Financial incentives for infection prevention and antimicrobial stewardship to reduce antibiotic use: Japan's nationwide observational study.

BACKGROUND: The Japanese government introduced financial incentives to reduce nationwide antibiotic use in hospital settings. AIM: This study aimed to determine whether the nationwide financial incentives for creating infection prevention and control (IPC) teams introduced in 2012 and antimicrobial stewardship (ASP) teams introduced in 2018 were associated with changes in antibiotic use and health resource utilization at a national level. METHODS: We conducted time-series analyses and a difference-in-differences study consisting of 3,057,517 inpatients with infectious diseases from 472 medical facilities during fiscal years 2011-2018 using a nationally representative inpatient database in Japan. The primary outcome was the days of therapy (DOT) of antibiotic use per 100 patient-days (PDs). The secondary outcomes consisted of types of antibiotic used, health resource utilization, and mortality. RESULTS: A total of 5,201,304 financial incentives were observed during 2012-2018, which resulted in a total of 12.1 billion JPY (≈110 million USD). Time-series analyses found decreasing trends in total antibiotic use (79.3-72.5 DOTs/100 PDs (8.6% reduction)) and carbapenem use (9.0-7.0 DOTs/100 PDs (7.8% reduction)) from 2011 to 2018 without adversely affecting other healthcare outcomes (e.g., mortality). In the difference-in-differences analyses, we did not observe meaningful changes in total antibiotic use between the incentivized and unincentivized hospitals for ASP teams, except for the northern part of Japan. No dose-response relationships were observed between the amount of financial incentives and reductions in antibiotic use during 2011-2019. CONCLUSIONS: Further research and efforts are needed to accelerate antimicrobial stewardship in hospital settings in Japan.

Comparison of postoperative infection after emergency inguinal hernia surgery with enterectomy between mesh repair and non-mesh repair: a national database analysis.

PURPOSE: Synthetic non-absorbable mesh is used for elective inguinal hernia repair but is not commonly used for incarcerated or strangulated inguinal hernia requiring enterectomy to reduce the risk of surgical-site infection. This study aimed to evaluate the safety of synthetic non-absorbable mesh repair in patients with incarcerated or strangulated inguinal hernia requiring enterectomy versus non-mesh repair. METHODS: We analyzed patients with incarcerated or strangulated inguinal hernia with enterectomy from April 2012 to March 2017 using a nationwide inpatient database in Japan. We conducted overlap propensity score-weighted analyses to compare surgical-site infection (SSI), duration of anesthesia, antibiotic use at > 3 days after surgery, postoperative hospital stay, and 30 day readmission. Two sensitivity analyses were performed. First, we compared the proportions of patients requiring wound culture at ≥ 3 days after surgery. Second, we performed overlap propensity score-weighted logistic regression analyses for surgical-site infection. RESULTS: We identified 668 eligible patients, comprising 223 patients with mesh repair and 445 with non-mesh repair. Overlap propensity score-weighted analyses showed no significant differences between the mesh repair and non-mesh repair groups for SSI (2.5 vs. 2.8%, P = 0.79). Secondary outcomes did not differ significantly between the groups. Proportion of wound culture at ≥ 3 days after surgery was similar in the two groups (11.1 vs. 14.6%, P = 0.18). Logistic regression analysis showed no significant association between mesh repair and SSI (odds ratio, 0.93; 95% confidence interval, 0.34-2.57). CONCLUSION: Synthetic non-absorbable mesh use may be safe for incarcerated or strangulated inguinal hernia requiring enterectomy.

Breast cancer surgery in patients with schizophrenia: short-term outcomes from a nationwide cohort.

BACKGROUND: Although patients with schizophrenia have a higher risk of developing breast cancer than the general population, studies that have investigated postoperative complications after breast cancer surgery in patients with schizophrenia are scarce. This study examined associations between schizophrenia and short-term outcomes following breast cancer surgery. METHODS: Patients who underwent surgery for stage 0-III breast cancer between July 2010 and March 2017 were identified from a Japanese nationwide inpatient database. Multivariable analyses were conducted to compare postoperative complications and hospitalization costs between patients with schizophrenia and those without any psychiatric disorder. Three sensitivity analyses were performed: a 1 : 4 matched-pair cohort analysis with matching for age, institution, and fiscal year at admission; analyses excluding patients with schizophrenia who were not taking antipsychotic medication; and analyses excluding patients with schizophrenia who were admitted to hospital involuntarily. RESULTS: The study included 3660 patients with schizophrenia and 350 860 without any psychiatric disorder. Patients with schizophrenia had a higher in-hospital morbidity (odds ratio (OR) 1.37, 95 per cent c.i. 1.21 to 1.55), with more postoperative bleeding (OR 1.34, 1.05 to 1.71) surgical-site infections (OR 1.22, 1.04 to 1.43), and sepsis (OR 1.20, 1.03 to 1.41). The total cost of hospitalization (coefficient €743, 95 per cent c.i. 680 to 806) was higher than that for patients without any psychiatric disorder. All sensitivity analyses showed similar results to the main analyses. CONCLUSION: Although causal inferences remain premature, multivariable regression analyses showed that schizophrenia was associated with greater in-hospital morbidity and higher total cost of hospitalization after breast cancer surgery than in the general population.

Rechallenge of voriconazole successfully tolerated after hepatic toxicity.

Infections caused by Aspergillus species are often life-threatening. Drugs effective for Aspergillus infection are limited. Voriconazole is one of the most important drugs, however, considerable portion of patients experience liver toxicity and have to stop the drug administration. We frequently experience liver toxicity even though the serum concentration of voriconazole is within the target range. Historically, in some life-threatening situations like tuberculosis, where a suitable alternative is unavailable, rechallenge has been attempted. However, there have been no report on the rechallenge of voriconazole. We report cases of successful re-administration of voriconazole after liver toxicity.

Stent as a bridge to surgery or immediate colectomy for malignant right colonic obstruction: propensity-scored, national database study.

BACKGROUND: The aim of this study was to compare perioperative outcomes of urgent colectomy and placement of a self-expanding metallic stent followed by colectomy for patients with malignant right colonic obstruction. Right-sided malignant obstruction is less common than left-sided. Stenting for malignant left colonic obstruction has been reported to reduce postoperative complications. However, the impact of stenting for malignant right colonic obstruction remains undefined. METHODS: The study included patients with right-sided malignant obstruction or stenosis undergoing colectomy between April 2012 and March 2017 identified from a nationwide database. Propensity score matching analysis was used to compare mortality and morbidity rates, proportion receiving a stoma and postoperative stay between urgent colectomy and stent groups. RESULTS: From 9572 patients, 1500 pairs were generated by propensity score matching. There was no significant difference in in-hospital mortality between the urgent colostomy and stent groups (1·6 versus 0·9 per cent respectively; P = 0·069). Complications were more common after urgent colectomy than stenting (22·1 versus 19·1 per cent; P = 0·042). Surgical-site infection was more likely with urgent colectomy (7·1 versus 4·4 per cent; P = 0·001). There was no significant difference between the two groups in anastomotic leakage (3·8 versus 2·6 per cent; P = 0·062). The proportion of patients needing a stoma was higher with urgent colectomy than primary treatment with stents (5·1 versus 1·7 per cent; P < 0·001). Postoperative stay was longer after urgent colectomy (15 versus 13 days; P < 0·001). CONCLUSION: Stenting followed by colectomy in patients with malignant right colonic obstruction may provide more favourable perioperative outcomes than urgent colectomy.

ANTECEDENTES: El objetivo de este estudio fue comparar los resultados perioperatorios entre la colectomía urgente y la colocación de una endoprótesis (stent) metálica autoexpandible seguida de colectomía en pacientes con obstrucción maligna del colon derecho. La obstrucción maligna del colon derecho es menos frecuente que la del colon izquierdo. Se ha demostrado que la colocación de una endoprótesis en la obstrucción maligna del colon izquierdo reduce las complicaciones postoperatorias. Sin embargo, el impacto de la colocación de una endoprótesis en la obstrucción maligna del colon derecho no está definido. MÉTODOS: Los pacientes con obstrucción o estenosis maligna del colon derecho sometidos a colectomía desde abril de 2012 hasta marzo de 2017 se analizaron a partir de una base de datos nacional. Se realizó un análisis mediante emparejamiento por puntaje de propensión para comparar la mortalidad, la morbilidad, el porcentaje de pacientes en los que se realizó un estoma y la estancia postoperatoria entre los grupos de colectomía urgente y endoprótesis. RESULTADOS: A partir de 9.572 pacientes, se generaron 1.500 parejas mediante emparejamiento por puntaje de propensión. No hubo diferencias significativas en la mortalidad hospitalaria entre los dos grupos (1,6% versus 0,9%, P = 0,07). Las complicaciones fueron más frecuentes después de la colectomía urgente en comparación con las endoprótesis (22,1% versus 19,1%, P = 0,04). La infección del sitio quirúrgico ocurrió con mayor frecuencia en el grupo de la colectomía urgente en comparación con el grupo de endoprótesis (7,1% versus 4,4%, P = 0,001). No se observaron diferencias significativas en la fuga anastomótica entre los dos grupos (3,8% versus 2,6%, P = 0,06). La proporción de pacientes que precisaron estomas fue mayor con la colectomía urgente en comparación con aquellos tratados inicialmente con endoprótesis (5,1% versus 1,7%, P < 0,001). La estancia postoperatoria fue más larga después de la colectomía urgente que tras la colocación de una endoprótesis (15 días versus 13 días, P < 0,001) CONCLUSIÓN: En pacientes con obstrucción maligna del colon derecho, la colocación de una endoprótesis seguida de colectomía puede proporcionar resultados perioperatorios más favorables en comparación con la colectomía urgente.

Evaluation of an amplicon-based custom gene panel for the diagnosis of hereditary tumors.

Genetic testing based on next-generation sequencing (NGS) analysis has recently been used to diagnose hereditary diseases. In this study, we explored the usefulness of our custom amplicon panel that targeted 23 genes related to hereditary tumors given in the American College of Medical Genetics and Genomics recommendations. We applied our custom NGS panel to samples from 12 patients previously diagnosed by Sanger sequencing as having the diseases or diagnosed clinically by meeting the diagnostic criteria in this study. Our gene panel not only successfully identified all variants detected by Sanger sequencing but also identified previously unrecognized variants that resulted in confirmation of the disease, or even in the revision of the diagnosis. For instance, a patient identified with an SDHD gene mutation actually had von Hippel-Lindau (VHL) syndrome, as determined by the presence of a pathogenic VHL gene variant. We also identified false-positive results that were generated by amplification of genome regions that are not intended to be investigated. In conclusion, NGS-based amplicon sequencing is a highly effective method to detect germline variants, as long as they are also carefully reviewed by manual inspection.

Liver resection with thrombectomy for patients with hepatocellular carcinoma and tumour thrombus in the inferior vena cava or right atrium.

BACKGROUND: Hepatocellular carcinoma (HCC) with tumour thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA) is a rare advanced disease state with a poor prognosis. The aim of this study was to examine survival after surgical resection. METHODS: Patients with HCC and TT of either the IVC or RA, who underwent liver resection between February 1997 and July 2017, were included. Their short- and long-term outcomes and surgical details were analysed retrospectively. RESULTS: Thirty-seven patients were included; 16 patients had TT in the IVC below the diaphragm, eight had TT in the IVC above the diaphragm, and 13 had TT entering the RA. Twelve patients had advanced portal vein TT (portal vein invasion (Vp) greater than Vp3 and Vp4), ten had bilobar disease, and 12 had extrahepatic disease. There were no in-hospital deaths, although two patients died within 90 days. Median survival did not differ between patients who had resection with curative intent (18·7 months) and those with residual tumour in the lung only (20·7 months), but survival was poor for patients with residual tumour in the liver (8·3 months). CONCLUSION: Liver resection with thrombectomy for advanced HCC with TT in the IVC or RA is safe and feasible, leading to moderate survival.

ANTECEDENTES: El carcinoma hepatocelular con trombo tumoral (TT) en la vena cava inferior (inferior vena cava, IVC) o en la aurícula derecha (right atrium, RA) es un estado avanzado de la enfermedad raro, con un pronóstico desfavorable. En este estudio analizamos la supervivencia después de la resección quirúrgica. MÉTODOS: Se incluyeron pacientes con carcinoma hepatocelular con TT en la IVC o en la RA, que se sometieron a resección hepática entre febrero de 1997 y julio de 2017. Los resultados a corto y a largo plazo de estos pacientes y los detalles quirúrgicos se analizaron retrospectivamente. RESULTADOS: Se incluyeron 37 pacientes. Entre estos pacientes, se identificaron 16 pacientes con TT en la IVC infradiafragmática, 8 pacientes con TT en la IVC supradiafragmática y 13 pacientes con TT entrando en la AR. Doce pacientes asociaron TT avanzado en la vena porta más allá de vp 3 y 4, 10 pacientes tenían enfermedad bilobar y 12 pacientes tenían enfermedad extrahepática. A pesar de que la tasa de mortalidad hospitalaria fue cero, dos pacientes fallecieron a los 90 días. Aunque la mediana del tiempo de supervivencia no fue diferente entre el grupo al que se le realizó resección con intención curativa (18,7 meses) y aquellos con tumor residual solo en el pulmón (20,7 meses), la supervivencia fue extremadamente pobre para los pacientes con tumor residual en el hígado (8,3 meses). CONCLUSIÓN: La resección hepática con trombectomía para el carcinoma hepatocelular avanzado con trombo tumoral en la vena cava inferior o en la aurícula derecha es segura y factible, asociándose a una supervivencia moderada.

Age in months and birth order in infant nonfatal injuries: A retrospective cohort study.

Objective: To examine the age in months at which infants visited outpatient clinics or emergency rooms for the first time for nonfatal injuries and to identify risk factors for the occurrence of these injuries. Study design: Retrospective cohort study. Methods: We used a health insurance claims database in Japan. Infants born between April 2012 and December 2014 were identified and followed until 12 months of age. We identified their first visit to outpatient clinics or emergency rooms because of nonfatal injuries (wounds/fractures, foreign bodies, and burns). Cox regression analysis was used to examine the association of nonfatal injuries with infants' sex, birth order, and parental age. Results: We identified 46,431 eligible infants. Of these, 7606 (16.4%) were brought to an outpatient clinic or emergency room for nonfatal injuries within 12 months of birth. Of the 7,606, 21.7% were aged ≤4 months and 44.7% â€‹≤ â€‹7 months. First-born infants were more likely to have wounds/fractures and burns. Conclusion: One-fifth of first nonfatal infant injuries occurred within 4 months of age. Healthcare providers should provide early education about injury prevention, especially to caregivers of first-born infants.

Secretory IgA accumulated in the airspaces of idiopathic pulmonary fibrosis and promoted VEGF, TGF-ß and IL-8 production by A549 cells.

Secretory IgA (SIgA) is a well-known mucosal-surface molecule in first-line defense against extrinsic pathogens and antigens. Its immunomodulatory and pathological roles have also been emphasized, but it is unclear whether it plays a pathological role in lung diseases. In the present study, we aimed to determine the distribution of IgA in idiopathic pulmonary fibrosis (IPF) lungs and whether IgA affects the functions of airway epithelial cells. We performed immunohistochemical analysis of lung sections from patients with IPF and found that mucus accumulated in the airspaces adjacent to the hyperplastic epithelia contained abundant SIgA. This was not true in the lungs of non-IPF subjects. An in-vitro assay revealed that SIgA bound to the surface of A549 cells and significantly promoted production of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß and interleukin (IL)-8, important cytokines in the pathogenesis of IPF. Among the known receptors for IgA, A549 cells expressed high levels of transferrin receptor (TfR)/CD71. Transfection experiments with siRNA targeted against TfR/CD71 followed by stimulation with SIgA suggested that TfR/CD71 may be at least partially involved in the SIgA-induced cytokine production by A549 cells. These phenomena were specific for SIgA, distinct from IgG. SIgA may modulate the progression of IPF by enhancing synthesis of VEGF, TGF-ß and IL-8.

Outcomes in two patients with vocal fold palsy who underwent revision arytenoid adduction surgery.

OBJECTIVE: This study investigated the position of adduction thread attachment, pulling direction and fixation position in revision arytenoid adduction surgery performed in two patients with left vocal fold palsy in whom satisfactory speech improvement had not been obtained by arytenoid adduction and type 1 thyroplasty. METHODS: Revision arytenoid adduction surgery was performed with the vocal fold in the midline position in both cases. A type 1 thyroplasty procedure was subsequently added in one case because of worsened quality of speech following arytenoid adduction. RESULTS AND CONCLUSION: Although the arytenoid adduction procedure is conceptually well established, there is still room for debate concerning the actual surgical procedures used. The technique described in this report is effective, suggesting that it is worthy of recognition as an index procedure.

Nationwide observational study of mortality from complicated intra-abdominal infections and the role of bacterial cultures.

BACKGROUND: The benefit of taking intra-abdominal cultures during source control procedures in patients with complicated intra-abdominal infection (CIAI) is unknown. The aim of this study was to evaluate whether intra-abdominal cultures reduce the mortality rate of CIAI. METHODS: The Japanese Diagnosis Procedure Combination database was used to identify adult patients with CIAI who had undergone source control procedures on the first day of admission to hospital between April 2014 and March 2016. In-hospital mortality was compared between patients who did and those who did not have intra-abdominal cultures taken. A generalized linear mixed-effect logistic regression model and a random intercept per hospital were used to adjust for baseline confounders and institutional differences. Subgroup analyses were also performed according to disease cause, site of onset and severity of CIAI. RESULTS: Intra-abdominal cultures were taken from 16 303 of 41 495 included patients. Multivariable logistic regression analysis showed that patients with intra-abdominal cultures had a significantly lower mortality than those without (odds ratio 0·85, 95 per cent c.i. 0·77 to 0·95). Subgroup analyses revealed statistically significant differences in mortality between patients with and without cultures among those with lower intestinal perforation, biliary tract infection/perforation, healthcare-associated CIAI and high-risk community-acquired CIAI. CONCLUSIONS: Intra-abdominal cultures obtained during source control procedures may reduce in-hospital mortality, especially in patients with lower intestinal perforation, biliary tract infection/perforation, or healthcare-associated or high-risk community-acquired CIAI.

Secretory immunoglobulin A induces human lung fibroblasts to produce inflammatory cytokines and undergo activation.

Immunoglobulin (Ig)A is the most abundant immunoglobulin in humans, and in the airway mucosa secretory IgA (sIgA) plays a pivotal role in first-line defense against invading pathogens and antigens. IgA has been reported to also have pathogenic effects, including possible worsening of the prognosis of idiopathic pulmonary fibrosis (IPF). However, the precise effects of IgA on lung fibroblasts remain unclear, and we aimed to elucidate how IgA activates human lung fibroblasts. We found that sIgA, but not monomeric IgA (mIgA), induced interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production by normal human lung fibroblasts (NHLFs) at both the protein and mRNA levels. sIgA also promoted proliferation of NHLFs and collagen gel contraction comparable to with transforming growth factor (TGF)-ß, which is involved in fibrogenesis in IPF. Also, Western blot analysis and real-time quantitative polymerase chain reaction (PCR) revealed that sIgA enhanced production of α-smooth muscle actin (α-SMA) and collagen type I (Col I) by NHLFs. Flow cytometry showed that NHLFs bound sIgA, and among the known IgA receptors, NHLFs significantly expressed CD71 (transferrin receptor). Transfection of siRNA targeting CD71 partially but significantly suppressed cytokine production by NHLFs co-cultured with sIgA. Our findings suggest that sIgA may promote human lung inflammation and fibrosis by enhancing production of inflammatory or fibrogenic cytokines as well as extracellular matrix, inducing fibroblast differentiation into myofibroblasts and promoting human lung fibroblast proliferation. sIgA's enhancement of cytokine production may be due partially to its binding to CD71 or the secretory component.

Preoperative oral care and effect on postoperative complications after major cancer surgery.

BACKGROUND: Improving patients' oral hygiene is an option for preventing postoperative pneumonia that may be caused by aspiration of oral and pharyngeal secretions. Whether preoperative oral care by a dentist can decrease postoperative complications remains controversial. A retrospective cohort study was undertaken to assess the association between preoperative oral care and postoperative complications among patients who underwent major cancer surgery. METHODS: The nationwide administrative claims database in Japan was analysed. Patients were identified who underwent resection of head and neck, oesophageal, gastric, colorectal, lung or liver cancer between May 2012 and December 2015. The primary outcomes were postoperative pneumonia and all-cause mortality within 30 days of surgery. Patient background was adjusted for with inverse probability of treatment weighting using propensity scoring. RESULTS: Of 509 179 patients studied, 81 632 (16·0 per cent) received preoperative oral care from a dentist. A total of 15 724 patients (3·09 per cent) had postoperative pneumonia and 1734 (0·34 per cent) died within 30 days of surgery. After adjustment for potential confounding factors, preoperative oral care by a dentist was significantly associated with a decrease in postoperative pneumonia (3·28 versus 3·76 per cent; risk difference - 0·48 (95 per cent c.i. -0·64 to-0·32) per cent) and all-cause mortality within 30 days of surgery (0·30 versus 0·42 per cent; risk difference - 0·12 (-0·17 to -0·07) per cent). CONCLUSION: Preoperative oral care by a dentist significantly reduced postoperative complications in patients who underwent cancer surgery.

Association between mode of anaesthesia and severe maternal morbidity during admission for scheduled Caesarean delivery: a nationwide population-based study in Japan, 2010-2013.

BACKGROUND: Although the incidence of maternal mortality during Caesarean delivery remains very low, the rate of severe maternal morbidity is increasing. Improvements in obstetric anaesthetic practice have resulted in a dramatic reduction in the risk of maternal death from general anaesthesia. Less clear is whether the risk of severe maternal morbidity differs according to mode of anaesthesia for women undergoing Caesarean delivery. We analysed the association between the mode of anaesthesia and severe maternal morbidity during Caesarean delivery using a nationally representative inpatient database. METHODS: We identified 89 225 women undergoing scheduled Caesarean delivery from the Diagnosis Procedure Combination database in Japan, 2010-2013. We defined severe maternal morbidity as the presence of any life-threatening complications and identified women with severe maternal morbidity from the database. Propensity score-matched analysis was carried out to compare the odds of severe maternal morbidity between women who underwent general vs neuraxial anaesthesia. RESULTS: Of 89 225 women, 10 058 received general anaesthesia and 79 167 received neuraxial anaesthesia. In the propensity score-matched analysis with 10 046 pairs, a higher incidence of severe maternal morbidity was observed among patients receiving general (2.00%) rather than neuraxial anaesthesia (0.76%). The odds ratio of severe maternal morbidity was 2.68 (95% CI, 1.97-3.64) among women receiving general compared with neuraxial anaesthesia. CONCLUSIONS: For scheduled Caesarean delivery, general anaesthesia compared with neuraxial anaesthesia is associated with greater odds for severe maternal morbidity. However, we should be cautious with interpretation of these findings because they may be explained by confounding indications.

Effectiveness of early administration of tranexamic acid in patients with severe trauma.

BACKGROUND: A reduction in mortality with the early use of tranexamic acid has been demonstrated in severely injured patients who are bleeding. However, the modest treatment effect with no reduction in blood transfusion has raised concerns. The aim of the present study was to estimate the effectiveness of regular use of tranexamic acid in severely injured patients. METHODS: This multicentre observational study used retrospectively collected data from consecutive injured patients (Injury Severity Score at least 16) treated in 15 Japanese academic institutions in 2012. A propensity score-matched analysis compared patients who did or did not receive tranexamic acid administration within 3 h of injury. Study outcomes included 28-day all-cause and cause-specific mortality, and need for blood transfusion. RESULTS: Of 796 eligible subjects, 281 were treated with tranexamic acid. Propensity score matching selected a total of 500 matched subjects (250 in each group). Tranexamic acid administration was associated with lower 28-day mortality (10·0 versus 18·4 per cent; difference -8·4 (95 per cent c.i. -14·5 to -2·3) per cent) and lower 28-day mortality from primary brain injury (6·0 versus 13·2 per cent; difference -7·2 (-12·3 to -2·1) per cent). However, there was no significant difference between groups in the need for blood transfusion (33·2 versus 34·8 per cent; difference -1·6 (-9·9 to 6·7) per cent). CONCLUSION: Early tranexamic acid use was associated with reduced mortality in severely injured patients, in particular those with a primary brain injury.

A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.

Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.

Association between hospital volume and in-hospital mortality following radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is a minimally invasive treatment for hepatocellular carcinoma (HCC). There is increasing evidence of an association between increasing hospital volume and lower postoperative mortality for many surgical procedures, but this is difficult to establish with minimally invasive treatments, where postoperative mortality is low. The aim of this study was to investigate the relationship between hospital volume and in-hospital mortality following RFA using a Japanese nationwide database. METHODS: Data from the Diagnostic Procedure Combination database were analysed from 1 July 2010 to 31 March 2012. Multivariable logistic regression was used to analyse the relationship between hospital volume and in-hospital mortality following RFA, with adjustment for patient background. RESULTS: Some 36 675 patients with HCC were identified in the database. The overall in-hospital mortality rate from RFA was 0·31 per cent. In-hospital mortality was significantly higher in low-volume than high-volume hospitals (odds ratio 2·57, 95 per cent c.i. 1·61 to 4·09; P < 0·001). Higher in-hospital mortality was significantly associated with older age and a higher Charlson Co-morbidity Index score. CONCLUSION: RFA for HCC was associated with acceptably low mortality in Japan, but in-hospital mortality following RFA was affected by hospital procedural volume.

Epidural analgesia is infrequently used in patients with acute pancreatitis : a retrospective cohort study.

BACKGROUNDS AND AIMS: Epidural analgesia is an option for pain control in patients with acute pancreatitis. The aim of this study is to describe characteristics, morbidity and mortality of patients with acute pancreatitis treated with epidural analgesia. PATIENTS AND METHODS: Data was extracted from a national inpatient database in Japan on patients hospitalized with acute pancreatitis between July 2010 and March 2013. A total of 44,146 patients discharged from acute care hospitals were included in this retrospective cohort study. The patient background, timing and duration of epidural analgesia, complications (epidural hematoma or abscess), surgery (for cholelithiasis / cholecystitis or complications) and mortality were verified. RESULTS: Epidural analgesia was used in 307 patients (0.70 %). The mean age was 64.0 years (standard deviation, 15.4 years) and 116 (37.8%) of the patients were female. The median duration of epidural analgesia was four days (interquartile range, 3-5 days). No patient underwent surgery for epidural hematoma or abscess. Six (2.0%) patients died during hospitalization. Most likely causes of death were pulmonary embolism, multiple organ failure, sepsis, and methicillin-resistant staphylococcus aureus enterocolitis. The responsible physician for 250 of the patients (81.4%) was a gastroenterological surgeon. Epidural analgesia was started on the day of surgery in 278 (90.6%) patients. CONCLUSION: Epidural analgesia is rarely used in patients with acute pancreatitis. None of the patients included in the study required surgery for epidural hematoma or abscess. Further research to evaluate the efficacy and safety of epidural analgesia in patients with acute pancreatitis is warranted.

Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome.

Somatic inactivating mutations in epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, the mechanisms by which combinatory mutations in epigenetic regulators promote the development of MDS remain unknown. Here we performed epigenomic profiling of hematopoietic progenitors in MDS mice hypomorphic for Tet2 following the loss of the polycomb-group gene Ezh2 (Tet2KD/KDEzh2Δ/Δ). Aberrant DNA methylation propagated in a sequential manner from a Tet2-insufficient state to advanced MDS with deletion of Ezh2. Hyper-differentially methylated regions (hyper-DMRs) in Tet2KD/KDEzh2Δ/Δ MDS hematopoietic stem/progenitor cells were largely distinct from those in each single mutant and correlated with transcriptional repression. Although Tet2 hypomorph was responsible for enhancer hypermethylation, the loss of Ezh2 induced hyper-DMRs that were enriched for CpG islands of polycomb targets. Notably, Ezh2 targets largely lost the H3K27me3 mark while acquiring a significantly higher level of DNA methylation than Ezh1 targets that retained the mark. These findings indicate that Ezh2 targets are the major targets of the epigenetic switch in MDS with Ezh2 insufficiency. Our results provide a detailed trail for the epigenetic drift in a well-defined MDS model and demonstrate that the combined dysfunction of epigenetic regulators cooperatively remodels the epigenome in the pathogenesis of MDS.