Measuring the Effect of Off-Balancing Vectors on the Delivery of High-Quality CPR during Ambulance Transport: A Proof of Concept Study.

AIM: This study aims to demonstrate the feasibility of quantifying the off-balancing vectors experienced during ambulance transport and comparing them to high-quality cardiopulmonary resuscitation (HQ-CPR) metrics. METHODS: Ten participants completed a total of 20 evolutions of compression-only HQ-CPR in an ambulance driven in a manner that minimized or increased linear and angular off-balancing vectors. Linear and angular velocity, linear and angular acceleration, and linear jerk were recorded. HQ-CPR variables measured were compression fraction and proportion of compressions with depth >5 cm (depth%), rate 100-120 (rate%), full chest recoil (recoil%), and hand position (hand%). A composite score was calculated: [(depth% + rate% + recoil% + hand%)/4) * compression fraction]. Difficulty of HQ-CPR performance was measured with the Borg rating of perceived exertion (RPE) Scale. A series of mixed effects models were fitted regressing each HQ-CPR metric on each off-balancing vector. RESULTS: HQ-CPR data and vector quantity data were successfully recorded in all evolutions. Rate% was negatively associated with increasing linear velocity (slope = -3.82, standard error [SE] 1.12, p = 0.005), linear acceleration (slope = -5.52, SE 1.93, p = 0.013), linear jerk (slope = -17.60, SE 5.78, p = 0.007), angular velocity (slope = -75.74, SE 22.72, p = 0.004), and angular acceleration (slope = -152.53, SE 59.60, p = 0.022). Compression fraction was negatively associated with increasing linear velocity (slope = -1.35, SE 0.37, p = 0.004), linear acceleration (slope = -1.67, SE 0.48, p = 0.003), linear jerk (slope = -4.90, SE 1.86, p = 0.018), angular velocity (slope = -25.66, SE 6.49, p = 0.001), and angular acceleration (slope = -45.35, SE 18.91, p = 0.031). Recoil% was negatively associated with increasing linear velocity (slope = -5.80, SE 2.21, p = 0.023) and angular velocity (slope = -116.96, SE 44.24, p = 0.019)). Composite score was negatively associated with increasing linear velocity (slope = -4.49, SE 1.45, p = 0.009) and angular velocity (slope = -86.13, SE 31.24, p = 0.014) and approached a negative association with increasing magnitudes of linear acceleration (slope -5.54, SE 2.93, p = 0.075), linear jerk (slope = -17.43, SE 8.80, p = 0.064), and angular acceleration (slope = -170.43, SE 80.73, p = 0.051). Borg RPE scale was positively associated with all off-balancing vectors. Depth%, hand%, mean compression depth, and mean compression rate were not correlated with any off-balancing vector. CONCLUSION: Off-balancing vector data can be successfully quantified during ambulance transport and compared with HQ-CPR performance parameters. Increasing off-balancing vectors experienced during ambulance transport are associated with worse HQ-CPR metrics and increased perceived physical exertion. These data may help guide future drive styles, ambulance design, or use of mechanical CPR devices to improve HQ-CPR delivery during selected patient transport scenarios.

Development of a model to measure the effect of off-balancing vectors on the delivery of high-quality CPR in a moving vehicle.

AIM: We sought to develop a model to measure the acceleration and jerk vectors affecting the performance of High-Quality Cardiopulmonary Resuscitation (HQ-CPR) during patient transport. METHODS: Three participants completed a total of eighteen rounds of compression only HQ-CPR in a moving vehicle. The vehicle was driven in a manner that either minimized or increased linear and angular vectors. The HQ-CPR variables measured were compression fraction (CF%), and percentages of compressions with correct depth > 5 cm (D%), rate 100-120 (R%), full recoil (FR%), and hand position (HP%). A composite HQ-CPR score was calculated: ((D% + R% + FR% + HP%)/4) * CF%). Linear and gyroscopic data were measured in the X, Y, and Z axes. The perceived difficulty in performing HQ-CPR was measured with the Borg Rating of Perceived Exertion Scale. RESULTS: HQ-CPR data, linear vector data, and gyroscopic data were successfully recorded in all trial evolutions. Univariate regression analysis demonstrated that HQ-CPR was negatively affected by increasing magnitudes of linear acceleration (B = -0.093%/m/s2, 95% CI [-0.17 - -0.02), p = 0.02], linear jerk (B = -0.134%/m/s3, 95% CI [-0.26 - -0.01], p = 0.04), angular velocity (B = -0.543%/radian/s, 95% CI [-0.98 - -0.11], p = 0.02), and angular acceleration (B = 0.863%/radian/s2, 95% CI [-1.69 - -0.03], p = 0.04). Increasing vectors were negatively associated with FR% and R%. No difference was seen in D%, HP%, or CF%. Borg Rating of Perceived Exertion was greater in dynamic driving evolutions (8 ± 1 vs 3.5 ± 1.53, p = 0.02). CONCLUSION: This model reliably measured linear and angular off-balancing vectors experienced during the delivery of HQ-CPR in a moving vehicle. In this preliminary report, compression rate and full recoil appear to be HQ-CPR variables most affected in a moving vehicle.

Evaluation of High Altitude Interstitial Pulmonary Edema in Healthy Participants Using Rapid 4-View Lung Ultrasound Protocol During Staged Ascent to Everest Base Camp.

INTRODUCTION: Prior research identified possible interstitial pulmonary fluid, concerning for early high altitude pulmonary edema (HAPE), in a large percentage of trekkers above 3000 m using a comprehensive 28-view pulmonary ultrasound protocol. These trekkers had no clinical symptoms of HAPE despite these ultrasound findings. The more common 4-view lung ultrasound protocol (LUP) is accurate in rapidly detecting interstitial edema during resource-rich care. The objective of this study was to evaluate whether the 4-view LUP detects interstitial fluid in trekkers ascending to Everest Base Camp. METHODS: Serial 4-view LUP was performed on 15 healthy trekkers during a 9-d ascent from Kathmandu to Everest Base Camp. Ascent protocols complied with Wilderness Medical Society guidelines for staged ascent. A 4-view LUP was performed in accordance with the published 2012 international consensus protocols on lung ultrasound. Symptom assessment and 4-view LUP were obtained at 6 waypoints along the staged ascent. A 4-view LUP was positive for interstitial edema if ≥3 B-lines were detected in 2 ultrasound windows. RESULTS: A single participant had evidence of interstitial lung fluid at 5380 m as defined by the 4-view LUP. There was no evidence of interstitial fluid in any participant below 5380 m. One participant was evacuated for acute altitude sickness at 4000 m but showed no preceding sonographic evidence of interstitial fluid. CONCLUSIONS: In this small study, sonographic detection of interstitial fluid, suggestive of early HAPE, was not identified by the 4-view LUP protocol.

Effect of Abdominal Ultrasound on Clinical Care, Outcomes, and Resource Use Among Children With Blunt Torso Trauma: A Randomized Clinical Trial.

Importance: The utility of the focused assessment with sonography for trauma (FAST) examination in children is unknown. Objective: To determine if the FAST examination during initial evaluation of injured children improves clinical care. Design, Setting, and Participants: A randomized clinical trial (April 2012-May 2015) that involved 975 hemodynamically stable children and adolescents younger than 18 years treated for blunt torso trauma at the University of California, Davis Medical Center, a level I trauma center. Interventions: Patients were randomly assigned to a standard trauma evaluation with the FAST examination by the treating ED physician or a standard trauma evaluation alone. Main Outcomes and Measures: Coprimary outcomes were rate of abdominal computed tomographic (CT) scans in the ED, missed intra-abdominal injuries, ED length of stay, and hospital charges. Results: Among the 925 patients who were randomized (mean [SD] age, 9.7 [5.3] years; 575 males [62%]), all completed the study. A total of 50 patients (5.4%, 95% CI, 4.0% to 7.1%) were diagnosed with intra-abdominal injuries, including 40 (80%; 95% CI, 66% to 90%) who had intraperitoneal fluid found on an abdominal CT scan, and 9 patients (0.97%; 95% CI, 0.44% to 1.8%) underwent laparotomy. The proportion of patients with abdominal CT scans was 241 of 460 (52.4%) in the FAST group and 254 of 465 (54.6%) in the standard care-only group (difference, -2.2%; 95% CI, -8.7% to 4.2%). One case of missed intra-abdominal injury occurred in a patient in the FAST group and none in the control group (difference, 0.2%; 95% CI, -0.6% to 1.2%). The mean ED length of stay was 6.03 hours in the FAST group and 6.07 hours in the standard care-only group (difference, -0.04 hours; 95% CI, -0.47 to 0.40 hours). Median hospital charges were $46 415 in the FAST group and $47 759 in the standard care-only group (difference, -$1180; 95% CI, -$6651 to $4291). Conclusions and Relevance: Among hemodynamically stable children treated in an ED following blunt torso trauma, the use of FAST compared with standard care only did not improve clinical care, including use of resources; ED length of stay; missed intra-abdominal injuries; or hospital charges. These findings do not support the routine use of FAST in this setting. Trial Registration: clinicaltrials.gov Identifier: NCT01540318.

ADAM10 and ADAM17 have opposite roles during sprouting angiogenesis.

During angiogenesis, endothelial tip cells start sprouting and express delta-like 4 (DLL4) downstream of vascular endothelial growth factor (VEGF). DLL4 subsequently activates Notch in the adjacent stalk cells suppressing sprouting. VEGF also activates A disintegrin and metalloproteases (ADAMs) that induce Notch ectodomain shedding. Although two major ADAMs, i.e. ADAM10 and ADAM17, have been implicated in Notch-signalling activation, their apparent different roles in angiogenesis have not been fully understood yet. The objective of this study was to determine the roles of ADAM10 and ADAM17 activity in angiogenesis. In mouse retinas, ADAM10 or γ-secretase inhibition induced vascular sprouting and density in vivo, whereas attenuation of both ADAM10 and ADAM17 activity produced the opposite phenotype. Retinal blood vessel analysis in ADAM17 hypomorphic mice confirmed the requirement for ADAM17 activity in angiogenesis. However, ADAM17 inhibition did not phenocopy blood vessel increase by Notch blockage. These observations suggest that ADAM17 regulates other fundamental players during angiogenesis besides Notch, which were not affected by ADAM10. By means of an angiogenesis proteome assay, we found that ADAM17 inhibition induced the expression of a naturally occurring inhibitor of angiogenesis Thrombospondin 1 (TSP1), whereas ADAM10 inhibition did not. Accordingly, ADAM17 overexpression downregulated TSP1 expression, and the TSP1 inhibitor LSKL rescued angiogenesis in the tube formation assay downstream of VEGF in the presence of ADAM17 inhibition. Finally, genetic and pharmacological ADAM17 blockade resulted in increased TSP1 expression in mouse retina. Altogether, our results show that ADAM10 and ADAM17 have opposite effects on sprouting angiogenesis that may be unrelated to Notch signalling and involves differentially expressed anti-angiogenic proteins such as TSP1.

Creation of a High-fidelity, Low-cost Pediatric Skull Fracture Ultrasound Phantom.

Over the past decade, point-of-care ultrasound has become a common tool used for both procedures and diagnosis. Developing high-fidelity phantoms is critical for training in new and novel point-of-care ultrasound applications. Detecting skull fractures on ultrasound imaging in the younger-than-2-year-old patient is an emerging area of point-of-care ultrasound research. Identifying a skull fracture on ultrasound imaging in this age group requires knowledge of the appearance and location of sutures to distinguish them from fractures. There are currently no commercially available pediatric skull fracture models. We outline a novel approach to building a cost-effective, simple, high-fidelity pediatric skull fracture phantom to meet a unique training requirement.

Novel path to IL-6 trans-signaling through thrombin-induced soluble IL-6 receptor release by platelets.

Interleukin (IL)-6 is a multifunctional cytokine with a critical role in inflammatory, immunoregulatory and haemopoietic responses. Its receptor consists of an ubiquitously expressed membrane transducing element (gp130) and of the specific element IL-6R-alpha (gp80), present only on hepatocytes and some leukocyte subsets. IL-6R-alpha also exists as soluble protein (sIL-6R) that, in the presence of IL-6, forms a complex able to bind gp130 and, thanks to the mechanism called trans-signaling, transduces IL-6 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator (STAT)-3. The aim of this study was to analyze the bidirectional relationships between platelet aggregation and IL-6-dependent effects. While platelets do not produce IL-6, we found that resting platelets express gp130, but not gp80, on their membranes. Upon activation by thrombin or calcium ionophore A23187, but not by ADP, the IL-6R-alpha is released in soluble form, while cangrelor, the specific inhibitor of P2Y12 receptor, can partially inhibit sIL-6R release. This sIL-6R is biologically active and, in the presence of IL-6, can trigger IL-6 trans-signaling, inducing an autocrine activation loop (as measured by an increase in gp80 and gp130 content) and STAT3 phosphorylation. On the other hand, IL-6 trans-signaling has no effect on platelet degranulation or aggregation by itself, nor on thrombin-induced platelet aggregation. Our data add an important piece to the puzzle of thrombosis and inflammation: in the presence of IL-6, which can be produced by stressed endothelial cells, the platelet-derived IL-6 trans-signaling could be crucial for the evolution of inflammation within a damaged vessel.

The Effect of Sustained Poor Air Quality on EMS Call Volume and Characteristics: A Time-Stratified Case-Crossover Study.

OBJECTIVES: As wildfires and air pollution become more common across the United States, it is increasingly important to understand the burden they place on public health. Previous studies have noted relationships between air quality and use of Emergency Medical Services (EMS), but until now, these studies have focused on day-to-day air quality. The goal of this study is to investigate the effect of sustained periods of poor air quality on EMS call characteristics and volume. METHODS: Using a time-stratified case-crossover design, the effect of exposure to periods of poor air quality on number and type of EMS calls in California, USA from 2014-2019 was observed. Poor air quality periods greater than three days were identified at the United States Environmental Protection Agency's (EPA's) Air Quality Index (AQI) levels of Unhealthy for Sensitive Groups (AQI 100) and Unhealthy (AQI 150). Periods less than three days apart were combined. Each poor air quality period was matched with two one-week controls, the first being the closest preceding week that did not intersect a different case. The second control was the closest week at least three days after the case and not intersecting with a different case. Due to seasonal variation in EMS usage, from the initial cases, cases were used only if it was possible to identify controls within 28 days of the case. A conditional Poisson regression calculated risk ratios for EMS call volume. RESULTS: Comparing the case periods to the controls, significant increases were found at AQI >100 for total number of calls, and the primary impressions categories of emotional state or behavior, level of consciousness, no patient complaint, other, respiratory, and abdominal. At an AQI >150, significance was found for the primary impressions categories of other, pain, respiratory, and digestive. CONCLUSION: These data demonstrate increased EMS calls during sustained poor air quality, and that several EMS primary impression categories are disproportionately affected. This study is limited by the imprecision of the primary impression's classification provided by the EMS clinician responding to the EMS call. More research is needed to understand the effects of periods of poor air quality on the EMS system for more efficient deployment of resources.

Prehospital Testing and Surveillance for SARS-CoV-2: A Special Report from the Sacramento (California USA) Mobile Integrated Health Unit.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has killed nearly 800,000 Americans since early 2020. The disease has disproportionately affected older Americans, men, persons of color, and those living in congregate living facilities. Sacramento County (California USA) has used a novel Mobile Integrated Health Unit (MIH) to test hundreds of patients who dwell in congregate living facilities, including skilled nursing facilities (SNF), residential care facilities (ie, assisted living facilities [ALF] and board and care facilities [BCF]), and inpatient psychiatric facilities (PSY), for SARS-CoV-2. METHODS: The MIH was authorized and rapidly created at the beginning of the COVID-19 pandemic as a joint venture between the Sacramento County Department of Public Health (SCDPH) and several fire-based Emergency Medical Services (EMS) agencies within the county to perform SARS-CoV-2 testing and surveillance in a prehospital setting at a number of congregate living facilities. All adult patients (≥18 years) who were tested for SARS-CoV-2 infection by the MIH from March 31, 2020 through April 30, 2020 and lived in congregate living facilities were included in this retrospective descriptive cohort. Demographic and laboratory data were collected to describe the cohort of patients tested by the MIH. RESULTS: During the study period, the MIH tested a total of 323 patients from 15 facilities in Sacramento County. The median age of patients tested was 66 years and the majority were female (72%). Overall, 72 patients (22%) tested positive for SARS-CoV-2 in congregate living settings, a higher rate of positivity than was measured across the county during the same time period. CONCLUSION: The MIH was a novel method of epidemic surveillance that succeeded in delivering effective and efficient testing to patients who reside in congregate living facilities and was able to accurately identify pockets of infection within otherwise low prevalence areas. Cooperative prehospital models are an effective model to deliver out-of-hospital testing and disease surveillance that may serve as a blueprint for community-based care delivery for a number of disease states and future epidemics or pandemics.

Manual versus Mechanical Delivery of High-Quality Cardiopulmonary Resuscitation on a River-Based Fire Rescue Boat.

OBJECTIVES: Studies have demonstrated the efficacy of mechanical devices at delivering high-quality cardiopulmonary resuscitation (HQ-CPR) in various transport settings. Herein, this study investigates the efficacy of manual and mechanical HQ-CPR delivery on a fire rescue boat. METHODS: A total of 15 active firefighter-paramedics were recruited for a prospective manikin-based trial. Each paramedic performed two minutes manual compression-only CPR while navigating on a river-based fire rescue boat. The boat was piloted in either a stable linear manner or dynamic S-turn manner to simulate obstacle avoidance. For each session of manual HQ-CPR, a session of mechanical HQ-CPR was also performed with a LUCAS 3 (Stryker; Kalamazoo, Michigan USA). A total of 60 sessions were completed. Parameters recorded included compression fraction (CF) and the percentage of compressions with correct depth >5cm (D%), correct rate 100-120 (R%), full release (FR%), and correct hand position (HP%). A composite HQ-CPR score was calculated as follows: ((D% + R% + FR% + HP%)/4) * CF%). Differences in magnitude of change seen in stable versus dynamic navigation within study conditions were evaluated with a Z-score calculation. Difficulty of HQ-CPR delivery was assessed utilizing the Borg Rating of Perceived Exertion Scale. RESULTS: Participants were mostly male and had a median experience of 20 years. Manual HQ-CPR delivered during stable navigation out-performed manual HQ-CPR delivered during dynamic navigation for composite score and trended towards superiority for FR% and R%. There was no difference seen for any measured variable when comparing mechanical HQ-CPR delivered during stable navigation versus dynamic navigation. Mechanical HQ-CPR out-performed manual HQ-CPR during both stable and dynamic navigation in terms of composite score, FR%, and R%. Z-score calculation demonstrated that manual HQ-CPR delivery was significantly more affected by drive style than mechanical HQ-CPR delivery in terms of composite HQ-CPR score and trended towards significance for FR% and R%. Borg Rating of Perceived Exertion was higher for manual CPR delivered during dynamic sessions than for stable sessions. CONCLUSION: Mechanical HQ-CPR delivery is superior to manual HQ-CPR delivery during both stable and dynamic riverine navigation. Whereas manual HQ-CPR delivery was worse during dynamic transportation conditions compared to stable transport conditions, mechanical HQ-CPR delivery was unaffected by drive style. This suggests the utility of routine use of mechanical HQ-CPR devices in the riverine patient transport setting.

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

Effects of Continuous Albuterol Inhalation on Serum Metabolome in Healthy Subjects: More Than Just Lactic Acid.

Treatment with ß2-agonists may cause elevated lactic acid, the end product of anaerobic metabolism of glucose. It has been proposed that lactic acidosis associated with ß2-agonists is caused by changes to direct biochemical impacts on glycolysis, gluconeogenesis, pyruvate metabolism, and free fatty acid production. However, much remains unknown, and there is a paucity of evidence regarding the underlying chemical changes associated with this lactic acidosis. The goal of our study was to investigate the impact of 1 hour of continuous albuterol on the untargeted serum metabolome of healthy subjects. Twenty-four healthy participants received 7.5 mg of continuous albuterol for 1 hour. Baseline, 1-hour, and 2-hour lactic acid levels were drawn. Samples obtained at baseline and 1 hour were sent for untargeted metabolomic profiling. Participants had a baseline lactic acid of 1.45 ± 0.46 mmol/L. On average, lactate levels increased 0.33 ± 0.67 mmol/L after 1 hour (P = .02) and remained elevated at 2 hours (0.32 ± 0.72 mmol/L, P = .02), although there was overlap in lactate levels across times. For metabolomic analysis, fatty acids, organic acids, and sugars were elevated, and amino acids were reduced. Lactic acid and pyruvic acid metabolites, however, did not significantly change (after false discovery rate adjustment). In healthy participants, continuous albuterol alters the serum metabolome, but this change may not be clinically significant. The data support recent hypotheses that ß2-receptor activation stimulates lactic acid production, altering aerobic glycolysis, gluconeogenesis, and free fatty acid production.

Evaluation of Serial Chest Radiographs of High-Altitude Pulmonary Edema Requiring Medical Evacuation from South Pole Station, Antarctica: From Diagnosis to Recovery.

INTRODUCTION: Chest radiography is a diagnostic tool commonly used by medical providers to assess high-altitude pulmonary edema (HAPE). Although HAPE often causes a pattern of pulmonary edema with right lower lung predominance, previous research has shown that there is no single radiographic finding associated with the condition. The majority of research involves a retrospective analysis of chest radiographs taken at the time of HAPE diagnosis. Little is known about the radiographic progression of HAPE during treatment or medical evacuation. MATERIALS AND METHODS: Three sequential chest radiographs were obtained from two patients diagnosed with HAPE at the Amundsen-Scott South Pole Station, Antarctica, who required treatment and medical evacuation. Deidentified and temporally randomized images were reviewed in a blinded fashion by two radiologists. A score of 0 (normal lung) to 4 (alveolar disease) was assigned for each of the four lung quadrants for an aggregate possible score ranging from 0 to 16 for each radiograph. RESULTS: Patient 1's initial radiograph showed severe HAPE with an initial score of 13. Despite a rapid clinical improvement after medical evacuation, he continued to show multifocal radiographic evidence of disease in all the lung quadrants on day 1 (score of 11) and day 2 (score of 5). Patient 2's radiographs showed less severe disease at presentation (score of 6). Despite the need for continued treatment, his radiographs showed a rapid improvement, with radiographic score decreasing to 3 on day 1 and 1 on day 3. CONCLUSION: The chest radiographs showed serial improvement after medical evacuation in both patients. There was not a strong correlation between clinical symptoms and radiographic severity in subsequent images.

Development of an interleukin (IL) 6 receptor antagonist that inhibits IL-6-dependent growth of human myeloma cells.

The pleiotropic cytokine interleukin 6 (IL-6) plays a role in the pathogenesis of various diseases, such as multiple myeloma, autoimmune and inflammatory diseases and osteoporosis. Therefore, specific inhibitors of IL-6 may have clinical applications. We previously succeeded in developing receptor antagonists of IL-6 that antagonized wild-type IL-6 activity on the human Epstein-Barr virus (EBV)-transformed B cell line CESS and the human hepatoma cell line HepG2. However, these proteins still had agonistic activity on the human myeloma cell line XG-1. We here report the construction of a novel mutant protein of IL-6 in which two different mutations are combined that individually disrupt the association of the IL-6/IL-6 receptor (R) alpha complex with the signaltransducing "beta" chain, gp130, but leave the binding of IL-6 to IL-6R alpha intact. The resulting mutant protein (with substitutions of residues Gln160 to Glu, Thr163 to Pro, and replacement of human residues Lys42-Ala57 with the corresponding residues of mouse IL-6) was inactive on XG-1 cells and weakly antagonized wild-type IL-6 activity on these cells. By introducing two additional substitutions (Phe171Leu, Ser177Arg), the affinity of the mutant protein for IL-6R alpha was increased fivefold, rendering it capable of completely inhibiting wild-type IL-6 activity on XG-1 cells. Moreover, this mutant also antagonized the activity of IL-6, but not that of leukemia inhibitory factor, oncostatin M, or GM-CSF on the human erythroleukemia cell line TF-1, demonstrating its specificity for IL-6. These data demonstrate the feasibility of developing specific IL-6R antagonists. The availability of such antagonists may offer an approach to specifically inhibit IL-6 activity in vivo.

Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice.

Soluble cytokine receptors modulate the activity of their cognate ligands. Interleukin (IL)-6 in association with the soluble IL-6 receptor (sIL-6R) can activate cells expressing the gp130 signal transducer lacking the specific IL-6R. To investigate the function of the IL-6-sIL-6R complex in vivo and to discriminate the function of the IL-6-sIL-6R complex from the function of IL-6 alone, we have established a transgenic mouse model. Double-transgenic mice coexpressing IL-6 and sIL-6R were generated and compared with IL-6 and sIL-6R single-transgenic mice. The main phenotype found in IL-6-sIL-6R mice was a dramatic increase of extramedullary hematopoietic progenitor cells in liver and spleen but not in the bone marrow. In IL-6 single-transgenic mice and sIL-6R single-transgenic mice no such effects were observed. The high numbers of hematopoietic progenitor cells were reflected by a strong increase of peripheral blood cell numbers. Therefore, activators of the gp130 signal transducer like the IL-6-IL-6R complex may represent most powerful stimulators for extramedullary hematopoietic progenitor cells. gp130 activators may become important for the expansion of hematopoietic progenitor cells in vivo and in vitro.

The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6.

Interleukin 6 (IL-6) is considered an important mediator of acute inflammatory responses. Moreover, IL-6 functions as a differentiation and growth factor of hematopoietic precursor cells, B cells, T cells, keratinocytes, neuronal cells, osteoclasts, and endothelial cells. IL-6 exhibits its action via a receptor complex consisting of a specific IL-6 receptor (IL-6R) and a signal transducing subunit (gp130). Soluble forms of both receptor components are generated by shedding and are found in patients with various diseases such as acquired immune deficiency syndrome, rheumatoid arthritis, and others. The function of the soluble (s)IL-6R in vivo is unknown. Since human (h)IL-6 acts on human and murine target cells, but murine IL-6 on murine cells only, we constructed transgenic mice expressing the hsIL-6R. We report here that in the presence of hsIL-6R, mice are hypersensitized towards hIL-6, mounting an acute phase protein gene induction at significantly lower IL-6 dosages compared to control animals. Furthermore, in hsIL-6R transgenic mice, the detected acute phase response persists for a longer period of time. The IL-6/IL-6R complex prolongs markedly the Il-6 plasma half-life. Our results reinforce the role of the hsIL-6R as an agonistic protein, help to understand the function of the hsIL-6R in vivo, and highlight the significance of the receptor in the induction of the acute phase response.

Serious Altitude Illness at the South Pole.

BACKGROUND: Gradual ascent is impractical for personnel deploying to the South Pole due to logistical challenges. Prevention of altitude illness relies on prophylactic medications such as acetazolamide and behavioral modifications including hydration and avoidance of overexertion. We present three recent cases of altitude illness that occurred in previously healthy individuals at the South Pole.CASE REPORTS: 1) A 52-yr-old woman not on prophylactics presented with headache and intractable vomiting 7 h after arriving and hiking around the station. She was treated with acetazolamide, dexamethasone, oxygen, and supportive care. Her symptoms resolved during the evacuation flight. 2) A 23-yr-old man presented with dyspnea at rest 3 d after arriving without prophylactic treatments. He had a Sao2 of 49%, wheezes and crackles on lung exam, and interstitial infiltrates on chest X-ray. His treatment included oxygen, nifedipine, acetazolamide, and dexamethasone. His symptoms resolved during the evacuation flight. 3) A 40-yr-old man presented with dyspnea after a series of strenuous workouts since his arrival 5 d prior. He had a Sao2 of 41%, and his chest X-ray was consistent with high altitude pulmonary edema. He was treated with oxygen, nifedipine, and fluids before descent to sea level, where his symptoms fully resolved 4 d later.DISCUSSION: These patients illustrate that altitude illness may develop despite medical screening, participant education, and availability of prophylactic medications based on published guidelines. These cases could be attributed to noncompliance and misinformation, bringing to light some of the challenges with managing more diverse populations that deploy to remote environments.Rose JS, Law J, Scheuring R, Ramage MH, McKeith JJ. Serious altitude illness at the South Pole. Aerosp Med Hum Perform. 2020; 91(1):46-50.

Structure of an extracellular gp130 cytokine receptor signaling complex.

The activation of gp130, a shared signal-transducing receptor for a family of cytokines, is initiated by recognition of ligand followed by oligomerization into a higher order signaling complex. Kaposi's sarcoma-associated herpesvirus encodes a functional homolog of human interleukin-6 (IL-6) that activates human gp130. In the 2.4 angstrom crystal structure of the extracellular signaling assembly between viral IL-6 and human gp130, two complexes are cross-linked into a tetramer through direct interactions between the immunoglobulin domain of gp130 and site III of viral IL-6, which is necessary for receptor activation. Unlike human IL-6 (which uses many hydrophilic residues), the viral cytokine largely uses hydrophobic amino acids to contact gp130, which enhances the complementarity of the viral IL-6-gp130 binding interfaces. The cross-reactivity of gp130 is apparently due to a chemical plasticity evident in the amphipathic gp130 cytokine-binding sites.

A randomized controlled trial comparing one-operator versus two-operator technique in ultrasound-guided basilic vein cannulation.

The basilic vein offers an alternative site for peripheral intravenous access for emergency access. The use of a two-operator ultrasound-guided basilic vein cannulation technique has been shown to be a safe and effective technique for use on Emergency Department patients. However, the one-operator technique is more customary by other services. We sought to compare the more customary one-person technique to the two-person technique in basilic vein cannulation in novice operators. This was a prospective, randomized controlled trial of two techniques of ultrasound-guided basilic vein cannulation (one-operator vs. two-operators) in healthy adult volunteers. Each volunteer underwent each technique, one technique on each arm. We selected the initial arm and technique using computer-generated block randomization. In the one-operator technique, a single operator held the transducer in transverse short-axis plane while attempting cannulation using a 20-gauge, 1.88-inch catheter. In the two-operator technique, a second operator held the transducer in place while the first operator attempted cannulation. The primary outcome variable was first-attempt cannulation success. Secondary outcome variables were overall success, number of attempts, time-to-cannulation, complications, and ease-of-technique rated by the operators. There were 32 subjects enrolled. One-operator first-attempt success was 18/32 (56%); two-operator was 21/32 (65%), with a mean difference in proportion of -9% (95% confidence interval [CI] -33-14%). Overall success for one operator was 23/32 (72%) and two-operator was 24/32 (75%), with mean difference in proportion of -3% (95% CI -24-18). The median number of attempts for one-operator was 1.6 (interquartile range [IQR] 1-5) and two-operator was 1.4 (IQR 1-5) (p=0.8). Time to cannulation for one-operator was 57 s (+/-62) and two-operator was 44 s (+/-37) (p=0.33). The median score for ease-of-technique for one-operator was 4.3 (IQR 1-6) and for two-operator was 3.6 (IQR 1-6) (p=0.26). There were no complications with either technique (95% CI 0-10%). Novice operators can reliably perform a basilic vein cannulation using ultrasound guidance. However, we were unable to demonstrate any advantage for any particular technique in cannulating the basilic vein.