We assessed the overall efficacy and safety of a long-acting muscarinic antagonist （LAMA） added to an inhaled corticosteroid （ICS） and long-acting beta-2 agonist （LABA） as a combination therapy （LAMA＋ICS/LABA） versus LAMA monotherapy in patients with chronic obstructive pulmonary disease （COPD）. The overall efficacy and safety of LAMA＋ICS/LABA versus LAMA in patients with COPD were assessed by a meta-analysis of randomized controlled trials （RCTs）. We identified LAMA＋ICS/LABA RCTs by searching PubMed, Scopus, and the Cochrane Library database. Primary efficacy outcomes were changes in forced expiratory volume in 1 second （FEV_1.0） from baseline. Incidences of all adverse events （AAEs） were the primary safety outcomes. Pooled estimates are presented as mean differences （MDs） or risk ratios （RRs） with 95％ confidence intervals （CIs）. Analyses included intention-to-treat cases. Three LAMA＋ICS/LABA RCTs met the criteria for inclusion in this study. The MD, RRs, and their 95％ CIs regarding changes in FEV1.0 for LAMA＋ICS/LABA compared with those of LAMA were 0.08 （0.04 to 0.13）; RRs and 95％ CIs for AAEs of LAMA＋ICS/LABA compared with those of LAMA were 1.03 （0.82 to 1.29）. Conclusions: Pulmonary function was significantly improved in the LAMA＋ICS/LABA group with no significant increase in AAE risk. These results provide important analysis regarding the overall efficacy and safety of LAMA＋ICS/LABA in patients with COPD.

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The overall efficacy and safety of anti-interleukin （IL）-5 therapies at currently recommended dosages and administration remain to be fully characterized. The present study was a meta-analysis of Phase 3 trials of the efficacy and safety of anti-IL-5 therapies at the currently recommended dosages and administration compared with placebo in patients with uncontrolled eosinophilic asthma. This meta-analysis complied with the PRISMA guidelines. The primary efficacy outcome was asthma exacerbation rate, and the primary safety outcomes included the incidence rates of all adverse events, asthma worsening, and injection site reactions. A subgroup analysis was also performed according to the type of anti-IL-5 agent. Pooled estimates are presented as rate ratios or relative risks （RRs） with 95% confidence intervals （CIs）. Analyses included intention-to-treat cases. Six randomized controlled trials of anti-IL-5 therapies met the inclusion criteria. The overall rate ratio for asthma exacerbation was 0.54 （95% CI 0.47-0.61）. The RRs （95% CIs） for the incidence of all adverse events, asthma worsening, and injection site reactions compared with placebo were 0.93 （0.89-0.96）, 0.63 （0.56-0.72）, and 1.59 （0.95-2.65）, respectively. The subgroup analysis revealed that the incidence of injection site reactions was significantly higher among mepolizumab- than placebo-treated patients, with an RR of 2.56 （95% CI 1.15-5.68）. These results suggest that anti-IL-5 therapies at the currently recommended dosages and administration are effective and generally well tolerated in patients with uncontrolled eosinophilic asthma. However, the occurrence of injection site reactions warrants specific attention, especially concerning mepolizumab administration.

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Medical specialists （scientists, doctors, nurses, pharmacists, etc.） are under strict scrutiny in contemporary society as they are held to a high standard and their crimes are loudly broadcasted through the mass media. In this study, we introduce three cases including the Novartis Case, involving a pharmaceutical company employee, the Mazindol Case involving a doctor, and the Muscle Relaxant Case involving a practical nurse. We analyzed each case, studying the risk and protective factors, to determine what caused the above-mentioned medical specialists to commit medical malpractice. In addition to identification and discussion of the key risk factors involved in each case, we propose prevention measures for medical specialists, particularly scientists, in order to avoid similar acts of misconduct in the future. We conclude that additional education and transparency regarding work performance are necessary to prevent such violations. To eliminate doubt, we recommend that electronic recording devices be used by medical specialists during experimentation.

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The relationship between the clinicopathological features and the grade of cellular dysplasia of the neoplastic glands in mass-forming gallbladder cancer was investigated. In this retrospective study, 41 mass-forming （≧1cm） gallbladder cancer specimens from 83 resected cases were examined. Tumors were classified into three groups: Group A had intraluminal masses consisting of neoplastic glands with only low-grade dysplasia; Group B had mixed low- and high-grade dysplasia, and Group C had only high-grade dysplasia. Of the 41 tumors, 13 were classified as Group A, 11 as Group B, and 17 as Group C. For Group A, B, and C, respectively, the mean tumor diameter was 1.6, 3.7 and 3.4cm; macroscopic type （pedunculated/semi-pedunculated/sessile） was 7/5/1, 4/6/1 and 0/10/7; frequency of an invasive component inside the mass was 0％, 9％ and 82％; and cell lineage （biliary/metaplastic/mixed） was 2/1/10, 8/1/2 and 14/1/2. In addition, invasion depth （Tis＋T1/T2/T3） was 13/0/0, 7/4/0 and 3/10/4; lymph node metastases were present in 0％, 9％ and 24％ of patients; 3-year survival rate was 100％, 100％ and 82％; and 5-year survival rate was 100％, 100％ and 69％, for A, B and C, respectively. Significant intergroup differences were seen for positive lymph node metastasis rate and 5-year survival rate. The present study indicates that the clinicopathological features of mass-forming gallbladder cancer are different depending on the grade of cellular dysplasia of the mass lesion. The tumors in Groups A and B were of lower malignancy than those in Group C and the prognosis of patients in the former groups was excellent. Group A and B tumors may be intracholecystic papillary-tubular neoplasms, a recently proposed new disease concept.

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The present study sought to compare the effectiveness of a proton pump inhibitor （PPI） with that of a histamine H₂ receptor antagonist （H2RA） for treating functional dyspepsia （FD） in a real-world setting. A multicenter, open-label, randomized trial was conducted. FD patients were randomly assigned to receive either 20mg, q.d., omeprazole （OPZ; a PPI） or 150mg, b.i.d., ranitidine hydrochloride （RAN; an H2RA） for 4 weeks. Any change in the total Gastrointestinal Symptom Rating Scale （GSRS） score （delta） at week 4 was the primary outcome measure. Secondary outcome measures were reductions in scores for individual items on the GSRS at week 4. As a subanalysis, patients were stratified according to Helicobacter pylori serology and the analyses were repeated. The mean （±SD） deltas in total GSRS score for the OPZ and RAN groups were 0.8±0.7 and 0.6±0.6, respectively （P＝0.098）; however, the delta in reflux score between the OPZ and RAN groups differed significantly （1.1±0.7 vs. 0.5±0.5, respectively; P＝0.001）. There were no significant differences between the two groups in any other scores for individual items on the GSRS. The results of the subanalysis were like those of the main analysis. The PPI and H2RA produced a comparable improvement in symptoms of FD in our patient cohort, thus we propose no advantage would be gained in using a PPI rather than an H2RA.

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Two oral transmucosal fentanyl formulations have been approved in Japan, a buccal tablet and a sublingual tablet. Both these dosage forms take effect rapidly and can be used for patients with cancer-related pain who have difficulty swallowing and taking oral medications; however, few patients have used these formulations, and suitable patient education by medical staff is needed. In addition, rapid-onset opioids might not reach their efficacy potential if administered improperly, and understanding individual patient needs with regard to treatment could affect subsequent evaluations of efficacy. Thus, the treating staff must work with their patients to maximize the proper use of such medicines. In our experience, the sublingual （S） tablet disintegrated in less than 1 minute, while the buccal （B） tablet took considerably longer, about 14 minutes. Moreover, the S tablet was easier to handle, had more favorable user impressions, and had little scattering in the disintegration time, all of which are clinically useful features. We collected further information that would be valuable for patient education, including tablet size and ease of opening the sheet （package） and removing the tablet. Furthermore, to promote proper use of the tablet by the patient, we explain the standard timing of the drug’s effectiveness, the need for proper handling of the drug, and attributes such as flavor, to minimize patient anxiety. The user impressions obtained in this study along with knowledge of product characteristics will improve patient education by medical staff and thus promote the medicines’ proper use.

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Osteoarthritis （OA） is a degenerative disease that occurs in joints throughout the body and includes various concomitant pathologies due to possible mechanical stress, such as destruction of cartilage, hyperplasic changes, and synovial inflammation. However, there have been few studies on the mechanical stress that is the basic cause of OA. Our goal was to establish an OA model at the cellular level, by measuring inflammatory cytokines and cartilage destruction markers that are induced after a mechanical stress load. Using a human synovial sarcoma cell line （SW982 cells）, we provided two types of mechanical stress load for 48hr: shaking stress （amplitude 2mm, speed range 1,000rpm）, and the addition of hydroxyapatite （5µg/ml） into the culture medium. Then we measured the phosphorylation activity of nuclear factor （NF）-κB transcription factor in the cell lysate, and the levels of tumor necrosis factor （TNF）-α and interleukin （IL）-6 as inflammatory cytokines, and the level of matrix metalloproteinase （MMP）-3 as a cartilage destruction marker, released in the medium. Shaking stress significantly induced phosphorylation of NF-κB and production of TNF-α, compared with untreated controls. On the other hand, hydroxyapatite stress only increased production of TNF-α. Both stresses together significantly induced phosphorylation of NF-κB and production of TNF-α, IL-6 and MMP-3 rather than a single stress load. In this study, markers related to inflammation and cartilage destruction （IL-6, TNF-α, and MMP-3） significantly increased. Therefore, we suggest that the mechanical stress load conditions used in this study might be useful as an OA model.

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Photokeratitis is a disease in which the ocular surface is directly affected by oxidative stress caused by exposure to ultraviolet （UV） light and oxygen. It is speculated that the production of free radicals and reactive oxygen species （ROS） is caused by UV-induced cytotoxicity. Recent studies have reported that catechins have antioxidant, antiallergic, antitumor, and antibacterial effects. The aim of our study was to investigate the mechanism of UV-induced cytotoxicity in cultured human corneal epithelial （HCE-T） cells and evaluate the protective effects of the catechins, （−）-epigallocatechin gallate （EGCG） and （−）-epigallocatechin 3-O-（3-O-methyl） gallate （EGCG3”Me）, on apoptosis. HCE-T cells were UV irradiated at 312nm （4.94mW/cm², 296mJ/cm²）. EGCG and EGCG3”Me were dissolved in methanol and adjusted to 5, 10, or 20µM. Absorption was measured from 250 to 400nm. EGCG and EGCG3”Me were pre-incubated for 1 hr. After UV irradiation, membrane lipid peroxide, tumor necrosis factor （TNF）-α production, ROS generation, caspase-3 and -8 activities, mitochondrial membrane potential, and cytochrome c levels were measured. Both EGCG and EGCG3”Me had UV absorption, and increased with concentration dependently. The increases in the levels of membrane lipid hyperoxidation, activation of caspase-3 and -8, production of TNF-α and ROS were found, by UV irradiation, to be significant. But these levels were significantly decreased by pretreatment with EGCG and EGCG3”Me. There were no changes in mitochondrial membrane potential and cytoplasmic cytochrome c levels after UV irradiation. Oxidative stress occurs early near the cell membrane in response to UV irradiation. As a result, TNF-α is induced, leading to apoptosis mainly through caspase-8 activation. Conversely, EGCG and EGCG3”Me absorb UV light directly and inhibit lipid peroxidation in the cell membrane. Catechins inhibit the apoptosis cascade by inactivating caspase-3 and caspase-8.

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Breast cancer patients must make their own decision of whether or not to undergo BRCA1/2 genetic testing. The present study investigated satisfaction surrounding this decision and the willingness to undergo BRCA1/2 genetic testing in the future among breast cancer patients who had not previously undergone BRCA1/2 testing despite a family history of breast cancer. Consent was obtained from 103 eligible patients selected from breast cancer patients who had presented with suspected hereditary breast and ovarian cancer and attended genetic counseling sessions at our institution. Consenting patients were then asked to complete a survey by questionnaire. Irrespective of their decision to undergo BRCA1/2 genetic testing, no patient reported being “not satisfied at all” or “not very satisfied”. Among the patients opting to not undergo BRCA1/2 genetic testing, 64％ responded that they would like to undergo BRCA1/2 genetic testing in the future. Compared with the patients who did not want to undergo testing, those who wanted to undergo were more likely to harbor impressions that BRCA1/2 genetic testing is “conducive to the selection of therapeutic modalities”, “helpful in deciding whether to undergo prophylactic surgery （oophorectomy, salpingectomy, and mastectomy）”, and “expensive”. Genetic counseling can improve satisfaction regarding the decision to undergo or not undergo BRCA1/2 genetic testing. However, there were some patients who opted not to undergo testing, but they were willing to undergo BRCA1/2 genetic testing in the future. Many of these patients might have found it cost-prohibitive to undergo testing immediately, despite realizing its benefits.

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Transcranial magnetic stimulation （TMS） could be a helpful addition to pharmacotherapy in treating depression; however, more evidence of its efficacy and safety is needed. This single-arm, open clinical study tested the efficacy and safety of TMS in 46 patients diagnosed with major depression or bipolar disorder. TMS was performed 30 times in total, with treatment frequencies of 3-5 times weekly. Patients were examined at the 10th and 20th treatments, after completion of TMS treatment, and at 2 and 4 weeks after completion of treatment. Primary efficacy endpoints were changes in Hamilton Depression Scale （HAMD-17） and Patient Health Questionnaire （PHQ-9） scores from baseline. Mean scores and changes in HAMD-17 and PHQ-9 were significantly decreased from baseline. The response rate at completion of treatment was 68.57％. Systolic blood pressure was significantly decreased at 4 weeks after completion of treatment. Adverse events were observed in 10 patients （21.74％）, including headache, discomfort, and fatigue. The present study found that patients with major depression or bipolar disorder who received TMS showed significant improvement in HAMD-17, PHQ-9, and Clinical Global Impression Scale scores.

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Deep vein thrombosis （DVT） was evaluated using virtual monochromatic imaging （VMI） with dual-energy analysis. We used data from 29 patients who were imaged at Showa University Hospital using the pulmonary embolism （PE）/DVT protocol and evaluated based on the diagnostic utility of VMI with dual-energy analysis. By VMI, we compared the computed tomography （CT） values of the femoral veins on both sides and the surrounding muscle tissues at 40keV and conventional imaging; two radiologists performed the visual evaluation in three stages. We also evaluated the CT values of thrombi for cases with DVT. We conducted a retrospective cohort study on 29 patients （18 males and 11 females） with a mean age of 66.8 （range: 31–86） years. DVT was confirmed in four of the subjects （13.7％）. Visual evaluation confirmed a significant difference between the CT values at 40keV and with conventional imaging （2.76 vs. 1.81; P＜0.05）. CT values in the femoral vein were 274.67 （range: 186.35–63.31） Hounsfield units （HU） at 40keV and 109.46 （range: 74.54–155.66） HU with conventional imaging （P＜0.05）. Contrast-to-noise ratios （CNRs） ［（femoral vein CT value−adductor muscle CT value）/adductor muscle standard deviation （SD）］ were 11.77 （range: 3.93–26.33） HU at 40keV and 9.87 （range: 1.28–27.56） HU with conventional imaging （P＜0.05）. The thrombus/femoral vein ratio （CT value） was 0.34 at 40keV and 0.59 with conventional imaging, while the CNR was 17.52 at 40keV and 4.32 with conventional imaging; both differences were significant. Low-voltage contrast CT is beneficial for enhancing images of veins and it may also be very useful for detecting DVT.

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In skiing, a strong correlation has long existed between injuries and the development of ski equipment. For instance, just one change in the shape of skis leads to changes in skiing style, which can make the skier adopt knee positions likely to create injury. In this review, we discuss the morphology of ski-related injuries. In the 18 years since 1996, 10,561 patients with skiing and snowboarding-related injuries visited the Ishiuchi Ski Clinic （Niigata Prefecture, Japan）. Of these, 3,703 patients had ski-related injuries. We reviewed patients’ medical records and questionnaires and observed their skiing using a video camera with 3-dimensional computer graphics software analysis. When knee sprains and fractures were considered together, the 18-year overall incidence was 30％, but in the 3-year period from 2009-2012, the incidence increased to 31％. Skiing style has changed from conventional alpine skiing to carving skiing, which has made the knee unstable, thereby increasing the risk of anterior cruciate ligament injury or tibial plateau fracture.

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Considering the increasing incidence of snowboarding-related wrist trauma, clarification of the morphology of such injuries and the development of preventive approaches are necessary. We compared the injury morphology of skiing-related and snowboarding-related wrist trauma, and conducted a related literature review. Participants included 10,561 individuals who consulted the Ishiuchi Ski Clinic for skiing-related and snowboarding-related injuries between December 1996 and March 2014. As well as reviewing medical records and questionnaire surveys, we also analyzed videotaped skiing and snowboarding events to examine the statistics and injury morphology of wrist trauma. Over the study period, there were 3,703 patients with skiing-related trauma, including 89 （2.4％） with wrist trauma, and 6,858 patients with snowboarding-related trauma, including 1,123 （16.4％） with wrist trauma. These 1,123 patients included 925 （13.5％） with fractures and 148 （2.2％） with sprains. The most common skiing-related injuries were knee sprains, including medial collateral and anterior cruciate ligament injuries （23.3％）. However, the most common snowboarding-related injuries were wrist fractures, including distal radius fractures （13.5％）. Trauma was most commonly caused by falling during ski runs or snowboarding jumps. Videos of snowboarders’ postures during landing revealed that wrist fractures often occurred when their palms impacted the ground in front of the board. The increased wrist trauma associated with snowboarding compared to skiing could be attributed to the following reasons: （ⅰ） absence of ski poles and use of the snowboarding posture （sideways stance with both feet fixed on the same board）; （ⅱ） bindings not releasing during falls; and （ⅲ） sudden hand impact caused by “reverse edge” falls on moderate slopes （hands hitting the snow before the trunk）. These cause wrist dorsiflexion, predisposing to traumatic injuries, during falls and jumps.

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