Cardioprotection against ischaemia/reperfusion injury in mice can be achieved by delayed ischaemic postconditioning (IPost) applied as late as 30 min after the onset of reperfusion. We determined the ...efficacy of delayed IPost in a rat model of myocardial infarction (MI) and investigated potential underlying mechanisms of this phenomenon. Rats were subjected to 20, 30 or 45 min of coronary artery occlusion followed by 120 min of reperfusion (I/R). Immediate and early IPost included six cycles of I/R (10/10 s) applied 10 s or 10 min after reperfusion onset. In the second series of experiments, the rats were subjected to 30 min of coronary occlusion followed by IPost applied 10 s, 10, 30, 45 or 60 min after the onset of reperfusion. Immediate and early IPost (applied 10 s or 10 min of reperfusion) established cardioprotection only when applied after a period of myocardial ischaemia lasting 30 min. Delayed IPost applied after 30 or 45 min of reperfusion reduced infarct sizes by 36 and 41 %, respectively (both
P
< 0.01). IPost applied 60 min after reperfusion onset was ineffective. Inhibition of RISK pathway (administration of ERK1/2 inhibitor PD-98059 or PI3K inhibitor LY-294002) abolished cardioprotection established by immediate IPost but had no effect on cardioprotection conferred by early IPost. Blockade of SAFE pathway using JAK/STAT inhibitor AG490 had no effect on the immediate or early IPost cardioprotection. Blockade of mitochondrial K
ATP
(mitoK
ATP
) channels (with 5-Hydroxydecanoate) abolished cardioprotection achieved by immediate and early IPost, but had no effect on cardioprotection when IPost was applied 30 or 45 min into the reperfusion period. Immediate IPost increased phosphorylation of PI3K-AKT and ERK1/2. Early or delayed IPost had no effect on phosphorylation of PI3K-AKT, ERK1/2 or STAT3. These data show that in the rat model, delayed IPost confers significant cardioprotection even if applied 45 min after onset of reperfusion. Cardioprotection induced by immediate and early postconditioning involves recruitment of RISK pathway and/or mitoK
ATP
channels, while delayed postconditioning appears to rely on a different mechanism.
Stratifying preoperative risk and guiding perioperative therapy objectively has acquired critical importance, given robust data demonstrating that morbidity following non-cardiac surgery confers ...substantially increased risk of death, even beyond hospital discharge. The development of useful perioperative biomarkers depends fundamentally on both prospective morbidity data that enable the identification of higher risk patients as well as the translational understanding of pathophysiological mechanisms underlying postoperative organ dysfunction, the development of which may be specific to the perioperative environment. The emergence of cardiac insufficiency, rather than cardiac ischaemia, as the dominant factor associated with excess risk of prolonged postoperative morbidity has promoted the application of biomarkers used commonly in cardiovascular medicine. Several novel, organ specific biomarkers offer potential perioperative application. Nevertheless, common tests/biomarkers that are widely available do provide valuable, objective information that is perhaps under-utilised perioperatively. Despite significant challenges, perioperative medicine presents exciting-arguably unique-opportunities for novel biomarker development.
Perioperative lymphopenia has been linked with an increased risk of postoperative infectious complications, but the mechanisms remain unclear. We tested the hypothesis that bioenergetic dysfunction ...is an important mechanism underlying lymphopenia, impaired functionality and infectious complications. In two cohorts of patients (61-82 years old) undergoing orthopaedic joint replacement (n=417 and 328, respectively), we confirmed prospectively that preoperative lymphopenia (≤1.3 x 10(9)·l(-1); <20% white cell count; prevalence 15-18%) was associated with infectious complications (relative risk 1.5 (95% confidence interval 1.1-2.0); P=0.008) and prolonged hospital stay. Lymphocyte respirometry, mitochondrial bioenergetics and function were assessed (n=93 patients). Postoperative lymphocytes showed a median 43% fall (range: 26-65%; P=0.029; n=13 patients) in spare respiratory capacity, the extra capacity available to produce energy in response to stress. This was accompanied by reduced glycolytic capacity. A similar hypometabolic phenotype was observed in lymphocytes sampled preoperatively from chronically lymphopenic patients (n=21). This hypometabolic phenotype was associated with functional lymphocyte impairment including reduced T-cell proliferation, lower intracellular cytokine production and excess apoptosis induced by a range of common stressors. Glucocorticoids, which are ubiquitously elevated for a prolonged period postoperatively, generated increased levels of mitochondrial reactive oxygen species, activated caspase-1 and mature interleukin (IL)-1β in human lymphocytes, suggesting inflammasome activation. mRNA transcription of the NLRP1 inflammasome was increased in lymphocytes postoperatively. Genetic ablation of the murine NLRP3 inflammasome failed to prevent glucocorticoid-induced lymphocyte apoptosis and caspase-1 activity, but increased NLRP1 protein expression. Our findings suggest that the hypometabolic phenotype observed in chronically lymphopenic patients and/or acquired postoperatively increases the risk of postoperative infection through glucocorticoid activation of caspase-1 via the NLRP1 inflammasome.
In the early days of the COVID-19 pandemic, there was a pressing need for an expansion of the ventilator capacity in response to the COVID19 pandemic. Reserved for dire situations, ventilator ...splitting is complex, and has previously been limited to patients with similar pulmonary compliances and tidal volume requirements. To address this need, we developed a system to enable rapid and efficacious splitting between two or more patients with varying lung compliances and tidal volume requirements. We present here a computational framework to both drive device design and inform patient-specific device tuning. By creating a patient- and ventilator-specific airflow model, we were able to identify pressure-controlled splitting as preferable to volume-controlled as well create a simulation-guided framework to identify the optimal airflow resistor for a given patient pairing. In this work, we present the computational model, validation of the model against benchtop test lungs and standard-of-care ventilators, and the methods that enabled simulation of over 200 million patient scenarios using 800,000 compute hours in a 72 h period.
IntroductionIntubation-related complications are less frequent when intubation is successful on the first attempt. The rate of first attempt success in the emergency department (ED) and intensive ...care unit (ICU) is typically less than 90%. The bougie, a semirigid introducer that can be placed into the trachea to facilitate a Seldinger-like technique of tracheal intubation and is typically reserved for difficult or failed intubations, might improve first attempt success. Evidence supporting its use, however, is from a single academic ED with frequent bougie use. Validation of these findings is needed before widespread implementation.Methods and analysisThe BOugie or stylet in patients Undergoing Intubation Emergently trial is a prospective, multicentre, non-blinded randomised trial being conducted in six EDs and six ICUs in the USA. The trial plans to enrol 1106 critically ill adults undergoing orotracheal intubation. Eligible patients are randomised 1:1 for the use of a bougie or use of an endotracheal tube with stylet for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is severe hypoxaemia, defined as an oxygen saturation less than 80% between induction until 2 min after completion of intubation. Enrolment began on 29 April 2019 and is expected to be completed in 2021.Ethics and disseminationThe trial protocol was approved with waiver of informed consent by the Central Institutional Review Board at Vanderbilt University Medical Center or the local institutional review board at an enrolling site. The results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences.Trial registration numberClinicalTrials.gov Registry (NCT03928925).
Abstract Patients presenting for cardiac surgery pose many challenges for the anaesthetist. The clinician has to manage both the presenting cardiac pathophysiology and, increasingly, significant ...co-morbid disease. Thorough preoperative assessment, investigation and preparation allow identification of those patients at higher risk of perioperative complications, and permits development of individualized care plans in order to minimize these risks. Assessment should be based on a focused anaesthetic history and examination, as well as analysis of cardiovascular investigations, including simple blood tests and complex investigations of cardiac anatomy and function. Scoring systems incorporating biomarkers are often employed as a means of risk stratification and can be used not only to aid perioperative planning and informed consent, but also as an audit and quality improvement tool. This article describes a structured approach to anaesthetic pre-assessment for patients undergoing cardiac surgery. Commonly used preoperative scoring systems are introduced, and the application and interpretation of commonly employed cardiac investigations are summarized.
Fixed mark grade boundaries for non-linear assessment scales fail to account for variations in assessment difficulty. Where assessment difficulty varies more than ability of successive cohorts or the ...quality of the teaching, anchoring grade boundaries to median cohort performance should provide an effective method for setting standards.
This study investigated the use of a modified Hofstee (MH) method for setting unsatisfactory/satisfactory and satisfactory/excellent grade boundaries for multiple choice question-style assessments, adjusted using the cohort median to obviate the effect of subjective judgements and provision of grade quotas.
Outcomes for the MH method were compared with formula scoring/correction for guessing (FS/CFG) for 11 assessments, indicating that there were no significant differences between MH and FS/CFG in either the effective unsatisfactory/satisfactory grade boundary or the proportion of unsatisfactory graded candidates (p > 0.05). However the boundary for excellent performance was significantly higher for MH (p < 0.01), and the proportion of candidates returned as excellent was significantly lower (p < 0.01). MH also generated performance profiles and pass marks that were not significantly different from those given by the Ebel method of criterion-referenced standard setting.
This supports MH as an objective model for calculating variable grade boundaries, adjusted for test difficulty. Furthermore, it easily creates boundaries for unsatisfactory/satisfactory and satisfactory/excellent performance that are protected against grade inflation. It could be implemented as a stand-alone method of standard setting, or as part of the post-examination analysis of results for assessments for which pre-examination criterion-referenced standard setting is employed.
This thesis explores how social networking platforms influence the production of identity, status and capital amongst adolescents. This includes an exploration of how some digital communication ...platforms have negatively impacted on the social experiences of some teenagers and resulted in these users adapting their digital communicative practices to overcome communicative challenges. The study draws upon data collected via 9 semi-structured interviews, 9 focus groups and 84 surveys with boys and girls aged 11-16 from three schools in England. It explores specific social norms which relate to gender, and how they are negotiated within both masculine and feminine interactions through the respective practices of banter and gossip or stalking. These interactional processes are used as a means of negotiating status and of in-group inclusion and out-group rejection (Goffman, 1963). Furthermore they are important elements in the formation of relationships, identity and social capital. For Bourdieu social capital is the aggregate of the actual or potential resources which are linked to possession of a durable network of more or less institutionalized relationships of mutual acquaintance and recognition (1980, 2). The production of social capital is linked to an individual s capacity to manage group norms and approved values. This study demonstrates that online displays of gender are part of adolescents attempts to generate social capital through gaining positive public affirmations (for example in the form of likes). This has led to a new form of capital which has been titled virtual capital , and which is revealed to be a crucial element in adolescents self-worth and status. Although social networking sites can facilitate the creation of these capitals, they can also simultaneously hinder their creation. Facebook s system of widespread automatic information sharing, alongside a lack user of control in managing the flow of data which is received and shared, has led to many teens experiencing challenges in how they produce identity and gain popularity. This has led to negative social experiences, a growing disillusionment with Facebook, and increased use of more contemporary platforms such as Snap Chat which offer a solution to these problems. Therefore this thesis presents findings on how adolescents use social networking to negotiate gender and identity, produce social status and how these attempts can be confounded by the very technology that facilitates their production.
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