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During the novel coronavirus disease (COVID-19) pandemic, emergency medical services (EMS) has borne a huge burden in transporting emergency patients. However, the protocol's effect on identifying emergency patients who are likely to have COVID-19 is unknown. We aimed to evaluate the diagnostic accuracy of a prehospital COVID-19 screening protocol for EMS. We conducted this population-based retrospective study in Nara Prefecture, Japan. The Nara Prefectural Government implemented a screening protocol for COVID-19 comprising the following symptom criteria (fever, cough, sore throat, headache, malaise, dysgeusia, or anosmia) and epidemiological criteria (contact history with confirmed COVID-19 cases or people with upper respiratory symptoms, or travel to areas with high infection rate). A patient meeting at least one criterion of each class was considered positive. We evaluated all 51,351 patients from the regional EMS database of the Nara Prefecture (emergency Medical Alliance for Total Coordination of Healthcare) who were registered from June 15, 2020 to May 31, 2021 and had results of COVID-19 reverse transcription polymerase chain reaction (RT-PCR) tests. We assessed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this protocol. We also assessed how these outcomes changed by adding vital signs and conducted a 10-fold and 100-fold prevalence simulation. The screening protocol was used for 246/51351 patients (0.5%). Among them, 31 tested positive after EMS transportation. This protocol's sensitivity, specificity, PPV, and NPV were 40.8%, 99.6%, 12.6%, and 99.9%, respectively. With the addition of ≥2 vital signs (body temperature ≥37.5 °C, respiratory rate ≥20 breaths/minute, and oxygen saturation 90%), sensitivity and PPV changed to 61.8% and 1.0%, respectively, while NPV remained 99.9%. With a 10-fold and 100-fold increase in disease, the protocol PPV would be 59.0% and 94.3%, and NPV would be 99.1% and 90.7%, respectively, and with additional vital signs, PPV would be 8.9% and 53.1%, and NPV would be 99.4% and 93.2%, respectively. This COVID-19 screening protocol helped enable EMS transport for patients with COVID-19 with a PPV of 12.6%. Adding other vital sign variables may improve its diagnostic value if the prevalence rate increases.

Caplacizumab is an anti-von Willebrand factor humanized single-variable-domain immunoglobulin fragment whose efficacy and safety in immune-mediated thrombotic thrombocytopenia purpura (iTTP) have been demonstrated in international studies. This prospective, open-label phase 2/3 study evaluated caplacizumab 10 mg administered daily during plasma exchange and for 30 days afterward, in combination with immunosuppressive treatment, in Japanese adults with a clinical diagnosis of iTTP (new or recurrent). The primary endpoint was prevention of iTTP recurrence; key secondary endpoints included time to platelet count response, time to organ damage normalization, and safety. Among 21 treated patients, 1 of 15 (6.7%) evaluable patients developed iTTP recurrence. Median time to normalization was 2.79 days for platelet count and 2.65 days for organ damage markers (n = 15). Treatment-emergent adverse events (TEAEs) were mostly mild to moderate in severity; the most frequently reported caplacizumab-related TEAEs were increased alanine aminotransferase, epistaxis, and gastrointestinal hemorrhage (all in 9.5% of patients). At least one bleeding event was reported in 7 of 21 patients (33%). Caplacizumab was effective in Japanese patients with iTTP, with a low rate of iTTP recurrence, rapid normalization of platelet counts and organ damage markers, and no unexpected TEAEs. Trial registration: ClinicalTrials.gov identifier, NCT04074187.

TAFRO syndrome is a systemic inflammatory, lymphoproliferative disorder, but the pathophysiology of the disease is unknown. It is typically characterized by thrombocytopenia, anasarca, a fever, reticulin fibrosis, renal dysfunction, and organomegaly. However, other manifestations have been also reported. We encountered a 43-year-old man with TAFRO syndrome who showed mediastinal panniculitis, liver damage, and adrenal lesions in addition to the core signs. He achieved complete remission with combination therapy of corticosteroids, tocilizumab, and cyclosporin, and remission was maintained even after drug discontinuation at 15 months. Atypical manifestations and complete remission of TAFRO syndrome were remarkable features of our case.

Background We compared the prognostic value of plasma high mobility group box 1 protein (HMGB1) and histone H3 levels with the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scores for 28-day in-hospital mortality in patients with DIC caused by various underlying diseases. Methods We conducted a multicenter prospective cohort study including two hematology departments, four emergency departments, and one general medicine department in Japan, between August 2017 and July 2021. We included patients diagnosed with DIC by the ISTH DIC scoring system. Results Overall, 104 patients were included: 50 with hematopoietic disorders, 41 with infections, and 13 with the other diseases. The 28-day in-hospital mortality rate was 21%. The receiver operator characteristic (ROC) curve showed that a DIC score of 6 points, plasma HMGB1 level of 8 ng/mL, and plasma histone H3 level of 2 ng/mL were the optimal cutoff points. The odds ratios of more than these optimal cutoff points of the DIC score, plasma HMGB1, and histone H3 levels were 1.58 (95% confidence interval [CI]: 0.60 to 4.17, p = 0.36), 5.47 (95% CI: 1.70 to 17.6, p = 0.004), and 9.07 (95% CI: 2.00 to 41.3, p = 0.004), respectively. The area under the ROC curve of HMGB1 (0.74, 95% CI: 0.63 to 0.85) was better than that of the ISTH DIC scores (0.55, 95% CI: 0.43 to 0.67, p = 0.03), whereas that of histone H3 was not (0.71, 95% CI: 0.60 to 0.82, p = 0.07). Calibration and net reclassification plots of HMGB1 identified some high-risk patients, whereas the ISTH DIC scores and histone H3 did not. The category-free net reclassification improvement of HMGB1 was 0.45 (95% CI: 0.01 to 0.90, p = 0.04) and that of histone H3 was 0.37 (95% CI: − 0.05 to 0.78, p = 0.08). Conclusions Plasma HMGB1 levels have a prognostic value for mortality in patients with DIC. This finding may help physicians develop treatment strategies.

Aims: The aim of this study was to evaluate the protective capacity of the exopolysaccharide-producing Lactobacillus rhamnosus V5 against invasion in vitro and in vivo with S. typhimurium. Methodology: We tested the antimicrobial activity of the compound extracted from the lactobacilli against S. typhimurium directly, also we tested the interference of this compound in S. typhimurium adherence and invasion of HeLa and HEp-2 cells (in vitro testings). For in vivo experiments, we used 16 BALB/c female mice. Through gavage method we introduced L. rhamnosus as probiotic and then infected mice with S. enterica serovar typhimurium. After euthanasia, spleen, liver and Peyer's patches removed for microbiological and histopathological analysis. Results: The results showed that lactobacilli were able to produce antimicrobial compounds against S. typhimurium. These lactobacilli inhibited the adhesion and invasion of S. typhimurium in HeLa and HEp-2 cells, respectively. The challenge assay in the murine model demonstrated a decrease in pathogen translocation in the spleen and liver from mice treated with probiotic as well as protection of ileal tissue in lactobacilli-treated mice. The histopathological analysis demonstrated the presence of prominent lymphoid nodules in the ileum from the non-treated lactobacilli mice. Conclusion: Our results suggest that L. rhamnosus improved the effectiveness of the intestinal barrier and, thus, could be a potential probiotic to control salmonellosis.

Background The functional dynamics of coagulation and fibrinolysis in patients with disseminated intravascular coagulation (DIC) vary due to the pathology and severity of various underlying diseases. Conventional measurements of hemostasis such as thrombin–antithrombin complex, plasmin-α2-plasmin-inhibitor complex, and fibrinogen-fibrin degradation products may not always reflect critical pathophysiologic mechanisms in DIC. This article aims to clarify the pathology of sepsis-associated DIC using assessment of comprehensive coagulation and fibrinolysis. Methods Plasma samples were obtained from 57 patients with sepsis-associated DIC at the time of initial diagnosis. Hemostasis parameters were quantified by clot-fibrinolysis waveform analysis (CFWA) and thrombin/plasmin generation assays (T/P-GA). The results were expressed as ratios relative to normal plasma. Results CFWA demonstrated that the maximum coagulation velocity (|min1|) ratio modestly increased to median 1.40 (min − max: 0.10 − 2.60) but the maximum fibrinolytic velocity (|FL-min1|) ratio decreased to 0.61 (0 − 1.19). T/P-GA indicated that the peak thrombin (Th-Peak) ratio moderately decreased to 0.71 (0.22 − 1.20), whereas the peak plasmin (Plm-Peak) ratio substantially decreased to 0.35 (0.02 − 1.43). Statistical comparisons identified a correlation between |min1| and Th-Peak ratios (ρ = 0.55, p Conclusion A pathological clarification of sepsis-associated DIC based on the assessment of coagulation and fibrinolysis dynamics may be useful for the hemostatic monitoring and management of optimal treatment in these individuals.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder caused by neutralizing anti-ADAMTS13 autoantibodies. In white individuals, HLA allele DRB1*11 is a predisposing factor for iTTP, whereas DRB1*04 is a protective factor. However, the role of HLA in Asians is unclear. In this study, we analyzed 10 HLA loci using next-generation sequencing in 52 Japanese patients with iTTP, and the allele frequency in the iTTP group was compared with that in a Japanese control group. We identified the following HLA alleles as predisposing factors for iTTP in the Japanese population: DRB1*08:03 (odds ratio [OR], 3.06; corrected P [Pc] = .005), DRB3/4/5*blank (OR, 2.3; Pc = .007), DQA1*01:03 (OR, 2.25; Pc = .006), and DQB1*06:01 (OR,: 2.41; Pc = .003). The estimated haplotype consisting of these 4 alleles was significantly more frequent in the iTTP group than in the control group (30.8% vs 6.0%; Pc < .001). DRB1*15:01 and DRB5*01:01 were weak protective factors for iTTP (OR, 0.23; Pc = .076; and OR, 0.23, Pc = .034, respectively). On the other hand, DRB1*11 and DRB1*04 were not associated with iTTP in the Japanese. These findings indicated that predisposing and protective factors for iTTP differ between Japanese and white individuals. HLA-DR molecules encoded by DRB1*08:03 and DRB1*11:01 have different peptide-binding motifs, but interestingly, bound to the shared ADAMTS13 peptide in an in silico prediction model.

Given the need to understand the virulence profile of Proteus mirabilis isolates from cellulitis in broiler chickens and their ability to cause lesions, the present study aimed to characterize genotypically and phenotypically the virulence profiles of two strains of P. mirabilis isolated from cellulitis in broilers, as well as to evaluate their ability to experimentally reproduce the lesions in vivo. The strain with the highest virulence potential (LBUEL-A33) possessed mrpA, pmfA, ucaA, atfA (fimbriae), zapA, ptA (proteases), hpmA (hemolysin), and ireA (siderophore) genes, formed a very strong biofilm, and expressed the pattern of aggregative adhesion and cytotoxicity in Vero cells. The strain with the lowest virulence potential (LBUEL-A34) did not present the pmfA and ucaA genes, but expressed the pattern of aggregative adhesion, formed a strong biofilm, and did not show cytotoxicity. Both strains developed cellulitis in an animal model within 24 h post-inoculation (PI), and the degree of lesions was not significantly altered up to 120 h PI. The LBUEL-A33 strain was also inoculated in combination with an avian pathogenic Escherichia coli (APEC 046), and the lesions showed no significant changes from the individual inoculation of these two strains. Histological analysis showed that the LBUEL-A33 strain developed characteristic cellulitis lesions. Thus, both strains of P. mirabilis isolated in our study have several virulence factors and the ability to develop cellulitis in broilers.

Bacterial resistance to conventional antibacterial agents is a clinical issue which requires the constant search for new therapies. This study evaluated the antibacterial activity of honey produced...

Hot water bathing – a Japanese traditional practice – has not been evaluated for its association with night- and sleep-time blood pressure (BP) in large population. In this longitudinal analysis, bathing parameters and ambulatory BP were repeatedly measured for 2 nights in 758 Japanese elderly individuals. Participants were divided into three groups according to tertile values of time soaked in the bathtub (Duration: tertile value, 11 and 15 min), time from bathing-end to bedtime (Time before bedtime: tertile value, 42 and 106 min), and temperature of hot water in the bathtub (Water temp: tertile value, 40.3 and 41.2 °C). Participants’ mean age was 70.9 years, and mean night- and sleep-time systolic BP (SBP) and dipping were 115.1 ± 16.1, 114.2 ± 16.2 mmHg, and 14.2 ± 8.8%, respectively. Multivariable mixed-effect linear regression models adjusted for potential confounding factors suggested that nighttime SBP was significantly lower in the intermediate Time before bedtime group by 1.7 mmHg (95% CI, 0.2–3.1) and in the short group by 1.9 mmHg (95% CI, 0.1–3.7) than that in the long group. Dipping was significantly greater in the intermediate Time before bedtime group by 1.8% (95% CI, 0.7–2.9) and in the short group by 1.8% (95% CI, 0.6–3.1) than that in the long group. These associations were consistent regarding sleep-time SBP. Conversely, Water temp and Duration did not significantly associate with any ambulatory BP parameter. Remarkably, Time before bedtime significantly prolonged with increases in tertiles of Water temp (P for trend = 0.006). In conclusion, the findings of this study revealed that Japanese hot water bathing, especially the short time from bathing-end to bedtime, was associated with lower night- and sleep-time BP and greater dipping in an elderly population., 博士（医学）・甲第751号・令和2年9月30日, This is a post-peer-review, pre-copyedit version of an article published in Chronobiology international. The final authenticated version is available online at: https://doi.org/10.1080/07420528.2019.1675685.

EP Figueiredo,1 JM Ribeiro,1 EK Nishio,1 S Scandorieiro,1 AF Costa,2 VF Cardozo,1 AG Oliveira,1 N Durán,2–4 LA Panagio,1 RKT Kobayashi,1 G Nakazato1 1Department of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina, Paraná, Brazil; 2NanoBioss, Institute of Chemistry, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil; 3Institute of Chemistry, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil; 4LNNano (National Laboratory of Nanotecnology), CNPEM, Campinas, São Paulo, BrazilCorrespondence: G NakazatoDepartment of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Campus Universitário, CEP, Londrina 86055-990, Paraná, BrazilTel +55 43 3371 4396Fax +55 43 3371 4788Email gersonakazato@yahoo.com.brBackground: Multidrug-resistant bacteria such as extended-spectrum beta-lactamase (ESBL), Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus (MRSA) pose a challenge to the human health care system. MRSA is among the major causes of hospital-acquired and community infections.Methods: Therefore, in the present study, we evaluated the antibacterial activity of silver nanoparticles synthesized by Fusarium oxysporum (AgNPbio) in combination with simvastatin against reference and multidrug-resistant bacterial strains.Results: Simvastatin showed a minimal inhibitory concentration (MIC) ranging from 0.062 to 0.25 mg mL−1 against MRSA. AgNPbio with a size of 77.68± 33.95 nm and zeta potential −34.6 ± 12.7 mV showed an MIC of 0.212 mg mL−1 against S. aureus including MRSA strains. The checkerboard assay and time-kill curves exhibited a synergistic effect of the simvastatin-AgNPbio combination on antibacterial activity against MRSA strains. The combination of simvastatin and AgNPbio demonstrated antibacterial activity against Escherichia coli producing ESBL. Scanning electron microscopy showed the formation of cell surface protrusions after treatment with AgNPbio and the formation of a large amorphous mass after treatment with simvastatin, both in MRSA.Conclusion: Our results indicate that the combination of AgNPbio and simvastatin could be a great future alternative in the control of bacterial infections, where, when combined with simvastatin, smaller doses of AgNPbio are required, with the same antibacterial activity.Keywords: antibacterial, metallic nanoparticles, multidrug-resistant bacterial, statins, synergism

Considering the worrying emergence of multidrug resistance, including in animal husbandry and especially in food-producing animals, the need to detect antimicrobial resistance strains in poultry environments is relevant, mainly considering a One Health approach. Thus, this study aimed to conduct longitudinal monitoring of antimicrobial resistance in broiler chicken farms, with an emphasis on evaluating the frequency of resistance to fosfomycin and β-lactams.

Coagulation and fibrinolytic mechanisms are enhanced in patients with coronavirus (COVID-19), but disturbances in the balance of both functions in COVID-19 patients remain unclear. We assessed global coagulation and fibrinolysis in plasma from 167 COVID-19 patients (mild/moderate/severe: 62/88/17, respectively) on admission using clot-fibrinolysis waveform analysis (CFWA). Maximum coagulation velocity (|min1|) and maximum fibrinolysis velocity (|FL-min1|) were expressed as ratios relative to normal plasma. Ten patients (6.0%) developed thrombosis, 5 (3.0%) had bleeding tendency, and 13 (7.8%) died during admission. FDP levels increased with severity of COVID-19 symptoms (mild/moderate/severe; median 2.7/4.9/9.9 μg/mL, respectively). The |min1| ratios were elevated in all categories (1.27/1.61/1.58) in keeping with enhanced coagulation potential, with significant differences between mild cases and moderate to severe cases. The |FL-min1| ratios were also elevated in all groups (1.19/1.39/1.40), reflecting enhanced fibrinolytic potential. These data identified coagulation dominance in moderate to severe cases, but balanced coagulation and fibrinolysis in mild cases. There were significant differences in FDP and TAT, but no significant differences in |min1| or |FL-min1| ratios, between patients with and without thrombosis. CFWA monitoring of coagulation and fibrinolysis dynamics could provide valuable data for understanding hemostatic changes and disease status in COVID-19 patients.

Super-elderly patients are often frail and the decision on surgical indications remains a difficult issue. The purpose of this study was to provide a certain preoperative surgical risk assessment tool for super-elderly people.We selected 112 individuals who were super-elderly patients aged90 years who had surgeries under general anesthesia in our department. Based on the quality of the postoperative outcome of each case, we categorized these patients into two groups: good and poor groups. We evaluated the fundamental examination items, such as American Society of Anesthesiologists physical status, skeletal muscle mass index and so on, and a couple of the well-known risk score systems represented by Estimation of Physiology Ability and Surgical Stress.A total of 85 of the 112 patients belonged to the good group and the rest belonged to the poor group. The quality of postoperative outcome is well characterized by Estimation of Physiology Ability and Surgical Stress (P = 0.001). Receiver operating characteristic analysis of Estimation of Physiology Ability and Surgical Stress for the quality of postoperative outcome shows sensitivity of 0.83 and specificity of 0.61. Multivariate logistic regression analysis showed that skeletal muscle mass index and American Society of Anesthesiologists physical status are prominent as the risk determinants affecting the quality of postoperative outcome. A scoring system based on the skeletal muscle mass index, which is a good index of sarcopenia, and American Society of Anesthesiologists physical status, named the "SAP score" has the following characteristics. P-value0.001, sensitivity 0.76 and specificity 0.91.Informed consent based on the risk score might be able to reduce the regrettable situation where it would have been better to have had surgery or not to have had surgery. Geriatr Gerontol Int 2022; 22: 271-277.

Proteus mirabilis is an opportunistic pathogen associated with a variety of infections in humans, especially those in the urinary tract. The isolation of this pathogen in foods of animal origin such as meat is poorly documented and should not be neglected, in view of the zoonotic risk that this can pose to human health. Thus, the objective of this study was to evaluate the prevalence, virulence profile, and similarity between P. mirabilis strains isolated from chicken, beef, and pork meat and those causing community-acquired urinary tract infections (UTI-CA), in order to better understand the role of this bacterium as a zoonotic pathogen. P. mirabilis was isolated from the three types of meat and was found to be more prevalent in chicken. All isolates exhibited several genotypic and phenotypic virulence characteristics, such as adhesion capacity in HEp-2 cell culture, biofilm formation, cytotoxicity in Vero cells and genes that express fimbriae (mrpA, pmfA, ucaA, atfA), hemolysin (hpmA), proteases (zapA and ptA) and siderophore receptor (ireA). UTI-CA strains showed a higher prevalence of ucaA and ireA genes, whereas those from the chicken meat had a higher prevalence of the atfA gene compared with the isolates from the beef and pork meat. It was observed that chicken meat and UTI-CA strains mainly formed very strong biofilms, whereas strains isolated from beef and pork formed more weak and moderate biofilms. Several strains from meat showed close genetic similarity to those from UTI-CA and had the same virulence profiles. Thus, meats may be an important source of the dissemination of P. mirabilis responsible for causing UTIs in the community.

STUDY OBJECTIVES: Passive body heating in controlled settings could shorten sleep onset latency (SOL). The hypothesized mechanism is vasodilation-induced heat loss before bedtime. However, this evidence is based on small sample–sized studies in specific populations. Thus, we analyzed the association of hot-water bathing and its before-bedtime timing with SOL and heat loss in a large study population of older adults. METHODS: We conducted a longitudinal analysis using repeated measurements of hot-water bathing and sleep among 1,094 older adults (mean age, 72.0 years). SOL was recorded using actigraphy and self-reported sleep estimates and was categorized into conditions (intervals of 1–60, 61–120, 121–180, and > 181 minutes between hot bath and bedtime) and compared with the control condition of no bathing. The heat-loss indicator, distal-proximal skin temperature gradient, was examined in the same categorization. RESULTS: Mixed-effects linear regression models suggested that the bathing conditions of 61–120 minutes and 121–180 minutes showed significantly shorter log-transformed actigraphic SOL by 0.23 log-minutes (95% confidence interval (CI), 0.03–0.42) and 0.32 log-minutes (95% CI, 0.09–0.56), shorter self-reported SOL by 0.16 log-minutes (95% CI, 0.02–0.30) and 0.18 log-minutes (95% CI, 0.01–0.35), and higher distal-proximal skin temperature gradient for 30 minutes before bedtime by 0.49°C (95% CI, 0.22–0.75) and 0.51°C (95% CI, 0.20–0.83), respectively, independent of potential confounders. CONCLUSIONS: Hot-water bathing before bedtime is significantly associated with shorter SOL and higher distal-proximal skin temperature gradient among the large-scale older population. This finding could enhance the generalizability of hot-water bathing habits for ameliorating sleep initiation difficulty. CITATION: Tai Y, Obayashi K, Yamagami Y, et al. Hot-water bathing before bedtime and shorter sleep onset latency are accompanied by a higher distal-proximal skin temperature gradient in older adults. J Clin Sleep Med. 2021;17(6):1257–1266.

This study discussed the use of antimicrobials in the commercial chicken production system and the possible factors influencing the presence of Extended-spectrum β-lactamase (ESBL)/AmpC producers strains in the broiler production chain. The aim of this study was to perform longitudinal monitoring of ESBL-producing and fosfomycin-resistant Escherichia coli from poultry farms in southern Brazil (Paraná and Rio Grande do Sul states) and determine the possible critical points that may be reservoirs for these strains. Samples of poultry litter, cloacal swabs, poultry feed, water, and beetles (Alphitobius sp.) were collected during three distinct samplings. Phenotypic and genotypic tests were performed for characterization of antimicrobial resistant strains. A total of 117 strains were isolated and 78 (66%) were positive for ESBL production. The poultry litter presented ESBL positive strains in all three sampled periods, whereas the cloacal swab presented positive strains only from the second period. The poultry litter represents a significant risk factor mainly at the beginning poultry production (odds ratio 6.43, 95% confidence interval 1–41.21, p < 0.05). All beetles presented ESBL positive strains. The predominant gene was blaCTX–M group 2, which occurred in approximately 55% of the ESBL-producing E. coli. The cit gene was found in approximately 13% of the ESBL-producing E. coli as AmpC type determinants. A total of 19 out of 26 fosfomycin-resistant strains showed the fosA3 gene, all of which produced ESBL. The correlation between fosA3 and blaCTX–M group 1 (blaCTX–M55) genes was significant among ESBL-producing E. coli isolated from Paraná (OR 3.66, 95% CI 1.9–9.68) and these genetic determinants can be transmitted by conjugation to broiler chicken microbiota strains. Our data revealed that poultry litter and beetles were critical points during poultry production and the presence of fosfomycin-resistant strains indicate the possibility of risks associated with the use of this antimicrobial during production. Furthermore, the genetic determinants encoding CTX-M and fosA3 enzymes can be transferred to E. coli strains from broiler chicken microbiota, thereby creating a risk to public health.

IntroductionSubcutaneous emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (PwHA) and factor VIII inhibitor. However, thrombotic events occurred in some PwHA with inhibitor who had received high cumulative doses of activated prothrombin complex concentrates at their breakthrough bleeds, when they were also given prophylactic emicizumab. After that, although the recommended guidance was proposed for bypassing agents (BPAs) therapy under emicizumab prophylaxis for haemostatic management, detailed investigation(s) is(are) required to elucidate the safe and appropriate dose of BPAs to use concomitantly with emicizumab prophylaxis.Methods and analysisIn the UNEBI Study, 60 PwHA with inhibitor will be enrolled for a maximum duration of 3 years, and samples of 20 events following concomitant use of BPAs with emicizumab will be collected. An ‘event’ is defined as obtaining blood samples before and after administration of BPA when a breakthrough bleed or a surgical procedure occurs. The coagulation potential in the obtained samples will be measured by global coagulation assays. The primary endpoint is the degree of improvement in the maximum coagulation rate by clot waveform analysis (CWA) before and after administration of fixed-dose BPAs. This parameter obtained from CWA, which is triggered with an optimally diluted mixture of prothrombin time/activated partial thromboplastin time-reagents, is reported to be an excellent marker for assessing the degree of improvement in coagulation potential in emicizumab-treated plasma.Ethics and disseminationThe UNEBI Study was approved by the Japan Certified Review Board of Nara Medical University. The results of the study will be communicated through publication in international scientific journals and presentations at (inter)national conferences.Trial registration numberjRCTs051190119.

Introduction: Patients with systemic autoimmune rheumatic diseases (SARDs) such as rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren syndrome, and systemic sclerosis, which are chronic inflammatory diseases, are prone to develop renal dysfunction, which is related to vascular endothelial cell damage. Material and Methods: We evaluated plasma levels of von Willebrand factor (VWF), VWF propeptide (VWF-pp), disintegrin-like and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and VWF multimer pattern in patients with SARDs at diagnosis and investigated whether they may serve as markers to identify patients destined to develop renal dysfunction within 1 year. Renal dysfunction was defined as subsequent reduced estimated glomerular filtration rate (eGFR) by >25% or the new appearance of abnormal urine findings such as proteinuria (protein > 30 mg/dL) or hematuria (red blood cells >20/HPF in urine sediments). Overall, 63 patients with SARDs were studied. Results and Conclusions: We observed a significant increase of VWF-pp and a significant decrease of ADAMTS13 in patients with SARDs compared with normal healthy controls. The highest level of VWF-pp was observed in patients with SLE among the groups. The levels of VWF and multimer pattern of VWF were not different compared with normal healthy controls. Von Willebrand factor propeptide predicted a subsequent decrease in eGFR at a cutoff point of 210% (sensitivity, 78.6%; specificity, 73.5%) and new urinary abnormal findings at a cutoff point of 232% (sensitivity, 77.8%; specificity, 77.8%) Using these cutoff points, multivariable analysis revealed that VWF-pp was a significant risk factor for renal dysfunction at an odds ratio of 8.78 and 22.8, respectively, and may lead to a new therapeutic approach to prevent vasculitis and renal dysfunction.

Acute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and may become fatal. In addition to its hemostatic functions, von Willebrand factor (VWF) is known to play a role in cross-talk between inflammation and thrombosis. We hypothesized that VWF may be involved in the pathophysiology of AKI, major causes of which include insufficient renal circulation or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the role of VWF in AKI using a mouse model of acute ischemia-reperfusion (I/R) kidney injury. We analyzed renal function and blood flow in VWF-gene deleted (knock-out; KO) mice. The functional regulation of VWF by ADAMTS13 or a function-blocking anti-VWF antibody was also evaluated in this pathological condition. Greater renal blood flow and lower serum creatinine were observed after reperfusion in VWF-KO mice compared with wild-type (WT) mice. Histological analysis also revealed a significantly lower degree of tubular damage and neutrophil infiltration in kidney tissues of VWF-KO mice. Both human recombinant ADAMTS13 and a function-blocking anti-VWF antibody significantly improved renal blood flow, renal function and histological findings in WT mice. Our results indicate that VWF plays a role in the pathogenesis of AKI. Proper functional regulation of VWF may improve the microcirculation and vessel function in the kidney, suggesting a novel therapeutic option against AKI.

Hepatic ischaemia–reperfusion (I/R) injury is a serious liver damage that critically influences the clinical outcome of liver surgery or transplantation. Since recent studies indicated the critical involvement of von Willebrand factor (VWF) in reperfusion injuries of brain and myocardium, we hypothesized that VWF-dependent thrombotic or inflammatory responses also play a role in hepatic I/R injury. Using a mouse model of hepatic I/R injury, we explored the functional relevance of the VWF–ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) axis in this pathologic condition. Time-course studies during hepatic I/R revealed significantly lower alanine aminotransferase (ALT) values, as well as greater hepatic blood flow, in VWF gene-deleted (KO) mice in comparison with wild-type (WT) mice. Histological analysis revealed a significantly lesser extent of neutrophil infiltration and hepatocellular necrosis in liver tissues of VWF-KO mice. Human recombinant ADAMTS13 significantly improved the impairment in ALT values and hepatic blood flow and decreased neutrophil infiltration within the liver tissue of WT mice. Real-time intravital imaging successfully visualized significantly reduced leukocyte–vessel wall interactions in I/R liver of VWF-KO mice. Taken together, our results indicate that VWF promotes neutrophil recruitment in ischaemic mouse liver, critically aggravating reperfusion injury, and suggest that functional regulation of VWF by ADAMTS13 represents a promising therapeutic option for hepatic I/R injury.

Introduction Immune-mediated thrombotic thrombocytopenic purpura (iTTP), or acquired TTP (aTTP), is a life-threatening thrombotic microangiopathy that requires prompt treatment to improve patient outcomes. Caplacizumab is a von Willebrand factor (VWF)-directed antibody fragment that rapidly inhibits VWF-platelet interaction and prevents microthrombi formation in iTTP. Based on efficacy and safety demonstrated in the Phase 3 HERCULES trial, caplacizumab, in conjunction with therapeutic plasma exchange (TPE) and immunosuppression, is approved in the USA and EU for aTTP. The aim of this Phase 2/3 study (NCT04074187), conducted in Japan, was to evaluate the efficacy and safety of caplacizumab in Japanese patients with iTTP. Methods Japanese patients aged ≥18 years with a clinical diagnosis of iTTP who had received ≤1 TPE were enrolled in this single-arm, open-label study. Patients received caplacizumab in conjunction with TPE and immunosuppression, during daily TPE, and for ≥30 days after discontinuation of TPE. Treatment extension was allowed for ≤8 weeks in case of persistent ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency defined by the investigator and patients were followed for 4 weeks after end of caplacizumab treatment. Primary endpoint was the proportion of patients with a recurrence of iTTP during the overall study period, assessed in the per-protocol (PP) population; recurrence rate ≤20% was the success criterion. Key secondary endpoints were assessed in the PP and modified intention-to-treat (mITT) populations. Treatment-emergent adverse events (TEAEs) were assessed in the safety population. PP population included patients who completed treatment and follow-up per protocol or had a recurrence of iTTP; mITT and safety populations included patients with ≥1 dose of caplacizumab. All analyses were descriptive. The study was conducted in accordance with the Declaration of Helsinki. Results A total of 21 patients were enrolled and treated with caplacizumab; 6 patients discontinued (adverse event: n=2, physician decision: n=4), and 15 patients were included in the PP population. In the mITT population, median age (range) was 59 (22-86) years; 16 (76%) patients presented with an initial episode; median (range) platelet count at baseline was 21.5 (8-78) ×10 9/L;10 (48%) patients received rituximab; median duration (range) of caplacizumab exposure during the overall treatment period was 35 (7-69) days. All patients in the PP population had ADAMTS13 activity Conclusions In Japanese patients with iTTP, caplacizumab in conjunction with TPE and immunosuppression was associated with a low rate of recurrence of iTTP and fast normalization of platelet count and organ damage markers. These findings are comparable to those in the HERCULES study, in which caplacizumab was associated with 12% recurrence rate and median (95% CI) time to platelet count normalization of 2.69 (1.89-2.83) days (Scully M, et al. N Engl J Med. 2019;380 [4]:335-346). Caplacizumab was well tolerated, and no new safety signals were identified in the Japanese population. Funding This research was funded by Sanofi. Figure 1 Figure 1. Disclosures Miyakawa: Sanofi: Research Funding; Zenyaku Kogyo: Consultancy; Sanofi: Consultancy; argenx: Consultancy, Research Funding. Imada: Celgene Co., Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.,: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co. Ltd.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria. Ichikawa: Sanofi: Honoraria; AstraZeneca: Honoraria; Chugai: Honoraria. Handa: Daiichi Sankyo: Research Funding; Janssen: Honoraria; BMS: Honoraria; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding. Matsushita: Shire/Takeda: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational and investigational support; CSL Behring: Honoraria; JB: Honoraria; KMB: Honoraria; Nichiyaku: Honoraria; Octapharm: Honoraria; Sysmex: Honoraria; Baltaxa/Shire/Takeda: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Educational and investigational support; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kirin: Honoraria. Hashimoto: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Ohshima: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Tahara: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Tanaka: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Matsumoto: Sanofi: Consultancy; Takeda: Consultancy; Alexion Pharma: Consultancy; Asahi Kasei Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Alfesa Pharma: Patents & Royalties: ELISA for measuring ADAMTS13 activity.

Infections caused by catheters and prostheses are serious problems in hospitals and the community alike, mainly due to biofilms being produced in these materials. So composites with antimicrobial action are important to prevent infections in these patients. Nanoparticle use has been applied in catheters and prostheses. The metallic nanoparticles showed different antimicrobial activity properties. In this chapter, we will discuss specific types of metallic nanoparticles (silver, copper, zinc, gold, aluminum, titanium, and iron) and their antimicrobial action. Three aspects are correlated with this activity: direct action, inhibition of biofilm formation, and drug delivery. Different types of nanoparticles and their characteristics (synthesis, size, and shape) showed different antimicrobial effects (types of microorganisms and action levels). The use of metallic nanoparticles is interesting in terms of the synergic effect on antimicrobial activity and impeding bacterial resistance. Our research group has studied antimicrobial (fungi and bacterial) and antibiofilm activity using metallic nanoparticles with different approaches in the biomedical field. This chapter is designed to provide information and to make a comparison between metallic nanoparticles applied in catheters and prostheses.