Endotoxemia Correlates with Kidney Function and Length of Stay in Critically Ill Patients.

INTRODUCTION: Endotoxin is a key driver of sepsis, which frequently causes acute kidney injury (AKI). However, endotoxins may also be found in non-bacteremic critically ill patients, likely from intestinal translocation. Preclinical models show that endotoxins can directly injure the kidneys, and in COVID-19 patients, endotoxemia correlated with AKI. We sought to determine correlations between endotoxemia and kidney and hospital outcomes in a broad group of critically ill patients. METHODS: In this single-center, serial prospective study, 124 predominantly Caucasian adult patients were recruited within 48 h of admission to Stony Brook University Hospital Intensive Care Unit (ICU). Demographics, vital signs, laboratory data, and outcomes were collected. Circulating endotoxin was measured on days 1, 4, and 8 using the endotoxin activity assay (EAA). The association of EAA with outcomes was examined with EAA: (1) categorized as <0.6, ≥0.6, and nonresponders (NRs); and (2) used as a continuous variable. RESULTS: Patients with EAA ≥0.6 had a higher prevalence of proteinuria, and lower arterial oxygen saturation (SaO2) to fraction of inspired oxygen (FiO2) (SaO2/FiO2) ratio versus patients with EAA <0.6. EAA levels positively correlated with serum creatinine (sCr) levels on day 1. Patients whose EAA level stayed ≥0.6 had a slower decline in sCr compared to those whose EAA started at ≥0.6 and subsequently declined. Patients with AKI stage 1 and EAA ≥0.6 on day 1 showed slower decline in sCr compared to patients with stage 1 AKI and EAA <0.6. EAA ≥0.6 and NR patients had longer hospital stay and delayed ICU discharge versus EAA <0.6. CONCLUSIONS: High EAA levels correlated with worse kidney function and outcomes. Patients whose EAA levels fell, and those with AKI stage I and day 1 EAA <0.6 recovered more quickly compared to those with EAA ≥0.6, suggesting that removal of circulating endotoxins may be beneficial in critically ill patients.

The association of QTc prolongation with cardiovascular events in cancer patients taking tyrosine kinase inhibitors (TKIs).

OBJECTIVE: To investigate the association between stages of QTc prolongation and the risk of cardiac events among patients on TKIs. METHODS: This was a retrospective cohort study performed at an academic tertiary care center of cancer patients who were taking TKIs or not taking TKIs. Patients with two recorded ECGs between January 1, 2009, and December 31, 2019, were selected from an electronic database. The QTc duration > 450ms was determined as prolonged. The association between QTc prolongation progression and events of cardiovascular disease were compared. RESULTS: This study included a total of 451 patients with 41.2% of patients taking TKIs. During a median follow up period of 3.1 years, 49.5% subjects developed CVD and 5.4% subjects suffered cardiac death in patient using TKIs (n = 186); the corresponding rates are 64.2% and 1.2% for patients not on TKIs (n = 265), respectively. Among patient on TKIs, 4.8% of subjects developed stroke, 20.4% of subjects suffered from heart failure (HF) and 24.2% of subjects had myocardial infarction (MI); corresponding incidence are 6.8%, 26.8% and 30.6% in non-TKIs. When patients were regrouped to TKIs versus non-TKIs with and without diabetes, there was no significant difference in the incidence of cardiac events among all groups. Adjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). There is a significant increased risk of HF events (HR, 95% CI: 2.12, 1.36-3.32) and MI events (HR, 95% CI: 1.78, 1.16-2.73) during the 1st visit. There are also trends for an increased incidence of cardiac adverse events associated with QTc prolongation among patient with QTc > 450ms, however the difference is not statistically significant. Increased cardiac adverse events in patients with QTc prolongation were reproduced during the 2nd visit and the incidence of heart failure was significantly associated with QTc prolongation(HR, 95% CI: 2.94, 1.73-5.0). CONCLUSION: There is a significant increased QTc prolongation in patients taking TKIs. QTc prolongation caused by TKIs is associated with an increased risk of cardiac events.

Delay-aware distributed program caching for IoT-edge networks.

Edge computing is a novel network architecture that is in proximity to the end devices in an Internet of Things (IoT). As the IoT becoming a major factor in our daily life, provisioning a low response time of the services to IoT users through edge computing is an important problem. Caching necessary program data for the task in an edge node effectively reduces the response time of the computation task. However, due to the increase of IoT users and devices, it is noteworthy that limited-resource edge nodes would receive a number of tasks, having a heavy burden of processing the requests. Therefore, the limited resource and caching space at cloudlet need the careful design of the caching algorithm to utilize the space of multiple edge nodes and relieve the burden of computations. In this paper, we propose a cooperative program caching system that makes different edge nodes cooperatively store program data and cache the replicas of the data requested frequently to handle a number of requests from IoT users. In particular, we develop a cooperative caching algorithm that caches the appropriate number of data replicas depending on the number of requests on each cloudlet and the popularity of the data to minimize the response time. The simulation results show that the proposed cooperative caching algorithm can effectively reduce the response time for IoT users compared to other existing algorithms.

IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment.

The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.

The Risk of QTc Prolongation in Non-Diabetic and Diabetic Patients Taking Tyrosine Kinase Inhibitors (TKIs)- A Patient Safety Project at a Private Oncology Practice.

Objective: To assess the prevalence of QTc prolongation in both non-diabetic and diabetic patients on TKIs. Some TKIs have been reported to cause QTc prolongation, which is prevalent in diabetes. However, there is no Risk Evaluation and Mitigation Strategy using series ECG to monitor those patients. Methods: Patients taking TKIs, with two ECGs recorded between 1 January 2010 and 31 December 2017 were selected from the electronic database. The QTc duration >450 ms was determined as prolonged. Percentage of QTc prolongation on participants were compared using Chi-Square test. Results: This study included 313 patients (age 66.1 ± 0.8 years and 57.5% are female) taking TKIs. In non-Diabetic patients, the prevalence of QTc prolongation is 19.1% (n = 253) before and 34.8% (n = 253) after treatment with TKIs (p < 0.001), respectively. In diabetic patients, the prevalence of QTc prolongation is 21.7% (n = 60) before and 40% (n = 60) after treatment with TKIs (p = 0.03), respectively. In addition, we examined the effect of modifying risk factors for cardiovascular disease (CVD) on the prevalence of QTc prolongation caused by TKIs. In non-diabetic patients, the prevalence of QTc prolongation is 33.3% (n = 57) before and 34.2% (n = 196) after risk factors modification (p = 0.91), respectively. In diabetic patients, the prevalence of QTc prolongation is 50% (n = 24) before and 33.3% (n = 36) after risk factors modification (p = 0.20), respectively. Conclusion: Use of TKIs is associated with a significantly increased risk of QTc prolongation for patients, particularly when patients are diabetic. Modification of risk factors for CVD does not significantly affect the prevalence of QTc prolongation caused by TKIs.

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells.

BACKGROUND & AIMS: Self-renewal and multipotent differentiation are cardinal properties of intestinal stem cells (ISCs), mediated in part by WNT and NOTCH signaling. Although these pathways are well characterized, the molecular mechanisms that control the 'stemness' of ISCs are still not well defined. Here, we investigated the role of Krüppel-like factor 5 (KLF5) in regulating ISC functions. METHODS: We performed studies in adult Lgr5EGFP-IRES-creERT2;Rosa26LSLtdTomato (Lgr5Ctrl) and Lgr5EGFP-IRES-creERT2;Klf5fl/fl;Rosa26LSLtdTomato (Lgr5ΔKlf5) mice. Mice were injected with tamoxifen to activate Cre recombinase, which deletes Klf5 from the intestinal epithelium in Lgr5ΔKlf5 but not Lgr5Crtl mice. In experiments involving irradiation, mice were subjected to 12 Gy total body irradiation (TBI). Tissues were collected for immunofluorescence (IF) analysis and next generation sequencing. Oganoids were derived from fluoresecence activated cell sorted- (FACS-) single cells from tamoxifen-treated Lgr5ΔKlf5 or Lgr5Crtl mice and examined by immunofluorescence stain. RESULTS: Lgr5+ ISCs lacking KLF5 proliferate faster than control ISCs but fail to self-renew, resulting in a depleted ISC compartment. Transcriptome analysis revealed that Klf5-null Lgr5+ cells lose ISC identity and prematurely differentiate. Following irradiation injury, which depletes Lgr5+ ISCs, reserve Klf5-null progenitor cells fail to dedifferentiate and regenerate the epithelium. Absence of KLF5 inactivates numerous selected enhancer elements and direct transcriptional targets including canonical WNT- and NOTCH-responsive genes. Analysis of human intestinal tissues showed increased levels of KLF5 in the regenerating epithelium as compared to those of healthy controls. CONCLUSION: We conclude that ISC self-renewal, lineage specification, and precursor dedifferentiation require KLF5, by its ability to regulate epigenetic and transcriptional activities of ISC-specific gene sets. These findings have the potential for modulating ISC functions by targeting KLF5 in the intestinal epithelium.

Correction to: The Role of Intestinal Stem Cells in Epithelial Regeneration Following Radiation-Induced Gut Injury.

[This corrects the article DOI: 10.1007/s40778-017-0103-7.].

SP and KLF Transcription Factors in Digestive Physiology and Diseases.

Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies have shown that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins.

The Role of Intestinal Stem Cells in Epithelial Regeneration Following Radiation-Induced Gut Injury.

PURPOSE OF REVIEW: Intestinal epithelial cells show remarkable plasticity in regenerating the epithelium following radiation injury. In this review, we explore the regenerative capacity and mechanisms of various populations of intestinal stem cells (ISCs) in response to ionizing radiation. RECENT FINDINGS: Ionizing radiation targets mitotic cells that include "active" ISCs and progenitor cells. Lineage-tracing experiments showed that several different cell types identified by a single or combination of markers are capable of regenerating the epithelium, confirming that ISCs exhibit a high degree of plasticity. However, the identities of the contributing cells marked by various markers require further validation. SUMMARY: Following radiation injury, quiescent and/or radioresistant cells become active stem cells to regenerate the epithelium. Looking forward, understanding the mechanisms by which ISCs govern tissue regeneration is crucial to determine therapeutic approaches to promote intestinal epithelial regeneration following injury.

Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice.

In response to ionizing radiation-induced injury, the normally quiescent intestinal stem cells marked by BMI1 participate in the regenerative response. Previously, we established a protective role for Krüppel-like factor 4 (KLF4) in the intestinal epithelium where it reduces senescence, apoptosis, and crypt atrophy following γ-radiation-induced gut injury. We also described a pro-proliferative function for KLF4 during the regenerative phase post irradiation. In the current study, using a mouse model in which Klf4 is deleted from quiescent BMI1(+) intestinal stem cells, we observed increased proliferation from the BMI1(+) lineage during homeostasis. In contrast, following irradiation, Bmi1-specific Klf4 deletion leads to decreased expansion of the BMI1(+) lineage due to a combination of reduced proliferation and increased apoptosis. Our results support a critical role for KLF4 in modulating BMI1(+) intestinal stem cell fate in both homeostasis and the regenerative response to radiation injury.

Effective Use of a Silicone-induced Capsular Flap in Secondary Asian Rhinoplasty.

SUMMARY: Performing secondary rhinoplasty in patients who underwent primary rhinoplasty using a silicone implant is difficult due to thinning of nasal skin and formation of a capsule. Excess capsule formation can cause capsular contracture, resulting in short nose deformity or implant deviation, migration, or implant demarcation. Revision rhinoplasty using a capsular flap, dorsal silicone implant, and tip plasty was performed in 95 Korean patients (91 women and 4 men; mean age, 27 years) who previously underwent primary augmentation rhinoplasty using silicone implants. The capsular flap was composed by creating a dual plane above the anterior capsule and below the posterior capsule. The existing silicone implant was removed, and a new silicone implant was placed under the posterior capsule. The patients were followed up for 6 months to 4 years (mean, 31.7 months). Of the 95 patients who underwent secondary augmentation rhinoplasty using a capsular flap, 88 patients (92.6%) showed satisfactory results. There was no hematoma or nasal skin vascular compromise. There was no visible or palpable capsule resorption or recurrent capsular contracture. Early implant malpositioning (within 30 days postoperatively) was observed in 4 patients, and tip shape dissatisfaction (within 60 days postoperatively) was reported by 3 patients. Four patients underwent revision surgery and had successful outcomes. Nasal augmentation using a silicone implant and capsular flap in secondary rhinoplasty avoids complications caused by removal of the capsule. Recurrent capsule formation or clinically noticeable resorption of the capsular flap was not observed in this study.

Double-eyelid surgery using septoaponeurosis junctional thickening results in dynamic fold in asians.

BACKGROUND: To avoid a static double-eyelid fold characterized by nonmobile overdepression of the fold, we propose a new surgical approach of using septoaponeurosis junctional thickening (SAJT) to create a dynamic fold. METHODS: Six hundred eighty patients underwent double-eyelid surgery using the SAJT fixation technique. The orbital septum was exposed and transversely opened superior to the incision margin. The lower septal stump was trimmed to expose the SAJT. The dermis and orbicularis oculi muscle of the lower flap of the upper eyelid were attached to the SAJT. Patients were followed for 2-8 years (mean, 3.6 y). Anatomic study with 28 upper eyelids from 28 Korean adult cadavers was performed to confirm the histological structure of the SAJT. RESULTS: This technique created a dynamic fold. When the eyes were open, the fold depth was moderate. When the eyes were closed, the fold site was smooth and not depressed. The surgery had a 95% patient satisfaction rate (365 responded as satisfied and 236 responded as very satisfied). Postoperative complications included partial or complete loss of the double-eyelid line in 14 and 4 cases, respectively, hypertrophic scar formation in 7 cases, and asymmetric fold in 8 cases. CONCLUSIONS: The authors introduce a double-eyelid surgery technique using the SAJT. This SAJT fixation technique creates a dynamic double-eyelid fold. Our study showed a high patient satisfaction rate and that the resulting fold mimics the movement of the congenital supratarsal fold in Asians.

The catalytic effect of Pt nanoparticles supported on silicon oxide nanowire.

3.5 nm sized Pt nanocatalysts supported on silicon oxide nanowires (SiO(X)NWs) were fabricated by decorating the SiO(X)NWs with Pt nanoparticles using a simple physical deposition system without any surface pretreatment. High curvature of the nanowire surface together with the weak metal-substrate interaction helped to maintain discrete particle morphology with spherical shapes during deposition. Catalytic efficiency of the SiO(X)NWs coated with Pt nanoparticles was demonstrated through reduction of methylene blue in the presence of sodium borohydride. It was demonstrated that the highly curved nanowire surface allowed the Pt nanoparticles to be loaded with increased particle density, providing a larger surface area for the catalytic reaction. It was also shown that a simple heat treatment in vacuum improves the effectiveness of the Pt nanoparticles as a catalyst without loss of catalytic activity when used repeatedly. We expect that this metal nanoparticle-decorated nanowire can be easily extended to other heterogeneous reactions and can also be used as a template for building three-dimensional hierarchical nanostructures.

Area-selective growth of amorphous carbon nanofibers via catalytic decomposition of polyimide thin film.

A dense layer of amorphous carbon nanofibers was fabricated by pyrolyzing a thin film of polyimide using a monolayer of gold nanoparticles as a catalyst.