Desflurane is risk factor for postoperative delirium in older patients' independent from intraoperative burst suppression duration.

Background: Postoperative Delirium (POD) is the most frequent neurocognitive complication after general anesthesia in older patients. The development of POD is associated with prolonged periods of burst suppression activity in the intraoperative electroencephalogram (EEG). The risk to present burst suppression activity depends not only on the age of the patient but is also more frequent during propofol anesthesia as compared to inhalative anesthesia. The aim of our study is to determine, if the risk to develop POD differs depending on the anesthetic agent given and if this correlates with a longer duration of intraoperative burst suppression. Methods: In this secondary analysis of the SuDoCo trail [ISRCTN 36437985] 1277 patients, older than 60 years undergoing general anesthesia were included. We preprocessed and analyzed the raw EEG files from each patient and evaluated the intraoperative burst suppression duration. In a logistic regression analysis, we assessed the impact of burst suppression duration and anesthetic agent used for maintenance on the risk to develop POD. Results: 18.7% of patients developed POD. Burst suppression duration was prolonged in POD patients (POD 27.5 min ± 21.3 min vs. NoPOD 21.4 ± 16.2 min, p < 0.001), for each minute of prolonged intraoperative burst suppression activity the risk to develop POD increased by 1.1% (OR 1.011, CI 95% 1.000-1.022, p = 0.046). Burst suppression duration was prolonged under propofol anesthesia as compared to sevoflurane and desflurane anesthesia (propofol 32.5 ± 20.3 min, sevoflurane 17.1 ± 12.6 min and desflurane 20.1 ± 16.0 min, p < 0.001). However, patients receiving desflurane anesthesia had a 1.8fold higher risk to develop POD, as compared to propofol anesthesia (OR 1.766, CI 95% 1.049-2.974, p = 0.032). Conclusion: We found a significantly increased risk to develop POD after desflurane anesthesia in older patients, even though burst suppression duration was shorter under desflurane anesthesia as compared to propofol anesthesia. Our finding might help to explain some discrepancies in studies analyzing the impact of burst suppression duration and EEG-guided anesthesia on the risk to develop POD.

Superinfections in COVID-19 patients receiving extracorporeal membrane oxygenation support.

BACKGROUND: The risk of superinfections and associations with mortality among patients with corona virus disease 2019 (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) is poorly elucidated. METHOD: We identified all patients with COVID-19 treated with VV-ECMO >24 h at Rigshospitalet, Denmark from March 2020 to December 2021. Data were obtained by review of medical files. Associations between superinfections and mortality were assessed by logistic regression analyses adjusted for sex and age. RESULTS: Fifty patients, median age 53 years (interquartile range [IQR] 45-59), 66% male, were included. Median time on VV-ECMO was 14.5 days (IQR 6.3-23.5), 42% were discharged from hospital alive. Bacteremia, ventilator associated pneumonia (VAP), invasive candidiasis, pulmonary aspergillosis, herpes simplex virus, and cytomegalovirus (CMV) were detected in 38%, 42%, 12%, 12%, 14%, and 20% of patients, respectively. No patients with pulmonary aspergillosis survived. CMV was associated with increased risk of death, odds ratio 12.6 (95% confidence interval 1.9-257, p = .05), whereas we found no associations between other superinfections and risk of death. CONCLUSION: Bacteremia and VAP are common but does not seem to affect mortality, whereas pulmonary aspergillosis and CMV are associated with poor prognosis among COVID-19 patients treated with VV-ECMO.

Species-agnostic polymeric formulations for inhalable messenger RNA delivery to the lung.

Messenger RNA has now been used to vaccinate millions of people. However, the diversity of pulmonary pathologies, including infections, genetic disorders, asthma and others, reveals the lung as an important organ to directly target for future RNA therapeutics and preventatives. Here we report the screening of 166 polymeric nanoparticle formulations for functional delivery to the lungs, obtained from a combinatorial synthesis approach combined with a low-dead-volume nose-only inhalation system for mice. We identify P76, a poly-ß-amino-thio-ester polymer, that exhibits increased expression over formulations lacking the thiol component, delivery to different animal species with varying RNA cargos and low toxicity. P76 allows for dose sparing when delivering an mRNA-expressed Cas13a-mediated treatment in a SARS-CoV-2 challenge model, resulting in similar efficacy to a 20-fold higher dose of a neutralizing antibody. Overall, the combinatorial synthesis approach allowed for the discovery of promising polymeric formulations for future RNA pharmaceutical development for the lungs.

In-hospital and 6-month outcomes in patients with COVID-19 supported with extracorporeal membrane oxygenation (EuroECMO-COVID): a multicentre, prospective observational study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been widely used in patients with COVID-19, but uncertainty remains about the determinants of in-hospital mortality and data on post-discharge outcomes are scarce. The aims of this study were to investigate the variables associated with in-hospital outcomes in patients who received ECMO during the first wave of COVID-19 and to describe the status of patients 6 months after ECMO initiation. METHODS: EuroECMO-COVID is a prospective, multicentre, observational study developed by the European Extracorporeal Life Support Organization. This study was based on data from patients aged 16 years or older who received ECMO support for refractory COVID-19 during the first wave of the pandemic-from March 1 to Sept 13, 2020-at 133 centres in 21 countries. In-hospital mortality and mortality 6 months after ECMO initiation were the primary outcomes. Mixed-Cox proportional hazards models were used to investigate associations between patient and management-related variables (eg, patient demographics, comorbidities, pre-ECMO status, and ECMO characteristics and complications) and in-hospital deaths. Survival status at 6 months was established through patient contact or institutional charts review. This study is registered with ClinicalTrials.gov, NCT04366921, and is ongoing. FINDINGS: Between March 1 and Sept 13, 2020, 1215 patients (942 [78%] men and 267 [22%] women; median age 53 years [IQR 46-60]) were included in the study. Median ECMO duration was 15 days (IQR 8-27). 602 (50%) of 1215 patients died in hospital, and 852 (74%) patients had at least one complication. Multiorgan failure was the leading cause of death (192 [36%] of 528 patients who died with available data). In mixed-Cox analyses, age of 60 years or older, use of inotropes and vasopressors before ECMO initiation, chronic renal failure, and time from intubation to ECMO initiation of 4 days or more were associated with higher in-hospital mortality. 613 patients did not die in hospital, and 547 (95%) of 577 patients for whom data were available were alive at 6 months. 102 (24%) of 431 patients had returned to full-time work at 6 months, and 57 (13%) of 428 patients had returned to part-time work. At 6 months, respiratory rehabilitation was required in 88 (17%) of 522 patients with available data, and the most common residual symptoms included dyspnoea (185 [35%] of 523 patients) and cardiac (52 [10%] of 514 patients) or neurocognitive (66 [13%] of 512 patients) symptoms. INTERPRETATION: Patient's age, timing of cannulation (<4 days vs ≥4 days from intubation), and use of inotropes and vasopressors are essential factors to consider when analysing the outcomes of patients receiving ECMO for COVID-19. Despite post-discharge survival being favourable, persisting long-term symptoms suggest that dedicated post-ECMO follow-up programmes are required. FUNDING: None.

N-glycosylation profiles of the SARS-CoV-2 spike D614G mutant and its ancestral protein characterized by advanced mass spectrometry.

N-glycosylation plays an important role in the structure and function of membrane and secreted proteins. The spike protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is heavily glycosylated and the major target for developing vaccines, therapeutic drugs and diagnostic tests. The first major SARS-CoV-2 variant carries a D614G substitution in the spike (S-D614G) that has been associated with altered conformation, enhanced ACE2 binding, and increased infectivity and transmission. In this report, we used mass spectrometry techniques to characterize and compare the N-glycosylation of the wild type (S-614D) or variant (S-614G) SARS-CoV-2 spike glycoproteins prepared under identical conditions. The data showed that half of the N-glycosylation sequons changed their distribution of glycans in the S-614G variant. The S-614G variant showed a decrease in the relative abundance of complex-type glycans (up to 45%) and an increase in oligomannose glycans (up to 33%) on all altered sequons. These changes led to a reduction in the overall complexity of the total N-glycosylation profile. All the glycosylation sites with altered patterns were in the spike head while the glycosylation of three sites in the stalk remained unchanged between S-614G and S-614D proteins.

High-throughput quantitation of SARS-CoV-2 antibodies in a single-dilution homogeneous assay.

SARS-CoV-2 emerged in late 2019 and has since spread around the world, causing a pandemic of the respiratory disease COVID-19. Detecting antibodies against the virus is an essential tool for tracking infections and developing vaccines. Such tests, primarily utilizing the enzyme-linked immunosorbent assay (ELISA) principle, can be either qualitative (reporting positive/negative results) or quantitative (reporting a value representing the quantity of specific antibodies). Quantitation is vital for determining stability or decline of antibody titers in convalescence, efficacy of different vaccination regimens, and detection of asymptomatic infections. Quantitation typically requires two-step ELISA testing, in which samples are first screened in a qualitative assay and positive samples are subsequently analyzed as a dilution series. To overcome the throughput limitations of this approach, we developed a simpler and faster system that is highly automatable and achieves quantitation in a single-dilution screening format with sensitivity and specificity comparable to those of ELISA.

How Does Telehealth Compare to In- Person Care? Qualitative Perspectives from an Outpatient Integrative Medicine Setting

Objective: Integrative medicine is a key framework for the treatment of chronic medical conditions, particularly chronic pain. In-person visits pose notable barriers for individuals with pain or limited mobility, particularly in rural or underserved areas. However, many barriers are pertinent to the expansion of telehealth use in integrative medicine settings, such as concerns about maintaining patient-clinician rapport in the delivery of holistic, relationship-based care. The COVID-19 pandemic served as impetus for an immediate and complete transition to telehealth services in this interdisciplinary outpatient integrative medicine clinic. This poster will present rich qualitative perspectives from multiple stakeholder levels on the experience of virtual visits to examine whether telehealth represents an acceptable, accessible, and high-quality option for providing integrative healthcare. Methods: Patients (N=180), providers (N=19), and administrative staff (N=7) in our outpatient integrative health clinic were surveyed about their experience of providing or receiving care via telehealth. Specifically, participants were asked to describe what telehealth visits were like in comparison to in-person visits. Free-text responses were analyzed for major and minor emergent themes. Results: Major themes identified from the data included acceptability, ease/convenience, comfort, interpersonal connection, technology difficulties, application of telehealth to group/movement classes, and equity/access. Overwhelmingly, participants described telehealth as an acceptable and adequate, at times equal or superior, alternative to in-person visits. Importantly, telehealth improved comfort for patients who could hold visits at home where they were most comfortable. Challenges were also welldescribed including technological issues and loss of interpersonal connection. Conclusion: Telehealth visits represent an acceptable, at times preferable, way to deliver care in an outpatient integrative medicine setting. Telehealth represents a particularly promising care modality for patients experiencing chronic pain or limited mobility, or those residing in rural and underserved communities. Detailed qualitative results provide rich perspective to inform future implementation and health policy regarding telehealth use.

Pivot to telehealth: Preference for telehealth measured quantitatively sustained over three months at outpatient center for integrative medicine

Objective: Interdisciplinary integrative medicine is key to treatment of chronic pain conditions. In-person visits can burden this population, particularly in rural and underserved areas with limited transportation options. Telehealth visits, were historically unsupported by payment models, delivery platforms, health and technological literacy, and clinician buy-in. The COVID-19 pandemic initiated a rapid transition to telehealth at our interdisciplinary outpatient integrative medicine center. This poster will describe the quantitative experience of telehealth integrative medicine services among stakeholders. Methods: Patients (n=472), clinicians (n=25), and staff (n=12) ranked telehealth vs in-person visits by survey with custom scale quality judgments and discrete choice after transitioning to telehealth and three months later. Results: Patient quality judgements significantly favored telehealth at baseline, B=.77 [0.29-1.25], SE=.25, t(712)= 3.15, p=.002, and increased in preference for telehealth at three months, B=.27 [-0.03-0.57], SE=.15, t(712)= 1.76, p=.079. Quality of technology, residing outside the county, and experiencing multiple disciplines predicted patient telehealth favorability. Clinicians did not favor one modality over the other, B=-1.00 [-1.56--0.44], SE=.29, t(799)=-3.48, p<.001. Patient discrete choice split at baseline and favored telehealth at three months. Overall, discrete choice favored telehealth at follow-up across clinicians and patients. Administrative staff's overall impression of telehealth was most favorable of all groups. Conclusion: Telehealth is a promising care modality for patients experiencing chronic pain. Far from a temporary preference, after three months, the majority of patients indicated they would choose telehealth visits over inperson visits, if they were equally safe. Policy that does not support telehealth for outpatient integrative medicine cannot do so under the name of patient preference, perceptions of quality, patient choice, or access.

COMPLEX VENOUS THROMBOEMBOLISM DECISION-MAKING IN POSTPARTUM PATIENT

Background May-Thurner syndrome and pregnancy are independent risk factors for the development of deep vein thrombosis (DVT). Emerging data suggests an association for venous thromboembolism (VTE) development in COVID-19 patients. Treatments for DVT vary and include thrombolysis, mechanical thrombectomy and long-term anticoagulation. We describe a unique case of this in a postpartum female. Case A 31 year old female G3P0121 and recent cesarean section 1 month ago presented with left lower extremity swelling, severely limited ambulation and 3+ edema of the left leg extending to the hip without any right leg edema. She was COVID-19 antibody positive. Occlusive DVTs were confirmed via venous duplex ultrasound and computed tomographic venography of the abdomen and pelvis, extending from distal inferior vena cava to the left popliteal vein. Decision-making Invasive venography confirmed the non-invasive imaging findings. After administering 12-14 mg of tissue plasminogen activator (tPA), multiple aspirations were performed using a rheolytic thrombectomy catheter. However persistent dense thrombus in the iliac and femoral veins remained, thus subsequent balloon angioplasty was performed but unsuccessful. Intravascular ultrasound confirmed the presence of May-Thurner syndrome at the junction of the left common iliac vein and the inferior vena cava. Finally an infusion catheter was placed for tPA. Within 48 hours, patient developed oliguric renal failure likely due to a combination of contrast-induced and pigment nephropathy requiring intermittent hemodialysis. Repeat ultrasound showed resolution of DVT along with improving edema and renal function. Warfarin was chosen for long-term anticoagulation due to renal failure and breast-feeding. Conclusion Pregnancy is a pro thrombotic state that may lead to VTE even in the postpartum period. Decision-making and treatment in these patients may be complex and require a multidisciplinary approach.

Rapid development of neutralizing and diagnostic SARS-COV-2 mouse monoclonal antibodies.

The need for high-affinity, SARS-CoV-2-specific monoclonal antibodies (mAbs) is critical in the face of the global COVID-19 pandemic, as such reagents can have important diagnostic, research, and therapeutic applications. Of greatest interest is the ~ 300 amino acid receptor binding domain (RBD) within the S1 subunit of the spike protein because of its key interaction with the human angiotensin converting enzyme 2 (hACE2) receptor present on many cell types, especially lung epithelial cells. We report here the development and functional characterization of 29 nM-affinity mouse SARS-CoV-2 mAbs created by an accelerated immunization and hybridoma screening process. Differing functions, including binding of diverse protein epitopes, viral neutralization, impact on RBD-hACE2 binding, and immunohistochemical staining of infected lung tissue, were correlated with variable gene usage and sequence.

Treatment of influenza and SARS-CoV-2 infections via mRNA-encoded Cas13a in rodents.

Cas13a has been used to target RNA viruses in cell culture, but efficacy has not been demonstrated in animal models. In this study, we used messenger RNA (mRNA)-encoded Cas13a for mitigating influenza virus A and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in mice and hamsters, respectively. We designed CRISPR RNAs (crRNAs) specific for PB1 and highly conserved regions of PB2 of influenza virus, and against the replicase and nucleocapsid genes of SARS-CoV-2, and selected the crRNAs that reduced viral RNA levels most efficiently in cell culture. We delivered polymer-formulated Cas13a mRNA and the validated guides to the respiratory tract using a nebulizer. In mice, Cas13a degraded influenza RNA in lung tissue efficiently when delivered after infection, whereas in hamsters, Cas13a delivery reduced SARS-CoV-2 replication and reduced symptoms. Our findings suggest that Cas13a-mediated targeting of pathogenic viruses can mitigate respiratory infections.