Soluble CD27 as a predictive biomarker for intra-tumoral CD70/CD27 interaction in nasopharyngeal carcinoma.

In CD70-expressing tumors, the interaction of CD70 on tumor cells with its lymphocyte receptor, CD27, is thought to play a role in immunosuppression in the tumor microenvironment and elevated serum levels of soluble CD27 (sCD27). Previous studies showed that CD70 is expressed in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related malignancy. However, the association between intratumoral CD70/CD27 expression and serum levels of sCD27 in NPC remains unclear. In the present study, we show that CD70 is primarily expressed by tumor cells in NPC and that CD27-positive lymphocytes infiltrate around tumor cells. NPC patients with CD27-positive lymphocytes had significantly better prognosis than patients lacking these cells. In addition, high CD70 expression by tumor cells tended to be correlated with shorter survival in NPC patients with CD27-positive lymphocytes. Serum sCD27 levels were significantly increased in patients with NPC and provided good diagnostic accuracy for discriminating patients from healthy individuals. The concentration of serum sCD27 in patients with CD70-positive NPC with CD27-positive lymphocytes was significantly higher than in patients with tumors negative for CD70 and/or CD27, indicating that the intratumoral CD70/CD27 interaction boosts the release of sCD27. Furthermore, positive expression of CD70 by NPC cells was significantly correlated with EBV infection. Our results suggest that CD70/CD27-targeted immunotherapies may be promising treatment options and that sCD27 may become an essential tool for evaluating the applicability of these therapies by predicting the intratumoral CD70/CD27 interaction in NPC.

Cardiac manifestations of human ACTA2 variants recapitulated in a zebrafish model.

The ACTA2 gene encodes actin α2, a major smooth muscle protein in vascular smooth muscle cells. Missense variants in the ACTA2 gene can cause inherited thoracic aortic diseases with characteristic symptoms, such as dysfunction of smooth muscle cells in the lungs, brain vessels, intestines, pupils, bladder, or heart. We identified a heterozygous missense variant of Gly148Arg (G148R) in a patient with a thoracic aortic aneurysm, dissection, and left ventricular non-compaction. We used zebrafish as an in vivo model to investigate whether or not the variants might cause functional or histopathological abnormalities in the heart. Following the fertilization of one-cell stage embryos, we injected in vitro synthesized ACTA2 mRNA of wild-type, novel variant G148R, or the previously known pathogenic variant Arg179His (R179H). The embryos were maintained and raised for 72 h post-fertilization for a heart analysis. Shortening fractions of heart were significantly reduced in both pathogenic variants. A histopathological evaluation showed that the myocardial wall of ACTA2 pathogenic variants was thinner than that of the wild type, and the total cell number within the myocardium was markedly decreased in all zebrafish with pathogenic variants mRNAs. Proliferating cell numbers were also significantly decreased in the endothelial and myocardial regions of zebrafish with ACTA2 variants compared to the wild type. These results demonstrate the effects of ACTA2 G148R and R179H on the development of left ventricle non-compaction and cardiac morphological abnormalities. Our study highlights the previously unknown significance of the ACTA2 gene in several aspects of cardiovascular development.

Detection of residual stones by peroral direct cholangioscopy in patients with intrahepatic stones after hepaticojejunostomy: a prospective study (with video).

BACKGROUND AND AIMS: The difficulty in radiographic confirmation of the presence of stones remains challenging in the treatment of intrahepatic bile duct (IHBD) stones in patients after hepaticojejunostomy (HJ). Peroral direct cholangioscopy (PDCS) enables direct observation of the bile duct and is useful for detecting and removing residual stones; however, its effectiveness is not clearly established in this clinical context. METHODS: This single-center, single-arm, prospective study included 44 patients with IHBD who underwent bowel reconstruction with HJ during the study period. Stone removal was performed by using short-type double-balloon enteroscopy. After balloon-occluded cholangiography, the double-balloon enteroscopy was exchanged for an ultra-slim endoscope through the balloon overtube for PDCS. The primary end point was the rate of residual stones detected by PDCS. Secondary end points were success rate of PDCS, residual stone removal with PDCS, procedure time for PDCS, procedure-related adverse events, and stone recurrence rate. RESULTS: PDCS was successful in 39 (89%) of 44 patients, among whom residual stones were detected in 16 (41%) (95% CI, 28%-54%). Twelve patients (75%) had residual stones <5 mm. Stone removal was successful in 15 (94%) patients, and median procedure time for PDCS was 16 minutes (interquartile range, 10-26 minutes). The rate of procedure-related adverse events was 7% (3 of 44); all adverse events improved with conservative treatment. During the median follow-up of 2.1 years (interquartile range, 1.4-3.3 years), the overall probability of recurrence-free status at 1, 2, and 3 years was 100%, 92%, and 86%, respectively. CONCLUSIONS: PDCS is a safe and effective procedure for complete stone removal in patients with IHBD stones after HJ.

Virtual indigo carmine chromoendoscopy images: A novel modality for peroral cholangioscopy using artificial intelligence technology (with video).

BACKGROUND AND AIMS: Accurately diagnosing biliary strictures is crucial for surgical decisions, and although peroral cholangioscopy (POCS) aids in visual diagnosis, diagnosing malignancies or determining lesion margins via this route remains challenging. Indigo carmine is commonly used to evaluate lesions during gastrointestinal endoscopy. We aimed to establish the utility of virtual indigo carmine chromoendoscopy (VICI) converted from POCS images using artificial intelligence. METHODS: This single-center, retrospective study analyzed 40 patients with biliary strictures who underwent POCS using white light imaging (WLI) and narrow-band imaging (NBI). A "cycle-consistent adversarial network" (CycleGAN) was used to convert the WLI into VICI of POCS images. Three experienced endoscopists evaluated WLI, NBI, and VICI via POCS in all patients. The primary outcome was the visualization quality of surface structures, surface microvessels, and lesion margins. The secondary outcome was diagnostic accuracy. RESULTS: VICI showed superior visualization of the surface structures and lesion margins compared with WLI (P<0.001) and NBI (P<0.001). The diagnostic accuracies were 72.5%, 87.5%, and 90.0% in WLI alone, WLI and VICI simultaneously, and WLI and NBI simultaneously, respectively. WLI and VICI simultaneously tended to result in higher accuracy than WLI alone (P=0.083) and the results were not significantly different from WLI and NBI simultaneously (P=0.65). CONCLUSIONS: VICI in POCS proved valuable for visualizing surface structures and lesion margins and contributed to higher diagnostic accuracy comparable to NBI. In addition to NBI, VICI may be a novel supportive modality for POCS.

A comparison of the clinical efficacy of tonsillectomy with steroid pulse therapy and tonsillectomy therapy alone for patients with immunoglobulin A nephropathy: a retrospective observational study.

BACKGROUND: Tonsillectomy with steroid pulse therapy (TSP) and tonsillectomy monotherapy (T) have improved the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, a consensus has not been reached on the best treatment for these patients. This study aimed to compare the efficacies of TSP and T. METHODS: Data of patients with IgAN who received TSP or T were retrospectively analyzed. The exclusion criterion was a serum creatinine level > 1.5 mg/dL. The clinical remission and renal survival rates were compared. RESULTS: Patients were divided into groups based on the treatment method: the TSP (n = 82) and T groups (n = 41). No significant differences were observed in patient characteristics, except for the observation period (TSP: 60 months, T: 113 months). The log-rank test revealed that the clinical remission rate was significantly higher in the TSP group than in the T group (p < 0.05). The superiority of TSP was also observed in the urinary protein excretion (> / = or < 1 g/day) of the two subgroups. According to the Cox proportional-hazards model, the treatment method and daily urinary protein extraction were independent factors affecting clinical remission. The 10-year renal survival rates in the TSP and T groups were 100% and 92.5%, respectively. The log-rank test revealed a tendency for a higher renal survival rate in the TSP group than in the T group (p = 0.09). CONCLUSION: The clinical remission rate was significantly higher with TSP than with T, regardless of urinary protein levels. TSP tended to have a better renal survival rate than T.

Anti-SARS-CoV-2 IgG antibody after the second and third mRNA vaccinations in staff and residents in a nursing home with a previous COVID-19 outbreak in Niigata, Japan.

This study measured IgG antibody titers against spike (S) and nucleocapsid (N) proteins of SARS-CoV-2 before vaccination and after the second and third doses of an mRNA vaccine in staff and residents of a nursing home in Niigata, Japan. The study included 52 staff members, of whom six (11.5%) were previously infected with SARS-CoV-2, and 32 older residents, of whom 22 (68.8%) were previously infected. All participants received the first two doses in April-July 2021 and a third dose in January-March 2022. In staff, the median anti-S antibody titers (interquartile range) in previously infected and SARS-CoV-2-naïve individuals before vaccination were 960 (592-1,926) and 0.5 (0.0-2.1) arbitrary units (AU)/mL. Anti-S antibody titers 5 months after the second and third doses in previously infected staff were 7,391 (5,230-7,747) and 10,195 (5,582-13,886) AU. In residents, the median anti-S antibody titers in previously infected and naïve individuals before vaccination were 734 (425-1,934) and 1.1 (0.0-3.1) AU/mL. Anti-S antibody titers at 5 months after the second and third doses in previously infected residents were 15,872 (9,683-21,557) and 13,813 (6,689-20,839) AU/mL; however, there were no significant differences in titers between the second and third doses in previously infected residents. Anti-N antibody titers were higher in previously infected than naïve individuals, and titers decreased chronologically.

Common Characteristics of Sinonasal Inflammation Associated with IgG4-Related Disease and Other Chronic Inflammatory Diseases: A Retrospective Observational Study.

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4, tissue infiltration of IgG4-positive cells, and fibrosis. Although a number of IgG4-RD patients show sinonasal involvement, there is little known about sinonasal inflammation associated with IgG4-RD. This study aimed to describe the clinicopathological features of sinonasal inflammation associated with IgG4-RD and to compare with other inflammatory diseases, such as eosinophilic chronic rhinosinusitis (ECRS) and granulomatosis with polyangiitis (GPA). METHODS: A retrospective analysis of clinicopathological features of patients with sinonasal lesions and high serum IgG4 was performed. Patient data were reviewed to determine whether they fulfilled the diagnostic criteria for other inflammatory diseases. RESULTS: Six of 7 patients were diagnosed with IgG4-RD, while 1 patient was diagnosed with GPA. In the 6 patients with IgG4-RD, intranasal findings showed nasal polyps in 3 patients (50%) and nasal crusting in the 3 patients (50%). Computed tomography showed ethmoid sinus involvement in 5 patients (83%). Five of the 6 patients (83%) were diagnosed with IgG4-RD based on nasal biopsy, whereas 1 patient (17%) was diagnosed based on lacrimal gland biopsy. Four patients fulfilled the Japanese epidemiological survey of refractory ECRS (JESREC) criteria. However, none of the patients showed eosinophil infiltration. Although the patient with GPA showed high levels of serum IgG4 and tissue infiltration of IgG4-positive cells in the nasal biopsy, the patient showed common clinical features of GPA. CONCLUSION: Patients with sinonasal inflammation associated with IgG4-RD had similar clinical characteristics with ECRS and GPA. Histopathological findings of the nasal biopsy from clinically diagnosed GPA was consistent with that of IgG4-RD. Sinonasal inflammation associated with IgG4-RD should be diagnosed based not only on tissue infiltration of IgG4-positive cells but in conjunction with clinical findings such as local nasal characteristics, involvement of other organs, and serum antineutrophil cytoplasmic antibody levels. IgG4-RD should be ruled out in patients with eosinophilia without histopathological eosinophil infiltration.

Efficacy of Cetuximab Combined with Paclitaxel in Patients with Recurrent Salivary Gland Carcinoma: A Retrospective Observational Study.

INTRODUCTION: Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy for patients with SGC. Our study described promising results of epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel in patients with SGC. METHODS: The medical records of patients with recurrent SGC treated with weekly cetuximab combined with paclitaxel (Cmab-PTX) between December 2017 and December 2022 at our institutions were retrospectively analyzed. RESULTS: Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months (range of 2-36 months). The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response and disease control rates were 71.4% and 85.7%, respectively. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. CONCLUSION: Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC. Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy in patients with SGC. Our study described promising results of cetuximab (Cmab), epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel (PTX) in patients with SGC. Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months. The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response rate was 71.4%. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. Our study revealed a preferable objective response rate of Cmab-PTX for patients with high-grade SGC. Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC.

Prognostic Value of the 18F-FDG PET/CT and Haematological Parameters in Head and Neck Cancer.

INTRODUCTION: Fluorine 18-fluoro-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used for the staging of head and neck cancer. This study aimed to evaluate the correlation between 18F-FDG PET/CT, haematological parameters and prognosis in patients with advanced head and neck cancer. METHODS: This was a single-institutional retrospective study of 83 patients with advanced head and neck squamous cell carcinoma (HNSCC) who underwent 18F-FDG PET/CT imaging before initial treatment between 2014 and 2018. 18F-FDG PET/CT after treatment was performed in 57 patients. The prognostic parameters of the pre- and post-treatment maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), total lesion glycolysis (TLG) of primary tumours and haematological parameters were analysed to evaluate the association between overall survival (OS) and progression-free survival (PFS). RESULTS: Pre-MTV, pre-TLG and post-SUVmax were significantly associated with poor OS and PFS (p < 0.05). Haematological parameters, including pretreatment neutrophil/lymphocyte ratio and C-reactive protein/albumin ratio, were associated with 18F-FDG PET/CT parameters. In multivariate analysis, post-SUVmax was an independent prognostic factor for OS and PFS. CONCLUSION: A correlation between PET/CT metabolic and haematological parameters was observed. The volume and intensity of 18F-FDG uptake region, in addition to haematological parameters, are feasible markers for predicting the progression of HNSCC in daily practice. Further, post-SUVmax could be an independent parameter for predicting poor survival.

Mitogen-activated protein kinase inhibition augments the T cell response against HOXB7-expressing tumor through human leukocyte antigen upregulation.

Homeobox B7 (HOXB7) is a master regulatory gene that regulates cell proliferation and activates oncogenic pathways. Overexpression of HOXB7 correlates with aggressive behavior and poor prognosis in patients with cancer. However, the expression and role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we observed that most samples from patients with oropharyngeal cancer and HNSCC expressed HOXB7. As no direct inhibitor has been reported, we identified a potent peptide epitope to target HOXB7-expressing tumors through immune cells. A novel HOXB7-derived peptide epitope (HOXB78-25 ) elicited antigen-specific and tumor-reactive promiscuous CD4+ T cell responses. These CD4+ T cells produced γ-interferon (IFN-γ) and had the direct ability to kill tumors through granzyme B. Notably, downregulation of HOXB7 using siRNA enhanced human leukocyte antigen class II expression on tumor cells by decreasing the phosphorylation of MAPK. Mitogen-activated protein kinase inhibition augmented IFN-γ production by HOXB7-reactive CD4+ T cell responses without decreasing the expression of HOXB7. These results suggest that combining HOXB7 peptide-based vaccine with MAPK inhibitors could be an effective immunological strategy for cancer treatment.

Brachyury-targeted immunotherapy combined with gemcitabine against head and neck cancer.

Brachyury is a transcription factor belonging to the T-box gene family and is involved in the posterior formation of the mesoderm and differentiation of chordates. As the overexpression of Brachyury is a poor prognostic factor in a variety of cancers, the establishment of Brachyury-targeted therapy would be beneficial for the treatment of aggressive tumors. Because transcription factors are difficult to treat with a therapeutic antibody, peptide vaccines are a feasible approach for targeting Brachyury. In this study, we identified Brachyury-derived epitopes that elicit antigen-specific and tumor-reactive CD4+ T cells that directly kill tumors. T cells recognizing Brachyury epitopes were present in patients with head and neck squamous cell carcinoma. Next, we focused on gemcitabine (GEM) as an immunoadjuvant to augment the efficacy of antitumor responses by T cells. Interestingly, GEM upregulated HLA class I and HLA-DR expression in tumor, followed by the upregulation of anti-tumor T cell responses. As tumoral PD-L1 expression was also augmented by GEM, PD-1/PD-L1 blockade and GEM synergistically enhanced the tumor-reactivity of Brachyury-reactive T cells. The synergy between the PD-1/PD-L1 blockade and GEM was also confirmed in a mouse model of head and neck squamous cell carcinoma. These results suggest that the combined treatment of Brachyury peptide with GEM and immune checkpoint blockade could be a promising immunotherapy against head and neck cancer.

The efficacy of non-anesthesiologist-administered propofol sedation with a target-controlled infusion system during double-balloon endoscopic retrograde cholangiopancreatography.

BACKGROUND: The sedation method used during double-balloon endoscopic retrograde cholangiopancreatography (DB-ERCP) differs among countries and/or facilities, and there is no established method. This study aimed to evaluate the efficacy of non-anesthesiologist-administered propofol (NAAP) sedation using a target-controlled infusion (TCI) system during DB-ERCP. METHODS: This retrospective study was conducted between May 2017 and December 2020 at an academic center. One hundred and fifty-six consecutive patients who underwent DB-ERCP were sedated by gastroenterologists using diazepam (n = 77) or propofol with a TCI system (n = 79), depending on the period. The primary endpoint was a comparison of poor sedation rates between the two groups. Poor sedation was defined as a condition requiring the use of other sedative agents or discontinuation of the procedure. Secondary endpoints were sedation-related adverse events and risk factors for poor sedation. RESULTS: Poor sedation occurred significantly more often in the diazepam sedation group (diazepam sedation, n = 12 [16%] vs. propofol sedation, n = 1 [1%]; P = 0.001). Vigorous body movements (3 or 4) (diazepam sedation, n = 40 [52%] vs. propofol sedation, n = 28 [35%]; P = 0.038) and hypoxemia (< 85%) (diazepam sedation, n = 7 [9%] vs. propofol sedation, n = 1 [1%]; P = 0.027) occurred significantly more often in the diazepam sedation group. In the multivariate analysis, age < 70 years old (OR, 10.26; 95% CI, 1.57-66.98; P = 0.015), BMI ≥ 25 kg/m2 (OR, 11.96; 95% CI, 1.67-85.69; P = 0.014), and propofol sedation (OR, 0.06; 95% CI, 0.01-0.58; P = 0.015) were associated factors for poor sedation. CONCLUSIONS: NAAP sedation with the TCI system during DB-ERCP was safer and more effective than diazepam sedation.

Plasmodesmata callose binding protein 2 contributes to the regulation of cambium/phloem formation and auxin response during the tissue reunion process in incised Arabidopsis stem.

Plants are exposed to a variety of biotic and abiotic stresses, including wounding at the stem. The healing process (tissue reunion) begins immediately after stem wounding. The plant hormone auxin plays an important role during tissue reunion. In decapitated stems, auxin transport from the shoot apex is reduced and tissue reunion does not occur but is restored by application of indole-3-acetic acid (IAA). In this study, we found that plasmodesmata callose binding protein 2 (PDCB2) affects the expansion of the cambium/phloem region via changes in auxin response during the process of tissue reunion. PDCB2 was expressed in the cortex and endodermis on the incised side of stems 1-3 days after incision. PDCB2-knockout plants showed reduced callose deposition at plasmodesmata and DR5::GUS activity in the endodermis/cortex in the upper region of the incision accompanied by an increase in size of the cambium/phloem region during tissue reunion. In addition, PIN(PIN-FORMED)3, which is involved in lateral auxin transport, was induced by auxin in the cambium/phloem and endodermis/cortex in the upper part of the incision in wild type, but its expression of PIN3 was decreased in pdcb2 mutant. Our results suggest that PDCB2 contributes to the regulation of cambium/phloem development via auxin response.

Prognostic factors for acute ischemic stroke in patients undergoing hemodialysis.

BACKGROUND: Acute ischemic stroke (AIS) is a critical complication in patients undergoing dialysis. Although the improvement of AIS management is an urgent requirement, few studies have evaluated the prognostic factors of AIS in these patients. This study aimed to assess the relationship between clinical factors in patients undergoing dialysis and the prognosis of AIS. METHODS: Among 1267 patients who were hospitalized for AIS in Sendai City Hospital from January 2015 to June 2020, 81 patients undergoing hemodialysis were retrospectively enrolled. Multivariate analysis was performed to evaluate the effect of baseline characteristics, dialysis factors, and neurological severity of patients at admission [National Institutes of Health Stroke Scale (NIHSS) score] on in-hospital mortality, physical disability, and the need for rehabilitation transfer. RESULTS: A higher NIHSS score was a critical risk factor for each outcome and the only significant factor for in-hospital mortality [odds ratio (OR)/point 1.156, 95% confidence interval (CI) 1.054-1.267]. The risk factors of physical disability were NIHSS score (OR/point 1.458, 95% CI 1.064-1.998), older age (OR/year 1.141, 95% CI 1.022-1.274), diabetic nephropathy (OR 7.096, 95% CI 1.066-47.218), and higher premorbid modified Rankin scale (mRS) score (OR/grade 2.144, 95% CI 1.155-3.978); while those of rehabilitation transfer were a higher NIHSS score (OR/point 1.253, 95% CI 1.080-1.455), dialysis vintage (OR/year 1.175, 95% CI 1.024-1.349), and intradialytic hypotension before onset (OR 5.430, 95% CI 1.320-22.338). CONCLUSIONS: Along with neurological severity, dialysis vintage, intradialytic hypotension, and diabetic nephropathy could worsen the prognosis of patients with AIS undergoing hemodialysis.

Chronic kidney disease and clinical outcomes in patients with COVID-19 in Japan.

BACKGROUND: Identifying predictive factors for coronavirus disease 2019 (COVID-19) is crucial for risk stratification and intervention. Kidney dysfunction contributes to the severity of various infectious diseases. However, the association between on-admission kidney dysfunction and the clinical outcome in COVID-19 patients is unclear. METHODS: This study was a multicenter retrospective observational cohort study of COVID-19 patients, diagnosed by polymerase chain reaction. We retrospectively analyzed 500 COVID-19 patients (mean age: 51 ± 19 years) admitted to eight hospitals in Japan. Kidney dysfunction was defined as a reduced estimated glomerular filtration rate (< 60 mL/min/1.73 m2) or proteinuria (≥ 1 + dipstick proteinuria) on admission. The primary composite outcome included in-hospital death, extracorporeal membrane oxygenation, mechanical ventilation (invasive and noninvasive methods), and intensive care unit (ICU) admission. RESULTS: Overall, 171 (34.2%) patients presented with on-admission kidney dysfunction, and the primary composite outcome was observed in 60 (12.0%) patients. Patients with kidney dysfunction showed higher rates of in-hospital death (12.3 vs. 1.2%), mechanical ventilation (13.5 vs. 4.0%), and ICU admission (18.1 vs. 5.2%) than those without it. Categorical and multivariate regression analyses revealed that kidney dysfunction was substantially associated with the primary composite outcome. Thus, on-admission kidney dysfunction was common in COVID-19 patients. Furthermore, it correlated significantly and positively with COVID-19 severity and mortality. CONCLUSIONS: On-admission kidney dysfunction was associated with disease severity and poor short-term prognosis in patients with COVID-19. Thus, on-admission kidney dysfunction has the potential to stratify risks in COVID-19 patients.

Sarcopenia and Frailty in Heart Failure: Is There a Biomarker Signature?

PURPOSE OF REVIEW: Sarcopenia and frailty are common in patients with heart failure (HF) and are strongly associated with prognosis. This review aims to examine promising biomarkers that can guide physicians in identifying sarcopenia and frailty in HF. RECENT FINDINGS: Traditional biomarkers including C-reactive protein, aminotransaminase, myostatin, and urinary creatinine as well as novel biomarkers including microRNAs, suppression of tumorigenicity 2 (ST2), galectin-3, and procollagen type III N-terminal peptide may help in predicting the development of sarcopenia and frailty in HF patients. Among those biomarkers, aminotransferase, urinary creatinine, and ST2 predicted the prognosis in HF patients with sarcopenia and frailty. This review outlines the current knowledge of biomarkers that are considered promising for diagnosing sarcopenia and frailty in HF. The listed biomarkers might support the diagnosis, prognosis, and therapeutic decisions for sarcopenia and frailty in HF patients.

Multijurisdictional Outbreak of Enterohemorrhagic Escherichia coli O157 Caused by Consumption of Ready-to-Eat Grilled Skewered Meat in Niigata, Japan.

Enterohemorrhagic Escherichia coli O157 (EHEC) causes severe complications such as hemolytic uremic syndrome. Contaminated ready-to-eat (RTE) food is one of the vehicles of multijurisdictional outbreaks of foodborne disease worldwide. Multijurisdictional (covering cities, towns, and villages) outbreaks of EHEC are usually linked to an increase in cases, and here we describe such an outbreak involving 29 cases in October 2017 in the Niigata Prefecture. After prefecture-wide active case finding, we conducted a case-control study of 29 cases with eligible data who tested positive for EHEC. To determine the association of the outbreak with risk factors, we compared these cases with 38 controls selected from family and acquaintances who were both symptom free and tested negative for EHEC. The largest number of cases was in the 20-29-year age group (7/29; 24%) and most were women (20/29; 69%). All 29 cases had an identical or similar multilocus variable number tandem-repeat analysis (MLVA) profile. Of these, 76% (22/29) had consumed some type of grilled skewered meat. Also, 69% (20/29) had consumed grilled skewered meat produced by company X. EHEC infection was strongly associated with the consumption of grilled skewered meat produced by any food processing company (odds ratio [OR] = 11.8, confidence interval [95% CI]: 3.7-37.4) and by company X (OR = 9.8, 95% CI: 3.2-30.7). At company X, the skewered meat was grilled to 95°C and then removed from the grilling area to meat trays. The meat trays were not sufficiently washed and disinfected. Testing indicated that the facility was negative for EHEC but four asymptomatic employees tested positive for EHEC. Company X was temporarily closed and voluntarily recalled the foods. We recommend that all employees sufficiently wash and disinfect meat trays to prevent contamination of RTE food, avoid cross-contamination of grilled skewered meat through the environment by regularly cleaning the facility, and appropriately practice self-health care.

Efficacy of preoperative autologous blood storage in one-stage bilateral total knee arthroplasty.

BACKGROUND: One-stage bilateral total knee arthroplasty (TKA) has the advantages of a single hospital stay, shorter rehabilitation, and reduced financial burden on patients. However, perioperative bleeding is greater with one-stage bilateral TKA than with unilateral TKA and is more likely to require allogeneic blood transfusion. At our hospital, we normally store autologous blood about 1 month before surgery to reduce the need for allogeneic blood transfusion and avoid its adverse reactions as much as possible. The purpose of this study was to determine the efficacy of preoperative autologous blood storage for patients undergoing one-stage bilateral TKA. METHODS: We retrospectively examined the allogeneic blood transfusion avoidance rate and the perioperative decrease in hemoglobin (Hb) level in 166 patients according to whether or not they had preoperative autologous blood stored. The patients for whom blood was stored were then subdivided according to whether the amount of blood stored was 400 mL or 200 mL. RESULTS: Excluding allogeneic transfusion cases, the mean perioperative decrease in Hb was significantly lower in the patients with stored blood than in those without stored blood (3.5 g/dL vs 4.4 g/dL, p < 0.001). The allogeneic blood transfusion avoidance rate was significantly higher in the group with stored blood (98.5% vs 86.7%, p < 0.01). In the group with stored blood, the transfusion avoidance rate was higher, but not significantly, in the subgroup with 400 mL of blood stored than in those with 200 mL of blood stored (100% vs 97.5%) and the mean perioperative decrease in Hb was 3.5 g/dL in both blood storage volume groups. CONCLUSIONS: Preoperative autologous blood storage can help increase the likelihood of avoiding allogeneic blood transfusion in patients undergoing one-stage bilateral TKA.

Genetic Deletion of AT1a Receptor or Na+/H+ Exchanger 3 Selectively in the Proximal Tubules of the Kidney Attenuates Two-Kidney, One-Clip Goldblatt Hypertension in Mice.

The roles of angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT1a receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT1a receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a−/−, proximal tubule (PT)-specific PT-Agtr1a−/− or PT-Nhe3−/− mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT1a receptors completely blocked the development of 2K1C hypertension in Agtr1a−/− mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a−/− mice or NHE3 in PT-Nhe3−/− mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT1 (AT1a)/NHE3 axis in the development of 2K1C Goldblatt hypertension.

Follow-up genotoxicity assessment of Ames-positive/equivocal chemicals using the improved thymidine kinase gene mutation assay in DNA repair-deficient human TK6 cells.

Genotoxicity testing plays an important role in the safety assessment of pharmaceuticals, pesticides and chemical substances. Among the guidelines for various genotoxicity tests, the in vitro genotoxicity test battery comprises the bacterial Ames test and mammalian cell assays. Several chemicals exhibit conflicting results for the bacterial Ames test and mammalian cell genotoxicity studies, which may stem from the differences in DNA repair capacity or metabolism, between different cell types or species. For better understanding the mechanistic implications regarding conflict outcomes between different assay systems, it is necessary to develop in vitro genotoxicity testing approaches with higher specificity towards DNA-damaging reagents. We have recently established an improved thymidine kinase (TK) gene mutation assay (TK assay) i.e. deficient in DNA excision repair system using human lymphoblastoid TK6 cells lacking XRCC1 and XPA (XRCC1-/-/XPA-/-), the core factors of base excision repair (BER) and nucleotide excision repair (NER), respectively. This DNA repair-deficient TK6 cell line is expected to specifically evaluate the genotoxic potential of chemical substances based on the DNA damage. We focussed on four reagents, N-(1-naphthyl)ethylenediamine dihydrochloride (NEDA), p-phenylenediamine (PPD), auramine and malachite green (MG) as the Ames test-positive chemicals. In our assay, assessment using XRCC1-/-/XPA-/- cells revealed no statistically significant increase in the mutant frequencies after treatment with NEDA, PPD and MG, suggesting the chemicals to be non-genotoxic in humans. The observations were consistent with that of the follow-up in vivo studies. In contrast, the mutant frequency was markedly increased in XRCC1-/-/XPA-/- cells after treatment with auramine. The results suggest that auramine is the genotoxic reagent that preferentially induces DNA damages resolved by BER and/or NER in mammals. Taken together, BER/NER-deficient cell-based genotoxicity testing will contribute to elucidate the mechanism of genotoxicity and therefore play a pivotal role in the accurate safety assessment of chemical substances.