss in NeuN staining and elevated CD68 and GFAP staining 7 days later; Depatux-M infusion was only associated with modest elevation in GFAP without loss of NeuN staining or elevated CD68-positive cells. Conclusion: Depatux-M is well tolerated when infused into normal brain and results in extended survival in orthotopic GBM PDXs. In contrast, ABBV-321, with a distinct PBD toxin, had a much narrower therapeutic window when delivered by CED. Citation Format: Kendra A. Porath, Ann Mladek, Rachael A. Vaubel, Michael S. Regan, Sonia Jain, Danielle Burgenske, Katrina Bakken, Brett Carlson, Margaret Connors, Zeng Hu, Lihong He, Paul A. Decker, Gaspar Kitange, Shiv Gupta, Nathalie Y. Agar, Thomas M. Feldsien, Didier R. Lefebvre, Jann N. Sarkaria. Convection enhanced delivery of EGFR-targeting antibody drug conjugates ABBV-321 and Depatux-M [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 334.