Ablation of specific insulin-like growth factor I forms reveals the importance of cleavage for regenerative capacity and glycosylation for skeletal muscle storage.

Insulin-like growth factor-I (IGF-I) facilitates mitotic and anabolic actions in all tissues. In skeletal muscle, IGF-I can promote growth and resolution of damage by promoting satellite cell proliferation and differentiation, suppressing inflammation, and enhancing fiber formation. While the most well-characterized form of IGF-I is the mature protein, alternative splicing and post-translational modification complexity lead to several additional forms of IGF-I. Previous studies showed muscle efficiently stores glycosylated pro-IGF-I. However, non-glycosylated forms display more efficient IGF-I receptor activation in vitro, suggesting that the removal of the glycosylated C terminus is a necessary step to enable increased activity. We employed CRISPR-Cas9 gene editing to ablate IGF-I glycosylation sites (2ND) or its cleavage site (3RA) in mice to determine the necessity of glycosylation or cleavage for IGF-I function in postnatal growth and during muscle regeneration. 3RA mice had the highest circulating and muscle IGF-I content, whereas 2ND mice had the lowest levels compared to wild-type mice. After weaning, 4-week-old 2ND mice exhibited higher body and skeletal muscle mass than other strains. However, by 16 weeks of age, muscle and body size differences disappeared. Even though 3RA mice had more IGF-I stored in muscle in homeostatic conditions, regeneration was delayed after cardiotoxin-induced injury, with prolonged necrosis most evident at 5 days post injury (dpi). In contrast, 2ND displayed improved regeneration with reduced necrosis, and greater fiber size and muscle mass at 11 and 21 dpi. Overall, these results demonstrate that while IGF-I glycosylation may be important for storage, cleavage is needed to enable IGF-I to be used for efficient activity in postnatal growth and following acute injury.

Magnitude and time to peak oxygenation effect of prone positioning in ventilated adults with COVID-19 related acute hypoxemic respiratory failure.

BACKGROUND: Prone positioning may improve oxygenation in acute hypoxemic respiratory failure and was widely adopted in COVID-19 patients. However, the magnitude and timing of its peak oxygenation effect remain uncertain with the optimum dosage unknown. Therefore, we aimed to investigate the magnitude of the peak effect of prone positioning on the PaO2 :FiO2 ratio during prone and secondly, the time to peak oxygenation. METHODS: Multi-centre, observational study of invasively ventilated adults with acute hypoxemic respiratory failure secondary to COVID-19 treated with prone positioning. Baseline characteristics, prone positioning and patient outcome data were collected. All arterial blood gas (ABG) data during supine, prone and after return to supine position were analysed. The magnitude of peak PaO2 :FiO2 ratio effect and time to peak PaO2 :FIO2 ratio effect was measured. RESULTS: We studied 220 patients (mean age 54 years) and 548 prone episodes. Prone positioning was applied for a mean (±SD) 3 (±2) times and 16 (±3) hours per episode. Pre-proning PaO2 :FIO2 ratio was 137 (±49) for all prone episodes. During the first episode. the mean PaO2 :FIO2 ratio increased from 125 to a peak of 196 (p < .001). Peak effect was achieved during the first episode, after 9 (±5) hours in prone position and maintained until return to supine position. CONCLUSIONS: In ventilated adults with COVID-19 acute hypoxemic respiratory failure, peak PaO2 :FIO2 ratio effect occurred during the first prone positioning episode and after 9 h. Subsequent episodes also improved oxygenation but with diminished effect on PaO2 :FIO2 ratio. This information can help guide the number and duration of prone positioning episodes.

Neuromuscular blockade and oxygenation changes during prone positioning in COVID-19.

PURPOSE: Neuromuscular blockers (NMBs) are often used during prone positioning to facilitate mechanical ventilation in COVID-19 related ARDS. However, their impact on oxygenation is uncertain. METHODS: Multi-centre observational study of invasively ventilated COVID-19 ARDS adults treated with prone positioning. We collected data on baseline characteristics, prone positioning, NMB use and patient outcome. We assessed arterial blood gas data during supine and prone positioning and after return to the supine position. RESULTS: We studied 548 prone episodes in 220 patients (mean age 54 years, 61% male) of whom 164 (75%) received NMBs. Mean PaO2:FiO2 (P/F ratio) during the first prone episode with NMBs reached 208 ± 63 mmHg compared with 161 ± 66 mmHg without NMBs (Δmean = 47 ± 5 mmHg) for an absolute increase from baseline of 76 ± 56 mmHg versus 55 ± 56 mmHg (padj < 0.001). The mean P/F ratio on return to the supine position was 190 ± 63 mmHg in the NMB group versus 141 ± 64 mmHg in the non-NMB group for an absolute increase from baseline of 59 ± 58 mmHg versus 34 ± 56 mmHg (padj < 0.001). CONCLUSION: During prone positioning, NMB is associated with increased oxygenation compared to non-NMB therapy, with a sustained effect on return to the supine position. These findings may help guide the use of NMB during prone positioning in COVID-19 ARDS.

High levels of psychosocial distress among Australian frontline healthcare workers during the COVID-19 pandemic: a cross-sectional survey.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a profound and prolonged impact on healthcare services and healthcare workers. AIMS: The Australian COVID-19 Frontline Healthcare Workers Study aimed to investigate the severity and prevalence of mental health issues, as well as the social, workplace and financial disruptions experienced by Australian healthcare workers during the COVID-19 pandemic. METHODS: A nationwide, voluntary, anonymous, single timepoint, online survey was conducted between 27 August and 23 October 2020. Individuals self-identifying as frontline healthcare workers in secondary or primary care were invited to participate. Participants were recruited through health organisations, professional associations or colleges, universities, government contacts and national media. Demographics, home and work situation, health and psychological well-being data were collected. RESULTS: A total of 9518 survey responses were received; of the 9518 participants, 7846 (82.4%) participants reported complete data. With regard to age, 4110 (52.4%) participants were younger than 40 years; 6344 (80.9%) participants were women. Participants were nurses (n=3088, 39.4%), doctors (n=2436, 31.1%), allied health staff (n=1314, 16.7%) or in other roles (n=523, 6.7%). In addition, 1250 (15.9%) participants worked in primary care. Objectively measured mental health symptoms were common: mild to severe anxiety (n=4694, 59.8%), moderate to severe burnout (n=5458, 70.9%) and mild to severe depression (n=4495, 57.3%). Participants were highly resilient (mean (SD)=3.2 (0.66)). Predictors for worse outcomes on all scales included female gender; younger age; pre-existing psychiatric condition; experiencing relationship problems; nursing, allied health or other roles; frontline area; being worried about being blamed by colleagues and working with patients with COVID-19. CONCLUSIONS: The COVID-19 pandemic is associated with significant mental health symptoms in frontline healthcare workers. Crisis preparedness together with policies and practices addressing psychological well-being are needed.

Coping strategies adopted by Australian frontline health workers to address psychological distress during the COVID-19 pandemic.

OBJECTIVES: The Australian COVID-19 Frontline Healthcare Workers Study investigated coping strategies and help-seeking behaviours, and their relationship to mental health symptoms experienced by Australian healthcare workers (HCWs) during the COVID-19 pandemic. METHODS: Australian HCWs were invited to participate a nationwide, voluntary, anonymous, single time-point, online survey between 27th August and 23rd October 2020. Complete responses on demographics, home and work situation, and measures of health and psychological wellbeing were received from 7846 participants. RESULTS: The most commonly reported adaptive coping strategies were maintaining exercise (44.9%) and social connections (31.7%). Over a quarter of HCWs (26.3%) reported increased alcohol use which was associated with a history of poor mental health and worse personal relationships. Few used psychological wellbeing apps or sought professional help; those who did were more likely to be suffering from moderate to severe symptoms of mental illness. People living in Victoria, in regional areas, and those with children at home were significantly less likely to report adaptive coping strategies. CONCLUSIONS: Personal, social, and workplace predictors of coping strategies and help-seeking behaviour during the pandemic were identified. Use of maladaptive coping strategies and low rates of professional help-seeking indicate an urgent need to understand the effectiveness of, and the barriers and enablers of accessing, different coping strategies.

Are Classic Bedside Exam Findings Required to Initiate Enteral Nutrition in Critically Ill Patients: Emphasis on Bowel Sounds and Abdominal Distension.

The general physical examination of a patient is an axiom of critical care medicine, but evidence to support this practice remains sparse. Given the lack of evidence for a comprehensive physical examination of the entire patient on admission to the intensive care unit, which most clinicians consider an essential part of care, should clinicians continue the practice of a specialized gastrointestinal system physical examination when commencing enteral nutrition in critically ill patients? In this review of literature related to gastrointestinal system examination in critically ill patients, the focus is on gastrointestinal sounds and abdominal distension. There is a summary of what these physical features represent, an evaluation of the evidence regarding use of these physical features in patients after abdominal surgery, exploration of the rationale for and against using the physical findings in routine practice, and detail regarding what is known about each feature in critically ill patients. Based on the available evidence, it is recommended that an isolated symptom, sign, or bedside test does not provide meaningful information. However, it is submitted that a comprehensive physical assessment of the gastrointestinal system still has a role when initiating or administering enteral nutrition: specifically, when multiple features are present, clinicians should consider further investigation or intervention.