Control Infusion Research Articles

Sodium Intermetallics Enable Stable Sodium Plating and Stripping

Sodium-based secondary batteries are emerging as promising complements and potential alternatives to lithium-ion batteries due to their analogous working mechanism but the greater availability of sodium precursors and the other elements making up the cathodes. Sodium metal batteries (SMBs) hold considerable promise due to the high theoretical capacity (1165 mAh g-1) of the metal anode and the associated low plating/stripping potential. Unfortunately, the metal dendrite growth and an associated unstable solid electrolyte interphase (SEI) prevail with SMBs in a wide range of electrolytes. Creating sodiophilic surfaces to promote metal wetting during deposition and simultaneously reduce the nucleation/growth overpotentials has been proven to be highly effective. In this work, a rapid annealing process is employed to fabricate chalcogen (sulfur, tellurium) intermetallic coated commercial copper foam (CF) as stable hosts for Na metal anodes, termed “S@CF” and “Te@CF”. These sodiophilic substrates demonstrate significantly improved sodium wettability, reduced plating/stripping overpotentials, and Coulombic efficiency (CE) in half-cell configurations. Symmetric cells made of Te@CF with thermally infused Na (Te@CF-TNa) showed stable cycling up to 7000 hours and full cells with Te@CF-TNa anodes and Na3V2(PO4)3 (NVP) cathodes give significantly improved rate capability (up to 30C) and cycling (>10000 cycles at 5C and 10C). Moreover, a prototype of a controllable Na thermal infusion process was proposed for the first time. Post-mortem analysis using cryogenic FIB-SEM (Cryo-EM) indicates that the early-stage electrodeposition behavior plays an important role in dictating the later-state electrochemical stability of the metal anodes. Sodium metal electrodeposits uniformly on the surface of Te@CF, resulting in dense and largely pore-free metal. By contrast, electrodeposition on the baseline uncoated CF collector results in filament-like sodium metal dendrites interspersed with pores and a solid electrolyte interphase (SEI). Density functional theory (DFT) and mesoscale calculations provide combined insights into the relationship between the substrate-metal interaction and the nucleation response, describing the underlying mechanisms that tailor an improved Na deposition morphology on the Te@CF substrate.

OA01 A case report of a patient with Type 1 diabetes mellitus and systemic lupus erythematosus: a management dilemma

Abstract Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. Up to 30% of patients with SLE will develop other autoimmune conditions. A few cases of SLE and Type 1 Diabetes Mellitus (T1DM) have been reported in literature. Corticosteroids which is key in induction therapy increases the risk of hyperglycemia and hypertension. Other immunosuppressive agents such as mycophenolate mofetil used in management of lupus nephritis increase the risk of hyperglycemia. This poses a challenge in the management of SLE in a patient with T1DM. Aim To describe a management dilemma in caring for a child with T1DM and SLE at a tertiary referral teaching hospital in Nairobi, Kenya. Method Retrospective chart review of a child with T1DM and SLE at Aga Khan University Medical College East Africa, Nairobi, Kenya. Results We discuss a 16-year-old male patient with T1DM since nine years of age on insulin and on follow up in the endocrine clinic. He presented with complaints of facial and lower limb swelling of three days and severe frontal headache associated with nausea for one day. He was also noted to have a strong family history of Sjogren’s disease and diabetes. His initial examination revealed hypertension with a blood pressure of 184/118 mmHg, facial and lower limb oedema. He was commenced on labetalol infusion and amlodipine for blood pressure control, and was to continue with his insulin regimen. Initial urinalysis showed proteinuria and hematuria. An impression of hypertensive emergency with nephropathy was made. Rheumatology review was requested. Investigations revealed an ANA titer of > 1:1280; anti-smith and anti dsDNA antibodies were positive; low C3 and low C4. Echo showed pleural effusion. The kidney biopsy showed features of proliferative lupus nephritis class IV with no features of diabetic nephropathy. A diagnosis of SLE was made and management initiated with hydroxychloroquine, methylprednisolone for three days then oral prednisolone and mycophenolate mofetil. During methylprednisolone therapy, the patient was noted to have unrecordably high blood glucose necessitating an insulin infusion for six days and close adjustment of insulin doses by the endocrinologist. Initially, after the 1st dose of methylprednisolone, his blood pressure seemed to improve. During the course of treatment, his blood pressure was elevated and difficult to control despite being on labetalol infusion, amlodipine, enalapril and carvedilol. Adjustment of antihypertensive drug doses and addition of hydralazine were made by the nephrologist, cardiologist and critical care specialist. He was eventually discharged with controlled blood glucose and blood pressure. He is currently doing well and is on follow up in the nephrology, rheumatology and endocrinology clinics. Conclusion Our case report highlights the challenges that arise while managing patients with SLE and other illnesses such as T1DM. It also points out the necessity of multi-disciplinary care. This may be a challenge in many African health facilities due to a low number of specialized doctors.

Https://medcraveonline.com/JACCOA/anesthetic-and-hemodynamic-management-in-patients-with-different-approaches-for-multiple-neurological-pathologies-case-report.html

Purpose: To evaluate the impact of three different effect-site concentrations of remifentanil [1.0, 2.0 and 2.5 ng.ml-1] on cough, heart rate and systolic blood pressure during extubation after balanced anesthesia with desflurane or sevoflurane. Design: Double-blinded controlled trial. Setting: Operating room. Patients: ASA I-II adults (n=451) who underwent elective procedures. Interventions: Subjects were randomly assigned to maintain remifentanil effect-site concentrations at 1.0, 2.0 and 2.5 ng.ml-1 by a target control infusion system after receiving balanced general anesthesia with remifentanil and sevoflurane vs. desflurane. Measurements: Cough severity (using a four-point intensity scale), heart rate and systolic blood pressure were registered during eye opening, tracheal extubation and 2.5 minutes after. Main Results: Cough was significantly reduced in all groups of remifentanil at 2.0 and 2.5 ng.ml-1 during eye opening, tracheal extubation and 2.5 minutes after, when compared with 1.0 ng.ml-1 [Risk ratio (95% CI) at tracheal extubation 0.35 (0.23-0.53) and 0.33 (0.21-0.52) for desflurane; 0.50 (0.35-0.73) and 0.45 (0.30-0.73) for sevoflurane, respectively. P < 0.001]. There were no significant differences on heart rate or systolic blood pressure values at these time points for any of the studied groups. Conclusion: In adult patients of elective procedures under balanced general anesthesia with sevoflurane or desflurane, maintaining a remifentanil effect-site concentration at 2.0-2.5ng.ml-1 significantly reduce the risk of cough but not hemodynamic responses during tracheal extubation.

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

A randomized controlled study to compare the dose requirement of oxytocin for management of uterine atony in patients receiving prophylactic phenylephrine during caesarean delivery

Background & Aims: Most common side effect of subarachnoid block during caesarean delivery is postspinal hypotension which can lead to increased maternal and neonatal morbidity and mortality. Phenylephrine has been shown to be effective in preventing commonly encountered hypotension associated with spinal anesthesia (60% to 70%) in obstetric patients and has become the vasopressor of choice. The following study was conducted to compare the dose requirement of intravenous oxytocin between patients receiving an infusion of prophylactic intravenous phenylephrine to those receiving a saline control infusion under spinal anesthesia in patients undergoing caesarean delivery. Material & Methods: It was a double-blinded, randomized controlled study having 48 subjects in test and control arm each. Results: The mean oxytocin dose administered was higher in the phenylephrine group than in the control group (6.1 ± 2.7 (IU) vs. 5.2 ± 2.3 IU, respectively). The proportion of patients who required a secondary uterotonic agent was higher in the phenylephrine intervention group (22% vs. 8%, respectively). Conclusion: Obstetricians and anesthesiologists must pay close attention to uterine tone for patients receiving a phenylephrine infusion for the prevention of postspinal hypotension and the increased dose requirement of oxytocin. Future multicentric studies are required to further establish the effects of continuous infusion as found in our study.

Intermetallics Based on Sodium Chalcogenides Promote Stable Electrodeposition–Electrodissolution of Sodium Metal Anodes

AbstractSodiophilic micro‐composite films of sodium‐chalcogenide intermetallics (Na2Te and Na2S) and Cu particles are fabricated onto commercial copper foam current collectors (Na2Te@CF and Na2S@CF). For the first time a controllable capacity thermal infusion process is demonstrated. Enhanced wetting by the metal electrodeposition leads to state‐of‐the‐art electrochemical performance. For example, Na2Te@CF‐based half‐cells demonstrate stable cycling at 6 mA cm−2 and 6 mAh cm−2, corresponding to 54 µm of Na electrodeposited/electrodissolved by geometric area. Sodium metal batteries with Na3V2 (PO4)3 cathodes are stable at 30C (7 mA cm−2) and for 10 000 cycles at 5C and 10C. Cross‐sectional cryogenic focused ion beam (cryo‐FIB) microscopy details deposited and remnant dissolved microstructures. Sodium metal electrodeposition onto Na2Te@CF is dense, smooth, and free of dendrites or pores. On unmodified copper foam, sodium grows in a filament‐like manner, not requiring cycling to achieve this geometry. Substrate–metal interaction critically affects the metal–electrolyte interface, namely the thickness and morphology of the solid electrolyte interphase. Density functional theory and mesoscale simulations provide insight into support‐adatom energetics, nucleation response, and early‐stage morphological evolution. On Na2Te sodium atomic dispersion is thermodynamically more stable than isolated clusters, leading to conformal adatom coverage of the surface.

Foliar spraying tea infusion decreases selenium uptake of Cyphomandra betacea in selenium‐contaminated soil

AbstractSelenium (Se) is one of the essential trace elements for human, but the Se deficiency of most areas resulting in low a Se content in fruits. To increase the Se uptake in fruit trees, the effects of foliar spraying four types of tea (black, green, white, and dark) infusions on the growth and Se uptake of Cyphomandra betacea were studied using a pot experiment. The white and dark tea infusions increased the biomass, superoxide dismutase activity, and catalase activity of C. betacea, while the black and green tea infusions had no significant effects. The green, white, and dark tea infusions increased the contents of photosynthetic pigments in C. betacea, the while the black tea infusions had no significant effects. The black, white, and dark tea infusions increased the peroxidase activity of C. betacea, while the green tea infusion decreased. All tea infusions increased the potassium (K) content in aboveground part of C. betacea and phosphorus (P) content in leaves to some extent. The different tea infusions decreased the Se contents in roots and shoots of C. betacea. Compared to the control, the black, green, white, and dark tea infusions decreased the Se contents in shoots by 16.67%, 27.30%, 33.33%, and 40.07%, respectively. Correlation analysis showed that the contents of P and K were negatively correlated with the Se content. Therefore, foliar spraying tea infusion can decrease the Se uptake in C. betacea, and the white and dark tea infusions can promote C. betacea growth.

Effect of common OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 polymorphisms on perioperative analgesic and propofol demands on patients subjected to thyroidectomy surgery

BackgroundPerioperative anesthetic and/or analgesic demand present considerable variation, and part of that variation appears to be genetic in origin. Here we investigate the impact of common polymorphisms in OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 genes, on the intra-operative consumption of remifentanil and propofol, as well as the postoperative analgesic needs, in patients subjected to thyroidectomy surgery.MethodsWe conducted a prospective cohort study with 90 patients scheduled to undergo elective thyroidectomy, under total intravenous anesthesia achieved by target control infusion (TCI) of propofol and remifentanil. Postoperative analgesics were administered by protocol and on-demand by the individual patient. Genotyping was established by PCR–RFLP methods. Genotyping data, intra-operative hemodynamics, and total consumption of remifentanil and propofol, as well as postoperative analgesic needs and pain perception, were recorded for each individual.ResultsPatients with the ABCB1 3435TT genotype appeared to experience significantly less pain within one hour post-operatively, compared to C carriers [mean VAS (SD) = 0.86 (1.22) vs. 2.42 (1.75); p = 0.017], a finding limited to those seeking rescue analgesic treatment. Intra-operatively, homozygotes patients for the minor allele of OPRM1 A118G and CYP2B6 G516T appeared to consume less remifentanil [mean (SD) = 9.12 (1.01) vs. 13.53 (5.15), for OPRM1 118GG and A carriers] and propofol [median (range) = 14.95 (11.53, 1359.5) vs. 121.4 (1.43, 2349.4), for CYP2B6 516TT and G carriers, respectively] but the difference was not statistically significant in our sample.ConclusionsThe ABCB1 C3435T polymorphism appears to affect the postoperative perception of surgical pain among patients with low pain threshold. The small number of minor allele homozygotes for the OPRM1 A118G and CYP2B6 G516T polymorphisms precludes a definitive conclusion regarding the inclusion of the latter in a TCI-programming algorithm, based on the results of this study.Clinical trial registration numberACTRN12616001598471.

Investigation of in-line filter replacement intervals for infusion

In-line filters in peripheral and central venous catheters are used to mechanically remove bacterial cells. A recent study indicated the extension of the use of infusion sets to seven days. There is no evidence regarding replacement intervals for in-line filters. We tested in-line filters that were continuously used for seven days for ability to remove bacteria as well as flow rate. Three different in-line filters were attached to an ELNEOPA-NF No.2® premixed infusion bag of intravenous hyperalimentation, into which Staphylococcus epidermidis ATCC12228 or Escherichia coli ATCC25922 was inoculated. These experiments were compared with a control infusion. The infusion was dropped at a flow rate of 40 mL/h and replaced at 24-h intervals for seven days. Samples were collected 24 h after drop initiation. S. epidermidis was not detected in droplets between Days 1 and 6, while in-line filters 1 and 2 showed droplets containing 6-10 CFU/mL on Day 7. E. coli was not detected in any of the filters. Flow rates below 40 mL/h were observed on Day 7 in in-line filter 3 in studies of S. epidermidis, and on Days 4 and 3 in in-line filters 2 and 3, respectively, in studies of E. coli. Our study revealed differences in bacterial removal and flow rate under high inoculation among each of three tested in-line filters. We suggest the continuous use of in-line filters for a maximum of six days, while reductions in flow rate after 48 h of continuous use should be carefully noted.

A Case of Sphingobacterium multivorum Bloodstream Infection in a Critically-Ill Patient.

Sir, Sepsis in intensive care units (ICUs) is common in immunocompromised individuals; herein, we discuss with the help of a case of sepsis due to Sphingobacteriummultivorum in an uncontrolled diabetic individual. A 40-year-old male with poorly controlled diabetes mellitus presented to our ICU with right thigh cellulitis and diabetic ketoacidosis (DKA). Subsequently, he developed inferior wall myocardial infarction and right ventricular dysfunction. On examination, he was in altered sensorium, hemodynamically unstable, and had respiratory distress. He was managed for all the above-mentioned issues, which comprised management of DKA and acute coronary syndrome (dual anti-platelets, heparin, statins) and included life support therapies in the form of invasive mechanical ventilation, central line placement, IV fluid resuscitation (guided by two-dimensional echocardiography, lung ultrasonography, and hemodynamic and oxygenation parameters), vasoactive drugs and other drugs such as anti-platelets, therapeutic heparinization, and IV insulin infusion for glycemic control (with emphasis on electrolytes also). The patient stayed in ICU for a prolonged period due to neuromuscular weakness, nosocomial infections, and ischemic cardiomyopathy. Later on, he developed a grade III sacral bedsore also. One of the bugs was S. multivorum cultured from his peripheral blood during an episode of high-grade fever. S. multivorum is a rare but important cause of bloodstream infection in critically ill populations. The bacterium is categorized under the genus Sphingobacterium (formerly known as Flavobacterium) are nonfermenting, catalase and oxidase positive, nonmotile, nonspore-forming Gram-negative rod, naturally found in soil, water, and plant materials.[1] Their nomenclature is secondary to the presence of large quantities of cellular sphingolipids. These rarely cause human diseases, but still, there are certain case reports about their association with infections like respiratory tract infections in patients with cystic fibrosis, soft-tissue infections, septicemia in hemodialysis patients, and meningitis.[2] The two species most commonly implicated are S. spiritivorum and S. multivorum. These are commonly found as commensals on human skin and predispose immunocompromised individuals to infections. However, there are case reports published about Sphingobacterium leading to cellulitis in an immunocompetent person also. In this patient, the isolate was S. multivorum which had led to bacteremia after 6 weeks of ICU stay. To our knowledge, this is the third rare case from India regarding S. multivorum infection in health-care settings. The probable source could have been the grade IV infected sacral bedsore. The bacterium was sensitive to piperacillin/tazobactam and levofloxacin and was resistant to ceftazidime, amikacin, imipenem, carbapenem, and aztreonam. The patient was also sensitive to trimethoprim/sulfamethoxazole (TMP/SMX) and was treated with (TMP/SMX). Sensitivity to other antibiotics was not done. The sensitivity profile of S. multivorum in some case reports depicts in Table 1.Table 1: Sensitivity of sphingobacterium multivorum isolates in case reportsThe information given in our case may be helpful in broadening our knowledge about infections with such bacteria. As these bacteria are rarely causative, though they have the capability to cause infection in immunocompetent individuals, hence these bacteria cannot be fully ignored. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

176: DILTIAZEM VERSUS METOPROLOL FOR ATRIAL FIBRILLATION WITH RAPID VENTRICULAR RATE IN THE ED

Introduction: Atrial fibrillation (AF) is the most prevalent persistent cardiac arrhythmia observed in clinical practice and the most common dysrhythmia treated by EM physicians. Due to the side effect profile of the two pharmacotherapeutic treatment methods (rate vs rhythm), rate control is considered the primary approach in most patients. According to the 2014 AHA/ACC/HRS guideline for patients with AF, both beta-blockers and non-dihydropyridine calcium channel blockers are recommended with the same level of evidence. Methods: This was a retrospective chart review of patients who came into the ED with AF with RVR. Patients included were administered oral diltiazem, IV diltiazem, and/or IV metoprolol for HR control. If patients didn’t meet any exclusion criteria, they were randomized to the study groups 1:2:2. The primary outcome measured was the percentage of patients with heart rate (HR) < 110 bpm within two hours post medication administration. Secondary outcomes included percentage of patients with HR < 110 bpm in four hours post medication administration, HR at 5 minutes, 15 minutes, 30 minutes, 1 hour, and 2 hours post medication administration, number of doses needed to achieve HR < 110 bmp, need for continuous rate control infusion, and need for administration of antiarrhythmic medications. Safety was assessed through the incidence of SBP < 90 and HR < 60. Kruskal-Wallis Test was performed to compare clinical endpoints. An alpha value of ≤ 0.05 was considered statistically significant. Results: Eighty-five patients were included in the study analysis. The primary outcome didn’t differ between the groups (56.3% oral diltiazem, 36.5% IV diltiazem and 46.1% IV metoprolol, p= 0.27, H statistic 2.613). The secondary outcome of percentage of patients with heart rate < 110 bpm four hours post medication administration did not differ between the groups (63.9% oral diltiazem, 48% IV metoprolol and 36.5% IV diltiazem, p= 0.074, H statistic 5.2026). There was a total of 14 times safety outcomes were experienced between the three groups. Conclusions: There was no difference between treatment groups in the percentage of patients with heart rate < 110 bpm two hours post medication administration. Further studies are needed to evaluate oral diltiazem in this setting compared to intravenous rate control therapy.

Abstract 11274: VERVE-101—An Investigational Single-Course Gene Editing Medicine Targeting PCSK9—Durably and Potently Lowers PCSK9 and LDL-C Concentrations in Non-Human Primates

Introduction: VERVE-101 is an in vivo CRISPR base editing therapy designed to alter a single DNA base in the PCSK9 gene, permanently inactivate hepatic expression, and thereby durably lower LDL cholesterol (LDL-C). Here, we test the efficacy, tolerability, and potential for germline editing of VERVE-101 in studies of 43 non-human primates. Methods: Cynomolgus monkeys were dosed with a single intravenous infusion of a vehicle control (N = 10) or VERVE-101 at a dose of 0.75 mg/kg (N = 4) or 1.5 mg/kg (N = 22) with subsequent assessment of liver PCSK9 editing, reductions in blood PCSK9 and LDL-C, and safety parameters. A second study evaluated sexually mature male non-human primates dosed with a vehicle control (N = 1) or 1.5 mg/kg of VERVE-101 (N=6) to assess for any germline cell editing. Results: Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg respectively. This translated into reductions in blood PCSK9 of 69% and 89% and reductions of LDL-C of 50% and 68% at the 0.75 and 1.5 mg/kg doses, respectively, measured one year after dosing ( Figure). Liver safety monitoring noted a transient rise in ALT and AST concentrations following infusion that fully resolved by day 14 with no accompanying change in total bilirubin. VERVE-101 did not impact glucose homeostasis, as assessed by serial monitoring of fasting glucose and hemoglobin A1c. In the study to assess germline editing, VERVE-101 was similarly well tolerated and no editing of PCSK9 was observed in sperm samples obtained 90 days after dosing. Conclusions: A single intravenous infusion of VERVE-101 in non-human primates was well-tolerated and led to 89% lower blood PCSK9 protein and 68% lower blood LDL-C at one year after dosing. These results support initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease, with initial patient dosing anticipated in mid-2022.

Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models.

VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study. Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu). Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals. VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.

Effect of arginine supplementation on the production of milk fat in dairy cows.

Arginine, one of the conditionally essential AA, has been reported to affect fat synthesis and metabolism in nonruminant animals by influencing adenosine monophosphate activated protein kinase (AMPK) in some organs. In dairy cows, the effect of Arg on milk fat production is not clear, and any potential mechanism that underlies the effect is unknown. We tested the hypothesis that Arg infusion would improve the production of milk fat, and explored possible mechanism that might underlie any effect. We used 6 healthy lactating cows at 20 ± 2 d in milk, in fourth parity, with a body weight of 508 ± 14 kg, body condition score of 3.0 ± 0, and a milk yield of 30.6 ± 1.8 kg/d (mean ± standard deviation). The cows were blocked by days in milk and milk yield and each cow received 3 treatments in a replicated 3 × 3 Latin square design, with each of the experimental periods lasting 7 d with a 14-d washout between each period. The treatments, delivered in random order, were (1) infusion of saline (control); (2) infusion of 0.216 mol/d of l-Arg in saline (Arg); (3) infusion of 0.868 mol/d of l-Ala in saline (the Arg and Ala treatments were iso-nitrogenous) through a jugular vein. On the last day of each experimental period, blood was sampled to measure insulin, nitric oxide, glucose, and nonesterified fatty acid, and the liver and mammary gland were biopsied to measure the expression of genes. Milk yield was recorded, and milk fat percentage was measured daily during each of the experimental periods. The yield and composition of fatty acid (FA) in milk was measured daily on the last 3 d during each of the experimental periods. The data were analyzed using a mixed model with treatment as a fixed factor, and cow, period, and block as random factors. The daily milk yield and milk fat yield when the cows were infused with Arg were 2.2 kg and 76 g, respectively, higher than that in control, and 1.8 kg and 111 g, respectively, higher than that in Ala. When the cows were infused with Arg they had higher concentration and yield of de novo synthesized FA, than when they received the control or Ala infusions, although milk fat percentage, daily feed intake, and the digestibility of nutrients were not affected by treatment. The serum concentration of nitric oxide and insulin were higher during Arg than during control or Ala, with no difference between control and Ala. In the liver, the expression of the genes coding for AMPK (PRKAA1, PRKAB1, and PRKAG1) and genes related to the oxidation of FA were higher during Arg than during control or Ala, whereas in the mammary gland the expression PRKAB1 was lowest, and the expression of genes involved in the synthesis of milk fat were highest, during Arg infusion. The results suggest the intravenous infusion of Arg enhanced the production of milk fat by promoting the de novo synthesis of FA and increasing milk yield.

Abstract P307: A Case Of Dual Tachycardia Presenting With Heart Failure Exacerbation

Dual tachycardia (DT) is the occurrence of simultaneous supraventricular tachycardia and ventricular tachycardia/fibrillation (VT/VF). With increasing interest in this uncommon arrhythmia due to difficulties with diagnosis and complexity of management, DT is identified in about 9% of double-chamber ICD interrogation. An 81 year old male with history of hypertension, ischemic cardiomyopathy status-post BiV AICD presented to ED with worsening exertional dyspnea, orthopnea and pedal edema. He was tachycardic (140 bpm) with bibasilar rales. BNP 655 pg/mL, cardiomegaly and pulmonary edema on chest x-ray. EKG revealed atrial fibrillation (AF) with rapid ventricular response. Echocardiogram revealed a reduced left ventricular ejection fraction &lt;20%. He was diuresed with furosemide, diltiazem infusion for rate control and heparin for anticoagulation. During admission, he developed two episodes of monomorphic VT in VF zone and was successfully cardioverted. During the initial episode, he was in AF and had a VT triggered by PVC which was successfully cardioverted to BiV Paced rhythm. However, he remained in AF which was converted to sinus rhythm after a second cardioversion. A repeat EKG revealed sinus rhythm with BiV paced rhythm. He was later transitioned to oral metoprolol, amiodarone to maintain rhythm control and apixaban. Dual tachyarrhythmia can be managed with medical therapy and/or catheter ablation. The termination of the trigger AF/PVC has been shown to reduce the recurrence of VT/VF episodes. Rhythm control for AF with antiarrhythmic therapy can reduce AF and PVC burden, improve BiV pacing, prevent ICD shocks and help reduce heart failure exacerbation.

Involvement of neurosteroids in the control of prolactin secretion in sheep under basal, stressful and pregnancy conditions

Prolactin (PRL) secretion by the anterior pituitary (AP) is responsive to changes in physiological conditions and many external factors that also affect brain neurosteroid levels. This study tested the hypothesis that neurosteroids can affect PRL secretion in sheep under basal, stressful and advanced pregnancy conditions. In Experiment 1, luteal-phase sheep were subjected to a three-day series of intracerebroventricular (icv.) control (n = 12) or allopregnanolone (AL, 4 × 15 μg/60 μL/30 min at 30-min intervals, n = 12) infusions. Acute stressful stimuli, isolation and partial movement restriction were applied on the third day of infusion to half of the animals in each group. In Experiment 2, pregnant sheep were subjected to a three-day series of icv. control (n = 6) or finasteride (4 × 25 μg/60 μL/30 min at 30-min intervals, n = 6) infusions during the 16th week of pregnancy. As a result, the relative abundance of PRL transcript increased in the AP of luteal-phase sheep treated with stress, AL and AL in combination with stress (P < 0.05 - P < 0.01) compared to controls. The level of PRL mRNA in stressed-AL-treated sheep was higher (P < 0.01) than in sheep only subjected to stress. The PRL protein content in the AP decreased in stressed-only sheep compared to controls (P < 0.05) and increased in stressed-AL-treated sheep compared to controls and other groups (P < 0.05 - P < 0.01). Plasma PRL concentration increased (P < 0.05 - P < 0.01) in stressed-only sheep compared to controls; AL infusion counteracted the stress-induced increase in PRL levels (P < 0.05 - P < 0.01) and had no effect in non-stressed animals. Inhibition of neurosteroid synthesis in the brain of pregnant sheep by finasteride caused transient increases (P < 0.05 - P < 0.001) in plasma PRL concentration compared to controls. In conclusion, the presented results indicate a bimodal effect of AL on PRL secretion in sheep: first at the molecular level – stimulation of PRL mRNA expression; second – inhibition of hormone release from pituitary lactotrophs. Both AL activities may involve various mechanisms regulating PRL secretion. In general, cerebral neurosteroids can affect the supply of pituitary PRL in the body under certain conditions, such as stress and pregnancy.

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.

781-P: Progressive Acceleration of Insulin Exposure over Seven Days of Infusion Set Wear

Insulin exposure and action are known to differ on each of 3 days of infusion set wear during CSII. We extend these observations to 1 week in a pilot phase study comparing conventional Teflon angled infusion sets to a prototype extended wear set using Capillary Biomedical SteadiFlow™ technology. Participants with T1DM for &amp;gt;12 months, A1C &amp;lt;8.5%, c-peptide &amp;lt;0.6 nmol/L, and ≥6 months use of Medtronic model 530G or higher were enrolled in a 2-period crossover euglycemic clamp study; clamps were performed after fasting overnight stabilization with IV insulin. Five men and 2 women, mean duration of diabetes 22.5 (16.6 SD) years and mean BMI 27.6 (3.8 SD) kg/m2 were enrolled; 4 completed all 8 clamps, 2 completed 7 clamps and 1 completed 1 clamp. We present the pharmacokinetic profiles of insulin lispro, 0.15 U/kg delivered by bolus infusion on Days 0, 3, 5 and 7 of infusion set wear. The Figure shows aggregate results from Control and Investigational infusion sets for insulin concentration (mean±SEM) vs. time by day of set wear. Statistically significant decreases from Day 0 to Day 7 were seen for tmax (p≤0.001) , t50% (early) (p&amp;lt;0.002) , t50% (late) (p&amp;lt;0.001) , and Mean Residence Time (p&amp;lt;0.001) . AUC0-300 declined by approximately 20% from Day 0 to Day 7 (p&amp;lt;0.11) . These results confirm and extend previous observations showing significant progressive acceleration of insulin exposure as a function of duration of infusion set wear time. Disclosure T.S.Bailey: Advisory Panel; Abbott Diabetes, CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Consultant; LifeScan, Sanofi, Research Support; Abbott Diabetes, Abbott Diagnostics, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Livongo, MannKind Corporation, Medtronic, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita Medical, Senseonics, ViaCyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker's Bureau; Becton, Dickinson and Company, Medtronic, Sanofi. J.R.Kastner: Consultant; Capillary Biomedical, Inc. P.Strange: Other Relationship; Capillary Biomedical, Inc., Stock/Shareholder; Capillary Biomedical, Inc. L.Shi: None. K.A.Oberg: Consultant; Beta Bionics, Inc., Companion Medical, Tandem Diabetes Care, Inc. J.I.Joseph: Advisory Panel; Capillary Biomedical, Inc., Stock/Shareholder; Capillary Biomedical, Inc. P.J.Strasma: Board Member; Capillary Biomedical, Inc., Employee; Capillary Biomedical, Inc., Stock/Shareholder; Capillary Biomedical, Inc. D.B.Muchmore: Consultant; Capillary Biomedical, Inc., Diasome, Zucara Therapeutics, Stock/Shareholder; Capillary Biomedical, Inc., Diasome. Funding National Institutes of Health (2R44DK110969-02)

Bolus versus continuous insulin infusion in immediate postoperative blood glucose control in liver transplantation: pragmatic clinical trial.

ABSTRACTObjective:To analyze the effectiveness and safety of two insulin therapy techniques (continuous and intermittent infusion) in the blood glucose control of people who have undergone liver transplantation, in the immediate postoperative period.Methods:The study was a prospective, open, pragmatic clinical trial with 42 participants, divided into two groups of 21 patients each, in the immediate postoperative period following liver transplantation. Participants in the Experimental Group and Control Group received continuous infusion and bolus insulin, respectively, starting at capillary blood glucose ≥150mg/dL.Results:There were no statistically significant differences in the blood glucose reduction time to reach the target range between the Experimental Group and Control Group in the transplanted patients (p=0.919). No statistically significant differences regarding the presence of low blood glucose (p=0.500) and in the initial blood glucose value (p=0.345) were found. The study identified the final blood glucose value in postoperative intensive care unit lower and statistically significant in the continuous infusion pump group in relation to the Bolus Group (p<0.001). Additionally, the variation of blood glucose reduction was higher and statistically significant in the continuous method group (p<0.05).Conclusion:The continuous infusion method was more effective in the blood glucose control of patients in the postoperative period following liver transplantation.Brazilian Registry of Clinical Trials:RBR-9Y5tbp

Dynamic Pressure Measurements During Vitrectomy in a Model of the Eye.

PurposeTo accurately evaluate pressure changes during vitrectomy in a rigid model of the vitreous chamber and to test the efficiency of the EVA phacovitrectomy system (Dutch Ophthalmic Research Center) in terms of compensation of intraocular pressure variations.MethodsWe tested 23-, 25-, and 27-gauge double-blade vitreous cutters in both vented global pressure control and automatic infusion compensation (AIC) modes in a vitreous chamber model, mimicking the real surgical procedure. Balanced salt solution and artificial vitreous, similar to the real vitreous body, were used. We tested both standard-flow (SF) and high-flow (HF) infusion systems, varying the infusion pressure between 20 and 40 mm Hg. In each experiment, flow rate was also measured.ResultsPressure drop was rapidly and efficiently compensated when 23- and 25-gauge cutters were used in AIC mode, with infusion pressures ranging between 30 and 55 mm Hg. The 27-gauge cutter was less efficient in compensating pressure variations. Pressure fluctuations related to the high-frequency motion of the cutter blade were small compared to the overall pressure variations. The use of the HF infusion system resulted in larger flow rates and lower pressure changes compared to the SF infusion system.ConclusionsDespite the rigid material of the model, the present pressure measurements are in line with previous studies performed on porcine eye. The use of AIC mode compensates intraoperative pressure drops efficiently, with both 23- and 25-gauge cutters. The HF infusion system is more efficient than the SF infusion system.Translational RelevanceThe AIC infusion mode efficiently compensates intraoperative pressure drops, in both 23- and 25-gauge experimental vitrectomy. The HF infusion system resulted in larger flow rate and lower pressure changes.