Elevated Doses Research Articles

INNV-21. COMPLETE RESPONSE TO ADJUVANT TEPOTINIB IN A PATIENT WITH NEWLY DIAGNOSED DISSEMINATED GLIOBLASTOMA (GBM) HARBORING MET AMPLIFICATION

Abstract MET oncogene encodes a receptor-tyrosine-kinase which drives cell proliferation, invasion and angiogenesis in a number of solid cancers including GBM where the incidence of MET amplification is 2-5%. Tepotinib is a highly selective blood-brain-barrier penetrant oral c-MET inhibitor recently FDA approved for MET-exon-14 altered non-small cell lung cancer (NSCLC). Here, we report complete radiographic response to tepotinib in a patient with newly-diagnosed disseminated GBM harboring MET amplification. A 29-years-old male presented with progressive headache. MRI brain showed a large heterogeneously enhancing intraventricular mass with epicenter in the right lateral ventricular trigone and enhancing nodules in bilateral cerebellum. MRI spine showed multifocal enhancement along the periphery of the cervicothoracic spinal cord and cauda equina concerning for leptomeningeal disease. He underwent right temporal lobectomy and subtotal resection of the mass. His KPS was 90 post-surgery due to dizziness. Pathology was consistent with GBM, IDH wild-type, MGMT-unmethylated and MET amplification at 7q31.2. He completed proton craniospinal irradiation at 3600cGy followed by boost to the tumor bed at 2400cGy without concurrent temozolomide (TMZ) due to the large radiation field. He completed two cycles of adjuvant TMZ which was put on hold due to myelosuppression. He subsequently started tepotinib monotherapy at 1000mg daily obtained on a compassionate IND. MRIs after one month of therapy showed resolution of areas of enhancement in the brain and spine. He had grade 1 creatinine elevation and abdominal discomfort and dose was reduced to 500mg daily after two cycles. Nineteen weeks after initiation of tepotinib, his complete response persists, and he remains clinically stable with mild chronic dizziness. Trials of targeted therapy in molecularly-unselected GBM have been largely disappointing, however, this case demonstrates the promise of targeting MET using tepotinib in GBM. A clinical trial of tepotinib in MET-amplified GBM and NSCLC brain metastasis is currently underway at MD Anderson.

(Poly)phenol toxicity in vivo following oral administration: A targeted narrative review of (poly)phenols from green tea, grape, and anthocyanin-rich extracts.

Fruit- and vegetable-derived (poly)phenols are secondary plant metabolites that may have beneficial effects on human health when consumed regularly. Recent years have seen rapid growth in both consumer demand for and research interest in (poly)phenol-rich dietary supplements, natural colorants, and functional foods. As these products continue to enter the marketplace and (poly)phenol intake patterns change from traditional food products to these sources, attention must be paid to the potential for toxicity from consuming elevated doses of (poly)phenols. To date, much remains unknown regarding the safety of high doses of (poly)phenols, especially in vivo. In this targeted narrative review, we summarize evidence from in vivo investigations of (poly)phenol toxicity after oral administration of green tea extracts, grape-derived phenolics, and anthocyanin-rich extracts. There is limited evidence of overt toxicity from oral ingestion of these (poly)phenol-rich sources, though more research on the safety of high doses-as well as defining what constitutes a "high" dose of both individual and complex mixtures of (poly)phenols-is needed before these observations can be used to create dietary guidance for consumers.

Pelvicaliceal Volume and Fluid Temperature Elevation During Laser Lithotripsy.

Background: While high-power laser systems facilitate successful ureteroscopic treatment of larger and more complex stones, they can substantially elevate collecting system fluid temperatures with potential thermal injury of adjacent tissue. The volume of fluid in which laser activation occurs is an important factor when assessing temperature elevation. The aim of this study was to measure fluid temperature elevation and calculate thermal dose from laser activation in fluid-filled glass bulbs simulating varying calix/pelvis volumes. Materials and Methods: Glass bulbs of volumes 0.5, 2.8, 4.0, 7.0, 21.0, and 60.8 mL were submerged in a 16-L tank of 37°C deionized (DI) water. A 230-μm laser fiber extending 5 mm from the tip of a ureteroscope was positioned in the center of each glass bulb. Irrigation with 0, 8, 15, and 40 mL/min of room temperature DI water was applied. Once steady-state temperature was achieved, a Ho:YAG laser was activated for 60 seconds at 40 W (0.5 J × 80 Hz, SP). Temperature was measured from a thermocouple affixed to the external tip of the ureteroscope. Thermal dose was calculated using the Dewey and Sapareto t43 methodology. Results: The extent of temperature elevation and thermal dose from laser activation were inversely related to the volume of fluid in each model and the irrigation rate. The time to threshold of thermal injury was only 3 seconds for the smallest model (0.5 mL) without irrigation but was not reached in the largest model (60.8 mL) regardless of irrigation rate. Irrigation delivered at 40 mL/min maintained safe temperatures below the threshold of tissue injury in all models with 1 minute of continuous laser activation. Conclusions: The volume of fluid in which laser activation occurs is an important factor in determining the extent of temperature elevation. Smaller volumes receive greater thermal dose and reach threshold of tissue injury more rapidly than larger volumes.

Impact of PSMA Targeted Gold Nanoparticles on Prostate Cancer Radiation Bystander Effect

Gold nanoparticles (GNPs) are effective radiosensitizers due to their ability to enhance ionizing radiation absorptance and deposit elevated dose in their vicinity. Radiation induced bystander effect (RIBE) expands radiation effects to non-targeted cells close to radiation-targeted cells, further improving radiation outcome. In this study, we investigated the impact of PSMA-targeted GNPs on RIBE. We hypothesize that the PSMA-targeted GNPs would intensify radiation effects by augmenting RIBE consequence as well as enhancing sensitivity of bystander cells to RIBE.Anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated onto PE Gylated GNPs through EDC/NHS chemistry. UV-Vis spectrophotometry and real time cell analysis were employed to evaluate the cellular uptake and biocompatibility, respectively, when LNCaP prostate cancer cells were treated with PSMA-targeted GNPs at varying concentrations. Then GNPs with biocompatible dosage were used for cancer cell treatments. The media transfer technique was performed to induce the RIBE effects on bystander cells. First, LNCaP cells pretreated with phosphate buffered saline (PBS) or GNPs for 24hrs were irradiated with 160kvP X-rays at varying doses (0∼8 Gy). The culture media from irradiated cells were collected and filtered (sterile 0.2µm polyethersulfone) to acquire PBS conditioned media (PBS-CM) and GNP conditioned media (GNP-CM). Then, the collected PBS-/GNP-CMs were transferred to non-irradiated LNCaP cells with/without GNPs for 24hrs to investigate RIBE effect. The final GNP-induced RIBE was evaluated via MTT cellular viability assay, clonogenic assay, γ-H2AX assay, as well as reactive oxygen species (ROS) assessment through 2',7'-dichlorofluorescein diacetate staining.PSMA-targeted GNPs showed minimal cytotoxicity in LNCaP cells up to 1mg/mL concentrations. Cellar uptake analysis demonstrated that GNPs were bound to cells within 30 mins, with maximum uptake at 250µg/mL. Compared to 2 Gy PBS-CM, 8 Gy PBS-CM demonstrated much higher RIBE response on the non-irradiated cells, showing the dose dependent RIBE in LNCaP cells. Compared to PBS-CM, GNP-CM exhibited much higher cell death in MTT assay, as well as demonstrated RIBE enhancement in γ-H2AX (133%) and clonogenic assays (120%) analysis. Moreover, GNP-CM showed elevated ROS expression (125%) than PBS-CM. In the presence of PBS-CM, the non-irradiated cells with GNPs showed increased cell death compared to that without GNPs, indicating that GNP would enhance the sensitivity of bystander cells to RIBE. This sensitivity enhancement ratio was also validated in γ-H2AX (120%) and clonogenic assays (120%).PSMA directed GNPs were associated with physical dose enhancement along with the enhanced RIBE, playing a critical role in increasing the overall radiosensitivity of prostate cancer cells. Our results also showed that PSMA-targeted GNPs enhanced the sensitivity of bystander cells to RIBE.

IMPACT OF CADMIUM TOXICITY ON LEAF AREA AND STOMATAL CHARACTERISTICS IN FABA BEAN

Although changes in stomatal response to elevated doses of cadmium has already been observed in several plants, few studies have focused on this phenomenon in more detail. The effects of different doses of cadmium Cd2+ (50 and 100 mg.kg-1 soil) on leaf area and stomatal characteristics (number of stomata, number of epidermal cells, stomatal index and size of stomata) of faba bean (Vicia faba L. cultivar Aštar) were studied after 15 days of heavy metal treatment. No visual changes on adaxial or abaxial side of leaves of the tested variety of faba bean were found. The leaf area was higher by 14.15 % at lower and by 12.23 % at the higher doses of Cd. The tested doses of Cd did not lead to a change in the number of stomata. The number of epidermal cells was increased on adaxial side by 4.98 % at dose Cd50. Stomatal index was decreased due to the effect of higher dose of cadmium by 11.38 % on adaxial side of leaves. In stomatal widths, decrease by 2.04 % (adaxial side) and 2.26 % (abaxial side) was observed at higher doses of Cd. In stomatal length decrease by 1.85 % was observed at higher dose of Cd on adaxial and decrease by 3.89 % (Cd50) and 4.63 % (Cd100) on abaxial side of leaves respectively. The variations of response could be signals of tolerance or adaptive mechanisms of the leaves of tested bean cultivar under the used concentrations of cadmium.

Effects of Metolazone Administration on Congestion, Diuretic Response and Renal Function in Patients with Advanced Heart Failure.

Background: Advanced heart failure (HF) is a condition often requiring elevated doses of loop diuretics. Therefore, these patients often experience poor diuretic response. Both conditions have a detrimental impact on prognosis and hospitalization. Aims: This retrospective, multicenter study evaluates the effect of the addition of oral metolazone on diuretic response (DR), clinical congestion, NTproBNP values, and renal function over hospitalization phase. Follow-up analysis for a 6-month follow-up period was performed. Methods: We enrolled 132 patients with acute decompensated heart failure (ADHF) in advanced NYHA class with reduced ejection fraction (EF < 40%) taking a mean furosemide amount of 250 ± 120 mg/day. Sixty-five patients received traditional loop diuretic treatment plus metolazone (Group M). The mean dose ranged from 7.5 to 15 mg for one week. Sixty-seven patients continued the furosemide (Group F). Congestion score was evaluated according to the ESC recommendations. DR was assessed by the formula diuresis/40 mg of furosemide. Results: Patients in Group M and patients in Group F showed a similar prevalence of baseline clinical congestion (3.1 ± 0.7 in Group F vs. 3 ± 0.8 in Group M) and chronic kidney disease (CKD) (51% in Group M vs. 57% in Group F; p = 0.38). Patients in Group M experienced a better congestion score at discharge compared to patients in Group F (C score: 1 ± 1 in Group M vs. 3 ± 1 in Group F p > 0.05). Clinical congestion resolution was also associated with weight reduction (−6 ± 2 in Group M vs. −3 ± 1 kg in Group F, p < 0.05). Better DR response was observed in Group M compared to F (940 ± 149 mL/40 mgFUROSEMIDE/die vs. 541 ± 314 mL/40 mgFUROSEMIDE/die; p < 0.01), whereas median ΔNTproBNP remained similar between the two groups (−4819 ± 8718 in Group M vs. −3954 ± 5560 pg/mL in Group F NS). These data were associated with better daily diuresis during hospitalization in Group M (2820 ± 900 vs. 2050 ± 1120 mL p < 0.05). No differences were found in terms of WRF development and electrolyte unbalance at discharge, although Group M had a significant saline solution administration during hospitalization. Follow-up analysis did not differ between the group but a reduced trend for recurrent hospitalization was observed in the M group (26% vs. 38%). Conclusions: Metolazone administration could be helpful in patients taking an elevated loop diuretics dose. Use of thiazide therapy is associated with better decongestion and DR. Current findings could suggest positive insights due to the reduced amount of loop diuretics in patients with advanced HF.

Levocarnitine supplementation for management of hypertriglyceridemia in patients receiving parenteral nutrition.

Levocarnitine deficiency has been observed in patients receiving parenteral nutrition (PN) and can cause or worsen hypertriglyceridemia. The objective was to characterize use of levocarnitine supplementation in PN and evaluate its effect on triglyceride levels in hospitalized adults. This retrospective, single-center study included patients with triglyceride levels ≥175 mg/dl while receiving PN who had a subsequent reduction in lipid injectable emulsion dose. A piecewise linear regression was used to evaluate trends in triglyceride levels before and after the intervention, defined as initiation of levocarnitine in PN for the levocarnitine group, or reduction in lipid injectable emulsion alone for the control group. Two hundred sixty-one patients who received PN had an elevated triglyceride level and lipid injectable emulsion dose reduction, of which 97 (37.2%) received levocarnitine in PN. The median (IQR) levocarnitine dose added to PN was 8.0 (5.7-9.9) mg/kg. Triglyceride levels at 30 days post-intervention did not differ between groups (125 vs 176 mg/dl, P = .345). The addition of levocarnitine to PN was associated with a significantly greater rate of reduction in triglyceride levels pre-intervention to post-intervention compared with a reduction in lipid injectable emulsion alone (-11 vs -3 mg/dl per day; 95% CI, -15 to -2; P = .012). In hospitalized adults with hypertriglyceridemia who had a lipid injectable emulsion dose reduction, the addition of levocarnitine in PN was not associated with a difference in triglyceride levels at 30 days; however, a greater rate of improvement in pre-intervention to post-intervention triglyceride levels was observed.

Low molecular weight heparin prophylaxis for placenta-mediated complications in women with F2G20210A mutation

Introduction. A prothrombin-mutant genotype is a known risk factor in gestational complications.Aim — efficacy assessment in pregravid heparin prevention of pre-eclampsia (PE) and foetal growth retardation (FGR) in females with F2G20210A genotype and suprathreshold prothrombin activity.Patients and methods. A single-centre randomised controlled study enrolled 80 pregnant women carrying prothrombin F2G20210A. The inclusion criterion was a pregravid plasma prothrombin activity &gt; 171 %. The study cohort consisted of 50 women (mean age 31.2 ± 3.7 years) receiving low molecular-weight heparin (LMWH) in menstrual cycle at weight-based elevated prevention doses. A comparison group comprised 30 pregnant women (mean age 31.3 ± 2.9 years) not receiving LMWH prophylaxis.Results. A pregravid start of LMWH treatment at high prophylactic doses in F2G20210A genotype carriers with prothrombin activity &gt; 171 % allowed an absolute risk reduction (ARR) of PE by 46.7 % [p = 0.0001; number needed to treat (NNT): 2.1; 95 % confidence interval (CI) 3.4–1.56], severe PE by 30.7 % [p = 0.0001; NTT: 3.3; 95 % CI (6.7–2.2)] and FGR by 30.7 % [p = 0.0001; NTT: 3.3; 95 % CI (6.7–2.2)].Conclusion. Use of LMWH is justified in prevention of placenta-mediated complications in F2G20210A genotype carriers with a suprathreshold-high prothrombin activity.

PD41-06 EFFECT OF PELVICALYCEAL FLUID VOLUME ON TEMPERATURE ELEVATION AND THERMAL DOSE DURING LASER LITHOTRIPSY

You have accessJournal of UrologySurgical Technology & Simulation: Instrumentation & Technology II (PD41)1 Sep 2021PD41-06 EFFECT OF PELVICALYCEAL FLUID VOLUME ON TEMPERATURE ELEVATION AND THERMAL DOSE DURING LASER LITHOTRIPSY Nikta R. Khajeh, Timothy L. Hall, Khurshid R. Ghani, and William W. Roberts Nikta R. KhajehNikta R. Khajeh More articles by this author , Timothy L. HallTimothy L. Hall More articles by this author , Khurshid R. GhaniKhurshid R. Ghani More articles by this author , and William W. RobertsWilliam W. Roberts More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002051.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: While high-power holmium lasers facilitate successful ureteroscopic treatment of larger and more complex stones, they can also substantially elevate fluid temperatures in the ureter and collecting system potentially causing thermal injury of the adjacent tissue. Fluid volume is an important factor when assessing temperature elevation. The aim of this study was to investigate temperature elevation and thermal dose from laser lithotripsy in model calyces/pelvises spanning a clinically relevant range of fluid volumes. METHODS: Glass bulbs of volumes 0.5, 2.8, 4.0, 7.0, 21.0, and 60.8 mL served as calyx/pelvis models. A single bulb was submerged in a tank of 37˚C deionized (DI) water to simulate core body temperature. A 230 µm core laser fiber extending 5 mm from the tip of a LithoVue ureteroscope was positioned in the center of the model. Irrigation settings of 0, 8, 15, and 40 ml/min with room temperature DI water were used while a P120 Ho:YAG laser was activated for 60 seconds at 40W (0.5 J x 80 Hz, SP). Temperature was measured every second by a thermocouple affixed 5 mm from the tip of the ureteroscope. 5 trials were run under each parameter. Thermal dose was calculated from the temperature curves using the Dewey and Sapareto t43 methodology with t43=120 equivalent minutes accepted as the threshold for thermal injury. RESULTS: The rate of temperature elevation and thermal dose from laser activation were inversely proportional to the volume of fluid in each model and the irrigation rate. The time to threshold for thermal injury was only 3 seconds for the smallest model (0.5 ml) without irrigation, while it was never reached in the largest model (60.8 mL), regardless of irrigation rate (table). 40 ml/min irrigation maintained safe temperatures below the threshold for injury in all models (figure). CONCLUSIONS: Clinicians should be mindful when using high power laser settings in confined calyxes, or tight spaces as heating of small volume fluid to dangerous levels can occur quickly. Source of Funding: Research grant from Boston Scientific © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e682-e683 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nikta R. Khajeh More articles by this author Timothy L. Hall More articles by this author Khurshid R. Ghani More articles by this author William W. Roberts More articles by this author Expand All Advertisement Loading ...

Segmentation of Colombian organic food consumers focused on the consumption of the Andean blackberry

As one of the most traditional Colombian fruits, the Andean blackberry is consumed either fresh or as juice or marmalade. However, recent research findings indicate that farmer and consumer’s health may be at risk owing to elevated doses of agrochemicals applied to produce the crop. Aiming to identify potential market opportunities for organic Andean blackberry, 164 organic consumers were surveyed using the “Gower’s distance” clustering technique for the assessment of 86 consumer response variables. These included consumer preferences associated with the Andean blackberry, the price they were paying for the non-organic product, their willingness to pay for its organic version, and the information they provided on environmental attitudes, perceptions about organic products, lifestyle, demographics, and socioeconomics. Of the three segments obtained from the cluster analysis, namely premium, medium and budget, medium consumers were the most knowledgeable about the benefits of the fruit, whereas those belonging to the budget segment attributed a higher value to money. In turn, premium consumers were willing to pay more for the organic version of the fruit. Regarding organics consumption across the three groups, the budget segment contained the highest number of consumers buying organics every week. The medium segment stood out for their recognition of the Colombian organic certification for ecological foods.

High-Dose Oral Posaconazole for the Treatment of Recalcitrant Fungal Keratitis.

To report the successful treatment of 3 cases of recalcitrant fungal keratitis (FK) with high-dose oral posaconazole. This is a series of 3 patients from a single academic center with a culture-positive FK who were treated with oral posaconazole after failing to respond to conventional treatments. All 3 patients had a history of contact lens wear. Two of the 3 cases were culture positive for Fusarium and the other for Paecilomyces . The infections of all 3 failed to respond to conventional antifungal therapies including varying combinations of topical, systemic, and intraocular antifungal therapies. All 3 cases rapidly responded to high-dose oral posaconazole ranging from 500 to 600 mg once daily. In 1 case, multiple courses of high-dose therapy were required to treat delayed recurrences of a latent infection. There were no significant adverse effects with the elevated dose, and treatment was administered with the guidance of an infectious disease specialist. In cases of recalcitrant FK failing to respond to conventional therapies, high-dose posaconazole, in the delayed-release tablet formulation, can be an effective treatment option.

Inhaled Corticosteroids Increase Risk of Nontuberculous Mycobacterial Lung Disease: A Nested Case-Control Study and Meta-analysis.

Studies on use of inhaled corticosteroids (ICS) and the risk of nontuberculous mycobacterial lung disease (NTM-LD) are limited and have some conflicting results. We recruited 1235 NTM-LD patients and found that ICS use within 1 year was associated with increased NTM-LD, and the risk increased with elevated ICS dose and cumulative duration. Discontinuation of ICS use for more than 120 days could reduce the risk of NTM-LD to an insignificant level. For NTM species, the development of NTM-LD by ICS was highest for Mycobacterium kansasii lung disease. The pooled results of the meta-analysis showed that ICS use might increase the risk of NTM-LD with dose response in medium and high dose of daily ICS. In addition, budesonide had a smaller impact on the risk of NTM-LD than other ICS medications. The present study and meta-analysis provide evidence for ICS adjustment, including dose, discontinuation effect, and medications to possibly reduce the risk of NTM-LD.

COMPARISON OF RADIATION DOSE AND IMAGE QUALITY IN HEAD CT SCANS AMONG MULTIDETECTOR CT SCANNERS.

The present study compares three different multidetector CT (MDCT) scanners for routine brain imaging in terms of image quality and radiation doses. The volume CT dose index (CTDIvol), dose-length product (DLP), and effective dose (E) were calculated. Subjective image assessment was obtained based on a scale ranging from 1 (unacceptable) to 5 (optimum). All images scored 3.5 or over, with the 160-slice MDCT images being favoured. For the 4-, 16- and 160-slice MDCT scanners, the respective median values for CTDIvol were 57 mGy, 41 mGy, and 28 mGy; DLP values were 901 mGy.cm, 680 mGy.cm, and 551 mGy.cm; and effective doses were 2 mSv, 1.5 mSv, and 1 mSv, respectively. Compared to the 160-slice MDCT, the dose values for the 4- and 16-slice units were significantly greater. In practice, the CT modality used must be carefully selected to avoid elevated radiation doses and maintain image quality.

Assessment of Heavy Metals and Related Impacts on Antioxidants and Physiological Parameters in Oil Refinery Workers in Iraq.

Background.Some heavy metals can be harmful to human health in elevated doses such as zinc (Zn) and magnesium (Mg), while others such as lead (Pb), cadmium (Cd), mercury (Hg), and copper (Cu) have harmful consequences to health even in small doses. Heavy metals and additives are incorporated into crude oil to enhance performance.3,4,5 Crude oil is well known to contain heavy metals like Cu, Cd, Ni and Pb.3,6,7Objective.The current study aimed to assess levels of heavy metals and the impact of these metals on antioxidant levels and physiological variables in the serum of oil refinery workers in Iraq.Methods.Heavy metals such as Pb, Cd, Hg, Zn, Cu and Mg were assessed in the serum of a sample of refinery workers (N=40) and a control group (N=20) using atomic absorption spectrometry (AAS). Additionally, levels of malondialdehyde (MDA), δ-aminolaevulinic acid dehydratase (ALAD) and total antioxidant capacity (TAC), and physiological variables such as blood urea, serum creatinine, glutamate-oxaloacetic transaminase (GOT), glutamate-pyruvic transaminase (GPT), and gamma-glutamyl transferase (GGT) were measured to assess impact of these heavy metals.Results.Mercury, Cd, and Pb were significantly elevated in the refinery worker group in comparison with the control group, while the levels of Zn, Cu, and Mg were significantly lower in the refinery worker group compared to the control group. There was a significant difference between the control group and the worker group for most of the antioxidants and functional variables. Total antioxidant capacity (TAC), δ-aminolevulinic acid dehydratase (ALAD), and malondialdehyde (MDA) were significantly lower in the worker group while blood urea, serum creatinine, glutamate pyruvate transaminase (GPT), and gamma-glutamyl transferase (GGT) showed a significant elevation in the workers' group. Glutamic oxaloacetic transaminase (GOT) showed no significant difference between the control group and the worker group.Conclusions.Refinery workers are at increased risk of having higher serum levels of Pb, Cd, and Hg compared to controls which can lead to an increase in oxidative stress, decrease in TAC, and decrease in the essential trace elements Zn, Cu and Mg.Participant Consent.ObtainedEthics Approval.This study was approved by the ethics committee within the Nineveh Health Department, Mosul, Iraq.Competing Interests.The authors declare no competing financial interests.

The incessant increase curve during oral glucose tolerance tests in Chinese adults with type 2 diabetes and its association with gut hormone levels

Glucose curve shapes during oral glucose tolerance tests (OGTTs) are mainly classified as incessant increase, monophasic and biphasic. Youth with an incessant increase curve have worse β-cell function. The aim of this paper was to investigate the incessant increase curve in Chinese adults with type 2 diabetes (T2DM), and its association with β-cell function and gut hormone levels. Eighty-nine Chinese patients (59 males and 30 females) were included in this study with a mean age of 50.56 ± 16.00 years. They were all recently diagnosed with T2DM and underwent 180-min OGTTs. Data on demographics, β-cell function, and insulin sensitivity were also collected. Gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and ghrelin, were also detected during the OGTT. A total of 39.3 % of subjects had an incessant increase in the glucose response curve, while 59.6 % had a monophasic curve. Because only one curve was classified as biphasic, patients with a biphasic curve were omitted from further research. Lower plasma C-peptide, HOMA2-β, area under the curve (AUC) of C-peptide, and ratio of AUC of insulin to AUC of glucose were found in patients with incessant increase curves compared to those with monophasic curves (P < 0.05). Higher glycated hemoglobin (HbA1c) was found in subjects with an incessant increase curve (P < 0.05). Importantly, fasting plasma ghrelin was lower and incremental ghrelin at 120 min was higher in the incessant increase group (P < 0.05), irrespective of age, sex, body mass index (BMI), fasting glucose, and fasting insulin. Time to peak is also a parameter of the OGTT curve shape. In the late-peak group, GLP-1 at 120 min and the AUC of GLP-1 were elevated compared with those in the early-peak group (P < 0.05). In Chinese adults with T2DM, the incessant increase in OGTT shape indicated impaired insulin secretion. Lower fasting ghrelin and absence of ghrelin drops after glucose load may be associated with the incessant increase OGTT shape. In addition, compensatory elevated GLP-1 dose not prevent peak delay in the OGTT curve. Gut hormones may have an effect on OGTT shapes in T2DM adults.

Phase II evaluation of the triple combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16 positive malignancies.

2501 Background: There are more than 630,000 cases of HPV associated malignancies including cervical, oropharyngeal and anal cancer worldwide annually. HPV 16 is responsible for the majority of these cases. About 15-20% of HPV associated malignancies respond to PD-(L)1 inhibitors, but for the overwhelming majority of patients who progress on these immunotherapies there is no effective standard of care therapy. Preclinical studies have shown that the triple combination of PDS0101 (Versamune-HPV), a liposomal multipeptide therapeutic vaccine targeting HPV 16 E6/E7, M9241, a tumor-targeting immunocytokine composed of IL-12 heterodimers fused to a monoclonal antibody targeting free DNA in necrotic tumor regions, and bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, resulted in maximum HPV-specific T cell responses, T cell tumor infiltration and tumor reduction as compared to any one or two of these agents alone. Methods: Fourteen pts with HPV 16+ relapsed or refractory advanced cancer were enrolled to the triple combination of PDS0101, M9241 and bintrafusp alfa (NCT04287868). Pts received bintrafusp alfa at 1200 mg flat dose i.v. every 2 weeks, M9241 at 16.8 mcg/kg s.c. every 4 weeks and PDS0101 given as two separate 0.5 ml s.c. injections every 4 weeks. Dose reductions of M9241 to 8 mcg/kg were allowed as well as skipped doses of any agent for ongoing toxicities. Results: Fourteen pts with advanced HPV 16+ cancers (5 cervical, 2 vaginal/vulvar, 4 anal, 3 oropharyngeal) were treated. 4/14 (28.6%) pts had a grade 3 treatment related toxicity including grade 3 hematuria in 2 pts with cervical ca and prior pelvic radiation and grade 3 AST/ALT elevation in 2 pts, one with anal ca and one with vaginal ca. For one patient with grade 3 AST/ALT elevation dose reduction of M9241 from 16.8 to 8 mcg/kg allowed for continued treatment with AST/ALT remaining at grade 1 or less. One additional patient had transient asymptomatic grade 4 neutropenia. No other treatment related grade 3 or greater toxicities were noted. 10/14 (71%) pts have had objective responses: 1 CR (anal ca) and 9 PRs (3 cervical, 2 vulvar/vaginal, 2 anal, 2 oropharyngeal) with 9/10 of these responses ongoing after a median 5 month of follow up. Of the 14 pts, 6 pts have checkpoint naïve disease and 8 pts have checkpoint refractory disease. 5/6 (83%) pts with checkpoint naïve disease and 5/8 (63%) pts with checkpoint refractory disease have had objective responses. Analyses of immune responses and other immune correlates are ongoing. Conclusions: Triple combination of PDS0101, M9241 and bintrafusp alfa appears to have a manageable safety profile along with early evidence of notable clinical activity for pts with both checkpoint naïve as well as checkpoint refractory HPV 16+ advanced malignancies. Clinical trial information: NCT04287868.

Successful Multiorgan Donation From a Brain-dead Donor Following Liquid Nicotine Voluntary Intoxication: A Case Report.

Successful Multiorgan Donation From a Brain-dead Donor Following Liquid Nicotine Voluntary Intoxication: A Case Report.

Cardiovascular dysfunction risk in young adults with congenital adrenal hyperplasia caused by 21-hydroxylase enzyme deficiency.

The association of congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase enzyme (21OHase) deficiency, duration of treatment and dosage with cardiovascular dysfunction in young adults remains unclear. We aimed to evaluate myocardial function, vascular structures and epicardial fat thickness in young adults with CAH as a result of 21OHase deficiency. Correlations between the duration and dose of glucocorticoid therapy and cardiovascular parameters were analysed. This case-control study of young adults (18-31years old) included 20 patients (5 men and 15 women) and 16 control subjects (8 men and 8 women). Echocardiographic analysis was performed using high-resolution ultrasound. No ultrasonographic changes in any indices of myocardial function, vascular structures and epicardial fat thickness were found in patients, except for an impaired left ventricular end-diastolic diameter in female patients (28.1±1.6 vs 26.0±2.4mm/m2 , P=.021), compared with those in individuals in the control group. Nevertheless, the individual patient values were within the normal range. Multiple linear regression analysis in female patients demonstrated that an elevated daily dose of glucocorticoids correlated with increased indices of left ventricular posterior wall thickness (Partial r=0.68, P=.007), left ventricular end-diastolic diameter (Partial r=0.62, P=.017), aortic diameter (Partial r=0.60, P=.022) and left carotid artery intima-media thickness (Partial r=0.61, P=.021), independently of treatment duration. No signs of cardiovascular dysfunction were observed in any patient. The daily dose of glucocorticoids may play a role in the mechanisms of some markers of cardiac hypertrophy, left ventricular and aortic dilation and subclinical atherosclerosis.

Assessment of Heart Rate Variability in Children with Cancer after Elevated Cumulative Anthracycline Dose: A Prospective Study

Objective: Anthracyclines which are the main drug of chemotherapy protocols had cardiotoxicity as the most frequent and well-known side effect. We aimed to evaluate prospectively the heart rate variability with 24-hour Holter electrocardiography (ECG) in children with cancer who treated with anthracycline drugs. Material and Methods: The 24-hour Holter ECG monitoring was performed at the baseline, at time of 120 mg/m 2 and ≥240 mg/m 2 of cumulative anthracycline dose in patients with cancer who treated with anthracycline. The time-domain and frequency-domain measurements of heart rate variability (HRV) were obtained. The patients were classified into three groups as Group1:at baseline (n=54), Group 2:≥120mg/m 2 (n=54), Group 3:≥240mg/m 2 (n=54). Results: The median age was 48 months (range 9-192 months). All types of cancer were 38 patients (70.4%) of acute leukemia, two patients (3.8%) of T lymphoblastic lymphoma, and 14patients (25.8%) of other childhood cancer who treated with anthracycline. However, all heart rate variability parameters were decreased after each increased cumulative anthracycline dose, especially time-domain parameters such as nSDNN index, rMSSD, pNN50, frequency parameters such as LF, HF, and Total power were significantly altered among Group1 and Group 3. LF/HF ratio was also statistically significantly increased in Group 3. According the heart rate parameters, the mean average heart rate, mean minimum heart rate and mean RR were statistically significantly prolonged from Group1 to Group 3. Conclusion: Heart rate variability parameters are a noninvasive technique to demonstrate cardiac autonomic neural dysfunction and early myocardial injury. The 24-hour Holter ECG may be used for detecting early cardiac dysautonomia effect during anthracycline treatment with each elevated 120mg/m 2 anthracycline of cumulative dose.

Sustained release of peptides and proteins from polymeric nanocarriers produced by inverse Flash NanoPrecipitation

Peptide and protein therapeutics generally exhibit high potency and specificity and are increasingly important segments of the pharmaceutical market. However, their clinical applications are limited by rapid clearance and poor membrane permeability. Encapsulation of the peptide or protein into a nano-scale carrier can modify its pharmacokinetics and biodistribution. This might be employed to promote uptake in desired cell types or tissues, to limit systemic exposure, or to reduce the need for frequent injections. We have recently described inverse Flash NanoPrecipitation (iFNP), a scalable technique to encapsulate water-soluble therapeutics into polymeric nanocarriers, and have demonstrated improvements in therapeutic loading of an order of magnitude over comparable approaches. Here, we describe the formulation parameters that control release rates of encapsulated model therapeutics polymyxin B, lysozyme, and bovine serum albumin from nanocarriers produced using iFNP. Using a neutropenic lung infection mouse model with a multi-drug resistant Acinetobacter baumannii clinical isolate, we demonstrate enhanced therapeutic effect and safety profile afforded by nanocarrier-encapsulated polymyxin B following pulmonary administration. The encapsulated formulation reduced toxicity observed at elevated doses and resulted in up to 2.7-log10 reduction in bacterial burden below that of unencapsulated polymyxin B. These results establish the promise of iFNP as a platform for nanocarrier delivery of water-soluble therapeutics.