SummaryDuring morphogenesis of mature HIV-1 cores, the viral capsid (CA) proteins assemble conical or tubular shells around the viral ribonucleoprotein complexes. This assembly step is mimicked in vitro through reactions in which CA proteins oligomerize to form long tubes, and this process can be modeled as consisting of a slow nucleation period followed by a rapid phase of tube growth. We have developed a novel fluorescence microscopy approach to monitor in vitro assembly reactions and have employed it, along with electron microscopy analysis, to characterize the assembly process. Our results indicate that temperature, salt concentration, and pH changes have differential effects on tube nucleation and growth steps. We also demonstrate that assembly can be unidirectional or bidirectional, that growth can be capped, and that proteins can assemble onto the surfaces of tubes, yielding multiwalled or nested structures. Finally, experiments show that a peptide inhibitor of in vitro assembly also can dismantle pre-existing tubes, suggesting that such reagents may possess antiviral effects against both viral assembly and uncoating. Our investigations help establish a basis for understanding the mechanism of mature HIV-1 core assembly, and avenues for antiviral inhibition.

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A number of cardiovascular and neurological diseases are characterized by a dysregulation of intravascular volume distribution. The veins and arteries of the visceral organs form the so-called splanchnic vascular compartment and are the largest reservoir for intravascular blood. The blood localized in the splanchnic compartment can be mobilized in and out of the compartment via passive compression or active neurohormonal recruitment. We studied the hemodynamic effects of splanchnic nerve stimulation during five cases of irreversible electroporation (IRE) in patients with pancreatic cancer. In IRE, repeated bursts of high-voltage electrical fields are applied to visceral beds for >1 min, which induces rapid increase in blood pressure, heart rate, and cardiac output. We present the first analysis into the hemodynamic changes with splanchnic nerve stimulation and explore potential mechanisms of the hyperdynamic state. Our analysis presents the first human report of splanchnic nerve stimulation to induce hypertension and volume redistribution, introducing the splanchnic nerves as a key component of cardiovascular regulation. Our case series provides the first detailed description of human hemodynamic effects with splanchnic nerve stimulation. Splanchnic nerve stimulation results in profound hemodynamic alteration with rapid onset of hypertension and blood mobilization.

Analgesia after total hip arthroplasty is often accomplished by the fascia iliaca compartment block, traditionally performed below the inguinal ligament, to anesthetize both femoral and lateral femoral cutaneous nerves. The course of the lateral femoral cutaneous nerve below the inguinal ligament is variable as opposed to consistent above the inguinal ligament in the pelvis. In this case series including 5 patients, we demonstrate that an ultrasound-guided suprainguinal fascia iliaca approach would consistently anesthetize the lateral femoral cutaneous nerve along with anterior cutaneous femoral nerve branches and provide cutaneous analgesia after total hip arthroplasty, as shown by decreased opioid consumption.

Pectoral nerve blocks have been described in the setting of breast surgery to provide chest wall analgesia. We report the first successful use of Pecs blocks to provide effective chest wall analgesia for a patient undergoing minimally invasive cardiac surgery with thoracotomy. We believe that these blocks may provide an important nonopioid option for the management of pain during recovery from minimally invasive cardiac surgery.

Critically ill patients are a heterogeneous group with diverse comorbidities and physiological derangements. The management of pain in the critically ill population is emerging as a standard of care in the intensive care unit (ICU). Pain control of critically ill patients in the ICU presents numerous challenges to intensivists. Inconsistencies in pain assessment, analgesic prescription and variation in monitoring sedation and analgesia result in suboptimal pain management. Inadequate pain control can have deleterious effects on several organ systems in critically ill patients. Therefore, it becomes incumbent on physicians and nurses caring for these patients to carefully evaluate their practice on pain management and adopt an optimal pain management strategy that includes a reduction in noxious stimuli, adequate analgesia and promoting education regarding sedation and analgesia to the ICU staff. Mechanistic approaches and multimodal analgesic techniques have been clearly demonstrated to be the most effective pain management strategy to improve outcomes. For example, recent evidence suggests that the use of short acting analgesics and analgesic adjuncts for sedation is superior to hypnotic based sedation in intubated patients. This review will address analgesia in the ICU, including opioid therapy, adjuncts, regional anaesthesia and non-pharmacological options that can provide a multimodal approach to treating pain.

In its severe manifestation, coronavirus disease 2019 (COVID-19) compromises oxygenation in a manner that is refractory to maximal conventional support and requires escalation to extracorporeal membrane oxygenation (ECMO). Maintaining ECMO support for extended durations requires a delicately balanced anticoagulation strategy to maintain circuit viability by preventing thrombus deposition while avoiding excessive anticoagulation yielding hemorrhage-a task that is complicated in COVID-19 secondary to an inherent hypercoagulable state. Bivalirudin, a member of the direct thrombin inhibitor drug class, offers potential advantages during ECMO, including to its ability to exert its effect by directly attaching to and inhibiting freely circulating and fibrin-bound thrombin. Herein, the successful use of an anticoagulation strategy using the off-label use of a continuous infusion of bivalirudin in a case of severe hypoxemic and hypercarbic respiratory failure caused by COVID-19 requiring venovenous ECMO is reported. Importantly, therapeutic anticoagulation intensity was achieved rapidly with stable pharmacokinetics, and there was no need for any circuit interventions throughout the patient's 27-day ECMO course. In COVID-19, bivalirudin offers a potential option for maintaining systemic anticoagulation during ECMO in a manner that may mitigate the prothrombotic nature of the underlying pathophysiologic state.

Background Shock severity predicts mortality in patients with cardiogenic shock (CS). We evaluated the association between pre-cannulation Society for Cardiovascular Angiography and Interventions (SCAI) shock classification and mortality among patients receiving venoarterial (VA) extracorporeal membrane oxygenation (ECMO) support for CS. Methods We included Extracorporeal Life Support Organization (ELSO) Registry patients from 2010 to 2020 who received VA ECMO for CS. SCAI shock stage was assigned based on hemodynamic support requirements prior to ECMO initiation. In-hospital mortality was analyzed using multivariable logistic regression. Results We included 12106 unique VA ECMO patient-runs with a median age of 57.9 (interquartile range 46.8, 66.1) years and 31.8% were females; 3472 (28.7%) were post-cardiotomy. The distribution of SCAI shock stages at ECMO initiation was: B, 821 (6.8%); C, 7518 (62.1%); D, 2973 (24.6%); and E, 794 (6.6%). During the index hospitalization, 6681 (55.2%) patients died. In-hospital mortality increased incrementally with SCAI shock stage (adjusted OR 1.24 per SCAI shock stage, 95% CI 1.17-1.32, p < 0.001): B, 47.5%; C, 52.8%; D, 60.8%; E, 65.1%. A higher SCAI shock stage was associated with increased in-hospital mortality in key subgroups, although the SCAI shock classification was only predictive of mortality in non-surgical (medical) CS, and not in post-cardiotomy CS. Conclusions The severity of shock prior to cannulation is a strong predictor of in-hospital mortality in patients receiving VA ECMO for CS. Using the pre-cannulation SCAI shock classification as a risk stratification tool can help clinicians refine prognostication for ECMO recipients and guide future investigations to improve outcomes.