Cardiac safety assessment of a novel recombinant bispecific antibody targeting the ether-à-go-go related gene 1 (hERG1)-ß1 integrin macromolecular complex.

Introduction: In the last decades, mounting evidence has pointed out the human ether-á-go-go-related gene (hERG1) potassium channel as a novel biomarker in human cancers. However, hERG1 sustains the cardiac repolarizing current IKr and its blockade can induce a prolonged QT interval at the ECG, which increases the risk of life-threatening arrhythmias. This represents a major hindrance for targeting hERG1 for antineoplastic therapeutic purposes. Based on our discovery that hERG1 resides in a macromolecular complex with the ß1 subunit of integrin adhesion receptors only in tumors, and not in the heart, we generated (and patented WO2019/015936) a novel engineered, single chain, bispecific antibody in the format of a diabody (scDb-hERG1-ß1). This antibody has been proven to target with high affinity the hERG1/ß1 integrin complex and to exert a good antineoplastic activity in preclinical mouse models. Methods: In the present study, we evaluated the cardiac safety of the scDb-hERG1-ß1, determining the action potential duration (APD) of human cardiomyocytes, either atrial (from valve-disease patients) or ventricular (from aortic stenosis patients). Cardiac cells were incubated in vitro with i) the scDb-hERG1-ß1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDb-hERG1-ß1 was assembled. All the tests were performed before and after treatment with the specific hERG1 blocker E4031. In addition, we have performed preliminary experiments, analyzing the effects of the scDb-hERG1/ß1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs. Results: The scDb-hERG1-ß1 did not produce any lengthening of APD compared to control (vehicle) conditions, either in atrial or ventricular cardiomyocytes, whereas both the hERG1-mAb and the scFv-hERG1 produced a significant APD prolongation. The addition of E4031 further prolonged APD. The scDb-hERG1-ß1 did not produce any alterations of the QT (and QTc) interval values, once injected intravenously in farm pigs. Discussion: Overall, the above evidences plead for the cardiac safety of the scDb-hERG1-ß1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.

Longitudinal assessment of inflammatory markers in the peripartum period by depressive symptom trajectory groups.

Objective: Mechanisms driving temporal fluctuations of inflammatory markers during pregnancy, and how these might differ between distinct perinatal depressive trajectories, are not well understood. The aim of this study was to investigate cytokines levels over the course of pregnancy in women with different trajectories of depressive symptoms peripartum, and relate the levels to levels of non-pregnant controls. Methods: Based on the Edinburgh Postnatal Depression Scale and/or selective serotonin reuptake inhibitors use, 131 women were categorized into: no (n = 65); antepartum (APD, n = 19), postpartum (PPD, n = 17) and persistent (n = 30) depressive symptoms. Plasma samples (n = 386) were analyzed for levels of interleukin (IL)-8, IL-18, Tumor necrosis factor-α, macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor A (VEGF-A) and fractalkine, at four different time-points (twice during pregnancy, during childbirth, and postpartum) using Bio-Plex Pro Human Cytokine Assays. Generalized linear mixed models were applied to analyze the associations between cytokine levels, time-point, perinatal depressive symptom trajectory group and their interaction. Results: For all markers but VEGF-A, pregnancy was associated with higher cytokine levels compared to the non-pregnant controls, with delivery being the most prominent time-point. For M-CSF, IL-18 and VEGF-A, levels were back to the non-pregnant status at postpartum week 8. An effect of perinatal depressive symptom trajectory groups on cytokine levels was found for VEGF-A. Women with PPD and women with APD had lower levels of VEGF-A throughout the study period compared to women with persistent depression, and women with PPD had lower levels compared to non-depressed women. Conclusions: Lower levels of VEGF-A were noted among women in some trajectories of depressive symptoms peripartum. The peripartum period is a time of tremendous immune system adaptations. Standardization of time-points for cytokine measurements in studies of perinatal depression are important in order to draw valid conclusions on the role of the immune system in perinatal depression.

The daily urban dynamic indicator: Gauging the urban dynamic in Porto during the COVID-19 pandemic.

The SARS-CoV-2 outbreak motivated the development of a myriad of weekly and daily indicators that track economic activity to estimate and predict the consequences of the pandemic. With some exceptions, these indicators are calculated at the country level and are mainly focused on tracking economic factors, disregarding local urban phenomena. To address this, we present the Urban Dynamic Indicator (UDI), a novel composite indicator designed to measure a city's daily urban dynamic. The UDI is applied to Porto municipality, in Portugal, and it corresponds to a latent factor obtained through a factor analysis over seasonal adjusted daily data regarding traffic intensity, public transportation usage, internet usage in public buses, NO2 emissions and noise level. The UDI's values show that, by the end of 2020, despite the approach of economic activity to its pre-pandemic values, as suggested by the Portuguese Daily Economic Indicator (DEI), Porto urban dynamic did not recover completely. The UDI enriches the information available for Porto city planners and policymakers to respond to crisis situations and to gauge the application of local policies that contribute to urban sustainable planning. Furthermore, the methodology defined in this work can be followed for the development of daily urban dynamic indicators elsewhere.

Peritoneal dialysis: Status report in South and South East Asia.

BACKGROUND: Peritoneal dialysis (PD) as a modality of kidney replacement therapy (KRT) is largely underutilized globally. We analyzed PD utilization, impact of economic status, projected growth and impact of state policy(s) on PD growth in South Asia and Southeast Asia (SA&SEA) region. METHODS: The National Nephrology Societies of the region responded to a questionnaire on KRT practices. The responses were based on the latest registry data, acceptable community-based studies and societal perceptions. The representative countries were divided into high income and higher-middle income (HI & HMI) and low income and lower-middle income (LI & LMI) groups. RESULTS: Data provided by 15 countries showed almost similar percentage of GDP as health expenditure (4%-7%). But there was a significant difference in per capita income (HI & HMI -US$ 28 129 vs. LI & LMI - US$ 1710.2) between the groups. Even after having no significant difference in monthly cost of haemodialysis (HD) and PD in LI & LMI countries, they have poorer PD utilization as compared to HI & HMI countries (3.4% vs. 10.1%); the reason being lack of formal training/incentives and time constraints for the nephrologist while lack of reimbursement and poor general awareness of modalities has been a snag for the patients. The region expects ≥10% PD growth in the near future. Hong Kong and Thailand with 'PD first' policy have the highest PD utilization. CONCLUSION: Important deterrents to PD underutilization were lack of PD centric policies, lackadaisical patient/physician's attitude, lack of structured patient awareness programs, formal training programs and affordability.

Analytical Evaluation of Signal-to-Noise Ratios for Avalanche- and Single-Photon Avalanche Diodes.

Performance of systems for optical detection depends on the choice of the right detector for the right application. Designers of optical systems for ranging applications can choose from a variety of highly sensitive photodetectors, of which the two most prominent ones are linear mode avalanche photodiodes (LM-APDs or APDs) and Geiger-mode APDs or single-photon avalanche diodes (SPADs). Both achieve high responsivity and fast optical response, while maintaining low noise characteristics, which is crucial in low-light applications such as fluorescence lifetime measurements or high intensity measurements, for example, Light Detection and Ranging (LiDAR), in outdoor scenarios. The signal-to-noise ratio (SNR) of detectors is used as an analytical, scenario-dependent tool to simplify detector choice for optical system designers depending on technologically achievable photodiode parameters. In this article, analytical methods are used to obtain a universal SNR comparison of APDs and SPADs for the first time. Different signal and ambient light power levels are evaluated. The low noise characteristic of a typical SPAD leads to high SNR in scenarios with overall low signal power, but high background illumination can saturate the detector. LM-APDs achieve higher SNR in systems with higher signal and noise power but compromise signals with low power because of the noise characteristic of the diode and its readout electronics. Besides pure differentiation of signal levels without time information, ranging performance in LiDAR with time-dependent signals is discussed for a reference distance of 100 m. This evaluation should support LiDAR system designers in choosing a matching photodiode and allows for further discussion regarding future technological development and multi pixel detector designs in a common framework.

Auditory processing disorder in children: the value of a multidisciplinary assessment.

PURPOSE: Auditory processing disorder (APD) may affect 0.2-5% of the paediatric population. The diagnosis of APD remains difficult because of polymorphic symptoms possibly entangled with other difficulties. The purpose of this study was to evaluate a new multi-disciplinary assessment in the French language. METHODS: The battery of tests was composed of: (a) APD targeted speech assessment: speech perception in noise, a dichotic test, temporal processing tests (patterns); (b) Psychometric assessment: sustained auditory attention, sustained visual attention, evaluation of cognitive functions; (c) phonemic identification and discrimination; (d) ENT examination, tonal and vocal audiometry and ABR recordings. The diagnosis was made if two of the targeted speech tests were 2 standard deviations (SDs) below the mean or if only one of the tests was 3 SDs below. The auditory attention tests, as well as the phonemic identification and discrimination tests were complementary to the diagnostic battery. However, they did not allow for the diagnosis of APD. RESULTS: 50 children suspected of APD benefited from this protocol, and 12 were excluded from the study. A diagnosis of APD was confirmed in 17 children (45%). 59% of the patients had associated disorders. The most effective tests for diagnosing APD were dichotic testing (p = 0.001) and pattern recognition (frequency, p = 0.001). The sustained auditory attention test (p = 0.01) and the phonemic identification and discrimination test reinforced the diagnosis of APD. CONCLUSION: It seems important to evaluate children suspected of APD with a multi-disciplinary protocol. It makes it possible to diagnose APD children, but also to identify attentional difficulties and cognitive disorders that may be associated.

Cost-Utility Analysis of Continuous Ambulatory Peritoneal Dialysis and Automated Peritoneal Dialysis for Thai Patients With End-Stage Renal Disease.

BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) is the first option for patients with end-stage renal disease under the benefit package of Thailand. Nevertheless, automated peritoneal dialysis (APD) may benefit these patients in terms of both medical and quality-of-life aspects, but it is more expensive. The economic evidence for the comparison between CAPD and APD is not inconclusive. Thus, this study aims to evaluate the cost-effectiveness of CAPD compared with APD in PD patients. OBJECTIVES: To assess the health-related quality of life and costs between patients treated with CAPD and APD. METHODS: A Markov model was developed to evaluate the cost-effectiveness of CAPD and APD from the societal perspective. Costs and outcomes were calculated over a lifetime horizon and discounted at an annual rate of 3%. The outcomes were presented as quality-adjusted life-years (QALYs) of CAPD and APD. Utility scores were calculated from the utility values of the 5-level EuroQol questionnaire. A probabilistic sensitivity analysis using 5000 Monte Carlo simulations was performed to evaluate the stability of the results. RESULTS: The costs of APD and CAPD were 12 868 080 and 11 144 786 Thai baht, respectively, whereas the QALYs were 24.28 and 24.72 QALYs, respectively. APD was more costly but less effective than CAPD. The most sensitive parameter was direct medical cost of outpatient visits. When the willingness-to-pay threshold was 160 000 Thai baht per QALY, the probability of APD providing a cost-effective alternative to CAPD was 19%. CONCLUSION: APD was not a cost-effective strategy as compared with CAPD at the current Thai threshold. These findings should encourage clinicians and policy makers to encompass the use of CAPD as a good value for money for PD treatment.

Ambulatory ECG-based T-wave alternans monitoring for risk assessment and guiding medical therapy: mechanisms and clinical applications.

Identification of individuals at risk for sudden cardiac death (SCD), the main cause of adult mortality in developed countries, remains a major challenge. The main contemporary noninvasive marker, left ventricular ejection fraction (LVEF), has not proved adequately reliable, as the majority of individuals who die suddenly have relatively preserved cardiac mechanical function. Monitoring of T-wave alternans (TWA), a beat-to-beat fluctuation in ST-segment or T-wave morphology, on ambulatory electrocardiogram (AECG) is an attractive approach on both scientific and clinical grounds. Specifically, TWA's capacity to assess risk for malignant arrhythmias has been shown to rest on sound electrophysiologic principles and AECG-based TWA monitoring can be performed in the flow of routine clinical evaluation. This review addresses: (1) electrophysiologic and ionic mechanisms underlying TWA's predictivity, (2) principles and practical aspects of AECG-based TWA monitoring, (3) clinical evidence supporting this approach to SCD risk stratification, and (4) current and potential applications in guiding medical therapy.

Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment.

INTRODUCTION: Unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high-throughput screening assays using cell lines. As a result of screening multiple ion-channels there is a need to integrate information, particularly for compounds affecting more than one current, and mathematical electrophysiology in-silico action potential models are beginning to be used for this. METHODS: We quantified the variability associated with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks® Quattro™ screens when detecting block of I(Kr) (hERG), I(Na) (NaV1.5), I(CaL) (CaV1.2), I(Ks) (KCNQ1/minK) and I(to) (Kv4.3/KChIP2.2), and the Molecular Devices FLIPR® Tetra fluorescence screen for I(CaL) (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. We examined how screening variability propagates through in-silico action potential models for whole cell electrical behaviour, and how confidence intervals on model predictions can be estimated with repeated simulations. RESULTS: There are significant levels of variability associated with high-throughput ion channel electrophysiology screens. This variability is of a similar magnitude for different cardiac ion currents and different compounds. Uncertainty in the Hill coefficients of reported concentration-effect curves is particularly high. Depending on a compound's ion channel blocking profile, the uncertainty introduced into whole-cell predictions can become significant. DISCUSSION: Our technique allows confidence intervals to be placed on computational model predictions that are based on high-throughput ion channel screens. This allows us to suggest when repeated screens should be performed to reduce uncertainty in a compound's action to acceptable levels, to allow a meaningful interpretation of the data.

Assessment of General and Cardiac Toxicities of Astemizole in Male Cynomolgus Monkeys: Serum Biochemistry and Action Potential Duration.

Toxicology screening following treatment with astemizole, a histamine receptor antagonist, at oral doses of 0, 10, 30 and 60 mg/kg was carried out in male cynomolgus monkeys (Macaca fascicularis). No dose-related changes in mortality, clinical signs, body weight changes, food consumption, or urine analysis occurred in any animal compared to the vehicle control. However, the high-dose group showed a decrease in BUN and ALP compared to vehicle control group. In addition, the levels of TG, AST, ALP and CK increased. Although astemizole did not produce significant toxicological changes at any dose tested, we predict that it can cause toxicological changes of the liver and heart based on the changes in the serum parameters related to the heart and liver. The Action Potential Duration (APD) was prolonged in the heart of 60 mg/kg treatment group compared to the control group. The APD increase in 60 mg/kg treatment group along the other related changes in toxicological parameters imply that astemizole has major cardiotoxic effects in the cynomolgus monkey. This study is a valuable assessment for predicting the general toxicity and cardiotoxic effects of antihistamine drugs using nonhuman primates.