Confidence intervals of prediction accuracy measures for multivariable prediction models based on the bootstrap-based optimism correction methods

In assessing prediction accuracy of multivariable prediction models, optimism corrections are essential for preventing biased results. However, in most published papers of clinical prediction models, the point estimates of the prediction accuracy measures are corrected by adequate bootstrap-based correction methods, but their confidence intervals are not corrected, e.g., the DeLong's confidence interval is usually used for assessing the C-statistic. These naive methods do not adjust for the optimism bias and do not account for statistical variability in the estimation of parameters in the prediction models. Therefore, their coverage probabilities of the true value of the prediction accuracy measure can be seriously below the nominal level (e.g., 95%). In this article, we provide two generic bootstrap methods, namely (1) location-shifted bootstrap confidence intervals and (2) two-stage bootstrap confidence intervals, that can be generally applied to the bootstrap-based optimism correction methods, i.e., the Harrell's bias correction, 0.632, and 0.632+ methods. In addition, they can be widely applied to various methods for prediction model development involving modern shrinkage methods such as the ridge and lasso regressions. Through numerical evaluations by simulations, the proposed confidence intervals showed favourable coverage performances. Besides, the current standard practices based on the optimism-uncorrected methods showed serious undercoverage properties. To avoid erroneous results, the optimism-uncorrected confidence intervals should not be used in practice, and the adjusted methods are recommended instead. We also developed the R package predboot for implementing these methods (https://github.com/nomahi/predboot). The effectiveness of the proposed methods are illustrated via applications to the GUSTO-I clinical trial

L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy

Lenvatinib is an oral tyrosine kinase inhibitor that acts on multiple receptors involved in angiogenesis. Lenvatinib is a standard agent for the treatment of several types of advanced cancers; however, it frequently causes muscle-related adverse reactions. Our previous study revealed that lenvatinib treatment reduced carnitine content and the expression of carnitine-related and oxidative phosphorylation (OXPHOS) proteins in the skeletal muscle of rats. Therefore, this study aimed to evaluate the effects of L-carnitine on myotoxic and anti-angiogenic actions of lenvatinib. Co-administration of L-carnitine in rats treated with lenvatinib for 2 weeks completely prevented the decrease in carnitine content and expression levels of carnitine-related and OXPHOS proteins, including carnitine/organic cation transporter 2, in the skeletal muscle. Moreover, L-carnitine counteracted lenvatinib-induced protein synthesis inhibition, mitochondrial dysfunction, and cell toxicity in C2C12 myocytes. In contrast, L-carnitine had no influence on either lenvatinib-induced inhibition of vascular endothelial growth factor receptor 2 phosphorylation in human umbilical vein endothelial cells or angiogenesis in endothelial tube formation and mouse aortic ring assays. These results suggest that L-carnitine supplementation could prevent lenvatinib-induced muscle toxicity without diminishing its antineoplastic activity, although further clinical studies are needed to validate these findings

Partial arch replacement of type A aortic dissection after thoracic endovascular aortic repair for type B dissection

Abstract Background Stent graft-induced new entry (SINE), defined as the stent graft-induced formation of a new entry point for blood to enter an area, is increasingly being observed after thoracic endovascular aortic repair (TEVAR) for Stanford type B aortic dissection worldwide. We herein describe a case of Stanford type A aortic dissection due to proximal SINE after TEVAR for Stanford type B dissection. Case presentation This case involved a 58-year-old man with type A aortic dissection due to SINE. Six years previously, he had developed severe back pain and was diagnosed with type B aortic dissection after computed tomography examination. Because the primary entry was positioned at the descending aorta, we conducted TEVAR for exclusion of the entry with a GORE TAG conformable thoracic aortic graft. He was thereafter followed by our hospital. Six years later, he developed jaw pain and was examined at another hospital. He was transferred to our hospital because of the possibility of type A dissection. Computed tomography revealed type A aortic dissection with proximal site SINE. Emergency partial arch replacement was conducted, and he was discharged on postoperative day 27. Because the entry was at the lesser curve of the arch, we excluded the entry and conducted partial arch replacement. Conclusions In this case, proximal SINE occurred 6 years after TEVAR. Because SINE may occur even in the long term after TEVAR, careful follow-up is necessary

A case of multiple median sternotomy for infection and expanding hematoma in 10 years

Abstract Background After a median sternotomy, mediastinitis may develop, necessitating reopening of the chest. Rarely, reoperation due to hematoma after cardiovascular surgery is experienced. In the present case, we experienced a patient who initially had mediastinitis, but later developed a chronic hematoma and underwent multiple surgeries. Case presentation The patient was a 40-year-old man who underwent aortic valve replacement for a bicuspid aortic valve and a graft for a dilated ascending aorta. Postoperatively, he developed hematoma in the anterior mediastinum on multiple occasions with repeated episodes of infection that required multiple median sternotomies. Conclusions We reported our experience with a rare case of multiple median sternotomies. In the early stage, mediastinitis due to infection was observed, and in the late stage, mediastinal dilatation due to hemorrhage was observed

Morphological Changes in Blood Cells in a Rat Model of Heatstroke: A Pilot Study

Despite the increasing threat of heatstroke with global warming, pathophysiologic injury continues to be defined. In addition, morphological changes of the peripheral blood cells in heatstroke have not been well characterized. We evaluated pathophysiologic changes in bone marrow and blood cells in a rat heatstroke model using a 39.5 °C climate chamber. After three hours of incubation, blood and bone marrow samples were collected for morphology, and the direct effects of heat on leukocytes in vitro were evaluated using time-lapse observation. The blood cell count and peripheral/bone marrow smear were examined either in a lethal model (core body temperature exceeded 42.5 °C) or in a sublethal model (<41.5 °C). Significant decreases in platelet and white blood counts occurred in the lethal model (>35% and >20% decreases, respectively) and changes were less in the sublethal model. Platelet clumping with the appearance of large platelets was observed. The neutrophils often demonstrated hyper-segmented nuclei, and lymphocytes showed reactive or blast-like changes. Further, the direct effect of heat on leukocytes noted apoptotic cell death at 41.5 °C, but subsequent necrosis at 43 °C. In summary, our rodent model showed that heatstroke causes platelet aggregation, leukocyte injury, and aponecrotic cell death. Such changes were milder and reversible in sublethal heatstroke. The appearance of immature cells may result from damage to the bone marrow microenvironment. These findings may provide useful information for potential diagnostic and therapeutic considerations