Bias amplification in the g-computation algorithm for time-varying treatments: a case study of industry payments and prescription of opioid products

BACKGROUND: It is often challenging to determine which variables need to be included in the g-computation algorithm under the time-varying setting. Conditioning on instrumental variables (IVs) is known to introduce greater bias when there is unmeasured confounding in the point-treatment settings, and this is also true for near-IVs which are weakly associated with the outcome not through the treatment. However, it is unknown whether adjusting for (near-)IVs amplifies bias in the g-computation algorithm estimators for time-varying treatments compared to the estimators ignoring such variables. We thus aimed to compare the magnitude of bias by adjusting for (near-)IVs across their different relationships with treatments in the time-varying settings. METHODS: After showing a case study of the association between the receipt of industry payments and physicians' opioid prescribing rate in the US, we demonstrated Monte Carlo simulation to investigate the extent to which the bias due to unmeasured confounders is amplified by adjusting for (near-)IV across several g-computation algorithms. RESULTS: In our simulation study, adjusting for a perfect IV of time-varying treatments in the g-computation algorithm increased bias due to unmeasured confounding, particularly when the IV had a strong relationship with the treatment. We also found the increase in bias even adjusting for near-IV when such variable had a very weak association with unmeasured confounders between the treatment and the outcome compared to its association with the time-varying treatments. Instead, this bias amplifying feature was not observed (i.e., bias due to unmeasured confounders decreased) by adjusting for near-IV when it had a stronger association with the unmeasured confounders (≥0.1 correlation coefficient in our multivariate normal setting). CONCLUSION: It would be recommended to avoid adjusting for perfect IV in the g-computation algorithm to obtain a less biased estimate of the time-varying treatment effect. On the other hand, it may be recommended to include near-IV in the algorithm unless their association with unmeasured confounders is very weak. These findings would help researchers to consider the magnitude of bias when adjusting for (near-)IVs and select variables in the g-computation algorithm for the time-varying setting when they are aware of the presence of unmeasured confounding

MRI of Early-Stage Lumbar Spondylolysis

Purpose : To analyze extraosseous signal changes (ESCs) on magnetic resonance imaging (MRI) in pediatric patients with stress fractures occurring in the lamina. Methods : This study was a retrospective review of 69 consecutive pediatric patients with stress fractures occurring in the lamina. We analyzed MRI scans obtained at the first presentation. Results : We used mainly axial short tau inversion recovery images acquired through the pedicle of these 84 fracture sites to identify the ESCs. These were then divided into three groups: “invisible” when no ESC was detected, “periosteal” for ESC seen on only the dorsal side of the lamina, and “perimuscular” for ESC distinctly spread around / in the paravertebral muscles. In total, 78 (92.9%) fracture sites showed ESCs on the dorsal side of the lamina among which 72 ESCs were located on only the “dorsal” side, while 6 ESCs were on the ventral side against the transverse process. Conclusion : ESCs on MRI were detected in more than 90% of patients before stress fracture became apparent in the lamina, which was considered similar to findings of periosteal thickening / edema detected at the onset of stress fracture in long bone

Design of engineered active zymogen of microbial transglutaminase

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Cores and pH-dependent Dynamics of Ferredoxin-NADP+ Reductase Revealed by Hydrogen/Deuterium Exchange

This research was originally published in the Journal of Biological Chemistry. Young-Ho Lee, Kosuke Tamura, Masahiro Maeda, Masaru Hoshino, Kazumasa Sakurai, Satoshi Takahashi, Takahisa Ikegami, Toshiharu Hase, and Yuji Goto. Cores and pH-dependent Dynamics of Ferredoxin-NADP+ Reductase Revealed by Hydrogen/Deuterium Exchange. J. Biol. Chem. 2007; 282, 5959-5967. © the American Society for Biochemistry and Molecular Biolog

Ganglion cyst arising from the infrapatellar fat pad in a child

A ganglion cyst is a cystic lesion containing myxoid matrix and lined by a pseudomembrane. A ganglion cyst arising from the infrapatellar fat pad is very rare, with only a few reports appearing in the literature, and the present case is the first report of this lesion in a child. A 10-year-old boy presented with right knee pain that showed no improvement despite resting from sports activity for 1 month. Magnetic resonance imaging revealed a multilobular mass between the infrapatellar fat pad and anterior cruciate ligament. Arthroscopic excision of the mass was performed. The mass was noted to arise from the infrapatellar fat pad and was filled with myxoid matrix. The histological diagnosis was a ganglion cyst. In active pediatric patients with pain or limited range of motion in the knee, physicians should consider the possibility of a ganglion cyst from the infrapatellar fat pad, despite its rarity

無歯顎患者における概形印象の精度に関する3次元評価 : 研究用模型と作業用模型の3次元形状の比較

Purpose: The aim of this study was to compare 3-dimensional surfaces of study and working casts for edentulous jaws and to evaluate the accuracy of preliminary impressions with a view to the future application of digital dentistry for edentulous jaws. Methods: Forty edentulous volunteers were serially recruited. Nine dentists took preliminary and final impressions in a routine clinical work-up. The study and working casts were digitized using a dental 3-dimensional scanner. The two surface images were superimposed through a least-square algorithm using imaging software and compared qualitatively. Furthermore, the surface of each jaw was divided into 6 sections, and the difference between the 2 images was quantitatively evaluated. Results: Overall inspection showed that the difference around residual ridges was small and that around borders were large. The mean differences in the upper and lower jaws were 0.26 mm and 0.45 mm, respectively. The maximum values of the differences showed that the upward change mainly occurred in the anterior residual ridge, and the downward change mainly in the posterior border seal, and the labial and buccal vestibules, whereas every border of final impression was shortened in the lower jaw. The accuracy in all areas except the border, which forms the foundation, was estimated to be less than 0.25 mm. Conclusion: Using digital technology, we here showed the overall and sectional accuracy of the preliminary impression for edentulous jaws. In our clinic, preliminary impressions have been made using an alginate material while ensuring that the requisite impression area was covered

Suppression of osteoclastogenesis via α2-adrenergic receptors

The sympathetic nervous system is known to regulate osteoclast development. However, the involvement of α2-adrenergic receptors (α2-ARs) in osteoclastogenesis is not well understood. In the present study, their potential role in osteoclastogenesis was investigated. Guanabenz, clonidine and xylazine were used as agonists of α2-ARs, while yohimbine and idazoxan were employed as antagonists. Using RAW264.7 pre-osteoclast and primary bone marrow cells, the mRNA expression of the osteoclast-related genes nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP) and cathepsin K was evaluated following induction with receptor activator of nuclear factor κB ligand (RANKL). TRAP staining was also conducted to assess effects on osteoclastogenesis in mouse bone marrow cells in vitro. Administration of 5-20 µM guanabenz (P<0.01, for RANKL-only treatment), 20 µM clonidine (P<0.05, for RANKL-only treatment) and 20 µM xylazine (P<0.05, for RANKL-only treatment) attenuated RANKL-induced upregulation of NFATc1, TRAP and cathepsin K mRNA. Furthermore, the reductions in these mRNAs by 10 µM guanabenz and 20 µM clonidine in the presence of RANKL were attenuated by 20 µM yohimbine or idazoxan (P<0.05). The administration of 5-20 µM guanabenz (P<0.01, for RANKL-only treatment) and 10-20 µM clonidine (P<0.05, for RANKL-only treatment) also decreased the number of TRAP-positive multi-nucleated osteoclasts. Collectively, the present study demonstrates that α2-ARs may be involved in the regulation of osteoclastogenesis

Orthosis stability and patient satisfaction

Purpose : To evaluate the stabilizing effects of a Fit Cure-Spine® semi-rigid thoracolumbar orthosis and wearer satisfaction after lumbar surgery. Methods : In study 1, the spinal angle, spinal motion angle, and distribution of load were measured in 8 adult male volunteers when the orthosis was worn (1) with no custom-made stay (CMS), (2) with a CMS in the prone position (P-CMS), and (3) with a CMS in the prone position and decreased lordosis (DP-CMS). In study 2, pain scale scores and responses to a questionnaire were recorded in 40 consecutive patients who underwent lumbar spinal surgery in our hospital. Results : In study 1, the mean lumbar lordosis when standing was similar to that in the prone position. When the trunk was bent forward, loads on the back support in P-CMS and DP-CMS were concentrated at the center of the CMS, unlike those for No-CMS. In study 2, there was a significant decrease in postoperative wound pain after wearing the Fit Cure-Spine orthosis for 2 weeks. Most patients who wore the orthosis were satisfied with their pain outcome. Conclusion : Adjustment to lumbar lordosis and the prone position was restricted in volunteers wearing the Fit Cure-Spine with a CMS

CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses

A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment