Gut Microbiome Is Related to Cognitive Impairment in Peritoneal Dialysis Patients.

Gut microbiota disturbances may influence cognitive function, increasing uremic toxins and inflammation in dialysis patients; therefore, we aimed to evaluate the association of the gut microbiota profile with cognitive impairment (CI) in patients on automated peritoneal dialysis (APD). In a cross-sectional study, cognitive function was evaluated using the Montreal Cognitive Assessment in 39 APD patients and classified as normal cognitive function and CI. The gut microbiota was analyzed using the 16S rRNA gene sequencing approach. All patients had clinical, biochemical and urea clearance evaluations. Eighty-two percent of patients were men, with a mean age of 47 ± 24 years and 11 (7-48) months on PD therapy; 64% had mild CI. Patients with CI were older (53 ± 16 vs. 38 ± 14, p = 0.006) and had a higher frequency of diabetes mellitus (56% vs. 21%, p = 0.04) and constipation (7% vs. 48%, p = 0.04) and lower creatinine concentrations (11.3 ± 3.7 vs. 14.9 ± 5.4, p = 0.02) compared to normal cognitive function patients. Patients with CI showed a preponderance of S24_7, Rikenellaceae, Odoribacteraceae, Odoribacter and Anaerotruncus, while patients without CI had a greater abundance of Dorea, Ruminococcus, Sutterella and Fusobacteria (LDA score (Log10) > 2.5; p < 0.05). After glucose and age adjustment, Odoribacter was still associated with CI. In conclusion, patients with CI had a different gut microbiota characterized by the higher abundance of indole-producing and mucin-fermenting bacteria compared to normal cognitive function patients.

Early Initiation of Sacubitril/Valsartan in Patients With Acute Heart Failure and Renal Dysfunction: An Analysis of the TRANSITION Study.

BACKGROUND: Treatment of patients with heart failure with reduced ejection fraction (HFrEF) and renal dysfunction (RD) is challenging owing to the risk of further deterioration in renal function, especially after acute decompensated HF (ADHF). METHODS AND RESULTS: We assessed the effect of RD (estimated glomerular filtration rate of ≥30 to <60 mL/min/1.73 m2) on initiation, up-titration, and tolerability of sacubitril/valsartan in hemodynamically stabilized patients with HFrEF admitted for ADHF (RD, n = 476; non-RD, n = 483). At week 10, the target dose of sacubitril/valsartan (97/103 mg twice daily) was achieved by 42% patients in RD subgroup vs 54% in non-RD patients (P < .001). Sacubitril/valsartan was associated with greater estimated glomerular filtration rate improvements in RD subgroup than non-RD (change from baseline least squares mean 4.1 mL/min/1.73 m2, 95% confidence interval 2.2-6.1, P < .001). Cardiac biomarkers improved significantly in both subgroups; however, compared with the RD subgroup, the improvement was greater in those without RD (N-terminal pro-brain natriuretic peptide, -28.6% vs -44.8%, high-sensitivity troponin T -20.3% vs -33.9%) (P < .001). Patients in the RD subgroup compared with those without RD experienced higher rates of hyperkalemia (16.3% vs 6.5%, P < .001), investigator-reported cardiac failure (9.7% vs 5.6%, P = .029), and renal impairment (6.4% vs 2.1%, P = .002). CONCLUSIONS: Most patients with HFrEF and concomitant RD hospitalized for ADHF tolerated early initiation of sacubitril/valsartan and showed significant improvements in estimated glomerular filtration rate and cardiac biomarkers. CLINICAL TRIAL REGISTRATION: NCT02661217.

Stage-specific nutritional management and developmental programming to optimize meat production.

Over the past few decades, genetic selection and refined nutritional management have extensively been used to increase the growth rate and lean meat production of livestock. However, the rapid growth rates of modern breeds are often accompanied by a reduction in intramuscular fat deposition and increased occurrences of muscle abnormalities, impairing meat quality and processing functionality. Early stages of animal development set the long-term growth trajectory of offspring. However, due to the seasonal reproductive cycles of ruminant livestock, gestational nutrient deficiencies caused by seasonal variations, frequent droughts, and unfavorable geological locations negatively affect fetal development and their subsequent production efficiency and meat quality. Therefore, enrolling livestock in nutritional intervention strategies during gestation is effective for improving the body composition and meat quality of the offspring at harvest. These crucial early developmental stages include embryonic, fetal, and postnatal stages, which have stage-specific effects on subsequent offspring development, body composition, and meat quality. This review summarizes contemporary research in the embryonic, fetal, and neonatal development, and the impacts of maternal nutrition on the early development and programming effects on the long-term growth performance of livestock. Understanding the developmental and metabolic characteristics of skeletal muscle, adipose, and fibrotic tissues will facilitate the development of stage-specific nutritional management strategies to optimize production efficiency and meat quality.

Predictors of Poor Outcomes in Young Non-Comorbid Patients with COVID-19.

Background: Prognostic factors in previously healthy young patients with COVID-19 remained understudied. Objectives: The objective of the study was to identify factors associated with in-hospital death or need for invasive mechanical ventilation (IMV) in young (aged ≤ 65 years) and previously healthy patients with COVID-19. Methods: We conducted a prospective cohort study that included patients admitted with COVID-19. The primary outcome was in-hospital death/need for IMV. Secondary outcomes included need for IMV during follow-up, days on IMV, length of stay (LOS), hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP), and pulmonary embolism (PE). Bivariate and multivariate analyses were performed. Results: Among 92 patients, primary outcome occurred in 16 (17%), death in 12 (13%), need for IMV in 16 (17%), HAP/VAP in 7 (8%), and PE in 2 (2%). Median LOS and IMV duration were 7 and 12 days, respectively. Independent associations were found between the primary outcome and male sex (Adjusted odds ratio [aOR] 7.1, 95%CI 1.1-46.0, p < 0.05), D-dimer levels > 1000ng/mL (aOR 9.0, 95%CI 1.6-49.1, p < 0.05), and RT-PCR Ct-value ≤ 24 on initial swab samples (aOR 14.3, 95%CI 2.0-101.5, p < 0.01). Conclusions: In young and non-comorbid COVID-19 patients, male sex, higher levels of D-dimer, and low SARS-CoV-2 RT-PCR Ct-value on an initial nasopharyngeal swab were independently associated with increased in-hospital mortality or need for IMV. (Rev Invest Clin. 2022;74(5):268-75).

Predictors of poor outcomes in young non-comorbid patients with COVID-19

ABSTRACT Background: Prognostic factors in previously healthy young patients with COVID-19 remained understudied. Objective: The objective of the study was to identify factors associated with in-hospital death or need for invasive mechanical ventilation (IMV) in young (aged ≤ 65 years) and previously healthy patients with COVID-19. Methods: We conducted a prospective cohort study that included patients admitted with COVID-19. The primary outcome was in-hospital death/need for IMV. Secondary outcomes included need for IMV during follow-up, days on IMV, length of stay (LOS), hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP), and pulmonary embolism (PE). Bivariate and multivariate analyses were performed. Results: Among 92 patients, primary outcome occurred in 16 (17%), death in 12 (13%), need for IMV in 16 (17%), HAP/VAP in 7 (8%), and PE in 2 (2%). Median LOS and IMV duration were 7 and 12 days, respectively. Independent associations were found between the primary outcome and male sex (Adjusted odds ratio [aOR] 7.1, 95%CI 1.1-46.0, p < 0.05), D-dimer levels > 1000ng/mL (aOR 9.0, 95%CI 1.6-49.1, p < 0.05), and RT-PCR Ct-value ≤ 24 on initial swab samples (aOR 14.3, 95%CI 2.0-101.5, p < 0.01). Conclusions: In young and non-comorbid COVID-19 patients, male sex, higher levels of D-dimer, and low SARS-CoV-2 RT-PCR Ct-value on an initial nasopharyngeal swab were independently associated with increased in-hospital mortality or need for IMV.

Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis.

IMPORTANCE: No therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic steatohepatitis (NASH). OBJECTIVE: To investigate the long-term relationship between bariatric surgery and incident major adverse liver outcomes and major adverse cardiovascular events (MACE) in patients with obesity and biopsy-proven fibrotic NASH without cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: In the SPLENDOR (Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk) study, of 25 828 liver biopsies performed at a US health system between 2004 and 2016, 1158 adult patients with obesity were identified who fulfilled enrollment criteria, including confirmed histological diagnosis of NASH and presence of liver fibrosis (histological stages 1-3). Baseline clinical characteristics, histological disease activity, and fibrosis stage of patients who underwent simultaneous liver biopsy at the time of bariatric surgery were balanced with a nonsurgical control group using overlap weighting methods. Follow-up ended in March 2021. EXPOSURES: Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy) vs nonsurgical care. MAIN OUTCOMES AND MEASURES: The primary outcomes were the incidence of major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality) and MACE (a composite of coronary artery events, cerebrovascular events, heart failure, or cardiovascular death), estimated using the Firth penalized method in a multivariable-adjusted Cox regression analysis framework. RESULTS: A total of 1158 patients (740 [63.9%] women; median age, 49.8 years [IQR, 40.9-57.9 years], median body mass index, 44.1 [IQR, 39.4-51.4]), including 650 patients who underwent bariatric surgery and 508 patients in the nonsurgical control group, with a median follow-up of 7 years (IQR, 4-10 years) were analyzed. Distribution of baseline covariates, including histological severity of liver injury, was well-balanced after overlap weighting. At the end of the study period in the unweighted data set, 5 patients in the bariatric surgery group and 40 patients in the nonsurgical control group experienced major adverse liver outcomes, and 39 patients in the bariatric surgery group and 60 patients in the nonsurgical group experienced MACE. Among the patients analyzed with overlap weighting methods, the cumulative incidence of major adverse liver outcomes at 10 years was 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01). The cumulative incidence of MACE at 10 years was 8.5% (95% CI, 5.5%-11.4%) in the bariatric surgery group and 15.7% (95% CI, 11.3%-19.8%) in the nonsurgical group (adjusted absolute risk difference, 13.9% [95% CI, 5.9%-21.9%]; adjusted hazard ratio, 0.30 [95% CI, 0.12-0.72]; P = .007). Within the first year after bariatric surgery, 4 patients (0.6%) died from surgical complications, including gastrointestinal leak (n = 2) and respiratory failure (n = 2). CONCLUSIONS AND RELEVANCE: Among patients with NASH and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and MACE.

Obesity Impairs Embryonic Myogenesis by Enhancing BMP Signaling within the Dermomyotome.

Obesity during pregnancy leads to adverse health outcomes in offspring. However, the initial effects of maternal obesity (MO) on embryonic organogenesis have yet to be thoroughly examined. Using unbiased single-cell transcriptomic analyses (scRNA-seq), the effects of MO on the myogenic process is investigated in embryonic day 9.5 (E9.5) mouse embryos. The results suggest that MO induces systematic hypoxia, which is correlated with enhanced BMP signaling and impairs skeletal muscle differentiation within the dermomyotome (DM). The Notch-signaling effectors, HES1 and HEY1, which also act down-stream of BMP signaling, suppress myogenic differentiation through transcriptionally repressing the important myogenic regulator MEF2C. Moreover, the major hypoxia effector, HIF1A, enhances expression of HES1 and HEY1 and blocks myogenic differentiation in vitro. In summary, this data demonstrate that MO induces hypoxia and impairs myogenic differentiation by up-regulating BMP signaling within the DM, which may account for the disruptions of skeletal muscle development and function in progeny.

Prevalence of mild cognitive impairment in automated peritoneal dialysis patients.

BACKGROUND: Cognitive deterioration decreases quality of life, self-care and adherence to treatment, increasing mortality risk. There is scarce information of cognitive impairment in peritoneal dialysis (PD) and data are controversial. Our aim was to determine the frequency and associated factors of cognitive impairment in patients on automated PD (APD). METHODS: In this cross-sectional study, 71 patients on APD underwent clinical, biochemical and cognitive function evaluation by means of the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Cognitive function was also evaluated in healthy controls. RESULTS: Participants mean age was 42 ± 16 years, 79% were men and dialysis vintage was 17 months ( interquartile range 7-32). In APD patients, cognitive impairment was present in 7% (mild deterioration) and 68% according to the MMSE and MoCA, respectively, and 4 and 37% in the healthy controls. Patients with cognitive impairment (according to MoCA) were older, with less education, had diabetes more frequently and higher serum glucose as well as lower serum creatinine, phosphorus and sodium concentrations than patients with normal cognitive function. In multiple linear regression analysis, predictors for the MoCA score (R2 = 0.63, P = 0.002) were education {B = 0.54 [95% confidence interval (CI) 0.20-0.89]; P = 0.003}, age [B = -0.11 (95% CI -0.21 to -0.01); P = 0.04], serum sodium [B = 0.58 (95% CI 0.05-1.11); P = 0.03] and creatinine concentration [B = 3.9 (95% CI 0.03-0.83); P = 0.03]. CONCLUSIONS: In this sample of APD patients, the prevalence of cognitive impairment by the MoCA was 65% and was associated with older age, lower education level and lower serum concentrations of sodium and creatinine.

Animal development in the secondary classroom: linking basic science to livestock production.

The field of life sciences encompasses a myriad of disciplines that collectively provide insight toward the intrinsic framework of life. Developmental physiology is one of these disciplines that can describe the origins of life at the molecular, cellular, tissue, and organismal level. However, organismal development is a continual process that transcends conception and progresses throughout the lifetime of an organism. In this Illumination, we discuss opportunities that secondary-level life science educators have when teaching developmental physiology through an agricultural lens. Specifically, we propose teaching about the origins of meat and milk, as a nontraditional approach for introducing developmental physiology to students. To justify this notion, we explore how novel research in livestock production focuses on meeting food demands imposed by our growing global population. In addition, we link these concepts to commonly employed standards in secondary-level science classrooms across the United States. In conclusion, the science of livestock production provides a window of opportunity for secondary-level physiology instructors to teach developmental physiology in a form that can readily adhere to institutionally employed standards.

Is peroral endoscopic myotomy (POEM) more effective than pneumatic dilation and Heller myotomy? A systematic review and meta-analysis.

BACKGROUND: Achalasia is a rare, chronic, and morbid condition with evolving treatment. Peroral endoscopic myotomy (POEM) has gained considerable popularity, but its comparative effectiveness is uncertain. We aim to evaluate the literature comparing POEM to Heller myotomy (HM) and pneumatic dilation (PD) for the treatment of achalasia. METHODS: We conducted a systematic review of comparative studies between POEM and HM or PD. A priori outcomes pertained to efficacy, perioperative metrics, and safety. Internal validity of observational studies and randomized trials (RCTs) was judged using the Newcastle Ottawa Scale and the Cochrane Risk of Bias 2.0 tool, respectively. RESULTS: From 1379 unique literature citations, we included 28 studies comparing POEM and HM (n = 21) or PD (n = 8), with only 1 RCT addressing each. Aside from two 4-year observational studies, POEM follow-up averaged ≤ 2 years. While POEM had similar efficacy to HM, POEM treated dysphagia better than PD both in an RCT (treatment "success" RR 1.71, 95% CI 1.34-2.17; 126 patients) and in observational studies (Eckardt score MD - 0.43, 95% CI - 0.71 to - 0.16; 5 studies; I2 21%; 405 patients). POEM needed reintervention less than PD in an RCT (RR 0.19, 95% CI 0.08-0.47; 126 patients) and HM in an observational study (RR 0.33, 95% CI 0.16, 0.68; 98 patients). Though 6-12 months patient-reported reflux was worse than PD in 3 observational studies (RR 2.67, 95% CI 1.02-7.00; I2 0%; 164 patients), post-intervention reflux was inconsistently measured and not statistically different in measures ≥ 1 year. POEM had similar safety outcomes to both HM and PD, including treatment-related serious adverse events. CONCLUSIONS: POEM has similar outcomes to HM and greater efficacy than PD. Reflux remains a critical outcome with unknown long-term clinical significance due to insufficient data and inconsistent reporting.

Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift.

Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models provide insight into the agonist-antagonist boundary of the analogues suggesting that the Arg557 residue in the S4-S5 linker might be important for sensing the agonist binding and transmitting signals. These results provide structural insights into the TRPV1 and the protein-ligand interactions at a molecular level.

Differential Pressure Spirometry for Mechanical Ventilation Using Dichotomic Search.

In invasive mechanical ventilation (IMV), it is critical that the flow value is estimated correctly, as it is used as a trigger variable for ventilatory assistance. Furthermore, the numerical integration of the flow allows the calculation of the total volume per breath (tidal volume), which clinicians use to identify trauma or lung capacity in the patient. The current COVID-19 pandemic has demonstrated the need to develop safe and efficient techniques for measuring this spirometry variable because many mechanical ventilators delivered to hospitals were unable to measure it directly. A good device to estimate flow is a D-lite sensor, which works by the Venturi effect, is cheap, reusable, and proximal to the patient. However, the regressions applied to the flow estimation model are limited for use in real conditions. This article presents a flow estimation method that uses a D-Lite device, a fraction of inspired oxygen (FiO2) cell, and two pressure sensors as critical items. Our novel method adapts the dichotomous search algorithm instead of conventional regression algorithms to estimate flow using a D-lite sensor; this change in the standard procedure allowed us a fast calibration process, a good low-flow estimation, and low computational time for flow estimation. The method was validated experimentally to compute the tidal volume according to the measurement requirement error range of +/-10%. The consideration of FiO2 percentage in the gas mixture and the good low-flow estimation make this novel method useful for real ventilation conditions. The flow calculations have been performed at different ambient conditions and compared with gas analyzers show an average relative error of up to 4.86%. Finally, we present an analysis of the error flow estimation considering the variation in each variable. Technical recommendations for applying this novel method to achieve IMV safely are presented, based on the capabilities of the embedded system used by developers.

Using e-notebooks to explore biochemistry with an agricultural lens.

The interdisciplinary subject of agricultural biochemistry can provide an abundance of didactic opportunities for educators teaching biochemistry and molecular biology in secondary-level science courses. This is especially true in present times when virtual-learning strategies supersede in-person instruction and contemporary approaches are needed to engage students with relevant applications of science. In this communication, we discuss how pairing daily lessons in agricultural biochemistry with periodic e-notebook usage further refines this strategy by promoting content-retrieval and providing educators with formative feedback on student progress in a simple and inexpensive manner.

From blood to milk: Graphical systems modeling in secondary-level biochemistry courses.

Given the present need for biochemistry and molecular biology educators to transform their courses into an online format, novel methods aimed at promoting student learning and engagement must be considered. Herein, we describe the integration of graphical systems modeling as a tool for introducing biochemistry to secondary-level students. We propose the use of graphic technologies as a way for students to create systems models that describe phenomena of life, such as lactation. Through these endeavors, educators can provide a virtual format for students to continue learning and completing assignments.

Impact of sleeve gastrectomy and Roux-en-Y gastric bypass on biopsy-proven non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Our aim was to study the long-term effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on NAFLD/NASH. METHODS: Between 2008 and 2015, 3813 patients had an intraoperative liver biopsy performed at the time of primary RYGB and SG at a single academic center. Utilizing strict inclusion criteria, 487 patients with biopsy-proven NAFLD who had abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values (≥ 40 IU/L) at baseline were identified. Matching of SG to RYGB patients (1:4) was performed via logistic regression and propensity scores adjusting for clinical and liver histological characteristics. Changes in liver function tests (LFTs) at least 1 year after surgery were compared to baseline values and between the surgical groups. RESULTS: A total of 310 (weighted) patients (SG n = 62, and RYGB n = 248) with a median follow-up time of 4 years (range, 1-10) were included in the analysis. The distribution of covariates was well-balanced after propensity matching. In 84% of patients, LFT values normalized after bariatric surgery at the last follow-up time. The proportions of patients having normalized LFT values did not differ significantly between the SG and RYGB groups (82% vs. 84%, p = 0.66). The AST decreased from (SG: 49.1 ± 21.5 vs. RYGB: 49.3 ± 22.0, p = 0.93) at baseline to (SG: 28.0 ± 16.5 vs. RYGB: 26.5 ± 15.5, p = 0.33) at the last follow-up. Similarly, a significant reduction in ALT values from (SG: 61.7 ± 30.0 vs. RYGB 59.4 ± 24.9, p = 0.75) at baseline to (SG: 27.2 ± 21.5 vs. RYGB: 26.1 ± 19.2, p = 0.52) at the last follow-up was observed. CONCLUSIONS: In patients with biopsy-proven NAFLD/NASH, abnormal LFTs are normalized in most SG and RYGB patients by the end of the first postoperative year and remain normal until the last follow-up. This study also suggests that both bariatric procedures are similarly effective in improving liver function.

Discovery of Nonpungent Transient Receptor Potential Vanilloid 1 (TRPV1) Agonist as Strong Topical Analgesic.

Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.

Efficacy and Safety of Edoxaban in Patients With Active Malignancy and Atrial Fibrillation: Analysis of the ENGAGE AF - TIMI 48 Trial.

Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF - TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230-771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78-3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07-2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83-1.42). Relative outcomes with higher-dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism ( HR , 0.60 [95% CI, 0.31-1.15] for malignancy versus HR , 0.89 [95% CI, 0.76-1.05] for no malignancy; interaction P=0.25) and major bleeding ( HR , 0.98 [95% CI, 0.69-1.40] for malignancy versus HR , 0.79 [95% CI, 0.69-1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher-dose edoxaban versus warfarin in patients with malignancy ( HR , 0.54; 95% CI, 0.31-0.93) compared with no malignancy ( HR , 1.02; 95% CI, 0.88-1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template.

A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1. Docking analysis of compound 27 in our hTRPV1 homology model indicated that its binding mode was similar with that of 1S.

Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation.

Transient receptor potential vanilloid type 1 (TRPV1), a heat-sensitive calcium channel protein, contributes to inflammation as well as to acute and persistent pain. Since TRPV1 occupies a central position in pathways of neuronal inflammatory signaling, it represents a highly attractive potential therapeutic target for neuroinflammation. In the present work, we have in silico identified a series of diarylurea analogues for hTRPV1, of which 11 compounds showed activity in the nanomolar to micromolar range as validated by in vitro biological assays. Then, we utilized molecular docking to explore the detailed interactions between TRPV1 and the compounds to understand the contributions of the different substituent groups. Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670 were important for the recognition of the small molecules by TRPV1. A hydrophobic group in R2 or a polar/hydrophilic group in R1 contributed significantly to the activities of the antagonists at TRPV1. In addition, the subtle different binding pose of meta-chloro in place of para-fluoro in the R2 group converted antagonism into partial agonism, as was predicted by our short-term molecular dynamics (MD) simulation and validated by bioassay. Importantly, compound 15, one of our best TRPV1 inhibitors, also showed potential binding affinity (1.39 µM) at cannabinoid receptor 2 (CB2), which is another attractive target for immuno-inflammation diseases. Furthermore, compound 1 and its diarylurea analogues were predicted to target the C-X-C chemokine receptor 2 (CXCR2), although bioassay validation of CXCR2 with these compounds still needs to be performed. This prediction from the modeling is of interest, since CXCR2 is also a potential therapeutic target for chronic inflammatory diseases. Our findings provide novel strategies to develop a small molecule inhibitor to simultaneously target two or more inflammation-related proteins for the treatment of a wide range of inflammatory disorders including neuroinflammation and neurodegenerative diseases with potential synergistic effect.

Morbidity and mortality in severely burned children with Clostridium difficile-associated diarrhea.

BACKGROUND: Clostridium difficile is a key culprit underlying nosocomial infectious diarrhea. We investigated the effect of C difficile-associated diarrhea (CDAD) on morbidity and mortality in severely burned children and CDAD risk factors. METHODS: After review of 2,840 records, 288 pediatric burn patients were identified as having stool output of >10 mL•kg(-1)•min(-1) for ≥2 successive days and had stool samples immunoassayed for toxins A and B. A case control analysis was performed by matching cases to controls via logistic regression and propensity scores so that age, admission time, and time of occurrence could be controlled; the endpoints were mortality and hospitalization time. RESULTS: Eighteen patients tested positive for C difficile toxins (median age, 4 years; mean total body surface area burned, 59%). In the CDAD group, unadjusted in-hospital mortality was 28% (odds ratio, 5.4; 95% CI, 1.7-16.7; P = .01). Hospitalization averaged 48 days in the CDAD group and 38 days in the non-CDAD group (P = .24). Duration of stay per percent total body surface area burned was greater in the CDAD group (0.82 ± 0.4 vs 0.60 ± 0.4; P = .03), as were prolonged bouts of diarrhea complicated by acidosis (13 ± 16 vs 4 ± 5 days; P < .005). Of the 18 possible risk factors evaluated, inhalation injury diagnosed at admission occurred more often in CDAD patients than matched controls (59% vs 31%; P = .04). CONCLUSION: CDAD during hospitalization is associated with greater mortality after burns. Inhalation injury increases the likelihood of C difficile infection. Whether C difficile infection is an indication of greater illness among certain burned patients is unknown.