Imaging physiological brain activity and epilepsy with Electrical Impedance Tomography

Electrical Impedance Tomography (EIT) allows reconstructing conductivity changes into images. EIT detects fast impedance changes occurring over milliseconds, due to ion channel opening, and slow impedance changes, appearing in seconds, due to cell swelling/increased blood flow. The purpose of this work was to examine the feasibility of using EIT for imaging a gyrencephalic brain with implanted depth electrodes during seizures. Chapter 1 summarises the principles of EIT. In Chapter 2, it is investigated whether recent technical improvements could enable EIT to image slow impedance changes upon visual stimulation non-invasively. This was unsuccessful so the remaining studies were undertaken on intracranial recordings. Chapter 3 presents a computer modelling study using data from patients, for whom the detection of simulated seizure-onset perturbations for both, fast and slow impedance changes, were improved with EIT compared to stereotactic electroencephalography (SEEG) detection or EEG inverse-source modelling. Chapter 4 describes the development of a portable EIT system that could be used on patients. The system does not require averaging and post-hoc signal processing to remove switching artefacts, which was the case previously. Chapter 5 describes the use of the optimised method in chemically-induced focal epilepsy in anaesthetised pigs implanted with depth electrodes. This shows for the first time EIT was capable of producing reproducible images of the onset and spread of seizure-related slow impedance changes in real-time. Chapter 6 presents a study on imaging ictal/interictal-related fast impedance changes. The feasibility of reconstructing ictal-related impedance changes is demonstrated for one pig and interictal-related impedance changes were recorded for the first time in humans. Chapter 7 summarises all work and future directions. Overall, this work suggests EIT in combination with SEEG has a potential to improve the diagnostic yield in epilepsy and demonstrates EIT can be performed safely and ethically creating a foundation for further clinical trials

Modelling and optimisation of the operation of a radiant warmer

This paper presents numerical calculations of the temperature field obtained for the case of a neonate placed under a radiant warmer. The results of the simulations show a very non-uniform temperature distribution on the skin of the neonate, which may cause increased evaporation leading to severe dehydration. For this reason, we propose some modifications on the geometry and operation of the radiant warmer, in order to make the temperature distribution more uniform and prevent the high temperature gradients observed on the surface of the neonate. It is concluded that placing a high conductivity blanket over the neonate and introducing additional screens along the side of the mattress, thus recovering the radiation heat escaping through the side boundaries, helped providing more uniform temperature fields.The European Union for the Marie Curie Fellowship grant awarded to the Centre for CFD, University of Leeds

Maternal factors, ultrasound and placental function parameters in early pregnancy as predictors of birth weight in low-risk populations and among patients with pre-gestational diabetes

Objectives: The aim of our work was to assess the usefulness of maternal factors, ultrasound and placental function parameters during early pregnancy as predictors of birth weight in populations of healthy pregnant women and women suffering from pregestational diabetes. Material and methods: A study group comprised 97 healthy women and 160 women with pregestational diabetes (PGDM, type 1), all in singleton pregnancy. Ultrasound examination was performed between weeks 11 and 14, and in weeks 20 and 30 of gestation, based on recommendations of the Polish Society of Gynecologists and Obstetricians, Ultrasonography Division. We also checked uterine artery blood flow parameters. During the first trimester consultation, all patients were surveyed and the following data were collected: age, BMI, reproductive history, comorbidities and smoking. We also collected blood samples and assessed PlGF, PAPP-A, and BhCG levels. Results: Our study showed that newborn birth weight negatively correlated with mother’s age, her diastolic blood pressure, PI of her uterine arteries and BhCG protein levels. Moreover, birth weight directly correlated with PlGF and PAPPA-A protein levels, and maternal early-pregnancy BMI. Conclusions: LGA diagnosis in the first trimester of pregnancy allows for selection and modification of some risk factors and closer monitoring of endangered fetuses throughout the pregnancy, with emphasis on the perinatal period. Parameters with confirmed usefulness in the prediction of birth weight in the first trimester included: maternal age, BMI, blood pressure, PAPP-A, BhCG and PlGF levels, fetal CRL and uterine artery PI

Mid-trimester ultrasound parameters for predicting birth weight in low risk pregnancies vs high-risk pregnancies complicated with pre-gestational diabetes mellitus

Objectives: The aim of the study was to assess the utility of mid-trimester ultrasound parameters in predicting birth weight in low-risk pregnancy and high-risk pregnancy complicated with pregestational diabetes mellitus. Material and methods: A study group comprised 97 healthy women and 160 women with pregestational diabetes (PGDM, type 1), all in singleton pregnancy. Ultrasound examination was performed between weeks 11 and 14, and in weeks 20 and 30 of gestation, based on recommendations of the Polish Society of Gynecologists and Obstetricians, Ultrasonography Division. We also checked uterine artery blood flow parameters. Results: There is a correlation between the birth weight and ultrasound-ascertained parameters, including those characterising uterine artery blood flow and foetal biometry [abdominal circumference (AC), femoral length (FL), biparietal dimension (BPD)].The biparietal dimension (BPD), head circumference (HC) abdominal circumference (AC) and pre-existing diabetes are the ultrasound predictors of LGA. The presence of an early-diastolic uterine artery blood flow waveform notching, as well as the uterine artery pulsatility index (UAPI), femoral length (FL) and hypertension in pregnancy are the ultrasound predictors of SGA. In the subset of women with pre-gestational diabetes (PGDM), there is a negative correlation between the birth weight and the uterine artery pulsatility index and early-diastolic uterine artery blood flow waveform notching. In women with pre-gestational diabetes mellitus (PGDM), femoral length (FL) is a significant predictor of LGA and in case of SGA significant predictors are uterine artery pulsatility index, artery blood flow waveform notching and femoral length (FL). Conclusions: Midtrimester ultrasound parameters with confirmed usefulness in the prediction of birth weight in low-risk pregnancy and high-risk pregnancy complicated with pregestational diabetes mellitus include: uterine artery PI, early-diastolic uterine artery blood flow waveform notching and foetal biometry

Guideline for Trustworthy Artificial Intelligence -- AI Assessment Catalog

Artificial Intelligence (AI) has made impressive progress in recent years and represents a key technology that has a crucial impact on the economy and society. However, it is clear that AI and business models based on it can only reach their full potential if AI applications are developed according to high quality standards and are effectively protected against new AI risks. For instance, AI bears the risk of unfair treatment of individuals when processing personal data e.g., to support credit lending or staff recruitment decisions. The emergence of these new risks is closely linked to the fact that the behavior of AI applications, particularly those based on Machine Learning (ML), is essentially learned from large volumes of data and is not predetermined by fixed programmed rules. Thus, the issue of the trustworthiness of AI applications is crucial and is the subject of numerous major publications by stakeholders in politics, business and society. In addition, there is mutual agreement that the requirements for trustworthy AI, which are often described in an abstract way, must now be made clear and tangible. One challenge to overcome here relates to the fact that the specific quality criteria for an AI application depend heavily on the application context and possible measures to fulfill them in turn depend heavily on the AI technology used. Lastly, practical assessment procedures are needed to evaluate whether specific AI applications have been developed according to adequate quality standards. This AI assessment catalog addresses exactly this point and is intended for two target groups: Firstly, it provides developers with a guideline for systematically making their AI applications trustworthy. Secondly, it guides assessors and auditors on how to examine AI applications for trustworthiness in a structured way

Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6

Ibrutinib may inhibitintestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER+) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER+ breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER+ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER+ breast cancers in obese postmenopausal women

Graft-versus-Host Disease Prophylaxis with Post- Transplantation Cyclophosphamide in Chronic Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation from an Unrelated or Mismatched Related Donor: A Comparative Study from the Chronic Malignancies Working Party of the EBMT (CMWP-EBMT).

peer reviewedOutcomes following allogeneic hematopoietic cell transplantation (allo-HCT) for chronic myeloid leukemia (CML) with post-transplantation cyclophosphamide (PTCy) using an unrelated donor (UD) or a mismatched related donor (MMRD) remain unknown. We report a retrospective comparison of PTCy-based allo-HCT from a UD, non-PTCy allo-HCT from a UD, and PTCy allo-HCT from an MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 and 2019 from a UD with either PTCy or non-PTCy graft-versus-host disease (GVHD) prophylaxis or from an MMRD using PTCy. The primary endpoint was GVHD-free/relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43% in the non-PTCy cohort, 37% in the PTCy-UD cohort, and 39% PTCy-MMRD cohort (P = .15). Multivariable analyses revealed no significant differences among the 3 cohorts in terms of overall survival (OS), progression-free survival, RI, and nonrelapse mortality. Factors independently associated with worse OS in the overall cohort were Karnofsky Performance Status 2 (HR, 1.58; 95% CI, 1.15 to 2.17; P = .005). These results suggest that allo-HCT in patients with CML using either a UD or an MMRD with PTCy-based GVHD prophylaxis are feasible transplantation, platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance of closely monitoring CML patients and proposing transplantation when indicated when still in CP1

Pharmacokinetic aspects of retinal drug delivery

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.Peer reviewe

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p