Erratum: Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.

[This corrects the article DOI: 10.1016/j.isci.2021.103463.].

Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.

Earlier and enhanced rehabilitation of mechanically ventilated patients in critical care: A feasibility randomised controlled trial.

BACKGROUND: Systematic reviews of early rehabilitation within intensive care units have highlighted the need for robust multi-centre randomised controlled trials with longer term follow up. This trial aims to explore the feasibility of earlier and enhanced rehabilitation for patients mechanically ventilated for ≥5days and to assess the impact on possible long term outcome measures for use in a definitive trial. METHODS: Patients admitted to a large UK based intensive care unit and invasively ventilated for ≥5days were randomised to the rehabilitation intervention or standard care on a 1:1 basis, stratified by age and SOFA score. The rehabilitation intervention involved a structured programme, with progression along a functionally based mobility protocol according to set safety criteria. RESULTS: 103 out of 128 eligible patients were recruited into the trial, achieving an initial recruitment rate of 80%. Patients in the intervention arm mobilized significantly earlier (8days vs 10 days, p=0.035), at a more acute phase of illness (SOFA 6 vs 4, p<0.05) and reached a higher level of mobility at the point of critical care discharge (MMS 7 vs 5, p<0.01). CONCLUSION: We have demonstrated the feasibility of introducing a structured programme of rehabilitation for patients admitted to critical care.

A comparison of earlier and enhanced rehabilitation of mechanically ventilated patients in critical care compared to standard care (REHAB): study protocol for a single-site randomised controlled feasibility trial.

BACKGROUND: Mortality from critical illness is improving, but survivors suffer from prolonged weakness and psychological and cognitive impairments. Maximising the recovery after critical illness has been highlighted as a research priority, especially in relation to an ageing population who present with higher rates of pre-morbid disability. Small studies have shown that starting rehabilitation early within the intensive care unit (ICU) improves short-term outcomes. Systematic reviews have highlighted the need for robust multicentre randomised controlled trials with longer term follow-up. METHODS: The study design is a randomised controlled study to explore the feasibility of providing earlier and enhanced rehabilitation to mechanically ventilated patients at high risk of ICU-acquired weakness within the ICU. The rehabilitation intervention involves a structured programme, with progression along a functionally based mobility protocol according to set safety criteria. The overall aim of the intervention is to commence mobilisation at an earlier time point in the patient's illness and increase mobility of the patient through their recovery trajectory. Participants will be randomised to enhanced rehabilitation or standard care, with the aim of recruiting at least 100 patients over 16 months. The trial design will assess recruitment and consent rates from eligible patients, compliance with the intervention, and assess a range of possible outcome measures for use in a definitive trial, with follow-up continuing for 12 months post hospital discharge. DISCUSSION: This study will evaluate the feasibility of providing an earlier and enhanced rehabilitation intervention to mechanically ventilated patients in critical care. We will identify strengths and weaknesses of the proposed protocol and the utility and characteristics of the outcome measures. The results from this study will inform the design of a phase III multicentre trial of enhanced rehabilitation for critically ill adults. TRIAL REGISTRATION: ISRCTN90103222, 13/08/2015; retrospectively registered.

The Sara Combilizer® as an early mobilisation aid for critically ill patients: A prospective before and after study.

BACKGROUND: Early mobility within the ICU is associated with a number of positive outcomes including reductions in ICU and hospital length of stay and better functional recovery. The exact definition of 'early' mobility is still not defined, with the actual ability to mobilise limited by a number of perceived factors. The Sara Combilizer® is a combined tilt table and stretcher chair, which allows passive transfer of patients out of bed. This study aimed to assess whether the introduction of the Sara Combilizer® reduced time taken to first mobilise for patients mechanically ventilated for at least five days and at risk of ICU acquired weakness. METHODS: Patients admitted to a large UK critical care unit during the trial period and ventilated for ≥5days were included in the study. Baseline data was collected prospectively for a period of four months. The Sara Combilizer® was then introduced for a one month training and familiarisation period, followed by a further four months prospective data collection. The primary outcome was time to first mobilisation, defined as a Manchester Mobility Score ≥2. RESULTS: Following the introduction of the Sara Combilizer®, time taken to mobilise reduced significantly from 13.6 to 10.6days (p=0.028). SOFA scores were significantly higher at the point of first mobilisation in the Combilizer group (mean: 2.9±0.5 vs. 5.1±2.4; p=0.005). There was no statistical difference in therapy time between the groups, or ICU or hospital length of stay. CONCLUSIONS: The introduction of the Sara Combilizer® was associated with a significant reduction in time to mobilise patients ventilated for ≥5days, and patients were mobilised with a higher degree of organ failure. This was achieved without any increase in therapy time. The Sara Combilizer® may be a useful adjunct to an early mobility protocol within the ICU.

Enhancing rehabilitation of mechanically ventilated patients in the intensive care unit: a quality improvement project.

PURPOSE: Prolonged periods of mechanical ventilation are associated with significant physical and psychosocial adverse effects. Despite increasing evidence supporting early rehabilitation strategies, uptake and delivery of such interventions in Europe have been variable. The objective of this study was to evaluate the impact of an early and enhanced rehabilitation program for mechanically ventilated patients in a large tertiary referral, mixed-population intensive care unit (ICU). METHOD: A new supportive rehabilitation team was created within the ICU in April 2012, with a focus on promoting early and enhanced rehabilitation for patients at high risk for prolonged ICU and hospital stays. Baseline data on all patients invasively ventilated for at least 5 days in the previous 12 months (n = 290) were compared with all patients ventilated for at least 5 days in the 12 months after the introduction of the rehabilitation team (n = 292). The main outcome measures were mobility level at ICU discharge (assessed via the Manchester Mobility Score), mean ICU, and post-ICU length of stay (LOS), ventilator days, and in-hospital mortality. RESULTS: The introduction of the ICU rehabilitation team was associated with a significant increase in mobility at ICU discharge, and this was associated with a significant reduction in ICU LOS (16.9 vs 14.4 days, P = .007), ventilator days (11.7 vs 9.3 days, P < .05), total hospital LOS (35.3 vs 30.1 days, P < .001), and in-hospital mortality (39% vs 28%, P < .05). CONCLUSION: A quality improvement strategy to promote early and enhanced rehabilitation within this European ICU improved levels of mobility at critical care discharge, and this was associated with reduced ICU and hospital LOS and reduced days of mechanical ventilation.