Frequency Titration Research Articles

Take Control. Period. - Needs Assessment Leading to the Development of a Digital Quality Improvement Intervention Designed to Enhance Adherence to Tranexamic Acid and Iron Supplementation in Women with Heavy Menstrual Bleeding

Introduction Heavy menstrual bleeding (HMB) affects up to 51% of all women and 93% of those with bleeding disorders. It is essentially universally associated with iron deficiency +/- anemia (ID/IDA), resulting in substantial fatigue and reduced quality of life. Despite the large body of evidence to support the use of tranexamic acid (TXA) in reducing HMB, in the real world, many patients report difficulty taking this medication on a consistent basis. Adherence to oral iron supplementation is similarly poor, despite its seemingly straightforward use. Our goal was to further understand the problem of adherence to these oral medications in women with HMB and to begin developing a potential digital solution. Methods We performed a retrospective practice audit of an outpatient hematology clinic between November, 2018 and January, 2019 to determine the baseline adherence to prescribed TXA and oral iron in women with HMB. We then conducted a root-cause-analysis to identify common themes affecting medication adherence and opportunities for patient education. Key contributing factors were determined based on quality improvement (QI) team brainstorming, practice audit, qualitative survey of patients and practitioners, and review of literature. Results There were 252 clinical encounters with women ≤55 years-old during this time frame. Of these, 85 involved active management of HMB, with 47 cases already prescribed TXA. Only including days with ≥2 patients on TXA, the median adherence rate per clinic was 33%. There were 114 encounters involving management of ID/IDA due to HMB, with 57 already on oral iron. The median adherence rate per clinic with ≥2 patients on oral iron was 40%. Common barriers to TXA adherence identified by the patient/practitioner survey included: need to take at least two large tablets three times per day during bleeding; premature cessation of TXA due to the perception of it interfering with "normal" blood loss; high cost of oral TXA; difficulty with dose and frequency titration; common side effects including nausea, diarrhea, and headache; concern regarding the potential thromboembolic risk of TXA, and the synergistic thromboembolic risk with TXA and estrogen based therapies. Common concerns with oral iron were: difficulty managing gastrointestinal side effects; not taking iron on an empty stomach or with acidic foods/beverages; cessation of therapy before iron stores are replete; forgetting to take doses; and high cost of polysaccharide and heme-based iron supplements. Conclusions HMB negatively impacts the quality of life and productivity of women of reproductive age. There is a robust body of evidence supporting TXA and iron supplementation in this context. Despite best efforts at counselling on proper utilization of these agents in clinic, baseline adherence was only 33% to TXA and 40% to oral iron. We identified numerous barriers to adherence that are amenable to QI initiatives. Using these results, we have begun to develop a multimodal, interactive website for women with HMB to improve adherence to TXA and oral iron, called "Take Control. Period." Future steps will be to evaluate changes in adherence to TXA and oral iron per patient per clinic week prospectively after digital intervention implementation. Disclosures Sholzberg: Novartis: Honoraria; Amgen: Honoraria, Research Funding.

Tumour Treating Fields (TTFields) have anti-proliferative effects on paediatric brain tumour cell lines at clinically deliverable field settings

Approximately 400 children in the UK are diagnosed with a CNS tumour each, which represents a quarter of childhood cancer cases in the UK. The overall 5-year survival rate of peadiatric brain tumour patients is roughly 75%, however survival still remains poor for some brain tumours, particularly high grade gliomas. Pre-clinical studies have shown efficacy of TTFields on high grade glioma cell lines, while TTFields have only been approved for adult Glioblastoma multiforme (GBM) patients in combination with the Stupp treatment protocol. The lack of overlapping toxicities associated with OptuneTM has made TTFields an attractive treatment strategy for poor prognosis brain tumours. The InovitroTM system is the laboratory testing system used to develop the clinically approved Optune system. InovitroTM was used to deliver TTFields over 72 hours at a range of clinically relevant frequencies (100-400kHz) and intensities (1-3V/cm) to a panel of paediatric GBM, Medulloblastoma and Ependymoma cell lines. The effects of TTFields on cell viability and cell cycle was assessed using metabolic viability tests (Presto blue), cell proliferation assays and cell cycle analysis using flow cytometry. TTFields treatment reduces cell viability of all paediatric brain tumour cell lines tested within the frequency titration. The optimum frequencies were between 200 and 300kHz for all cell lines tested. TTFields treatment had significant effects on cell cycling relative to control cells. This preliminary study has confirmed the efficacy of electric fields on paediatric brain tumour cell lines. The optimum frequencies for the paediatric GBM cell lines did not uniformly fall into the 200kHz range as previously reported for glioma cell lines. This report warrants further study into the potential for TTFields therapy for paediatric patients.

Abstract 5361: In vitro results and electric fields simulations suggest Tumor Treating Fields (TTFields) to be an effective treatment against Mesothelioma

Abstract Mesothelioma is an aggressive cancer affecting the membrane lining of the lungs and abdomen, and is associated with poor prognosis. Current available treatment options for Mesothelioma, including surgery, radiation therapy and chemotherapy, offer only modest improvement in survival, therefore emphasizing the desperate need for new treatment options. Tumor Treating Fields (TTFields) is a treatment modality based on non-invasive application of low intensity intermediate frequency alternating electric fields that disrupt mitosis. The goal of the present work was to determine whether TTFields in combination with standard of care drugs, could serve as an effective treatment against Mesothelioma. TTFields were applied to Mesothelioma cell cultures using the inovitro system. Cytotoxicity and effect on clonogenicity were determined following 72 hours of TTFields treatment. Combination index (CI) was calculated for the treatment of TTFields with each of the following drugs: Paclitaxel, Cisplatin, Pemetrexed and Vinorelbine. Finite Element Mesh (FEM) simulations were performed using the Sim4life software package (ZMT, Zurich, Switzerland) for the calculations of the electric fields intensities in the mesothelium of a realistic human computational phantom. Frequency titration experiments revealed 150 kHz to be the optimal TTFields frequency for Mesothelioma cell cultures, leading to 69% reduction in the number of cells (p<0.001) and 78% reduction in clonogenicity (p<0.05) as compared to control. The combined treatment of TTFields with Paclitaxel, Cisplatin, Pemetrexed and Vinorelbine resulted in combination index of 0.99, 0.88, 1.29 and 1.13, respectively. FEM simulations demonstrated that electric field intensities within the mesothelium are approximately 2 V/cm RMS which is above the minimal threshold required for TTFields effect. Taken together, these results suggest that combining TTFields therapy with systemic chemotherapy may be an approach that offers enhanced treatment efficacy for Mesothelioma. A clinical study testing the combined efficacy of TTFields Cisplatin and Pemetrexed is under development. Citation Format: Moshe Giladi, Mijal Munster, Roni Blat, Rosa Schneiderman, Yaara Porat, Zeev Bomzon, Noa Urman, Tali Voloshin, Eilon David Kirson, Uri Weinberg, Yoram Palti. In vitro results and electric fields simulations suggest Tumor Treating Fields (TTFields) to be an effective treatment against Mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5361. doi:10.1158/1538-7445.AM2015-5361

Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.

Effects of pulse amplitude, pulse frequency, and stimulus duration on seizure threshold: a laboratory investigation.

Stimulus intensity during electroconvulsive therapy (ECT) is reckoned in units of charge (mC). The values of pulse amplitude, pulse width, pulse frequency, and stimulus duration can be varied to yield different composite stimuli, all of which have the same charge. There is little information on the extent to which variations in these stimulus parameters influence the seizure threshold at constant charge in the context of ECT. We administered once daily electroconvulsive shocks (ECS) to two groups of rats, starting with a stimulus intensity of 1 mC and increasing in 1 mC steps until the thresholds of each of three different types of seizure were identified. In one group (n = 10), the charge was raised first by increasing pulse amplitude and later by increasing pulse frequency. In the other group (n = 10), the charge was raised by increasing the stimulus duration only. The mean seizure threshold ranged from 8.4 to 11.4 mC, depending on the type of seizure described, in the group in which pulse amplitude and frequency were manipulated; this range was 2.5 to 5.5 mC in the group in which the stimulus duration was manipulated (p < 0.001 for each of three types of seizures). Rats (n = 7) that did not convulse with an 8-mC stimulus in the amplitude and frequency group all convulsed with a 5-mC stimulus from the stimulus duration schedule. The first manifestation of seizure activity was significantly less likely to be generalized with amplitude and frequency titration than with stimulus duration titration (20% vs. 90%, respectively). The mean motor seizure durations (at different thresholds) were comparable with the two methods of stimulus titration. Seizure thresholds are lower when stimulus duration is the parameter that is increased during dose titration. The many clinical implications of this finding require study.

Dose and frequency titration of somatostatin analogues in the treatment of acromegaly - an injection of expediency?

Dose and frequency titration of somatostatin analogues in the treatment of acromegaly - an injection of expediency?

The Relative Efficiency of Altering Pulse Frequency or Train Duration When Determining Seizure Threshold

In 12 depressed inpatients referred for bilateral electroconvulsive therapy (ECT), each patient was titrated at the first treatment session by using an ascending method-of-limits procedure with a step-wise increase in pulse frequency (frequency titration) or train duration (duration titration). At the second treatment session, seizure threshold was redetermined by using the method (frequency or duration titration) not used at the first treatment. Frequency or duration was maintained at the lowest level when the other parameter was titrated. Seizure threshold was significantly lower with duration titration (mean, 90 mC; SD, 27.3) than frequency titration (mean, 114 mC; SD, 35.6; p = 0.03). On average, patients in the duration-titration group required 1.2 (SD, 0.6) subconvulsive stimulations before a seizure was elicited, and patients in the frequency-titration group required 1.7 (SD, 0.9) subconvulsive stimulations before a seizure was elicited, a nonsignificant difference. These findings suggest that to elicit a seizure during ECT, increasing train duration may be slightly more efficient than increasing frequency. Basic and other clinical research findings indicate that increasing pulse width may be an inefficient way to elicit a seizure. Therefore the following sequence in the determination of seizure threshold is worth considering when using dose-titration or related techniques: the train duration should be increased first before increasing pulse frequency, and the decision to increase pulse width should be reserved for patients who do not seize at the maximal duration and frequency settings. Further empiric research is needed to establish the utility of this approach.

Parametric Changes in Response Equilibrium During an Intra-cranial Self Stimulation (ICSS) Task: Can Reward Value be Assessed Independently of Absolute Threshold?

EASTERLING, K.W. AND S.G. HOLTZMAN. Parametric changes in response equilibrium during an intra-cranial self stimulation (ICSS) task: can reward value be assessed independently of absolute threshold? NEUROSCI BIOBEHAV REV 21(1) 55–65, 1997.—Traditional ICSS methodologies have attempted to evaluate changes in the rewarding value of brain stimulation by assessing the lowest value of the stimulation that will support responding. However, orderly changes in supra-threshold indicants of hedonic magnitude such as titration point have been shown. In the present experiments, rats were trained to respond on two ICSS autotitration schedules in which every response on one lever produced stimulation of the medial forebrain bundle, and every Xth response decreased either the stimulation current or the stimulation frequency. At any time, a response on a second “reset” lever restored the stimulation current or frequency available on the stimulation lever to its starting level and operationally defined changes in “reward value”. In order to study this titration point measure, two response requirements (responses/stepdown; step size) and two stimulation parameters (initial stimulation level; train duration) were systematically varied. Under both current and frequency titration schedules, data indicated that response rate and titration point remained stable over repeated trials and multiple testing days—parameters being constant. Across all conditions, compared to the frequency titration schedule, subjects responding under the current titration schedule showed significantly higher titration points and lower rates of responding. Indicating the independence of rate and titration point data, parametric manipulations did not affect titration point and rate data concurrently. Results support the conclusion that titration point is a relative measure of “reward value” that is generally independent of response rate, but that is affected by manipulations that alter the amount of stimulation available between “resets”. Additional work is needed in order to determine the relationship between the magnitude of stimulation needed to maintain minimal responding and that needed to maintain response equilibrium in an autotitration task. Copyright © 1996 Elsevier Science Ltd.

High frequency titration of polyelectrolytes

High frequency titration of polyelectrolytes

Apparatus for the recording of automatic high frequency titrations

A new type of oscillometer made from a series of solid state circuits suitable for automatic titration and recording is described. The apparatus is simple and easy to build in the laboratory. The output potential of the recorder is obtained by unbalancing a differential amplifier. A peak, having height proportional to the frequency of the oscillating circuit is obtained at each addition of the reagent, added by means of an electric burette. The two branches of the titration curve are obtained by joining the tops of the peaks. Reactions of precipitation, neutralization, complexation and oxidation-reduction were carried out in order to check the apparatus. The system has been shown to permit a good reproducibility of results even at long time intervals. The system developed has been directed furthermore to automatic continuous monitoring of remote laboratory and pollution control.

Apparatus for the recording of automatic high frequency titrations

Summary A new type of oscillometer made from a series of solid state circuits suitable for automatic titration and recording is described. The apparatus is simple and easy to build in the laboratory. The output potential of the recorder is obtained by unbalancing a differential amplifier. A peak, having height proportional to the frequency of the oscillating circuit is obtained at each addition of the reagent, added by means of an electric burette. The two branches of the titration curve are obtained by joining the tops of the peaks. Reactions of precipitation, neutralization, complexation and oxidation-reduction were carried out in order to check the apparatus. The system has been shown to permit a good reproducibility of results even at long time intervals. The system developed has been directed furthermore to automatic continuous monitoring of remote laboratory and pollution control.

Zur halogenaddition an cyclopentadien

By means of high frequency titration, the effects of conductivity for the intermediates of electrophilic addition of halogen to cyclopentadiene in different solvents and solvent mixtures have been determined. Based on the change of conductivity and in the case of the addition of bromine derived from the analysis of products, the experiments characterizes the intermediate state and the function of counter-ion in the concurrence-reactions of addition and polymerization.

A paper chromatographic investigation of the thiourea complexes of copper(I) silver(I) and gold(I)

Several thiourea complexes of formula M 1Tu x A (M I = Cu(I), Ag(I) and A = ClO 4, BF 4, CF 3COO, CH 3COO or HCOO; or M 1 = Au(I) and A = ClO 4, BF 4, CF 3COO, Cl or Br; Tu = thiourea) were prepared; the maximum Tu:M ratio is 3:1 for Cu(I) and Ag(I) and 2:1 for Au(I). The same maximum of 3:1 is observed on high frequency titration of the Ag(I) salts with thiourea in methyl cellosolve. Some of these complexes, undecomposed and in compact spots, may be eluted on chromatographic paper with a mixture of ketones and an aqueous solution of the corresponding sodium salt, or with a mixture of alcohols and an aqueous solution of the corresponding free acid. The Tu:M ratio is 5:2 for Cu(I) perchlorate and fluoroborate in ketones, while it is always 2:1 for the other complexes of Cu(I), Ag(I) and Au(I), irrespective of the anion, the solvent and the amount of aqueous solution in the mixture. The composition of the eluted complexes was determined by a radiochemical method after exchange with 35S-labelled thiourea. The R F values of the eluted complexes depend on the anion, the solvent and the amount of aqueous solutions in the mixture.

Aluminium(III)-iminodiacetic acid complexes in 0·M sodium perchlorate medium

Complex formation by aluminium(III) and iminodiacetic acid has been investigated in a constant ionic strength medium (0·5M NaClO 4) at 25°C by means of potentiometric titrations with a glass electrode. In the same ionic medium and temperature over all formation constants of the acid have been determined. log β 1L=9·17±0·01 log β 2L=11·73±0·01 log β 3L=13·49±0·01 At pH between 2 and 3·5 and in the chosen concentration ranges (2·43 ⩽ C M ⩽ 7·29 mM; 1·57 ⩽ C L ⩽ 12·7 mM) the experimental data can be explained by the formation of two mononuclear complexes according to the equilibria: Al 3++L 2−⇋AIL + log β 1=8·10±0·012 Al 3++2L 2−⇋AIL 2 − log β 2=15·07±0·03. The stochiometric ratio of these equilibria are in agreement with the data obtained from high frequency titrations.

Direkter nachweis der ionaren zwischenstufe bei der elektrophilen bromaddition an olefine

By means of high frequency titration, the “effects of conductivity” for the intermediates of electrophilic addition of bromine to olefinic compounds in polar solvents and solvent mixtures have been determined. The change of conductivity depends on solvation by the different solvents. The results characterize the intermediate of the reaction as an equilibrium between ion pairs and self-solvated ions.

High frequency titration methods in the investigation of complex formation

High frequency titration is a valuable tool in the study of complex formation in solutions, and the breaks in the titration curves can be used, in conjunction with the results of other physical methods, to determine the composition of the complexes formed. High frequency titration and other methods have been used to study the complexes formed by thorium, indium, plutonium(V) and boron with various complexing agents, and to develop methods for the determination of thorium and yttrium in rare earth mixtures, and of indium in the presence of zinc, cadmium, aluminium, nickel and cobalt.

High frequency titrations of polydicarboxylic acid copolymers: Polyitaconic acid‐Co‐styrene and polymaleic acid‐Co‐styrene

AbstractA useful method, more rapid and more accurate than elemental analysis, has been developed to determine the composition of copolymers of itaconic anhydride and maleic anhydride with styrene. The method involves a high frequency titration of the sample. The method can also be used to detect traces of acidic impurities in polymers and in the identification of mixtures of similar acidic copolymers. Titration indicates that the acid segments in the copolymers of itaconic acid–styrene, maleic acid–styrene, and the homopolymer polyitaconic acid act as dibasic acids. The method appears to have a sensitivity that permits identification and approximate resolution of two carboxylate species in the same polymer.

Determination of some cations by high frequency titration technique using potassium chromate as precipitant

Estimations of lead, barium, thallium and silver have been carried out in aqueous or ethanol-water media using a 30 Mc. unit. It has been found that lead and barium can be estimated by both direct and reverse titrations in aqueous medium. In case of silver and thallium (I), the addition of an equal volume of ethanol or methanol to the solution to be titrated was found essential for accuracy and reproducibility. Limits of tolerance for some ionic constituents which are frequently associated with these cations have also been determined. Thallium has been estimated by both direct as well as reverse titrations, but in case of silver, reverse titrations gave low results. The method requires much less time for the estimations as compared to other methods and the results fall within the ordinary limits of accuracy required.

A novel instrument for dielectric measurements with applications to chemical analysis

A novel instrument for the measurement of dielectric constant, loss and conductivity at high frequencies is described. It can be used for high frequency titrations and in other chemical applications. With cells of specific design measurements can be made up to = 100 and tan δ = 0.25 at a frequency of 3 Mc/s. The method is moderately simple as it depends on the phase characteristic of a patented auxiliary tuned circuit controlling an oscillator. Measurements are easily made and the instrument has been used to introduce automatic methods into distillation and extraction processes.

A study of some solvents as media for the high frequency titration of weak acids

Six solvents, with different basicities and dielectric constants, were studied to determine their suitability as media for high frequency (HF) titrations of weak acids. There is no definite correlation between the slopes of the HP response and conductance curves and the two properties, dielectric constant or basicity, of the solvent. The apparent strength of the acid or base in these solvents is not due to any single solvent property but it is a combination of the properties of the solute and the solvent. In general, from this and other papars, solvents with relatively high dielectric constants and very weakly basic properties are most likely to be successful solvents for non-aqueous HF and conductance titrations.