Hepatitis C virus E1 recruits high-density lipoprotein to support infectivity and evade antibody recognition.

Hepatitis C virus (HCV) is a member of the Flaviviridae family; however, unlike other family members, the HCV virion has an unusually high lipid content. HCV has two envelope glycoproteins, E1 and E2. E2 contributes to receptor binding, cell membrane attachment, and immune evasion. In contrast, the functions of E1 are poorly characterized due, in part, to challenges in producing the protein. This manuscript describes the expression and purification of a soluble E1 ectodomain (eE1) that is recognized by conformational, human monoclonal antibodies. eE1 forms a complex with apolipoproteins AI and AII, cholesterol, and phospholipids by recruiting high-density lipoprotein (HDL) from the extracellular media. We show that HDL binding is a function specific to eE1 and HDL hinders recognition of E1 by a neutralizing monoclonal antibody. Either low-density lipoprotein or HDL increases the production and infectivity of cell culture-produced HCV, but E1 preferentially selects HDL, influencing both viral life cycle and antibody evasion.IMPORTANCEHepatitis C virus (HCV) infection is a significant burden on human health, but vaccine candidates have yet to provide broad protection against this infection. We have developed a method to produce high quantities of soluble E1 or E2, the viral proteins located on the surface of HCV. HCV has an unusually high lipid content due to the recruitment of apolipoproteins. We found that E1 (and not E2) preferentially recruits host high-density lipoprotein (HDL) extracellularly. This recruitment of HDL by E1 prevents binding of E1 by a neutralizing antibody and furthermore prevents antibody-mediated neutralization of the virus. By comparison, low-density lipoprotein does not protect the virus from antibody-mediated neutralization. Our findings provide mechanistic insight into apolipoprotein recruitment, which may be critical for vaccine development.

Preoperative Quadratus Lumborum Block Reduces Opioid Requirements in the Immediate Postoperative Period Following Hip Arthroscopy: A Randomized, Blinded Clinical Trial.

PURPOSE: To examine acute postoperative opioid consumption in patients undergoing hip arthroscopy and randomized to either receive a preoperative lateral quadratus lumborum block or sham injection. METHODS: This trial randomized 46 subjects undergoing hip arthroscopy with a single surgeon to receive a preoperative lateral quadratus lumborum block (40 mL, ropivacaine 0.25%) or sham injection. The primary outcome was postoperative opioid consumption in patients with and without a block. All opioid medications were converted to morphine milligram equivalents for comparisons. Categorical data were compared with χ2 tests and Fisher exact tests where appropriate. Continuous data were compared with 2-sided t-test and Wilcoxon rank-sum tests. RESULTS: Forty-six subjects scheduled for elective hip arthroscopy were successfully consented and randomized. Demographic and clinical characteristics did not differ. Postoperative opioid consumption decreased 28.3% in patients who received a preoperative lateral quadratus lumborum block (P = .04). Total perioperative opioid consumption (intraoperative and postoperative combined) was reduced 20% in the block group; however, this did not achieve statistical significance (P = .05). Three subjects in the sham group (12.5%) required unblinding for a rescue block in the postoperative anesthetic care unit (PACU) for uncontrolled pain despite systemic analgesics. While cold sensation was decreased postoperatively over the abdomen (P < .001) and anterior thigh (P = .03) in the block group, other PACU variables did not differ, including VAS pain scores, motor function, side effects, PACU duration, and patient satisfaction. CONCLUSIONS: Opioid consumption was reduced in patients who received a preoperative lateral quadratus lumborum block combined with a standardized, multimodal protocol as compared with patients who did not receive a block. Our findings support the growing evidence that quadratus lumborum blocks are an effective component of multimodal analgesia options for patients undergoing elective hip arthroscopy. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Anesthetic Management of Severe Pulmonary Hypertension in Pregnancy.

Pregnancy entails significant changes in maternal physiology that are not well-tolerated in patients with pulmonary arterial hypertension. The profound changes in plasma volume, cardiac output, and systemic vascular resistance can lead to increased strain placed on the right ventricle, leading to right-heart failure and cardiovascular collapse. Given the complex and sometimes opposing physiologic changes, managing these patients can be challenging. As such, these patients have a significantly increased reported maternal mortality rate. This report describes a parturient with newly diagnosed severe pulmonary arterial hypertension and her anesthetic management.

A Challenging Cesarean Delivery and Perioperative Course in a Former Polysubstance Abuser Without the Use of Traditional Opioids.

Substance abuse is a major challenge in the United States. According to the Human Resources and Services Administration, we are in an opioid crisis with over 130 people a day dying from opioid-related drug overdoses. As awareness of this epidemic has grown, there has been an increase in patients coming in for surgery requesting a narcotic-free anesthetic. This presents both a challenge and an opportunity for the anesthesiologist who has a duty to respect the patient's autonomy while simultaneously achieving the appropriate perioperative outcome. The considerations are especially important in the vulnerable population of pregnant women.

Examination of intra-operative core temperature in joint arthroplasty: a single-institution prospective observational study.

PURPOSE: Peri-operative hypothermia is associated with increased blood loss, delayed wound healing, and surgical site infections. However, it is not known when or how rapidly hypothermia develops during arthroplasty. This study observed patients undergoing lower extremity arthroplasty to identify the times of greatest heat loss or gain. METHODS: This single-institution prospective observational study enrolled 120 patients undergoing elective knee or hip arthroplasty for peri-operative temporal temperature measurements at ten prespecified intervals. Incidence of hypothermia was the primary outcome. A secondary aim was to identify patient and operative factors associated with hypothermia. Descriptive statistics were calculated for fixed time variables. Associations for the occurrence of hypothermia over time were conducted using generalized linear mixed models with a logit link and a random subject effect to account for repeated measures on the same individual over time. RESULTS: Most patients, 72.6%, experienced hypothermia with 20.6% hypothermic for over one hour and 47.1% hypothermic after surgery. In the multivariable model, increased odds of hypothermia were associated with female gender (P = 0.017), knee arthroplasty (P < 0.001), neuraxial anaesthesia (P < 0.001), lower patient pre-operative temperature (P < 0.001), and lower operating room temperature (P = 0.042). A 0.5 °C decrease in patient pre-operative temperature or operating room temperature was associated with a 97 and 11% increase in the odds of hypothermia, respectively, controlling for other factors. CONCLUSION: In our series, peri-operative hypothermia remains common for patients undergoing arthroplasty. Female gender, low pre-operative temperature, knee arthroplasty, and neuraxial anesthesia were associated with hypothermia. Further preventative strategies and studies on interventions to reduce hypothermia are needed.

It Is Not Always the Epidural: A Case Report of Anterior Spinal Artery Ischemia in a Trauma Patient.

Motor vehicle collisions impact millions of people annually resulting in multiinjury trauma. Anesthesiologists are consulted for rib fracture analgesia to improve respiratory mechanics and prevent intubation. This report describes a trauma patient who developed hypotension and lower extremity weakness after epidural placement for multiple rib fractures. Initially, hypotension was attributed to neuraxial sympathectomy. However, physical examination also indicated anterior spinal artery ischemia. Regional anesthesia and acute pain teams must be able to both identify contraindications and complications of regional techniques and discern when complications are not a result of regional interventions to initiate prompt management and definitive care.

Hip Hemiarthroplasty in Two Patients with Severe Aortic Stenosis: Ethical Questions from an Anesthesiologist's Perspective.

As the population ages, geriatric patients with preexisting cardiac disease are presenting for noncardiac surgery in escalating numbers. The decision to proceed with surgery in such patients often is multifactorial. With this in mind, we describe 2 patients with severe aortic stenosis who required hip operations: one urgent and one elective. Both patients had different anesthetic plans and did well intraoperatively. However, both patients died postoperatively because of their comorbidities. Although published guidelines are sparse, we hope this report will increase awareness and discussion about caring for geriatric patients with severe aortic stenosis.

Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen-Disparate Murine Model.

In the current study we evaluated the effects of immunoproteasome inhibition using ONX 0914 (formerly PR-957) to ameliorate graft-versus-host disease (GVHD). ONX 0914, an LMP7-selective epoxyketone inhibitor of the immunoproteasome, has been shown to reduce cytokine production in activated monocytes and T cells and attenuate disease progression in mouse models of rheumatoid arthritis, colitis, systemic lupus erythematosus, and, more recently, encephalomyelitis. Inhibition of LMP7 with ONX 0914 in the B10.BR→CBA MHC-matched/minor histocompatibility antigen (miHA)-disparate murine blood and marrow transplant (BMT) model caused a modest but significant improvement in the survival of mice experiencing GVHD. Concomitant with these results, in vitro mixed lymphocyte cultures revealed that stimulator splenocytes, but not responder T cells, treated with ONX 0914 resulted in decreased IFN-γ production by allogeneic T cells in both MHC-disparate (B10.BR anti-B6) and miHA-mismatched (B10.BR anti-CBA) settings. In addition, a reduction in the expression of the MHC class I-restricted SIINFEKL peptide was observed in splenocytes from transgenic C57BL/6-Tg(CAG-OVA)916Jen/J mice exposed to ONX 0914. Taken together, these data support that LMP7 inhibition in the context of BMT modulates allogeneic responses by decreasing endogenous miHA presentation and that the consequential reduction in allogeneic stimulation and cytokine production reduces GVHD development.