Autoimmune retinopathy in a patient with smoldering multiple myeloma: a case report.

PURPOSE: Multiple myeloma (MM) is a plasma cell dyscrasia leading to proliferation of monoclonal plasma cells. Ocular involvement in multiple myeloma is uncommon but can occur. The ocular manifestations of MM may include the cornea, uvea, and retinal vasculature. We present a rare case of autoimmune retinopathy associated with smoldering MM. CASE: A 76-year-old female with no significant past medical or ocular history presented with four months of worsening vision, difficulty with night driving, and loss of peripheral vision. Examination was notable for pallor of the optic nerves and vascular attenuation. Visual field testing demonstrated significant and progressive field loss in both eyes. An electroretinogram was extinguished under all conditions. Serum protein electrophoresis showed a significant elevation of IgG with an M-spike, and a subsequent bone marrow biopsy was performed showing 12.5% plasma cells, consistent with the diagnosis of MM. CAR antibody testing was positive for anti-enolase, anti-GAPDH, and anti-Rab6 antibodies, consistent with autoimmune retinopathy. DISCUSSION: Autoimmune retinopathy associated with MM is exceedingly rare. Management of this condition is challenging, as treatment of the underlying disease does not often lead to improvement in visual symptoms. Ultimately, visual prognosis is very poor, and both patients and clinicians should be aware of the guarded visual potential. CONCLUSION: The association of autoimmune retinopathy with multiple myeloma is rare. It is crucial for physicians to be aware of such manifestations to ensure timely and appropriate diagnosis and management for patients.

Weather Patterns and the Frequency of Ophthalmology Consultations in the Emergency Setting.

PURPOSE: To determine if weather patterns are associated with the frequency of ophthalmology consultations in the Emergency Room (ER) and trauma settings. METHODS: Hospital-based ophthalmology consultations between January 1, 2015 and December 31, 2020 at the University of Maryland Medical Center (UMMC) were included in the BALCITE (BALtimore Consultation, Inpatient, and Trauma of the Eye) database. Encounters were filtered to the general ER, the R. Crowley Adams Shock Trauma Center, and consultations within 24 h of admission where a delay was attributed to bed assignment. Weather data from the National Climatic Data Center (NCDC) for Baltimore, Maryland, was matched to the day of the initial encounter. RESULTS: A total of 3,877 patients were included. Overall, there was a significant association between increasing daily average temperature (R2 = .152, p = 0.0003) and daily maximum temperature (R2 = .243, p < 0.001) with incidence of ophthalmology consultations. There was no significant decrease in consultations with increasing precipitation (R2 = -.007, p = 0.7477). For trauma-related consultations, there was not a significant association between consultation incidence and average daily temperature (R2 = .011, p = 0.2013), maximum daily temperature (R2 = -0.012, p = 0.6529), or precipitation levels (R2 = .075, p = 0.24). The months with the highest consultation volume were September, August, and July, and the lowest numbers in April, March, and February. CONCLUSIONS: Emergency ophthalmology consultations increased with increasing daily temperature. Trauma-specific consultations did not show a significant association with weather patterns. This information may prove useful to ER providers and ophthalmologists in order to help predict frequency of consultations and better deploy personnel and resources.

The Effect of Fluid Pre-loading on Vital Signs and Hemodynamic Parameters in a Porcine Model of Lipopolysaccharide-Induced Endotoxemia.

Background Animal models of distributive hypotension and resuscitation allow the assessment of hemodynamic monitoring modalities and resuscitation strategies. The fluid-first paradigm for resuscitation is currently being challenged with clinical trials. In this investigation, venous return and perfusion are assessed, and full hemodynamics are characterized, in a porcine model of endotoxemic hypotension with and without fluid pre-loading. Methods Two groups of six pigs had the induction of standardized endotoxemic hypotension ("critical hypotension"). Group 1 underwent four 10 cc/kg crystalloid boluses, and Group 2 was not fluid pre-resuscitated. Both groups underwent progressive norepinephrine (NE) up-titration to 0.25 mcg/kg/minute over 30 minutes. Vital signs, central parameters, and laboratory values were obtained at baseline, "critical hypotension," after each bolus and during NE administration. Results Endotoxemia decreased the systemic vascular resistance (SVR) in Group 1 (1031±106 dyn/s/cm-5 versus 738±258 dyn/s/cm-5; P=0.03) and Group 2 (1121±196 dyn/s/cm-5 versus 759±342 dyn/s/cm-5; P=0.003). In Group 1, the four fluid boluses decreased heart rate (HR), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) (P<0.05). No changes were observed in blood pressure, cardiac output (CO), or lactate. NE up-titration increased HR in Group 1 and decreased CVP in both groups. Higher final CVP (11 {3} versus 4 {4} mmHg; P=0.01) and PCWP (5 {1} versus 2 {2} mmHg; P=0.005) values were observed in Group 1 relative to Group 2, reflecting increased venous return. Conclusions Porcine endotoxemic hypotension and resuscitation were robustly characterized. In this model, fluid loading improved venous return with NE, though perfusion (CO) was preserved by increased NE-induced chronotropy.

Compound Heterozygous LTBP2 Mutations Associated With Juvenile-Onset Open-Angle Glaucoma and Marfan-Like Phenotype.

This case report describes a patient diagnosed at age 13 years with glaucoma who later presented with elevated intraocular pressure, severe cupping, open iridocorneal angle, and lens dislocation.

Central Venous Waveform Analysis and Cardiac Output in a Porcine Model of Endotoxemic Hypotension and Resuscitation.

BACKGROUND: Cardiac output (CO) is a valuable proxy for perfusion, and governs volume responsiveness during resuscitation from distributive shock. The underappreciated venous system has nuanced physiology that confers valuable hemodynamic information. In this investigation, deconvolution of the central venous waveform by the fast Fourier transformation (FFT) algorithm is performed to assess its ability to constitute a CO surrogate in a porcine model of endotoxemia-induced distributive hypotension and resuscitation. STUDY DESIGN: Ten pigs were anesthetized, catheterized, and intubated. A lipopolysaccharides infusion protocol was used to precipitate low systemic vascular resistance hypotension. Four crystalloid boluses (10 cc/kg) were then given in succession, after which heart rate, mean arterial pressure, thermodilution-derived CO, central venous pressure (CVP), and the central venous waveform were collected, the last undergoing fast Fourier transformation analysis. The amplitude of the fundamental frequency of the central venous waveform's cardiac wave (f0-CVP) was obtained. Heart rate, mean arterial pressure, CVP, f0-CVP, and CO were plotted over the course of the boluses to determine whether f0-CVP tracked with CO better than the vital signs, or than CVP itself. RESULTS: Distributive hypotension to a 25% mean arterial pressure decrement was achieved, with decreased systemic vascular resistance (mean 918 ± 227 [SD] dyne/s/cm-5 vs 685 ± 180 dyne/s/cm-5; p = 0.038). Full hemodynamic parameters characterizing this model were reported. Slopes of linear regression lines of heart rate, mean arterial pressure, CVP, f0-CVP, and CO were -2.8, 1.7, 1.8, 0.40, and 0.35, respectively, demonstrating that f0-CVP values closely track with CO over the 4-bolus range. CONCLUSIONS: Fast Fourier transformation analysis of the central venous waveform may allow real-time assessment of CO during resuscitation from distributive hypotension, possibly offering a venous-based approach to clinical estimation of volume responsiveness.

Factors Associated with Mortality in Patients with COVID-19 Receiving Prolonged Ventilatory Support.

Background: Since its emergence in early 2020, coronavirus disease 2019 (COVID-19)-associated pneumonia has caused a global strain on intensive care unit (ICU) resources with many intubated patients requiring prolonged ventilatory support. Outcomes for patients with COVID-19 who receive prolonged intubation (>21 days) and possible predictors of mortality in this group are not well established. Patients and Methods: Data were prospectively collected from adult patients with COVID-19 requiring mechanical ventilation from March 2020 through December 2021 across a system of 11 hospitals. The primary end point was in-hospital mortality. Factors associated with mortality were evaluated using univariable and multivariable logistic regression analyses. Results: Six hundred six patients were placed on mechanical ventilation for COVID-19 pneumonia during the study period, with in-hospital mortality of 40.3% (n = 244). Increased age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09), increased creatinine (OR, 1.40; 95% CI, 1.08-1.82), and receiving corticosteroids (OR, 2.68; 95% CI, 1.20-5.98) were associated with mortality. Intubations lasting longer than 21 days (n = 140) had a lower in-hospital mortality of 25.7% (n = 36; p < 0.001). Increasing Elixhauser comorbidity index (OR, 1.12; 95% CI, 1.04-1.19) and receiving corticosteroids (OR, 1.92; 95% CI, 1.06-3.47) were associated with need for prolonged ventilation. In this group, increased age (OR, 1.06; 95% CI, 1.01-1.08) and non-English speaking (OR, 3.74; 95% CI, 1.13-12.3) were associated with mortality. Conclusions: In-hospital mortality in mechanically ventilated patients with COVID-19 pneumonia occurs primarily in the first 21 days after intubation, possibly related to the early active inflammatory process. In patients on prolonged mechanical ventilation, increased age and being non-English speaking were associated with mortality.

Perioperative Coagulation Changes in Total Pancreatectomy and Islet Autotransplantation.

OBJECTIVES: Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure. METHODS: This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals. RESULTS: Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation. CONCLUSIONS: Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.

Outcomes of Patients Undergoing Interfacility Extracorporeal Membrane Oxygenation Transfer Based on Cannulation Location and Mode of Transport.

As the use of extracorporeal membrane oxygenation (ECMO) expands, so has the need for interfacility transfer to ECMO centers. However, the impact of these transfers has not been fully studied. This study evaluates complications and inhospital mortality in adult patients treated with venovenous (V-V) ECMO based on institutional location of cannulation and mode of transport. DESIGN: Retrospective cohort study. SETTING: Large midwestern ECMO center. PATIENTS: Adult patients receiving VV-ECMO. INTERVENTIONS: Need for transfer to ECMO center following VV-ECMO cannulation. MEASUREMENTS AND MAIN RESULTS: The study included 102 adult patients, 57% of which were cannulated at an outside institution prior to transfer. Of these, 60% were transported by ground, and the remainder were transported by air. Risk-adjusted logistic regression did not reveal any significant increase in odds for any complication or inhospital mortality between the groups based on location of cannulation or mode of transport. CONCLUSIONS: This study supports the practice of interfacility ECMO transfer with no difference in outcomes or inhospital mortality based on institutional location of cannulation or mode of transport.

Evaluation of Minnesota Score in the Allocation of Venovenous Extracorporeal Membrane Oxygenation During Resource Scarcity.

Background: In this study, we evaluate the previously reported novel Minnesota Score for association with in-hospital mortality and allocation of venovenous extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome with or without SARS-CoV-2 pneumonia. Methods: This was a retrospective cohort study across four extracorporeal membrane oxygenation centers in Minnesota. Logistic regression was used to assess the relationship between the scores and in-hospital mortality, duration of ECMO cannulation, and discharge disposition. Priority groups were established statistically by maximizing the sum of sensitivity and specificity and compared to the previous qualitatively established priority groups. Results: Of 124 patients included in the study, 38% were treated for COVID-19 acute respiratory distress syndrome. The median age was 48 years, and 73% were male. The in-hospital mortality rate was 38%. The Minnesota Score was significantly associated with in-hospital mortality only (OR 1.13, p=0.02). Statistically determined cut points were similar to qualitative cut points. SARS-CoV-2 status did not change the findings. Conclusions: In our patient cohort, the Minnesota Score is associated with increased mortality. With further validation, proposed priority groups could be utilized for allocation of ECMO in times of increasing scarcity.

Comparison of Outcomes and Process of Care for Patients Treated at Hospitals Dedicated for COVID-19 Care vs Other Hospitals.

Importance: Early in the SARS-CoV-2 pandemic, the M Health Fairview Hospital System established dedicated hospitals for establishing cohorts and caring for patients with COVID-19, yet the association between treatment at COVID-19-dedicated hospitals and mortality and complications is not known. Objective: To analyze the mortality rate and complications associated with treatment at the COVID-19-dedicated hospitals. Design, Setting, and Participants: This retrospective cohort study evaluated data prospectively collected from March 1, 2020, through June 30, 2021, from 11 hospitals in Minnesota, including 2 hospitals created solely to care for patients with COVID-19. Data obtained included demographic characteristics, treatments, and outcomes of interest for all patients with a confirmed COVID-19 infection admitted to this hospital system during the study period. Exposures: Patients were grouped based on whether they received treatment from 1 of the 2 COVID-19-dedicated hospitals compared with the remainder of the hospitals within the hospital system. Main Outcomes and Measures: Multivariate analyses, including risk-adjusted logistic regression and propensity score matching, were performed to evaluate the primary outcome of in-hospital mortality and secondary outcomes, including complications and use of COVID-specific therapeutics. Results: There were 5504 patients with COVID-19 admitted during the study period (median age, 62.5 [IQR, 45.0-75.6] years; 2854 women [51.9%]). Of these, 2077 patients (37.7%) (median age, 63.4 [IQR, 50.7-76.1] years; 1080 men [52.0%]) were treated at 1 of the 2 COVID-19-dedicated hospitals compared with 3427 (62.3%; median age, 62.0 [40.0-75.1] years; 1857 women (54.2%) treated at other hospitals. The mortality rate was 11.6% (n = 241) at the dedicated hospitals compared with 8.0% (n = 274) at the other hospitals (P < .001). However, risk-adjusted in-hospital mortality was significantly lower for patients in the COVID-19-dedicated hospitals in both the unmatched group (n = 2077; odds ratio [OR], 0.75; 95% CI, 0.59-0.95) and the propensity score-matched group (n = 1317; OR, 0.78; 95% CI, 0.58-0.99). The rate of overall complications in the propensity score-matched group was significantly lower (OR, 0.81; 95% CI, 0.66-0.99) and the use of COVID-19-specific therapeutics including deep vein thrombosis prophylaxis (83.9% vs 56.9%; P < .001), high-dose corticosteroids (56.1% vs 22.2%; P < .001), remdesivir (61.5% vs 44.5%; P < .001), and tocilizumab (7.9% vs 2.0; P < .001) was significantly higher. Conclusions and Relevance: In this cohort study, COVID-19-dedicated hospitals had multiple benefits, including providing high-volume repetitive treatment and isolating patients with the infection. This experience suggests improved in-hospital mortality for patients treated at dedicated hospitals owing to improved processes of care and supports the use of establishing cohorts for future pandemics.

Increasing Mortality in Venovenous Extracorporeal Membrane Oxygenation for COVID-19-Associated Acute Respiratory Distress Syndrome.

OBJECTIVES: Determine the factors associated with mortality in venovenous extracorporeal membrane oxygenation (V-V ECMO) patients with COVID-19 infection and provide an updated report of clinical outcomes for patients treated with V-V ECMO for COVID-19 in Minnesota. DESIGN: Multicenter prospective observational study. SETTING: The four adult Extracorporeal Life Support Organization-certified Centers of Excellence in Minnesota. PATIENTS: A total of 100 patients treated with V-V ECMO for COVID-19-associated acute respiratory distress syndrome (ARDS) from March 2020 to May 2021. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 60-day survival for patients treated with V-V ECMO for COVID-19. Outcomes of patients treated from November 2020 to May 2021(cohort 2) were compared with data from a previous cohort of patients, collected from March 2020 to October 2020 (cohort 1). The data from both cohorts were merged into a single dataset (Combined Cohort). Survival on V-V ECMO due to COVID-19-associated ARDS significantly decreased after October 2020 (63% vs 41%; p = 0.026). The median interval from hospital admission to V-V ECMO cannulation was significantly associated with 60-day mortality (10 d [6-14 d] in nonsurvivors vs 7 d [4-9 d] in survivors; p = 0.001) in the Combined Cohort and was also significantly longer in cohort 2 than cohort 1 (10 d [7-14 d] vs 6 d [4-10 d]; p < 0.001). In the Combined Cohort, the 60-day survival for patients who did not receive steroids was 86% (n = 12) versus 45% (n = 39) for patients who received at least one dose of steroids (p = 0.005). CONCLUSIONS: There was a significant increase in mortality for patients treated with V-V ECMO for COVID-19-associated ARDS in cohort 2 compared with cohort 1. Further research is required to determine the cause of the worsening trend in mortality.

Attitudes and Perceptions Toward the Use of Medical Marijuana by Glaucoma Specialists.

PRCIS: With expanding legality of medical marijuana (MMJ) in the United States, it is important for ophthalmologists to have greater understanding of the implications of MMJ and glaucoma treatment and how it can impact their patients. PURPOSE: Previous work has demonstrated that inhaled tetrahydrocannabinol can lower intraocular pressure. The stance of the American Glaucoma Society (AGS) is that MMJ is not an acceptable treatment for glaucoma. The purpose of this study is to evaluate the glaucoma specialists' perceptions and attitudes toward the use of MMJ for glaucoma. METHODS: An electronic survey was sent to members of the AGS which addressed attitudes and perceptions on the use of MMJ in the management of glaucoma. Study questions included practitioner demographics, previous experiences with patients discussing the topic, prescribing patterns, and knowledge regarding the use of MMJ for the treatment of glaucoma. RESULTS: Thirty-seven percent of respondents reported having patients who cited using MMJ for their glaucoma, and 38% of respondents were asked about MMJ by their patients at least once per week. Fifty-five percent of respondents had patients who asked them for MMJ prescriptions. When asked if they felt if there was a possible role for marijuana in the management of glaucoma patients, 27% of survey takers responded yes. Fourteen percent of survey respondents kept information on MMJ in their office. Finally, 76% of participants responded they would be interested in additional education on the topic. CONCLUSIONS: Over 25% of the glaucoma specialists responded that MMJ had a role in the treatment of glaucoma, despite the recommendation of the professional society. This group was least likely to have received education on the topic. Given the expanding legality and curiosity of patients with regards to marijuana in the United States, it is important for ophthalmologists to have a greater understanding of the implications of marijuana in glaucoma.

Iris Atrophy After Administration of Intracameral Dexycu in Routine Cataract Surgery: A Case Series.

ABSTRACT: Dexycu (Icon Bioscience INC, Newark, CA) is an FDA-approved single-dose, sustained release intracameral steroid designed to mitigate postoperative inflammation after cataract surgery as an alternative to topical steroid therapy. The purpose of this study was to look at long-term and adverse events associated with Dexycu use. Eighteen eyes from nine patients who underwent cataract surgery were included. Patients were followed for an average of 97 days (range 28-319 days) after surgery on the first eye. Thirteen eyes were treated with Dexycu, and the other five eyes were treated with standard postoperative anti-inflammatory drops. Four of the thirteen eyes receiving Dexycu developed clinically evident iris atrophy (30.7%). None of the five eyes treated with traditional anti-inflammatory drops developed iris atrophy. The Dexycu intraocular dexamethasone implant was designed to mitigate postoperative inflammation and reduce need for topical therapy but may be associated with other potential adverse effects that warrant consideration.

Risk Factors of Mortality for Patients Receiving Venovenous Extracorporeal Membrane Oxygenation for COVID-19 Acute Respiratory Distress Syndrome.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) for select adults with severe acute respiratory distress syndrome (ARDS) cause by coronavirus disease 2019 (COVID-19) infection is a guideline-supported therapy with associated hospital survival of 62%-74%, similar to expected survival with VV-ECMO for other indications. However, ECMO is a resource-heavy intervention, and these patients often require long ECMO runs and prolonged intensive care unit (ICU) care. Identifying factors associated with mortality in VV-ECMO patients with COVID-19 infection can inform the evaluation of ECMO candidates as well as prognostication for those patients on prolonged VV-ECMO. Patients and Methods: This was a retrospective cohort study that included all patients who received either VV- or venoarteriovenous (VAV)-ECMO at one of four ECMO Centers of Excellence in the state of Minnesota between March 1, 2020 and November 1, 2020. The primary outcome was 60-day survival. Secondary outcomes were hospital complications, infectious complications, and complications from ECMO. Results: There were 46 patients who met criteria during this study period and 30 survived to 60-day follow-up (65.2%). Prior to cannulation, older patient age (55.5 in non-survivors vs. 49.1 years in survivors; p = 0.03), lower P/F ratio (62.1 vs. 76.2; p = 0.04), and higher sequential organ failure assessment (SOFA) score (8.1 vs. 6.6; p = 0.02) were identified as risk factors for mortality. After ECMO cannulation, increased mortality was associated with increased number of antibiotic days (25.9 vs. 14.5; p = 0.04), increased number of transfusions (23.9 vs. 9.9; p = 0.03), elevated white blood cell (WBC) count at post-ECMO days one through three, elevated D-dimer at post-ECMO day 21-27, and decreased platelet count from post-ECMO days 14 and onward using univariable analysis. Conclusions: Multiple markers of infection including leukocytosis, thrombocytopenia, and increased antibiotic days are associated with increased mortality in patients placed on VV-ECMO for COVID-19 infection and subsequent ARDS. Knowledge of these factors may assist with determining appropriate candidates for this limited resource as well as direct goals of care in prolonged ECMO courses.

Venoarteriovenous ECMO in Concomitant Acute Respiratory Distress Syndrome and Cardiomyopathy Associated with COVID-19 Infection.

In the most severe cases, novel coronavirus (SARS-CoV-2) infection leads to Acute Respiratory Distress Syndrome which may be refractory to standard medical interventions including mechanical ventilation. There are growing reports of the use of venovenous (VV) extracorporeal membrane oxygenation (ECMO) in these cases. A subset of critically ill COVID-19 patients develops cardiomyopathy as well, manifested by cardiogenic shock with reduced ejection fraction, dysrhythmias, and subsequent increase in mortality. One strategy for managing ARDS with an element of cardiogenic shock is venoarteriovenous (VAV) ECMO. Less than 1% of the cases in the worldwide ELSO COVID-19 database employed any form of hybrid cannulation. To date, there has only been one reported case of patient salvage with arterial or partial arterial support. We present a case that demonstrates the potential role of VAV ECMO in the case of concomitant severe ARDS with cardiomyopathy in the setting of COVID-19 infection.

The Use of Venovenous Extracorporeal Membrane Oxygenation in COVID-19 Infection: One Region's Comprehensive Experience.

Severe acute respiratory distress syndrome (ARDS) unresponsive to conventional intensive care unit (ICU) management is an accepted indication for venovenous extracorporeal membrane oxygenation (V-V ECMO) support. The frequency with which patients with coronavirus disease 2019 (COVID-19) pneumonia are selected for V-V ECMO has not been described. This was a cohort study including all patients placed on either V-V ECMO or venoarteriovenous ECMO at the four adult ECMO Centers of Excellence. Primary outcomes evaluated were survival to decannulation from the ECMO circuit, survival to discharge, and 60-day survival. Secondary outcomes were hospital length of stay (LOS), ICU LOS, length of ECMO cannulation, and length of intubation. During the study period, which corresponded to the first surge in COVID-19 hospitalizations in Minnesota, 35 patients with ARDS were selected for V-V ECMO support out of 1,849 adult ICU patients with COVID-19 infection in the state (1.9% incidence; 95% CI, 1.3-2.6%). This represents 46 (95% CI, 34-61) expected V-V ECMO patients per 100,000 confirmed positive cases of COVID-19. Twenty-six of the 35 patients (74.3%) supported with V-V ECMO survived to 60-day post-ECMO decannulation. Recent studies have demonstrated ongoing success rescuing patients with severe ARDS in COVID-19 infection. Our data add to the support of ECMO and the consideration for encouraging cooperation among regional ECMO centers to ensure access to this highest level of care. Finally, by evaluating all the patients of a single region, we estimate overall need for this resource intensive intervention based on the overall number of COVID-19 cases and ICU admissions.

Probing the functions of the paramyxovirus glycoproteins F and HN with a panel of synthetic antibodies.

Paramyxoviruses are enveloped negative-strand RNA viruses that are significant human and animal pathogens. Most paramyxoviruses infect host cells via the concerted action of a tetrameric attachment protein (variously called HN, H, or G) that binds either sialic acid or protein receptors on target cells and a trimeric fusion protein (F) that merges the viral envelope with the plasma membrane at neutral pH. F initially folds to a metastable prefusion conformation that becomes activated via a cleavage event during cellular trafficking. Upon receptor binding, the attachment protein, which consists of a globular head anchored to the membrane via a helical tetrameric stalk, triggers a major conformation change in F which results in fusion of virus and host cell membranes. We recently proposed a model for F activation in which the attachment protein head domains move following receptor binding to expose HN stalk residues critical for triggering F. To test the model in the context of wild-type viral glycoproteins, we used a restricted-diversity combinatorial Fab library and phage display to rapidly generate synthetic antibodies (sAbs) against multiple domains of the paramyxovirus parainfluenza 5 (PIV5) pre- and postfusion F and HN. As predicted by the model, sAbs that bind to the critical F-triggering region of the HN stalk do not disrupt receptor binding or neuraminidase (NA) activity but are potent inhibitors of fusion. An inhibitory prefusion F-specific sAb recognized a quaternary antigenic site and may inhibit fusion by preventing F refolding or by blocking the F-HN interaction. Importance: The paramyxovirus family of negative-strand RNA viruses cause significant disease in humans and animals. The viruses bind to cells via their receptor binding protein and then enter cells by fusion of their envelope with the host cell plasma membrane, a process mediated by a metastable viral fusion (F) protein. To understand the steps in viral membrane fusion, a library of synthetic antibodies to F protein and the receptor binding protein was generated in bacteriophage. These antibodies bound to different regions of the F protein and the receptor binding protein, and the location of antibody binding affected different processes in viral entry into cells.