Factors associated with cardiac implantable electronic device-related infections, New South Wales, 2016-21: a retrospective cohort study.

OBJECTIVES: To quantify the rate of cardiac implantable electronic device (CIED)-related infections and to identify risk factors for such infections. DESIGN: Retrospective cohort study; analysis of linked hospital admissions and mortality data. SETTING, PARTICIPANTS: All adults who underwent CIED procedures in New South Wales between 1 January 2016 and 30 June 2021 (public hospitals) or 30 June 2020 (private hospitals). MAIN OUTCOME MEASURES: Proportions of patients hospitalised with CIED-related infections (identified by hospital record diagnosis codes); risk of CIED-related infection by patient, device, and procedural factors. RESULTS: Of 37 675 CIED procedures (23 194 men, 63.5%), 500 were followed by CIED-related infections (median follow-up, 24.9 months; interquartile range, 11.2-40.8 months), including 397 people (1.1%) within twelve months of their procedures, and 186 of 10 540 people (2.5%) at high risk of such infections (replacement or upgrade procedures; new cardiac resynchronisation therapy with defibrillator, CRT-D). The overall infection rate was 0.50 (95% confidence interval [CI], 0.45-0.54) per 1000 person-months; it was highest during the first month after the procedure (5.60 [95% CI, 4.89-6.42] per 1000 person-months). The risk of CIED-related infection was greater for people under 65 years of age than for those aged 65-74 years (adjusted hazard ratio [aHR], 1.71; 95% CI, 1.32-2.23), for people with CRT-D devices than for those with permanent pacemakers (aHR, 1.46; 95% CI, 1.02-2.08), for people who had previously undergone CIED procedures (two or more v none: aHR, 1.51; 95% CI, 1.02-2.25) or had CIED-related infections (aHR, 11.4; 95% CI, 8.34-15.7), or had undergone concomitant cardiac surgery (aHR, 1.62; 95% CI, 1.10-2.39), and for people with atrial fibrillation (aHR, 1.33; 95% CI, 1.11-1.60), chronic kidney disease (aHR, 1.54; 95% CI, 1.27-1.87), chronic obstructive pulmonary disease (aHR, 1.37; 95% CI, 1.10-1.69), or cardiomyopathy (aHR 1.60; 95% CI, 1.25-2.05). CONCLUSIONS: Knowledge of risk factors for CIED-related infections can help clinicians discuss them with their patients, identify people at particular risk, and inform decisions about device type, upgrades and replacements, and prophylactic interventions.

Real-world evidence on the association between cardiac implantable electronic device infection and all-cause mortality.

AIMS: An infection following cardiac implantable electronic device (CIED) procedure is a serious complication, but its association with all-cause mortality is inconsistent across observational studies. To quantify the association between CIED infection and all-cause mortality in a large, contemporary cohort from New South Wales, Australia. METHODS AND RESULTS: This retrospective cohort study used linked hospital and mortality data and included all patients aged >18 years who underwent a CIED procedure between July 2017 and September 2022. Cardiac implantable electronic device infection was defined by the presence of relevant diagnosis codes. Cox regression to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the association of CIED infection with mortality, at 1-year, and at the end of follow-up, with CIED infection included as a time-dependent variable, and other potential risk factors for mortality included as fixed covariates. We followed 37,750 patients with CIED procedures {36% female, mean age [standard deviation (SD)] 75.8 [12.7] years}, and 487 (1.3%) CIED infections were identified. We observed 5771 (15.3%) deaths during an average follow-up of 25.2 (SD 16.8) months. Compared with no infection group, patients with CIED infection had a higher Kaplan-Meier mortality rate (19.4 vs. 6.8%) and adjusted hazard of mortality (aHR 2.73, 95% CI 2.10-3.54) at 12 months post-procedure. These differences were attenuated but still remained significant at the end of follow-up (aHR 1.83, 95% CI 1.52-2.19). CONCLUSION: In a complete, state-wide cohort of CIED patients, infection was associated with higher risks of both short-term and long-term mortality.

Reimbursement Coverage Decision Making for Digital Health Technologies in South Korea: Does It Fit the Value Framework Used in Traditional Medical Technologies?

OBJECTIVES: The introduction of digital health technologies (DHTs) that have the potential to improve health outcomes and lower the costs of healthcare services has seen an explosion in recent years. Indeed, the expectation that these innovative technologies can ultimately fill a gap in the patient-healthcare provider model of care with the hope of bending the continuously increasing healthcare expenditure curve has not yet been realized in many countries including South Korea (from herein referred to as Korea). We examine reimbursement coverage decision making status for DHTs in South Korea. METHODS: We examine the regulatory landscape, health technology assessment process, and reimbursement coverage determination for DHTs in Korea. RESULTS: We identified the specific challenges and opportunities for reimbursement coverage of DHTs. CONCLUSIONS: To ensure DHTs can be used effectively in medical practice, a more flexible and nontraditional approach to assessment, reimbursement, and payment determination is required.

Current Medical Technology Reimbursement System in Japan.

OBJECTIVES: The process for reimbursement of medical technologies in Japan is complex, and to date, it has not been well described overall. This article aims to provide an overview of the reimbursement system for medical technologies in Japan, including the reimbursement application process and the payment decision making. METHODS: Conduct review for relevant health policy and regulation and gather opinion from the key stakeholders. RESULTS: The Japanese functional category listing system for the reimbursement of medical technologies is a unique fee-for-service payment system, and the timing for the listing is dependent on the application category. A key positive aspect of the current system is the level of transparency and the predictable pathway for reimbursement of new medical technologies. Conversely, the current reimbursement process may not capture the true extent of the innovation of new technologies, especially when creating a new functional category and/or a new medical procedure coding. CONCLUSIONS: There are potential areas where changes could improve access, efficiencies, and value, such as the price revision system based on the market survey, the foreign average price assessment, and the health technology assessment system. These additions and modifications in policy and regulation of reimbursement will help facilitate the effective and efficient access to new innovative medical technologies within the context of a sustainable and affordable National Health Insurance system in Japan.

Coverage with Evidence Development Programs for Medical Technologies in Asia-Pacific Regions: A Case Study of Japan and South Korea.

In this article, the operational characteristics of coverage with evidence development (CED) programs in Asia-Pacific regions, focusing on two countries-Japan and South Korea-are reviewed. Both countries recommended the introduction of CED to overcome the barrier of lack of robust clinical evidence in the early stages of the introduction of a medical technology. However, each country has a unique approach to CED implementation that reflects the differences in establishment and healthcare and policy environments. Japan adopted a "Challenge Application (CA)" program in 2018, and South Korea introduced the "Conditional Selective Benefit (CSB)" program in 2014. Despite the positive effects of CED programs, their governance and implementation should be improved to benefit patients in both countries from the improved access to new and innovative medical technologies. To this end, CED practices in the United States (the USA) can provide insights on how to improve CED operations in both countries.

Delayed Patient Access to Innovative Medical Technologies in South Korea: A Lead-Time Analysis of Reimbursement Coverage Determinations.

Background and ObjectivesTimely access to innovative medical technologies driven by accelerated patient access pathways can substantially improve the health outcomes of patients who often have few therapeutic alternatives. We analyzed lead-times for the medical procedure reimbursement coverage process undertaken in South Korea from 2014 to 2017, which is considered one of the most important factors contributing to delays in patient access to new medical technologies. METHODS: This analysis was performed using the open datasets source of "Medical Procedure Expert Evaluation Committee (MPEEC)" meeting results and medical procedure coverage application information published on the Health Insurance Review and Assessment Service Web site. RESULTS: From 2014 to 2017, 90 percent of all new coverage determinations took on average >250 days with almost 20 percent taking more than 2 years (>750 days), The average lead-time from the medical procedure coverage application to MPEEC meeting in 2015 was 435.0 ± 214.7 days (n = 26), which was significantly shorter than the average lead-time in 2014 (624.9 ± 290.3 days, n = 16) (p < .05). The average lead-time from application to official enforcement in 2015 was significantly shorter than that of 2014 (540.8 ± 217.4; n = 16 versus 734.1 ± 299.7 days; n = 26, respectively) (p < .05). CONCLUSIONS: While this analysis showed a general trend of a reduction in the time taken to receive a positive coverage determination for a new medical technology, the average lead-time remains well over the government mandated 100 days. To continue this trend and further enhance the patient access pathway for medical procedure coverage determinations, some measures can be applied. In particular, the extended "One-Stop Service" program encompassing coverage determinations is one such recommendation that could be considered.

Neuroprotectant effects of iso-osmolar D-mannitol to prevent Pacific ciguatoxin-1 induced alterations in neuronal excitability: a comparison with other osmotic agents and free radical scavengers.

The basis for the neuroprotectant effect of D-mannitol in reducing the sensory neurological disturbances seen in ciguatera poisoning, is unclear. Pacific ciguatoxin-1 (P-CTX-1), at a concentration 10 nM, caused a statistically significant swelling of rat sensory dorsal root ganglia (DRG) neurons that was reversed by hyperosmolar 50 mM D-mannitol. However, using electron paramagnetic resonance (EPR) spectroscopy, it was found that P-CTX-1 failed to generate hydroxyl free radicals at concentrations of toxin that caused profound effects on neuronal excitability. Whole-cell patch-clamp recordings from DRG neurons revealed that both hyper- and iso-osmolar 50 mM D-mannitol prevented the membrane depolarisation and repetitive firing of action potentials induced by P-CTX-1. In addition, both hyper- and iso-osmolar 50 mM D-mannitol prevented the hyperpolarising shift in steady-state inactivation and the rise in leakage current through tetrodotoxin (TTX)-sensitive Na(v) channels, as well as the increased rate of recovery from inactivation of TTX-resistant Na(v) channels induced by P-CTX-1. D-Mannitol also reduced, but did not prevent, the inhibition of peak TTX-sensitive and TTX-resistant I(Na) amplitude by P-CTX-1. Additional experiments using hyper- and iso-osmolar D-sorbitol, hyperosmolar sucrose and the free radical scavenging agents Trolox and L-ascorbic acid showed that these agents, unlike D-mannitol, failed to prevent the effects of P-CTX-1 on spike electrogenesis and Na(v) channel gating. These selective actions of D-mannitol indicate that it does not act purely as an osmotic agent to reduce swelling of nerves, but involves a more complex action dependent on the Na(v) channel subtype, possibly to alter or reduce toxin association.

Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons.

The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Nav) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Nav channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons, P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Nav currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP, and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Nav channel gating, observed clinically in response to ciguatera poisoning.

Cost analysis of the treatment of schizophrenia in Thailand: a simulation model comparing olanzapine, risperidone, quetiapine, ziprasidone and haloperidol.

OBJECTIVES: To compare the annual costs of treating schizophrenia with four atypical antipsychotics-olanzapine, risperidone, quetiapine and ziprasidone and one typical antipsychotic: haloperidol in Thailand MATERIAL AND METHOD: The present study used a cost analysis model. The model simulated treatment of schizophrenics for 12 months with the data from international literature review. A comprehensive search of pharmacoeconomic literature was carried out in order to identify studies to be included in the present review. Model parameter used data from the searches of 1175 publications but merely 31 of them were relevant to the objectives of the present study. Costs associated with olanzapine, risperidone, quetiapine, ziprasidone and haloperidol therapy were calculated over a period of 12-months. This analysis included health care costs and costs associated with productivity losses. RESULTS: The total cost from the cost analysis was as follows: Haloperidol gives the lowest annual cost of THB 86,004, within the atypical antipsychotics, Olanzapine produces an annual cost of THB 103,225 compared to THB 104,564 with risperidone, 118,314 with ziprazidone. The cost ranges up to THB 146,526 for quetiapine therapy. CONCLUSION: Treatment with olanzapine appears to be more cost-effective than that with the other atypical antipsychotics in Thai schizophrenic patients.

Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel.

Delta-atracotoxins (delta-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an "inhibitor cystine-knot" motif with structural but not sequence homology to a variety of other spider and marine snail toxins. Delta-atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion alpha-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, delta-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of delta-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion alpha-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, delta-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3.

Synthesis and characterization of delta-atracotoxin-Ar1a, the lethal neurotoxin from venom of the Sydney funnel-web spider (Atrax robustus).

Delta-atracotoxin-Ar1a (delta-ACTX-Ar1a) is the major polypeptide neurotoxin isolated from the venom of the male Sydney funnel-web spider, Atrax robustus. This neurotoxin targets both insect and mammalian voltage-gated sodium channels, where it competes with scorpion alpha-toxins for neurotoxin receptor site-3 to slow sodium-channel inactivation. Progress in characterizing the structure and mechanism of action of this toxin has been hampered by the limited supply of pure toxin from natural sources. In this paper, we describe the first successful chemical synthesis and oxidative refolding of the four-disulfide bond containing delta-ACTX-Ar1a. This synthesis involved solid-phase Boc chemistry using double coupling, followed by oxidative folding of purified peptide using a buffer of 2 M GdnHCl and glutathione/glutathiol in a 1:1 mixture of 2-propanol (pH 8.5). Successful oxidation and refolding was confirmed using both chemical and pharmacological characterization. Ion spray mass spectrometry was employed to confirm the molecular weight. (1)H NMR analysis showed identical chemical shifts for native and synthetic toxins, indicating that the synthetic toxin adopts the native fold. Pharmacological studies employing whole-cell patch clamp recordings from rat dorsal root ganglion neurons confirmed that synthetic delta-ACTX-Ar1a produced a slowing of the sodium current inactivation and hyperpolarizing shifts in the voltage-dependence of activation and inactivation similar to native toxin. Under current clamp conditions, we show for the first time that delta-ACTX-Ar1a produces spontaneous repetitive plateau potentials underlying the clinical symptoms seen during envenomation. This successful oxidative refolding of synthetic delta-ACTX-Ar1a paves the way for future structure-activity studies to determine the toxin pharmacophore.