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BackgroundAnti-MDA5 antibody positive dermatomyositis (MDA5-DM) is characterized by high mortality due to rapid progressive ILD. MDA5 is a cytosolic protein and a family of RIG-I like receptor, which functions as a virus RNA sensor and induces the production of such as type-1 IFN. Although little is known about the pathogenesis of MDA5-DM, it is notable that the similarities were reported between COVID-19 infection and MDA5-DM. It may suggest that there is a common underlying autoinflammatory mechanism. We reported that in MDA5-DM, (1) RIG-I-like receptor signaling is enhanced and (2) antiviral responses such as type 1 IFN signaling are also enhanced as compare with anti-ARS-antibody positive DM, and (3) the key for survival is suppression of RIG-I-like and IFN signaling (EULAR2022, POS0390). We also found that a significant role for uncontrolled macrophage in the pathogenesis of ILD by our autopsy case. Recently, it has been reported that tacrolimus (TAC) and cyclophosphamide (CY) combination therapy (TC-Tx) has improved the prognosis of cases with early onset of the disease, but there are cases that cannot be saved. Therefore, we devised BRT therapy (BRT-Tx). The Tx combines baricitinib (BAR), which inhibits GM-CSF and IFN-mediated signaling and effectively suppresses uncontrolled macrophages, with rituximab (RTX) and TAC, which rapidly inhibits B and T cell interaction and ultimately prevents anti-MDA5 antibody production.ObjectivesTo determine the differences in gene expression between BRT and TC-Tx for MDA5-DM in peripheral blood.MethodsTotal of 6 MDA5-DM (TC: 3, BRT: 3) were included and all of them had multiple poor prognostic factors. Peripheral whole blood was collected at just before and 2-3 months after the treatment. RNA was extracted, and quantified using a next-generation sequencer. Differentially Expressed Genes (DEGs) were identified by pre vs. post treatment. Gene Ontology (GO), clustering and Gene Set Variation Analysis (GSVA) were performed to DEGs. As one BRT case was added since our last year's report, we also reanalyzed the surviving vs. fatal cases. The IFN signature was scored separately for Types 1, 2, and 3, and the changes between pre- and post-treatment were investigated.ResultsTwo of three cases with TC died during treatment, while all three cases on BRT recovered. The cluster analysis of the DEGs separated deaths from survivors, not by type of treatment. Comparing surviving and dead cases, GO analysis revealed that the immune system via immunoglobulins and B cells was significantly suppressed in surviving cases. GO analysis of DEGs in each therapeutic group showed that expression of B cell-related genes such as lymphocyte proliferation and B cell receptor signaling pathway were significantly suppressed in BRT-Tx. On the other hand, TC-Tx significantly suppressed such pathways as cell proliferation and cell surface receptor signaling, and was less specific for the target cells than BRT-Tx. The changes in IFN signature score after treatment showed an increase in type 2 and 3 IFN scores in all fatal cases and an increase in type 1 IFN score in one fatal case.ConclusionBRT-Tx significantly suppressed gene expression associated with B cells, while TC-Tx was characterized by low specificity of therapeutic targets and suppression of total cell proliferation. Comparison of surviving and dead cases revealed that the combination of RTX contributed to the success of treatment, as suppression of the immune system mediated by immunoglobulins and B cells is the key for survival. Analysis of the IFN signature revealed an increase in IFN score after treatment in fatal cases, indicating that the combination of BAR is beneficial. The superiority of BRT-Tx seems clear from the fact that all patients survived with BRT-Tx while only one/three patients survived with TC-Tx.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsMoe Sakamoto: None declared, Yu Nakai: None declared, Yoshiharu Sato: None declared, Yoshinobu Koyama Speakers bureau: Abbvie, Asahikasei, Ayumi, BMS, Esai, Eli-Lilly, Mitsubishi Tanabe, Grant/research support from: Abbvie, GSK.
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Objectives: Various reagents and equipment for testing SARS-CoV-2 infections have been developed, particularly rapid molecular tests based on polymerase chain reaction (PCR). Methods: We evaluated the analytical performance of four rapid molecular tests for SARS-CoV-2. We used 56 nasopharyngeal swabs from patients with confirmed SARS-CoV-2 infection;36 diagnosed as positive by the AmpdirectTM 2019-nCoV Detection Kit (Shimadzu assay) were considered as true-positive samples. Results: The sensitivity of CobasR Liat SARS-CoV-2 and Flu A/B (Cobas) was the highest among the four molecular test kits. The limit of detection was 1.49 x 10-2 copies/ micro L (95% confidence interval [CI]: 1.46x10-2-1.51 x 10-2 copies/ micro L) for Cobas;1.43 x 10-1 copies/ micro L (95% CI: 8.01x10-3-2.78 x 10-1 copies/ micro L) for XpertR Xpress SARS-CoV-2 test (Xpert);2.00 x 10-1 copies/ micro L (95% CI: 1.95x10-1-2.05 x 10-1 copies/ micro L) for FilmArray Respiratory Panel v2.1 (FilmArray);and 3.33 x 10 copies/ micro L (95% CI: 1.93 x 10-4.72x10 copies/ micro L) for Smart GeneR SARS-CoV-2 (Smart gene). Cobas also had a high sensitivity (100%) compared with Shimadzu assay. The sensitivities of Xpert, FilmArray, and Smart Gene were 97.2%, 97.2%, and 75.0%, respectively. The specificity of all tests was 100%. Conclusions: In conclusion, the four rapid SARS-CoV-2 molecular test kits have high specificity and sensitivity for detecting SARS-CoV-2. As they are easy to use, they could be a useful method for detecting SARS-CoV-2.
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Ionizable lipids with branched tails have been used in lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics like COVID-19 vaccines. However, due to the limited commercial availability of branched ingredients, a systematic analysis of how the branched tails affect LNP quality has been lacking to date. Herein, a-branched tail lipids are focused, as they can be synthesized from simple commercially available chemicals, and the length of each chain can be independently controlled. Furthermore, symmetry and total carbon number can be used to describe a-branched tails, facilitating the design of a systematic lipid library to elucidate "structure-property-function" relationships. Consequently, a lipid library is developed containing 32 different types of a-branched tails. This library is used to demonstrate that branched chains increase LNP microviscosity and headgroup ionization ability in an acidic environment, which in turn enhances the stability and in vivo efficacy of mRNA-LNPs. Of the branched lipids, CL4F 8-6 LNPs carrying Cas9 mRNA and sgRNA could achieve 54% genome editing and 77% protein reduction with a single dose of 2.5 mg kg(-1). This mechanism-based data on branched lipids is expected to provide insights into rational lipid design and effective gene therapy in the future.
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The deterioration of chemicals contained in safety devices is an important issue because such devices must be ready for emergencies and should remain functional for a long period of time, even when exposed to degrading environments. In this study, we focused on the influence of ozone disinfection on chemicals present in safety devices as ozone can be used for virus inactivation in compartments housing these devices. Specifically, we conducted accelerated deterioration tests to evaluate the effects of ozone exposure on guanidine nitrate (GN).Under the experimental conditions of this study, ozone-containing water deteriorated GN, whereas no change was observed in GN exposed to dry ozone. The ion chromatography (IC) analysis of the deteriorated product suggested that GN decomposed into nitrate ions, while capillary electrophoresis (CE) revealed a transformation of guanidine ions into ammonium ions. These results imply that GN deterioration produces ammonium nitrate. Additionally, ultraviolet-visible spectroscopy revealed the reaction products between GN and ozone, which were considered electrically neutral because of their absence in the results of IC and CE analyses.In a differential accelerating rate calorimeter, decomposition started at a lower temperature for the deteriorated GN than for the pristine sample. This indicates that the deterioration products affected the thermal decomposition behavior of GN. This change in exothermic and pressure-release behavior is considered to have an impact on the performance of pyrotechnics using GN.
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As the news coverage on COVID-19 continues to accumulate, there is a need to analyze this coverage to critically examine the role of the mass media during the pandemic. This cross-cultural study conducts a qualitative analysis and quantitative comparison of the American, German, and Japanese quality newspaper coverage of COVID-19. Following a thematic analysis approach, this study analyzed 117 newspaper articles through the creation of a codebook with 133 codes. Results show how the media in all countries underrated the risk of the pandemic in its initial stage, while also focusing on people's fear of the pandemic. In American and Japanese newspapers exists a tendency for criticism against the Chinese government, while German newspaper articles appear critical of the use of face masks. The methodological approach of this study highlights the merits of combining qualitative analysis and quantitative comparison to identify and cross-culturally compare elusive themes in media texts. © 2022 IEEE.
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Objectives: In Shiga Prefecture, the third wave of a novel coronavirus infection (COVID-IQ) caused an imminent tightness of hospital beds. In this study, we constructed a mathematical model of infectious disease to conduct a sensitivity analysis and evaluated the effectiveness of policy interventions and medical systems management to avoid the shortage of hospital beds.
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Background: Early approval of COVID-19 vaccine has significant benefits for cancer patients treated under the COVID-19 pandemic worldwide. However, there has been limited reports that investigated the safety and efficacy of vaccination in cancer patients and the optimal timing of vaccination during chemotherapy. We therefore investigated the effects of vaccination on treatment in cancer patients receiving chemotherapy. Methods: Our retrospective observational study included 52 patients with gastrointestinal (GI) cancer receiving chemotherapy at the medical hospital of Tokyo Medical and Dental University in Tokyo who had two doses of mRNA COVID-19 vaccine (Pfizer-BioNTech or Moderna) between May 2021 and September 2021. All patients had no history of COVID-19 infection. Treatment- and vaccination-related adverse events were recorded by outpatient interviews and self-reports. All adverse events were evaluated using CTCAE v5.0. Results: Characteristics of patients were as follows (N = 52): median age, 70y (range, 49-89);male/female, 30/22;ECOG PS 0, 75%;local/metastatic, 12/40;mean BMI, 23.4±4.1;comorbidities in 36 (cardiovascular in 24, diabetes in 8, kidney disease in 8, liver disease in 6, lung disease in 1);treatment (cytotoxic in 45, biologics in 23, immune checkpoint inhibitor in 4). Of the 52 patients, 45 received chemotherapy prior to vaccination;days from last dose to first vaccination, median 11 (range, 1-70);days from first to second vaccinations, median 21 (range, 21-41);days from first vaccination to chemotherapy, median 10 (range, 2-34). 11 patients (24.4%) changed treatment schedule: 3 for safety reasons, 4 for myelosuppression and 4 for convenience. 4 patients stopped treatment due to disease progression. Following the first vaccination, 37 patients (82.2%) had adverse events (AEs): injection site pain (n = 35), fatigue (n = 6), fever (n = 3), headache (n = 2), gastrointestinal symptoms (n = 2), redness (n = 1), insomnia (n = 1). There was no treatment- and vaccine-related deaths. Conclusions: Our findings suggest that vaccine-related AEs in GI cancer patients receiving chemotherapy are tolerable, and treatment schedule changes could be minimized. Although careful monitoring is required, COVID-19 vaccination is also recommended for cancer patients toward the convergence of the COVID-19 pandemic.
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Objectives An effective vaccine against SARS-CoV-2 is essential to mitigate the COVID-19 pandemic. In these several months, a number of groups have started to report humoral responses and side effects after BNT162b2 vaccinations. Although these reports demonstrate the safety and efficacy, further studies are warranted to verify these findings. Here we examined the levels of SARS-CoV-2 antibodies in Japanese healthy volunteers who underwent BNT162b2 vaccine, to assess the humoral responses and side effects. Methods Forty-one healthy volunteers' samples were used for the measurement of SARS-CoV-2 antibodies with chemiluminescent assays against the Receptor Binding Domain (RBD) of the virus. We also measured the side effects of the vaccination. Results Although the levels of IgM varied, all participants were seronegative for IgM and IgG before vaccination, and both IgM and IgG were significantly increased after the vaccinations. We further analyzed the humoral responses in relation to age, and found that the IgG levels for 14 days and 35 days, and IgM levels for 14 days after vaccination showed clear declining trends with age. Commonly reported side effects in the participants were sore arm/pain (90.0%) after the first dose, and generalized weakness/fatigue (70.0%), fever (57.5%), and sore arm/pain (90.0%) after the second dose. Conclusions BNT162b2 vaccination generates sufficient production of IgG especially after the second dose, though the response decreases age-dependently. The high frequencies of generalized weakness/fatigue, fever, and sore arm/pain were not negligible, especially after the second dose. This may be associated with the age characteristics of the population.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rapidly spreading globally. Early diagnosis plays an essential role in controlling the infection. Therefore, early and accurate SARS-CoV-2 detection assays along with easy operation are required. The aim of this study was to compare the clinical performance of the Ampdirect™ 2019-nCoV Detection Kit (SHIMADZU assay), which does not require RNA purification steps, with that of the preexisting SARS-CoV-2 detection assays, which use a purified RNA template. A total of 71 samples (65 nasopharyngeal specimens and 6 sputum specimens) were collected from 32 individuals, including patients infected with SARS-CoV-2 and those with suspected infection. The sensitivity and kappa (κ) coefficient were assessed between the SARS-CoV-2 detection assays using the reference standard, which was defined as a true positive result by any one of the four SARS-CoV-2 detection assays. The overall sensitivity and κ coefficient of the SHIMADZU assay were 86.0% (95% confidence interval [CI]: 77.9-94.2) and 0.83 (95% CI: 0.69-0.96), respectively. In particular, among the 18 samples collected within 10 days from symptom onset, the sensitivity and κ coefficient of the SHIMADZU assay were 100% and 1.0, respectively. Although a relatively small number of samples was evaluated, the SHIMADZU assay showed good analytical performance and as such would be highly useful for the detection of SARS-CoV-2. The test can be performed easily and quickly and has the potential for future applications in situations where a highly sensitive diagnosis is required. © 2021
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Poor healthcare infrastructure is the main barrier for providing quality healthcare services to rural communities in developing countries. Thus, these populations remain unreached, and there is a need to establish a method for ensuring the provision of appropriate and adequate healthcare services to these individuals. The portable health clinic (PHC) system has been developed as an effective telemedicine system to meet this objective. A trained village health worker can use this simple system for collecting vital information of the patient, upload the data to the online server, and connect village patients with a remote doctor to enable the provision of online consultancy using video conferencing. Although the PHC was initially developed to ensure primary healthcare service with a focus on non-communicable diseases, a major cause of death, gradually, tele-pathology, tele-eye care, maternal and child health care, and COVID-19 care modules have been added to provide special treatment in these areas as per local needs. The modular PHC system will continue to grow with the addition of novel features that aim to address the local needs. The low-cost and easy operation of the PHC system make it ideal for ensuring global health coverage in communities where inadequate medical facilities and poor-quality healthcare resources remain major issues. © 2021 The authors and IOS Press.
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Background: 5Ms provide a framework for the care of older adults1. We present a case in which 5Ms were used in inpatient geriatric consultation on a senior psychiatric unit. Case: A 71-year-old male was hospitalized for worsening paranoia with increased frequency of falls and weight loss due to eating refusal. He has a PMH of schizoaffective disorder, traumatic brain injury, and HTN. We identified the following using 5Ms as the structure for consultation: 1) Mind: MOCA of 16/30 compared to 23/30 1 year prior, PHQ-9 of 23 from 11 points 6 months prior, and severe decrease in his interests after the start of SARS COV-2 pandemic. 2) Mobility: Get Up and Go Test <20 seconds, 3 falls in preceding 24 hours. 3) Medications: Recent increase in clonazepam from 0.25 to 0.5 mg twice daily, sertraline 100 mg daily, aripiprazole 30 mg daily, trazodone 50 mg nightly, losartan discontinued for hypotension. 4) Multi-Complexity: He has a long history of schizoaffective disorder requiring multiple lengthy hospitalizations in the past. At age 63, he sustained a subdural hematoma during a bicycle accident that resulted in gradual decline in cognition and memory. His brother is the only remaining kin and has durable power of attorney for finances, but not for healthcare. 5) Matters Most: He is independent with ADLs and dependent for all iADLs. He wishes to return home after discharge, which his brother is amenable to only if his paranoia can be controlled. Discussion: In this case scenario, we present a patient with repeated hospitalizations who required a multi-model assessment of his medical, psychiatric, and psychosocial background to effectively arrive to a care plan. Through the framework of 5Ms, such complex cases can be effectively and comprehensively cared for with the assistance of an interdisciplinary team. We shared our findings with the interdisciplinary team that resulted in iADL re-training, acceptance and commitment therapy, evaluation for assistive devices, and management of polypharmacy by discontinuing trazodone, de-escalating clonazepam and sertraline, and initiating clozapine and mirtazapine to provide goal-aligned care.
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Background: Telestroke network can provide rapid access to specialized treatment and improves on-site management of acute stroke patients through the “hub-and-spoke” model. In the northern part of Okayama Prefecture, there has been a regional gap of stroke care due to the shortage of stroke specialists and facilities. In addition, due to the novel coronavirus disease 2019 (COVID-19), it is required to reduce the unnecessary contact with stroke patients from other hospitals. Aim: We organized a novel cost-free telestroke network with an image and video sharing for neurological diseases in the northern part of Okayama Prefecture to improve the stroke management in the area. Method: We prepared the tablet device on which Skype® application was installed for each hospital and recruited the patients who visited or hospitalized in the spoke hospitals and were suspected to have some neurological diseases from April 2019 to May 2020. The patient's clinical data were recorded and analyzed. Results: During the study period, 5 patients were recruited including the cases with the initial diagnosis of stroke or brain tumor. Among them, 2 cases were transferred to the hub hospital, 2 cases were transferred to other hospitals, and 1 case was treated on site under specialist's advice. Conclusion: The new telestroke network system may be beneficial for acute stroke management and reducing the unnecessary patient's transfer in the rural area, especially under coexistence with COVID-19.
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[Purpose] To examine the health-related quality of life of community-dwelling elderly by age group in the early stage of the coronavirus disease (COVID-19) pandemic. [Participants and Methods] The subjects were 201 older adults who had attended a university open lecture at least once in the past. Responses to a questionnaire, sent to the participants on April 1st, 2020, were compared with those collected after the most recent open lecture. The questionnaire items included age, outing frequency, and the Short Form-36 item health survey ver.2 (SF-36). [Results] For those in their 60s and 70s, the scores for “Physical functioning”, “Social functioning” and “Mental health” were significantly lower after the start of the COVID-19 pandemic than before. For those in their 80s, there was no significant difference between the SF-36 scores recorded before and after the start of the COVID-19 pandemic. [Conclusion] Care for older adults in an emergency situation should be tailored according to age group. © 2020, Society of Physical Therapy Science (Rigaku Ryoho Kagakugakkai). All rights reserved.
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The emergence of novel, as well as re-emergence of serious respiratory viral diseases in the current decade is of particular concern. Fatal acute respiratory distress syndrome (ARDS) with rapid deterioration of vital organ functions has been observed in some patients infected with the highly pathogenic influenza virus strains, severe acute respiratory syndrome coronavirus (SARS-CoV), and middle east respiratory syndrome corona virus (MERS-CoV). The common manifestations of virus-induced fatal ARDS are cytokine storm and activation of monocytes/macrophages, characterized as secondary hemophagocytic syndrome (HPS)/hemophagocytic lymphohistiocytosis (HLH). However, infection-induced HPS/HLH is likely to be under-recognized, which could contribute to the serious progression and high mortality. Since there are no established criteria for the diagnosis of infection-induced HPS/HLH, early recognition is crucial for any reasonable attempt at curative treatment. Etoposide (ET), a cytotoxic agent, and corticosteroids (CS), with their strong anti-inflammatory activities, have been used to treat other diseases with similar pathophysiology, namely, cytokine-activated macrophages and hemophagocytic activity, but it remains unknown whether these agents can also influence the clinical outcomes in patients with fatal ARDS and secondary HPS/HLH. We established an animal model of fatal ARDS, with severe lung injury, hypercytokinemia, and hemophagocytosis. Using this animal model, we demonstrated that combined therapy with ET plus CS, targeting monocytes/macrophages, but not inflammatory cytokines, had the potential to attenuate the severity of fatal ARDS. Specific treatment against HPS/HLH, including combined ET plus CS therapy, could be considered in patients with fatal ARDS complicated by secondary HPS/HLH. To improve the outcomes in patients with infection-induced fatal ARDS, clinical and basic science studies are needed in the future to elucidate the mechanisms underlying the pathogenesis of ARDS and identify new treatment targets.
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This paper presents and evaluates a new educational tool and a model for learning theory and practice of game development, by involving geographically separated and culturally different industrial and academic organizations. We propose a TRIAD education model, which is as an extension to the conventional project-based learning, by uniting industry staff, faculty members, and students in an online discussion space. This model is a two-phase cyclic model where in Phase-1) industry members and academic staff discuss the progress of PBL transparently, showing the cross-cultural gaps and advising how to solve them, and in Phase-2) students make progress on the projects. Additionally, the TRIAD model adopts asynchronous text messaging as a core communication method, which is suitable for a multi-timezone situation, as well as exchanges of self-reviews from students and feedback from instructors. The online space not only facilitates interns in overcoming the hurdles represented by the gaps between the industry and academia, but it also visualizes the students' implicit educational progress by periodically analyzing all stored data by applying quantitative text analysis methods. This paper shows the result of an empirical study by utilizing this TRIAD model and analytics tool conducted at a large-scale Japanese game company with over 2,000 employees focusing on two students from the division of game development at a university in Sweden. We applied a quantitative text analysis tool for this model during an on-going internship program to clarify how students change their thoughts and behaviors by acquiring cross-cultural professionalism in the game industry. In addition, the result indicates that this TRIAD model is resilient, even under the COVID-19 epidemic situation due to its text-based approach. © 2020 IEEE.