Use of the Ferroelectric Ceramic Bismuth Titanate as an Ultrasonic Transducer for High Temperatures and Nuclear Radiation.

Ultrasonic transducers are often used in the nuclear industry as sensors to monitor the health and process status of systems or the components. Some of the after-effects of the Fukushima Daiichi earthquake could have been eased if sensors had been in place inside the four reactors and sensed the overheating causing meltdown and steam explosions. The key element of ultrasonic sensors is the piezoelectric wafer, which is usually derived from lead-zirconate-titanate (Pb(Zr, Ti)O3, PZT). This material loses its piezoelectrical properties at a temperature of about 200 °C. It also undergoes nuclear transmutation. Bismuth titanate (Bi4Ti3O12, BiTi) has been considered as a potential candidate for replacing PZT at the middle of this temperature range, with many possible applications, since it has a Curie-Weiss temperature of about 650 °C. The aim of this article is to describe experimental details for operation in gamma and nuclear radiation concomitant with elevated temperatures and details of the performance of a BiTi sensor during and after irradiation testing. In these experiments, bismuth titanate has been demonstrated to operate up to a fast neutron fluence of 5 × 1020 n/cm2 and gamma radiation of 7.23 × 1021 (gamma/cm2). The results offer a perspective on the state-of the-art for a possible sensor for harsh environments of high temperature, Gamma radiation, and nuclear fluence.

State-of-the-Art and Practical Guide to Ultrasonic Transducers for Harsh Environments Including Temperatures above 2120 °F (1000 °C) and Neutron Flux above 1013 n/cm2.

In field applications currently used for health monitoring and nondestructive testing, ultrasonic transducers primarily employ PZT5-H as the piezoelectric element for ultrasound transmission and detection. This material has a Curie-Weiss temperature that limits its use to about 210 °C. Some industrial applications require much higher temperatures, i.e., 1000-1200 °C and possible nuclear radiation up to 1020 n/cm2 when performance is required in a reactor environment. The goal of this paper is the survey and review of piezoelectric elements for use in harsh environments for the ultimate purpose for structural health monitoring (SHM), non-destructive evaluation (NDE) and material characterization (NDMC). The survey comprises the following categories: 1. High-temperature applications with single crystals, thick-film ceramics, and composite ceramics, 2. Radiation-tolerant materials, and 3. Spray-on transducers for harsh-environment applications. In each category the known characteristics are listed, and examples are given of performance in harsh environments. Highlighting some examples, the performance of single-crystal lithium niobate wafers is demonstrated up to 1100 °C. The wafers with the C-direction normal to the wafer plane were mounted on steel cylinders with high-temperature Sauereisen and silver paste wire mountings and tested in air. In another example, the practical use in harsh radiation environments aluminum nitride (AlN) was found to be a good candidate operating well in two different nuclear reactors. The radiation hardness of AlN was evident from the unaltered piezoelectric coefficient after a fast and thermal neutron exposure in a nuclear reactor core (thermal flux = 2.12 × 1013 ncm-2; fast flux 2 (>1.0 MeV) = 4.05 × 1013 ncm-2; gamma dose rate: 1 × 109 r/h; temperature: 400-500 °C). Additionally, some of the high-temperature transducers are shown to be capable of mounting without requiring coupling material. Pulse-echo signal amplitudes (peak-to-peak) for the first two reflections as a function of the temperature for lithium niobate thick-film, spray-on transducers were observed to temperatures of about 900 °C. Guided-wave send-and-receive operation in the 2-4 MHz range was demonstrated on 2-3 mm thick Aluminum (6061) structures for possible field deployable applications where standard ultrasonic coupling media do not survive because of the harsh environment. This approach would benefit steam generators and steam pipes where temperatures are above 210 °C. In summary, there are several promising approaches to ultrasonic transducers for harsh environments and this paper presents a survey based on literature searches and in-house laboratory observations.

Longitudinal Evaluation of Noninvasive Biomarkers for Eosinophilic Esophagitis.

BACKGROUND: The diagnosis and management of eosinophilic esophagitis (EoE) often requires multiple endoscopies. Serum biomarkers can be elevated in EoE patients, but their clinical utility in diagnosis and assessing response to treatment is not well established. GOALS: To evaluate serum biomarkers in EoE subjects compared with controls and assess longitudinally in response to treatment. STUDY: We conducted a prospective cohort study of children and adults undergoing esophagogastroduodenoscopy for suspected EoE. After completing an 8-week course of proton-pump inhibitor therapy, esophageal mucosal biopsies were obtained, as well as, serum analysis of absolute eosinophil count (AEC), eotaxin-3, eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP) and interleukin-5. Subjects with normal endoscopic and histologic findings constituted controls. Those meeting criteria for EoE underwent repeat esophagogastroduodenoscopy and biomarker measurements following treatment with topical steroids for 8 weeks. RESULTS: Median levels of AEC (263.50 vs. 102 cu/mm, P<0.001), ECP (26.98 vs. 5.20 ng/mL, P<0.001) and EDN (31.70 vs. 14.18 ng/mL, P=0.004) were significantly elevated in EoE subjects compared with controls and correlated with esophageal eosinophilia. Levels of AEC (odds ratio, 1.79; 95% confidence interval, 1.28-2.64) and ECP (odds ratio, 1.61; 95% confidence interval, 1.23-2.36) were associated with a diagnosis of EoE. Among the 5 biomarkers evaluated, only AEC significantly predicted esophageal eosinophilia following topical steroid therapy in EoE subjects (P=0.006). CONCLUSIONS: AEC, ECP, and EDN were higher in EoE subjects compared with controls and correlated with degree of esophageal eosinophilia. Furthermore, AEC predicted post-treatment eosinophilia, suggesting a potential role in monitoring EoE disease activity.

Retrospective Evaluation of Drug-Drug Interactions With Erlotinib and Gefitinib Use in the Military Health System.

Background: Erlotinib and gefitinib are epidermal growth factor receptor-tyrosine kinase inhibitors approved for non-small cell lung cancer treatment by the US Food and Drug Administration. Drug-drug interactions (DDIs) with these agents are vague and poorly understood. Because DDIs can have an effect on clinical outcomes, we aimed to identify drugs that interact with erlotinib or gefitinib and describe their clinical manifestations. Methods: A retrospective analysis was performed on the health records of patients in the US Department of Defense Cancer Registry (retrieved September 2021), Comprehensive Ambulatory/Professional Encounter Records, and Pharmacy Data Transaction Service database (both retrieved May 2022). Patients' medical history, diagnoses, and demographics were extracted and analyzed for differences in adverse effects when these agents were used alone vs concomitantly with other prescription drugs. Patients' diagnoses and prescription drug use were extracted to compare completed vs discontinued treatment groups, identify medications commonly co-administered with erlotinib or gefitinib, and evaluate DDIs with antidepressants. Results: Of 387 patients using erlotinib, 264 completed treatments; 28 of 33 patients using gefitinib completed treatment. The P value for erlotinib discontinuation when used alone vs concomitantly was < .001, and the P value for gefitinib discontinuation was .06. Patients who took erlotinib or gefitinib concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 1 to 75 prescription drugs, and those in the completed group were prescribed 3 to 103. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment. Conclusions: This review cannot conclude that concomitant use with prescription drug(s) resulted in erlotinib or gefitinib discontinuation. There were no significant DDIs determined between erlotinib or gefitinib and antidepressants.

Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine.

Objective: To evaluate drug-drug interactions (DDIs) between gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs). Methods: In vitro supersomes were used to identify CYP isoenzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) involved in drug metabolism, and in vitro pooled cryopreserved primary human hepatocytes were employed to investigate DDIs. Results: The isoenzymes that showed drug degradation are listed in parentheses beside the respective drug: gefitinib (CYP2D6, 3A4, 1A2, 2C9, and 2C19), losartan (CYP2C9 and 3A4), citalopram (CYP2D6, 2C19, 3A4, and 2C9), fluoxetine (CYP2D6, 2C9, and 2C19), fluvoxamine (CYP2D6, 2C9, and 2C19), paroxetine (CYP2D6, 3A4, and 2C9), sertraline (CYP2D6, 2C9, 2C19, 1A2, and 3A4), and venlafaxine (CYP2D6 and 2C19).DDIs from human hepatocytes assays revealed that gefitinib had significant metabolic changes in (1:1) combination with paroxetine or sertraline (p-value â€‹= â€‹0.042 and 0.025 respectively) and (1:1:1) combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline (p-value â€‹= â€‹0.009, 0.027, 0.048, and 0.037 respectively). Losartan showed significant changes in (1:1:1) combination with gefitinib and fluoxetine or sertraline (p-value â€‹= â€‹0.026 and 0.008 respectively). Fluoxetine, fluvoxamine, and paroxetine underwent significant changes in (1:1:1) combination with gefitinib and losartan (p-value â€‹= â€‹0.003, 0.022, and 0.046 respectively). Sertraline had significant changes within all combinations: DDIs with gefitinib alone and in combination with gefitinib and losartan (p-value â€‹= â€‹0.009 and 0.008 respectively). Citalopram and venlafaxine appeared to be unaffected by any combination. Conclusion: The study provides a clear proof-of concept for in vitro metabolic DDI testing. While identifying compounds by their inhibition potential can help better predict their metabolism, it cannot resolve problems that arise from DDIs since the overall degree of effectiveness is unknown. As shown in this study, gefitinib has been identified as a weak CYP2C19 and 2D6 inhibitor, however, gefitinib can have significant DDIs with sertraline. Furthermore, multiple drug combinations (1:1:1) can change the significance of previously determined DDIs in (1:1) combination. Thus, in vitro assays can potentially provide better guidance for multidrug regimens with minimal risk for DDIs.

The use of dried blood spot cards to assess serologic responses of individuals vaccinated against measles, hepatitis A, tetanus, influenza and varicella zoster.

Traditional blood sampling by venipuncture is cumbersome and relatively expensive. Dried blood spot (DBS) sampling is desirable because of its ease of sample collection, transportation and storage. It has been used in clinical diagnosis but not been thoroughly studied for the potential use to assess the immune status of individuals following natural infection or preventive vaccination. The goal of this study was to compare DBS to traditional blood samplings in detection of antibodies in individuals vaccinated against measles, hepatitis A, tetanus, influenza and varicella zoster. Enzyme linked immunosorbent assay (ELISA) was used to test DBS eluates and serum samples for antibodies against measles, varicella, tetanus and hepatitis A. Sensitivities, specificities, and correlation coefficients were evaluated to compare optical density (OD) values of paired serum and DBS samples. The long-term stability of DBS samples at different temperatures was assessed using simulated immune measles blood. DBS OD was highly correlated with serum OD for antibodies to measles (r = 0.93), varicella (r = 0.82), and tetanus (r = 0.91). Sensitivities of DBS OD ranged from 86-99% and specificities ranged from 96-100% using cut-offs established by each assay. By contrast, the hepatitis A data showed a low sensitivity (31%) and weak correlation (r = 0.14) between DBS and serum samples. Antibody titers in serum samples for anti-influenza A (H1N1 and H3N1) failed to correlate in DBS eluates in HAI and MN assays. DBS samples were stable for 4 weeks when stored at room temperature and for 6 months at 4°C. DBS sampling was sensitive, specific, and highly correlated with traditional venipuncture sampling in detection of antibodies against measles, tetanus and varicella zoster, but not hepatitis A and influenza. Thus, the success of using DBS sampling to assess the antibody levels in immunized individuals may be dependent on the pathogens and the development of the assay used.

Pre-clinical drug-drug interaction (DDI) of gefitinib or erlotinib with Cytochrome P450 (CYP) inhibiting drugs, fluoxetine and/or losartan.

OBJECTIVE: To evaluate drug-drug interactions (DDIs) between gefitinib or erlotinib with fluoxetine, and/or losartan. METHODS: Human pooled microsomes, supersomes, and cryopreserved human hepatocytes were used to monitor DDIs in vitro. RED (Rapid Equilibrium Dialysis) protein binding was employed to investigate other pharmacokinetics. RESULTS: Gefitinib is significantly metabolized by Cytochrome P450 (CYP) 2D6 and CYP3A4, with less than 80% of the drug remaining. Erlotinib is significantly metabolized by CYP3A4, CYP2D6, and CYP1A2. Although gefitinib and erlotinib were metabolized by the same CYP isoenzymes, the metabolites formed from degradation of the two drugs were different.Fluoxetine inhibited CYP2D6 and CYP3A4 metabolism of gefitinib with an IC50 of 65.12 ± 1.88 µM and 4.11 ± 2.26 µM, respectively. Fluoxetine also inhibited CYP2D6 and CYP3A4 metabolism of erlotinib with an IC50 of 7.06 ± 1.54 µM and 4.57 ± 1.22 µM, respectively.For hepatocytes, fluoxetine affected the metabolism of gefitinib or erlotinib, while losartan had no effect. Gefitinib and erlotinib inhibited the metabolism of fluoxetine and losartan. Two-drug combinations involving gefitinib or erlotinib with fluoxetine or losartan yielded insignificant (p-value ≥ 0.05) differences in metabolism. However, combinations involving three drugs yielded significant degrees of inhibition (p-value ≤ 0.05). Three drug combinations involving fluoxetine and losartan with gefitinib or erlotinib yielded significant degrees of inhibition of the metabolism of gefitinib, but not for that of erlotinib. CONCLUSION: As could be predicted by previous studies involving the inhibitory effect of fluoxetine on CYP3A4 and CYP2D6, and studies involving CYP metabolism of gefitinib and erlotinib, the tests performed here confirmed that fluoxetine has an inhibitory effect on metabolism of gefitinib or erlotinib by the main CYP isoenzymes involved. This study suggests a variable inhibitory effect of fluoxetine particularly on CYP2D6 activity towards gefitinib or erlotinib; erlotinib metabolism is less affected. Likewise, the combination of fluoxetine and losartan does not significantly affect hepatocyte metabolism of erlotinib, but does for that of gefitinib. The results presented in this study thus indicate a need for DDI assays to involve multiple drugs to properly study multidrug regimens.

Varicella zoster virus--specific immune response after treatment with sodium stibogluconate for cutaneous leishmaniasis.

Sodium stibogluconate has been associated with the reactivation of varicella zoster virus (VZV) in otherwise healthy adults who receive the drug as treatment for cutaneous leishmaniasis. Ten patients receiving daily sodium stibogluconate underwent phlebotomy at baseline and at day 10. Flow cytometry-based immunophenotyping, VZV-specific IgG levels, and lymphocyte proliferative responses and intracellular cytokine secretion to VZV, cytomegalovirus, tetanus toxoid, superantigen, and mitogens were performed at both time points. The absolute number of total leukocytes, total lymphocytes, and lymphocyte subsets decreased overall without predilection for any particular subset of lymphocytes, such that the percentage of the total lymphocyte population for each lymphocyte subset did not change significantly (except for a marginal increase in percentage of cytotoxic T cells). Antibodies to VZV were measured in seven patients before and after treatment, and did not change. Lymphocyte proliferative responses to VZV and other antigens and mitogens did not change from baseline. The mechanism for the increased rate of VZV reactivation after treatment with sodium stibogluconate remains undefined.

An enantioselective fluorescence sensing assay for quantitative analysis of chiral carboxylic acids and amino acid derivatives.

A chiral 1,8-diacridylnaphthalene-derived fluorosensor exhibiting a C(2)-symmetric cleft designed for stereoselective interactions with hydrogen bond donors has been used for the determination of both concentration and enantiomeric composition of carboxylic acids and amino acid derivatives.

Psychophysiological Investigation of Combat Veterans with Subthreshold Post-traumatic Stress Disorder Symptoms.

OBJECTIVE: Military service members (SMs) with subthreshold combat-related post-traumatic stress disorder (PTSD) symptoms often have clinically significant functional impairment, even though they do not meet full PTSD criteria. We therefore assessed the psychophysical responses of SMs, upon their return from Afghanistan or Iraq, to a fear conditioning paradigm to better understand the biological underpinnings of symptom severity. METHODS: Heart rate (HR), skin conductance, electromyography startle, and respiratory rate (RR) were monitored throughout three distinct phases of the paradigm-fear acquisition, fear inhibition, and fear extinction-while plasma catecholamines (epinephrine, norepinephrine, and dopamine) were measured at the end of fear inhibition. RESULTS: Those with higher PTSD symptom severity demonstrated elevations in HR and startle response to danger cues; elevated self-reported depression and anxiety; impaired functional status; poor skin conductance discrimination between danger and safety; and increases in HR and RR during fear extinction. Moreover, an inverse relationship was seen between plasma dopamine and HR during fear inhibition for those with high symptoms. CONCLUSION: Overall, the physiological responses we observed in our subthreshold PTSD population parallel what has been previously observed in full PTSD, making a case for addressing subthreshold PTSD symptoms in combat veterans.

Biomarkers of post-deployment resilience among military service members.

The development of PTSD after military deployment is influenced by a combination of biopsychosocial risk and resilience factors. In particular, physiological factors may mark risk for symptom progression or resiliency. Research in civilian populations suggests elevated catecholamines after trauma are associated with PTSD months following the trauma. However, less is known regarding physiological markers of PTSD resilience among post-deployment service members (SM). We therefore assessed whether catecholamines obtained shortly after deployment were associated with combat-related PTSD symptoms three months later. Eighty-seven SMs completed the Clinician-Administered PTSD Scale for DSM-IV and blood draws within two months after return from deployment to Iraq or Afghanistan ("Time 1" or "T1") and three months later ("Time 2" or "T2"). Linear regression analyses demonstrated that lower norepinephrine at T1 was associated with lower PTSD symptoms at T2. In particular, T1 norepinephrine was positively associated with T2 symptom intensity and avoidance symptoms. The present findings represent a biologically-informed method of assessing PTSD resilience after deployment, which may aid clinicians in providing tailored treatments for those in the greatest need. Further research is needed to validate these findings and incorporate physiological measures within an assessment battery.

Catecholamine responses to virtual combat: implications for post-traumatic stress and dimensions of functioning.

Posttraumatic stress disorder (PTSD) symptoms can result in functional impairment among service members (SMs), even in those without a clinical diagnosis. The variability in outcomes may be related to underlying catecholamine mechanisms. Individuals with PTSD tend to have elevated basal catecholamine levels, though less is known regarding catecholamine responses to trauma-related stimuli. We assessed whether catecholamine responses to a virtual combat environment impact the relationship between PTSD symptom clusters and elements of functioning. Eighty-seven clinically healthy SMs, within 2 months after deployment to Iraq or Afghanistan, completed self-report measures, viewed virtual-reality (VR) combat sequences, and had sequential blood draws. Norepinephrine responses to VR combat exposure moderated the relationship between avoidance symptoms and scales of functioning including physical functioning, physical-role functioning, and vitality. Among those with high levels of avoidance, norepinephrine change was inversely associated with functional status, whereas a positive correlation was observed for those with low levels of avoidance. Our findings represent a novel use of a virtual environment to display combat-related stimuli to returning SMs to elucidate mind-body connections inherent in their responses. The insight gained improves our understanding of post-deployment symptoms and quality of life in SMs and may facilitate enhancements in treatment. Further research is needed to validate these findings in other populations and to define the implications for treatment effectiveness.

Swallowed glucocorticoid therapy for eosinophilic esophagitis in children does not suppress adrenal function.

OBJECTIVE: The purpose of this study was to examine the effect of chronic swallowed glucocorticoids on adrenal function during the treatment of eosinophilic esophagitis (EoE) in children. METHODS: Serum cortisol levels were obtained in children with EoE pre- and post-treatment with swallowed glucocorticoids. Exclusion criteria included those on any additional steroid therapy. Once diagnosed with EoE by esophageal biopsy, subjects were treated based on current standard of care with either swallowed fluticasone or budesonide. At the time of follow-up, esophagogastroduodenoscopy and blood sampling was repeated. Both pre- and post-treatment serum cortisol samples were collected fasting, between 07:00 and 10:00, and determined using a competitive binding method assay. The distribution of differences in cortisol levels between the pre- and post-treatment samples satisfied the assumption for normality and were subsequently analyzed using the paired t-test. RESULTS: Pre- and post-treatment serum cortisol levels were examined in 14 children who met clinical and histological diagnostic criteria for EoE. Mean age was 10.1 years (range 2-17 years) with 71% male and 29% female subjects. Swallowed glucocorticoid treatment included fluticasone in 79% and budesonide in 21% of subjects. Mean dosage of fluticasone was 704 µg daily (range 220-880 µg daily) and budesonide 0.8 mg daily (range 0.5-1 mg daily), along with a mean treatment length of 17 weeks (range 8-43 weeks). No significant difference in serum cortisol was found following treatment with swallowed fluticasone or budesonide (mean change 1.9 µg/dL, p=0.75, SD of the change=21.2). CONCLUSIONS: Swallowed glucocorticoid therapy does not appear to significantly affect the adrenal axis in children, and therefore, may represent a safe therapy for EoE.