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Abstract Background Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the “The lower is the better” concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a “threshold” value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. Methods For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the “threshold” value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C − threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. Results For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01–1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. Conclusions Our analysis model suggests that a “threshold” value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. Trial registration http://www.clinicaltrials.gov . Unique identifier: NCT01042730.

Background: Familial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a severe inherited disease without effective treatment. Patients with FLD develop severe low HDL, corneal opacity, hemolytic anemia, and renal injury. Objective: We developed genetically modified adipocytes (GMAC) secreting LCAT (LCAT-GMAC) for ex vivo gene therapy. GMACs were prepared from the patient’s adipocytes to express LCAT by retroviral gene transduction to secrete functional enzymes. This study aimed to evaluate the safety and efficacy of LCAT-GMAC implantation in an FLD patient. Methods: Proliferative preadipocytes were obtained from a patient using a ceiling culture and retrovirally transduced with LCAT. After obtaining enough cells by expansion culture of the transduced cells, the resulting LCAT-GMACs were implanted into a patient with FLD. To evaluate the safety and efficacy, we analyzed the outcome of the autologous implantation for 24 weeks of observation and subsequent 240 weeks of the follow-up periods. Results: This first-in-human autologous implantation of LCAT-GMACs was shown to be safe by evaluating adverse events. The LCAT-GMAC implantation increased serum LCAT activity by approximately 50% of the baseline and sustained over three years. Consistent with increased LCAT activity, intermediate-density lipoprotein (IDL) and free cholesterol levels of the small and very small HDL fractions decreased. We found the hemoglobin/haptoglobin complex in the hemolyzed pre-implantation sera of the patient. After one week of the implantation, the hemoglobin/haptoglobin complex almost disappeared. Immediately after the implantation, the patient's proteinuria decreased temporarily to mild levels and gradually increased to the baseline. At 48 weeks after implantation, the patient's proteinuria deteriorated with the development of mild hypertension. By the treatment with antihypertensives, the patient's blood pressure normalized. With the normalization of blood pressure, the proteinuria rapidly decreased to mild proteinuria levels. Conclusions: LCAT-GMAC implantation in a patient with FLD is shown to be safe and appears to be effective, in part, for treating anemia and proteinuria in FLD.

Backgrounds: Despite the absolute need for life-long treatment of inherited and genetic diseases, there has been little effort to develop such treatments for most of these conditions due to their rarity. Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is recognized as one such orphan disease. We have been developing an adipocyte-based ex vivo gene therapy/regenerative medicine, a novel methodology that differs from the adeno-associated virus-mediated in vivo gene therapy or ex vivo gene-transduced hematopoietic cell therapy, to treat familial LCAT deficiency. Recently, a first-in-human (FIH) clinical study was conducted under the Act on Securement of Safety of Regenerative Medicine, wherein a patient with familial LCAT deficiency was treated. To obtain approval to put this treatment into practical use, a clinical trial has been designed with reference to the FIH clinical study. Methods: An interventional, open-label, unblinded dose-escalation trial was planned, referring to previous FIH clinical study. The trial aims to evaluate the safety of the investigational product in relation to the characteristics of the investigational product (ex vivo gene/cell therapy product by retroviral vector-mediated LCAT gene transduction) using two doses, and the efficacy of the treatment will be evaluated exploratively. A total of three patients will be enrolled sequentially and followed for 24 weeks after administration. This study is designed as a multicenter trial, with Chiba University Hospital administering and evaluating the safety/efficacy of the investigational products at the prescribed visit. Conclusion: This clinical trial is expected to facilitate the provision of lifelong treatment to many patients with LCAT deficiency. Trial registration number: Japan Registry of Clinical Trials (jRCT2033200096).

Two-phase pressure drop in the debris has been studied by many researchers concerning the debris cooling characteristics during a severe accident in a nuclear reactor. However, its flow regime transition of the two-phase flow in the debris has not been well understood, which strongly affects the interfacial drag and the pressure drop. Conventional models for gas-liquid two-phase flow pressure drop have not been established to evaluate interfacial drag accurately. In this study, high-speed imaging of a two-dimensional network model was performed to clarify the effect of flow patterns on interfacial drag and pressure drop. Usually, it would not be easy to visualize such two-phase flow behavior in a randomly packed bed due to the reflection/refraction of light and/or overlapping bubbles, even if the test section is made of transparent materials. Therefore, in this study, a test section, which simulates a two-dimensional network of porous structures, was fabricated to avoid overlapping bubbles. The two-phase flow pattern in the porous structure has been identified by high-speed imaging of the two-dimensional network model. The flow regime map based on the flow pattern visualization results is applied to the pressure drop evaluation and it could reduce the overestimation of experimental values. The experimental results suggested that the interfacial drag term should be modified in the gas-liquid two-phase flow pressure drop model.

Pneumorrhachis refers to the clinical presentation of air within the spinal canal, and it is rarely associated with pneumomediastinum, particularly in young children. Pneumorrhachis associated with pneumomediastinum is generally asymptomatic. Here we report 2 unusual cases involving very young children with pneumorrhachis secondary to pneumomediastinum and present a review of the relevant literature. Case 1 involved a 4-year-old girl who presented with wheezing, violent coughing, and dyspnea associated with bronchiolitis. Case 2 involved a 3-year-old boy who presented with wheezing, violent coughing, and dyspnea associated with interstitial pneumonia possibly caused by graft-versus-host disease with human herpesvirus 6 infection after allogeneic hematopoietic stem cell transplantation. In both cases, pneumorrhachis improved with oxygen inhalation therapy and treatment of the underlying disease. Pneumorrhachis is rarely associated with neurological problems; however, decompressive laminectomy may be indicated to relieve the air block. Because pneumorrhachis is rare in children and neurological sequelae may be difficult to identify, close clinical, and radiographic observations are necessary. Plain radiography is not sufficient, and computed tomography should be performed to rule out intraspinal air. Keywords: Pneumorrhachis, Pneumomediastinum, Children

Introduction. We retrospectively examined the relationship between daily proton pump inhibitor (PPI) use and severity of upper gastrointestinal bleeding (UGIB), mainly in the elderly. Methods. We included 97 patients with nonvariceal UGIB diagnosed at our hospital from January 2012 to October 2017. Bleeding severity was assessed using the shock index (SI) and estimated bleeding volume; 49 patients met the criterion for the mild group and 48 for the moderate/severe group. The effect of PPI use on bleeding severity was compared between the groups. The relationships of PPI use and dose with the clinical symptoms of UGIB were also analyzed. Results. Among the 97 patients, 17 (17.5%) habitually used PPIs. The rate of habitual PPI use was significantly higher in the mild group, indicating as an independent factor contributing to a reduction in the severity of UGIB in a multiple logistic regression analysis (30.6% vs. 4.2%; OR 10.147; 95% CI 2.174–47.358, P

In neutron transmission spectroscopic imaging, the transmission spectrum of each pixel on a two-dimensional detector is analyzed and the real-space distribution of microscopic information in an object is visualized with a wide field of view by mapping the obtained parameters. In the analysis of the transmission spectrum, since the spectrum can be classified with certain characteristics, it is possible for machine learning methods to be applied. In this study, we selected the subject of solid–liquid phase fraction imaging as the simplest application of the machine learning method. Firstly, liquid and solid transmission spectra have characteristic shapes, so spectrum classification according to their fraction can be carried out. Unsupervised and supervised machine learning analysis methods were tested and evaluated with simulated datasets of solid–liquid spectrum combinations. Then, the established methods were used to perform an analysis with actual measured spectrum datasets. As a result, the solid–liquid interface zone was specified from the solid–liquid phase fraction imaging using machine learning analysis.

Background and study aims Duplication cysts of the ileum are rare and present with non-specific clinical manifestations such as abdominal pain, vomiting, melena, and intussusception. Therefore, preoperative diagnosis is difficult. Here, we report a case of duplication cyst of the small intestine that was diagnosed preoperatively using double-balloon enteroscopy. A 19-year-old man presented with severe iron deficiency anemia, abdominal pain, and exertional dyspnea. Gastroscopy and colonoscopy revealed no remarkable findings. Abdominal computed tomography revealed a cystic structure in the ileum. Therefore, we performed double-balloon enteroscopy via the anal route. The intestinal tract was bifurcated, with one segment ending in a blind sac containing normal villi and an ulceration. Tc-99 m pertechnetate scintigraphy showed no accumulation in the lesion. Accordingly, we diagnosed a duplication cyst and suspected that this was the cause of severe anemia. Following small bowel resection with cyst excision and anastomosis, the anemia and presenting symptoms resolved. This report highlights the usefulness of double-balloon enteroscopy of the small intestine for preoperative diagnosis of the obscure gastrointestinal bleeding, including duplication cysts.

Liquid inlet behavior to a heat surface in micro-bubble emission boiling (MEB) was investigated by flow measurement using particle image velocimetry (PIV). Subcooled pool boiling experiments under atmospheric pressure were carried out using a heat surface with a diameter of 10 mm. An upper end of a heater block made of copper was used as the heat surface. Working fluid was the deionized water and the subcooling was varied from 40 K to 70 K. Three K-type thermocouples were installed in the copper block to measure the temperature gradient, and the heat flux and wall superheat were estimated from these temperature data to make a boiling curve. The flow visualization around the heat surface was carried out using a high-speed video camera and a light sheet. The microbubbles generated in the MEB were used as tracer particles and the velocity field was obtained by PIV analysis of the acquired image sequence. As a result, the higher heat fluxes than the critical heat flux could be obtained in the MEB region. In addition, the distribution characteristics of the velocity in MEB region were studied using the PIV results and the location of the stagnation point in the velocity fields was discussed.

Yasushi SaitoPresident, Chiba University, Chiba, JapanAbstract: Pitavastatin is a potent HMG-CoA reductase inhibitor and efficient hepatocyte low-density lipoprotein cholesterol (LDL-C) receptor inducer, producing robust reduction of the serum LDL-C levels, even at a low dose. Pitavastatin and its lactone form are minimally metabolized by CYP enzymes, and are therefore associated with minimal drug–drug interactions (DDIs). Pitavastatin 2 to 4 mg has potent LDL-C-reducing activity, equivalent to that of atorvastatin 10 to 20 mg; several clinical trials have revealed consistently superior high-density lipoprotein cholesterol (HDL-C) elevating activity of pitavastatin than that of atorvastatin. Pitavastatin-induced HDL-C elevation has been shown to be sustained, even incremental, in long-term clinical trials. Pitavastatin was as well-tolerated as atorvastatin or simvastatin in double-blind randomized clinical trials. Two-year long-term safety and effectiveness of pitavastain has been confirmed in a large-scale, prospective post-marketing surveillance. The safety and efficacy profile of pitavastatin is favorable for the treatment of dyslipidemia, especially in metabolic syndrome patients. In addition to control of LDL-C, adequate control of triglyceride (TG) and HDL-C, hypertension and hyperglycemia is also necessary in metabolic syndrome patients. Pitavastatin produces adequate control of LDL-C and TG, along with potent and incremental HDL-C elevation, with a low frequency of DDIs.Keywords: HMG-CoA reductase inhibitor, pitavastatin, eff icacy, safety, drug–drug interaction

Background and study aims: Primary neoplasms of the small intestine are relatively rare in all age groups, accounting for about 5 % of all gastrointestinal tumors 1. Cavernous hemangiomas of the small intestine are also rare, can cause gastrointestinal bleeding, and are extremely difficult to diagnose preoperatively 2. We present a patient who presented with melena and iron deficiency anemia, for whom wireless capsule endoscopy and single-balloon enteroscopy facilitated the diagnosis of cavernous hemangioma.