Free energies of membrane stalk formation from a lipidomics perspective

Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at coarse-grained resolution. The method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes

Reducing work pressure and IT problems and facilitating IT integration and audit & feedback help adherence to perioperative safety guidelines: a survey among 95 perioperative professionals

Background: To improve perioperative patient safety, guidelines for the preoperative, peroperative, andpostoperative phase were introduced in the Netherlands between 2010 and 2013. To help the implementation ofthese guidelines, we aimed to get a better understanding of the barriers and drivers of perioperative guidelineadherence and to explore what can be learned for future implementation projects in complex organizations.Methods: We developed a questionnaire survey based on the theoretical framework of Van Sluisveld et al. forclassifying barriers and facilitators. The questionnaire contained 57 statements derived from (a) an instrument formeasuring determinants of innovations by the Dutch Organization for Applied Scientific Research, (b) interviewswith quality and safety policy officers and perioperative professionals, and (c) a publication of Cabana et al. Thetarget group consisted of 232 perioperative professionals in nine hospitals. In addition to rating the statements on afive-point Likert scale (which were classified into the seven categories of the framework: factors relating to theintervention, society, implementation, organization, professional, patients, and social factors), respondents wereinvited to rank their three most important barriers in a separate, extra open-ended question.Results: Ninety-five professionals (41%) completed the questionnaire. Fifteen statements (26%) were considered tobe barriers, relating to social factors (N = 5), the organization (N = 4), the professional (N = 4), the patient (N = 1),and the intervention (N = 1). An integrated information system was considered an important facilitator (70.4%) aswell as audit and feedback (41.8%). The Barriers Top-3 question resulted in 75 different barriers in nearly allcategories. The most frequently reported barriers were as follows: time pressure (16% of the total number ofbarriers), emergency patients (8%), inefficient IT structure (4%), and workload (3%).Conclusions: We identified a wide range of barriers that are believed to hinder the use of the perioperative safetyguidelines, while an integrated information system and local data collection and feedback will also be necessary toengage perioperative teams. These barriers need to be locally prioritized and addressed by tailored implementationstrategies. These results may also be of relevance for guideline implementation in general in complex organizations.Trial registration: Dutch Trial Registry: NTR3568.Keywords: Guideline adherence, Implementation, Implementation barriers, Implementation facilitators, Patientsafety, Perioperative car

Feasibility and usability of a regional hub model for colorectal cancer services during the COVID-19 pandemic

The outbreak of the COVID-19 pandemic produced unprecedented challenges, at a global level, in the provision of cancer care. With the ongoing need in the delivery of life-saving cancer treatment, the surgical management of patients with colorectal cancer required prompt significant transformation. The aim of this retrospective study is to report the outcome of a bespoke regional Cancer Hub model in the delivery of elective and essential colorectal cancer surgery, at the height of the first wave of the COVID-19 pandemic. 168 patients underwent colorectal cancer surgery from April 1st to June 30th of 2020. Approximately 75% of patients operated upon underwent colonic resection, of which 47% were left-sided, 34% right-sided and 12% beyond total mesorectal excision surgeries. Around 79% of all resectional surgeries were performed via laparotomy, and the remainder 21%, robotically or laparoscopically. Thirty-day complication rate, for Clavien-Dindo IIIA and above, was 4.2%, and 30-day mortality rate was 0.6%. Re-admission rate, within 30 days post-discharge, was 1.8%, however, no patient developed COVID-19 specific complications post-operatively and up to 28 days post-discharge. The established Cancer Hub offered elective surgical care for patients with colorectal cancer in a centralised, timely and efficient manner, with acceptable post-operative outcomes and no increased risk of contracting COVID-19 during their inpatient stay. We offer a practical model of care that can be used when elective surgery "hubs" for streamlined delivery of elective care needs to be established in an expeditious fashion, either due to the COVID-19 pandemic or any other future pandemics

Increased adherence to perioperative safety guidelines associated with improved patient safety outcomes:a stepped-wedge, cluster-randomised multicentre trial

Background: National Dutch guidelines have been introduced to improve suboptimal perioperative care. A multifaceted implementation programme (IMPlementatie Richtlijnen Operatieve VEiligheid [IMPROVE]) has been developed to support hospitals in applying these guidelines. This study evaluated the effectiveness of IMPROVE on guideline adherence and the association between guideline adherence and patient safety. Methods: Nine hospitals participated in this unblinded, superiority, stepped-wedge, cluster RCT in patients with major noncardiac surgery (mortality risk >= 1%). IMPROVE consisted of educational activities, audit and feedback, reminders, organisational, team-directed, and patient-mediated activities. The primary outcome of the study was guideline adherence measured by nine patient safety indicators on the process (stop moments from the composite STOP bundle, and timely administration of antibiotics) and on the structure of perioperative care. Secondary safety outcomes included in-hospital complications, postoperative wound infections, mortality, length of hospital stay, and unplanned care. Results: Data were analysed for 1934 patients. The IMPROVE programme improved one stop moment: 'discharge from recovery room' (+16%; 95% confidence interval [CI], 9-23%). This stop moment was related to decreased mortality (-3%; 95% CI, -4% to -1%), fewer complications (-8%; 95% CI, -13% to -3%), and fewer unscheduled transfers to the ICU (-6%; 95% CI, -9% to -3%). IMPROVE negatively affected one other stop moment - 'discharge from the hospital' - possibly because of the limited resources of hospitals to improve all stop moments together. Conclusions: Mixed implementation effects of IMPROVE were found. We found some positive associations between guideline adherence and patient safety (i.e. mortality, complications, and unscheduled transfers to the ICU) except for the timely administration of antibiotics

Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis

Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa

Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles

The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society

Statement on bioinformatics and capturing the benefits of genome sequencing for society

The HUGO Committee on Ethics, Law and Society (CELS) undertook a Working Group exploration of the key ethical issues arising from genome sequencing in 2013. The Imagined Futures paper the group subsequently published proposed points to consider when applying genomic bioinformatics to data repositories used in genomic medicine and research ( http://www.hugo-international.org/Resources/Documents/CELS_Article-ImaginedFutures_2014.pdf ). Given the ever-increasing power to sequence the human genome rapidly and inexpensively-as well as trends toward "Big Data" and "Open Science"-we take this opportunity to update and refine the key findings of that paper