Comorbid Medical Conditions as Predictors of Overall Survival in Glioblastoma Patients

Glioblastoma (GBM) is an aggressive central nervous system tumor with a poor prognosis. This study was conducted to determine any comorbid medical conditions that are associated with survival in GBM. Data were collected from medical records of all patients who presented to VCU Medical Center with GBM between January 2005 and February 2015. Patients who underwent surgery/biopsy were considered for inclusion. Cox proportional hazards regression modeling was performed to assess the relationship between survival and sex, race, and comorbid medical conditions. 163 patients met inclusion criteria. Comorbidities associated with survival on individual-characteristic analysis included: history of asthma (Hazard Ratio [HR]: 2.63; 95% Confidence Interval [CI]: 1.24–5.58; p = 0.01), hypercholesterolemia (HR: 1.95; 95% CI: 1.09–3.50; p = 0.02), and incontinence (HR: 2.29; 95% CI: 0.95–5.57; p = 0.07). History of asthma (HR: 2.22; 95% CI: 1.02–4.83; p = 0.04) and hypercholesterolemia (HR: 1.99; 95% CI: 1.11–3.56; p = 0.02) were associated with shorter survival on multivariable analysis. Surgical patients with GBM who had a prior history of asthma or hypercholesterolemia had significantly higher relative risk for mortality on individual-characteristic and multivariable analyses

Australian residential aged care home staff experiences of implementing an intervention to improve palliative and end-of-life care for residents: A qualitative study

Access to high-quality and safe evidence-based palliative care (PC) is important to ensure good end-of-life care for older people in residential aged care homes (RACHs). However, many barriers to providing PC in RACHs are frequently cited. The Quality End-of-Life Care (QEoLC) Project was a multicomponent intervention that included training, evidence-based tools and tele-mentoring, aiming to equip healthcare professionals and careworkers in RACHs with knowledge, skills and confidence in providing PC to residents. This study aims to understand: (1) the experiences of healthcare professionals, careworkers, care managers, planners/implementers who participated in the implementation of the QEoLC Project; and (2) the barriers and facilitators to the implementation. Staff from two RACHs in New South Wales, Australia were recruited between September to November 2021. Semi-structured interviews and thematic data analysis were used. Fifteen participants (seven health professionals [includes one nurse, two clinical educators, three workplace trainers, one clinical manager/nurse], three careworkers and five managers) were interviewed. Most RACH participants agreed that the QEoLC Project increased their awareness of PC and provided them with the skills/confidence to openly discuss death and dying. Participants perceived that the components of the QEoLC Project had the following benefits for residents: more appropriate use of medications, initiation of timely pain management and discussions with families regarding end-of-life care preferences. Key facilitators for implementation were the role of champions, the role of the steering committee, regular clinical meetings to discuss at-risk residents and mentoring. Implementation barriers included: high staff turnover, COVID-19 pandemic, time constraints, perceived absence of executive sponsorship, lack of practical support and systems-related barriers. The findings underline the need for strong leadership, supportive organisational culture and commitment to the implementation of processes for improving the quality of end-of-life care. Furthermore, the results highlight the need for codesigning the intervention with RACHs, provision of dedicated staff/resources to support implementation, and integration of project tools with existing systems for achieving effective implementation outcomes

Evolutionary History of a Specialized P450 Propane Monooxygenase

The evolutionary pressures that shaped the specificity and catalytic efficiency of enzymes can only be speculated. While directed evolution experiments show that new functions can be acquired under positive selection with few mutations, the role of negative selection in eliminating undesired activities and achieving high specificity remains unclear. Here we examine intermediates along the ‘lineage’ from a naturally occurring C12–C20 fatty acid hydroxylase (P450BM3) to a laboratory-evolved P450 propane monooxygenase (P450PMO) having 20 heme domain substitutions compared to P450BM3. Biochemical, crystallographic, and computational analyses show that a minimal perturbation of the P450BM3 fold and substrate-binding pocket accompanies a significant broadening of enzyme substrate range and the emergence of propane activity. In contrast, refinement of the enzyme catalytic efficiency for propane oxidation (not, vert, similar 9000-fold increase in kcat/Km) involves profound reshaping and partitioning of the substrate access pathway. Remodeling of the substrate-recognition mechanisms ultimately results in remarkable narrowing of the substrate profile around propane and enables the acquisition of a basal iodomethane dehalogenase activity as yet unknown in natural alkane monooxygenases. A highly destabilizing L188P substitution in a region of the enzyme that undergoes a large conformational change during catalysis plays an important role in adaptation to the gaseous alkane. This work demonstrates that positive selection alone is sufficient to completely respecialize the cytochrome P450 for function on a nonnative substrate

Structure-Function Relationships Affecting the Sensing Mechanism of Monolayer-Protected Cluster Doped Xerogel Amperometric Glucose Biosensors

A systematic study of the structure–function relationships critical to understanding the sensing mechanism of 1st generation amperometric glucose biosensors with an embedded nanoparticle (NP) network is presented. Xerogel-based films featuring embedded glucose oxidase enzyme and doped with alkanethiolate-protected gold NPs, known as monolayer protected clusters (MPCs), exhibit significantly enhanced performance compared to analogous systems without NPs including higher sensitivity, faster response time, and extended linear/dynamic ranges. The proposed mechanism involves diffusion of the glucose to glucose oxidase within the xerogel, enzymatic reaction production of H2O2 with subsequent diffusion to the embedded network of MPCs where it is oxidized, an event immediately reported via fast electron transfer (ET) through the MPC system to the working electrode. Various aspects of the film construct and strategy are systematically probed using amperometry, voltammetry, and solid-state electronic conductivity measurements, including the effects of MPC peripheral chain length, MPC functionalization via place-exchange reaction, MPC core size, and the MPC density or concentration within the xerogel composite films. The collective results of these experiments support the proposed mechanism and identify interparticle spacing and the electronic communication through the MPC network is the most significant factor in the sensing scheme with the diffusional aspects of the mechanism that may be affected by film/MPC hydrophobicity and functionality (i.e., glucose and H2O2 diffusion) shown to be less substantial contributors to the overall enhanced performance. Understanding the structure–function relationships of effective sensing schemes allows for the employment of the strategy for future biosensor design toward clinically relevant targets

Viral elements and their potential influence on microbial processes along the permanently stratified Cariaco Basin redoxcline

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mara, P., Vik, D., Pachiadaki, M. G., Suter, E. A., Poulos, B., Taylor, G. T., Sullivan, M. B., & Edgcomb, V. P. Viral elements and their potential influence on microbial processes along the permanently stratified Cariaco Basin redoxcline. ISME Journal, (2020), doi:10.1038/s41396-020-00739-3.Little is known about viruses in oxygen-deficient water columns (ODWCs). In surface ocean waters, viruses are known to act as gene vectors among susceptible hosts. Some of these genes may have metabolic functions and are thus termed auxiliary metabolic genes (AMGs). AMGs introduced to new hosts by viruses can enhance viral replication and/or potentially affect biogeochemical cycles by modulating key microbial pathways. Here we identify 748 viral populations that cluster into 94 genera along a vertical geochemical gradient in the Cariaco Basin, a permanently stratified and euxinic ocean basin. The viral communities in this ODWC appear to be relatively novel as 80 of these viral genera contained no reference viral sequences, likely due to the isolation and unique features of this system. We identify viral elements that encode AMGs implicated in distinctive processes, such as sulfur cycling, acetate fermentation, signal transduction, [Fe–S] formation, and N-glycosylation. These AMG-encoding viruses include two putative Mu-like viruses, and viral-like regions that may constitute degraded prophages that have been modified by transposable elements. Our results provide an insight into the ecological and biogeochemical impact of viruses oxygen-depleted and euxinic habitats.This work was supported by the National Science Foundation grant OCE-1336082 to VPE, OCE-1335436 to GTT, OCE-1536989, a Moore Foundation Award (#3790) to MBS, and WHOI subaward A101259 to MP. The sequencing conducted by the U.S. Department of Energy Joint Genome Institute is supported by the Office of Science of the U.S. Department of Energy under contract no. DE-AC02-05CH11231

Energy- and flux-budget (EFB) turbulence closure model for the stably stratified flows. Part I: Steady-state, homogeneous regimes

We propose a new turbulence closure model based on the budget equations for the key second moments: turbulent kinetic and potential energies: TKE and TPE (comprising the turbulent total energy: TTE = TKE + TPE) and vertical turbulent fluxes of momentum and buoyancy (proportional to potential temperature). Besides the concept of TTE, we take into account the non-gradient correction to the traditional buoyancy flux formulation. The proposed model grants the existence of turbulence at any gradient Richardson number, Ri. Instead of its critical value separating - as usually assumed - the turbulent and the laminar regimes, it reveals a transition interval, 0.1< Ri <1, which separates two regimes of essentially different nature but both turbulent: strong turbulence at Ri<<1; and weak turbulence, capable of transporting momentum but much less efficient in transporting heat, at Ri>1. Predictions from this model are consistent with available data from atmospheric and lab experiments, direct numerical simulation (DNS) and large-eddy simulation (LES).Comment: 40 pages, 6 figures, Boundary-layer Meteorology, resubmitted, revised versio

Oxygen Activation and Radical Transformations in Heme Proteins and Metalloporphyrins

As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O_2 and its derived intermediates such as hydrogen peroxide to afford a variety of metal–oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal–oxo species, are the basis for the various biological functions of O_2-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O2 storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O_2 activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron–oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs

Psychosocial drivers for change: understanding and promoting stakeholder engagement in local adaptation to climate change in three European Mediterranean case studies

Stakeholder engagement in the processes of planning local adaptation to climate change faces many challenges. The goal of this work was to explore whether or not the intention of engaging could be understood (Study 1) and promoted (Study 2), by using an extension of the theory of planned behaviour. In Study 1, stakeholders from three European Mediterranean case studies were surveyed: Baixo Vouga Lagunar (Portugal), SCOT Provence Méditerranée (France), and the island of Crete (Greece) (N = 115). Stakeholders' intention of engaging was significantly predicted by subjective norm (which was predicted by injunctive normative beliefs towards policy-makers and stakeholders) and by perceived behavioural control (which was predicted by knowledge of policy and instruments). Study 2 was conducted in the Baixo Vouga Lagunar case study and consisted of a two-workshop intervention where issues on local and regional adaptation, policies, and engagement were presented and discussed. A within-participants comparison of initial survey results with results following the workshops (NT1 = 12, NT2 = 15, NT3 = 12) indicated that these were successful in increasing stakeholders' intention of engaging. This increase was paired with a) an increase in injunctive normative beliefs towards policy-makers and consequently in subjective norm, and to b) a decrease in perceived complexity of planning local adaptation and an increase in knowledge regarding adaptation to climate change.info:eu-repo/semantics/acceptedVersio