Predictive and protective factors for failing first pass intubation in prehospital rapid sequence intubation: an aetiology and risk systematic review with meta-analysis.

BACKGROUND: Prehospital rapid sequence intubation first pass success rates vary between 59% and 98%. Patient morbidity is associated with repeat intubation attempts. Understanding what influences first pass success can guide improvements in practice. We performed an aetiology and risk systematic review to answer the research question 'what factors are associated with success or failure at first attempt laryngoscopy in prehospital rapid sequence intubation?'. METHODS: MEDLINE, EMBASE, CINAHL, and Cochrane Library were searched on March 3, 2023 for studies examining first pass success rates for rapid sequence intubation of prehospital live patients. Screening was performed via Covidence, and data synthesised by meta-analysis. The review was registered with PROSPERO and performed and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Reasonable evidence was discovered for predictive and protective factors for failure of first pass intubation. Predictive factors included age younger than 1 yr, the presence of blood or fluid in the airway, restricted jaw or neck movement, trauma patients, nighttime procedures, chronic or acute distortions of normal face/upper airway anatomy, and equipment issues. Protective factors included an experienced intubator, adequate training, use of certain videolaryngoscopes, elevating the patient on a stretcher in an inclined position, use of a bougie, and laryngeal manoeuvres. CONCLUSIONS: Managing bloody airways, positioning well, using videolaryngoscopes with bougies, and appropriate training should be further explored as opportunities for prehospital services to increase first pass success. Heterogeneity of studies limits stronger conclusions. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42022353609).

Outcomes of Aortobifemoral Bypass Based on Configuration of the Proximal Anastomosis.

BACKGROUND: Aortobifemoral bypass (ABF) remains an important treatment modality in the revascularization of aortoiliac occlusive disease. Despite ABF being performed for decades, questions remain regarding the preferred technique for the proximal anastomosis, specifically whether an end-to-end (EE) or an end-to-side (ES) configuration is superior. The goal of this study was to compare the outcomes of ABF based on proximal configuration. METHODS: We queried the Vascular Quality Initiative registry for ABF procedures performed between 2009 and 2020. Univariate and multivariate logistic regression analyses were used to compare perioperative and 1-year outcomes between EE and ES configurations. RESULTS: Of the 6,782 patients (median [interquartile range] age, 60.0 [54-66 years]) who underwent ABF, 3,524 (52%) had an EE proximal anastomosis and 3,258 (48%) had an ES proximal anastomosis. Postoperatively, the ES cohort had a higher frequency of extubation in the operating room (80.3% vs. 77.4%; P < 0.01), lower change in renal function (8.8% vs. 11.5%; P < 0.01), and lower use of vasopressors (15.6% vs. 19.1%; P < 0.01), but higher rates of unanticipated return to the operating room (10.2% vs. 8.7%; P = 0.037) compared with the EE configuration. At 1-year follow-up, the ES cohort had a significantly lower primary graft patency rate (87.5% vs. 90.2%; P < 0.01) and higher rates of graft revision (4.8% vs. 3.1%; P < 0.01) and claudication symptoms (11.6% vs. 9.9%; P < 0.01). The ES configuration was significantly associated with a higher rate of 1-year major limb amputations in univariate (1.6% vs. 0.9%; P < 0.01) and multivariate (odds ratio, 1.95, confidence interval, 1.18-3.23, P=<0.01) analyses. CONCLUSIONS: While the ES cohort seemed to have less physiologic insult immediately postoperatively, the EE configuration appeared to have improved 1-year outcomes. To our knowledge, this study is one of the largest population-based studies comparing the outcomes of the proximal anastomotic configurations. Longer-term follow-up is needed to determine which configuration is optimal.

Outcomes of operative and nonoperative management of blunt thoracic aortic injury.

OBJECTIVE: Although the current guidelines for the management of blunt traumatic aortic injury (BTAI) have recommended intervention for grade 2 injuries or higher, a national trend has occurred for aggressive endovascular treatment of low-grade BTAIs. Little is known about the natural history of grade 1 and 2 injuries treated nonoperatively. We hypothesized that most of these low-grade injuries would remain stable with nonoperative management. METHODS: We performed a review of BTAIs at a large referral level 1 trauma center from 2004 to 2020. The injuries were graded using a standard 1 to 4 scale. The outcomes of the nonoperative and thoracic endovascular aortic repair (TEVAR) management strategies were compared, including post-trauma morbidity, mortality, reinterventions, and lesion stability. RESULTS: A total of 176 patients with BTAIs and sufficient imaging studies and follow-up data available were identified during the study period, including 36 with grade 1, 24 with grade 2, 115 with grade 3, and 1 with a grade 4 injury. Of these 176 patients, 112 had undergone TEVAR and 64 had been treated nonoperatively. Most of the patients (90.2%) who had undergone TEVAR had had grade 3 injuries. Nonoperative management was performed for 97.2% of the grade 1 injuries and 62.5% of the grade 2 injuries. Endovascular reintervention after TEVAR was rare (2.7%). The rates of post-trauma morbidity within 30 days (stroke, 3.6% vs 3.1%; myocardial infarction/arrhythmia, 8.9% vs 1.6%; respiratory failure, 31.2% vs 28.1%; acute kidney injury, 9.8% vs 12.5%; urinary tract infection, 2.7% vs 4.8%; gastrointestinal bleeding, 3.6% vs 0.0%; pulmonary embolism, 10.9% vs 4.5%) and 1-year mortality after discharge (1.8% vs 3.1%) were comparable between the operative and nonoperative groups. The median follow-up was 1501 days (interquartile range [IQR], 475.6-2804 days) for the TEVAR group and 1170.5 days (IQR, 317-2173 days) for the nonoperative group. No lesion progression had occurred in the patients with low-grade (grade 1-2) injuries managed nonoperatively. Resolution of grade 1 and 2 injury had occurred in 20% of the patients at 30 days, which had improved to 44% at long-term follow-up. Fourteen patients with grade 3 injuries (12.2% of the grade 3 injuries in our series) were also observed and did not require future intervention. These patients had generally had smaller pseudoaneurysms with minimal periaortic hematoma. None of these 14 patients had experienced progression or rupture during follow-up (median, 454.5 days; IQR, 81-1199 days) using computed tomography. CONCLUSIONS: Nonoperative management of low-grade BTAIs did not result in long-term aortic complications or the need for reintervention. We found that grade 3 injuries with smaller pseudoaneurysms and minimal periaortic hematoma can be safely observed if the patients can be appropriately followed up. Thus, the indications for treatment of select grade 3 injuries merit further consideration.

The Use of Paclitaxel-Coated Devices in the Treatment of Peripheral Arterial Disease is Not Associated With Increased Mortality or Amputations.

BACKGROUND: Strategies for the most effective treatment for peripheral arterial disease (PAD) remain controversial among clinicians. Several trials have shown improved primary patency of femoropopliteal interventions with the utilization of paclitaxel-coated balloons or stents compared to conventional balloons or stents. However, a 2018 meta-analysis suggested an increased mortality risk for patients receiving drug-coated balloons or stents (DCBS), resulting in an international pause in the use of DCBS. A 2021 meta-analysis by the same group suggested an increased risk of major amputation following DCBS use in peripheral arterial revascularization procedures. Here we report our long-term institutional outcomes comparing uncoated devices to DCBS. METHODS: A retrospective review of all patients who underwent peripheral arterial angioplasty, stenting, atherectomy, or a combination between 2011 and 2020 within a regional healthcare system was performed. Univariate, multivariate, and survival analyses were performed using standard statistical methods to assess the primary end points of overall survival, 5-year survival, and amputation-free survival. RESULTS: A total of 2,717 patients were identified, of whom 1,965 were treated with conventional uncoated devices and 752 were treated with DCBS. A univariate analysis showed that patients treated with non-DCBS had higher rates of overall mortality, major amputations, and mortality at 1, 3, and 5 years. A multivariable analysis demonstrated that the use of conventional devices, age, diabetes, chronic kidney disease, myocardial infarction, transient ischemic attack, warfarin use, and atrial fibrillation all significantly increased the risk of 5-year mortality, overall mortality, and combined mortality and/or amputation. CONCLUSIONS: DCBS are not associated with increased mortality or worse amputation-free survival in this real-world cohort of patients treated for PAD. Our data suggest that mortality is more closely linked with pre-existing patient comorbidities rather than device selection at the time of revascularization.

TOK channels use the two gates in classical K+ channels to achieve outward rectification.

TOKs are outwardly rectifying K+ channels in fungi with two pore-loops and eight transmembrane spans. Here, we describe the TOKs from four pathogens that cause the majority of life-threatening fungal infections in humans. These TOKs pass large currents only in the outward direction like the canonical isolate from Saccharomyces cerevisiae (ScTOK), and distinct from other K+ channels. ScTOK, AfTOK1 (Aspergillus fumigatus), and H99TOK (Cryptococcus neoformans grubii) are K+ -selective and pass current above the K+ reversal potential. CaTOK (Candida albicans) and CnTOK (Cryptococcus neoformans neoformans) pass both K+ and Na+ and conduct above a reversal potential reflecting the mixed permeability of their selectivity filter. Mutations in CaTOK and ScTOK at sites homologous to those that open the internal gates in classical K+ channels are shown to produce inward TOK currents. A favored model for outward rectification is proposed whereby the reversal potential determines ion occupancy, and thus, conductivity, of the selectivity filter gate that is coupled to an imperfectly restrictive internal gate, permitting the filter to sample ion concentrations on both sides of the membrane.

An Evidence-Based Care Protocol Improves Outcomes and Decreases Cost in Pediatric Appendicitis.

BACKGROUND: Appendicitis is a common indication for urgent abdominal surgery in the pediatric population. The postoperative management varies significantly in time to discharge and cost of care. The objective of this study was to investigate whether implementation of an evidence-based protocol after an appendectomy would lead to decreased length of stay and cost of care. METHODS: In 2014 at the Children's Hospital of Pittsburgh, an initiative to develop an evidenced-based protocol to treat appendicitis was undertaken. A work group was formed of pediatric surgeons and other important personnel to determine best practices. Treatment pathways were created. Pathways differed with recommendation on postoperative antibiotic choice and duration, diet initiation, and discharge criteria. Data were prospectively gathered from all patients (ages 0-18 y) with acute appendicitis from January 2015 to December 2016. Primary outcomes were length of stay and cost of care. Secondary outcomes were surgical site infection, readmission rate, and duration of postoperative antibiotics. RESULTS: Among the 1289 patients, 481 patients were in the preprotocol cohort and 808 patients were in the postprotocol cohort. 27% of patients had an intraoperative diagnosis of complicated appendicitis. There was a significantly shorter length of stay in the postprotocol cohort (P < 0.001). Median costs for the whole cohort decreased 0.6% and 24.6% for patients with complicated appendicitis after protocol initiation (P < 0.01). CONCLUSIONS: This study has demonstrated that introduction of an evidence-based clinical care protocol for pediatric patients with appendicitis leads to shorter hospital stay and decreased hospital costs.

Heme promotes transcriptional and demethylase activities of Gis1, a member of the histone demethylase JMJD2/KDM4 family.

The yeast Gis1 protein is a transcriptional regulator belonging to the JMJD2/KDM4 subfamily of demethylases that contain a JmjC domain, which are highly conserved from yeast to humans. They have important functions in histone methylation, cellular signaling and tumorigenesis. Besides serving as a cofactor in many proteins, heme is known to directly regulate the activities of proteins ranging from transcriptional regulators to potassium channels. Here, we report a novel mechanism governing heme regulation of Gis1 transcriptional and histone demethylase activities. We found that two Gis1 modules, the JmjN + JmjC domain and the zinc finger (ZnF), can bind to heme specifically in vitro. In vivo functional analysis showed that the ZnF, not the JmjN + JmjC domain, promotes heme activation of transcriptional activity. Likewise, measurements of the demethylase activity of purified Gis1 proteins showed that full-length Gis1 and the JmjN + JmjC domain both possess demethylase activity. However, heme potentiates the demethylase activity of full-length Gis1, but not that of the JmjN + JmjC domain, which can confer heme activation of transcriptional activity in an unrelated protein. These results demonstrate that Gis1 represents a novel class of multi-functional heme sensing and signaling proteins, and that heme binding to the ZnF stimulates Gis1 demethylase and transcriptional activities.

Glial and neuronal expression of the Inward Rectifying Potassium Channel Kir7.1 in the adult mouse brain.

Inward Rectifying Potassium channels (Kir) are a large family of ion channels that play key roles in ion homeostasis and neuronal excitability. The most recently described Kir subtype is Kir7.1, which is known as a K+ transporting subtype. Earlier studies localised Kir7.1 to subpopulations of neurones in the brain. However, the pattern of Kir7.1 expression across the brain has not previously been examined. Here, we have determined neuronal and glial expression of Kir7.1 in the adult mouse brain, using immunohistochemistry and transgenic mouse lines expressing reporters specific for astrocytes [glial fibrillary acidic protein-enhanced green fluorescent protein (GFAP-EGFP], myelinating oligodendrocytes (PLP-DsRed), oligodendrocyte progenitor cells (OPC, Pdgfra-creERT2 /Rosa26-YFP double-transgenic mice) and all oligodendrocyte lineage cells (SOX10-EGFP). The results demonstrate significant neuronal Kir7.1 immunostaining in the cortex, hippocampus, cerebellum and pons, as well as the striatum and hypothalamus. In addition, astrocytes are shown to be immunopositive for Kir7.1 throughout grey and white matter, with dense immunostaining on cell somata, primary processes and perivascular end-feet. Immunostaining for Kir7.1 was observed in oligodendrocytes, myelin and OPCs throughout the brain, although immunostaining was heterogeneous. Neuronal and glial expression of Kir7.1 is confirmed using neurone-glial cortical cultures and optic nerve glial cultures. Notably, Kir7.1 have been shown to regulate the excitability of thalamic neurones and our results indicate this may be a widespread function of Kir7.1 in neurones throughout the brain. Moreover, based on the function of Kir7.1 in multiple transporting epithelia, Kir7.1 are likely to play an equivalent role in the primary glial function of K+ homeostasis. Our results indicate Kir7.1 are far more pervasive in the brain than previously recognised and have potential importance in regulating neuronal and glial function.

Murine sepsis phenotypes and differential treatment effects in a randomized trial of prompt antibiotics and fluids.

BACKGROUND: Clinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids. METHODS: We performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n = 118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N = 73 mice), inflammatory cytokines measured at 24 h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0 h) vs. delayed (2 to 4 h) antibiotics or fluids initiated after physiologic deterioration. RESULTS: Latent class mixture modeling derived a two-class model in cohort 1. Class 2 (N = 97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p < 0.001) and lower heart rate at 7 h after injury (mean (SD) 564 (55) vs. 626 (35) beats per minute, p < 0.001). Overall mortality was similar between phenotypes (p = 0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24 h after CLP (p = 0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p = 0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p = 0.02). CONCLUSIONS: We identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.

Blue light reduces organ injury from ischemia and reperfusion.

Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (ß3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury.

Translational Sepsis Research: Spanning the Divide.

OBJECTIVE: Our knowledge of the molecular mechanisms of sepsis has attained exponential growth. Yet, the pillars of its care remain antibiotics, fluid resuscitation, and physiologic support of failing organ systems. The inability to bring biologic breakthroughs to the bedside is not for lack of effort. Over 60 clinical trials of novel therapies, each heavily supported by the momentum of biologic data suggesting clinical utility, have been conducted and have failed to identify benefit. This mass of "negative" clinical data abut an equally towering mound of knowledge of sepsis biology, which collectively have led investigators to ask, "what happened?" DATA SOURCES: Review of published scientific literature via MEDLINE searches using key terms related to the article topics. STUDY SELECTION: Original articles, review articles, and systematic reviews were considered. DATA EXTRACTION: Articles were selected for inclusion based upon author consensus. DATA SYNTHESIS: Here, we present a synthetic review of some of the challenges in translating experimental animal models of sepsis to the bedside. We commence with the concept that the heterogeneity in the kinetics of the sepsis response serves as an important, often underappreciated but surmountable, source of translational impedance. Upon this groundwork, we discuss distinctions between animal experimentation and clinical trial design in the elements for hypothesis testing: cohort selection, power and sample size, randomization and blinding, and timing of intervention. From this concept, we develop a contextual framework for advancing the paradigm of animal-based investigations to facilitate science that transitions from molecule to medicine. CONCLUSIONS: A persistent divide exists between the laboratory and clinical research arenas, which may be addressable via systematic targeting of identified translational gaps.

Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial.

OBJECTIVES: Sepsis, the acute organ dysfunction caused by a dysregulated host response to infection, poses a serious public health burden. Current management includes early detection, initiation of antibiotics and fluids, and source control as necessary. Although observational data suggest that delays of even a few hours in the initiation of antibiotics or IV fluids is associated with survival, these findings are controversial. There are no randomized data in humans, and prior animal studies studied time from experimental manipulation, not from the onset of clinical features of sepsis. Using a recently developed murine cecal ligation and puncture model that precisely monitors physiologic deterioration, we hypothesize that incremental hourly delays in the first dose of antibiotics, in the first bolus of fluid resuscitation, or a combination of the two at a clinically relevant point of physiologic deterioration during polymicrobial sepsis will shorten survival. DESIGN: Randomized laboratory animal experimental trial. SETTING: University basic science laboratory. SUBJECTS: Male C57BL/6J, female C57BL/6J, aged (40-50 wk old) male C57BL/6J, and BALB/C mice. INTERVENTIONS: Mice (n = 200) underwent biotelemetry-enhanced cecal ligation and puncture and were randomized after meeting validated criteria for acute physiologic deterioration. Treatment groups consisted of a single dose of imipenem/cilastatin, a single bolus of 30 mL/kg fluid resuscitation, or a combination of the two. Mice were allocated to receive treatment at the time of meeting deterioration criteria, after a 2-hour delay or after a 4-hour delay. MEASUREMENTS AND MAIN RESULTS: Hourly delays in the initiation of antibiotic therapy led to progressively shortened survival in our model (p < 0.001). The addition of fluid resuscitation was unable to rescue animals, which received treatment 4 hours after meeting enrollment criteria. Systemic inflammation was increased, and host physiology was increasingly deranged with hourly delays to antibiotics. CONCLUSIONS: We conclude that antibiotic therapy is highly time sensitive, and efforts should be made to deliver this critical therapy as early as possible in sepsis, perhaps extending into the first point of medical contact outside the hospital.

Blue Light Enhances Bacterial Clearance and Reduces Organ Injury During Sepsis.

OBJECTIVES: The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. DESIGN: Laboratory animal research, pilot human feasibility trial. SETTING: University basic science laboratory and tertiary care hospital. SUBJECTS: Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. INTERVENTIONS: Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. MEASUREMENTS AND MAIN RESULTS: Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERBα and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. CONCLUSIONS: Modifying the spectrum of light may offer therapeutic utility in sepsis.

Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.

During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (ΔΨ) and mitophagy has not been identified. Mitochondria also buffer Ca2+, and their buffering capacity is dependent on ΔΨ Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of ΔΨ with either pharmacologic depolarization or LPS leads to Ca2+-dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in in vivo models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.-Zhang, X., Yuan, D., Sun, Q., Xu, L., Lee, E., Lewis, A. J., Zuckerbraun, B. S., Rosengart, M. R. Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.

The influence of alkalosis on repeated high-intensity exercise performance and acid-base balance recovery in acute moderate hypoxic conditions.

PURPOSE: Exacerbated hydrogen cation (H+) production is suggested to be a key determinant of fatigue in acute hypoxic conditions. This study, therefore, investigated the effects of NaHCO3 ingestion on repeated 4 km TT cycling performance and post-exercise acid-base balance recovery in acute moderate hypoxic conditions. METHODS: Ten male trained cyclists completed four repeats of 2 × 4 km cycling time trials (TT1 and TT2) with 40 min passive recovery, each on different days. Each TT series was preceded by supplementation of one of the 0.2 g kg-1 BM NaHCO3 (SBC2), 0.3 g kg-1 BM NaHCO3 (SBC3), or a taste-matched placebo (0.07 g kg-1 BM sodium chloride; PLA), administered in a randomized order. Supplements were administered at a pre-determined individual time to peak capillary blood bicarbonate concentration ([HCO3-]). Each TT series was also completed in a normobaric hypoxic chamber set at 14.5% FiO2 (~ 3000 m). RESULTS: Performance was improved following SBC3 in both TT1 (400.2 ± 24.1 vs. 405.9 ± 26.0 s; p = 0.03) and TT2 (407.2 ± 29.2 vs. 413.2 ± 30.8 s; p = 0.01) compared to PLA, displaying a very likely benefit in each bout. Compared to SBC2, a likely and possible benefit was also observed following SBC3 in TT1 (402.3 ± 26.5 s; p = 0.15) and TT2 (410.3 ± 30.8 s; p = 0.44), respectively. One participant displayed an ergolytic effect following SBC3, likely because of severe gastrointestinal discomfort, as SBC2 still provided ergogenic effects. CONCLUSION: NaHCO3 ingestion improves repeated exercise performance in acute hypoxic conditions, although the optimal dose is likely to be 0.3 g kg-1 BM.

Use of Biotelemetry to Define Physiology-Based Deterioration Thresholds in a Murine Cecal Ligation and Puncture Model of Sepsis.

OBJECTIVES: Murine models of critical illness are commonly used to test new therapeutic interventions. However, these interventions are often administered at fixed time intervals after the insult, perhaps ignoring the inherent variability in magnitude and temporality of the host response. We propose to use wireless biotelemetry monitoring to define and validate criteria for acute deterioration and generate a physiology-based murine cecal ligation and puncture model that is more similar to the conduct of human trials of sepsis. DESIGN: Laboratory and animal research. SETTING: University basic science laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Mice underwent cecal ligation and puncture, and an HD-X11 wireless telemetry monitor (Data Sciences International) was implanted that enabled continuous, real-time measurement of heart rate, core temperature, and mobility. We performed a population-based analysis to determine threshold criteria that met face validity for acute physiologic deterioration. We assessed construct validity by temporally matching mice that met these acute physiologic deterioration thresholds with mice that had not yet met deterioration threshold. We analyzed matched blood samples for blood gas, inflammatory cytokine concentration, cystatin C, and alanine aminotransferase. MEASUREMENTS AND MAIN RESULTS: We observed that a 10% reduction in both heart rate and temperature sustained for greater than or equal to 10 minutes defined acute physiologic deterioration. There was significant variability in the time to reach acute deterioration threshold across mice, ranging from 339 to 529 minutes after cecal ligation and puncture. We found adequate construct validity, as mice that met criteria for acute deterioration had significantly worse shock, systemic inflammation (elevated tumor necrosis factor-α, p = 0.003; interleukin-6, p = 0.01; interleukin-10, p = 0.005), and acute kidney injury when compared with mice that had not yet met acute deterioration criteria. CONCLUSIONS: We defined a murine threshold for acute physiologic deterioration after cecal ligation and puncture that has adequate face and construct validity. This model may enable a more physiology-based model for evaluation of novel therapeutics in critical illness.

Efficacy of Nasal Cannula Oxygen as a Preoxygenation Adjunct in Emergency Airway Management.

STUDY OBJECTIVE: Although preoxygenation for emergency airway management is usually performed with nonrebreather face masks or bag-valve-mask devices, some clinicians also deliver supplemental high-flow oxygen by nasal cannula. We aim to measure the efficacy of supplemental nasal cannula oxygen delivery to conventional bag-valve-mask and nonrebreather face mask preoxygenation both with and without a simulated face mask leak. METHODS: We conducted a randomized crossover trial using healthy volunteers. We randomized subjects to preoxygenation with bag-valve-mask or nonrebreather face mask. In random sequence, subjects underwent 3-minute trials of preoxygenation with oxygen through mask alone at 15 L/min, oxygen through mask at 15 L/min with standardized leak, oxygen through mask at 15 L/min+oxygen through nasal cannula at 10 L/min, and oxygen through mask at 15 L/min+oxygen through nasal cannula at 10 L/min with standardized leak. The primary outcome was single-breath exhalation end-tidal oxygen (eto2). We compared eto2 between preoxygenation modalities, using nonparametric techniques. RESULTS: We enrolled 60 subjects (30 nonrebreather face mask and 30 bag-valve-mask). In scenarios without a mask leak, eto2 was similar between bag-valve-mask and bag-valve-mask+nasal cannula (mean 79% versus 75%; difference -3%; 95% confidence interval [CI] -8% to 1%). In bag-valve-mask scenarios with a mask leak, eto2 was higher for bag-valve-mask+nasal cannula than bag-valve-mask alone (mean 66% versus 41%; difference 25%; 95% CI 21% to 29%). eto2 was higher for nonrebreather face mask+nasal cannula than nonrebreather face mask (mean 67% versus 52%; difference 15%; 95% CI 12% to 18%). In nonrebreather face mask scenarios with a mask leak, eto2 was higher for nonrebreather face mask+nasal cannula than nonrebreather face mask (mean 65% versus 48%; difference 17%; 95% CI 13% to 20%). CONCLUSION: Although not aiding bag-valve-mask preoxygenation with a good mask seal, supplemental nasal cannula oxygen improved preoxygenation efficacy in the presence of a bag-valve-mask mask leak. Supplemental nasal cannula oxygen improved nonrebreather face mask preoxygenation both with and without a mask leak. Supplemental nasal cannula oxygen may be helpful for preoxygenation before emergency airway management.

Next-generation Digital Earth.

A speech of then-Vice President Al Gore in 1998 created a vision for a Digital Earth, and played a role in stimulating the development of a first generation of virtual globes, typified by Google Earth, that achieved many but not all the elements of this vision. The technical achievements of Google Earth, and the functionality of this first generation of virtual globes, are reviewed against the Gore vision. Meanwhile, developments in technology continue, the era of "big data" has arrived, the general public is more and more engaged with technology through citizen science and crowd-sourcing, and advances have been made in our scientific understanding of the Earth system. However, although Google Earth stimulated progress in communicating the results of science, there continue to be substantial barriers in the public's access to science. All these factors prompt a reexamination of the initial vision of Digital Earth, and a discussion of the major elements that should be part of a next generation.

Sustained life-like waveform capnography after human cadaveric tracheal intubation.

INTRODUCTION: Fresh frozen cadavers are effective training models for airway management. We hypothesised that residual carbon dioxide (CO2) in cadaveric lung would be detectable using standard clinical monitoring systems, facilitating detection of tracheal tube placement and further enhancing the fidelity of clinical simulation using a cadaveric model. METHODS: The tracheas of two fresh frozen unembalmed cadavers were intubated via direct laryngoscopy. Each tracheal tube was connected to a self-inflating bag and a sidestream CO2 detector. The capnograph display was observed and recorded in high-definition video. The cadavers were hand-ventilated with room air until the capnometer reached zero or the waveform approached baseline. RESULTS: A clear capnographic waveform was produced in both cadavers on the first postintubation expiration, simulating the appearances found in the clinical setting. In cadaver one, a consistent capnographic waveform was produced lasting over 100 s. Maximal end-tidal CO2 was 8.5 kPa (65 mm Hg). In cadaver two, a consistent capnographic waveform was produced lasting over 50 s. Maximal end-tidal CO2 was 5.9 kPa (45 mm Hg). CONCLUSIONS: We believe this to be the first work to describe and quantify detectable end-tidal capnography in human cadavers. We have demonstrated that tracheal intubation of fresh frozen cadavers can be confirmed by life-like waveform capnography. This requires further validation in a larger sample size.

Describing the development and implementation of a novel collaborative multidisciplinary approach to deliver foot health supports for individuals experiencing homelessness and its outcomes.

Basic foot care is a real need of people experiencing homelessness. To improve access to foot health for this group, three services structured to provide healthcare support for people experiencing homelessness collaborated in metropolitan Melbourne, Australia: an established nurse-led Homeless Persons Program (HPP), a specialty community health podiatry clinic servicing people experiencing homelessness, and a charity supporting disadvantaged communities providing free socks, foot first aid kits and second-hand footwear for distribution by nurses and podiatrists of participating services. This paper outlines the implementation and evaluation of this collaboration. A four stage implementation approach was used, addressing: 1. Who needs to do what differently? 2. What are the barriers and enablers that need to be addressed? 3. Which intervention components could overcome the modifiable barriers and enhance the enablers? 4. How can the changes be measured? The evaluation prospectively collected information about how HPP nurses referred adults to podiatry, and whether the referred individuals accessed the podiatry clinic, the outcomes of the podiatry visit, and how many received footwear, socks and foot first aid kits provided by the non-profit organisation. Over 1st June 2019 and 31st December 2020, 52 individuals were identified as adults who could potentially benefit from podiatry by the HPP nurses, of which 33 accessed podiatry. Those who did not visit the podiatry clinic were more likely to be born outside of Australia, live in more precarious housing (crisis accommodation and rough sleeping), have slightly more predisposing factors for homelessness, but have fewer medical, psychological and cognitive conditions. A structured approach including processes, education, regular, outreach to youth refuges and formal outcome monitoring enabled foot health care access in people experiencing homelessness. Further research is needed to ascertain how to support participants at risk of foot problems to access podiatry before their foot health issue reaches crisis point.