Comparative pathogenicity of influenza virus-induced pneumonia mouse model following intranasal and aerosolized intratracheal inoculation.

BACKGROUND: Infection of mice with mouse-adapted strains of influenza virus has been widely used to establish mouse pneumonia models. Intranasal inoculation is the traditional route for constructing an influenza virus-induced pneumonia mouse model, while intratracheal inoculation has been gradually applied in recent years. In this article, the pathogenicity of influenza virus-induced pneumonia mouse models following intranasal and aerosolized intratracheal inoculation were compared. METHODS: By comparing the two ways of influenza inoculation, intranasal and intratracheal, a variety of indices such as survival rate, body weight change, viral titer and load, pathological change, lung wet/dry ratio, and inflammatory factors were investigated. Meanwhile, the transcriptome was applied for the initial exploration of the mechanism underlying the variations in the results between the two inoculation methods. RESULTS: The findings suggest that aerosolized intratracheal infection leads to more severe lung injury and higher viral loads in the lungs compared to intranasal infection, which may be influenced by the initial site of infection, sialic acid receptor distribution, and host innate immunity. CONCLUSION: Intratracheal inoculation is a better method for modelling severe pneumonia in mice than intranasal infection.

Adipose Tissue-Resident Sphingomonas Paucimobilis Suppresses Adaptive Thermogenesis by Reducing 15-HETE Production and Inhibiting AMPK Pathway.

Obesity represents a low-grade chronic inflammation status, which is associated with compromised adaptive thermogenesis. However, the mechanisms underlying the defective activation of thermogenesis in chronic inflammation remain unclear. Here, a chronic inflammatory model is first estabolished by injecting mice with low-dose lipopolysaccharide (LPS) before cold exposure, and then it is verified that LPS treatment can decrease the core body temperature of mice and alter the microbial distribution in epididymal white adipose tissue (eWAT). An adipose tissue-resident bacterium Sphingomonas paucimobilis is identified as a potential inhibitor on the activation of brown fat and browning of inguinal WAT, resulting in defective adaptive thermogenesis. Mechanically, LPS and S. paucimobilis inhibit the production and release of 15-HETE by suppressing its main metabolic enzyme 12 lipoxygenase (12-LOX) and 15- Hydroxyeicosatetraenoic acid (15-HETE) rescues the impaired thermogenesis. Interestingly, 15-HETE directly binds to AMP-activated protein kinase α (AMPKα) and elevates the phosphorylation of AMPK, leading to the activation of uncoupling protein 1 (UCP1) and mitochondrial oxidative phosphorylation (OXPHOS) complexes. Further analysis with human obesity subjects reveals that individuals with high body mass index displayed lower 15-HETE levels. Taken together, this work improves the understanding of how chronic inflammation impairs adaptive thermogenesis and provides novel targets for alleviating obesity.

Racial Disparities in Palliative Care at End-of-Life in Children with Advanced Heart Disease in the South.

OBJECTIVE: To examine specialty pediatric palliative care (SPPC) and end-of-life care for children with advanced heart disease in Alabama, including rates of and disparities in SPPC involvement. STUDY DESIGN: We performed a retrospective study from electronic health records of children (≤21 years at death) who died with advanced heart disease at a single institution between 2012 and 2019 (n = 128). The main outcome was SPPC consult; we assessed clinical and sociodemographic factors associated with SPPC. RESULTS: The median age at death was 6 months (IQR = 1-25 months) with 80 (63%) ≤1 year; 46% were Black and 45% non-Hispanic White. Seventy (55%) children had critical congenital heart disease, 45 (35%) non-critical congenital heart disease, and 13 (10%) acquired heart disease. Twenty-nine children (22%) received SPPC. Children ≤1 year at time of death and Black children were less likely to receive SPPC (aOR [95% CI]: 0.2 [0.1-0.6], reference >1 year; 0.2 [0.1-0.7], reference non-Hispanic White). SPPC was associated with death while receiving comfort-focused care (30.6 [4.5-210]), do not resuscitate orders (8.2 [2.1-31.3]), and hospice enrollment (no children without SPPC care were enrolled in hospice) but not medically intense end-of-life care (intensive care unit admission, mechanical ventilation, hemodialysis, or cardiopulmonary resuscitation) or death outside the intensive care unit. CONCLUSIONS: Children dying with advanced heart disease in Alabama did not have routine SPPC involvement; infants and Black children had lower odds of SPPC. SPPC was associated with more comfort-focused care. Disparities in SPPC utilization for children with advanced heart disease need further examination.

Lipid-lowering effects of gefarnate in statin-treated patients with residual hypertriglyceridemia: a randomized controlled study.

BACKGROUND: The prevention of coronary artery disease (CAD) faces dual challenges: the aspirin-induced gastrointestinal injury, and the residual cardiovascular risk after statin treatment. Geraniol acetate (Gefarnate) is an anti-ulcer drug. It was reported that geraniol might participate in lipid metabolism through a variety of pathways. The aim of this study was to assess the lipid-lowering effects of gefarnate in statin-treated CAD patients with residual hypertriglyceridemia. METHODS: In this prospective, open-label, randomized, controlled trial, 69 statin-treated CAD patients with residual hypertriglyceridemia were randomly assigned to gefarnate group and control group, received gefarnate (100 mg/3 times a day) combined with statin and statin alone, respectively. At baseline and after one-month treatment, the levels of plasma triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol were tested. RESULTS: After one-month gefarnate treatment, triglyceride level was significantly lowered from 2.64 mmol/L to 2.12 mmol/L (P = 0.0018), LDL-C level lowered from 2.7 mmol/L to 2.37 mmol/L (P = 0.0004), HDL-C level increased from 0.97 mmol/L to 1.17 mmol/L (P = 0.0228). Based on statin therapy, gefarnate could significantly reduce the plasma triglyceride level (P = 0.0148) and increase the plasma HDL-C level (P = 0.0307). Although the LDL-C and total cholesterol levels tended to decrease, there was no statistically significant difference. CONCLUSIONS: The addition of gefarnate to statin reduced triglyceride level and increased HDL-C level to a significant extent compared to statin alone in CAD patients with residual hypertriglyceridemia. This suggested that gefarnate might provide the dual benefits of preventing gastrointestinal injury and lipid lowering in CAD patients.

Thyroid hormone receptor-beta agonist HSK31679 alleviates MASLD by modulating gut microbial sphingolipids.

BACKGROUND & AIMS: As the first approved medication for metabolic dysfunction-associated steatohepatitis (MASH), the thyroid hormone receptor-ß (THR-ß) agonist MGL-3196 (resmetirom) has garnered much attention as a liver-directed, bioactive oral drug. However, studies on MGL-3196 have also identified remarkable heterogeneity of individual clinical efficacy and its interference with gut microbiota in host hepatoenteral circulation remains to be elucidated. METHODS: We compared MASH attenuation by MGL-3196 and its derivative drug HSK31679 between germ-free (GF) and specific-pathogen free (SPF) mice to evaluate the role of gut microbiota. Then cross-omics analyses of microbial metagenome, metabolome and single-cell RNA-sequencing were applied to a randomized, double-blind, placebo-controlled multiple ascending dose cohort receiving HSK31679 treatment (n = 32) or placebo (n = 8), to comprehensively investigate the altered gut microbiota metabolism and circulating immune signatures. RESULTS: HSK31679 outperformed MGL-3196 in ameliorating MASH diet-induced steatohepatitis of SPF mice but not GF mice. In the multiple ascending dose cohort of HSK31679, the relative abundance of B. thetaiotaomicron was significantly enriched, impairing glucosylceramide synthase (GCS)-catalyzed monoglucosylation of microbial Cer(d18:1/16:0) and Cer(d18:1/24:1). In contrast to the non-inferior effect of MGL-3196 and HSK31679 on MASH resolution in GFBTΔGCS mice, HSK31679 led to superior benefit on steatohepatitis in GFBTWT mice, due to its steric hindrance of R123 and Y401 of gut microbial GCS. For participants with high fecal GCS activity, the administration of 160 mg HSK31679 induced a shift in peripheral compartments towards an immunosuppressive niche, characterized by decreased CD8α+ dendritic cells and MINCLE+ macrophages. CONCLUSIONS: This study provided novel insights into the gut microbiota that are key to the efficacy of HSK31679 treatment, revealing microbial GCS as a potential predictive biomarker in MASH, as well as a new target for further microbiota-based treatment strategies for MASH. IMPACT AND IMPLICATIONS: Remarkable heterogeneity in individual clinical efficacy of thyroid hormone receptor-ß agonists and their interferences with the microbiome in host hepatoenteral circulation are poorly understood. In our current germ-free mouse models and a randomized, double-blind, multiple-dose cohort study, we identified microbial glucosylceramide synthase as a key mechanistic node in the resolution of metabolic dysfunction-associated steatohepatitis. Microbial glucosylceramide synthase activity could be a predictive biomarker of response to HSK31679 treatment or a new target for microbiota-based therapeutics in metabolic dysfunction-associated steatohepatitis.

Association between frailty and overall survival among older adults with hepatocellular carcinoma.

INTRODUCTION: Older adults undergoing cancer treatment often experience more treatment-related toxicities and increased risk of mortality compared to younger patients. The role of frailty among older individuals as a predictor of outcomes has gained growing significance. We evaluated the association between frailty and overall survival (OS) in patients with hepatocellular carcinoma (HCC) ≥60 years. MATERIALS AND METHODS: Older adults ≥60 years with HCC enrolled in a prospective single-institution registry underwent a patient-reported geriatric assessment (GA) covering multiple health domains related to prior to their initial medical oncology appointment. Frailty was measured using a 44-item deficit accumulation frailty index. We categorized patients as robust, pre-frail, and frail using standard cutpoints. The primary outcome was overall survival (OS). Univariable and multivariable models were built to evaluate the association between frailty and OS after adjusting for potential confounders. RESULTS: Total of 116 older adults with HCC with a median age of 67 years were enrolled; 82% male, 27% Black, and 78% with stage III/IV disease. Overall, 19 (16.3%) were robust, 39 (33.6%) pre-frail, and 58 (50.1%) frail. There were 76 patients receiving liver directed therapy. Of these, 13 (17%) were robust, 26 (34%) were pre-frail, and 37 (49%) were frail. Over a median follow up of 0.9 years, 53 patients died. After adjusting for age, stage, etiology, and Child-Pugh class, being frail (vs. robust) was associated with worse OS (hazard ratio (HR) 2.6 [95% CI 1.03-6.56]; p = 0.04). DISCUSSION: Half of the participants in this study were frail, which was independently associated with worse survival in adults ≥60 years of age with HCC. Identification of pre-treatment frailty may allow opportunities to guide treatment decisions and prognostication.

COVID-19 Disease in Children With ALL Receiving Maintenance Therapy: Do Not Discount the Risk.

PURPOSE: Unlike most childhood cancers, therapy for ALL includes a prolonged maintenance phase during which children typically resume regular activities. Physicians need data regarding the persistent impact of COVID-19 in this population to help guide families after the pandemic. METHODS: The Pediatric Oncology COVID-19 Case Report (POCC) collects deidentified data (sociodemographics, clinical data [cancer, COVID-19 course]) on children, adolescents, and young adults with cancer and COVID-19 from 104 US pediatric oncology institutions. The analysis presented here compares children (≤21 years) with ALL in maintenance (ALL-MTN) with all other children with cancer and COVID-19. Multivariable analyses adjust for age, race/ethnicity, insurance, absolute neutrophil count at the time of infection, vaccination, and comorbidities. RESULTS: Compared with other children reported to POCC (n = 1,190), those in ALL-MTN (n = 481) were less often hospitalized (23% v 29%, P = .01) or admitted to the intensive care unit (ICU: 3% v 5%, P = .01); these findings persisted in multivariable analysis (hospitalization: odds ratio [OR], 0.7 [95% CI, 0.6 to 0.9]; ICU: OR, 0.5 [95% CI, 0.2 to 0.8]). However, cancer-directed therapy was changed more often for children in ALL-MTN (50% v 33%, P ≤ .01; OR, 2.0 [95% CI, 1.6 to 2.5[). Vaccination was an independent prognostic factor in our multivariable model, decreasing odds of hospitalization (OR, 0.7 [95% CI, 0.5 to 0.9]). CONCLUSION: Children in ALL-MTN required fewer hospitalizations and ICU admissions but more therapy modifications than other children with cancer. Vaccination against COVID-19 reduced the odds of hospitalization.

Characteristics of childhood cancer survivors attending a specialized survivorship clinic in the Deep South.

PURPOSE: Childhood cancer survivors carry a high burden of late-occurring treatment-related morbidity. Long-term risk-based anticipatory surveillance allows for early detection and management of complications. We sought to examine demographic, clinical, and social characteristics associated with survivorship clinic attendance at the Taking on Life after Cancer (TLC) Clinic at the Children's Hospital of Alabama. METHODS: The cohort included 1122 TLC-eligible patients diagnosed with cancer between 2000 and 2016. The outcome of interest was ≥1 TLC visit. Univariable logistic regression modeling assessed cancer type, treatment era, age, sex, race/ethnicity, payer type, rural/urban residency, and distance from clinic. Significant variables (P<0.1) were retained in multivariable modeling. RESULTS: The median age at diagnosis was 7 years old (0-19); 47% were female, 69% non-Hispanic White, 25% African American; 45% leukemia or lymphoma, 53% solid or CNS tumor, 3% other. We found that among 1122 survivors eligible to attend a survivorship clinic in the Deep South, only 52% attended. Odds of attendance were lower among survivors diagnosed at an older age, those with cancers other than leukemia/lymphoma, those lacking private insurance, and those living farther from the clinic. Race/ethnicity and rurality were not associated with clinic attendance. CONCLUSION: Just over half of eligible survivors attended survivorship clinic. Factors associated with non-attendance can be used to guide development of intervention strategies to ensure that childhood cancer survivors receive optimal long-term follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: Measures of healthcare access (insurance status and distance to care) were identified as potential intervention targets to improve uptake of survivorship care.

Characterization of Siderophore Produced by Bacillus velezensis YL2021 and Its Application in Controlling Rice Sheath Blight and Rice Blast.

Bacillus velezensis YL2021 has extensive antimicrobial activities against phytopathogens, and its genome harbors a catechol-type siderophore biosynthesis gene cluster. Here, we describe the characterization of siderophore produced by strain YL2021 and its antimicrobial activity in vitro and in vivo. A few types of siderophores were detected by chrome azurol S plates coupled with Arnow's test, purified and identified by Reversed-phase high-performance liquid chromatography (RP-HPLC). We found that strain YL2021 can produce different antimicrobial compounds under low-iron M9 medium or iron-sufficient LB medium although antimicrobial activities can be easily observed on the two media as described above in vitro. Strain YL2021 can produce at least three catechol-type siderophores in low-iron M9 medium while no siderophore was produced in LB medium. Among them, the main antimicrobial siderophore produced by strain YL2021 was bacillibactin, with m/z of 882, based on the liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, which has broad-spectrum antimicrobial activities against Gram-positive, Gram-negative bacteria, the oomycete Phytophthora capsici and phytopathogenic fungi. Moreover, the antifungal activity of siderophore including bacillibactin observed in vitro was correlated with control efficacies against rice sheath blight disease caused by Rhizoctonia solani and rice blast disease caused by Magnaporthe oryzae in vivo. Collectively, the results demonstrate that siderophore including bacillibactin produced by Bacillus velezensis YL2021 is a promising biocontrol agent for application in rice disease control.

Correlation between postoperative chemotherapy regimen and survival in patients with resectable gastric adenocarcinoma accompanied with vascular cancer thrombus.

BACKGROUND: Patients with resectable gastric adenocarcinoma accompanied by vascular cancer thrombus (RGAVCT) have a poor prognosis, with a 5-year survival rate ranging from 18.42%-53.57%. These patients need a reasonable postoperative treatment plan to improve their prognosis. AIM: To determine the most effective postoperative chemotherapy regimen for patients with RGAVCT. METHODS: We retrospectively collected the clinicopathological data of 530 patients who underwent radical resection for gastric cancer between January 2017 and January 2022 and who were pathologically diagnosed with gastric adenocarcinoma with a choroidal cancer embolus. Furthermore, we identified the high-risk variables that can influence the prognosis of patients with RGAVCT by assessing the clinical and pathological features of the patients who met the inclusion criteria. We also assessed the significance of survival outcomes using Mantel-Cox univariate and multivariate analyses. The subgroups of patients with stages I, II, and III disease who received single-, dual-, or triple-drug regimens following surgery were analyzed using SPSS 25.0 and the ggplot2 package in R 4.3.0. RESULTS: In all, 530 eligible individuals with RGAVCT were enrolled in this study. The median overall survival (OS) of patients with RGAVCT was 24 months, and the survival rates were 80.2%, 62.5%, and 42.3% at 12, 24, and 59 months, respectively. Preoperative complications, tumor size, T stage, and postoperative chemotherapy were identified as independent factors that influenced OS in patients with RGAVCT according to the Cox multivariate analysis model. A Kaplan-Meier analysis revealed that chemotherapy had no effect on OS of patients with stage I or II RGAVCT; however, chemotherapy did have an effect on OS of stage III patients. Stage III patients who were treated with chemotherapy consisting of dual- or triple-agent regimens had better survival than those treated with single-agent regimens, and no significant difference was observed in the survival of patients treated with chemotherapy consisting of dual- or triple-agent regimens. CONCLUSION: For patients with stage III RGAVCT, a dual-agent regimen of postoperative chemotherapy should be recommended rather than a triple-agent treatment, as the latter is associated with increased frequency of adverse events.

Intrinsic capacity and survival among older adults with gastrointestinal malignancies: The Cancer and Aging Resilience Evaluation registry.

BACKGROUND: Intrinsic capacity (IC) was introduced by the World Health Organization (WHO) as a marker of healthy aging, and is defined as the combination of an individual's physical, mental, and psychological capacities. This study aimed to assess IC via a patient-reported geriatric assessment (GA) and evaluate its association with survival among older adults with gastrointestinal (GI) malignancies. METHODS: Data were used from a single-institution prospective registry of older adults undergoing GA before cancer therapy. Key domains of IC (vitality, locomotion, and sensory [hearing and visual], psychological, and cognitive capacities) were captured via GA, and each was given a score of 0 or 1 (0, impaired) to compute the total IC score (range, 0-6, where 6 indicates no impairment and ≤5 indicates impairment in ≥1 domains). A frailty index (FI) was measured via the deficit accumulation method. Cox regression models and Kaplan-Meier curves were used to examine the impact of IC impairment on survival. RESULTS: The study included 665 patients; the median age was 68 years, 57.4% were men, and 72.9% were White. The median IC score was 4, and 79.3% of participants showed impairment in ≥1 domains of IC. Most commonly impaired domains were locomotion (48.7%) and vitality (43.9%). IC was inversely associated with FI (Spearman coefficient, -0.75; p < .001). IC impairment was associated with inferior overall survival (score, 4-5: adjusted hazard ratio [aHR], 1.7; 95% CI, 1.11-2.48; score, 2-3: aHR, 1.9; 95% CI, 1.30-2.85; score, 0-1: aHR, 1.9; 95% CI, 1.11-2.48). CONCLUSIONS: IC impairment is associated with frailty and reduced overall survival in older patients with GI malignancies. GA can be used to screen for IC impairment as recommended by the WHO. PLAIN LANGUAGE SUMMARY: The World Health Organization introduced intrinsic capacity as a marker of healthy aging. Intrinsic capacity is the combination of an individual's physical, mental, and psychological capacities. It contains six key domains: vitality, locomotion, and sensory (hearing and visual), psychological, and cognitive capacities. Older adults with cancer are susceptible to a decrease in intrinsic capacity as a result of cancer and the aging process. In this study, we aimed to assess the intrinsic capacity for patients with gastrointestinal cancer and also identify whether there exists any association of intrinsic capacity with overall survival. We identified that approximately 80% of this population had one or more impaired domains, and more intrinsic capacity impairment was associated with reduced overall survival.

Cardiac Dysfunction Among Breast Cancer Survivors: Role of Cardiotoxic Therapy and Cardiovascular Risk Factors.

PURPOSE: Cardiac dysfunction is the leading cause of mortality among 10-year breast cancer survivors. Limited information regarding long-term risks of cardiac dysfunction after cardiotoxic therapy (anthracyclines, trastuzumab/pertuzumab, radiation) has precluded development of surveillance guidelines for the survivors. METHODS: Patients with breast cancer who completed cardiotoxic therapy underwent echocardiographic screening every 2 years. New-onset cardiac dysfunction was defined as left ventricular ejection fraction (LVEF) <50% after cardiotoxic therapy initiation and included early- and late-onset cardiac dysfunction. RESULTS: We evaluated 2,808 echocardiograms in 829 breast cancer survivors; the median age at breast cancer diagnosis was 54.2 years (range, 20.3-86.3); the median follow-up was 8.6 years (1.8-39.8); 39.7% received anthracyclines, 16% received trastuzumab/pertuzumab, 6.2% received both anthracyclines and trastuzumab/pertuzumab, and 38.1% received radiation alone. The cumulative incidence of cardiac dysfunction increased from 1.8% at 2 years to 15.3% at 15 years from cardiotoxic therapy initiation. Multivariable Cox regression analysis identified the following risk factors: non-Hispanic Black race (hazard ratio [HR], 2.15 [95% CI], 1.37 to 3.38), cardiotoxic therapies (anthracyclines: HR, 2.35 [95% CI, 1.25 to 4.4]; anthracyclines and trastuzumab/pertuzumab: HR, 3.92 [95% CI, 1.74 to 8.85]; reference: left breast radiation alone), selective estrogen receptor modulators (HR, 2.0 [95% CI, 1.2 to 3.33]), and precancer hypertension (HR, 3.16 [95% CI, 1.63 to 6.1]). Late-onset cardiac dysfunction was most prevalent among anthracycline- and radiation-exposed patients; early-onset cardiac dysfunction was most prevalent among patients exposed to anthracyclines and trastuzumab/pertuzumab; equal prevalence of both early- and late-onset cardiac dysfunction was observed in trastuzumab-/pertuzumab-exposed patients. Adjusted longitudinal analyses revealed an annual decline in LVEF by 0.29% (P = .009) over 20 years from breast cancer diagnosis. CONCLUSION: These findings provide evidence to support echocardiographic surveillance for several years after cardiotoxic therapy and also suggest a need to examine the efficacy of management of cardiovascular risk factors to mitigate risk.

Ketogenic diet-induced bile acids protect against obesity through reduced calorie absorption.

The low-carbohydrate ketogenic diet (KD) has long been practiced for weight loss, but the underlying mechanisms remain elusive. Gut microbiota and metabolites have been suggested to mediate the metabolic changes caused by KD consumption, although the particular gut microbes or metabolites involved are unclear. Here, we show that KD consumption enhances serum levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA) in mice to decrease body weight and fasting glucose levels. Mechanistically, KD feeding decreases the abundance of a bile salt hydrolase (BSH)-coding gut bacterium, Lactobacillus murinus ASF361. The reduction of L. murinus ASF361 or inhibition of BSH activity increases the circulating levels of TDCA and TUDCA, thereby reducing energy absorption by inhibiting intestinal carbonic anhydrase 1 expression, which leads to weight loss. TDCA and TUDCA treatments have been found to protect against obesity and its complications in multiple mouse models. Additionally, the associations among the abovementioned bile acids, microbial BSH and metabolic traits were consistently observed both in an observational study of healthy human participants (n = 416) and in a low-carbohydrate KD interventional study of participants who were either overweight or with obesity (n = 25). In summary, we uncover a unique host-gut microbiota metabolic interaction mechanism for KD consumption to decrease body weight and fasting glucose levels. Our findings support TDCA and TUDCA as two promising drug candidates for obesity and its complications in addition to a KD.

COVID-19 infection in children, adolescents, and young adults with Down syndrome and hematologic malignancies.

INTRODUCTION: Children, adolescents, and young adults (CAYAs) with Down syndrome (DS) and hematologic malignancies are particularly vulnerable to infections and related complications. There are limited data regarding COVID-19 infections in this group. We aimed to understand the clinical course of COVID-19 in this population. METHODS: This observational study leverages the de-identified clinical and sociodemographic data captured by the Pediatric Oncology COVID-19 Case Report Registry (POCC) regarding CAYAs with cancer and COVID-19. We evaluated CAYAs (≤21 years at COVID-19 infection) with hematologic malignancies and COVID-19 reported from April 1, 2020 to May 2, 2023, comparing those with and without DS. Using multivariable logistic regression, we examined rates of hospitalization, intensive care unit (ICU) admission, respiratory support, and changes in cancer-directed therapy. RESULTS: Among 1408 CAYAs with hematologic malignancies, 55 had DS (CAYA-DS). CAYA-DS had higher rates of hospitalization, ICU admission, and respiratory support (p < .001) than CAYAs without DS. Similarly, multivariable analyses found higher odds of hospitalization (odds ratio [OR] = 2.8, 95% confidence interval [CI]: 1.5-5.1), ICU admission (OR = 4.2, 95% CI: 1.9-9.1), and need for respiratory support (OR = 4.2, 95% CI: 2.0-8.8) among CAYA-DS. Modifications to cancer-directed therapy were more common among CAYA-DS when related to neutropenia (p = .001), but not when unrelated to neutropenia (p = .88); CAYA-DS did not have higher odds of changes to cancer-directed therapy (OR = 1.20, 95% CI: 0.7-2.1). CONCLUSIONS: We identify CAYA-DS with hematologic malignancies as a vulnerable subpopulation at greater risk for severe COVID-19 infection. This can inform conversations with patients and families regarding therapeutic and preventive measures, as well as the risks and benefits of modifying chemotherapy in the setting of COVID-19.

Reversible Snapping of Constrained Anisotropic Hydrogels Upon Light Stimulations.

Creatures, such as Venus flytrap and hummingbirds, capable of rapid predation through snap-through transition, provide paradigms for the design of soft actuators and robots with fast actions. However, these artificial "snappers" usually need contact stimulations to trigger the flipping. Reported here is a constrained anisotropic poly(N-isopropylacrylamide) hydrogel showing fast snapping upon light stimulation. This hydrogel is prepared by flow-induced orientation of nanosheets (NSs) within a rectangular tube. The precursor containing gold nanoparticles is immediately exposed to UV light for photopolymerization to fix the ordered structure of NSs. Two ends of the slender gel are clamped to form a buckle with bistability nature, which snaps to the other side upon laser irradiation. Systematic experiments are conducted to investigate the influences of power intensity and irradiation angle of the laser, as well as thickness and buckle height of the gel, on the snapping behaviors. The fast snapping is further used to kick a plastic bead and control the switch state. Furthermore, synergetic or oscillated snapping of the gel with two buckles of opposite directions is realized by inclined irradiation of a laser or horizontal irradiation with two lasers, respectively. Such light-steered snapping of hydrogels should merit designing soft robots, energy harvests, etc.

Current understanding of the role of DDX21 in orchestrating gene expression in health and diseases.

RNA helicases are involved in almost all biological events, and the DDXs family is one of the largest subfamilies of RNA helicases. Recently, studies have reported that RNA helicase DDX21 is involved in several biological events, specifically in orchestrating gene expression. Hence, in this review, we provide a comprehensive overview of the function of DDX21 in health and diseases. In the genome, DDX21 contributes to genome stability by promoting DNA damage repair and resolving R-loops. It also facilitates transcriptional regulation by directly binding to promoter regions, interacting with transcription factors, and enhancing transcription through non-coding RNA. Moreover, DDX21 is involved in various RNA metabolism such as RNA processing, translation, and decay. Interestingly, the activity and function of DDX21 are regulated by post-translational modifications, which affect the localization and degradation of DDX21. Except for its role of RNA helicase, DDX21 also acts as a non-enzymatic function in unwinding RNA, regulating transcriptional modifications and promoting transcription. Next, we discuss the potential application of DDX21 as a clinical predictor for diseases, which may facilitate providing novel pharmacological targets for molecular therapy.

Biomarkers of bleeding and venous thromboembolism in patients with acute leukemia.

BACKGROUND: Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. OBJECTIVES: To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients. METHODS: We examined plasma levels of activators, inhibitors, and biomarkers of the coagulation and fibrinolytic pathways in patients aged ≥18 years with newly diagnosed acute leukemia compared with those of normal controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and DVT in acute leukemia patients. The study included 358 patients with acute leukemia (29 with acute promyelocytic leukemia [APL], 253 with non-APL acute myeloid leukemia, and 76 with acute lymphoblastic leukemia) and 30 normal controls. RESULTS: Patients with acute leukemia had higher levels of extracellular vesicle tissue factor (EVTF) activity, phosphatidylserine-positive extracellular vesicles, plasminogen activator inhibitor-1, plasmin-antiplasmin complexes, and cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared with normal controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among acute leukemia patients. There were 41 bleeding and 23 DVT events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (subdistribution hazard ratio, 2.30; 95% CI, 0.99-5.31), whereas high levels of plasminogen activator inhibitor-1 were associated with increased risk of DVT (subdistribution hazard ratio, 3.00; 95% CI, 0.95-9.47) in these patients. CONCLUSION: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and DVT.

Intervertebral disc injury triggers neurogenic inflammation of adjacent healthy discs.

BACKGROUND CONTEXT: Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multisegmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? PURPOSE: This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. STUDY DESIGN: This was an experimental study. METHODS: Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8-9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1ß, and IL-6 mRNA levels in the injured (Co8-9) and adjacent discs (Co7-8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7-8 and Co8-9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7-8 and Co8-9 intervertebral discs showed roughly the same trend as mRNA levels. CONCLUSIONS: Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. CLINICAL SIGNIFICANCE: This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain.

Adolescents and young adults with cancer: the clinical course of COVID-19 infections.

Adolescents and young adults (ie, individuals aged 15-39 years, known as AYAs) with cancer face unique vulnerabilities yet remain underrepresented in clinical trials, including adult registries of COVID-19 in cancer (AYAs: 8%-12%). We used the Pediatric Oncology COVID-19 Case Report to examine the clinical course of COVID-19 among AYAs with cancer. The Pediatric Oncology COVID-19 Case Report collects deidentified clinical and sociodemographic data regarding individuals aged from birth to 39 years with cancer (37%) and COVID-19 from more than 100 institutions. Between April 1, 2020, and November 28, 2023, 191 older AYAs (individuals 22-39 years of age) and 640 younger AYAs (individuals 15-21 years of age) were captured. Older AYAs were less often hospitalized (P < .001), admitted to the intensive care unit (P = .02), and required respiratory support (P = .057). In multivariable analyses, older AYAs faced 80% lower odds of intensive care unit admission but 2.3-times greater odds of changes to cancer-directed therapy. Unvaccinated patients had 5.4-times higher odds of intensive care unit admission. Among AYAs with cancer, the COVID-19 course varies by age. These findings can inform oncology teams directing COVID-19 management and prevention in AYA patients with cancer.