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IntroductionThe coronavirus disease 2019 (COVID-19) epidemic has been emerged worldwide. Although several medications have been approved for treating moderate-to-severe COVID-19, no treatment strategy has been established for mild COVID-19 patients who do not require oxygen administration. The spread of SARS -CoV-2 has been mostly through patients with mild COVID-19; therefore, treating patients with mild COVID-19 is critical in society. Clarithromycin is a macrolide antimicrobial agent that has been widely used for bacterial respiratory infectious diseases. Clarithromycin also acts an immunomodulating drug and suppresses cytokine storms in viral respiratory diseases, including influenza infection. In this study, we aimed to evaluate the efficacy of clarithromycin in patients with mild COVID-19. Methods and analysisThis is a multicenter, open-label, randomized controlled, 3-armed parallel group comparison, exploratory trial. Subjects with mild COVID-19 pneumonia who did not require oxygen administration were enrolled and randomly assigned in a 1:1:1 ratio to Group A (administration of clarithromycin 800 mg/day), Group B (administration of clarithromycin 400 mg/day), or Group C (standard treatment without clarithromycin). The primary endpoint was the number of days required to improve clinical symptoms as measured by the severity score. Secondary endpoints included days to recover the body temperature, proportion of subjects with oxygen administration, inflammatory cytokines, viral load, serum immunoglobulins, peripheral blood lymphocytes, blood biomarkers, and pneumonia infiltrations. Ethics and disseminationThe study protocol was approved by the Clinical Research Review Board of Nagasaki University in accordance with the Clinical Trials Act in Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all participants. The results of this study will be reported as journal publications. RegistrationThis study was registered at the Japan Registry of Clinical Trials (registration number: jRCTs071210011). Strengths and limitations of this studyO_LIThis is the first randomized controlled trial to evaluate the efficacy of clarithromycin against COVID-19 pneumonia, especially in patients with mild COVID-19 pneumonia who do not require oxygen administration. C_LIO_LITo date, no treatment strategy has been established for mild COVID-19 pneumonia. C_LIO_LIThe major limitations of this study are its exploratory nature and relatively small sample size. C_LIO_LIAnother limitation is the open-label study design and generalizability because this study was conducted only in Japan with Japanese patients. C_LI
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SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10-17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure. Author SummarySARS-CoV-2 infection presents a wide spectrum of clinical manifestations ranging from asymptomatic to fatal respiratory failure. The determinants for failure in viral control and/or fatal disease progression have not been elucidated fully. Both acquired immune effectors, antibodies and CD8+ T cells, are considered to contribute to viral control. However, it remains unknown whether a deficiency in either of these two arms is directly linked to failure in the control of SARS-CoV-2 replication. In the present study, to know the requirement of CD8+ T cells for viral control after the establishment of infection, we examined the effect of CD8+ cell depletion by monoclonal anti-CD8 antibody administration in the subacute phase on SARS-CoV-2 replication in cynomolgus macaques. Unexpectedly, our analysis revealed no significant impact of CD8+ cell depletion on viral replication, indicating that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but this study suggests that CD8+ T-cell dysfunction may not solely lead to viral control failure or fatal disease progression.
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BACKGROUND@#Promotion of oral health in children is recognized as one of the components of health-promoting schools (HPSs). However, few studies have addressed supportive school environments for children's oral health. This study aimed to evaluate the status of dental caries in school children at HPSs, with the objective of examining the impact of a supportive school environment for oral health, considering the lifestyles of individual children and the socioeconomic characteristics of their communities.@*METHODS@#Data of 2043 5th-grade students in 21 elementary schools in Ichikawa city between 2008 and 2013 were analyzed. Children's oral health status was evaluated using the decayed, missing, and filled permanent teeth (DMFT) index. A self-reported lifestyle questionnaire, a survey of the school environment promoting tooth-brushing, and community socioeconomic characteristics derived from the National Census data were included in the analyses. Bivariate analyses were conducted to evaluate the children's DMFT status, and zero-inflated negative binominal (ZINB) regression was used to assess the relationships between DMFT and other variables.@*RESULTS@#Prevalence of dental caries in the permanent teeth of 5th-grade children (aged 10-11 years) was 33.3%, with a mean DMFT score (± SD) of 0.83 ± 1.50. According to multilevel ZINB regression analysis, children from schools with after-lunch tooth-brushing time showed a higher odds ratio (OR) for excess zero DMFT (OR = 1.47, 95% CI = 1.00-2.15, P = 0.049) as compared to those from schools without it. Neither bivariate analysis nor ZINB model analysis revealed any significant influence of children's gender or use of a toothpaste with fluoride.@*CONCLUSIONS@#The school-based environment supportive of oral health was significantly associated with a zero DMFT status in children. School-based efforts considering the socioeconomic characteristics of the area warrant attention even with declining prevalence of dental caries.
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Background: We retrospectively compared endscopic gastroduodenal stenting with gastrojejunostomy as a means of palliating malignant gastric and duodenal obstruction. Methods: This retrospective study investigated patients treated for malignant gastric and duodenal obstruction from April 2011 to April 2015 at Shikoku Cancer Center. Results: Of the 40 patients in this study, 25 underwent gastroduodenal stenting and 15 had operative gastrojejunostomy. Comparing the stenting and operative patients, technical success rate was 100% in both group, clinical success rate was 84% in stenting patients and 93% in operative patients. The median time to fluid intake was significantly shorter in stenting patients than operative patients(0 day vs 2 days, p=0.0003), and the median time to intake of solids was also significantly shorter in stenting patients(1day vs 3 days, p<0.0001).The median hospital stay was significantly shorter in stenting patients(9 days vs 23 days, p=0.0116). Median cost of hospitalization is more expensive in operative patients than stenting patients(¥1,106,170 vs ¥752,290, p=0.0052). Conclusion: Our study suggested that gastoroduodenal stent was less length of time to fluid/solid intake, and less costly than gastrojejunostomy.
