Innovative experimental animal models for real-time comparison of antithrombogenicity between two oxygenators using dual extracorporeal circulation circuits and indocyanine green fluorescence imaging.

BACKGROUND: Antithrombogenicity of extracorporeal membrane oxygenation (ECMO) devices, particularly oxygenators, is a current problem, with numerous studies and developments underway. However, there has been limited progress in developing methods to accurately compare the antithrombogenicity of oxygenators. Animal experiments are commonly conducted to evaluate the antithrombogenicity of devices; however, it is challenging to maintain a steady experimental environment. We propose an innovative experimental animal model to evaluate different devices in a constant experimental environment in real-time. METHODS: This model uses two venous-arterial ECMO circuits attached to one animal (one by jugular vein and carotid artery, one by femoral vein and artery) and real-time assessment of thrombus formation in the oxygenator by indocyanine green (ICG) fluorescence imaging. Comparison studies were conducted using three pigs: one to compare different oxygenators (MERA vs. CAPIOX) (Case 1), and two to compare antithrombotic properties of the oxygenator (QUADROX) when used under different hydrodynamic conditions (continuous flow vs. pulsatile flow) (Cases 2 and 3). RESULTS: Thrombi, visualized using ICG imaging, appeared as black dots on a white background in each oxygenator. In Case 1, differences in the site of thrombus formation and rate of thrombus growth were observed in real-time in two oxygenators. In Case 2 and 3, the thrombus region was smaller in pulsatile than in continuous conditions. CONCLUSIONS: We devised an innovative experimental animal model for comparison of antithrombogenicity in ECMO circuits. This model enabled simultaneous evaluation of two different ECMO circuits under the same biological conditions and reduced the number of sacrificed experimental animals.

Changes in the Characteristics and Outcomes of COVID-19 Patients from the Early Pandemic to the Delta Variant Epidemic: A Nationwide Population-based Study.

The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed because of virus mutations, vaccine dissemination, treatment development and policies, among other factors. These factors have a dynamic and complex effect on the characteristics and outcomes of patients. Therefore, there is an urgent need to understand those changes and update the evidence. We used a large-scale real-world data set of 937,758 patients with COVID-19 from a nationwide claims database that included outpatients and inpatients in Japan to investigate the changes in their characteristics, outcomes and risk factors for severity/mortality from the early pandemic to the delta variant-predominant waves. The severity of COVID-19 was defined according to the modified World Health Organization clinical-progression ordinal scale. With changing waves, mean patient age decreased, and proportion of patients with comorbidities decreased. The incidences of "severe COVID-19 or death (i.e. ≥severe COVID-19)" and "death" markedly declined (5.0% and 2.9%, wild-type-predominant; 4.6% and 2.2%, alpha variant-predominant and 1.4% and 0.4%, delta variant-predominant waves, respectively). Across the wave shift, risk factors for ≥severe COVID-19 and death, including older age, male, malignancy, congestive heart failure and chronic obstructive pulmonary disease, were largely consistent. The significance of some factors, such as liver disease, varied as per the wave. This study, one of the largest population-based studies on COVID-19, showed that patient characteristics and outcomes changed during the waves. Risk factors for severity/mortality were similar across all waves, but some factors were inconsistent. These data suggest that the clinical status of COVID-19 will change further with the coming epidemic wave.

Clinical practice of high-flow nasal cannula therapy in COVID-19 pandemic era: a cross-sectional survey of respiratory physicians.

BACKGROUND: Despite the rapid widespread use of a high-flow nasal cannula (HFNC) during the COVID-19 pandemic, its indications and appropriate use as perceived by physicians remain poorly known. METHODS: In September 2021, we sent a questionnaire to each respiratory physician from 15 institutions in Shizuoka prefecture, Japan. In this survey, we compared the perceptions of HFNC indications and interventions during implementation to those of non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV). Furthermore, this study examined concerns about SARS-CoV-2 infection spread and psychological distress experienced among respondents. RESULTS: Of the 140 respiratory physicians contacted, 87 (62.1%) completed the survey. The results indicate that 96.5% of the respondents agreed with the indication of HFNC for COVID-19, whereas only 13.7% agreed with NIV. The physicians reported that patients with HFNC had a lower frequency of sustained sedation, physical restraint, and implementation in the ICU than that of patients with NIV and IMV. The HFNC was introduced as a respiratory modality following conventional oxygen therapy (COT) in patients with COVID-19, regardless of full or do-not-intubate codes. Additionally, they reported that patients with COVID-19 switched from COT to HFNC significantly earlier than those without COVID-19. Simultaneously, this survey revealed persistent concerns of SARS-CoV-2 infection spread and psychological distress (47.1% and 53.3%, respectively) among respiratory physicians during HFNC use. CONCLUSION: Clinically, HFNC is considered useful for COVID-19 patients by most respiratory physicians. However, HFNC remains a concern for COVID-19 spread and psychological distress among several respiratory physicians, indicating the need for urgent action.

Relationship Between High Organ Donation Rates and COVID-19 Vaccination Coverage.

Background: Besides attaining the goal of self-protection, the rollout of vaccination programs also encourages altruistic practices. Therefore, the progress in vaccination against coronavirus disease (COVID-19) in each country may be related to the prevalence of cooperative and altruistic practices in health care. I hypothesized that in countries where organ donation is popular, individuals would exhibit a greater tendency to become vaccinated. Methods: I examined the correlation between the level of progress of COVID-19 vaccination and the status of organ donation just before the pandemic in Organization for Economic Co-operation and Development (OECD) countries. Publicly available statistical information on the progress of immunization and organ donation was used. Univariate and multivariate analyses were conducted to examine common drivers of immunization and organ donation. Results: In OECD countries, progress in vaccination was found to be significantly correlated with the status of organ donation in each country. This relationship was stable after the summer (September 1: Pearson's r = 0.442, October 1: 0.457, November 1: 0.366). The results of the univariate and multivariate analyses showed that high trust in medical professionals was significantly correlated with both the "progress of vaccinations" and "organ donations." Conclusions: Progress in COVID-19 vaccination and organ donation status for transplantation have similar trends, and both may involve people's trust in medical personnel and public health systems. Similar to the efforts to obtain organ donors, governments around the world need to take further steps to ensure that vaccination programs are supported by people's trust and sense of solidarity.

Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants.

Background: The immune profile against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by Omicron in individuals with various immune histories. Methods: The neutralization susceptibility of the variants, including Omicron and their ancestors, was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections of Alpha/Delta with multiple time intervals following vaccination. Findings: Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against Omicron was induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies. Conclusions: Immune histories with breakthrough infections can overcome the resistance to infection by Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against Omicron and future variants. Funding: This study was supported by grants from the Japan Agency for Medical Research and Development (AMED).

Transient leukocytopenia following combination therapy for COVID-19.

BACKGROUND: Combination therapy with dexamethasone, remdesivir, and baricitinib has become a promising treatment for moderate or severe COVID-19; however, we have observed transient leukocytopenia in COVID-19 patients who received combination therapy. METHODS: Twelve consecutive COVID-19 patients treated with combination therapy were included in this retrospective analysis. Blood cell counts collected at the following three time points were analyzed: before the start of therapy (period 1), within 24 h of starting therapy (period 2), and within 48 h of period 2 (period 3). RESULTS: The leukocyte count significantly decreased in period 2 compared to period 1 and then significantly increased in period 3 without withdrawal of baricitinib. The neutrophil count transiently decreased in period 2 and recovered in period 3. CONCLUSIONS: Clinicians should be aware of transient leukocytopenia in patients with COVID-19 during the early phase of combination therapy.

Novel application of indocyanine green fluorescence imaging for real-time detection of thrombus in a membrane oxygenator.

Extracorporeal membrane oxygenation (ECMO) plays an important role in the coronavirus disease 2019 (COVID-19) pandemic. Management of thrombi in ECMO is generally an important issue; especially in ECMO for COVID-19 patients who are prone to thrombus formation, the thrombus formation in oxygenators is an unresolved issue, and it is very difficult to deal with. To prevent thromboembolic complications, it is necessary to develop a method for early thrombus detection. We developed a novel method for detailed real-time observation of thrombi formed in oxygenators using indocyanine green (ICG) fluorescence imaging. The purpose of this study was to verify the efficacy of this novel method through animal experiments. The experiments were performed three times using three pigs equipped with veno-arterial ECMO comprising a centrifugal pump (CAPIOX SL) and an oxygenator (QUADROX). To create thrombogenic conditions, the pump flow rate was set at 1 L/min without anticoagulation. The diluted ICG (0.025 mg/mL) was intravenously administered at a dose of 10 mL once an hour. A single dose of ICG was 0.25mg. The oxygenator was observed with both an optical detector (PDE-neo) and the naked eye every hour after measurement initiation for a total of 8 hours. With this dose of ICG, we could observe it by fluorescence imaging for about 15 minutes. Under ICG imaging, the inside of the oxygenator was observed as a white area. A black dot suspected to be the thrombus appeared 6-8 hours after measurement initiation. The thrombus and the black dot on ICG imaging were finely matched in terms of morphology. Thus, we succeeded in real-time thrombus detection in an oxygenator using ICG imaging. The combined use of ICG imaging and conventional routine screening tests could compensate for each other's weaknesses and significantly improve the safety of ECMO.

SARS-CoV-2 Human Challenge Trials: Rethinking the Recruitment of Healthy Young Adults First.

In the midst of the ongoing Covid-19 pandemic, researchers across the globe are still working to develop effective vaccines. To expedite this process even further, human challenge trials have been proposed by the World Health Organization (WHO) as an alternative to conventional approaches. In such trials, healthy volunteers are deliberately infected with the pathogen of interest, enabling scientists to study the infection process and facilitate further research on treatments or prophylactics, including vaccines. While human challenge trials would offer a collective benefit to society, minimizing the risks is always difficult. Ethical controversy thus inevitably surrounds these trials. Typically, healthy young adults are recruited to serve as the first candidate subjects for human challenge trials because they are generally considered to represent a low-risk population. Here, we present three reasons for doubt about this healthy-young-adults-first criterion and give justification for also recruiting healthy older adults (or not-young adults), meaning those over 30 years of age, to participate in such trials for SARS-CoV-2.