Engineering a "muco-trapping" ACE2-immunoglobulin hybrid with picomolar affinity as an inhaled, pan-variant immunotherapy for COVID-19.

Soluble angiotensin-converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a "muco-trapping" ACE2-Fc conjugate, termed ACE2-(G4S)6-Fc, comprised of the extracellular segment of ACE2 (lacking the C-terminal collectrin domain) that is linked to mucin-binding IgG1-Fc via an extended glycine-serine flexible linker. ACE2-(G4S)6-Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2-Fc decoys or similar truncated ACE2-Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2-(G4S)6-Fc effectively trapped fluorescent SARS-CoV-2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2-(G4S)6-Fc in hamsters as late as 2 days postinfection provided a 10-fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2-(G4S)6-Fc as an inhaled immunotherapy for COVID-19, as well as other emerging viruses that bind ACE2 for cellular entry.

Inhaled "Muco-Trapping" Monoclonal Antibody Effectively Treats Established Respiratory Syncytial Virus (RSV) Infections.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via the apical membrane and almost exclusively sheds progeny virions back into the airway mucus (AM), making RSV difficult to target by systemically administered therapies. An inhalable "muco-trapping" variant of motavizumab (Mota-MT), a potent neutralizing mAb against RSV F is engineered. Mota-MT traps RSV in AM via polyvalent Fc-mucin bonds, reducing the fraction of fast-moving RSV particles in both fresh pediatric and adult AM by ≈20-30-fold in a Fc-glycan dependent manner, and facilitates clearance from the airways of mice within minutes. Intranasal dosing of Mota-MT eliminated viral load in cotton rats within 2 days. Daily nebulized delivery of Mota-MT to RSV-infected neonatal lambs, beginning 3 days after infection when viral load is at its maximum, led to a 10 000-fold and 100 000-fold reduction in viral load in bronchoalveolar lavage and lung tissues relative to placebo control, respectively. Mota-MT-treated lambs exhibited reduced bronchiolitis, neutrophil infiltration, and airway remodeling than lambs receiving placebo or intramuscular palivizumab. The findings underscore inhaled delivery of muco-trapping mAbs as a promising strategy for the treatment of RSV and other acute respiratory infections.

No Miracles in Two Minutes: A Randomized Controlled Study on the Impact of Preparatory Expansive Posing on Anesthesiology Residents' Performance in Mock Structured Oral Examinations.

Background: The objective of this study was to evaluate the impact of engaging in preparatory expansive posing on the performance of anesthesiology trainees during a mock structured oral examination. Methods: A total of 38 clinical residents at a single institution participated in this prospective randomized controlled study. Participants were stratified by clinical anesthesia year and randomly assigned to 1 of 2 orientation rooms to prepare for the examination. The preparatory expansive posing participants stood for 2 minutes with their hands and arms above their heads and with their feet approximately 1 ft apart. Conversely, the control participants sat quietly in a chair for 2 minutes. All participants then received the same orientation and examination. Faculty evaluation of resident performance, residents' self-assessment of performance, and anxiety score were collected. Results: There was no evidence to support our primary hypothesis that residents who engaged in preparatory expansive posing for 2 minutes prior to a mock structured oral examination would score higher than their control counterparts (P = .68). There was no evidence to support our secondary hypotheses that preparatory expansive posing increases self-assessment of one's performance (P = .31) or reduces perceived anxiety during a mock structured oral examination (P = .85). Conclusions: Preparatory expansive posing did not improve anesthesiology residents' mock structured oral examination performance or self-assessment of their performance, nor did it reduce their perceived anxiety. Preparatory expansive posing is likely not a useful technique in improving the performance of residents in structured oral examinations.

Comparison of Landmark-Guided Versus Fluoroscopy-Guided Cerebrospinal Fluid Drain-Related Complications After Aortic Repairs.

OBJECTIVE: Cerebrospinal fluid drains (CSFDs) are efficacious in preventing spinal cord injury after thoracic or thoracoabdominal aortic repair with extensive coverage. Increasingly, fluoroscopy is used to guide placement instead of the traditional landmark-based approach, but it is unknown which approach is associated with fewer complications. DESIGN: A retrospective cohort study. SETTING: In the operating room. PARTICIPANTS: Patients having undergone thoracic or thoracoabdominal aortic repair with a CSFD over a 7-year period at a single center. INTERVENTIONS: No intervention. MEASUREMENTS AND MAIN RESULTS: Groups were reviewed and statistically compared with respect to baseline characteristics, ease of CSFD placement, and major and minor complications directly related to placement. A total of 150 CSFDs were placed with landmark guidance as opposed to 95 with fluoroscopy guidance. Compared to the landmark group, patients with fluoroscopy-guided CSFDs were older (p < 0.008), had lower American Society of Anesthesiologists physical status scores (p = 0.008), required fewer CSFD placement attempts (p = 0.011), had the CSFD in place for longer duration (p < 0.001), and had a similar incidence of CSFD-related complications (p > 0.999). Composites of both major (4.5% of cases) and minor CSFD-related complications (6.1% of cases), the primary outcomes of the study, occurred with similar incidences between the 2 groups (p > 0.999 for both comparisons) after adjusting potential confounders. CONCLUSIONS: In patients undergoing thoracic or thoracoabdominal aortic repairs, there were no significant differences in the risk of major and minor CSFD-related complications between fluoroscopic guidance and the landmark approach. Although the authors' institution is a high-volume center for this type of procedure, the study was limited by a small sample size. Hence, regardless of the technique used for the placement of CSFD, the risks related to the placement should be balanced carefully against the potential benefits resulting from spinal cord injury prevention. Fluoroscopy-aided insertion of CSFD requires fewer attempts and, hence, may be better tolerated by patients.

Normalizing salt content by mixing native human airway mucus samples normalizes sample rheology.

Across the globe, millions of people are affected by muco-obstructive pulmonary diseases like cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In MOPDs, the airway mucus becomes hyperconcentrated, increasing viscoelasticity and impairing mucus clearance. Research focused on treatment of MOPDs requires relevant sources of airway mucus both as a control sample type and as a basis for manipulation to study the effects of additional hyperconcentration, inflammatory milieu, and biofilm growth on the biochemical and biophysical properties of mucus. Endotracheal tube mucus has been identified as a prospective source of native airway mucus given its several advantages over sputum and airway cell culture mucus such as ease of access and in vivo production that includes surface airway and submucosal gland secretions. Still, many ETT samples suffer from altered tonicity and composition from either dehydration, salivary dilution, or other contamination. Herein, the biochemical compositions of ETT mucus from healthy human subjects were determined. Samples were characterized in terms of tonicity, pooled, and restored to normal tonicity. Salt-normalized ETT mucus exhibited similar concentration-dependent rheologic properties as originally isotonic mucus. This rheology agreed across spatial scales and with previous reports of the biophysics of ETT mucus. This work affirms previous reports of the importance of salt concentration on mucus rheology and presents methodology to increase yield native airway mucus samples for laboratory use and manipulation.

Cerebrospinal Fluid Drainage for Prevention of Spinal Cord Ischemia in Thoracic Endovascular Aortic Surgery-Pros and Cons.

Thoracic endovascular aortic repair (TEVAR) carries a risk of spinal cord ischemia (SCI) which exerts a devastating impact on patient's quality of life and life expectancy. Although routine prophylactic cerebrospinal fluid (CSF) drainage is not unequivocally supported by current data, several studies have demonstrated favorable outcomes. Patients at high risk for SCI following TEVAR likely will benefit from prophylactic CSF drains. However, the intervention is not risk free, and thorough risk/benefit analysis should be individualized to each patient.

Hypothermia and Prolonged Time From Procedure End to Extubation After Endovascular Thoracic Aortic Surgery.

OBJECTIVE: Perioperative hypothermia (core temperature <36°C) occurs in 50%-to-80% of patients recovering from thoracic aortic surgery, though its effects have not been described fully in this context. The authors, therefore, sought to characterize the incidence of perioperative hypothermia and its association with time from procedure end to extubation in endovascular aortic surgical patients. DESIGN: A retrospective cohort study. SETTING: At a single academic tertiary center. PARTICIPANTS: Patients recovering from thoracic aortic surgery with lumbar drains. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A total of 196 patients were included in this study, 55 of whom were hypothermic with temperatures <35.0°C at the end of surgery. Though the unadjusted time to extubation was not statistically different in the hypothermic group (median 8 minutes, IQR 5-13.5 minutes) compared to the normothermic group (median 7 minutes, IQR 4-12 minutes; p = 0.062), multivariate predictors of increased time from procedure end to extubation included hypothermia (p = 0.011), age (p = 0.009), diabetes (p = 0.015), history of carotid disease (p = 0.040), and crystalloid volume (p = 0.019). CONCLUSIONS: Hypothermia in patients recovering from endovascular aortic surgery was associated with prolonged time from procedure end to extubation. Because of the retrospective observational nature of the authors' analysis, it was not possible to determine the extent to which prolonged mechanical ventilation was influenced by low temperature.

Utilizing multimodal analgesia to evaluate postoperative analgesic requirements in kidney transplant recipients.

The use of non-opioid analgesics following surgery has proven beneficial in managing pain and decreasing adverse outcomes following surgery. Data assessing outcomes related to opioid use is limited in kidney transplant recipients (KTRs). We evaluated the effectiveness of implementing a reduced to no opioid use protocol in KTRs. This retrospective cohort study included adult KTRs between January 2017 and July 2019 with a multimodal analgesic protocol (MAP), focused on limiting opioids, implemented in August 2018. We compared analgesic requirements in morphine milligram equivalents (MME) during transplant admissions between the MAP cohort and traditional cohort. There were 217 KTRs who met the criteria. Inpatient opioid use was significantly reduced in the MAP cohort (16.5 ± 19.2 MME/day vs 24.7 ± 19.7 MME/day; P <.05) with no significant difference in pain scores. No use of opioids within six months of discharge was significantly increased in the MAP cohort (50% vs 7%; P <.001), and there were no reported deaths at six months in either cohort. The use of multimodal analgesia is beneficial in KTRs to provide adequate pain control with limited to no exposure of opioids during admission or at discharge.

Anesthesia for Combined Heart and Liver Transplantation.

A heart or liver transplantation procedure performed in isolation itself presents multiple challenges for the perioperative team. Accordingly, combining both transplants yields a vastly more complicated surgery, with many unique multisystem and multidisciplinary considerations. Although combined heart and liver transplantations are being performed with increasing frequency, nationwide experience is relatively limited at most institutions. The aim of this review is to discuss the perioperative challenges presented to the anesthesiology teams and provide evidence-based guidance for the management of these daunting procedures.