Cooperative & competitive binding of anti-myosin tail antibodies revealed by super-resolution microscopy.

The MF30 monoclonal antibody, which binds to the myosin subfragment-2 (S2), was found to increase the extent of myofibril shortening. Yet, previous observations found no effect of this antibody on actin sliding over myosin during in vitro motility assays with purified proteins in which myosin binding protein C (MyBPC) was absent. MF30 is hypothesized to enhance the availability of myosin heads (subfragment-1 or S1) to bind actin by destabilizing the myosin S2 coiled-coil and sterically blocking S2 from binding S1. The mechanism of action likely includes MF30's substantial size, thereby inhibiting S1 heads and MyBPC from binding S2. Hypothetically, MF30 should enhance the ON state of myosin, thereby increasing muscle contraction. Our findings indicate that MF30 binds preferentially to the unfolded heavy chains of S2, displaying positive cooperativity. However, the dose-response curve of MF30's enhancement of myofibril shortening did not suggest complex interactions with S2. Single, double, and triple-stained myofibrils with increasing amounts of antibodies against myosin rods indicate a possible competition with MyBPC. Additional assays revealed decreased fluorescence intensity at the C-zone (central zone in the sarcomere, where MyBPC is located), where MyBPC may inhibit MF30 binding. Another monoclonal antibody named MF20, which binds to the light meromyosin (LMM) without affecting myofibril contraction, showed less reduction in fluorescence intensity at the C-zone in expansion microscopy than MF30. Expansion microscopy images of myofibrils labeled with MF20 revealed labeling of the A-band (anisotropic band) and a slight reduction in the labeling at the C-zone. The staining pattern obtained from the expansion microscopy image was consistent with images from photolocalization microscopy which required the synthesis of unique photoactivatable quantum dots, and Zeiss Airyscan imaging as well as alternative expansion microscopy digestion methods. Consistent with the hypothesis that MF30 competes with MyBPC binding to S2, cardiac tissue from MyBPC knockout mice was stained more intensely, especially in the C-zone, by MF30 compared to the wild type.

Erector spinae plane block: the ultimate 'plan A' block?

The erector spinae plane block (ESPB) is one of seven 'Plan A' blocks proposed by Regional Anaesthesia UK, covering the key areas of commonly encountered surgeries and acute pain. Unlike the other six blocks, the ESPB can be performed at all levels of the spine and provides analgesia to most regions of the body, leading to the argument that the ESPB is the ultimate Plan A block. Current studies show a high level of evidence supporting use in thoracoabdominal surgery but a lack of benefit in upper and lower limb surgery compared with local infiltration and other Plan A blocks. Thus, there is insufficient evidence to support the claim that the erector spinae plane block is the ultimate Plan A block.

Oxygenation during the apnoeic phase preceding intubation in adults in prehospital, emergency department, intensive care and operating theatre environments.

BACKGROUND: Apnoeic oxygenation is the delivery of oxygen during the apnoeic phase preceding intubation. It is used to prevent respiratory complications of endotracheal intubation that have the potential to lead to significant adverse events including dysrhythmia, haemodynamic decompensation, hypoxic brain injury and death. Oxygen delivered by nasal cannulae during the apnoeic phase of intubation (apnoeic oxygenation) may serve as a non-invasive adjunct to endotracheal intubation to decrease the incidence of hypoxaemia, morbidity and mortality. OBJECTIVES: To evaluate the benefits and harms of apnoeic oxygenation before intubation in adults in the prehospital, emergency department, intensive care unit and operating theatre environments compared to no apnoeic oxygenation during intubation. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 4 November 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs that compared the use of any form of apnoeic oxygenation including high flow and low flow nasal cannulae versus no apnoeic oxygenation during intubation. We defined quasi-randomization as participant allocation to each arm by means that were not truly random, such as alternation, case record number or date of birth. We excluded comparative prospective cohort and comparative retrospective cohort studies, physiological modelling studies and case reports. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. hospital stay and 2. incidence of severe hypoxaemia. Our secondary outcomes were 3. incidence of hypoxaemia, 4. lowest recorded saturation of pulse oximetry (SpO2), 5. intensive care unit (ICU) stay, 6. first pass success rate, 7. adverse events and 8. MORTALITY: We used GRADE to assess certainty of evidence. MAIN RESULTS: We included 23 RCTs (2264 participants) in our analyses. Eight studies (729 participants) investigated the use of low-flow (15 L/minute or less), and 15 studies (1535 participants) investigated the use of high-flow (greater than 15 L/minute) oxygen. Settings were varied and included the emergency department (2 studies, 327 participants), ICU (7 studies, 913 participants) and operating theatre (14 studies, 1024 participants). We considered two studies to be at low risk of bias across all domains. None of the studies reported on hospital length of stay. In predominately critically ill people, there may be little to no difference in the incidence of severe hypoxaemia (SpO2 less than 80%) when using apnoeic oxygenation at any flow rate from the start of apnoea until successful intubation (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.66 to 1.11; P = 0.25, I² = 0%; 15 studies, 1802 participants; low-certainty evidence). There was insufficient evidence of any effect on the incidence of hypoxaemia (SpO2 less than 93%) (RR 0.58, 95% CI 0.23 to 1.46; P = 0.25, I² = 36%; 3 studies, 489 participants; low-certainty evidence). There may be an improvement in the lowest recorded oxygen saturation, with a mean increase of 1.9% (95% CI 0.75% to 3.05%; P < 0.001, I² = 86%; 15 studies, 1525 participants; low-certainty evidence). There may be a reduction in the duration of ICU stay with the use of apnoeic oxygenation during intubation (mean difference (MD) ‒1.13 days, 95% CI ‒1.51 to ‒0.74; P < 0.0001, I² = 46%; 5 studies, 815 participants; low-certainty evidence). There may be little to no difference in first pass success rate (RR 1.00, 95% CI 0.93 to 1.08; P = 0.79, I² = 0%; 8 studies, 826 participants; moderate-certainty evidence). There may be little to no difference in incidence of adverse events including oral trauma, arrhythmia, aspiration, hypotension, pneumonia and cardiac arrest when apnoeic oxygenation is used. There was insufficient evidence about any effect on mortality (RR 0.84, 95% CI 0.70 to 1.00; P = 0.06, I² = 0%; 6 studies, 1015 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There was some evidence that oxygenation during the apnoeic phase of intubation may improve the lowest recorded oxygen saturation. However, the differences in oxygen saturation were unlikely to be clinically significant. This did not translate into any measurable effect on the incidence of hypoxaemia or severe hypoxaemia in a group of predominately critically ill people. We were unable to assess the influence on hospital length of stay; however, there was a reduction in ICU stay in the apnoeic oxygenation group. The mechanism for this is unclear as there was little to no difference in first pass success or adverse event rates.

Early Albumin Exposure After Cardiac Surgery.

OBJECTIVES: To determine whether the early use of albumin after cardiac surgery in the first 24 hours in the intensive care unit (ICU) is associated with reduced mortality. DESIGN: A single-center nonrandomized retrospective cohort study using the Medical Information Mart in Intensive Care IV database. SETTING: A single cardiothoracic ICU in the United States during a period between 2008 to 2019. PARTICIPANTS: Patients undergoing valvular and/or cardiac bypass graft surgeries. INTERVENTIONS: Albumin administered during the first 24 hours of the ICU admission. MEASUREMENTS AND MAIN RESULTS: A total of 8,136 patients were included in this study, of whom 4,444 (54.6%) received albumin at any stage during the first 24 hours of ICU admission, and 69 (1.6%) of those patients died. The patient population exposed to albumin had higher comorbidities and illness severity compared to the no-albumin group. Patients exposed to albumin during the first 24 hours of ICU admission had a statistically significant reduction in mortality (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.48-0.97, p < 0.05) after adjustment for age, the Oxford Acute Severity of Illness Score, and the Charlson comorbidity index. A sensitivity analysis of patients who received albumin at any stage during ICU admission showed increased mortality (OR, 1.93; 95% CI, 1.26-3.07, p < 0.01). Patients exposed to albumin had a significant increase in adjusted ICU length of stay (LOS) (geometric mean ratio 1.09; 95% CI, 1.05-1.10, p = < 0.001) and hospital LOS (geometric mean ratio 1.08; 95% CI, 1.05-1.10, p < 0.001). CONCLUSIONS: Exposure to albumin in the first 24 hours after cardiac surgery is associated with a reduction in adjusted hospital mortality and an increase in both hospital and ICU lengths of stay.

Outcomes of Prolonged ICU Stay for Patients Undergoing Cardiac Surgery in Australia and New Zealand.

OBJECTIVE: To determine the effect of intensive care unit (ICU) length of stay (LOS) on hospital mortality and non-home discharge for patients undergoing cardiac surgery over a 16-year period in Australia and New Zealand. DESIGN: A retrospective, multicenter cohort study covering the period January 1, 2004 to December 31, 2019. SETTING: One hundred one hospitals in Australia and New Zealand that submitted data to the Australia New Zealand Intensive Care Society Adult Patient Database. PARTICIPANTS: Adult patients (aged >18) who underwent coronary artery bypass grafting, valve surgery, or combined valve + coronary artery surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors analyzed 252,948 cardiac surgical patients from 101 hospitals, with a median age of 68.3 years (IQR 60-75.5), of whom 74.2% (187,632 of 252,948) were male patients. A U-shaped relationship was observed between ICU LOS and hospital mortality, with significantly elevated mortality at short (<20 hours) and long (>5 days) ICU LOS, which persisted after adjustment for illness severity and across clinically important subgroups (odds ratio for mortality with ICU LOS >5 days = 3.21, 95% CI 2.88-3.58, p < 0.001). CONCLUSIONS: Prolonged duration of ICU LOS after cardiac surgery is associated with increased hospital mortality in a U-shaped relationship. An ICU LOS >5 days should be considered a meaningful definition for prolonged ICU stay after cardiac surgery.

Comparison of Supraglottic Airway Devices With Endotracheal Intubation in Low-Risk Patients for Cesarean Delivery: Systematic Review and Meta-analysis.

BACKGROUND: The safety and adverse event rate of supraglottic airway (SGA) devices for cesarean delivery (CD) is poorly characterized. The primary aims of this review were to determine whether the first-pass success was higher and time to insertion for SGA was faster than endotracheal intubation for elective CD. The secondary aim was to determine the airway-related adverse event rate associated with SGA use compared to endotracheal intubation in elective CD under general anesthesia (GA). METHODS: Six databases were systematically searched until September 2019. Included studies reported on the use of SGA in comparison to endotracheal tube intubation. A comparative meta-analysis between SGA and endotracheal intubation was performed using RevMan 5.3 software. Dichotomous outcomes were reported using an odds ratio (OR) with 95% confidence interval (CI). The results for continuous outcomes were reported using a weighted mean difference (WMD) with 95% CI. RESULTS: Fourteen studies with 2236 patients compared SGA and endotracheal intubation. Overall, there was no statistically significant difference in first-attempt success rate (OR = 1.92; 95% CI, 0.85-4.32; I = 0%; P = .44). There was no clinically significant difference in time to insertion (WMD = -15.80 seconds; 95% CI, -25.30 to -6.31 seconds; I= 100%; P = .001). Similarly, there was no difference in any adverse event rate except sore throat which was reduced with the use of an SGA (OR = 0.16; 95% CI, 0.08-0.32; I= 53%; P < .001). CONCLUSIONS: Despite the reasonable insertion success rate and safety profile of SGAs demonstrated in this meta-analysis, the analysis remains underpowered and therefore inconclusive. At present, further studies are required before the use of an SGA as the first-line airway for an elective CD can be recommended.

Standard dose epinephrine versus placebo in out of hospital cardiac arrest: A systematic review and meta-analysis.

INTRODUCTION: Out of hospital cardiac arrest (OHCA) is a time critical and heterogeneous presentation. The most appropriate management strategies remain an issue for debate. The aim of this systematic review and meta-analysis was to determine the association of epinephrine versus placebo with return of spontaneous circulation, survival to hospital admission, survival to hospital discharge and neurological outcomes in out of hospital cardiac arrest. METHODS: A systematic review of five databases was performed from inception to August 2018. Only randomised controlled trials were considered eligible for inclusion. The primary outcome was survival to hospital discharge. Secondary outcomes were ROSC, survival to hospital admission, neurological function on discharge and three-month survival. All studies were assessed for level of evidence and risk of bias. RESULTS: Five randomised controlled trials with 17,635 patients were identified for inclusion. Use of epinephrine was associated with increased ROSC (OR = 3.10; 95% CI = 2.16 to 4.45; I2 = 74%; p < 0.0001) and increased survival to hospital admission OR = 2.52; 95% CI = 1.63 to 3.88; I2 = 94%; p < 0.0001). However, epinephrine was not associated with increased survival to discharge (OR = 1.09; 95% CI = 0.48 to 2.47; I2 = 77%; p = 0.84) or differences in neurological outcomes (OR = 0.81; 95% CI = 0.34 to 1.96). DISCUSSION: This study was a systematic review and meta-analysis of epinephrine versus placebo in OHCA. The use of epinephrine was associated with improved ROSC and survival to hospital admission. However, use of epinephrine was not associated with a significant difference in survival to hospital discharge, neurological outcomes or survival to 3 months. Further research is required to control for the confounders during inpatient management.

Investigating the Impact of Community Volunteerism on the Mental Health of Medical Students.

OBJECTIVE: This study aimed to analyze the impact of community service on the mental health of medical students through their perception of stress. METHODS: The 10-item Perceived Stress Scale was used to measure the stress levels of 82 medical students over a 3-month period. Additional survey questions gauged students' weekly volunteer experiences in clinical and nonclinical settings and their perceived effects on stress and quality of life. RESULTS: Results found an inverse relationship between the number of clinical volunteer hours and perceived stress (P = .0497). Nonclinical and total volunteer hours were correlated with both reduced perceived stress levels (nonclinical P = .0095, total P = .0052) and better quality of life (nonclinical P = .0301, total P = .0136). All individual perceived stress scores fell into the low or moderate stress ranges of the Perceived Stress Scale per the week-to-week analysis. CONCLUSION: The preliminary results raised important research questions about the impact of volunteering on medical student perceived stress. As medical students face higher levels of stress in comparison to the general population, it is exceedingly important to determine methods to decrease their risk of compromising their mental health. This study may aid in decision-making and research in favor of or against offering community service opportunities as part of the core medical education curriculum.

Cricoid pressure during intubation: A systematic review and meta-analysis of randomised controlled trials.

PURPOSE: This systematic review and meta-analysis aimed to determine whether cricoid pressure protects against aspiration and whether this technique adversely affects intubating conditions in adult patients. METHODS: A systematic review of five databases was performed for randomised controlled trials comparing cricoid pressure to no cricoid or sham cricoid during intubation. The primary outcome was incidence of aspiration and the secondary outcomes included first attempt intubation success, time to intubation, Cormack and Lehane Grade 3 or 4 and difficult intubation. RESULTS: The search identified twelve high quality RCTs with 4,862 patients for inclusion. Among four studies reporting the primary outcome, there was no difference (RR=1.18; 95%CI=0.71 to 1.96; I2=0%; p=0.51). Only 3 studies were in patients at high risk of aspiration. There was significantly worse first attempt success (RR= 0.94; 95%CI= 0.89 to 0.99; I2=66%; p=0.02), time to intubation (WMD= 6.77seconds; 95%CI=4.40 to 9.14seconds; I2=97%) and laryngoscopy views (RR=1.69; 95%CI=1.41 to 2.02;I2=1%; p<0.00001) with cricoid pressure. CONCLUSIONS: Cricoid pressure failed to show any increase in protection from aspiration and may increase difficulty of intubation. Further studies in high-risk patients, such as intensive care patients, are required.