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Aims/Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have shown beneficial effects on cardiometabolic risk factors (hemoglobin A1c, body mass index, systolic blood pressure) in patients with type 2 diabetes mellitus. We compared combined cardiometabolic effects of SGLT2i on hemoglobin A1c, body mass index and systolic blood pressure versus dipeptidyl peptidase‐4 inhibitors (DPP4i) in Japanese patients with type 2 diabetes mellitus. Materials and Methods This Japanese retrospective cohort study used the JMDC claims database. Patients newly treated with an SGLT2i (n = 18,936) or DPP4i (n = 55,484) were enrolled (January 2015–March 2020) and matched 1:1 using the propensity score. The primary end‐point was the proportion of patients achieving a composite outcome (i.e., simultaneous absolute/percent reduction in hemoglobin A1c ≥0.5%, body mass index ≥3% and systolic blood pressure ≥2 mmHg) 1 year after first SGLT2i or DPP4i prescription; Mantel–Haenszel common risk difference and its 95% confidence interval were estimated. Other end‐points included treatment persistence, with the associated hazard ratio calculated using the Cox proportional hazards model. Results After matching, patient characteristics were balanced (7,302 patients each). The proportion of patients achieving the composite outcome was significantly greater in patients receiving an SGLT2i than those receiving a DPP4i (31.0% [1,279/4,120] vs 12.9% [524/4,070], risk difference 18.6%, 95% confidence interval 16.3, 20.9, P < 0.001). Risk of treatment discontinuation was significantly lower in the SGLT2i group than in the DPP4i group (hazard ratio 0.85, 95% confidence interval 0.81, 0.90, P < 0.001). Conclusions In the present study, SGLT2i showed favorable cardiometabolic risk reduction and longer treatment persistence than DPP4i in Japanese patients with type 2 diabetes mellitus. In this large retrospective cohort study using a Japanese administrative database, the proportion of patients with type 2 diabetes mellitus achieving a simultaneous improvement in hemoglobin A1c, body mass index and systolic blood pressure was significantly greater in patients newly treated with a sodium–glucose cotransporter 2 inhibitor than those newly treated with a dipeptidyl peptidase‐4 inhibitor. Furthermore, sodium–glucose cotransporter 2 inhibitor treatment showed better treatment persistence than dipeptidyl peptidase‐4 inhibitor treatment.

Background The incidences of postoperative pulmonary complications (PPCs) such as atelectasis, pneumonia and pleural effusion after major surgery range from <1 to 23%. Atelectasis after abdominal surgery increases the duration of hospitalization and short-term mortality rate, but there are few reports about atelectasis after hepatectomy. The effectiveness of prone position drainage as physiotherapy has been reported, but it remains unclarified whether prone positioning prevents atelectasis after hepatectomy. This study aimed to evaluate the effect of the prone position on the incidence of atelectasis after hepatectomy. Methods We retrospectively analyzed the incidence of PPCs after hepatectomy at a single center. Patients were divided into two cohorts. The earlier cohort ( n  = 165) underwent hepatectomy between January 2016 and March 2018 and was analyzed to identify the risk factors for atelectasis and short-term outcomes; the later cohort ( n  = 51) underwent hepatectomy between April 2018 and March 2019 and underwent prone position drainage in addition to regular mobilization postoperatively. The incidences of PPCs were compared between the two cohorts. Results Independent risk factors for atelectasis were anesthetic duration ( P  = 0.016), operation time ( P  = 0.046) and open surgery ( P  = 0.011). The incidence of atelectasis was significantly lower in the later cohort (9.8%) than the earlier cohort (34.5%, P  < 0.001). Moreover, the later cohort had a significantly shorter duration of oxygen support ( P  < 0.001) and postoperative hospitalization ( P  < 0.001). After propensity score-matching, the incidence of atelectasis remained significantly lower in the later cohort ( P  = 0.027). Conclusion Prone position drainage may decrease the incidence of atelectasis after hepatectomy and improve the short-term outcomes.

Background Use of real-world evidence (RWE) has been limited for evaluating effectiveness because of the lack of confidence in its reliability. Examining whether a rigorously designed observational study using real-world data (RWD) can reproduce the results of a randomized controlled trial (RCT) will provide insights into the implementation of high-quality RWE studies that can produce valid conclusions. Objective We aimed to replicate published RCTs using a Japanese claims and health checkup database and examine whether the emulated RWE studies’ results agree with those of the original RCTs. Methods We selected three RCTs on diabetes medications for replication in patients with type 2 diabetes. The study outcome was either the change or percentage change in HbA1c levels from baseline. We designed three observational studies using the RWD to mimic the critical study elements of the respective RCTs as closely as possible. We performed 1:1 propensity score nearest-neighbor matching to balance the groups for potential confounders. The differences in outcomes between the groups and their 95% confidence intervals (CIs) were calculated in each RWE study, and the results were compared with those of the RCT. Results Patient characteristics, such as age, sex, and duration of diabetes, differed between the RWE studies and RCTs. In Trial 1 emulation, the percentage changes in HbA1c levels were larger in the treatment group than in the comparator group (difference −6.21, 95% confidence interval (CI) −11.01 to −1.40). In Trial 2, the change in HbA1c level was larger in the treatment group (difference −0.01; 95% CI −0.25 to 0.23), and in Trial 3, it was smaller in the treatment group (difference 0.46; 95% CI −0.01 to 0.94). These results did not show regulatory or estimate agreement with the RCTs. Conclusions None of the three emulated RWE studies using this claims and health checkup database reproduced the same conclusions as the RCTs. These discrepancies could largely be attributed to design differences between RWE studies and RCTs, primarily due to the lack of necessary data in the database. This particular RWD source may not be the best fit for evaluating treatment effects using laboratory data as the study outcome.

Background Most studies of risk factors for new low back pain (LBP) have been conducted in Western populations, but because of cultural and environmental differences, the impact of causal factors may not be the same in other countries. We used longitudinal data from the Cultural and Psychosocial Influences on Disability (CUPID) study to assess risk factors for new onset of disabling LBP among Japanese workers. Methods Data came from a 1-year prospective follow-up of nurses, office workers, sales/marketing personnel, and transportation workers, initially aged 20–59 years, who were employed in or near Tokyo. A baseline questionnaire included items on past history of LBP, personal characteristics, ergonomic work demands, and work-related psychosocial factors. Further information about LBP was collected at follow-up. Analysis was restricted to participants who had been free from LBP during the 12 months before baseline. Logistic regression was used to assess baseline risk factors for new onset of disabling LBP (i.e. LBP that had interfered with work) during the 12 months of follow-up. Results Among 955 participants free from LBP during the 12 months before baseline, 58 (6.1%) reported a new episode of disabling LBP during the 12-month follow-up period. After mutual adjustment in a multivariate logistic regression analysis, which included the four factors that showed associations individually ( p  < 0.1) in analyses adjusted only for gender and age, the highest odds ratio (OR) was for past history of LBP (2.8, 95% [confidence interval {CI}]: 1.6–4.9), followed by working ≥60 h per week (1.8, 95% CI: 1.0–3.5) and lifting weights ≥25 kg by hand (1.6, 95% CI: 0.9–3.0). When past history of LBP was excluded from the model, ORs for the remaining risk factors were virtually unchanged. Conclusions Our findings suggest that among Japanese workers, as elsewhere, past history of LBP is a major risk factor for the development of new episodes of disabling back pain. They give limited support to the association with occupational lifting that has been observed in earlier research, both in Japan and in Western countries. In addition, they suggest a possible role of long working hours, which merits further investigation.

Background Rupture of an atherosclerotic plaque and subsequent exposure of the subendothelial prothrombotic matrix to blood cause arterial thrombosis. Circulating platelets play an indispensable role in the growth of arterial thrombi partially owing to their unique ability to adhere to the subendothelial matrix and to aggregate to each other under flow conditions. Recently, the Total Thrombus-formation Analysis System (T-TAS) was developed for ex vivo analysis of the thrombogenic potential of whole blood samples under flow conditions. Despite the potential clinical utility of the T-TAS in assessing the risk for thrombosis and bleeding, reference intervals for T-TAS analysis in healthy individuals have not been determined. Methods In total, 122 whole blood samples were collected from healthy volunteers ranging in age from 25 to 45 years. T-TAS analysis and hematological, physiological, and lifestyle assessments were conducted in these subjects. Whole blood samples anticoagulated with hirudin were perfused into a collagen-coated microchip (PL chip). The time to 10 kPa and the area under the flow pressure curve up to 10 min (AUC 10 ) were analyzed as representative variables for thrombogenic potential. Reference intervals, which were defined as 2.5–97.5 percentiles, were determined. Additionally, univariate and multivariate analyses were performed to identify factors associated with the AUC 10 in the T-TAS. Results The time to 10 kPa and the AUC 10 widely varied, even in healthy volunteers. The reference intervals were 1.50–4.02 min and 223.4–456.8, respectively, at a shear rate of 1500 s − 1 . Univariate and multivariate analyses showed that platelet counts were most significantly associated with the AUC 10 of the T-TAS. The presence of one or more cardiovascular risk factors of a high body mass index, a high pulse pressure, high fasting serum glucose levels, high low-density lipoprotein-cholesterol levels, a history of smoking, and no habitual exercise, had the second largest effect on the AUC 10 of the T-TAS. Conclusions Healthy volunteers who had any cardiovascular risk factors showed augmented thrombogenicity, even in artificial uniform capillaries, compared with those without any risk factors in the T-TAS.

ABSTRACT Long‐duration spaceflight is associated with an increased risk of urolithiasis, and the pain caused by urinary calculi could result in loss of human performance and mission objectives. The present study investigated the risk of urolithiasis in astronauts during 6 months on the International Space Station, and evaluated whether the suppression of bone resorption by the bisphosphonate, alendronate (ALN), can reduce the risk. A total of 17 astronauts were included into the analysis: exercise using the advanced resistive exercise device (ARED) plus weekly oral 70 mg alendronate (ARED+ALN group, n = 7) was compared to resistive exercise alone (ARED group, n = 10). Urine volume decreased in both groups during spaceflight but recovered after return. The ARED group showed increased urinary calcium excretion from the 15th to 30th day of spaceflight, whereas urinary calcium was slightly decreased in the ARED+ALN group. Urinary N‐terminal telopeptide (NTX) and helical peptide (HP) of type I collagen, as bone resorption markers, were elevated in the ARED group during and until 0 days after spaceflight, while there was no elevation in these parameters in the ARED+ALN group. Urinary oxalate and uric acid excretion tended to be higher in the ARED group than in the ARED+ALN group during spaceflight. These results demonstrate that astronauts on long‐duration spaceflights may be at high risk for the formation of urinary calcium oxalate and calcium phosphate stones through increased urinary excretion of oxalate and uric acid, from degraded type I collagen, as well as of calcium from enhanced bone resorption. Our findings suggest that increased bone resorption during spaceflight, as a risk factor for urinary calculus formation, could be effectively prevented by an inhibitor of bone resorption. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background To understand the extent to which a large-scale healthcare claims database (DB) captures the safety profile of eribulin mesylate (Halaven ® , Eisai Co., Ltd., Japan), we compared patient characteristics, drug use, and adverse events (AEs) between data for patients treated with eribulin retrieved from a DB and data for metastatic breast cancer patients from a conventional prospective post-marketing surveillance (PMS). Methods We descriptively summarized patient characteristics and AEs of 551 and 951 patients retrieved from DB and PMS, respectively, during 2011‒2013. Using 2814 patient data from the DB during 2011‒2016, the drug use and AE incidence over time were assessed. Results In both datasets, 99.8% were females, and the mean age was 57.8 ± 10.7 years. The mean number of eribulin administration was 11.1 ± 10.9 and 10.1 ± 7.8 in DB and PMS, respectively. Although, overall, the difference in AE incidence between the two datasets was moderate, gaps were larger for nausea (DB: 73.32% vs. PMS: 15.77%), neutropenia (20.87% vs. 66.67%), stomatitis (37.39% vs. 10.94%), and alopecia (0.36% vs. 12.09%). During 2011‒2016, the observed incidence of anemia or pyrexia significantly decreased (trend test, p  = 0.0009 for both). Conclusion Generally, patient characteristics, drug use, and AE incidence between the DB and PMS were comparable; however, AEs such as neutropenia may require defining based on the laboratory data to achieve more comparable results in DBs. Besides the usefulness of healthcare claims DBs for long-term assessments, they may also serve as a good complementary to PMS in the pharmacovigilance of eribulin.

The emergence of trastuzumab has drastically changed therapy for breast cancer. Trastuzumab (Herceptin; Genentech) is a recombinant humanized monoclonal antibody that targets an epitope in the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. HER2 is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival, and differentiation via multiple signal transduction pathways. Overexpression of HER2 or amplification of the HER2 gene occurs in 20%-30% of human breast cancers. Preclinical models have demonstrated that this antibody has significant antitumor activity as a single agent, and it also has a synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancers that overexpress HER2 have shown trastuzumab to have clinical activity when used as monotherapy, while also improving survival when used as a first-line therapy in combination with chemotherapy. At present, clinical investigations are focusing attention on the efficacy of trastuzumab in both the adjuvant and neoadjuvant setting, as well as in the metastatic setting. In this review, we describe the developments and current status of trastuzumab-based treatment for breast cancer.

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.