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BackgroundHealth information systems (HISs) are continuously targeted by hackers, who aim to bring down critical health infrastructure. This study was motivated by recent attacks on health care organizations that have resulted in the compromise of sensitive data held in HISs. Existing research on cybersecurity in the health care domain places an imbalanced focus on protecting medical devices and data. There is a lack of a systematic way to investigate how attackers may breach an HIS and access health care records. ObjectiveThis study aimed to provide new insights into HIS cybersecurity protection. We propose a systematic, novel, and optimized (artificial intelligence–based) ethical hacking method tailored specifically for HISs, and we compared it with the traditional unoptimized ethical hacking method. This allows researchers and practitioners to identify the points and attack pathways of possible penetration attacks on the HIS more efficiently. MethodsIn this study, we propose a novel methodological approach to ethical hacking in HISs. We implemented ethical hacking using both optimized and unoptimized methods in an experimental setting. Specifically, we set up an HIS simulation environment by implementing the open-source electronic medical record (OpenEMR) system and followed the National Institute of Standards and Technology’s ethical hacking framework to launch the attacks. In the experiment, we launched 50 rounds of attacks using both unoptimized and optimized ethical hacking methods. ResultsEthical hacking was successfully conducted using both optimized and unoptimized methods. The results show that the optimized ethical hacking method outperforms the unoptimized method in terms of average time used, the average success rate of exploit, the number of exploits launched, and the number of successful exploits. We were able to identify the successful attack paths and exploits that are related to remote code execution, cross-site request forgery, improper authentication, vulnerability in the Oracle Business Intelligence Publisher, an elevation of privilege vulnerability (in MediaTek), and remote access backdoor (in the web graphical user interface for the Linux Virtual Server). ConclusionsThis research demonstrates systematic ethical hacking against an HIS using optimized and unoptimized methods, together with a set of penetration testing tools to identify exploits and combining them to perform ethical hacking. The findings contribute to the HIS literature, ethical hacking methodology, and mainstream artificial intelligence–based ethical hacking methods because they address some key weaknesses of these research fields. These findings also have great significance for the health care sector, as OpenEMR is widely adopted by health care organizations. Our findings offer novel insights for the protection of HISs and allow researchers to conduct further research in the HIS cybersecurity domain.

Abstract T‐wave alternans (TWA) has been used for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death (SCD) in multiple clinical settings; however, possible mechanism(s) underlying the spontaneous transition from cellular alternans reflected by TWA to arrhythmias in impaired repolarization remains unclear. The healthy guinea pig ventricular myocytes under E‐4031 blocking IKr (0.1 μM, N = 12; 0.3 μM, N = 10; 1 μM, N = 10) were evaluated using whole‐cell patch‐clamp. The electrophysiological properties of isolated perfused guinea pig hearts under E‐4031 (0.1 μM, N = 5; 0.3 μM, N = 5; 1 μM, N = 5) were evaluated using dual‐ optical mapping. The amplitude/threshold/restitution curves of action potential duration (APD) alternans and potential mechanism(s) underlying the spontaneous transition of cellular alternans to ventricular fibrillation (VF) were examined. There were longer APD80 and increased amplitude and threshold of APD alternans in E‐4031 group compared with baseline group, which was reflected by more pronounced arrhythmogenesis at the tissue level, and were associated with steep restitution curves of the APD and the conduction velocity (CV). Conduction of AP alternans augmented tissue's functional spatiotemporal heterogeneity of regional AP/Ca alternans, as well as the AP/Ca dispersion, leading to localized uni‐directional conduction block that spontaneous facilitated the formation of reentrant excitation waves without the need for additional premature stimulus. Our results provide a possible mechanism for the spontaneous transition from cardiac electrical alternans in cellular action potentials and intercellular conduction without the involvement of premature excitations, and explain the increased susceptibility to ventricular arrhythmias in impaired repolarization. In this study, we implemented voltage‐clamp and dual‐optical mapping approaches to investigate the underlying mechanism(s) for the arrhythmogenesis of cardiac alternans in the guinea pig heart at cellular and tissue levels. Our results demonstrated a spontaneous development of reentry from cellular alternans, arising from a combined actions of restitution properties of action potential duration, conduction velocity of excitation wave and interplay between alternants of action potential and the intracellular Ca handling. We believe this study provides new insights into underlying the mechanism, by which cellular cardiac alternans spontaneously evolves into cardiac arrhythmias.

Rationale: Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated. Objective: To explore the potential role of ER stress–mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. Methods and results: Mouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1–GRP75–VDAC1 (inositol 1,4,5-trisphosphate receptor 1–glucose-regulated protein 75–voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. Conclusions: The IP3R1–GRP75–VDAC1 complex mediates ER stress–mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.

Information security recognised the human as the weakest link. Despite numerous international or sector-specific standards and frameworks, the information security community has not yet adopted formal mechanisms to manage human errors that cause information security breaches. Such techniques have been however established within the safety field where human reliability analysis (HRA) techniques are widely applied. In previous work we developed Information Security Core Human Error Causes (IS-CHEC) to fill this gap. This case study presents empirical research that uses IS-CHEC over a 12 month period within two participating public and private sector organisations in order to observe and understand how the implementation of the IS-CHEC information security HRA technique affected the respective organisations. The application of the IS-CHEC technique enabled the proportions of human error related information security incidents to be understood as well as the underlying causes of these incidents. The study captured the details of the incidents in terms of the most common underlying causes, selection of remedial and preventative measures, volumes of reported information security incidents, proportions of human error, common tasks undertaken at the time the incident occurred, as well as the perceptions of key individuals within the participating organisations through semi-structured interviews. The study confirmed in both cases that the vast majority of reported information security incidents relate to human error, and although the volumes of human error related incidents pertaining to both participating organisations fluctuated over the 12 month period, the proportions of human error remained consistently as the majority root cause.

The objective of the research was to establish data relating to underlying causes of human error which are the most common cause of information security incidents within a private sector healthcare organization. A survey questionnaire was designed to proactively apply the IS-CHEC information security human reliability analysis (HRA) technique. The IS-CHEC technique questionnaire identified the most likely core human error causes that could result in incidents, their likelihood, the most likely tasks that could be affected, suggested remedial and preventative measures, systems or processes that would be likely to be affected by human error and established the levels of risk exposure. The survey was operational from 15th November 2018 to 15th December 2018. It achieved a response rate of 65% which equated to 485 of 749 people targeted by the research. The research found that, in the case of this particular participating organization, the application of the IS-CHEC technique through a questionnaire added beneficial value as an enhancement to a standard approach of holistic risk assessment. The research confirmed that the IS-CHEC in questionnaire form can be successfully applied within a private sector healthcare organization and also that a distributed approach for information security human error assessment can be successfully undertaken in order to add beneficial value. The results of this paper indicate, from the questionnaire responses supplied by employees, that organizational focus on its people and their working environment can improve information security posture and reduce the likelihood of associated information security incidents through a reduction in human error.

T-wave alternans (TWA) reflects every-other-beat alterations in the morphology of the electrocardiogram ST segment or T wave in the setting of a constant heart rate, hence, in the absence of heart rate variability. It is believed to be associated with the dispersion of repolarization and has been used as a non-invasive marker for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death as numerous studies have shown. This review aims to provide up-to-date review on both experimental and simulation studies in elucidating possible mechanisms underlying the genesis of TWA at the cellular level, as well as the genesis of spatially concordant/discordant alternans at the tissue level, and their transition to cardiac arrhythmia. Recent progress and future perspectives in antiarrhythmic therapies associated with TWA are also discussed.

Abstract Background Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3. Methods The ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I K1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry. Results Amiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue’s temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue. Conclusions At the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.

Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology.The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue.At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide.The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.