Diagnostic Accuracy of Clinical Pathways for Suspected Acute Myocardial Infarction in the Out-of-Hospital Environment.

STUDY OBJECTIVE: Chest pain is one of the most common reasons for emergency ambulance calls. Patients are routinely transported to the hospital to prevent acute myocardial infarction (AMI). We evaluated the diagnostic accuracy of clinical pathways in the out-of-hospital environment. The Troponin-only Manchester Acute Coronary Syndromes decision aid and History, ECG, Age, Risk Factors, Troponin score require cardiac troponin (cTn) measurement, whereas the History and ECG-only Manchester Acute Coronary Syndromes decision aid and History, ECG, Age, Risk Factors score do not. METHODS: We conducted a prospective diagnostic accuracy study at 4 ambulance services and 12 emergency departments between February 2019 and March 2020. We included patients who received an emergency ambulance response in whom paramedics suspected AMI. Paramedics recorded the data required to calculate each decision aid and took venous blood samples in the out-of-hospital environment. Samples were tested using a point-of-care cTn assay (Roche cobas h232) within 4 hours. The target condition was a diagnosis of type 1 AMI, adjudicated by 2 investigators. RESULTS: Of 817 included participants, 104 (12.8%) had AMI. Setting the cutoff at the lowest risk group, Troponin-only Manchester Acute Coronary Syndromes had 98.3% sensitivity (95% confidence interval 91.1% to 100%) and 25.5% specificity (21.4% to 29.8%) for type 1 AMI. History, ECG, Age, Risk Factors, Troponin had 86.4% sensitivity (75.0% to 98.4%) and 42.2% specificity (37.5% to 47.0%); History and ECG-only Manchester Acute Coronary Syndromes had 100% sensitivity (96.4% to 100%) and 3.1% specificity (1.9% to 4.7%), whereas History, ECG, Age, Risk Factors had 95.1% sensitivity (88.9% to 98.4%) and 12.1% specificity (9.8% to 14.8%). CONCLUSION: With point-of-care cTn testing, decision aids can identify patients at a low risk of type 1 AMI in the out-of-hospital environment. When used alongside clinical judgment, and with appropriate training, such tools may usefully enhance out-of-hospital risk stratification.

Detecting cortical responses to continuous running speech using EEG data from only one channel.

OBJECTIVE: To explore the detection of cortical responses to continuous speech using a single EEG channel. Particularly, to compare detection rates and times using a cross-correlation approach and parameters extracted from the temporal response function (TRF). DESIGN: EEG from 32-channels were recorded whilst presenting 25-min continuous English speech. Detection parameters were cross-correlation between speech and EEG (XCOR), peak value and power of the TRF filter (TRF-peak and TRF-power), and correlation between predicted TRF and true EEG (TRF-COR). A bootstrap analysis was used to determine response statistical significance. Different electrode configurations were compared: Using single channels Cz or Fz, or selecting channels with the highest correlation value. STUDY SAMPLE: Seventeen native English-speaking subjects with mild-to-moderate hearing loss. RESULTS: Significant cortical responses were detected from all subjects at Fz channel with XCOR and TRF-COR. Lower detection time was seen for XCOR (mean = 4.8 min) over TRF parameters (best TRF-COR, mean = 6.4 min), with significant time differences from XCOR to TRF-peak and TRF-power. Analysing multiple EEG channels and testing channels with the highest correlation between envelope and EEG reduced detection sensitivity compared to Fz alone. CONCLUSIONS: Cortical responses to continuous speech can be detected from a single channel with recording times that may be suitable for clinical application.

External validation of the Manchester Acute Coronary Syndromes ECG risk model within a pre-hospital setting.

OBJECTIVES: The Manchester Acute Coronary Syndromes ECG (MACS-ECG) prediction model calculates a score based on objective ECG measurements to give the probability of a non-ST elevation myocardial infarction (NSTEMI). The model showed good performance in the emergency department (ED), but its accuracy in the pre-hospital setting is unknown. We aimed to externally validate MACS-ECG in the pre-hospital environment. METHODS: We undertook a secondary analysis from the Pre-hospital Evaluation of Sensitive Troponin (PRESTO) study, a multi-centre prospective study to validate decision aids in the pre-hospital setting (26 February 2019 to 23 March 2020). Patients with chest pain where the treating paramedic suspected acute coronary syndrome were included. Paramedics collected demographic and historical data and interpreted ECGs contemporaneously (as 'normal' or 'abnormal'). After completing recruitment, we analysed ECGs to calculate the MACS-ECG score, using both a pre-defined threshold and a novel threshold that optimises sensitivity to differentiate AMI from non-AMI. This was compared with subjective ECG interpretation by paramedics. The diagnosis of AMI was adjudicated by two investigators based on serial troponin testing in hospital. RESULTS: Of 691 participants, 87 had type 1 AMI and 687 had complete data for paramedic ECG interpretation. The MACS-ECG model had a C-index of 0.68 (95% CI: 0.61 to 0.75). At the pre-determined cut-off, MACS-ECG had 2.3% (95% CI: 0.3% to 8.1%) sensitivity, 99.5% (95% CI: 98.6% to 99.9%) specificity, 40.0% (95% CI: 10.2% to 79.3%) positive predictive value (PPV) and 87.6% (87.3% to 88.0%) negative predictive value (NPV). At the optimal threshold for sensitivity, MACS-ECG had 50.6% sensitivity (39.6% to 61.5%), 83.1% specificity (79.9% to 86.0%), 30.1% PPV (24.7% to 36.2%) and 92.1% NPV (90.4% to 93.5%). In comparison, paramedics had a sensitivity of 71.3% (95% CI: 60.8% to 80.5%) with 53.8% (95% CI: 53.8% to 61.8%) specificity, 19.7% (17.2% to 22.45%) PPV and 93.3% (90.8% to 95.1%) NPV. CONCLUSION: Neither MACS-ECG nor paramedic ECG interpretation had a sufficiently high PPV or NPV to 'rule in' or 'rule out' NSTEMI alone.

Head Injury Evaluation and Ambulance Diagnosis (HOME) Study protocol: a feasibility study assessing the implementation of the Canadian CT Head Rule in the prehospital setting.

INTRODUCTION: Traumatic brain injury (TBI) is a common presentation in the prehospital environment. At present, paramedics do not routinely use tools to identify low-risk patients who could be left at scene or taken to a local hospital rather than a major trauma centre. The Canadian CT Head Rule (CCHR) was developed to guide the use of CT imaging in hospital. It has not been evaluated in the prehospital setting. We aim to address this gap by evaluating the feasibility and acceptability of implementing the CCHR to patients and paramedics, and the feasibility of conducting a full-scale clinical trial of its use. METHODS AND ANALYSIS: We will recruit adult patients who are being transported to an emergency department (ED) by ambulance after suffering a mild TBI. Paramedics will prospectively collect data for the CCHR. All patients will be transported to the ED, where deferred consent will be taken and the treating clinician will reassess the CCHR, blinded to paramedic interpretation. The primary clinical outcome will be neurosurgically significant TBI. Feasibility outcomes include recruitment and attrition rates. We will assess acceptability of the CCHR to paramedics using the Ottawa Acceptability of Decision Rules Instrument. Interobserver reliability of the CCHR will be assessed between paramedics and the treating clinician in the ED. Participating paramedics and patients will be invited to participate in semistructured interviews to explore the acceptability of trial processes and facilitators and barriers to the use of the CCHR in practice. Data will be analysed thematically. We anticipate recruiting approximately 100 patients over 6 months. ETHICS AND DISSEMINATION: This study was approved by the Health Research Authority and the Research Ethics Committee (REC reference: 22/NW/0358). The results will be published in a peer-reviewed journal, presented at conferences and will be incorporated into a doctoral thesis. TRIAL REGISTRATION NUMBER: ISRCTN92566288.

Developing an alternative care pathway for emergency ambulance responses for adults with epilepsy: A Discrete Choice Experiment to understand which configuration service users prefer. Part of the COLLABORATE project.

INTRODUCTION: To identify service users' preferences for an alternative care pathway for adults with epilepsy presenting to the ambulance service. METHODS: Extensive formative work (qualitative, survey and knowledge exchange) informed the design of a stated preference discrete choice experiment (DCE). This hypothetical survey was hosted online and consisted of 12 binary choices of alternative care pathways described in terms of: the paramedic's access to medical records/ 'care plan', what happens next (described in terms of conveyance), time, availability of epilepsy specialists today, general practitioner (GP) notification and future contact with epilepsy specialists. DCE scenarios were described as: (i) typical seizure at home. (ii) typical seizure in public, (iii) atypical seizure. Respondents were recruited by a regional English ambulance service and by national public adverts. Participants were randomised to complete 2 of the 3 DCEs. RESULTS: People with epilepsy (PWE; n = 427) and friends/family (n = 167) who completed the survey were representative of the target population. PWE preferred paramedics to have access to medical records, non-conveyance, to avoid lengthy episodes of care, availability of epilepsy specialists today, GP notification, and contact with epilepsy specialists within 2-3 weeks. Significant others (close family members or friends) preferred PWE experiencing an atypical seizure to be conveyed to an Urgent Treatment Centre and preferred shorter times. Optimal configuration of services from service users' perspective far out ranked current practice (rank 230/288 possible configurations). DISCUSSION: Preferences differ to current practice but have minimal variation by seizure type or stakeholder. Further work on feasibility of these pathways in England, and potentially beyond, is required.

Research priorities for the management of major trauma: an international priority setting partnership with the James Lind Alliance.

OBJECTIVE: The objective of this study is to determine research priorities for the management of major trauma, representing the shared priorities of patients, their families, carers and healthcare professionals. DESIGN/SETTING: An international research priority-setting partnership. PARTICIPANTS: People who have experienced major trauma, their carers and relatives, and healthcare professionals involved in treating patients after major trauma. The scope included chest, abdominal and pelvic injuries as well as major bleeding, multiple injuries and those that threaten life or limb. METHODS: A multiphase priority-setting exercise was conducted in partnership with the James Lind Alliance over 24 months (November 2021-October 2023). An international survey asked respondents to submit their research uncertainties which were then combined into several indicative questions. The existing evidence was searched to ensure that the questions had not already been sufficiently answered. A second international survey asked respondents to prioritise the research questions. A final shortlist of 19 questions was taken to a stakeholder workshop, where consensus was reached on the top 10 priorities. RESULTS: A total of 1572 uncertainties, submitted by 417 respondents (including 132 patients and carers), were received during the initial survey. These were refined into 53 unique indicative questions, of which all 53 were judged to be true uncertainties after reviewing the existing evidence. 373 people (including 115 patients and carers) responded to the interim prioritisation survey and 19 questions were taken to a final consensus workshop between patients, carers and healthcare professionals. At the final workshop, a consensus was reached for the ranking of the top 10 questions. CONCLUSIONS: The top 10 research priorities for major trauma include patient-centred questions regarding pain relief and prehospital management, multidisciplinary working, novel technologies, rehabilitation and holistic support. These shared priorities will now be used to guide funders and teams wishing to research major trauma around the globe.

Route of drug administration in out-of-hospital cardiac arrest: A protocol for a randomised controlled trial (PARAMEDIC-3).

Aims: The PARAMEDIC-3 trial evaluates the clinical and cost-effectiveness of an intraosseous first strategy, compared with an intravenous first strategy, for drug administration in adults who have sustained an out-of-hospital cardiac arrest. Methods: PARAMEDIC-3 is a pragmatic, allocation concealed, open-label, multi-centre, superiority randomised controlled trial. It will recruit 15,000 patients across English and Welsh ambulance services. Adults who have sustained an out-of-hospital cardiac arrest are individually randomised to an intraosseous access first strategy or intravenous access first strategy in a 1:1 ratio through an opaque, sealed envelope system. The randomised allocation determines the route used for the first two attempts at vascular access. Participants are initially enrolled under a deferred consent model.The primary clinical-effectiveness outcome is survival at 30-days. Secondary outcomes include return of spontaneous circulation, neurological functional outcome, and health-related quality of life. Participants are followed-up to six-months following cardiac arrest. The primary health economic outcome is incremental cost per quality-adjusted life year gained. Conclusion: The PARAMEDIC-3 trial will provide key information on the clinical and cost-effectiveness of drug route in out-of-hospital cardiac arrest.Trial registration: ISRCTN14223494, registered 16/08/2021, prospectively registered.

Should video laryngoscopy or direct laryngoscopy be used for adults undergoing endotracheal intubation in the pre-hospital setting? A critical appraisal of a systematic review.

The safety and utility of endotracheal intubation by paramedics in the United Kingdom is a matter of debate. Considering the controversy surrounding the safety of paramedic-performed endotracheal intubation, any interventions that enhance patient safety should be evaluated for implementation based on solid evidence of their effectiveness. A systematic review performed by Hansel and colleagues (2022) sought to assess compare video laryngoscopes against direct laryngoscopes in clinical practice. This commentary aims to critically appraise the methods used within the review by Hansel et al (2022) and expand upon the findings in the context of clinical practice.

Impact of COVID-19 on out-of-hospital cardiac arrest care processes.

Early bystander cardiopulmonary resuscitation, use of defibrillators (including automated external defibrillators) and timely treatment by emergency medical services are known to increase the chances of survival for a patient experiencing an out-of-hospital cardiac arrest (OHCA); however, the impact of the COVID-19 pandemic on this is unclear from examining previous literature. This commentary critically appraises a recent systematic review and meta-analysis which assesses the effect of the COVID-19 pandemic on pre-hospital care for OHCA.

Towards exploring current challenges and future opportunities relating to the prehospital triage of patients with traumatic brain injury: a mixed-methods study protocol.

INTRODUCTION: Traumatic brain injury (TBI) is a major global health burden that results in disability and loss of health. Identifying those patients who require specialist neuroscience care can be challenging due to the low accuracy of existing prehospital trauma triage tools. Despite the widespread use of decision aids to 'rule out' TBI in hospitals, they are not widely used in the prehospital environment. We aim to provide a snapshot of current prehospital practices in the UK, and to explore facilitators and challenges that may be encountered when adopting new tools for decision support. METHODS AND ANALYSIS: A mixed-methods study will be conducted using a convergent design approach. In the first phase, we will conduct a national survey of current practice in which every participating ambulance service in the UK will receive an online questionnaire, and only one response is required. In the second phase, semistructured interviews will be conducted to explore the perceptions of ambulance service personnel regarding the implementation of new triage methods that may enhance triage decisions. The survey questions and the interview topic guide were piloted and externally reviewed. Quantitative data will be summarised using descriptive statistics; qualitative data will be analysed thematically. ETHICS AND DISSEMINATION: This study has been approved by the Health Research Authority (REC reference 22/HRA/2035). Our findings may inform the design of future care pathways and research as well as identify challenges and opportunities for future development of prehospital triage tools for patients with suspected TBI. Our findings will be published in peer-reviewed journals, relevant national and international conferences, and will be included in a PhD thesis.

Three generalizability studies of the components of perceived coach support.

Coaches are important providers of social support, but what influences us to perceive our coaches as supportive or unsupportive? We investigated the extent to which perceptions of coach support reflect characteristics of athletes and coaches, as well as relational components. In three studies, athletes judged the actual or hypothetical supportiveness of various coaches. The methods of generalizability theory permitted us to conclude that perceptions of coach support primarily reflected relational components, with characteristics both of athletes and coaches also independently playing (lesser) roles. These findings suggest that athletes may systematically disagree on the supportiveness of their coaches.

Prehospital triage tools in major trauma: a critical appraisal of a systematic review.

Effective triage is critical to ensure patients suffering major trauma are identified and access a pathway to definitive major trauma care, typically provided in a major trauma centre as part of an established major trauma system. The pre-hospital triage of trauma patients often relies upon the use of major trauma triage tools; this commentary critically appraises a recent systematic review which sought to evaluate and compare the accuracy of pre-hospital triage tools for major trauma.

Prehospital Airway Management.

The prehospital emergency airway management is a key moderating factor for patient survival and mortality rates. There has been much debate around the optimum method of prehospital emergency airway management. This commentary critically appraises a recent systematic review which assesses the harms and benefits of three different airway management strategies for a range of emergency clinical scenarios.

The diagnostic accuracy of prehospital triage tools in identifying patients with traumatic brain injury: A systematic review.

INTRODUCTION: Prehospital care providers are usually the first responders for patients with traumatic brain injury (TBI). Early identification of patients with TBI enables them to receive trauma centre care, which improves outcomes. Two recent systematic reviews concluded that prehospital triage tools for undifferentiated major trauma have low accuracy. However, neither review focused specifically on patients with suspected TBI. Therefore, we aimed to systematically review the existing evidence on the diagnostic performance of prehospital triage tools for patients with suspected TBI. METHODS: A comprehensive search of the current literature was conducted using Medline, EMBASE, CINAHL Plus and the Cochrane library (inception to 1st June 2021). We also searched Google Scholar, OpenGrey, pre-prints (MedRxiv) and dissertation databases. We included all studies published in English language evaluating the accuracy of prehospital triage tools for TBI. We assessed methodological quality and risk of bias using a modified Quality Assessment of Diagnostic Studies (QUADAS-2) tool. Two reviewers independently performed searches, screened titles and abstracts and undertook methodological quality assessments. Due to the heterogeneity in the population of interest and prehospital triage tools used, a narrative synthesis was undertaken. RESULTS: The initial search identified 1787 articles, of which 8 unique eligible studies met the inclusion criteria (5 retrospective, 2 prospective, 1 mixed). Overall, sensitivity of triage tools studied ranged from 19.8% to 87.9% for TBI identification. Specificity ranged from 41.4% to 94.4%. Two decision tools have been validated more than once: HITS-NS (2 studies, sensitivity 28.3-32.6%, specificity 89.1-94.4%) and the Field Triage Decision Scheme (4 studies, sensitivity 19.8-64.5%, specificity 77.4%-93.1%). Existing tools appear to systematically under-triage older patients. CONCLUSION: Further efforts are needed to improve and optimise prehospital triage tools. Consideration of additional predictors (e.g., biomarkers, clinical decision aids and paramedic judgement) may be required to improve diagnostic accuracy.

Use of a modified Delphi process to develop research priorities in major trauma.

PURPOSE: The burden of major trauma within the UK is ever increasing. There is a need to establish research priorities within the field. Delphi methodology can be used to develop consensus opinion amongst a group of stakeholders. This can be used to prioritise clinically relevant, patient-centred research questions to guide future funding allocations. The aim of our study was to identify key future research priorities pertaining to the management of major trauma in the UK. METHODS: A three-phased modified Delphi process was undertaken. Phase 1 involved the submission of research questions by members of the trauma community using an online survey (Phase 1). Phases 2 and 3 involved two consecutive rounds of prioritisation after questions were subdivided into 6 subcategories: Brain Injury, Rehabilitation, Trauma in Older People, Pre-hospital, Interventional, and Miscellaneous (Phases 2 and 3). Cut-off points were agreed by consensus amongst the steering subcommittees. This established a final prioritised list of research questions. RESULTS: In phase 1, 201 questions were submitted by 65 stakeholders. After analysis and with consensus achieved, 186 questions were taken forward for prioritisation in phase 2 with 114 included in phase 3. 56 prioritised major trauma research questions across the 6 categories were identified with a clear focus on long-term patient outcomes. Research priorities across the patient pathway from roadside to rehabilitation were deemed of importance. CONCLUSIONS: Consensus within the major trauma community has identified 56 key research questions across 6 categories. Dissemination of these questions to funding bodies to allow for the development of high-quality research is now required. There is a clear indication for targeted multi-centre multi-disciplinary research in major trauma.

PRe-hospital Evaluation of Sensitive TrOponin (PRESTO) Study: multicentre prospective diagnostic accuracy study protocol.

INTRODUCTION: Within the UK, chest pain is one of the most common reasons for emergency (999) ambulance calls and the most common reason for emergency hospital admission. Diagnosing acute coronary syndromes (ACS) in a patient with chest pain in the prehospital setting by a paramedic is challenging. The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision rule is a validated tool used in the emergency department (ED) to stratify patients with suspected ACS following a single blood test.We are seeking to evaluate the diagnostic accuracy of the T-MACS decision aid algorithm to 'rule out' ACS when used in the prehospital environment with point-of-care troponin assays. If successful, this could allow paramedics to immediately rule out ACS for patients in the 'very low risk' group and avoid the need for transport to the ED, while also risk stratifying other patients using a single blood sample taken in the prehospital setting. METHODS AND ANALYSIS: We will recruit patients who call emergency (999) ambulance services where the responding paramedic suspects cardiac chest pain. The data required to apply T-MACS will be prospectively recorded by paramedics who are responding to each patient. Paramedics will be required to draw a venous blood sample at the time of arrival to the patient. Blood samples will later be tested in batches for cardiac troponin, using commercially available troponin assays. The primary outcome will be a diagnosis of acute myocardial infarction, established at the time of initial hospital admission. The secondary outcomes will include any major adverse cardiac events within 30 days of enrolment. ETHICS AND DISSEMINATION: The study obtained approval from the National Research Ethics Service (reference: 18/ES/0101) and the Health Research Authority. We will publish our findings in a high impact general medical journal. TRIAL REGISTRATION NUMBER: Registration number: ClinicalTrials.gov, study ID: NCT03561051.

Pulmonary vein encircling ablation alters the atrial electrophysiologic response to autonomic stimulation.

OBJECTIVE: Pulmonary vein encircling ablation is often effective in the treatment of atrial fibrillation (AF). The success of the procedure does not depend upon creation of continuous lines of block. Thus mechanisms by which pulmonary vein encircling can cure AF remain unclear. Stimulation of cardiac autonomic ganglia alters atrial refractoriness and potentiates AF. We hypothesized that pulmonary vein encircling alters atrial autonomic function and that these alterations account in part for prevention of AF recurrences following ablation. METHODS: Atrial effective refractory periods (ERP) and AF inducibility were quantified in ten dogs before and during central autonomic nerve stimulation. Pulmonary vein encircling ablation was then performed and electrophysiologic testing repeated. In two dogs subjected to sham procedures measurements were repeated without performance of ablation. Hearts were examined histologically. RESULTS: Autonomic nerve stimulation led to decreased atrial refractoriness and increased AF inducibility and duration. Each of these effects were attenuated following pulmonary vein encircling (e.g., mean ERP decreased before (-23.7 +/- 1.8, p < 0.001) but not after ablation (-2.3 +/- 1.9, p = 0.25); AF inducibility increased by 26% before vs. 5% after ablation). No attenuation was seen in the sham operated animals. Histologic analysis following pulmonary vein encircling demonstrated destruction of some but not all autonomic ganglia. CONCLUSION: Autonomic stimulation shortens atrial refractory periods and potentiates AF. Pulmonary vein encircling ablation partially destroys atrial autonomic inputs, attenuates the refractory period shortening effect of autonomic stimulation and decreases AF inducibility. Destruction of autonomic ganglia may contribute to the anti-fibrillatory effects of pulmonary vein encircling and warrants further investigation.

The acute effects of different whole body vibration amplitudes on the endocrine system of young healthy men: a preliminary study.

Whole body vibration (WBV) has been suggested as an alternative form of exercise producing adaptive responses similar to that of resistance training. Very limited information is available on the effects of different vibration parameters on anabolic hormones. In this study, we compared the acute effects of different WBV amplitudes on serum testosterone (T) and insulin growth factor-1 (IGF-1). Nine healthy young recreationally active adult males (age 22 +/- 2 years, height 181 +/- 6.3 cm, weight 77.4 +/- 9.5 kg) voluntarily participated in this randomized controlled (cross-over design) study. The subjects performed 20 sets of 1 min each of WBV exercise in the following conditions: Non-vibration condition (control), low amplitude vibration [low (30 Hz, 1.5 mm peak-to-peak amplitude)] and high amplitude vibration [high (30 Hz, 3 mm peak-to-peak amplitude)]. Blood samples were collected before, after 10 sets, at the end (20th set) and after 24 h of the exercise bout. WBV exercise did not produce significant changes in serum T and IGF-1 either with low or high amplitude when compared with the control condition. The results of this study demonstrate that a single session of WBV exposure with a frequency of 30 Hz and amplitudes of 1.5 and 3 mm does not noticeably alter serum T and IGF-1 levels.

Evaluation of novel particles as pulmonary delivery systems for insulin in rats.

The purpose of the study was to evaluate the influence of calcium phosphate (CAP) and polyethylene glycol (PEG) particles on the systemic delivery of insulin administered by the pulmonary route. Two methods of pulmonary delivery were employed: intratracheal instillation and spray instillation. Insulin-CAP-PEG particles in suspension (1.2 U/kg, 110-140 micro L) were administered to the lungs of fasted rats by intratracheal instillation (INCAPEG) or spray instillation (SINCAPEG). Control treatments consisted of insulin solution (1.2 U/kg) by intratracheal instillation, spray instillation, and subcutaneous administration (SC). Plasma concentrations of insulin and glucose were determined by chemiluminescence and colorimetric methods, respectively. Data were analyzed by compartmental and non-compartmental methods, and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin disposition were determined. PK analysis suggested that insulin administered in particles had a longer half-life, a longer mean residence time, and a smaller rate of elimination than insulin in solution. In addition, insulin bioavailability after SINCAPEG was 1.8-fold that of insulin solution administered SC. PD analysis showed that smaller areas under the effect curve and, conversely, larger areas above the effect curve were obtained after INCAPEG in comparison to insulin solution. The magnitude of this effect was increased after SINCAPEG. The presence of CAP-PEG particles appears to positively influence the disposition of insulin administered to the lungs of Sprague-Dawley rats. Spray instillation appears to be a more efficient method of delivering insulin to the lungs of rats than intratracheal instillation.

The complete genome sequence of Thermoproteus tenax: a physiologically versatile member of the Crenarchaeota.

Here, we report on the complete genome sequence of the hyperthermophilic Crenarchaeum Thermoproteus tenax (strain Kra1, DSM 2078(T)) a type strain of the crenarchaeotal order Thermoproteales. Its circular 1.84-megabase genome harbors no extrachromosomal elements and 2,051 open reading frames are identified, covering 90.6% of the complete sequence, which represents a high coding density. Derived from the gene content, T. tenax is a representative member of the Crenarchaeota. The organism is strictly anaerobic and sulfur-dependent with optimal growth at 86°C and pH 5.6. One particular feature is the great metabolic versatility, which is not accompanied by a distinct increase of genome size or information density as compared to other Crenarchaeota. T. tenax is able to grow chemolithoautotrophically (CO2/H2) as well as chemoorganoheterotrophically in presence of various organic substrates. All pathways for synthesizing the 20 proteinogenic amino acids are present. In addition, two presumably complete gene sets for NADH:quinone oxidoreductase (complex I) were identified in the genome and there is evidence that either NADH or reduced ferredoxin might serve as electron donor. Beside the typical archaeal A0A1-ATP synthase, a membrane-bound pyrophosphatase is found, which might contribute to energy conservation. Surprisingly, all genes required for dissimilatory sulfate reduction are present, which is confirmed by growth experiments. Mentionable is furthermore, the presence of two proteins (ParA family ATPase, actin-like protein) that might be involved in cell division in Thermoproteales, where the ESCRT system is absent, and of genes involved in genetic competence (DprA, ComF) that is so far unique within Archaea.