Toho University Ohashi Medical Center

Abstract The Tokyo Guidelines 2013 (TG13) for acute cholangitis and cholecystitis were globally disseminated and various clinical studies about the management of acute cholecystitis were reported by many researchers and clinicians from all over the world. The 1 st edition of the Tokyo Guidelines 2007 ( TG 07) was revised in 2013. According to that revision, the TG 13 diagnostic criteria of acute cholecystitis provided better specificity and higher diagnostic accuracy. Thorough our literature search about diagnostic criteria for acute cholecystitis, new and strong evidence that had been released from 2013 to 2017 was not found with serious and important issues about using TG 13 diagnostic criteria of acute cholecystitis. On the other hand, the TG 13 severity grading for acute cholecystitis has been validated in numerous studies. As a result of these reviews, the TG 13 severity grading for acute cholecystitis was significantly associated with parameters including 30‐day overall mortality, length of hospital stay, conversion rates to open surgery, and medical costs. In terms of severity assessment, breakthrough and intensive literature for revising severity grading was not reported. Consequently, TG 13 diagnostic criteria and severity grading were judged from numerous validation studies as useful indicators in clinical practice and adopted as TG 18/ TG 13 diagnostic criteria and severity grading of acute cholecystitis without any modification. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47 . Related clinical questions and references are also included.

We propose a new flowchart for the treatment of acute cholecystitis (AC) in the Tokyo Guidelines 2018 (TG18). Grade III AC was not indicated for straightforward laparoscopic cholecystectomy (Lap-C). Following analysis of subsequent clinical investigations and drawing on Big Data in particular, TG18 proposes that some Grade III AC can be treated by Lap-C when performed at advanced centers with specialized surgeons experienced in this procedure and for patients that satisfy certain strict criteria. For Grade I, TG18 recommends early Lap-C if the patients meet the criteria of Charlson comorbidity index (CCI) ≤5 and American Society of Anesthesiologists physical status classification (ASA-PS) ≤2. For Grade II AC, if patients meet the criteria of CCI ≤5 and ASA-PS ≤2, TG18 recommends early Lap-C performed by experienced surgeons; and if not, after medical treatment and/or gallbladder drainage, Lap-C would be indicated. TG18 proposes that Lap-C is indicated in Grade III patients with strict criteria. These are that the patients have favorable organ system failure, and negative predictive factors, who meet the criteria of CCI ≤3 and ASA-PS ≤2 and who are being treated at an advanced center (where experienced surgeons practice). If the patient is not considered suitable for early surgery, TG18 recommends early/urgent biliary drainage followed by delayed Lap-C once the patient's overall condition has improved. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease. METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority. RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority). CONCLUSIONS: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).

BACKGROUND: Patients with suspected thoracic aortic dissection require early and accurate diagnosis. Aortography has been replaced by less invasive imaging techniques including transesophageal echocardiography (TEE), helical computed tomography (CT), and magnetic resonance imaging (MRI); however, accuracies have varied from trial to trial, and which imaging technique should be applied to which risk population remains unclear. We systematically reviewed the diagnostic accuracy of these imaging techniques in patients with suspected thoracic aortic dissection. METHODS: Published English-language reports on the diagnosis of thoracic aortic dissection by TEE, helical CT, or MRI were identified from electronic databases. Sensitivity, specificity, and positive and negative likelihood ratios were pooled in a random-effects model. RESULTS: Sixteen studies involving a total of 1139 patients were selected. Pooled sensitivity (98%-100%) and specificity (95%-98%) were comparable between imaging techniques. The pooled positive likelihood ratio appeared to be higher for MRI (positive likelihood ratio, 25.3; 95% confidence interval, 11.1-57.1) than for TEE (14.1; 6.0-33.2) or helical CT (13.9; 4.2-46.0). If a patient had shown a 50% pretest probability of thoracic aortic dissection (high risk), he or she had a 93% to 96% posttest probability of thoracic aortic dissection following a positive result of each imaging test. If a patient had a 5% pretest probability of thoracic aortic dissection (low risk), he or she had a 0.1% to 0.3% posttest probability of thoracic aortic dissection following a negative result of each imaging test. CONCLUSION: All 3 imaging techniques, ie, TEE, helical CT, and MRI, yield clinically equally reliable diagnostic values for confirming or ruling out thoracic aortic dissection.

In some cases, laparoscopic cholecystectomy (LC) may be difficult to perform in patients with acute cholecystitis (AC) with severe inflammation and fibrosis. The Tokyo Guidelines 2018 (TG18) expand the indications for LC under difficult conditions for each level of severity of AC. As a result of expanding the indications for LC to treat AC, it is absolutely necessary to avoid any increase in bile duct injury (BDI), particularly vasculo-biliary injury (VBI), which is known to occur at a certain rate in LC. Since the Tokyo Guidelines 2013 (TG13), an attempt has been made to assess intraoperative findings as objective indicators of surgical difficulty; based on expert consensus on these difficulty indicators, bail-out procedures (including conversion to open cholecystectomy) have been indicated for cases in which LC for AC is difficult to perform. A bail-out procedure should be chosen if, when the Calot's triangle is appropriately retracted and used as a landmark, a critical view of safety (CVS) cannot be achieved because of the presence of nondissectable scarring or severe fibrosis. We propose standardized safe steps for LC to treat AC. To achieve a CVS, it is vital to dissect at a location above (on the ventral side of) the imaginary line connecting the base of the left medial section (Segment 4) and the roof of Rouvière's sulcus and to fulfill the three criteria of CVS before dividing any structures. Achieving a CVS prevents the misidentification of the cystic duct and the common bile duct, which are most commonly confused. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

The initial management of patients with suspected acute biliary infection starts with the measurement of vital signs to assess whether or not the situation is urgent. If the case is judged to be urgent, initial medical treatment should be started immediately including respiratory/circulatory management if required, without waiting for a definitive diagnosis. The patient's medical history is then taken; an abdominal examination is performed; blood tests, urinalysis, and diagnostic imaging are carried out; and a diagnosis is made using the diagnostic criteria for cholangitis/cholecystitis. Once the diagnosis has been confirmed, initial medical treatment should be started immediately, severity should be assessed according to the severity grading criteria for acute cholangitis/cholecystitis, and the patient's general status should be evaluated. For mild acute cholangitis, in most cases initial treatment including antibiotics is sufficient, and most patients do not require biliary drainage. However, biliary drainage should be considered if a patient does not respond to initial treatment. For moderate acute cholangitis, early endoscopic or percutaneous transhepatic biliary drainage is indicated. If the underlying etiology requires treatment, this should be provided after the patient's general condition has improved; endoscopic sphincterotomy and subsequent choledocholithotomy may be performed together with biliary drainage. For severe acute cholangitis, appropriate respiratory/circulatory management is required. Biliary drainage should be performed as soon as possible after the patient's general condition has been improved by initial treatment and respiratory/circulatory management. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

OBJECTIVE: The aim of the study was to confirm the noninferiority of mesorectal excision (ME) alone to ME with lateral lymph node dissection (LLND) in terms of efficacy. BACKGROUND: Lateral pelvic lymph node metastasis is occasionally found in clinical stage II or III lower rectal cancer, and ME with LLND is the standard procedure in Japan. ME alone, however, is the international standard surgical procedure for rectal cancer. METHODS: Eligibility criteria included histologically proven rectal cancer at clinical stage II/III; main lesion located in the rectum, with the lower margin below the peritoneal reflection; no lateral pelvic lymph node enlargement; Peformance Status of 0 or 1; and age 20 to 75 years. Patients were intraoperatively allocated to undergo ME with LLND or ME alone in a randomized manner. The primary endpoint was relapse-free survival, with a noninferiority margin for the hazard ratio of 1.34. Secondary endpoints included overall survival and local-recurrence-free survival. Analysis was by intention to treat. RESULTS: In total, 701 patients were randomized to the ME with LLND (n = 351) and ME alone (n = 350) groups. The 5-year relapse-free survival in the ME with LLND and ME alone groups were 73.4% and 73.3%, respectively (hazard ratio: 1.07, 90.9% confidence interval 0.84-1.36), with a 1-sided P value for noninferiority of 0.0547. The 5-year overall survival, and 5-year local-recurrence-free survival in the ME with LLND and ME alone groups were 92.6% and 90.2%, and 87.7% and 82.4%, respectively. The numbers of patients with local recurrence were 26 (7.4%) and 44 (12.6%) in the ME with LLND and ME alone groups, respectively (P = 0.024). CONCLUSIONS: The noninferiority of ME alone to ME with LLND was not confirmed in the intent-to-treat analysis. ME with LLND had a lower local recurrence, especially in the lateral pelvis, compared to ME alone.

Antimicrobial therapy is a mainstay of the management for patients with acute cholangitis and/or cholecystitis. The Tokyo Guidelines 2018 (TG18) provides recommendations for the appropriate use of antimicrobials for community-acquired and healthcare-associated infections. The listed agents are for empirical therapy provided before the infecting isolates are identified. Antimicrobial agents are listed by class-definitions and TG18 severity grade I, II, and III subcategorized by clinical settings. In the era of emerging and increasing antimicrobial resistance, monitoring and updating local antibiograms is underscored. Prudent antimicrobial usage and early de-escalation or termination of antimicrobial therapy are now important parts of decision-making. What is new in TG18 is that the duration of antimicrobial therapy for both acute cholangitis and cholecystitis is systematically reviewed. Prophylactic antimicrobial usage for elective endoscopic retrograde cholangiopancreatography is no longer recommended and the section was deleted in TG18. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

OBJECTIVE: The purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non-Group 1 agents, either macrocyclic or linear protein interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease. MATERIALS AND METHODS: This study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedent's tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non-Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test. RESULTS: Of the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus). CONCLUSION: Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.

BACKGROUND: The Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were published in 2007 as the world's first guidelines for acute cholangitis and cholecystitis. The diagnostic criteria and severity assessment of acute cholecystitis have since been widely used all over the world. A validation study of TG07 has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. In addition, considerable new evidence referring to acute cholecystitis as well as evaluations of TG07 have been published. Consequently, we organized the Tokyo Guidelines Revision Committee to evaluate TG07, recognize new evidence, and conduct a multi-center analysis to revise the guidelines (TG13). METHODS AND MATERIALS: We retrospectively analyzed 451 patients with acute cholecystitis from multiple tertiary care centers in Japan. All 451 patients were first evaluated using the criteria in TG07. The "gold standard" for acute cholecystitis in this study was a diagnosis by pathology. The validity of TG07 diagnostic criteria was investigated by comparing clinical with pathological diagnosis. RESULTS: Of 451 patients evaluated, a total of 227 patients were given a diagnosis of acute cholecystitis by pathological examination (prevalence 50.3 %). TG07 criteria provided a definite diagnosis of acute cholecystitis in 224 patients. The sensitivity of TG07 diagnostic criteria for acute cholecystitis was 92.1 %, and the specificity was 93.3 %. Based on the preliminary results, new diagnostic criteria for acute cholecystitis were proposed. Using the new criteria, the sensitivity of definite diagnosis was 91.2 %, and the specificity was 96.9 %. The accuracy rate was improved from 92.7 to 94.0 %. In regard to severity grading among 227 patients, 111 patients were classified as Mild (Grade I), 104 as Moderate (Grade II), and 12 as Severe (Grade III). CONCLUSION: The proposed new diagnostic criteria achieved better performance than the diagnostic criteria in TG07. Therefore, the proposed criteria have been adopted as new diagnostic criteria for acute cholecystitis and are referred to as the 2013 Tokyo Guidelines (TG13). Regarding severity assessment, no new evidence was found to suggest that the criteria in TG07 needed major adjustment. As a result, TG07 severity assessment criteria have been adopted in TG13 with minor changes.

BACKGROUND: Prasugrel is an antiplatelet agent that shows more prompt, potent, and consistent platelet inhibition than clopidogrel. The objective of this study was to confirm the efficacy and safety of prasugrel at loading/maintenance doses of 20/3.75 mg. METHODS AND RESULTS: Japanese patients (n=1,363) with acute coronary syndrome undergoing percutaneous coronary intervention were randomized to either prasugrel (20/3.75 mg) or clopidogrel (300/75 mg), both in combination with aspirin (81-330 mg for the first dose and 81-100 mg/day thereafter), for 24-48 weeks. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE) at 24 weeks, defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke. We compared the incidence of MACE between the 2 groups using point estimates. Safety outcomes included the incidence of bleeding events until 2 weeks after the last dose. The incidence of MACE at 24 weeks was 9.4% in the prasugrel group and 11.8% in the clopidogrel group (risk reduction 23%, hazard ratio 0.77, 95% confidence interval 0.56-1.07). The incidence of non-coronary artery bypass graft-related major bleeding was similar in both groups (1.9% vs. 2.2%). CONCLUSIONS: Prasugrel 20/3.75 mg was associated with a low incidence of ischemic events, similar to the results of TRITON-TIMI 38, and with a low risk of clinically serious bleeding in Japanese ACS patients.

Since the publication of the Tokyo Guidelines in 2007 and their revision in 2013, appropriate management for acute cholecystitis has been more clearly established. Since the last revision, several manuscripts, especially for alternative endoscopic techniques, have been reported; therefore, additional evaluation and refinement of the 2013 Guidelines is required. We describe a standard drainage method for surgically high-risk patients with acute cholecystitis and the latest developed endoscopic gallbladder drainage techniques described in the updated Tokyo Guidelines 2018 (TG18). Our study confirmed that percutaneous transhepatic gallbladder drainage should be considered the first alternative to surgical intervention in surgically high-risk patients with acute cholecystitis. Also, endoscopic transpapillary gallbladder drainage or endoscopic ultrasound-guided gallbladder drainage can be considered in high-volume institutes by skilled endoscopists. In the endoscopic transpapillary approach, either endoscopic naso-gallbladder drainage or gallbladder stenting can be considered for gallbladder drainage. We also introduce special techniques and the latest outcomes of endoscopic ultrasound-guided gallbladder drainage studies. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

In 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were first published in the Journal of Hepato-Biliary-Pancreatic Surgery. The fundamental policy of TG07 was to achieve the objectives of TG07 through the development of consensus among specialists in this field throughout the world. Considering such a situation, validation and feedback from the clinicians' viewpoints were indispensable. What had been pointed out from clinical practice was the low diagnostic sensitivity of TG07 for acute cholangitis and the presence of divergence between severity assessment and clinical judgment for acute cholangitis. In June 2010, we set up the Tokyo Guidelines Revision Committee for the revision of TG07 (TGRC) and started the validation of TG07. We also set up new diagnostic criteria and severity assessment criteria by retrospectively analyzing cases of acute cholangitis and cholecystitis, including cases of non-inflammatory biliary disease, collected from multiple institutions. TGRC held meetings a total of 35 times as well as international email exchanges with co-authors abroad. On June 9 and September 6, 2011, and on April 11, 2012, we held three International Meetings for the Clinical Assessment and Revision of Tokyo Guidelines. Through these meetings, the final draft of the updated Tokyo Guidelines (TG13) was prepared on the basis of the evidence from retrospective multi-center analyses. To be specific, discussion took place involving the revised new diagnostic criteria, and the new severity assessment criteria, new flowcharts of the management of acute cholangitis and cholecystitis, recommended medical care for which new evidence had been added, new recommendations for gallbladder drainage and antimicrobial therapy, and the role of surgical intervention. Management bundles for acute cholangitis and cholecystitis were introduced for effective dissemination with the level of evidence and the grade of recommendations. GRADE systems were utilized to provide the level of evidence and the grade of recommendations. TG13 improved the diagnostic sensitivity for acute cholangitis and cholecystitis, and presented criteria with extremely low false positive rates adapted for clinical practice. Furthermore, severity assessment criteria adapted for clinical use, flowcharts, and many new diagnostic and therapeutic modalities were presented. The bundles for the management of acute cholangitis and cholecystitis are presented in a separate section in TG13. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

A new compound with an immunosuppressive property was purified from culture filtrates of Isaria sinclairii and was chemically modified to FTY720. Rat spleen cells incubated with FTY720 demonstrated features characteristic of apoptosis--such as the absence of surface microvilli, chromatin condensation, and the formation of apoptotic bodies--by electron microscopy, and genemic DNA fragmentation by agarose gel electrophoresis. When FTY720 was administered in liver-allografted rats at a dose of 0.5 mg/kg from day 1 to day 14 after transplantation, the recipients survived significantly longer than the control group. Pretransplant treatment with 5 mg/kg of FTY720 one day before and on the day of grafting induced a remarkable prolongation of recipient survival, and three of 10 recipients survived for longer than 50 days. Furthermore, administration of FTY720 at 5 mg/kg on days 3 and day 4 after grafting also prolonged survival. In canine kidney allografting, a pretransplant 2-day course of FTY720 at 5 mg/kg prolonged graft survival. Daily administration of FTY720 in combination with CsA resulted in a significant prolongation of graft survival in a synergistic manner. In addition, FTY720 appeared to be nontoxic in canine recipients. These results demonstrated that FTY720, having a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation.

Management bundles that define items or procedures strongly recommended in clinical practice have been used in many guidelines in recent years. Application of these bundles facilitates the adaptation of guidelines and helps improve the prognosis of target diseases. In Tokyo Guidelines 2013 (TG13), we proposed management bundles for acute cholangitis and cholecystitis. Here, in Tokyo Guidelines 2018 (TG18), we redefine the management bundles for acute cholangitis and cholecystitis. Critical parts of the bundles in TG18 include the diagnostic process, severity assessment, transfer of patients if necessary, and therapeutic approach at each time point. Observance of these items and procedures should improve the prognosis of acute cholangitis and cholecystitis. Studies are now needed to evaluate the dissemination of these TG18 bundles and their effectiveness. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Since the publication of the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07), diagnostic criteria and severity assessment criteria for acute cholangitis have been presented and extensively used as the primary standard all over the world. However, it has been found that there are crucial limitations in these criteria. The diagnostic criteria of TG07 do not have enough sensitivity and specificity, and its severity assessment criteria are unsuitable for clinical use. A working team for the revision of TG07 was organized in June, 2010, and these criteria have been updated through clinical implementation and its assessment by means of multi-center analysis. The diagnostic criteria of acute cholangitis have been revised as criteria to establish the diagnosis where cholestasis and inflammation demonstrated by clinical signs or blood test in addition to biliary manifestations demonstrated by imaging are present. The diagnostic criteria of the updated Tokyo Guidelines (TG13) have high sensitivity (87.6 %) and high specificity (77.7 %). TG13 has better diagnostic capacity than TG07. Severity assessment is classified as follows: Grade III: associated with organ failure; Grade II: early biliary drainage should be conducted; Grade1: others. As for the severity assessment criteria of TG07, separating Grade II and Grade I at the time of diagnosis was impossible, so they were unsuitable for clinical practice. Therefore, the severity assessment criteria of TG13 have been revised so as not to lose the timing of biliary drainage or treatment for etiology. Based on evidence, five predictive factors for poor prognosis in acute cholangitis--hyperbilirubinemia, high fever, leukocytosis, elderly patient and hypoalbuminemia--have been extracted. Grade II can be diagnosed if two of these five factors are present. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

We propose a management strategy for acute cholangitis and cholecystitis according to the severity assessment. For Grade I (mild) acute cholangitis, initial medical treatment including the use of antimicrobial agents may be sufficient for most cases. For non-responders to initial medical treatment, biliary drainage should be considered. For Grade II (moderate) acute cholangitis, early biliary drainage should be performed along with the administration of antibiotics. For Grade III (severe) acute cholangitis, appropriate organ support is required. After hemodynamic stabilization has been achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. In patients with Grade II (moderate) and Grade III (severe) acute cholangitis, treatment for the underlying etiology including endoscopic, percutaneous, or surgical treatment should be performed after the patient's general condition has been improved. In patients with Grade I (mild) acute cholangitis, treatment for etiology such as endoscopic sphincterotomy for choledocholithiasis might be performed simultaneously, if possible, with biliary drainage. Early laparoscopic cholecystectomy is the first-line treatment in patients with Grade I (mild) acute cholecystitis while in patients with Grade II (moderate) acute cholecystitis, delayed/elective laparoscopic cholecystectomy after initial medical treatment with antimicrobial agent is the first-line treatment. In non-responders to initial medical treatment, gallbladder drainage should be considered. In patients with Grade III (severe) acute cholecystitis, appropriate organ support in addition to initial medical treatment is necessary. Urgent or early gallbladder drainage is recommended. Elective cholecystectomy can be performed after the improvement of the acute inflammatory process. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Background: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous “more versus less statins” trials. However, no clear evidence for more versus less statins has been established in an Asian population. Methods: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) &lt;120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. Results: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P &lt;0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69–0.95; P =0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73–0.93; P =0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (&lt;95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. Conclusions: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01042730.

Upon infection of a host, the pathogenic fungus Aspergillus fumigatus is attacked by the reactive oxygen species produced by phagocytic cells. Detoxification of hydrogen peroxide by catalases was proposed as a way to overcome this host response. A. fumigatus produces three active catalases; one is produced by conidia, and two are produced by mycelia. The mycelial catalase Cat1p was studied previously. Here we characterized the two other catalases, their genes, and the phenotypes of gene-disrupted mutants. CatAp, a spore-specific monofunctional catalase, is resistant to heat, metal ions, and detergent. This enzyme is a dimeric protein with 84.5-kDa subunits. The 749-amino-acid polypeptide exhibits high levels of similarity to the Aspergillus nidulans CatA catalase and to bacterial catalase HPII of Escherichia coli. In spite of increased sensitivity to H(2)O(2), killing of DeltacatA conidia by alveolar macrophages and virulence in animals were similar to the killing of conidia by alveolar macrophages and virulence in animals observed for the wild type. In contrast to the Cat1p and CatAp catalases, the mycelial Cat2p enzyme is a bifunctional catalase-peroxidase and is sensitive to heat, metal ions, and detergent. This enzyme, an 82-kDa monomer, is homologous to catalase-peroxidases of several fungi and bacteria. Surprisingly, mycelium of the double Deltacat1Deltacat2 mutant with no catalase activity exhibited only slightly increased sensitivity to H(2)O(2) and was as sensitive to killing by polymorphonuclear neutrophils as mycelium of the wild-type strain. However, this mutant exhibited delayed infection in the rat model of aspergillosis compared to infection by the wild-type strain. These results indicate that conidial catalase is not a virulence factor and that mycelial catalases transiently protect the fungus from the host.

Aortic valve disease is usually treated by prosthetic valve replacement. We have performed aortic valve plasty (AVP) using glutaraldehyde-treated autologous pericardium. AVP was performed for 88 patients from April 2007 through August 2009. Sixty-five patients had aortic stenosis, and 23 patients had aortic regurgitation (AR). Twenty-one patients showed bicuspid aortic valves, and one patient showed quadricuspid valve. There were 43 males and 45 females. Their mean age was 70.6±10.5 years old. First, diseased leaflets excised. Then, the distance between each commissure was measured. The new leaflet were trimmed with an original template from a glutaraldehyde-treated autologous pericardium sample. Finally, the annular margin of the pericardial leaflet was running sutured to each annulus. There was no operative mortality or embolic event. Postoperative echocardiography revealed a mean peak pressure gradient (PG) of 19.0±9.1 mmHg one week after surgery. Thirty-two patients had echocardiography one year after surgery. The peak PG became 12.9±5.8 mmHg. Ten patients showed no AR, 20 patients showed trivial AR, and two patients showed mild AR. Freedom from reoperation is 100% at three years follow-up.