Effect of Automated Closed-loop ventilation versus convenTional VEntilation on duration and quality of ventilation in critically ill patients (ACTiVE) - study protocol of a randomized clinical trial

BACKGROUND: INTELLiVENT-Adaptive Support Ventilation (ASV) is a fully automated closed-loop mode of ventilation for use in critically ill patients. Evidence for benefit of INTELLiVENT-ASV in comparison to ventilation that is not fully automated with regard to duration of ventilation and quality of breathing is largely lacking. We test the hypothesis that INTELLiVENT-ASV shortens time spent on a ventilator and improves the quality of breathing. METHODS: The "Effects of Automated Closed-loop VenTilation versus Conventional Ventilation on Duration and Quality of Ventilation" (ACTiVE) study is an international, multicenter, two-group randomized clinical superiority trial. In total, 1200 intensive care unit (ICU) patients with an anticipated duration of ventilation of &gt; 24 h will be randomly assigned to one of the two ventilation strategies. Investigators screen patients aged 18 years or older at start of invasive ventilation in the ICU. Patients either receive automated ventilation by means of INTELLiVENT-ASV, or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is the number of days free from ventilation and alive at day 28; secondary endpoints are quality of breathing using granular breath-by-breath analysis of ventilation parameters and variables in a time frame of 24 h early after the start of invasive ventilation, duration of ventilation in survivors, ICU and hospital length of stay (LOS), and mortality rates in the ICU and hospital, and at 28 and 90 days. DISCUSSION: ACTiVE is one of the first randomized clinical trials that is adequately powered to compare the effects of automated closed-loop ventilation versus conventional ventilation on duration of ventilation and quality of breathing in invasively ventilated critically ill patients. The results of ACTiVE will support intensivist in their choices regarding the use of automated ventilation. TRIAL REGISTRATION: ACTiVE is registered in clinicaltrials.gov (study identifier: NCT04593810 ) on 20 October 2020.</p

Identify facilitators and challenges in computerized checklist implementation

Safety checklists have been considered as a promising tool for improving patient safety for decades. Computerized checklists have better performance compared with paper-based checklists, though there are barriers to their adoption. Given previous literature, it is still unclear what assists implementations and their challenges. To address this issue, this paper summarizes the implementation of two successful computerized checklist implementations in two countries for two different clinical scenarios and analyzes their facilitators and challenges.</p

A paraplegic patient with fever and leucocytosis: not always what it seems

A 54-year-old obese woman with a history of spina bifida was admitted to the hospital with malaise and fever accompanied by leucocytosis, thrombocytosis, and hypercalcaemia. As treatment for neurogenic bladder dysfunction she had a suprapubic catheter. Diagnostic workup for osteomyelitis revealed an unknown mass originating from the urinary bladder on MRI of the pelvis. Further diagnostic analyses showed that the mass was a squamous-cell carcinoma (SCC) with laboratory abnormalities as paraneoplastic phenomena mediated by PTH-related peptide and cytokines released by the SCC. Despite radiotherapy the patient died within two months after initial diagnosis. Squamous-cell carcinoma of the bladder is rare in western countries. In unresectable or metastatic disease survival rates are low due to low responsiveness to standard chemotherapy. Concurrent chemoradiotherapy might be an alternative in unresectable or locally advanced disease; however, evidence to support this is lacking. The poor survival in these patients raises the question of whether high-risk groups for SCC of the bladder, like paraplegic patients or patient with neurogenic bladder dysfunction, should receive screening even though the ideal starting point and frequency are still unknown.

Implementation of an automated early warning scoring system in a surgical ward:practical use and effects on patient outcomes

Introduction Early warning scores (EWS) are being increasingly embedded in hospitals over the world due to their promise to reduce adverse events and improve the outcomes of clinical patients. The aim of this study was to evaluate the clinical use of an automated modified EWS (MEWS) for patients after surgery. Methods This study conducted retrospective before-and-after comparative analysis of non-automated and automated MEWS for patients admitted to the surgical high-dependency unit in a tertiary hospital. Operational outcomes included number of recorded assessments of the individual MEWS elements, number of complete MEWS assessments, as well as adherence rate to related protocols. Clinical outcomes included hospital length of stay, in-hospital and 28-day mortality, and ICU readmission rate. Results Recordings in the electronic medical record from the control period contained 7929 assessments of MEWS elements and were performed in 320 patients. Recordings from the intervention period contained 8781 assessments of MEWS elements in 273 patients, of which 3418 were performed with the automated EWS system. During the control period, 199 (2.5%) complete MEWS were recorded versus 3991 (45.5%) during intervention period. With the automated MEWS systems, the percentage of missing assessments and the time until the next assessment for patients with a MEWS of 2 decreased significantly. The protocol adherence improved from 1.1% during the control period to 25.4% when the automated MEWS system was involved. There were no significant differences in clinical outcomes. Conclusion Implementation of an automated EWS system on a surgical high dependency unit improves the number of complete MEWS assessments, registered vital signs, and adherence to the EWS hospital protocol. However, this positive effect did not translate into a significant decrease in mortality, hospital length of stay, or ICU readmissions. Future research and development on automated EWS systems should focus on data management and technology interoperability.</p

Advanced practice providers versus medical residents as leaders of rapid response teams:A 12-month retrospective analysis

Purpose In a time of worldwide physician shortages, the advanced practice providers (APPs) might be a good alternative for physicians as the leaders of a rapid response team. This retrospective analysis aimed to establish whether the performance of APP-led rapid response teams is comparable to the performance of rapid response teams led by a medical resident of the ICU. Material and methods In a retrospective single-center cohort study, the electronic medical record of a tertiary hospital was queried during a 12-months period to identify patients who had been visited by our rapid response team. Patient- and process-related outcomes of interventions of rapid response teams led by an APP were compared with those of teams led by a medical resident using various parameters, including the MAELOR tool, which measures the performance of a rapid response team. Results In total, 179 responses of the APP-led teams were analyzed, versus 275 responses of the teams led by a resident. Per APP, twice as many calls were handled than per resident. Interventions of teams led by APPs, and residents did not differ in number of admissions (p = 0.87), mortality (p = 0.8), early warning scores (p = 0.2) or MAELOR tool triggering (p = 0.19). Both groups scored equally on time to admission (p = 0.67) or time until any performed intervention. Conclusion This retrospective analysis showed that the quality of APP-led rapid response teams was similar to the quality of teams led by a resident. These findings need to be confirmed by prospective studies with balanced outcome parameters

Chora z niedowładem kończyn dolnych, gorączką i leukocytozą: infekcja to nie wszystko

Pięćdziesięcioczteroletnia chora z otyłością i wywiadem rozszczepu kręgosłupa została przyjęta do szpitala z powodu złego samopoczucia oraz gorączki, którym towarzyszyły leukocytoza, trombocytoza oraz hiperkalcemia. Ze względu na neurogenną dysfunkcję pęcherza moczowego chora miała założony stały cewnik nadłonowy. W ramach diagnostyki, z powodu podejrzenia zapalenia kości i szpiku, wykonano badanie rezonansu magnetycznego (MRI) miednicy, w którym uwidoczniono obecność guza pęcherza moczowego, zajmującego kanał przetoki nadpęcherzowej. W toku dalszej diagnostyki potwierdzono rozpoznanie raka płaskonabłonkowego pęcherza moczowego, z wtórnym zespołem paranowotworowym spowodowanym nadmierną sekrecją peptydu PTH-podobnego oraz cytokin. Mimo zastosowanej radioterapii chora zmarła po 2 miesiącach od ustalenia rozpoznania. Rak płaskonabłonkowy pęcherza moczowego występuje rzadko w krajach uprzemysłowionych. Rokowanie w przypadku niekwalifikującego się do resekcji lub przerzutowego raka płaskonabłonkowego pęcherza moczowego jest niekorzystne, głównie ze względu na wysoką oporność tego nowotworu na chemioterapię. Jednoczesna radiochemioterapia jest alternatywną opcją postępowania dla chorych z miejscowo zaawansowanym rakiem płaskonabłonkowym pęcherza moczowego niekwalifikującym się do resekcji, choć brakuje dowodów naukowych oceniających skuteczność takiego leczenia. Niekorzystne rokowanie zmusza do refleksji nad wartością badań przesiewowych w przypadkach wysokiego ryzyka, takich jak chorzy z niedowładem kończyn dolnych lub neurogenną dysfunkcją pęcherza. Niemniej brakuje danych pozwalających określić optymalny czas rozpoczęcia obserwacji oraz częstotliwość dalszych badań kontrolnych

Syntaxin 5 Is Required for Copper Homeostasis in Drosophila and Mammals

Copper is essential for aerobic life, but many aspects of its cellular uptake and distribution remain to be fully elucidated. A genome-wide screen for copper homeostasis genes in Drosophila melanogaster identified the SNARE gene Syntaxin 5 (Syx5) as playing an important role in copper regulation; flies heterozygous for a null mutation in Syx5 display increased tolerance to high dietary copper. The phenotype is shown here to be due to a decrease in copper accumulation, a mechanism also observed in both Drosophila and human cell lines. Studies in adult Drosophila tissue suggest that very low levels of Syx5 result in neuronal defects and lethality, and increased levels also generate neuronal defects. In contrast, mild suppression generates a phenotype typical of copper-deficiency in viable, fertile flies and is exacerbated by co-suppression of the copper uptake gene Ctr1A. Reduced copper uptake appears to be due to reduced levels at the plasma membrane of the copper uptake transporter, Ctr1. Thus Syx5 plays an essential role in copper homeostasis and is a candidate gene for copper-related disease in humans

Macrophage-derived IL-1β and TNF-α regulate arginine metabolism in neuroblastoma

© 2018 American Association for Cancer Research. Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1b and TNFa in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1b and TNFa established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL1b and TNFa in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Abstract: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era