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Intensive care survivors often experience post-intensive care sequelae, which are frequently gathered together under the term “post-intensive care syndrome” (PICS). The consequences of PICS on quality of life, health-related costs and hospital readmissions are real public health problems. In the present Viewpoint, we summarize current knowledge and gaps in our understanding of PICS and approaches to management.

Muscle wasting in the critically ill is up to 2% per day and delays patient recovery and rehabilitation. It is linked to inflammation, organ failure and severity of illness. The aims of this study were to understand the relationship between muscle depth loss, and nutritional and inflammatory markers during prolonged critical illness. Secondly, to identify when during critical illness catabolism might decrease, such that targeted nutritional strategies may logically be initiated. This study was conducted in adult intensive care units in two large teaching hospitals. Patients anticipated to be ventilated for >48 hours were included. Serum C-reactive protein (mg/L), urinary urea (mmol/24h), 3-methylhistidine (μmol/24h) and nitrogen balance (g/24h) were measured on days 1, 3, 7 and 14 of the study. Muscle depth (cm) on ultrasound were measured on the same days over the bicep (bicep and brachialis muscle), forearm (flexor compartment of muscle) and thigh (rectus femoris and vastus intermedius). Seventy-eight critically ill patients were included with mean age of 59 years (SD: 16) and median Intensive care unit (ICU) length of stay of 10 days (IQR: 6-16). Starting muscle depth, 8.5cm (SD: 3.2) to end muscle depth, 6.8cm (SD: 2.2) were on average significantly different over 14 days, with mean difference -1.67cm (95%CI: -2.3 to -1cm), p<0.0001. Protein breakdown and inflammation continued over 14 days of the study. Our patients demonstrated a continuous muscle depth loss and negative nitrogen balance over the 14 days of the study. Catabolism remained dominant throughout the study period. No obvious 'nutritional tipping point\" to identify anabolism or recovery could be identified in our cohort. Our ICU patient cohort is one with a moderately prolonged stay. This group showed little consistency in data, reflecting the individuality of both disease and response. The data are consistent with a conclusion that a time based assumption of a tipping point does not exist. International Standard Randomised Controlled Trial Number: ISRCTN79066838. Registration 25 July 2012.

Prognostication is an essential tool for risk adjustment and decision making in the intensive care unit (ICU). Research into prognostication in ICU has so far been limited to data from admission or the first 24 hours. Most ICU admissions last longer than this, decisions are made throughout an admission, and some admissions are explicitly intended as time-limited prognostic trials. Despite this, temporal changes in prognostic ability during ICU admission has received little attention to date. Current predictive models, in the form of prognostic clinical tools, are typically derived from linear models and do not explicitly handle incremental information from trends. Machine learning (ML) allows predictive models to be developed which use non-linear predictors and complex interactions between variables, thus allowing incorporation of trends in measured variables over time; this has made it possible to investigate prognosis throughout an admission. This study uses ML to assess the predictability of ICU mortality as a function of time. Logistic regression against physiological data alone outperformed APACHE-II and demonstrated several important interactions including between lactate & noradrenaline dose, between lactate & MAP, and between age & MAP consistent with the current sepsis definitions. ML models consistently outperformed logistic regression with Deep Learning giving the best results. Predictive power was maximal on the second day and was further improved by incorporating trend data. Using a limited range of physiological and demographic variables, the best machine learning model on the first day showed an area under the receiver-operator characteristic curve (AUC) of 0.883 (σ = 0.008), compared to 0.846 (σ = 0.010) for a logistic regression from the same predictors and 0.836 (σ = 0.007) for a logistic regression based on the APACHE-II score. Adding information gathered on the second day of admission improved the maximum AUC to 0.895 (σ = 0.008). Beyond the second day, predictive ability declined. This has implications for decision making in intensive care and provides a justification for time-limited trials of ICU therapy; the assessment of prognosis over more than one day may be a valuable strategy as new information on the second day helps to differentiate outcomes. New ML models based on trend data beyond the first day could greatly improve upon current risk stratification tools.

Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intact ompK36 gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by KP sequence types ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. We show that in the absence of antibiotics KP mutants harbouring these L3 insertions exhibit both an in vitro and in vivo competitive disadvantage relative to the isogenic parental strain expressing wild type OmpK36. We propose that this explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.

Carbapenem-resistance in Klebsiella pneumoniae (KP) sequence type ST258 is mediated by carbapenemases (e.g. KPC-2) and loss or modification of the major non-selective porins OmpK35 and OmpK36. However, the mechanism underpinning OmpK36-mediated resistance and consequences of these changes on pathogenicity remain unknown. By solving the crystal structure of a clinical ST258 OmpK36 variant we provide direct structural evidence of pore constriction, mediated by a di-amino acid (Gly115-Asp116) insertion into loop 3, restricting diffusion of both nutrients (e.g. lactose) and Carbapenems. In the presence of KPC-2 this results in a 16-fold increase in MIC to Meropenem. Additionally, the Gly-Asp insertion impairs bacterial growth in lactose-containing medium and confers a significant in vivo fitness cost in a murine model of ventilator-associated pneumonia. Our data suggests that the continuous selective pressure imposed by widespread Carbapenem utilisation in hospital settings drives the expansion of KP expressing Gly-Asp insertion mutants, despite an associated fitness cost. Carbapenem-resistance in Klebsiella pneumoniae sequence type ST258 can be enhanced by modification of the porins OmpK35 and OmpK36. Here, Wong et al. solve the crystal structure of a clinical ST258 OmpK36 variant, elucidating the mechanism of resistance and consequences on pathogenicity in vivo.

Healthcare teams are expected to deliver high quality and safe clinical care, a goal facilitated by an environment of psychological safety. We hypothesised that an individual’s personality would influence psychological safety, perceived stressors in the clinical environment and confer a suitability for different professional roles. Staff members were recruited from the Emergency or Critical Care Departments of one National Health Service Trust. Qualitative interviews explored participants’ experiences of personality, incorporating quantitative surveys to evaluate psychological safety and perceived stressors. The 16 Primary Factor Assessment provided a quantitative measure of personality. Participants demonstrated midrange scores for most personality traits, highlighting an ability to adapt to changing environments and requirements. There was a signal that different personality traits predominated between the two professional groups, and that certain traits were significantly associated with higher psychological safety and certain perceived stressors. Personality was described as having a strong influence on teamwork, the working environment and leadership ability. Our analysis highlights that personality can influence team dynamics and the suitability of individuals for certain clinical roles. Understanding the heterogeneity of personalities of team members and their likely responses to challenge may help leaders to support staff in times of challenge and improve team cohesiveness.

In a phase 1 trial, six healthy male volunteers received 0.1 mg per kilogram of body weight of a superagonistic anti-CD28 monoclonal antibody. Unexpectedly, all six volunteers had a transient critical illness characterized by multiorgan failure. These events give a view of a specific form of the cytokine-release syndrome in the absence of underlying medical disease. Six volunteers who received the anti-CD28 monoclonal antibody had a transient critical illness characterized by multiorgan failure. These events give a view of a specific form of the cytokine-release syndrome in the absence of underlying medical disease. On March 13, 2006, eight healthy male volunteers participated in a double-blind, randomized, placebo-controlled phase 1 study of the safety of TGN1412 (TeGenero), a novel monoclonal antibody. The study drug is a recombinantly expressed, humanized superagonist anti-CD28 monoclonal antibody of the IgG4κ subclass that stimulates and expands T cells independently of the ligation of the T-cell receptor. 1 In contrast to other antibodies in clinical use or in clinical trials, TGN1412 directly stimulates the immune response in vivo. In preclinical models, the stimulation of CD28 with TGN1412 (or with murine-antibody counterparts) preferentially activated and expanded type 2 helper T cells 2 and, . . .

In this review, we seek to highlight how critical illness and critical care affect longer-term outcomes, to underline the contribution of ICU delirium to cognitive dysfunction several months after ICU discharge, to give new insights into ICU acquired weakness, to emphasize the importance of value-based healthcare, and to delineate the elements of family-centered care. This consensus of 29 also provides a perspective and a research agenda about post-ICU recovery.

Physical rehabilitation of critically ill patients may improve physical outcomes; however, the relative benefits and risks with patients requiring vasoactive drugs is currently unknown. A feasibility study is needed to inform the design of a future trial required to address this issue. A two-phase exploratory observational feasibility study was carried out: A retrospective study to clarify the current practice of rehabilitation with patients receiving vasoactive drugs to inform future trial interventions and design.A prospective study exploring recruitment and outcome measurement. Intensive care patients receiving vasoactive drugs were recruited and asked about the acceptability of a future trial. The feasibility of using an adverse event tool was measured during rehabilitation. Patients were followed up after 60 days to describe the feasibility of measuring outcomes for a future trial. Retrospective study (n = 78): Twenty-one percent of patients took part in physical rehabilitation whilst receiving vasoactive drugs. Of 321 days with vasoactive drugs administered, physical rehabilitation occurred on 27 days (8%). Prospective study (n = 40): Eighty-one percent of participants indicated acceptability of being recruited into a future trial (n = 37). Eighty-eight percent of clinicians found it acceptable to randomise patients into either early rehabilitation or standard care. The adverse event tool was implemented by researchers with 2% loss of information. Finally, a 100% follow-up rate at day 60 was achieved for mortality outcomes. Follow-up rates were 70% for the EQ-5D (5 level), 65% for the World Health Organisation's Disability Assessment Schedule 2.0 and RAND 36-item Health Survey 1.0 and 26% for the 6-minute walk test. This study found a low frequency of physical rehabilitation occurring with intensive care patients receiving vasoactive drugs. A high proportion of clinicians and patients found a future RCT within this patient group acceptable. Mortality and patient-reported outcomes were the most feasible to measure.