Proarrhythmic major adverse cardiac events with donepezil: A systematic review with meta-analysis.

BACKGROUND: Cholinesterase inhibitors (ChEIs) are regularly used in Alzheimer's disease. Of the three ChEIs approved for dementia, donepezil is among the most prescribed drugs in the United States with nearly 6 million prescriptions in 2020; however, it is classified as a "known risk" QT interval-prolonging medication (QTPmed). Given this claim is derived from observational data including single case reports, we aimed to evaluate high-quality literature on the frequency and nature of proarrhythmic major adverse cardiac events (MACE) associated with donepezil. METHODS: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onwards for randomized controlled trials (RCTs) involving patients age ≥18 years comparing donepezil to placebo. The MACE composite included mortality, sudden cardiac death, non-fatal cardiac arrest, Torsades de pointes, ventricular tachyarrhythmia, seizure or syncope. Random-effects meta-analyses were performed with a treatment-arm continuity correction for single and double zero event studies. RESULTS: Sixty RCTs (n = 12,463) were included. Twenty-five of 60 trials (n = 5886) investigated participants with Alzheimer's disease and 33 trials monitored electrocardiogram data. The mean follow-up duration was 31 weeks (SD = 36). Mortality was the most commonly reported MACE (252/331, 75.8% events), the remainder were syncope or seizures, with no arrhythmia events. There was no increased risk of MACE with exposure to donepezil compared to placebo (risk ratio [RR] 1.08, 95% CI 0.88-1.33, I2 = 0%) and this was consistent in the subgroup analysis of trials including participants with cardiovascular morbidities (RR 1.14, 95% CI 0.88-1.47). Subgroup analysis suggested a trend toward more events with donepezil with follow-up ≥52 weeks (RR: 1.32, 0.98-1.79). CONCLUSIONS: This systematic review with meta-analysis found donepezil may not be arrhythmogenic. Donepezil was not associated with mortality, ventricular arrhythmias, seizure or syncope, although longer durations of therapy need more study. Further research to clarify actual clinical outcomes related to QTPmed is important to inform prescribing practices.

Hydroxychloroquine-Chloroquine, QT-Prolongation, and Major Adverse Cardiac Events: A Meta-analysis and Scoping Review.

OBJECTIVES: We aimed to evaluate the high-quality literature on the frequency and nature of major adverse cardiac events (MACE) associated with either hydroxychloroquine (HCQ) or chloroquine (CQ). DATA SOURCES: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onward using search strategies created in collaboration with medical science librarians. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials (RCTs) published in English language from January 1996 to September 2022, involving adult patients at least 18 years of age, were selected. Outcomes of interest were death, arrhythmias, syncope, and seizures. Random-effects meta-analyses were performed with a Treatment Arm Continuity Correction for single and double zero event studies. DATA SYNTHESIS: By study drug, there were 31 HCQ RCTs (n = 6677), 9 CQ RCTs (n = 622), and 1 combined HCQ-CQ trial (n = 105). Mortality was the most commonly reported MACE at 220 of 255 events (86.3%), with no reports of torsades de pointes or sudden cardiac death. There was no increased risk of MACE with exposure to HCQ-CQ compared with control (risk ratio [RR] = 0.90, 95% CI = 0.69-1.17, I2 = 0%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: These findings have important implications with respect to patient reassurance and updated guidance for prescribing practices of these medications. CONCLUSIONS: Despite listing as QT-prolonging meds, HCQ-CQ did not increase the risk of MACE.

The influence mechanism of source experience of the knowledge on the knowledge transfer performance: The role of political skill and knowledge barriers.

Exploring the relationship between characteristics of the source of knowledge and knowledge transfer performance seems to be crucial in order to make up for the lack of research on the political skills of knowledge sources in the process of knowledge transfer. For this reason, this study conducts a paired-sample questionnaire survey to achieve the research purpose. One direct supervisor was paired with 1∼4 subordinates; 274 other-reported questionnaires were sent out to supervisors and 1,096 self-reported questionnaires to subordinates. A total of 214 valid supervisor questionnaires and 630 valid subordinate questionnaires were collected. The finding demonstrates that knowledge sources with political skills can reduce knowledge barriers to knowledge transfer as well as affect knowledge transfer performance. This research presents a valid model that comprises the antecedents (characteristics of the knowledge source), mediators (knowledge barriers), moderators (political skill), and consequences of knowledge transfer performance of firms. Moreover, this study provides several meaningful directions for future research.

A Cross-Level Investigation of Team-Member Exchange on Team and Individual Job Crafting with the Moderating Effect of Regulatory Focus.

Within the framework of regulatory focus theory, this study examines the issues of job crafting. This study adopts purposive sampling as a means to collect data. A total of 123 teams with 514 members were invited to participate in the survey, and 91 teams with 354 members provided valid questionnaire responses for data analysis. Mplus 7.0 was applied to conduct data analysis and verification. Data analysis demonstrates that (1) team-member exchange (TMX) exerts a positive influence on team job crafting and individual job crafting; (2) team job crafting positively affects individual job crafting; (3) TMX can positively affect individual job crafting via team job crafting; and (4) a prevention focus has a moderated mediation effect on the indirect relationship between TMX and individual job crafting. Based on its findings, this study has both practical and theoretical implications. Academically, it can be regarded as a pioneering academic endeavor. Practically, this study can enhance teamwork, postulate job flow, and promote the quality of member relationships, thus boosting individual job crafting performance.

Biophysical Insights into How Spike Threshold Depends on the Rate of Membrane Potential Depolarization in Type I and Type II Neurons.

Dynamic spike threshold plays a critical role in neuronal input-output relations. In many neurons, the threshold potential depends on the rate of membrane potential depolarization (dV/dt) preceding a spike. There are two basic classes of neural excitability, i.e., Type I and Type II, according to input-output properties. Although the dynamical and biophysical basis of their spike initiation has been established, the spike threshold dynamic for each cell type has not been well described. Here, we use a biophysical model to investigate how spike threshold depends on dV/dt in two types of neuron. It is observed that Type II spike threshold is more depolarized and more sensitive to dV/dt than Type I. With phase plane analysis, we show that each threshold dynamic arises from the different separatrix and K+ current kinetics. By analyzing subthreshold properties of membrane currents, we find the activation of hyperpolarizing current prior to spike initiation is a major factor that regulates the threshold dynamics. The outward K+ current in Type I neuron does not activate at the perithresholds, which makes its spike threshold insensitive to dV/dt. The Type II K+ current activates prior to spike initiation and there is a large net hyperpolarizing current at the perithresholds, which results in a depolarized threshold as well as a pronounced threshold dynamic. These predictions are further attested in several other functionally equivalent cases of neural excitability. Our study provides a fundamental description about how intrinsic biophysical properties contribute to the threshold dynamics in Type I and Type II neurons, which could decipher their significant functions in neural coding.

Input-output relation and energy efficiency in the neuron with different spike threshold dynamics.

Neuron encodes and transmits information through generating sequences of output spikes, which is a high energy-consuming process. The spike is initiated when membrane depolarization reaches a threshold voltage. In many neurons, threshold is dynamic and depends on the rate of membrane depolarization (dV/dt) preceding a spike. Identifying the metabolic energy involved in neural coding and their relationship to threshold dynamic is critical to understanding neuronal function and evolution. Here, we use a modified Morris-Lecar model to investigate neuronal input-output property and energy efficiency associated with different spike threshold dynamics. We find that the neurons with dynamic threshold sensitive to dV/dt generate discontinuous frequency-current curve and type II phase response curve (PRC) through Hopf bifurcation, and weak noise could prohibit spiking when bifurcation just occurs. The threshold that is insensitive to dV/dt, instead, results in a continuous frequency-current curve, a type I PRC and a saddle-node on invariant circle bifurcation, and simultaneously weak noise cannot inhibit spiking. It is also shown that the bifurcation, frequency-current curve and PRC type associated with different threshold dynamics arise from the distinct subthreshold interactions of membrane currents. Further, we observe that the energy consumption of the neuron is related to its firing characteristics. The depolarization of spike threshold improves neuronal energy efficiency by reducing the overlap of Na(+) and K(+) currents during an action potential. The high energy efficiency is achieved at more depolarized spike threshold and high stimulus current. These results provide a fundamental biophysical connection that links spike threshold dynamics, input-output relation, energetics and spike initiation, which could contribute to uncover neural encoding mechanism.

Spike-frequency adaptation of a two-compartment neuron modulated by extracellular electric fields.

Spike-frequency adaptation has been shown to play an important role in neural coding. Based on a reduced two-compartment model, here we investigate how two common adaptation currents, i.e., voltage-sensitive potassium current (I(M)) and calcium-sensitive potassium current (I(AHP)), modulate neuronal responses to extracellular electric fields. It is shown that two adaptation mechanisms lead to distinct effects on the dynamical behavior of the neuron to electric fields. These effects depend on a neuronal morphological parameter that characterizes the ratio of soma area to total membrane area and internal coupling conductance. In the case of I(AHP) current, changing the morphological parameter switches spike initiation dynamics between saddle-node on invariant cycle bifurcation and supercritical Hopf bifurcation, whereas it only switches between subcritical and supercritical Hopf bifurcations for I(M) current. Unlike the morphological parameter, internal coupling conductance is unable to alter the bifurcation scenario for both adaptation currents. We also find that the electric field threshold for triggering neuronal steady-state firing is determined by two parameters, especially by the morphological parameter. Furthermore, the neuron with I(AHP) current generates mixed-mode oscillations through the canard phenomenon for some small values of the morphological parameter. All these results suggest that morphological properties play a critical role in field-induced effects on neuronal dynamics, which could qualitatively alter the outcome of adaptation by modulating internal current between soma and dendrite. The findings are readily testable in experiments, which could help to reveal the mechanisms underlying how the neuron responds to electric field stimulus.

Neuronal spike initiation modulated by extracellular electric fields.

Based on a reduced two-compartment model, the dynamical and biophysical mechanism underlying the spike initiation of the neuron to extracellular electric fields is investigated in this paper. With stability and phase plane analysis, we first investigate in detail the dynamical properties of neuronal spike initiation induced by geometric parameter and internal coupling conductance. The geometric parameter is the ratio between soma area and total membrane area, which describes the proportion of area occupied by somatic chamber. It is found that varying it could qualitatively alter the bifurcation structures of equilibrium as well as neuronal phase portraits, which remain unchanged when varying internal coupling conductance. By analyzing the activating properties of somatic membrane currents at subthreshold potentials, we explore the relevant biophysical basis of spike initiation dynamics induced by these two parameters. It is observed that increasing geometric parameter could greatly decrease the intensity of the internal current flowing from soma to dendrite, which switches spike initiation dynamics from Hopf bifurcation to SNIC bifurcation; increasing internal coupling conductance could lead to the increase of this outward internal current, whereas the increasing range is so small that it could not qualitatively alter the spike initiation dynamics. These results highlight that neuronal geometric parameter is a crucial factor in determining the spike initiation dynamics to electric fields. The finding is useful to interpret the functional significance of neuronal biophysical properties in their encoding dynamics, which could contribute to uncovering how neuron encodes electric field signals.

Effects of extremely low-frequency magnetic fields on the response of a conductance-based neuron model.

To provide insights into the modulation of neuronal activity by extremely low-frequency (ELF) magnetic field (MF), we present a conductance-based neuron model and introduce ELF sinusoidal MF as an additive voltage input. By analyzing spike times and spiking frequency, it is observed that neuron with distinct spiking patterns exhibits different response properties in the presence of MF exposure. For tonic spiking neuron, the perturbations of MF exposure on spike times is maximized at the harmonics of neuronal intrinsic spiking frequency, while it is maximized at the harmonics of bursting frequency for burst spiking neuron. As MF intensity increases, the perturbations also increase. Compared with tonic spiking, bursting dynamics are less sensitive to the perturbations of ELF MF exposure. Further, ELF MF exposure is more prone to perturb neuronal spike times relative to spiking frequency. Our finding suggests that the resonance may be one of the neural mechanisms underlying the modulatory effects of the low-intensity ELF MFs on neuronal activities. The results highlight the impacts of ELF MFs exposure on neuronal activity from the single cell level, and demonstrate various factors including ELF MF properties and neuronal spiking characteristics could determine the outcome of exposure. These insights into the mechanism of MF exposure may be relevant for the design of multi-intensity magnetic stimulus protocols, and may even contribute to the interpretation of MF effects on the central nervous systems.

Exploring how extracellular electric field modulates neuron activity through dynamical analysis of a two-compartment neuron model.

To investigate how extracellular electric field modulates neuron activity, a reduced two-compartment neuron model in the presence of electric field is introduced in this study. Depending on neuronal geometric and internal coupling parameters, the behaviors of the model have been studied extensively. The neuron model can exist in quiescent state or repetitive spiking state in response to electric field stimulus. Negative electric field mainly acts as inhibitory stimulus to the neuron, positive weak electric field could modulate spiking frequency and spike timing when the neuron is already active, and positive electric fields with sufficient intensity could directly trigger neuronal spiking in the absence of other stimulations. By bifurcation analysis, it is observed that there is saddle-node on invariant circle bifurcation, supercritical Hopf bifurcation and subcritical Hopf bifurcation appearing in the obtained two parameter bifurcation diagrams. The bifurcation structures and electric field thresholds for triggering neuron firing are determined by neuronal geometric and coupling parameters. The model predicts that the neurons with a nonsymmetric morphology between soma and dendrite, are more sensitive to electric field stimulus than those with the spherical structure. These findings suggest that neuronal geometric features play a crucial role in electric field effects on the polarization of neuronal compartments. Moreover, by determining the electric field threshold of our biophysical model, we could accurately distinguish between suprathreshold and subthreshold electric fields. Our study highlights the effects of extracellular electric field on neuronal activity from the biophysical modeling point of view. These insights into the dynamical mechanism of electric field may contribute to the investigation and development of electromagnetic therapies, and the model in our study could be further extended to a neuronal network in which the effects of electric fields on network activity may be investigated.

Upper cervical cord enterogenous cyst mimicking transient ischaemic attacks.

A 76-year-old woman presenting with tetraparesis, left-sided hemisensory loss and occasional neck pain was urgently admitted to our department. A cervical spine MRI scan revealed a partially cystic lesion compressing the cord at the C2-4 level. The lesion was surgically excised. The histopathological diagnosis was that of an enterogenous cyst. No postoperative complications were noted and the patient significantly recovered from the preoperative tetraparesis. Eleven months before surgery, a waxing and waning presentation of the myelopathic signs with normal neuroradiological findings on a non-contrast-enhanced head CT scan, had unfortunately led to the misdiagnosis of transient ischaemic attacks and ischaemic stroke which delayed the treatment of an essentially benign disease the total surgical excision of which not only is usually curative but also improves the preoperative signs and symptoms.

Can intravenous paracetamol reduce opioid use in preoperative hip fracture patients?

Pain due to intra- and extracapsular hip fractures is usually treated with opioid medication. Paracetamol (acetaminophen in North America) has better bioavailability when given intravenously than orally and has been successfully used in the postoperative care of orthopedic patients. However, no study has evaluated its use in the preoperative trauma patient. Our unit conducted a prospective, consecutive cohort study to investigate the opioid-sparing effect of regularly administered intravenous paracetamol compared with oral paracetamol in preoperative hip fracture patients. The total opioid dose given, based on conversion to intravenous morphine, and the reported pain score were evaluated in 75 patients. There were 28 patients in the control group who were give routine oral paracetamol and oral opioids, with morphine for breakthrough pain. There were 47 patients in the study group who received only routine intravenous paracetamol, with opioids reserved for breakthrough pain. The patients in the 2 groups had similar characteristics. The mean preoperative oral paracetamol dose for the control group was 7.2 g compared with 6.3 g in the study group. There was a significant reduction (P<.005) in the mean total intravenous morphine with intravenous paracetamol (6.5 mg) compared with oral paracetamol (21.8 mg). There was no difference in the mean pain score between the groups, 2.1 vs 1.8 (P=.3). Intravenous paracetamol had a significant opioid-sparing effect and satisfactory pain relief in preoperative hip fracture patients.

Propagation of spiking regularity and double coherence resonance in feedforward networks.

We investigate the propagation of spiking regularity in noisy feedforward networks (FFNs) based on FitzHugh-Nagumo neuron model systematically. It is found that noise could modulate the transmission of firing rate and spiking regularity. Noise-induced synchronization and synfire-enhanced coherence resonance are also observed when signals propagate in noisy multilayer networks. It is interesting that double coherence resonance (DCR) with the combination of synaptic input correlation and noise intensity is finally attained after the processing layer by layer in FFNs. Furthermore, inhibitory connections also play essential roles in shaping DCR phenomena. Several properties of the neuronal network such as noise intensity, correlation of synaptic inputs, and inhibitory connections can serve as control parameters in modulating both rate coding and the order of temporal coding.

Cannulated screw fixation of fracture neck of femur in children with osteogenesis imperfecta.

Osteogenesis imperfecta is a disorder of abnormality in collagen metabolism due to genetic defects, which causes fragility fracture in children. Fragility fracture of the neck of femur can be difficult to treat in adults. The difficulties increase exponentially in children. The challenge becomes more severe when there is an intramedullary rod in situ in the femoral shaft. It is a technically demanding work to fix fracture caused by osteogenesis imperfecta. There is hardly any published study on the difficult fixation of fracture neck of femur in osteogensis imperfecta. Therefore, we present two cases using cannulated screw fixation for this type of fracture for the benefit of other orthopaedic surgeons.