Prevention of limb ischemia in patients with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is primarily achieved through the use of distal perfusion catheters (DPC). Our objective was to assess the role of DPC, and specifically the size of the catheter, in reducing the incidence of acute limb ischemia (ALI) through a meta-analysis. Seventeen studies met criteria for analysis. Pooled analysis included a total of 2,040 patients, of which 904 patients received ECMO with DPC and 1,136 patients underwent ECMO without DPC. Compared with ECMO alone, ECMO with DPC, regardless of size, significantly decreased ALI (relative risk [RR]: 0.49, 95% confidence interval [CI]: 0.31-0.77; p = 0.002). When comparing reactive versus prophylactic placement of DPC, prophylactic DPC was associated with significantly decreased ALI (RR: 0.41, 95% CI: 0.24-0.71; p = 0.02). No differences in mortality (RR: 0.89, 95% CI: 0.76-1.03; p = 0.12) and bleeding events (RR: 1.43, 95% CI: 0.41-4.96; p = 0.58) were observed between the two groups. This analysis demonstrates that the placement of DPC, if done prophylactically and regardless of size, is associated with a reduced risk of ALI versus the absence of DPC placement, but is not associated with differences in mortality or bleeding events.

BACKGROUND:Ex vivo lung perfusion (EVLP) enables lung resuscitation before transplantation, and training is key, particularly in low-volume settings. To enable technique refinement and continuing education, we sought to demonstrate the value of a low-cost, high-fidelity EVLP simulator that would allow reproducible clinical scenarios.METHODS:In partnership with our EVLP manufacturer, we utilized the XPS™ Jensen Lung with our clinical system. The Jensen Lung has two simulated lung bladders and an in-line polymethylpentene fiber oxygenator. It allows titration of ventilator support which aids in accurate clinical simulation. For simulations, blood gases (BGs) were obtained and compared with integrated in-line perfusate gas monitors (PGMs). PaO2 , PCO2 , and pH were measured and compared.RESULTS:The PGM and BG values were not significantly different throughout the range of FiO2 and sweep gas flow rates evaluated. The "delta" PaO2 was measured between LA and PA and did not show any change between approaches. The pH measurement between BG and PGM was not significantly different.CONCLUSIONS:The XPS™ Jensen Lung simulator allows for a high-fidelity simulator of clinical EVLP. The correlation of the PGM and the BG measurement of the PaO2 and pH allow for a low-cost simulation, as the PGMs are in line in the circuit, and enable real-time tracking of perfusate gas parameters with the PGM. Implementation of a standardized clinical EVLP training program allows the maintenance of technique and enables clinical simulation training without the need for costly animal perfusions and the use of multiple BG measurements.

IMPORTANCE Improved strategies are needed to decrease opioid use after cesarean delivery but still adequately control postoperative pain. Although transcutaneous electrical stimulation devices have proven effective for pain control after other surgical procedures, they have not been tested as part of a multimodal analgesic protocol after cesarean delivery, the most common surgical procedure in the United States.OBJECTIVE To determine whether treatment with a noninvasive high-frequency electrical stimulation device decreases opioid use and pain after cesarean delivery.DESIGN, SETTING, AND PARTICIPANTS This triple-blind, sham-controlled randomized clinical trial was conducted from April 18, 2022, to January 31, 2023, in the labor and delivery unit at a single tertiary academic medical center in Ohio. Individuals were eligible for the study if they had a singleton or twin gestation and underwent a cesarean delivery. Of 267 people eligible for the study, 134 (50%) were included.INTERVENTION Participants were randomly assigned in a 1:1 ratio to a high-frequency (20 000 Hz) electrical stimulation device group or to an identical-appearing sham device group and received 3 applications at the incision site in the first 20 to 30 hours postoperatively. MAIN OUTCOMES AND MEASURES The primary outcome was inpatient postoperative opioid use, measured in morphine milligram equivalents (MME). Secondary outcomes included pain scores, measured with the Brief Pain Inventory questionnaire (scale, 0-10, with 0 representing no pain), MME prescribed at discharge, and receipt of additional opioid prescriptions in the postpartum period. Normally distributed data were assessed using t tests; otherwise via Mann-Whitney or chi 2 tests as appropriate. Analyses were completed following intention-to-treat principles.RESULTS Of 134 postpartum individuals who underwent a cesarean delivery (mean [SD] age, 30.5 [4.6] years; mean [SD] gestational age at delivery, 38 weeks 6 days [8 days]), 67 were randomly assigned to the functional device group and 67 to the sham device group. Most were multiparous, had prepregnancy body mass index (calculated as weight in kilograms divided by height in meters squared) higher than 30, were privately insured, and received spinal anesthesia. One participant in the sham device group withdrew consent prior to treatment. Individuals assigned to the functional device used significantly less opioid medication prior to discharge (median [IQR], 19.75 [0-52.50] MME) than patients in the sham device group (median [IQR], 37.50 [7.50-67.50] MME; P = .046) and reported similar rates of moderate to severe pain (85% vs 91%; relative risk [RR], 0.77 [95% CI, 0.55-1.29]; P = .43) and mean pain scores (3.59 [95% CI, 3.21-3.98] vs 4.46 [95% CI, 4.01-4.92]; P = .004). Participants in the functional device group were prescribed fewer MME at discharge (median [IQR], 82.50 [0-90.00] MME vs 90.00 [75.00-90.00] MME; P < .001). They were also more likely to be discharged without an opioid prescription (25% vs 10%; RR, 1.58 [95% CI, 1.08-2.13]; P = .03) compared with the sham device group. No treatment-related adverse events occurred in either group.CONCLUSIONS AND RELEVANCE In this randomized clinical trial of postoperative patients following cesarean delivery, use of a high-frequency electrical stimulation device as part of a multimodal analgesia protocol decreased opioid use in the immediate postoperative period and opioids prescribed at discharge. These findings suggest that the use of this device may be a helpful adjunct to decrease opioid use without compromising pain control after cesarean delivery.

ImportanceImproved strategies are needed to decrease opioid use after cesarean delivery but still adequately control postoperative pain. Although transcutaneous electrical stimulation devices have proven effective for pain control after other surgical procedures, they have not been tested as part of a multimodal analgesic protocol after cesarean delivery, the most common surgical procedure in the United States.ObjectiveTo determine whether treatment with a noninvasive high-frequency electrical stimulation device decreases opioid use and pain after cesarean delivery.Design, Setting, and ParticipantsThis triple-blind, sham-controlled randomized clinical trial was conducted from April 18, 2022, to January 31, 2023, in the labor and delivery unit at a single tertiary academic medical center in Ohio. Individuals were eligible for the study if they had a singleton or twin gestation and underwent a cesarean delivery. Of 267 people eligible for the study, 134 (50%) were included.InterventionParticipants were randomly assigned in a 1:1 ratio to a high-frequency (20 000 Hz) electrical stimulation device group or to an identical-appearing sham device group and received 3 applications at the incision site in the first 20 to 30 hours postoperatively.Main Outcomes and MeasuresThe primary outcome was inpatient postoperative opioid use, measured in morphine milligram equivalents (MME). Secondary outcomes included pain scores, measured with the Brief Pain Inventory questionnaire (scale, 0-10, with 0 representing no pain), MME prescribed at discharge, and receipt of additional opioid prescriptions in the postpartum period. Normally distributed data were assessed using t tests; otherwise via Mann-Whitney or χ2 tests as appropriate. Analyses were completed following intention-to-treat principles.ResultsOf 134 postpartum individuals who underwent a cesarean delivery (mean [SD] age, 30.5 [4.6] years; mean [SD] gestational age at delivery, 38 weeks 6 days [8 days]), 67 were randomly assigned to the functional device group and 67 to the sham device group. Most were multiparous, had prepregnancy body mass index (calculated as weight in kilograms divided by height in meters squared) higher than 30, were privately insured, and received spinal anesthesia. One participant in the sham device group withdrew consent prior to treatment. Individuals assigned to the functional device used significantly less opioid medication prior to discharge (median [IQR], 19.75 [0-52.50] MME) than patients in the sham device group (median [IQR], 37.50 [7.50-67.50] MME; P = .046) and reported similar rates of moderate to severe pain (85% vs 91%; relative risk [RR], 0.77 [95% CI, 0.55-1.29]; P = .43) and mean pain scores (3.59 [95% CI, 3.21-3.98] vs 4.46 [95% CI, 4.01-4.92]; P = .004). Participants in the functional device group were prescribed fewer MME at discharge (median [IQR], 82.50 [0-90.00] MME vs 90.00 [75.00-90.00] MME; P < .001). They were also more likely to be discharged without an opioid prescription (25% vs 10%; RR, 1.58 [95% CI, 1.08-2.13]; P = .03) compared with the sham device group. No treatment-related adverse events occurred in either group.Conclusions and RelevanceIn this randomized clinical trial of postoperative patients following cesarean delivery, use of a high-frequency electrical stimulation device as part of a multimodal analgesia protocol decreased opioid use in the immediate postoperative period and opioids prescribed at discharge. These findings suggest that the use of this device may be a helpful adjunct to decrease opioid use without compromising pain control after cesarean delivery.

Both endovascular repair (EVR) and open repair (OR) surgery of thoraco-abdominal aortic aneurysms cause spinal cord (SC) injury that can lead to paraparesis or paraplegia. It has been assumed that mechanisms responsible for SC damage after EVR are similar to those after OR. This pilot study compared the pathophysiology of SC injury after EVR versus OR using a newly developed EVR dog model. An increasing number of stents similar to those used in patients were inserted in the aorta of three dogs to ensure thoracic or thoracic plus lumbar coverage. The aorta of OR dogs was cross-clamped for 45 min. Behavior assessment demonstrated unique patterns of proprioceptive ataxia and evolving paraparesis in EVR versus irreversible paraplegia in OR. MRI showed posterior signal in lumbar SC after EVR versus central cord edema after OR. Histopathology showed white matter edema in L3–L5 localized to the dorsal column medial lemniscus area associated with loss of myelin basic protein but not neurons after EVR, versus massive neuronal loss in the gray matter in L3–L5 after OR. Metabolome analysis demonstrates a distinctive chemical fingerprint of cellular processes in both interventions. Our results call for the development of new therapeutics tailored to these distinct pathophysiologic findings.

Transcriptional repression involves a class of proteins called corepressors that link transcription factors to chromatin remodeling complexes. In plants such as Arabidopsis thaliana, the most prominent corepressor is TOPLESS (TPL), which plays a key role in hormone signaling and development. Here we present the crystallographic structure of the Arabidopsis TPL N-terminal region comprising the LisH and CTLH (C-terminal to LisH) domains and a newly identified third region, which corresponds to a CRA domain. Comparing the structure of TPL with the mammalian TBL1, which shares a similar domain structure and performs a parallel corepressor function, revealed that the plant TPLs have evolved a new tetramerization interface and unique and highly conserved surface for interaction with repressors. Using site-directed mutagenesis, we validated those surfaces in vitro and in vivo and showed that TPL tetramerization and repressor binding are interdependent. Our results illustrate how evolution used a common set of protein domains to create a diversity of corepressors, achieving similar properties with different molecular solutions.

Activated forms of jasmonic acid (JA) are central signals coordinating plant responses to stresses, yet tools to analyse their spatial and temporal distribution are lacking. Here we describe a JA perception biosensor termed Jas9-VENUS that allows the quantification of dynamic changes in JA distribution in response to stress with high spatiotemporal sensitivity. We show that Jas9-VENUS abundance is dependent on bioactive JA isoforms, the COI1 co-receptor, a functional Jas motif and proteasome activity. We demonstrate the utility of Jas9-VENUS to analyse responses to JA in planta at a cellular scale, both quantitatively and dynamically. This included using Jas9-VENUS to determine the cotyledon-to-root JA signal velocities on wounding, revealing two distinct phases of JA activity in the root. Our results demonstrate the value of developing quantitative sensors such as Jas9-VENUS to provide high-resolution spatiotemporal data about hormone distribution in response to plant abiotic and biotic stresses.

The plant hormone auxin is a key morphogenetic regulator acting from embryogenesis onwards. Transcriptional events in response to auxin are mediated by the auxin response factor (ARF) transcription factors and the Aux/IAA (IAA) transcriptional repressors. At low auxin concentrations, IAA repressors associate with ARF proteins and recruit corepressors that prevent auxin-induced gene expression. At higher auxin concentrations, IAAs are degraded and ARFs become free to regulate auxin-responsive genes. The interaction between ARFs and IAAs is thus central to auxin signalling and occurs through the highly conserved domain III/IV present in both types of proteins. Here, we report the crystal structure of ARF5 domain III/IV and reveal the molecular determinants of ARF-IAA interactions. We further provide evidence that ARFs have the potential to oligomerize, a property that could be important for gene regulation in response to auxin.