A personalized antibody score for predicting individual COVID-19 vaccine-elicited antibody levels from basic demographic and health information

Antibody titers wane after two-dose COVID-19 vaccinations, but individual variation in vaccine-elicited antibody dynamics remains to be explored. Here, we created a personalized antibody score that enables individuals to infer their antibody status by use of a simple calculation. We recently developed a mathematical model of B cell differentiation to accurately interpolate the longitudinal data from a community-based cohort in Fukushima, Japan, which consists of 2,159 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time course of the vaccine-elicited antibody response, we first elucidated individual background factors that contributed to the main features of antibody dynamics, i.e., the peak, the duration, and the area under the curve. We found that increasing age was a negative factor and a longer interval between the two doses was a positive factor for individual antibody level. We also found that the presence of underlying disease and the use of medication affected antibody levels negatively, whereas the presence of adverse reactions upon vaccination affected antibody levels positively. We then applied to these factors a recently proposed computational method to optimally fit clinical scores, which resulted in an integer-based score that can be used to evaluate the antibody status of individuals from their basic demographic and health information. This score can be easily calculated by individuals themselves or by medical practitioners. There is a potential usefulness of this score for identifying vulnerable populations and encouraging them to get booster vaccinations. Significance statementDifferent individuals show different antibody titers even after the same COVID-19 vaccinations, making some individuals more prone to breakthrough infections than others. Such variability remains to be clarified. Here we used mathematical modeling to reconstruct individual post-vaccination antibody dynamics from a cohort of 2,159 individuals in Fukushima, Japan. Machine learning identified several positive and negative factors affecting individual antibody titers. Positive factors included adverse reactions after vaccinations and a longer interval between two vaccinations. Negative factors included age, underlying medical conditions, and medications. We combined these factors and developed an "antibody score" to estimate individual antibody dynamics from basic demographic and health information. This score can help to guide individual decision-making about taking further precautions against COVID-19.

Stratifying elicited antibody dynamics after two doses of SARS-CoV-2 vaccine in a community-based cohort in Fukushima, Japan

Recent studies have provided insights into the effect of vaccine boosters on recall immunity. Given the limited global supply of COVID-19 vaccines, identifying vulnerable populations with lower sustained vaccine-elicited antibody titers is important for targeting individuals for booster vaccinations. Here we investigated longitudinal data in a cohort of 2,526 people in Fukushima, Japan, from April 2021 to December 2021. Antibody titers following two doses of a COVID-19 vaccine were repeatedly monitored and information on lifestyle habits, comorbidities, adverse reactions, and medication use was collected. Using mathematical modeling and machine learning, we stratified the time-course patterns of antibody titers and identified vulnerable populations with low sustained antibody titers. Moreover, we showed that only 5.7% of the participants in our cohort were part of the "durable" population with high sustained antibody titers, which suggests that this durable population might be overlooked in small cohorts. We also found large variation in antibody waning within our cohort. There is a potential usefulness of our approach for identifying the neglected vulnerable population.

Different efficacies of neutralizing antibodies and antiviral drugs on SARS-CoV-2 Omicron subvariants, BA.1 and BA.2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2 has spread in many countries, replacing the earlier Omicron subvariant BA.1 and other variants. Here, using a cell culture infection assay, we quantified the intrinsic sensitivity of BA.2 and BA.1 compared with other variants of concern, Alpha, Gamma, and Delta, to five approved-neutralizing antibodies and antiviral drugs. Our assay revealed the diverse sensitivities of these variants to antibodies, including the loss of response of both BA.1 and BA.2 to casirivimab and of BA.1 to imdevimab. In contrast, EIDD-1931 and nirmatrelvir showed a more conserved activities to these variants. The viral response profile combined with mathematical analysis estimated differences in antiviral effects among variants in the clinical concentrations. These analyses provide essential evidence that gives insight into variant emergences impact on choosing optimal drug treatment.

Characterization of various remdesivir-resistant mutations of SARS-CoV-2 by mathematical modeling and molecular dynamics simulation.

Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection. Significance StatementConsidering the emerging Omicron strain, quick characterization of SARS-CoV-2 mutations is important. However, owing to the difficulties in genetically modifying SARS-CoV-2, limited groups have produced multiple mutant viruses. Our cutting-edge reverse genetics technique enabled construction of eight reporter-carrying mutant SARS-CoV-2 in this study. We developed a mathematical model taking into account sequential changes and identified antiviral effects against mutant viruses with differing propagation capacities and lethal effects on cells. In addition to identifying the positions of mutations, we analyzed the structural changes in SARS-CoV-2 NSP12 by computer simulation to understand the mechanism of resistance. This multidisciplinary approach promotes the evaluation of future resistance mutations.

Designing isolation guidelines for COVID-19 patients utilizing rapid antigen tests: a simulation study using viral dynamics models

Appropriate isolation guidelines for COVID-19 patients are warranted. Currently, isolating for fixed time is adapted in most countries. However, given the variability in viral dynamics between patients, some patients may no longer be infectious by the end of isolation (thus they are redundantly isolated), whereas others may still be infectious. Utilizing viral test results to determine ending isolation would minimize both the risk of ending isolation of infectious patients and the burden due to redundant isolation of noninfectious patients. In our previous study, we proposed a computational framework using SARS-CoV-2 viral dynamics models to compute the risk and the burden of different isolation guidelines with PCR tests. In this study, we extend the computational framework to design isolation guidelines for COVID-19 patients utilizing rapid antigen tests. Time interval of tests and number of consecutive negative tests to minimize the risk and the burden of isolation were explored. Furthermore, the approach was extended for asymptomatic cases. We found the guideline should be designed considering various factors: the infectiousness threshold values, the detection limit of antigen tests, symptom presence, and an acceptable level of releasing infectious patients. Especially, when detection limit is higher than the infectiousness threshold values, more consecutive negative results are needed to ascertain loss of infectiousness. To control the risk of releasing of infectious individuals under certain levels, rapid antigen tests should be designed to have lower detection limits than infectiousness threshold values to minimize the length of prolonged isolation, and the length of prolonged isolation increases when the detection limit is higher than the infectiousness threshold values, even though the guidelines are optimized for given conditions.

Safely return to schools and offices: early and frequent screening with high sensitivity antigen tests effectively identifies COVID-19 patients

BackgroundIn-person interaction at school and offices offers invaluable experience to students and benefits to companies. In the midst of the pandemic, ways to safely go back to schools and offices have been argued. Centers for Disease Control and Prevention (CDC) recommends taking all precautions such as vaccination and universal indoor masking. However, even if all the precautions are implemented and transmission is perfectly prevented in the facilities, they may be infected outside of the facilities, which would be a source of transmission in the facilities. Therefore, identifying those infected outside of the facility through screening is essential to safely go back to schools or offices. However, studies investigating the effectiveness of screening are limited. Further, it is not well clarified now which screening strategy (e.g., low or high sensitivity antigen tests, intervals and the number of tests) effectively identify infected and infectious individuals to avoid transmission in facilities MethodsWe assessed the effectiveness of various screening strategies in schools and offices through quantitative simulation. The effectiveness was assessed by the proportion of identified infected and infectious participants. Infection dynamics in the facility is governed by transmission dynamics of the population they belong to, and the screening is initiated at different epidemic phases: growth, peak, and declining phases. The viral load trajectory over time for each infected individual was modelled by the viral dynamics model, and the transmission process at the population level was modelled by a deterministic compartment model. The model parameters were estimated from clinical and epidemiological data. Screening strategies were varied by antigen tests with different sensitivity and schedules of screening over 10 days. ResultsUnder the daily screening, we found high sensitivity antigen tests (the detection limit: 6.3 x 104 copies/mL) yielded 88% (95%CI 86-89) of effectiveness by the end of 10 days screening period, which is about 20% higher than that with low sensitivity antigen tests (2.0 x 106 copies/mL). Comparing screening scenarios with different schedules, we found early and frequent screening is the key to maximize the effectiveness. Sensitivity analysis revealed that less frequent tests might be an option when the number of antigen tests is limited especially when the screening is performed at the growth phase. DiscussionHigh sensitivity antigen tests, high frequency screening, and immediate initiation of screening are the key to safely restart educational and economic activities allowing in-person interactions. Our computational framework is useful in assessment of screening strategies by incorporating additional factors for specific situations.

Estimation of the incubation period of COVID-19 using viral load data

The incubation period, or the time from infection to symptom onset of COVID-19 has been usually estimated using data collected through interviews with cases and their contacts. However, this estimation is influenced by uncertainty in recalling effort of exposure time. We propose a novel method that uses viral load data collected over time since hospitalization, hindcasting the timing of infection with a mathematical model for viral dynamics. As an example, we used the reported viral load data from multiple countries (Singapore, China, Germany, France, and Korea) and estimated the incubation period. The median, 2.5, and 97.5 percentiles of the incubation period were 5.23 days (95% CI: 5.17, 5.25), 3.29 days (3.25, 3.37), and 8.22 days (8.02, 8.46), respectively, which are comparable to the values estimated in previous studies. Using viral load to estimate the incubation period might be a useful approach especially when impractical to directly observe the infection event.

Rethinking antiviral effects for COVID-19 in clinical studies: early initiation is key to successful treatment

Development of an effective antiviral drug for COVID-19 is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence for effective drugs from clinical studies is limited. The lack of evidence could be in part due to heterogeneity of virus dynamics among patients and late initiation of treatment. We first quantified the heterogeneity of viral dynamics which could be a confounder in compassionate use programs. Second, we demonstrated that an antiviral drug is unlikely to be effective if initiated after a short period following symptom onset. For accurate evaluation of the efficacy of an antiviral drug for COVID-19, antiviral treatment should be initiated before or soon after symptom onset in randomized clinical trials. One Sentence SummaryStudy design to evaluate antiviral effect.

Multidrug treatment with nelfinavir and cepharanthine against COVID-19

Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.

Inferring Timing of Infection Using Within-host SARS-CoV-2 Infection Dynamics Model: Are "Imported Cases" Truly Imported?

In countries/communities at risk of future outbreaks of COVID-19, ascertaining whether cases are imported or the result of local secondary transmission is important for government to shape appropriate public health strategies. In this study, we propose a novel approach to identify the timing of infection, whereby we developed a within-host model to capture viral load dynamics post-symptom onset. We submit our approach allow us to differentiate imported cases from local secondary cases. To illustrate our method, we use the initial reported cases in Singapore, where the first reported 18 cases were considered imported, as these individuals had recent travel history to Wuhan, China, which is a hotspot of COVID-19 outbreak. With additional information regarding day of entrance in Singapore, we were able to infer whether these were infected locally or prior to arriving in Singapore. Of all the cases, we identified 6 as likely evidence of ongoing secondary transmission within Singapore. In an early phase of outbreaks, collecting viral load data over time from cases from symptom onset is highly recommended.

Modelling SARS-CoV-2 Dynamics: Implications for Therapy

The scientific community is focussed on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data collected from the same specimen (throat / nasal swabs or nasopharyngeal / sputum / tracheal aspirate), we compare within-host dynamics for patients infected in the current outbreak with analogous dynamics for MERS-CoV and SARS-CoV infections. Our quantitative analyses revealed that SARS-CoV-2 infection dynamics are more severe than those for mild cases of MERS-CoV, but are similar to severe cases, and that the viral dynamics of SARS-CoV infection are similar to those of MERS-CoV in mild cases but not in severe case. Consequently, SARS-CoV-2 generates infection dynamics that are more severe than SARS-CoV. Furthermore, we used our viral dynamics model to predict the effectiveness of unlicensed drugs that have different methods of action. The effectiveness was measured by AUC of viral load. Our results indicated that therapies that block de novo infections or virus production are most likely to be effective if initiated before the peak viral load (which occurs around three days after symptom onset on average), but therapies that promote cytotoxicity are likely to have only limited effects. Our unique mathematical approach provides insights into the pathogenesis of SARS-CoV-2 in humans, which are useful for development of antiviral therapies. Significance StatementAntiviral agents with different mechanisms of action have different curative effects depending on precisely when therapy is initiated. Based on a model of viral dynamics, parameterised using viral load data from SARS-CoV-2 infected patients reported by Zou et al. (1), computer simulations were performed. We propose that effective treatment of SARS-CoV-2 infection requires an appropriate choice of class-specific drugs and initiation timing as reported for treatment of other viral infections (2); otherwise, antivirals do not have a significant effect on the within-host viral dynamics of SARS-CoV-2 and are wasted.

EEG Revealed That Fragrances Positively Affect Menopausal Symptoms in Mid-life Women

During mid-life, women experienced not only physical but also neurological transition. Because of this, many women suffer from physiological and/or psychological menopausal symptoms. Although hormone therapy (HT) was broadly used to alleviate menopausal symptoms, HT showed inconsistent effects in case of psychological symptoms. Moreover, mid-life women’s brains have distinct characteristics than in other periods of life, it is needed to study psychological symptoms in shifted brain network of mid-life women. As an alternative, inhalation of fragrances may alleviate psychological menopausal symptoms. To characterize the alleviation mechanism by fragrances, we tested the effect of fragrances on menopausal symptoms using electroencephalographic (EEG) methods. We hypothesized that fragrance could restore mid-life women’s brain response to stressful situations. We tested six fragrance conditions, including no-odor condition (solvent only) in twenty-eight mid-life women (49.75 years±3.49).Our results showed that fragrances increased alpha power and decreased β/α ratio depending on the severity of menopausal symptoms in a stressful situation. Our study would be helpful in psychological menopausal symptom alleviation as well as fragrance screening for well-being in mid-life.

Effects of Intra-abdominal Pressure with Visual Feedback on Muscle Activation of Upper Trapezius and Sternomastoid during Forced Inspiration in Individuals with Costal Respiration

Purpose@#This study analyzed the immediate effects of intra-abdominal pressure with visual feedback on the muscle activation of the upper trapezius and sternomastoid during natural inspiration and forced inspiration in individuals with costal respiration. @*Methods@#The eighteen individuals with upper costal breathing pattern participated in this study. Surface electromyography was used to analyze the muscle activity of the upper trapezius and sternomastoid during natural inspiration and forced inspiration before and after intra-abdominal pressure. @*Results@#A significant difference in muscle activation was observed with the muscle type, inspiration type, and test session (p0.05). A comparison of the difference between the pre-test and post-test during forced inspiration revealed the upper trapezius to be significantly larger than the sternomastoid (p0.05). @*Conclusion@#The intra-abdominal pressure has positive effects on correcting the breathing patterns in individuals with costal respiration.

Effects of Intra-abdominal Pressure with Visual Feedback on Muscle Activation of Upper Trapezius and Sternomastoid during Forced Inspiration in Individuals with Costal Respiration

Purpose@#This study analyzed the immediate effects of intra-abdominal pressure with visual feedback on the muscle activation of the upper trapezius and sternomastoid during natural inspiration and forced inspiration in individuals with costal respiration. @*Methods@#The eighteen individuals with upper costal breathing pattern participated in this study. Surface electromyography was used to analyze the muscle activity of the upper trapezius and sternomastoid during natural inspiration and forced inspiration before and after intra-abdominal pressure. @*Results@#A significant difference in muscle activation was observed with the muscle type, inspiration type, and test session (p0.05). A comparison of the difference between the pre-test and post-test during forced inspiration revealed the upper trapezius to be significantly larger than the sternomastoid (p0.05). @*Conclusion@#The intra-abdominal pressure has positive effects on correcting the breathing patterns in individuals with costal respiration.

Minimal Stitch Canalicular Repair of Canalicular Lacerations

PURPOSE: To examine the results of minimal stitch on the restoration of tissue after canalicular laceration. METHODS: We have operated using sutures of tissues around canalicular laceration by inserting bicanalicular silicone stents and minimal horizontal mattress sutures with 8-0 Vicryl in cases of canalicular laceration instead of the existing method for the past 6 years. The ages of patients ranged from 2 to 76 years (average age 39.8+/-17.4 years), with most patients in their thirties (12 patients, 40%), 30 cases underwent canalicular repair with minimal stitch and bicanalicular silicone stent insertion within 24 hours after trauma. The silicone stent was removed 3 months after the operation if the patient did not complain of epiphroa while the canalicular remained open. RESULTS: Twenty-five eyes (83.3%) showed symptom improvement and good passage in lacrimal syringing test in 4~12 months (average: 6.8+/-2.2 months) of follow-up study. Complications included one case each of fistula formation, stent prolapse, and wound infection, and two cases of canalicular stenosis. CONCLUSIONS: We recommend this method because of its satisfying success ratio.

A Case of Recurrent Transient Global Amnesia

Transient global amnesia(TGA) is a transient neurological syndrome, which occurs mostly once in life. Although the pathophysiology of TGA is not yet clear, there are well-known precipitating events such as emotional stress, physical exertion, sexual intercourse, painful experiences, and immersion in cold water. We report a 67-year-old man who developed recurrent amnestic episodes fulfilling the criteria for TGA. He had vascular risk factors and precipitating events. We suggest that the number of trigger events and vascular risk factors is associated with TGA recurrence.

Bilateral Facial Nerve Palsy after Mycoplasma Pneumoniae Infection: A Variant of Guillain-Barre Syndrome?

A 9-year-old girl presented with bilateral facial weakness since 10 days after upper respiratory infection. Blink reflex studies and nerve conduction studies suggested bilateral lesions of proximal facial nerves. Her serum was strongly positive for IgM antibodies to Mycoplasma pneumoniae and mildly for IgM to galactocerebroside and albuminocytologic dissociation was found in her cerebrospinal fluid. This case is of the bilateral facial neuropathy by Mycoplasma pneumoniae infection suggesting a variant of Guillain-Barre syndrome.

Assessment for the Role of Serotonin Receptor Subtype 3 for the Analgesic Action of Morphine at the Spinal Level / 대한통증학회지

BACKGROUND: Serotonin 3 receptor is involved in the modulation of nociceptive transmission in the spinal cord. The serotonin 3 receptor antagonist has been used for the management of opioid-induced nausea and vomiting. The aim of this study was to examine whether the analgesic effect of morphine is antagonized by serotonin 3 receptor antagonists at the spinal level. METHODS: Rats were implanted with lumbar intrathecal catheters. For nociception, a formalin solution (5%, 50microliter) was injected into the hind paw of male Sprague-Dawley rats. To determine whether the effect of intrathecal morphine was mediated via serotonin 3 receptors, serotonin 3 receptor antagonists were intrathecally administered 10 min prior to the morphine delivery. Following the formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. RESULTS: Intrathecal morphine produced a dose-dependent suppression of the flinches in both phases during the formalin test. The analgesic action of morphine was not reversed by serotonin 3 receptor antagonists (LY-278, 584, ondansetron), which had little per se effect on the formalin-induced nociception. CONCLUSIONS: Spinal serotonin 3 receptors may not be involved in the analgesia of morphine on a nociceptive state evoked by a formalin stimulus.

Study for the Antinociceptive Effect and Toxicity of Chronic Intrathecal Infusion of Cannabinoids in Rats / 대한통증학회지

BACKGROUND: Cannabinoids have shown antinociceptive action. The aims of this study were to examine the effect of chronic infusion of a cannabinoids receptors agonist (WIN 55, 212-2) for thermal nociception at the spinal level, and to also observe the development of toxicity. METHODS: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters with the nociceptive response (withdrawal response latency) determined by exposing the plantar surface of the hindpaw to radiant heat. Initially, the effect of intrathecal WIN 55, 212-2 was evaluated followed by the change in the effect at 1, 2, 3 and 4 weeks after repeated infusion. Finally, the histopathological findings were assessed 1 and 4 weeks following the infusion of WIN 55, 212-2. RESULTS: Intrathecal WIN 55, 212-2 was found to produce a limited antinociception during the thermal test. %MPE of WIN 55, 212-2 at 1, 2, 3, and 4 weeks after infusion was not different from each other. No abnormal pathological findings were observed following a chronic intrathecal infusion of WIN 55, 212-2. CONCLUSIONS: WIN 55, 212-2, a cannabinoids receptors agonist, may be useful in the management of thermal nociception, without changing the effectiveness or causing the toxicity following a chronic infusion at the spinal level.

Vocal Cord Paralysis after the Coronary Artery Bypass Graft: A Case Report / 대한구급학회지

Surgical trauma has long been recognized as the most common cause of unilateral and bilateral vocal cord paralysis. We experienced a case of bilateral vocal cord paralysis after off-pump coronary artery bypass graft. The patient was repeated intubation and extubation after operation in surgical intensive care unit. Fiberoptic bronchoscopy revealed bilateral vocal cord paralysis in the patient. The patient recovered after permanent tracheotomy. We reported a case of vocal cord paralysis after coronary artery bypass graft.