Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.
Although hypervirulent Klebsiella pneumoniae (hvKp) has been associated with severe community-acquired infections that occur among relatively healthy individuals, information about hvKp infections in health care settings remains limited. Here, we systematically analyzed the clinical and molecular characteristics of K. pneumoniae isolates causing bloodstream infections in a cross-sectional study. Clinical characteristics of K. pneumoniae bloodstream infections from hospitals across Japan were analyzed by a review of the medical records. Whole-genome sequencing of the causative isolates was performed. Bacterial species were confirmed and hvKp were identified using whole-genome sequencing data. Clinical characteristics of hvKp infections were compared with those of non-hvKp infections by bivariate analyses. Of 140 cases of K. pneumoniae bloodstream infections, 26 cases (18.6%) were caused by various clones of hvKp defined by the carriage of cardinal virulence genes. Molecular identification revealed that 24 (17.1%) and 14 (10%) cases were caused by Klebsiella variicola and Klebsiella quasipneumoniae, respectively. Patients with hvKp infections had higher proportions of diabetes mellitus (risk ratio [RR], 1.75; 95% confidence interval [CI], 1.05 to 2.94), and their infections had significantly higher propensity to involve pneumonia (RR, 5.85; 95% CI, 1.39 to 24.6), liver abscess (RR, 5.85; 95% CI, 1.39 to 24.6), and disseminated infections (RR, 6.58; 95% CI, 1.16 to 37.4) than infections by other isolates. More than one-half of hvKp infections were health care associated or hospital acquired, and a probable event of health care-associated transmission of hvKp was documented. hvKp isolates, which are significantly associated with severe and disseminated infections, are frequently involved in health care-associated and hospital-acquired infections in Japan.
The aim of this study was to establish a pressure ulcer model that visualizes the microcirculation, and to examine the participation of ischemia-reperfusion injury in the pathophysiology of pressure ulcers. An original system composed of a new skin fold chamber and compression device allowed loading quantitative vertical stress to the skin. An intravital microscopic technique enabled direct visualization of the microcirculation in the physiological condition and in response to pressure application. To estimate the effect of ischemia-reperfusion injury, animals were divided into two groups: the compression-release group (n = 8), in which the animals received four cycles of compression-release which consisted of 2 hours of compression followed by 1 hour of pressure release; and the compression alone group (n = 8) in which the animals underwent continuous compression for 8 hours. Functional capillary density was quantified before the compression procedure and on day 1 (35 hours) after the first evaluation. The cyclic compression-release procedure significantly decreased functional capillary density as compared to continuous compression, indicating that in our experimental setting repetition of ischemia-reperfusion cycle more severely damaged the microcirculation than single prolonged ischemic insult. This finding supports the significant contribution of ischemia-reperfusion injury to the pathophysiology of pressure ulcers at the level of dynamic in vivo microcirculation.
Background: Fluoroquinolones are a popular alternative to trimethoprim-sulfamethoxazole for Stenotrophomonas maltophilia infections. Objectives: To compare the effects of fluoroquinolones and trimethoprim-sulfamethoxazole on mortality of S. maltophilia infections. Data sources: PubMed and EMBASE. Study eligibility criteria: Clinical studies reporting mortality outcomes of S. maltophilia infections. Participants: Patients with clinical infections caused by S. maltophilia. Interventions: Fluoroquinolone monotherapy in comparison with trimethoprim-sulfamethoxazole monotherapy.Methods: Systematic review with meta-analysis technique. Results: Seven retrospective cohort and seven caseecontrol studies were included. Three cohort studies were designed to compare the two drugs, whereas others had other purposes. A total of 663 patients were identified, 332 of which were treated with trimethoprim-sulfamethoxazole (50.1%) and 331 with fluoroquinolones (49.9%). Three cohort studies were designed to compare the effect of the two drugs, whereas the others had other purposes. Levofloxacin was most frequently used among fluoroquinolones (187/331, 56.5%), followed by ciprofloxacin (114/331, 34.4%). The overall mortality rate was 29.6%. Using pooled ORs for the mortality of each study, fluoroquinolone treatment (OR 0.62, 95% CI 0.39e0.99) was associated with survival benefit over trimethoprim-sulfamethoxazole treatment, with low heterogeneity (I 2 ¼ 18%). Specific fluoroquinolones such as ciprofloxacin (OR 0.44, 95% CI 0.17e1.12) and levofloxacin (OR 0.78, 95% CI 0.48e1.26) did not show a significant difference in comparison with trimethoprimsulfamethoxazole. In the sub-group analyses of adult and bacteraemic patients, significant differences in mortality were not observed between fluoroquinolones and trimethoprim-sulfamethoxazole.
IntroductionAlthough oxygen is essential for the wound healing process, tissue hypoxia is known to stimulate angiogenesis. To explore these inconsistent findings, we estimated the influence of the oxygen environment on wound healing with our original model.MethodsExperiment 1 (Establishment of the model): To modify the topical oxygen tension, oxygen impermeable (polyvinylidene chloride) and permeable (polymethylpentene) membranes were applied to symmetrical excisional wounds in ddy mice (n = 6). Oxygen tension under the membrane was quantified with a device using photo-quenching technique. Experiment 2 (Influence of oxygen environment on wound healing): The wound area, granulation thickness and vascular density were analyzed under different oxygen environments (n = 24).ResultsExperiment 1: The permeable group maintained equivalent oxygen level to atmosphere (114.1±29.8 mmHg on day 7), while the impermeable group showed extremely low oxygen tension (5.72±2.99 mmHg on day 7). Accordingly, each group was defined as the normoxia group and the hypoxia group. Experiment 2: Percent decrease in wound size was significantly enhanced in the normoxia group (11.1±1.66% on day 7) in comparison with the hypoxia group (27.6±3.47% on day 7). The normoxia group showed significantly thicker granulation tissue than the hypoxia group (491.8±243.2 vs. 295.3±180.9 µm). Contrarily, the vascular density of the hypoxia group significantly increased on day 7 (0.046±0.025 vs. 0.011±0.008 mm2/mm2).ConclusionsOur original model successfully controlled local oxygen concentration around the wound, and the hypoxic wounds showed increased angiogenesis but with a smaller amount of granulation tissue and delayed wound closure. Enhanced neovascularization in the hypoxic group likely implies compensative response to an insufficient ambient oxygen supply.
Background Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of coronavirus disease 2019 (COVID-19), data on the clinical characteristics of COVID-19 patients with cancer are limited. This study aimed to evaluate the clinical characteristics and outcomes including mortality and viral shedding period in COVID-19 patients with cancer in Japan. Methods We retrospectively analyzed 32 patients with a history of cancer who were referred to our hospital between January 31, 2020 and May 25, 2020. We evaluated the association between clinical outcomes and potential prognostic factors using univariate analyses. Results The median age was 74.5 (range 24-90) years and 22 patients (69%) were men. A total of 11 patients (34%) died. Our analyses demonstrated that the mortality was significantly associated with lymphocyte count, albumin, lactate dehydrogenase, serum ferritin, and C-reactive protein on admission. The median period between illness onset and the first effective negative SARS-CoV-2 PCR result was 22 days (interquartile range 18-25) in survivors. Of four patients with hematological malignancy who developed COVID-19 within the rest period of chemotherapy, three died and the other patient, who received bendamustine plus rituximab therapy, had the longest duration of viral shedding (56 days). Conclusion Our study suggested that the risk factors for mortality previously reported in general COVID-19 patients, including lymphocytopenia, were also effective in cancer patients. Patients who received cytotoxic chemotherapy recently or were treated with chemotherapy, which can lead to lymphocyte reduction, had poor prognosis and prolonged periods of viral shedding.
The oxygen consumption of keloids and hypertrophic scars has never been quantitatively presented, although abnormal metabolic conditions must be associated with their pathophysiology. We invented an original measurement system equipped with a Clark oxygen electrode for ex vivo samples. The measurement of a mouse wound-healing model revealed immature repairing tissues consumed more oxygen than mature tissues. This finding is in accord with the current thinking and supported the validity of our measurement system. The analysis of fresh human samples clearly demonstrated the high oxygen consumption rate of keloid hypertrophic scars and the comparatively low consumption of mature scars. A high oxygen consuming potential, as well as insufficient oxygen diffusion, may possibly contribute to the pathophysiology of keloids and hypertrophic scars.
Although previous reports have suggested the efficacy of autologous bone marrow-impregnated collagen matrix experimentally and clinically, we occasionally encounter difficult wounds that fail to respond to the treatment. The current study retrospectively investigated the factors that affect clinical outcomes based on the hypothesis that periwound microcirculation may play a significant role. Fifty-three patients with chronic wounds received surgical debridement, followed by application of an autologous bone marrow-impregnated collagen matrix. The periwound transcutaneous oxygen tension (TcPO(2)) was evaluated (n=39). The patients were retrospectively divided into successful and unsuccessful subgroups. Successful treatment was defined as wound closure by spontaneous healing or skin graft. The TcPO(2) of the unsuccessful subgroup significantly decreased after debridement while that of the successful subgroup increased. Among various parameters, the TcPO(2) at 4 days after debridement showed the strongest association with the success of the treatment. As reference data, we collected the information of the patients (n=22) who received standard wound care, and they showed the same trend wherein the TcPO(2) of the unsuccessful subgroup markedly decreased after debridement. Reactivity of the wound microcirculation to increased wound perfusion in response to the surgical debridement might be a key determinant for successful wound healing.
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