Addressing Methodologic Challenges and Minimizing Threats to Validity in Synthesizing Findings from Individual-Level Data Across Longitudinal Randomized Trials

Integrative Data Analysis (IDA) encompasses a collection of methods for data synthesis that pools participant-level data across multiple studies. Compared with single-study analyses, IDA provides larger sample sizes, better representation of participant characteristics, and often increased statistical power. Many of the methods currently available for IDA have focused on examining developmental changes using longitudinal observational studies employing different measures across time and study. However, IDA can also be useful in synthesizing across multiple randomized clinical trials to improve our understanding of the comprehensive effectiveness of interventions, as well as mediators and moderators of those effects. The pooling of data from randomized clinical trials presents a number of methodological challenges, and we discuss ways to examine potential threats to internal and external validity. Using as an illustration a synthesis of 19 randomized clinical trials on the prevention of adolescent depression, we articulate IDA methods that can be used to minimize threats to internal validity, including (1) heterogeneity in the outcome measures across trials, (2) heterogeneity in the follow-up assessments across trials, (3) heterogeneity in the sample characteristics across trials, (4) heterogeneity in the comparison conditions across trials, and (5) heterogeneity in the impact trajectories. We also demonstrate a technique for minimizing threats to external validity in synthesis analysis that may result from non-availability of some trial datasets. The proposed methods rely heavily on latent variable modeling extensions of the latent growth curve model, as well as missing data procedures. The goal is to provide strategies for researchers considering IDA.

     

Usefulness of Intraoperative Continuous Infusion of Tranexamic Acid during Emergency Surgery for Type A Acute Aortic Dissection

Purpose: We investigated the influence of intraoperative continuous tranexamic acid (TA) infusion on the amount of blood transfusion required in emergency surgery for type A acute aortic dissection.Methods: The study was based on the data of 55 consecutive patients who underwent surgery for type A acute aortic dissection. The patients were divided into 2 groups for comparison: Group T, consisting of 26 patients who received intraoperative continuous infusion of TA, and Group N, consisting of 29 patients who did not receive TA infusion during the surgery.Results: The mean amounts of blood transfusion required during and after surgery were compared between the 2 groups: they were 10.5 ± 8.7 and 16.2 ± 10.0 units of mannitol-adenine-phosphate-added red cell concentrate, 9.3 ± 8.6 and 17.1 ± 10.0 units of fresh frozen plasma, and 20.4 ± 12.2 and 29.7 ± 14.9 units of platelet concentrate, respectively, in Groups T and N. Thus, the amount of each of these blood products required was significantly reduced in Group T.Conclusions: During emergency surgery for type A acute aortic dissection, continuous infusion of TA resulted in a significant reduction in the amount of blood transfusion required.     

Selective Estrogen Receptor Modulation by Larrea nitida on MCF-7 Cell Proliferation and Immature Rat Uterus

Larrea nitida is a plant that belongs to the Zygophyllaceae family and is widely used in South America to treat inflammatory diseases, tumors and menstrual pain. However, its pharmacological activity remains unclear. In this study we evaluated the property of selective estrogen receptor modulator (SERM) of Larrea nitida extracts (LNE) as a phytoestrogen that can mimic, modulate or disrupt the actions of endogenous estrogens, depending on the tissue and relative amount of other SERMs. To investigate the property of SERM of LNE, we performed MCF-7 cell proliferation assays, estrogen response element (ERE)-luciferase reporter gene assay, human estrogen receptor (hER) binding assays and in vivo uterotrophic assay. To gain insight into the active principles, we performed a bioassay-guided analysis of LNE employing solvents of various polarities and using classical column chromatography, which yielded 16 fractions (LNs). LNE showed high binding affinities for hERα and hERβ with IC₅₀ values of 1.20 ×10⁻⁷ g/ml and 1.00×10⁻⁷ g/ml, respectively. LNE induced 17β-estradiol (E2)-induced MCF-7 cell proliferation, however, it reduced the proliferation in the presence of E2. Furthermore, LNE had an atrophic effect in the uterus of immature rats through reducing the expression level of progesterone receptor (PR) proteins. LN08 and LN10 had more potent affinities for binding on hER α and β than other fractions. Our results indicate that LNE had higher binding affinities for hERβ than hERα, and showed SERM properties in MCF-7 breast cancer cells and the rat uterus. LNE may be useful for the treatment of estrogen-related conditions, such as female cancers and menopause.     

Senp2 expression was induced by chronic glucose stimulation in INS1 cells,and it was required for the associated induction of Ccnd1 and Mafa

Post-translational modification by bonding of small ubiquitin-like modifier (SUMO) peptides influences various cellular functions, and is regulated by SUMO-specific proteases (SENPs). Several proteins have been suggested to have diverse impact on insulin synthesis and secretion through SUMO modification in β cells. However, the role of SUMO modification in β cell mass has not been established. Here, we examined the changes in expression of Senp in INS1 cells and pancreatic islets under diabetes-relevant stress conditions and associated changes in β cell mass. Treatment with 25 mM glucose for 72 h induced Senp2 mRNA expression but not that of Senp1 in INS1 cells. Immunohistochemical staining with anti-SENP2 antibody on human pancreas sections revealed that SENP2 was localized in the nucleus. Moreover, in a patient with type 2 diabetes, SENP2 levels were enhanced, especially in the cytoplasm. Senp2 cytoplasmic levels were also increased in islet cells in obese diabetic mice. Cell number peaked earlier in INS1 cells cultured in high-glucose conditions compared to those cultured in control media. This finding was associated with increased Ccnd1 mRNA expression in high-glucose conditions, and siRNA-mediated Senp2 suppression abrogated it. Mafa expression, unlike Pdx1, was also dependent on Senp2 expression during high-glucose conditions. In conclusion, Senp2 may play a role in β cell mass in response to chronic high-glucose through Cyclin D1 and Mafa.