Summary The cellular and viral determinants required for HIV-1 infection of nondividing cells have been a subject of intense scrutiny. Here we identify the 68 kDa subunit of cleavage factor Im, CPSF6, as an inhibitor of HIV-1 infection. When enriched in the cytoplasm by high level expression or mutation, CPSF6 prevents nuclear entry of the virus. Similar to TRIM5 and Fv1 type restrictions, CPSF6 targets the viral capsid (CA). N74D mutation of the HIV-1 CA leads to a loss of interaction with CPSF6 and evasion of the nuclear import restriction. Interestingly, N74D mutation of CA changes HIV-1 nucleoporin (NUP) requirements. Whereas wild-type HIV-1 requires NUP153, N74D HIV-1 mimics the NUP requirements of feline immunodeficiency virus (FIV) and is more sensitive to NUP155 depletion. These findings reveal a remarkable flexibility in HIV-1 nuclear transport and highlight a single residue in CA as essential in regulating interactions with NUPs.

Background Intraoperative burst-suppression is associated with postoperative delirium. Whether this association is causal remains unclear. Therefore, the authors investigated whether burst-suppression during cardiopulmonary bypass (CPB) mediates the effects of known delirium risk factors on postoperative delirium. Methods This was a retrospective cohort observational substudy of the Minimizing ICU [intensive care unit] Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) trial. The authors analyzed data from patients more than 60 yr old undergoing cardiac surgery (n = 159). Univariate and multivariable regression analyses were performed to assess for associations and enable causal inference. Delirium risk factors were evaluated using the abbreviated Montreal Cognitive Assessment and Patient-Reported Outcomes Measurement Information System questionnaires for applied cognition, physical function, global health, sleep, and pain. The authors also analyzed electroencephalogram data (n = 141). Results The incidence of delirium in patients with CPB burst-suppression was 25% (15 of 60) compared with 6% (5 of 81) in patients without CPB burst-suppression. In univariate analyses, age (odds ratio, 1.08 [95% CI, 1.03 to 1.14]; P = 0.002), lowest CPB temperature (odds ratio, 0.79 [0.66 to 0.94]; P = 0.010), alpha power (odds ratio, 0.65 [0.54 to 0.80]; P < 0.001), and physical function (odds ratio, 0.95 [0.91 to 0.98]; P = 0.007) were associated with CPB burst-suppression. In separate univariate analyses, age (odds ratio, 1.09 [1.02 to 1.16]; P = 0.009), abbreviated Montreal Cognitive Assessment (odds ratio, 0.80 [0.66 to 0.97]; P = 0.024), alpha power (odds ratio, 0.75 [0.59 to 0.96]; P = 0.025), and CPB burst-suppression (odds ratio, 3.79 [1.5 to 9.6]; P = 0.005) were associated with delirium. However, only physical function (odds ratio, 0.96 [0.91 to 0.99]; P = 0.044), lowest CPB temperature (odds ratio, 0.73 [0.58 to 0.88]; P = 0.003), and electroencephalogram alpha power (odds ratio, 0.61 [0.47 to 0.76]; P < 0.001) were retained as predictors in the burst-suppression multivariable model. Burst-suppression (odds ratio, 4.1 [1.5 to 13.7]; P = 0.012) and age (odds ratio, 1.07 [0.99 to 1.15]; P = 0.090) were retained as predictors in the delirium multivariable model. Delirium was associated with decreased electroencephalogram power from 6.8 to 24.4 Hertz. Conclusions The inference from the present study is that CPB burst-suppression mediates the effects of physical function, lowest CPB temperature, and electroencephalogram alpha power on delirium. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background: Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m 2 ] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. Methods: In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012-2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015-2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. Results: The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m 2 ), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m 2 ). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13-0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74). Conclusion: Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.

Summary and Background Data: VV ECMO can be utilized as an advanced therapy in select patients with COVID-19 respiratory failure refractory to traditional critical care management and optimal mechanical ventilation. Anticipating a need for such therapies during the pandemic, our center created a targeted protocol for ECMO therapy in COVID-19 patients that allows us to provide this life-saving therapy to our sickest patients without overburdening already stretched resources or excessively exposing healthcare staff to infection risk. Methods: As a major regional referral program, we used the framework of our well-established ECMO service-line to outline specific team structures, modified patient eligibility criteria, cannulation strategies, and management protocols for the COVID-19 ECMO program. Results: During the first month of the COVID-19 outbreak in Massachusetts, 6 patients were placed on VV ECMO for refractory hypoxemic respiratory failure. The median (interquartile range) age was 47 years (43–53) with most patients being male (83%) and obese (67%). All cannulations were performed at the bedside in the intensive care unit in patients who had undergone a trial of rescue therapies for acute respiratory distress syndrome including lung protective ventilation, paralysis, prone positioning, and inhaled nitric oxide. At the time of this report, 83% (5/6) of the patients are still alive with 1 death on ECMO, attributed to hemorrhagic stroke. 67% of patients (4/6) have been successfully decannulated, including 2 that have been successfully extubated and one who was discharged from the hospital. The median duration of VV ECMO therapy for patients who have been decannulated is 12 days (4–18 days). Conclusions: This is 1 the first case series describing VV ECMO outcomes in COVID-19 patients. Our initial data suggest that VV ECMO can be successfully utilized in appropriately selected COVID-19 patients with advanced respiratory failure.

Rationale: Obesity is characterized by elevated pleural pressure (P PL) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). Objectives: To determine the effects of lung recruitment maneuver (LRM) in the presence of elevated P PL on hemodynamics, left and right ventricular pressures and pulmonary vascular resistance. We hypothesized that elevated P PL protects the cardiovascular system against high airway pressures and prevents lung overdistension. Methods: First, an interventional crossover trial in adult subjects with ARDS and BMI≥35 kg/m 2 (n=21) was performed to explore the hemodynamic consequences of LRM. Second, cardiovascular function was studied during low/high PEEPs in a model of swine with ARDS and high P PL (n=9) versus healthy swine with normal P PL (n=6). Measurements and Main Results: Subjects with ARDS and obesity (BMI=57±12 kg/m 2) following LRM, required an increase in PEEP of 8[7, 10] cmH 2 O above traditional ARDSnet settings to improve lung function, oxygenation and ventilation/perfusion matching, without impairment of hemodynamics or right heart function. ARDS swine with high P PL demonstrated unchanged transmural left ventricle pressure and systemic blood pressure after LRM protocol. Pulmonary artery hypertension decreased 8[13, 4] mmHg, as did vascular resistance 1.5[2.2, 0.9] WU, and transmural right ventricle pressure 10[15, 6] mmHg during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized ventilation/perfusion ratio.

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P ¼ 0.04), procalcitonin levels (P ¼ 0.02), and IL-6 levels (P ¼ 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P ¼ 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.

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Intraoperative transesophageal echocardiography (TEE) is a helpful diagnostic tool when hemodynamic compromise is encountered during noncardiac surgery. At our institution, a Rescue Echo Protocol was created to provide a structured means for requesting and performing a rescue TEE. We analyzed our institutional utilization of this service and found that it was used throughout the spectrum of patients' American Society of Anesthesiologists classifications and surgical services. We demonstrated that 72.9% of rescue examinations resulted in a change in management, supporting the use of TEE as a diagnostic tool during hemodynamic compromise.