Analysis of Urinary Retention Caused by Selective ß 3-adrenoceptor Agonists Using the Japanese Adverse Drug Event Report Database (JADER).

Overactive bladder (OAB) is a frequent chronic disorder which impairs quality of life by frequent, uncontrollable urination. Newly developed selectiveß 3-adrenoceptor agonists (sß 3-agonists) have the same efficacy in treating OAB but significantly fewer side effects than the traditionally used anti-muscarinics. However, safety data on these compounds are scarce. In this study, we analysed the occurrence of adverse effects in patients taking sß 3-agonists and their characteristics using the JADER database. The most frequently reported adverse effect associated with the use of sß 3-agonists was urinary retention [mirabegron; crude reporting odds ratios (ROR): 62.1, 95% confidence interval (CI): 52.0-73.6, P<0.001, vibegron; crude ROR: 250, 95% CI : 134-483, P<0.001]. Data from patients with urinary retention were stratified by sex. In both men and women, the rate of urinary retention was higher when using the mirabegron/anti-muscarinic drug when compared to mirabegron monotherapy; its occurrence was higher in men with a history of benign prostatic hypertrophy than in those without. Weibull analysis showed that approximately 50% of sß 3 agonist-induced urinary retention occurred within 15 days after initiation of treatment, and then gradually decreased. Although sß 3-agonists are useful against OAB, they may induce several side effects, especially urinary retention, which can further evolve into more severe conditions. Urinary retention occurs more frequently in patients concomitantly taking medication that either increases urethral resistance or has organic factors that block the urethra. When using sß 3-agonists, the concomitantly used medications and underlying diseases should be thoroughly reviewed, and safety monitoring should be instituted early during the treatment.

CHEMORESISTANCE RELATED TO HYPOXIA ADAPTATION IN MESOTHELIOMA CELLS FROM TUMOR SPHEROIDS.

BACKGROUND: Hypoxia has been noted as a key factor for induction and maintenance of cancer stemness thereby leading to therapy resistance. Three-dimensional (3D) spheroid models demonstrate a heterogeneity of hypoxic regions replicating the in vivo situation within tumors. Utilizing an established 3D spheroid model, we investigated whether extrinsic hypoxia reinforced chemoresistance in malignant pleural mesothelioma (MPM) spheroids. MATERIALS AND METHODS: Tumor spheres were generated from Meso-1 (a typical human MPM cell line) cells having high spheroid-forming ability. To induce hypoxia condition, we utilized a hypoxia chamber with regulation of O2 and CO2 levels. Cell viability was estimated by a WST-8 assay. Real-time polymerase chain reaction and Western blot were performed to evaluate the expression at mRNA and protein levels. RESULTS: Compared with cells cultured in the two-dimensional monolayer model, tumor sphere cells showed elevated mRNA levels of cancer stemness markers (CD26, CD44 and ABCG2) and protein levels of the stemness and hypoxia adaptation markers (ABCG2, ALDH1A1 and HIFs). Correlating with this, 3D spheroid cells were more resistant to permetrexed and topotecan than the two-dimensional cells, indicative of their potential for hypoxic adaptation. Furthermore, significantly stronger resistance to both chemotherapeutic agents was observed in spheroid cells upon hypoxic challenge compared to spheroid cells under normoxia. CONCLUSION: From the present data, it is concluded that hypoxia adaptation of MPM cells from tumor spheres could enhance their chemoresistance.

Genetic diversity of Lactobacillus delbrueckii isolated from raw milk in Hokkaido, Japan.

Lactic acid bacteria (LAB) play important roles in acid production and flavor formation in fermented dairy products. Lactic acid bacteria strains with distinct characteristics confer unique features to products. Diverse LAB have been identified in raw milk and traditional fermented milk prepared from raw milk. However, little is known about LAB in raw milk in Japan. To preserve diverse LAB as potential starters or probiotics for future use, we have isolated and identified various kinds of LAB from raw milk produced in Japan. In this study, we focused on Lactobacillus delbrueckii, one of the most important species in the dairy industry. We identified L. delbrueckii subspecies isolated from raw milk in Hokkaido, Japan, by analyzing intraspecific diversity using 4 distinct methods, hsp60 cluster analysis, multilocus sequence analysis, core-genome analysis, and whole-genome analysis based on average nucleotide identity. The subspecies distribution and a new dominant subset of L. delbrueckii from raw milk in Japan were revealed. The discovery of new strains with different genotypes is important for understanding the geographic distribution and characteristics of the bacteria and further their use as a microbial resource with the potential to express unconventional flavors and functionalities. The strains identified in this study may have practical applications in the development of fermented dairy products.

Novel Amiloride Derivatives That Inhibit Bacterial Motility across Multiple Strains and Stator Types.

The bacterial flagellar motor (BFM) is a protein complex that confers motility to cells and contributes to survival and virulence. The BFM consists of stators that are ion-selective membrane protein complexes and a rotor that directly connects to a large filament, acting as a propeller. The stator complexes couple ion transit across the membrane to torque that drives rotation of the motor. The most common ion gradients that drive BFM rotation are protons (H+) and sodium ions (Na+). The sodium-powered stators, like those in the PomA/PomB stator complex of Vibrio spp., can be inhibited by sodium channel inhibitors, in particular, by phenamil, a potent and widely used inhibitor. However, relatively few new sodium motility inhibitors have been described since the discovery of phenamil. In this study, we characterized two possible motility inhibitors, HM2-16F and BB2-50F, from a small library of previously reported amiloride derivatives. We used three approaches: effect on rotation of tethered cells, effect on free-swimming bacteria, and effect on rotation of marker beads. We showed that both HM2-16F and BB2-50F stopped rotation of tethered cells driven by Na+ motors comparable to phenamil at matching concentrations and could also stop rotation of tethered cells driven by H+ motors. Bead measurements in the presence and absence of stators confirmed that the compounds did not inhibit rotation via direct association with the stator, in contrast to the established mode of action of phenamil. Overall, HM2-16F and BB2-50F stopped swimming in both Na+ and H+ stator types and in pathogenic and nonpathogenic strains. IMPORTANCE Here, we characterized two novel amiloride derivatives in the search for antimicrobial compounds that target bacterial motility. These compounds were shown to inhibit flagellar motility at 10 µM across multiple strains: from nonpathogenic Escherichia coli with flagellar rotation driven by proton or chimeric sodium-powered stators, to proton-powered pathogenic E. coli (enterohemorrhagic E. coli or uropathogenic E. coli [EHEC or UPEC, respectively]), and finally, sodium-powered Vibrio alginolyticus. Broad antimotility compounds such as these are important tools in our efforts to control virulence of pathogens in health and agricultural settings.

Development of retake support system for lateral knee radiographs by using deep convolutional neural network.

INTRODUCTION: Lateral radiography of the knee joint is frequently performed; however, the retake rate is high owing to positioning errors. Therefore, in this study, to reduce the required number and time of image retakes, we developed a system that can classify the tilting directions of lateral knee radiographs and evaluated the accuracy of the proposed method. METHODS: Using our system, the tilting directions of a lateral knee radiographs were classified into four direction categories. The system was developed by training the DCNN based on 50 cases of Raysum images and tested on three types test dataset; ten more cases of Raysum images, one case of flexed knee joint phantom images and 14 rejected knee joint radiographs. To train a deep convolutional neural network (DCNN), we employed Raysum images created via three-dimensional (3D) X-ray computed tomography (CT); 11 520 Raysum images were created from 60 cases of 3D CT data by changing the projection angles. Thereby, we obtained pseudo images attached with correct labels that are essential for training. RESULTS: The overall accuracy on each test dataset was 88.5 ± 7.0% (mean ± standard deviation), 81.4 ± 11.2%, and 73.3 ± 9.2%. The larger the tilting degree of the knee joint, the higher the classification accuracy. CONCLUSION: DCNN could classify the tilting directions of a knee joint from lateral knee radiographs. Using Raysum images made it possible to facilitate creating dataset for training DCNN. The possibility was indicated for using support system of lateral knee radiographs. IMPLICATIONS FOR PRACTICE: The system may also reduce the burden on patients and increase the work efficiency of radiological technologists.

Juzentaihoto extract suppresses adipocyte hypertrophy and improves hyperglycemia in KKAy mice.

Juzentaihoto is a herbal medicine with reported anti-inflammatory effects, and it is predicted to improve inflammation and insulin sensitivity within obesity. In the present study, juzentaihoto hot water extract (JTT) was administered to obese type 2 diabetic model mice (KKAy) for 56 days. In addition, the effects of JTT on the adipose tissue, glucose metabolism, and blood lipids were evaluated for examining its impact on insulin sensitivity and obesity. As a result of JTT administration, KKAy mice exhibited suppressed adipocyte hypertrophy, decreased the mRNA levels of tumor necrosis factor α, and increased the mRNA levels of adiponectin in epididymal fat tissue. In addition, fasting blood glucose levels, blood triglyceride, and total cholesterol decreased. In summary, these data indicated that JTT administration suppressed the production of inflammatory cytokines and increased adiponectin levels in the adipose tissue. Therefore, with improved insulin sensitivity, blood glucose, and lipid decreased.

Effect of high ligation on survival of patients undergoing surgery for primary colorectal cancer and synchronous liver metastases.

BACKGROUND: Although R0 surgery is recommended for stage IV colorectal cancer, the degree of required lymphadenectomy has not been established. The aim of this study was to investigate the prognostic impact of high ligation (HL) of the feeding artery and the number of retrieved lymph nodes after R0 surgery for colorectal cancer and synchronous colorectal cancer liver metastasis (CRLM). METHODS: This was a multi-institutional retrospective analysis of patients with colorectal cancer and synchronous CRLM who had R0 surgery between January 1997 and December 2007. Clinical and pathological features were compared in patients who underwent HL and those who had a low ligation (LL). Kaplan-Meier analysis was performed to estimate the effect of HL on overall survival (OS). The impact of several risk factors on survival was analysed using the Cox proportional hazards model. RESULTS: Of 549 patients, 409 (74·5 per cent) had HL. Median follow-up was 51·4 months. HL significantly improved the 5-year OS rate (58·2 per cent versus 49·3 per cent for LL; P = 0·017). Multivariable analysis revealed HL to be a significant prognostic factor compared with LL (5-year mortality: hazard ratio (HR) 0·68, 95 per cent c.i. 0·51 to 0·90; P = 0·007). In subgroup analysis, the positive effect of HL on OS was greatest in patients with lymph node metastasis. CONCLUSION: HL of the feeding artery was associated with improved OS in patients with colorectal cancer and synchronous CRLM after R0 surgery.

ANTECEDENTES: Aunque se recomienda una cirugía R0 para el cáncer colorrectal (colorectal cancer, CRC) en estadio IV, no se ha establecido el grado de linfadenectomía requerida. El objetivo de este estudio fue investigar el impacto pronóstico de la ligadura alta (high ligation, HL) de la arteria que irriga el tumor y el número de ganglios linfáticos (lymph nodes, LN) identificados después de cirugía R0 en pacientes con cáncer colorrectal y metástasis hepáticas sincrónicas (colorectal cancer liver metastasis, CRLM). MÉTODOS: En este estudio se realizó un análisis retrospectivo multicéntrico de pacientes con CRC y CRLM sincrónicas en los que se realizó una cirugía R0 desde enero de 1997 hasta diciembre de 2007. Se compararon las características clínicas y patológicas entre los pacientes a los que, durante la cirugía R0, se practicó una HL frente a los que no se practicó esta técnica. El análisis de Kaplan-Meier se realizó para estimar el efecto de la HL en la supervivencia global (overall survival, OS). El impacto de varios factores de riesgo sobre la supervivencia se analizó utilizando el modelo de Cox de riesgo proporcional. RESULTADOS: Sobre un total de 549 pacientes, se realizó una HL en 409 (74,5%), y el período de seguimiento medio en esta cohorte fue de 51,4 meses. La HL mejoró significativamente la tasa de OS a los 5 años (HL 37,7% versus no HL 27,1%, P = 0,02). El análisis multivariable mostró que la HL era un factor pronóstico significativo en comparación con la no realización de una HL (cociente de riesgos instantáneos, hazard ratio, HR de muerte a 5 años = 0,68 (i.c. del 95% 0,51-0,90), P < 0,01)). En el análisis de subgrupos, el efecto positivo de la HL sobre la OS fue mayor en pacientes con metástasis ganglionares. CONCLUSIÓN: La ligadura alta de la arteria que irriga el tumor se asoció con una mejor OS en pacientes con CRC y CRLM sincrónicas después de una cirugía R0.

Smectic Liquid-Crystalline Structure of Skyrmions in Chiral Magnet Co_{8.5}Zn_{7.5}Mn_{4}(110) Thin Film.

The organizing of magnetic skyrmions shows several forms similar to atomic arrays of solid states. Using Lorentz transmission electron microscopy, we report the first direct observation of a stable liquid-crystalline structure of skyrmions in chiral magnet Co_{8.5}Zn_{7.5}Mn_{4}(110) thin film, caused by magnetic anisotropy and chiral surface twist. Elongated skyrmions are oriented and periodically arranged only in the ⟨110⟩ directions, whereas they exhibit short-range order along the ⟨001⟩ directions, indicating a smectic skyrmion state. In addition, skyrmions possess anisotropic interaction with an opposite sign depending on the crystal orientation, in contrast to existing isotropic interaction.

Quality control of hospital preparations: Establishment of a simple and rapid method for quantifying ulinastatin in vaginal suppositories.

Ulinastatin vaginal suppositories, used to prevent threatened premature delivery, are frequently used in hospitals. However, there is no established method for quantifying ulinastatin contained in suppositories. Therefore, we investigated a simple and efficient method for quantifying ulinastatin contained in suppositories. Our analytical method involved removal of the base; optimising the enzyme inhibition reaction time and enzyme reaction time; and measuring the absorbance. The modified method was reproducible, operation time was significantly shortened, and cost was reduced to approximately 1/17 of that of the previously reported method. This simple and rapid quantitative method could contribute to the improvement of quality control of ulinastatin vaginal suppositories as an extemporaneous hospital preparation.

Efficacy of discontinuing risedronate for patients with systemic lupus erythematosus: a prospective study.

Objective The objective of this study is to investigate the effectiveness of discontinuation of risedronate for patients with systemic lupus erythematosus (SLE) treated with glucocorticoid (GC). Methods The participants were patients with SLE treated with prednisolone (PSL) ≥ 2 mg/day and risedronate for at least three years. Lumbar spine and total hip bone mineral density (BMD) measurements were taken at baseline and 24 and 48 weeks after discontinuation of risedronate, and bone turnover markers were evaluated at baseline, 12, 24, 36, and 48 weeks. Results A total of 36 patients were enrolled, 25 of whom discontinued risedronate. The mean age was 46.8 ± 11.2 years, and 23 were female. The mean duration of GC treatment was 14.8 ± 11.4 years, the mean dose of PSL was 7.8 ± 3.9 mg/day, and the mean duration of risedronate was 5.8 ± 2.4 years. Seventeen patients showed decreased lumbar spine BMD at 48 weeks after discontinuation of risedronate, with a mean lumbar spine lumbar decrease of 1.42% ± 3.20% ( p = 0.034); 17 patients (71%) showed a decreased total hip BMD at 48 weeks after discontinuation of risedronate, with a mean total hip BMD decrease of 0.99% ± 2.10% ( p = 0.021). Serum tartrate-resistant acid phosphatase 5b (TRACP-5b) ≥ 309 mU/dl at baseline was a risk factor for decreased total hip BMD at 48 weeks compared with serum TRACP-5b < 309 mU/dl (56% vs 0%, p = 0.0098). One patient developed a clinical fracture of the lumbar spine at 20 weeks. Conclusions Discontinuation of risedronate treatment in patients with SLE who had received GC therapy led to decreases in lumbar spine and total hip BMD, particularly in patients with high baseline serum TRACP-5b levels.

Complex evolution of the GSTM gene family involves sharing of GSTM1 deletion polymorphism in humans and chimpanzees.

BACKGROUND: The common deletion of the glutathione S-transferase Mu 1 (GSTM1) gene in humans has been shown to be involved in xenobiotic metabolism and associated with bladder cancer. However, the evolution of this deletion has not been investigated. RESULTS: In this study, we conducted comparative analyses of primate genomes. We demonstrated that the GSTM gene family has evolved through multiple structural variations, involving gene duplications, losses, large inversions and gene conversions. We further showed experimentally that the GSTM1 was polymorphically deleted in both humans and also in chimpanzees, through independent deletion events. To generalize our results, we searched for genic deletions that are polymorphic in both humans and chimpanzees. Consequently, we found only two such deletions among the thousands that we have searched, one of them being the GSTM1 deletion and the other surprisingly being another metabolizing gene, the UGT2B17. CONCLUSIONS: Overall, our results support the emerging notion that metabolizing gene families, such as the GSTM, NAT, UGT and CYP, have been evolving rapidly through gene duplication and deletion events in primates, leading to complex structural variation within and among species with unknown evolutionary consequences.

Evaluation of hydrogen absorption cells for observations of the planetary coronas.

Newly designed Lyman-alpha absorption cells for imaging hydrogen planetary corona were characterized using an ultra high resolution Fourier transform spectrometer installed on the DESIRS (Dichroïsme Et Spectroscopie par Interaction avec le Rayonnement Synchrotron) beamline of Synchrotron SOLEIL in France. The early absorption cell installed in the Japanese Mars orbiter NOZOMI launched in 1998 had not been sufficiently optimized due to its short development time. The new absorption cells are equipped with the ability to change various parameters, such as filament shape, applied power, H2 gas pressure, and geometrical configuration. We found that the optical thickness of the new absorption cell was ∼4 times higher than the earlier one at the center wavelength of Lyman-alpha absorption, by optimizing the condition to promote thermal dissociation of H2 molecules into two H atoms on a hot tungsten filament. The Doppler temperature of planetary coronas could be determined with an accuracy better than 100 K with the performance of the newly developed absorption cell.

Non-traumatic hemorrhage is controlled with REBOA in acute phase then mortality increases gradually by non-hemorrhagic causes: DIRECT-IABO registry in Japan.

PURPOSE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is now a feasible and less invasive resuscitation procedure. This study aimed to compare the clinical course of trauma and non-trauma patients undergoing REBOA. METHODS: Patient demographics, etiology, bleeding sites, hemodynamic response, length of critical care, and cause of death were recorded. Characteristics and outcomes were compared between non-trauma and trauma patients. Kaplan-Meier survival analysis was then conducted. RESULTS: Between August 2011 and December 2015, 142 (36 non-trauma; 106 trauma) cases were analyzed. Non-traumatic etiologies included gastrointestinal bleeding, obstetrics and gynecology-derived events, visceral aneurysm, abdominal aortic aneurysm, and post-abdominal surgery. The abdomen was a common bleeding site (69%), followed by the pelvis or extra-pelvic retroperitoneum. None of the non-trauma patients had multiple bleeding sites, whereas 45% of trauma patients did (P < 0.001). No non-trauma patients required resuscitative thoracotomy compared with 28% of the trauma patients (P < 0.001). Non-trauma patients presented a lower 24-h mortality than trauma patients (19 vs. 51%, P = 0.001). The non-trauma cases demonstrated a gradual but prolonged increased mortality, whereas survival in trauma cases rapidly declined (P = 0.009) with similar hospital mortality (68 vs. 64%). Non-trauma patients who survived for 24 h had 0 ventilator-free days and 0 ICU-free days vs. a median of 19 and 12, respectively, for trauma patients (P = 0.33 and 0.39, respectively). Non-hemorrhagic death was more common in non-trauma vs. trauma patients (83 vs. 33%, P < 0.001). CONCLUSIONS: Non-traumatic hemorrhagic shock often resulted from a single bleeding site, and resulted in better 24-h survival than traumatic hemorrhage among Japanese patients who underwent REBOA. However, hospital mortality increased steadily in non-trauma patients affected by non-hemorrhagic causes after a longer period of critical care.

The use of aortic balloon occlusion in traumatic shock: first report from the ABO trauma registry.

PURPOSE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique for temporary stabilization of patients with non-compressible torso hemorrhage. This technique has been increasingly used worldwide during the past decade. Despite the good outcomes of translational studies, clinical studies are divided. The aim of this multicenter-international study was to capture REBOA-specific data and outcomes. METHODS: REBOA practicing centers were invited to join this online register, which was established in September 2014. REBOA cases were reported, both retrospective and prospective. Demographics, injury patterns, hemodynamic variables, REBOA-specific data, complications and 30-days mortality were reported. RESULTS: Ninety-six cases from 6 different countries were reported between 2011 and 2016. Mean age was 52 ± 22 years and 88% of the cases were blunt trauma with a median injury severity score (ISS) of 41 (IQR 29-50). In the majority of the cases, Zone I REBOA was used. Median systolic blood pressure before balloon inflation was 60 mmHg (IQR 40-80), which increased to 100 mmHg (IQR 80-128) after inflation. Continuous occlusion was applied in 52% of the patients, and 48% received non-continuous occlusion. Occlusion time longer than 60 min was reported as 38 and 14% in the non-continuous and continuous groups, respectively. Complications, such as extremity compartment syndrome (n = 3), were only noted in the continuous occlusion group. The 30-day mortality for non-continuous REBOA was 48%, and 64% for continuous occlusion. CONCLUSIONS: This observational multicenter study presents results regarding continuous and non-continuous REBOA with favorable outcomes. However, further prospective studies are needed to be able to draw conclusions on morbidity and mortality.

18F-fluorodeoxyglucose specimen-positron emission mammography delineates tumour extension in breast-conserving surgery: Preliminary results.

OBJECTIVES: We aimed to determine whether high-resolution specimen-positron emission mammography (PEM) using fluorodeoxyglucose (18F-FDG) can reveal extension of breast cancer in breast-conserving surgery (BCS), and assess the safety of radiation exposure to medical staff. METHODS: Sixteen patients underwent positron emission tomography, and then BCS with intraoperative frozen section analysis on the same day. Resected specimens with remaining 18F-FDG accumulation were scanned by high-resolution PEM. At least 1 day after surgery, tumour extension was evaluated by three independent experienced readers and by binarized images from the specimen-PEM data. Intraoperative exposure of medical staff to 18F-FDG was measured. RESULTS: Specimen-PEM evaluations of binarized images and the three investigators detected all (100 %, 12/12) invasive lesions and 94.4 % (17/18) of in situ lesions using both methods. The positive predictive value of the accumulated lesions was 74.4 % (29/39) for the binarized images and 82.9 % (29/35) for the three investigators. Analysis of intraoperative frozen sections detected 100 % (2/2) of the margin-positive cases, also detected by both specimen-PEM evaluation methods with no false-positive margin cases. The mean exposure of the medical staff to 18F was 18 µSv. CONCLUSIONS: Specimen-PEM detected invasive and in situ lesions with high accuracy and allowable radiation exposure. KEY POINTS: • Specimen-PEM detected invasive and in situ lesions with high accuracy. • Specimen-PEM predicted complete resection with the same accuracy as frozen section analysis. • Breast-conserving surgery after fluorodeoxyglucose injection was performed with low medical staff exposure.

Clinical significance of Aspergillus species isolated from respiratory specimens in patients with Mycobacterium avium complex lung disease.

Chronic pulmonary aspergillosis (CPA) is associated with mortality in patients with Mycobacterium avium complex lung disease (MAC-LD). An Aspergillus-positive respiratory specimen often reflects colonization, and thus the clinical significance of Aspergillus isolation in MAC-LD patients is not well understood. The objective of this study was to investigate the clinical characteristics and outcomes of MAC-LD patients in whom Aspergillus was isolated from respiratory specimens. We performed a retrospective review of the medical records of 329 MAC-LD patients. We compared the characteristics and mortality rates between patients with Aspergillus isolation and those without. All Aspergillus species detected from respiratory specimens within the follow-up period were reviewed. Aspergillus was detected in 40 (12.2%) of the 329 patients. There were no significant differences in the clinical characteristics and mortality rates between patients with and without Aspergillus isolation. Among the 40 patients with Aspergillus isolation, 9 (22.5%) developed CPA. CPA was most often caused by A. fumigatus. In the 40 Aspergillus-positive patients, patients with A. fumigatus isolation had a significantly higher mortality rate than those without (P < 0.001). The multivariate Cox proportional hazards model showed older age (P = 0.050), presence of respiratory comorbidities (P = 0.008), hypoalbuminemia (P < 0.001), and isolation of A. fumigatus (P = 0.005) to be prognostic factors for mortality in MAC-LD patients. There was no significant difference in the mortality rates between patients with Aspergillus isolation and those without. However, isolation of A. fumigatus may be associated with poor prognosis in MAC-LD patients.

Significance of measurement of serum trough level and anti-drug antibody of adalimumab as personalised pharmacokinetics in patients with Crohn's disease: a subanalysis of the DIAMOND trial.

BACKGROUND: Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear. AIM: To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. METHODS: We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. RESULTS: There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 µg/mL vs 5.4 ± 4.3 µg/mL: P <.001). Adalimumab trough level of 5.0 µg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. CONCLUSION: Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146).

Prediction of muscle strength and postoperative function after knee flexor muscle resection for soft tissue sarcoma of the lower limbs.

INTRODUCTION: Oncological margins and prognosis are the most important factors for operative planning of soft tissue sarcomas, but prediction of postoperative function is also necessary. The purpose of this study was to predict the knee flexion strength and postoperative function after knee flexor muscle resection for soft tissue sarcoma of the lower limbs. MATERIALS AND METHODS: Seventeen patients underwent knee flexor muscle resection for soft tissue sarcoma of the lower limbs between 1991 and 2015. The type of resected muscles was surveyed, knee flexion strength (ratio of affected to unaffected side) was evaluated using the Biodex System isokinetic dynamometer, and differences between the type of resected muscles were examined. The Musculoskeletal Tumor Society (MSTS) score, Toronto Extremity Salvage Score (TESS), European Quality of Life-5 Dimensions (EQ-5D), and Short Form 8 (SF-8) were used to assess postoperative function and examine correlations with flexion strength. The cutoff value for flexion strength to predict good postoperative results was calculated by a receiver operating characteristic (ROC) curve and Fisher's exact test. RESULTS: Median flexion strength decreased in the resection of sartorius (97.8%), gracilis (95.4%), gastrocnemius (85.2%; interquartile range (IQR): 85.0-86.2), medial hamstrings (semimembranosus and semitendinosus, 76.2%; IQR: 73.3-78.0), lateral hamstrings (long and short head of biceps femoris, 66.1%; IQR: 65.9-70.4), and bilateral hamstrings (27.3%; IQR: 26.6-31.5). A significant difference was observed between lateral and bilateral hamstrings resection (P=0.049). Flexion strength was associated with lower functional scales (MSTS score, P=0.021; TESS, P=0.008; EQ-5D, P=0.034). Satisfactory function was obtained at a flexion strength cutoff value of 65.7%, and strength remained above the cutoff value up to unilateral hamstrings resection. DISCUSSION: Greater knee flexor muscles resection can result in functional deficits that are associated with decreased flexion strength. If continuity of unilateral hamstrings is maintained, good postoperative results can be expected. LEVEL OF EVIDENCE: IV, retrospective study.