Bunnjessen7227

RESULTS Postoperative hypothermia decreased by 48%, from a baseline of 20.3% (January 2011 to September 2013) to 10.5% by June 2015. Strategies associated with decreased hypothermia include >90% compliance with patient euthermia (36.1-37.9°C) at times of OR arrival (odds ratio 0.58; 95% confidence interval [CI] 0.43-0.79; P 74°F (odds ratio 0.78; 95% CI 0.62-0.999; P = .05). Hyperthermia increased from a baseline of 1.1% to 2.2% during the project. No thermal burns were reported. CONCLUSIONS Reducing postoperative hypothermia is possible. Key practices include prewarming the OR and compliance with strategies to maintain euthermia at select time points throughout the perioperative period. Copyright © 2020 by the American Academy of Pediatrics.OBJECTIVE To determine the frequency and relative importance of symptoms experienced by adults with Huntington disease (HD) and to identify factors associated with a higher disease burden. METHODS We performed 40 qualitative interviews (n = 20 with HD, n = 20 caregivers) and analyzed 2,082 quotes regarding the symptomatic burden of HD. We subsequently performed a cross-sectional study with 389 participants (n = 156 with HD [60 of whom were prodromal], n = 233 caregivers) to assess the prevalence and relative importance (scale 0-4) of 216 symptoms and 15 symptomatic themes in HD. Cross-correlation analysis was performed based on sex, disease duration, age, number of CAG repeats, disease burden, Total Functional Capacity score, employment status, disease status, and ambulatory status. RESULTS The symptomatic themes with the highest prevalence in HD were emotional issues (83.0%), fatigue (82.5%), and difficulty thinking (77.0%). The symptomatic themes with the highest relative importance to participants were difficulty thinking (1.91), impaired sleep or daytime sleepiness (1.90), and emotional issues (1.81). High Total Functional Capacity scores, being employed, and having prodromal HD were associated with a lower prevalence of symptomatic themes. Despite reporting no clinical features of the disease, prodromal individuals demonstrated high rates of emotional issues (71.2%) and fatigue (69.5%). There was concordance between the prevalence of symptoms reported by manifest individuals and caregivers. CONCLUSIONS Many symptomatic themes affect the lives of those with HD. These themes have a variable level of importance to the HD population and are identified both by those with HD and by their caregivers. © 2020 American Academy of Neurology.Understanding how to promote organ and appendage regeneration is a key goal of regenerative medicine. The frog, Xenopus, can achieve both scar-free healing and tissue regeneration during its larval stages, although it predominantly loses these abilities during metamorphosis and adulthood. This transient regenerative capacity, alongside their close evolutionary relationship with humans, makes Xenopus an attractive model to uncover the mechanisms underlying functional regeneration. Here, we present an overview of Xenopus as a key model organism for regeneration research and highlight how studies of Xenopus have led to new insights into the mechanisms governing regeneration. © 2020. Published by The Company of Biologists Ltd.Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues, but is up-regulated in a diverse set of hematologic and solid malignancies. Thus, ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning, and again co-crystallized with hROR2-Kr. We show that the affinity matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T-cell engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily O-glycosylated single transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs (HUVECs), we found that treatment with tumor necrosis factor-α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN (EMCN-CTF) 3-4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase (MMP) inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA, significantly reduced basal and TNF-α-induced cell-surface EMCN cleavage. The release of EMCN-CTF by the TNF-α treatment was blocked by chemical inhibition of either ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte-EC interactions during inflammation, we propose that EMCN represents a potential therapeutic target to manage vascular inflammation. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Cell polarity is a fundamental feature of all multicellular organisms. In plants, prominent cell polarity markers are PIN auxin transporters crucial for plant development. To identify novel components involved in cell polarity establishment and maintenance, we carried out a forward genetic screening with PIN2PIN1-HA;pin2 Arabidopsis plants, which ectopically express predominantly basally localized PIN1 in the root epidermal cells leading to agravitropic root growth. From the screen, we identified the regulator of PIN polarity 12 (repp12) mutation, which restored gravitropic root growth and caused PIN1-HA polarity switch from basal to apical side of root epidermal cells. Complementation experiments established the repp12 causative mutation as an amino acid substitution in Aminophospholipid ATPase3 (ALA3), a phospholipid flippase with predicted function in vesicle formation. ala3 T-DNA mutants show defects in many auxin-regulated processes, in asymmetric auxin distribution and in PIN trafficking. Analysis of quintuple and sextuple mutants confirmed a crucial role of ALA proteins in regulating plant development and in PIN trafficking and polarity. Genetic and physical interaction studies revealed that ALA3 functions together with GNOM and BIG3 ARF GEFs. Taken together, our results identified ALA3 flippase as an important interactor and regulator of ARF GEF functioning in PIN polarity, trafficking and auxin-mediated development. © 2020 American Society of Plant Biologists. All rights reserved.INTRODUCTION Forty per cent of people with diabetes who heal from a foot ulcer recur within 1 year. The aim was to develop a prediction model for plantar foot ulcer recurrence and to validate its predictive performance. RESEARCH DESIGN AND METHODS Data were retrieved from a prospective analysis of 171 high-risk patients with 18 months follow-up. Demographic, disease-related, biomechanical and behavioral factors were included as potential predictors. Two logistic regression models were created. Model 1 for all recurrent plantar foot ulcers (71 cases) and model 2 for those ulcers indicated to be the result of unrecognized repetitive stress (41 cases). Ten-fold cross-validation, each including five multiple imputation sets, was used to internally validate the prediction strategy; model performance was assessed in terms of discrimination and calibration. RESULTS The presence of a minor lesion, living alone, increased barefoot peak plantar pressure, longer duration of having a previous foot ulcer and less variation in daily stride count were predictors of the first model. The area under the receiver operating curve was 0.68 (IQR 0.61-0.80) and the Brier score was 0.24 (IQR 0.20-0.28). The predictors of the second model were presence of a minor lesion, longer duration of having a previous foot ulcer and location of the previous foot ulcer. The area under the receiver operating curve was 0.76 (IQR 0.66-0.87) and the Brier score was 0.17 (IQR 0.15-0.18). CONCLUSIONS These validated prediction models help identify those patients that are at increased risk of plantar foot ulcer recurrence and for that reason should be monitored more carefully and treated more intensively. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.OBJECTIVE Familial combined hyperlipidemia (FCHL) is common among survivors of a premature myocardial infarction. FCHL patients are characterized by visceral obesity, fatty liver, and insulin resistance. The aim of the present study was to determine the incidence and determinants of type 2 diabetes (T2D) in a longitudinal cohort of FCHL pedigrees. RESEARCH DESIGN AND METHODS FCHL patients, their unaffected relatives and spouses included in our baseline cohort in 1998-2005 (n=596) were re-invited to determine the incidence of self-reported T2D (that was confirmed by medical records), used as the primary outcome measure. The Fatty Liver Index (FLI) and Homeostasis Model Assessment Insulin Resistance (HOMA2-IR) were used as markers of fatty liver and insulin resistance, respectively. A subset of the original cohort underwent ultrasound of the liver, and subcutaneous and visceral fat in 2002-2005 (n=275; 'ultrasound subcohort'). RESULTS Follow-up data (median 15 years) was acquired for 76%. The incidence rate of ed by BMJ.OBJECTIVE The optimal diet to improve glycemia in patients with type 2 diabetes remains unclear. Low carbohydrate, high fat (LCHF) diets can improve glycemic control, but have not been investigated in real-world settings. RESEARCH DESIGN AND METHODS We investigated effects of the LCHF diet compared with usual care in a community-based cohort of patients with type 2 diabetes by performing a retrospective study of 49 patients who followed the LCHF diet for ≥3 months, and compared glycemic outcomes with age-matched and body mass index (BMI)-matched controls who received usual care (n=75). The primary outcome was change in A1C from baseline to the end of follow-up. RESULTS Compared with the usual care group, the LCHF group showed a significantly greater reduction in A1C (-1.29% (95% CI -1.75 to -0.82; p less then 0.001)) and body weight (-12.8 kg (95% CI -14.7 to -10.8; p less then 0.001) at the end of follow-up after adjusting for age, sex, baseline A1C, BMI, baseline insulin dose. Of the patients initially taking insulin therapy in the LCHF group, 100% discontinued it or had a reduction in dose, compared with 23.