The p24-family and COPII subunit SEC24C facilitate the clearance of alpha1-antitrypsin Z from the endoplasmic reticulum to lysosomes.

A subpopulation of the alpha-1-antitrypsin misfolding Z mutant (ATZ) is cleared from the endoplasmic reticulum (ER) via an ER-to-lysosome-associated degradation (ERLAD) pathway. Here, we report that the COPII subunit SEC24C and the p24-family of proteins facilitate the clearance of ATZ via ERLAD. In addition to the previously reported ERLAD components calnexin and FAM134B, we discovered that ATZ coimmunoprecipitates with the p24-family members TMP21 and TMED9. This contrasts with wild type alpha1-antitrypsin, which did not coimmunoprecipitate with FAM134B, calnexin or the p24-family members. Live-cell imaging revealed that ATZ and the p24-family members traffic together from the ER to lysosomes. Using chemical inhibitors to block ER exit or autophagy, we demonstrated that p24-family members and ATZ co-accumulate at SEC24C marked ER-exit sites or in ER-derived compartments, respectively. Furthermore, depletion of SEC24C, TMP21, or TMED9 inhibited lysosomal trafficking of ATZ and resulted in the increase of intracellular ATZ levels. Conversely, overexpression of these p24-family members resulted in the reduction of ATZ levels. Intriguingly, the p24-family members coimmunoprecipitate with ATZ, FAM134B, and SEC24C. Thus, we propose a model in which the p24-family functions in an adaptor complex linking SEC24C with the ERLAD machinery for the clearance of ATZ.

Transport of Peripartum Patients for Medical Management: Predictors of Any Intervention During Transport.

Background When obstetric patients present to a hospital without obstetric consultants for medical care, they are often transferred for a higher level of care. Factors associated with patient care during transport between hospitals are unknown. Our study investigated factors associated with care intensity. Methods We retrospectively reviewed charts from peripartum adult patients who were transported to our academic quaternary center between January 1, 2012, and April 19, 2020. We excluded patients transported for gynecologic or fetus-related complications. We defined any transport interventions as any ventilator management, any titration of continuous infusions, and any continuation or initiation of medication during transport. Results We included 126 patients, and the mean age (SD) was 29 (7) years. There were 87 (695) antepartum patients, with nine (7%) requiring mechanical ventilation. Of the patients, 98 (78%) received at least one intervention during transport. Transport time (OR: 1.03, 95% CI: 1.001-1.06, P = 0.040), preeclampsia (OR: 3.8, 95% CI: 1.1-12.7, P = 0.030), and any obstetric hemorrhage (OR: 8.3, 95% CI: 1.03-68, P = 0.047), either antepartum or postpartum, were associated with higher likelihood of receiving any intervention. Conclusions Peripartum patients often received interventions during transport. Preeclampsia and hemorrhage were associated with the likelihood of interventions. Transport clinicians should be prepared when transporting these patients. Further studies are needed to confirm our observations.

Discrepancy Between Invasive and Noninvasive Blood Pressure Measurements in Patients with Sepsis by Vasopressor Status.

INTRODUCTION: Blood pressure (BP) monitoring is an essential component of sepsis management. The Surviving Sepsis Guidelines recommend invasive arterial BP (IABP) monitoring, although the benefits over non-invasive BP (NIBP) monitoring are unclear. This study investigated discrepancies between IABP and NIBP measurement and their clinical significance. We hypothesized that IABP monitoring would be associated with changes in management among patients with sepsis requiring vasopressors. METHODS: We performed a retrospective study of adult patients admitted to the critical care resuscitation unit at a quaternary medical center between January 1-December 31, 2017. We included patients with sepsis conditions AND IABP monitoring. We defined a clinically significant BP discrepancy (BPD) between NIBP and IABP measurement as a difference of > 10 millimeters of mercury (mm Hg) AND change of BP management to maintain mean arterial pressure ≥ 65 mm Hg. RESULTS: We analyzed 127 patients. Among 57 (45%) requiring vasopressors, 9 (16%) patients had a clinically significant BPD vs 2 patients (3% odds ratio [OR] 6.4; 95% CI: 1.2-30; P = 0.01) without vasopressors. In multivariable logistic regression, higher Sequential Organ Failure Assessment (SOFA) score (OR 1.33; 95% CI: 1.02-1.73; P = 0.03) and serum lactate (OR 1.27; 95% CI: 1.003-1.60, P = 0.04) were associated with increased likelihood of clinically significant BPD. There were no complications (95% CI: 0-0.02) from arterial catheter insertions. CONCLUSION: Among our population of septic patients, the use of vasopressors was associated with increased odds of a clinically significant blood pressure discrepancy between IABP and NIBP measurement. Additionally, higher SOFA score and serum lactate were associated with higher likelihood of clinically significant blood pressure discrepancy. Further studies are needed to confirm our observations and investigate the benefits vs the risk of harm of IABP monitoring in patients with sepsis.

Arterial or cuff pressure: Clinical predictors among patients in shock in a critical care resuscitation unit.

OBJECTIVES: Blood pressure (BP) measurement is essential for managing patients with hypotension. There are differences between invasive arterial blood pressure (IABP) and noninvasive blood pressure (NIBP) measurements. However, the clinical applicability of these differences in patients with shock [need for vasopressor or serum lactate ≥ 4 millimole per liter (mmol/L)] has not been reported. This study investigated differences in IABP and NIBP as well as changes in clinical management in critically ill patients with shock. METHODS: This was a retrospective study involving adult patients admitted to the Critical Care Resuscitation Unit (CCRU). Adult patients who received IABP upon admission between 01/01/2017-12/31/2017 with non-hypertensive diseases were eligible. The primary outcome, clinically relevant difference (CRD), was defined as difference of 10 mm of mercury (mmHg) between IABP and NIBP and change of blood pressure management according to goal mean arterial pressure (MAP) ≥ 65 mmHg. We performed forward stepwise multivariable logistic regression to measure associations. RESULTS: Sample size calculation recommended 200 patients, and we analyzed 263. 121 (46%) patients had shock, 23 (9%) patients had CRD. Each mmol/L increase in serum lactate was associated with 11% higher likelihood of having CRD (OR 1.11, 95%CI 1.002-1.2). Peripheral artery disease and any kidney disease was significantly associated with higher likelihood of MAP difference ≥ 10 mmHg. CONCLUSION: Approximately 9% of patients with shock had clinically-relevant MAP difference. Higher serum lactate was associated with higher likelihood of CRD. Until further studies are available, clinicians should consider using IABP in patients with shock.

Blood pressure management in emergency department patients with spontaneous intracerebral hemorrhage.

INTRODUCTION: Despite the well documented importance of blood pressure management in patients with spontaneous intracerebral hemorrhage (sICH), little is known about whether emergency departments (EDs) are able to achieve close monitoring and precise management. Our study characterizes ED monitoring and management of blood pressure in sICH patients. METHODS: This is a retrospective study of adults with sICH and elevated intracranial pressure. Patients who were admitted from any referring ED to our CCRU from 1 August 2013 to 30 September 2015 were included. We graphically assessed the association between average minutes between blood pressure measurements and average minutes between administration of antihypertensives. We also performed logistic regression to evaluate factors associated with close blood pressure monitoring and the achievement of goal blood pressure in patients with sICH who presented with hypertension. RESULTS: Of 115 patients, 73 presented to the ED with SBP above 160 mmHg. Length of stay in the ED was significantly associated with a longer period between blood pressure measurements. Longer periods between blood pressure measurements were a significant determinant of failure to achieve blood pressure goal in sICH patients. Longer periods between blood pressure measurements were significantly associated with longer periods between administration of antihypertensives. CONCLUSION: Our study suggests that blood pressure monitoring is related to the frequency of blood pressure interventions and achievement of adequate blood pressure control in patients with sICH. There is significant variability in EDs' achievement of the recommended close blood pressure monitoring and management in patients with sICH.