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Background & aims Indirect calorimetry (IC) is the gold-standard for determining measured resting energy expenditure (mREE) in critical illness. When IC is not available, predicted resting energy expenditure (pREE) equations are commonly utilized, which often inaccurately predict metabolic demands leading to over- or under-feeding. This study aims to longitudinally assess mREE via IC in critically ill patients with SARS-CoV-2 (COVID-19) infection throughout the entirety of, often prolonged, intensive care unit (ICU) stays and compare mREE to commonly utilized pREE equations. Methods This single-center prospective cohort study of 38 mechanically ventilated COVID-19 patients from April 1, 2020 to February 1, 2021. The Q-NRG® Metabolic Monitor was used to obtain IC data. The Harris-Benedict (HB), Mifflin St-Jeor (MSJ), Penn State University (PSU), and weight-based equations from the American Society of Parenteral and Enteral Nutrition – Society of Critical Care Medicine (ASPEN-SCCM) Clinical Guidelines were utilized to assess the accuracy of common pREE equations and their ability to predict hypo/hypermetabolism in COVID-19 ICU patients. Results The IC measures collected revealed a relatively normometabolic or minimally hypermetabolic mREE at 21.3 kcal/kg/d or 110% of predicted by the HB equation over the first week of mechanical ventilation (MV). This progressed to significant and uniquely prolonged hypermetabolism over successive weeks to 28.1 kcal/kg/d or 143% of HB predicted by MV week 3, with hypermetabolism persisting to MV week 7. Obese individuals displayed a more truncated response with significantly lower mREE versus non-obese patients in MV week 1 (19.5 ± 1.0 kcal/kg/d vs 25.1 ± 1.8 kcal/kg/d, respectively; p

The Orinoco goose, (Neochen jubata) is a grazing herbivore of open habitats that was once widely distributed in tropical South America. Centuries of overhunting and habitat loss have reduced it to widely scattered remnant populations; it is categorized as Near Threatened globally. Within the Cerrado biome, the Middle Araguaia River houses the largest remnant population. In August 2017, a study was started to assess the situation of the Orinoco Goose in the regions of Araguaia National Park, Cantão State Park, and adjacent rice fields. We conducted counts from an aerial census (a 700 km transect), monthly boat censuses (40 km) and land censuses in rice plantations. The aircraft census counted 367 individuals in August 2017, while monthly monitoring of a stretch of the lower Javaés River over more than two years showed a seasonal population variation associated with the flood regime, with the species virtually disappearing during the flood period between January and April when river beaches are submerged. During this period, large flocks of about 1,000 Orinoco Geese were discovered not far away, concentrated in small stretches of rice plantation agro-systems in the region. This behavioral seasonal concentration makes the species susceptible to poisoning and epizootic diseases. The findings suggest the need to re-categorize the Orinoco Goose population of the Middle Araguaia River as “Threatened” for the State of Tocantins due to the decline observed in the last 10 years, the maximum estimated population size, and the significant seasonal concentrations in a restricted area. At the same time, it is necessary to develop an action plan for its conservation in the surroundings of Ilha do Bananal, and throughout Brazil, where its threat status must be reviewed.

Background: Opioid use has come under increasing scrutiny, driven in part by the opioid crisis and growing concerns that up to 6% of opioid-naïve patients may become chronic opioid users. This has resulted in a revaluation of perioperative practice. For this reason, we implemented a multidisciplinary pathway to reduce perioperative opioid usage through education and standardization of practice. Methods: A single centre retrospective evaluation was performed after one year, comparing the outcomes to those of the two years prior to pathway implementation. Comparisons were made between pre- vs. post pathway change by 2:1 propensity matching between cohorts. Univariate linear regression models were created using demographic variables with those that were pResults: We found that intraoperative opioid use was significantly decreased 38.2mg(28.3) vs. 18.0mg(40.4) oral morphine equivalents (OME), pConclusions: These findings underscore the effectiveness of a multidisciplinary approach to reduce opioids. Furthermore, it demonstrates improved patient outcomes as measured by both shorter PACU and hospital length of stay, in addition to almost 50% reduction in perioperative opioid use.

Purpose of review Addressing the reduced quality of life that affects ICU survivors is the most pressing challenge in critical care medicine. In order to meet this challenge, we must translate lessons learnt from assessing and training athletes to the clinical population, utilizing measurable and targeted parameters obtained during cardiopulmonary exercise testing (CPET). Recent findings Critical illness survivors demonstrate a persistent reduction in their physical and metabolic function. This manifests in reduced aerobic exercise capacity and metabolic inflexibility. CPET-guided targeted metabolic conditioning has proved beneficial in several clinical populations, including those undergoing high-risk surgery, and could be successfully applied to the rehabilitation of ICU survivors. Summary CPET shows great promise in the guidance of rehabilitation in functionally limited ICU survivors. Parallels in the physiological response to exercise in athletes and clinical populations with the stress and consequences of critical illness must be investigated and ultimately applied to the burgeoning population of ICU survivors in order to treat the consequences of survival from critical illness.

Background and Aims The incidence of frailty is increasing as the population ages, which has important clinical implications given the associations between frailty and poor outcomes in the bladder cancer population. Due to a multi-organ system decline and decreased physiologic reserve, frail patients are vulnerable to stressors of disease and have poorer mortality and morbidity rates than their nonfrail peers. The association between frailty and poor outcomes has been documented across multiple populations, including radical cystectomy, creating a need for frailty assessments to be used preoperatively for risk stratification. We aim to provide a review of the common frailty assessments and their relevance to radical cystectomy patients. Findings A variety of assessments for frailty exist, from short screening items to comprehensive geriatric assessments. The syndrome spans multiple organ systems, as do the potential diagnostic instruments. Some instruments are less practical for use in clinical practice by urologists, such as the Canadian Study of Health and Aging Frailty Index and Comprehensive Geriatric Assessment. The tool most studied in radical cystectomy is the modified Frailty Index, associated with high grade complications and 30-days mortality. Frailty often coexists with malnutrition and sarcopenia, stressing the importance of screening for and addressing these syndromes to improve patient's perioperative outcomes. Conclusions There is no universally agreed upon frailty assessment, but the most studied in radical cystectomy is the modified Frailty Index, providing valuable data with which to counsel patients preoperatively. Alterations in immune phenotypes provide potential future diagnostic biomarkers for frailty.

ObjectiveMultimodal analgesia has gained popularity in total hip arthroplasty (THA) and total knee arthroplasty (TKA), but large multicenter studies evaluating specific analgesic combinations are lacking.DesignA retrospective study using the Premier Healthcare Database (2009–2014).SubjectsAdults who underwent elective primary THA or TKA.MethodsWe categorized day-of-surgery analgesic exposure using eight mutually exclusive categories: acetaminophen (Ac), nonsteroidal anti-inflammatory drugs (Ns), gabapentinoids (Ga; gabapentin or pregabalin), Ac+Ns, Ac+Ga, Ns+Ga, Ac+Ns+Ga, and none of the three drugs. Multilevel models measured associations of the analgesic categories with a composite of postoperative pulmonary complications (PPCs).ResultsAmong 863,139 patients, 75.2% received at least one of the three drugs. In multilevel models, compared with none of the three drugs, Ga use was associated with increased odds of PPCs when used alone (adjusted odds ratio [aOR] = 1.35, 95% confidence interval [CI] = 1.27 to 1.44), combined with Ac (aOR = 1.16, 95% CI = 1.08 to 1.26), or combined with Ns (aOR = 1.28, 95% CI = 1.21 to 1.34). In contrast, the Ac+Ns pair was associated with decreased odds of PPCs (OR = 0.86, 95% CI = 0.83 to 0.90) and lower opioid consumption. Ac+Ns+Ga was not associated with PPCs, whereas it was associated with the lowest opioid consumption on the day of surgery.ConclusionsGabapentinoids, alone and in single combination with either acetaminophen or nonsteroidal anti-inflammatory drugs, were associated with higher PPCs, whereas the Ac+Ns pair was associated with fewer PPCs and an opioid-sparing effect. Ac+Ns+Ga was not associated with PPCs, whereas it was associated with the lowest opioid consumption on the day of surgery.

Background Gabapentinoids are commonly prescribed in perioperative multimodal analgesia protocols. Despite widespread use, the optimal dose to reduce opioid consumption while minimizing risks is unknown. We assessed dose-dependent effects of gabapentinoids on opioid consumption and postoperative pulmonary complications following total hip or knee arthroplasty (THA or TKA). We hypothesized that use of a gabapentinoid on the day of THA or TKA is associated with an increased risk of postoperative pulmonary complications in a dose-response fashion compared with the risk for patients who did not receive the drug. Methods Using the Premier Database, we identified adults who underwent elective primary THA or TKA from 2009 to 2014. The exposure was receipt of a gabapentinoid (gabapentin or pregabalin) on the day of surgery. Gabapentin dose was categorized into 5 groups: none, 1 to 350, 351 to 700, 701 to 1,050, and >1,050 mg per day. Pregabalin dose was categorized into 4 groups: none, 1 to 110, 111 to 250, and >250 mg per day. The primary outcome was a composite of postoperative pulmonary complications, defined as respiratory failure, pneumonia, reintubation, pulmonary edema, noninvasive ventilation, or invasive mechanical ventilation. Results Of 858,306 patients who underwent THA or TKA, 11.0% received gabapentin and 10.2% received pregabalin. The mean age (and standard deviation) of the patients was 65.6 ± 10.7 years, 39.6% were male, 78.2% were Caucasian, and 55.2% were covered by Medicare. In multilevel regression analysis, receipt of gabapentinoid at any dose on the day of surgery was associated with increased odds of postoperative pulmonary complications. Compared with no exposure to the drug being used by the particular group, all dose ranges of gabapentin and pregabalin were associated with greater odds of postoperative pulmonary complications (odds ratio, 95% confidence interval = 1.51, 1.40 to 1.63, for >1,050 mg of gabapentin and 1.81, 1.57 to 2.09, for >250 mg of pregabalin). We found no clinically meaningful associations between exposure to either gabapentin or pregabalin and perioperative opioid consumption or the length of the hospital stay. Conclusions Exposure to gabapentinoids at any dose on the day of THA or TKA was associated with increased odds of postoperative pulmonary complications in a dose-response fashion, with minimal effects on perioperative opioid consumption. Level of evidence Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Complications after major surgery account for a disproportionate amount of in-hospital morbidity and mortality. Recent efforts have focused on preoperative optimization in an attempt to modify the risk associated with major surgery. Underaddressed, but important, modifiable risk factors are physical fitness and nutritional status. Surgical patients are particularly at risk of 3 related, but distinct, conditions: frailty, sarcopenia, and reduced physical fitness. Exercise-based prehabilitation strategies have shown promise in terms of improving aerobic fitness, although their impact on key clinical perioperative outcome measures have not been fully determined. Preoperative nutritional status also has a strong bearing on perioperative outcome.

Addressing the reduced quality of life that affects ICU survivors is the most pressing challenge in critical care medicine. In order to meet this challenge, we must translate lessons learnt from assessing and training athletes to the clinical population, utilizing measurable and targeted parameters obtained during cardiopulmonary exercise testing (CPET).Critical illness survivors demonstrate a persistent reduction in their physical and metabolic function. This manifests in reduced aerobic exercise capacity and metabolic inflexibility. CPET-guided targeted metabolic conditioning has proved beneficial in several clinical populations, including those undergoing high-risk surgery, and could be successfully applied to the rehabilitation of ICU survivors.CPET shows great promise in the guidance of rehabilitation in functionally limited ICU survivors. Parallels in the physiological response to exercise in athletes and clinical populations with the stress and consequences of critical illness must be investigated and ultimately applied to the burgeoning population of ICU survivors in order to treat the consequences of survival from critical illness.

BACKGROUND There is a need for standardized and cost-effective identification of frailty risk. The objective was to validate the Hospital Frailty Risk Score which utilizes International Classification Diagnoses in a cohort of older surgical patients, assess the score as an independent risk factor for adverse outcomes and compare discrimination properties of the frailty risk score with other risk stratification scores. METHODS Data were analysed from all patients ≥65 years undergoing primary surgical procedures from 2006-2018. Patients were categorized based on the frailty risk score. The primary outcomes were 30-day mortality and 180-day risk of readmission. RESULTS Of 16 793 patients evaluated, 7480 (45%), 7605 (45%) and 1708 (10%) had a low, intermediate and high risk of frailty. There was a higher incidence of 30-day mortality for individuals with intermediate (2.9%) and high (8.3%) compared with low (1.4%) risk of frailty (P

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes a project at an academic tertiary-care medical center aimed at identifying surgical patients with uncontrolled diabetes early in the preoperative process to improve their perioperative glycemic control and surgical outcomes.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer’s Disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. OBJECTIVES: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age ≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event (AE) rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. METHODS: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive drug or placebo before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuro-inflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. CONCLUSION: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

Background Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. Methods The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. Discussion We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties.

BACKGROUND: Elevated high-sensitivity troponin (hsTnT) after noncardiac surgery is associated with higher mortality, but the temporal relationship between early elevated troponin and the later development of noncardiac morbidity remains unclear. METHODS: Prospective observational study of patients aged ≥45 yr undergoing major noncardiac surgery at four UK hospitals (two masked to hsTnT). The exposure of interest was early elevated troponin, as defined by hsTnT >99th centile (≥15 ng L(−1)) within 24 h after surgery. The primary outcome was morbidity 72 h after surgery, defined by the Postoperative Morbidity Survey (POMS). Secondary outcomes were time to become morbidity-free and Clavien–Dindo ≥grade 3 complications. RESULTS: Early elevated troponin (median 21 ng L(−1) [16–32]) occurred in 992 of 4335 (22.9%) patients undergoing elective noncardiac surgery (mean [standard deviation, sd] age, 65 [11] yr; 2385 [54.9%] male). Noncardiac morbidity was more frequent in 494/992 (49.8%) patients with early elevated troponin compared with 1127/3343 (33.7%) patients with hsTnT

Objective Experimental animal models demonstrate that autonomic activity regulates systemic inflammation. By contrast, human studies are limited in number and exclusively use heart rate variability (HRV) as an index of cardiac autonomic regulation. HRV measures are primarily dependent on, and need to be corrected for, heart rate. Thus, independent autonomic measures are required to confirm HRV-based findings. Here, the authors sought to replicate the findings of preceding HRV-based studies by using HRV-independent, exercise-evoked sympathetic and parasympathetic measures of cardiac autonomic regulation to examine the relationship between autonomic function and systemic inflammation. Methods Sympathetic function was assessed by measuring heart rate changes during unloaded pedaling prior to onset of exercise, divided into quartiles; an anticipatory heart rate (AHRR) rise during this period is evoked by mental stress in many individuals. Parasympathetic function was assessed by heart rate recovery (HRR) 60 s after finishing cardiopulmonary exercise testing, divided into quartiles. Parasympathetic dysfunction was defined by delayed heart rate recovery (HRR) ≤12.beats.min −1 , a threshold value associated with higher cardiovascular morbidity/mortality in the general population. Systemic inflammation was primarily assessed by neutrophil-lymphocyte ratio (NLR), where a ratio >4 is prognostic across several inflammatory diseases and correlates strongly with elevated plasma levels of pro-inflammatory cytokines. High-sensitivity C-reactive protein (hsCRP) was also measured. Results In 1624 subjects (65 ± 14 y; 67.9% male), lower HRR (impaired vagal activity) was associated with progressively higher NLR (p = 0.004 for trend across quartiles). Delayed HRR, recorded in 646/1624 (39.6%) subjects, was associated with neutrophil-lymphocyte ratio >4 (relative risk: 1.43 (95%CI: 1.18–1.74); P = 0.0003). Similar results were found for hsCRP (p = 0.045). By contrast, AHRR was not associated with NLR (relative risk: 1.24 (95%CI: 0.94–1.65); P = 0.14). Conclusions Delayed HRR, a robust measure of parasympathetic dysfunction, is independently associated with leukocyte ratios indicative of systemic inflammation. These results further support a role for parasympathetic modulation of systemic inflammation in humans.

Systemic arterial pulse pressure (systolic minus diastolic pressure) ≤53 mm Hg in patients with cardiac failure is correlated with reduced stroke volume and is independently associated with accelerated morbidity and mortality. Given that deconditioned surgical and heart failure patients share similar cardiopulmonary physiology, we examined whether lower pulse pressure is associated with excess morbidity after major surgery.This was a prospective observational cohort study of patients deemed by their preoperative assessors to be at higher risk of postoperative morbidity. Preoperative pulse pressure was calculated before cardiopulmonary exercise testing. The primary outcome was any morbidity (PostOperative Morbidity Survey) occurring within 5 days of surgery, stratified by pulse pressure threshold ≤53 mm Hg. The relationship between pulse pressure, postoperative morbidity, and oxygen pulse (a robust surrogate for left ventricular stroke volume) was examined using logistic regression analysis (accounting for age, sex, BMI, cardiometabolic co-morbidity, and operation type).The primary outcome occurred in 578/660 (87.6%) patients, but postoperative morbidity was more common in 243/ 660 patients with preoperative pulse pressure ≤53 mm Hg{odds ratio (OR): 2.24 [95% confidence interval (CI): 1.29-3.38]; P0.001). Pulse pressure ≤53 mm Hg [OR:1.23 (95% CI: 1.03-1.46); P=0.02] and type of surgery were independently associated with all-cause postoperative morbidity (multivariate analysis). Oxygen pulse90% of population-predicted normal values was associated with pulse pressure ≤ 53 mm Hg [OR: 1.93 (95% CI: 1.32-2.84); P=0.007].In deconditioned surgical patients, lower preoperative systemic arterial pulse pressure is associated with excess morbidity. These data are strikingly similar to meta-analyses identifying low pulse pressure as an independent risk factor for adverse outcomes in cardiac failure. Low preoperative pulse pressure is a readily available measure, indicating that detailed physiological assessment may be warranted.ISRCT registry, ISRCTN88456378.

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).

Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function.Laboratory/clinical investigations.University laboratory/medical centers.Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients.Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed.Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006).Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.

Background: Delirium is a common post-operative complication, particularly in older adults undergoing major or emergency procedures. It is associated with increased length of intensive care and hospital stay, post-operative mortality and subsequent dementia risk. Current methods of predicting delirium incidence, duration and severity have limitations. Investigation of blood and cerebrospinal fluid (CSF) biomarkers linked to delirium may improve understanding of the underlying pathophysiology, particularly with regard to the extent this is shared or distinct with underlying dementia. Together, these have the potential for development of better risk stratification tools and perioperative interventions. Methods: 200 patients over the age of 70 scheduled for surgery with routine spinal anaesthetic will be recruited from UK hospitals. Their cognitive and functional baseline status will be assessed pre-operatively by telephone. Time-matched CSF and blood samples will be taken at the time of surgery and analysed for known biomarkers of neurodegeneration and neuroinflammation. Patients will be assessed daily for delirium until hospital discharge and will have regular cognitive follow-up for two years. Primary outcomes will be change in modified Telephone Interview for Cognitive Status (TICS-m) score at 12 months and rate of change of TICS-m score. Delirium severity, duration and biomarker levels will be treated as exposures in a random effects linear regression models. PRIMED Risk has received regulatory approvals from Health Research Authority and London – South East Research Ethics Committee. Discussion: The main anticipated output from this study will be the quantification of biomarkers of acute and chronic contributors to cognitive impairment after surgery. In addition, we aim to develop better risk prediction models for adverse cognitive outcomes.

Complications after major surgery account for a disproportionate amount of in-hospital morbidity and mortality. Recent efforts have focused on preoperative optimization in an attempt to modify the risk associated with major surgery. Underaddressed, but important, modifiable risk factors are physical fitness and nutritional status. Surgical patients are particularly at risk of 3 related, but distinct, conditions: frailty, sarcopenia, and reduced physical fitness. Exercise-based prehabilitation strategies have shown promise in terms of improving aerobic fitness, although their impact on key clinical perioperative outcome measures have not been fully determined. Preoperative nutritional status also has a strong bearing on perioperative outcome.

Background Systemic inflammation is pivotal in the pathogenesis of cardiovascular disease. As inflammation can directly cause cardiomyocyte injury, we hypothesised that established systemic inflammation, as reflected by elevated preoperative neutrophil-lymphocyte ratio (NLR) >4, predisposes patients to perioperative myocardial injury. Methods We prospectively recruited 1652 patients aged ≥45 yr who underwent non-cardiac surgery in two UK centres. Serum high sensitivity troponin T (hsTnT) concentrations were measured on the first three postoperative days. Clinicians and investigators were blinded to the troponin results. The primary outcome was perioperative myocardial injury, defined as hsTnT≥14 ng L−1 within 3 days after surgery. We assessed whether myocardial injury was associated with preoperative NLR>4, activated reactive oxygen species (ROS) generation in circulating monocytes, or both. Multivariable logistic regression analysis explored associations between age, sex, NLR, Revised Cardiac Risk Index, individual leukocyte subsets, and myocardial injury. Flow cytometric quantification of ROS was done in 21 patients. Data are presented as n (%) or odds ratio (OR) with 95% confidence intervals. Results Preoperative NLR>4 was present in 239/1652 (14.5%) patients. Myocardial injury occurred in 405/1652 (24.5%) patients and was more common in patients with preoperative NLR>4 [OR: 2.56 (1.92–3.41); P Conclusions Preoperative NLR>4 is associated with perioperative myocardial injury, independent of conventional risk factors. Systemic inflammation may contribute to the development of perioperative myocardial injury. Clinical trial registration NCT01842568.

Background Elevated preoperative heart rate (HR) is associated with perioperative myocardial injury and death. In apparently healthy individuals, high resting HR is associated with development of cardiac failure. Given that patients with overt cardiac failure have poor perioperative outcomes, we hypothesized that subclinical cardiac failure, identified by cardiopulmonary exercise testing, was associated with elevated preoperative HR > 87 beats min −1 (HR > 87). Methods This was a secondary analysis of an observational cohort study of surgical patients aged ≥45 yr. The exposure of interest was HR > 87, recorded at rest before preoperative cardiopulmonary exercise testing. The predefined outcome measures were the following established predictors of mortality in patients with overt cardiac failure in the general population: ventilatory equivalent for carbon dioxide ( V ˙ E / V ˙ co 2 ) ratio ≥34, heart rate recovery ≤6 and peak oxygen uptake ( V ˙ o 2 ) ≤14 ml kg −1 min −1 . We used logistic regression analysis to test for association between HR > 87 and markers of cardiac failure. We also examined the relationship between HR > 87 and preoperative left ventricular stroke volume in a separate cohort of patients. Results HR > 87 was present in 399/1250 (32%) patients, of whom 438/1250 (35%) had V ˙ E / V ˙ co 2 ratio ≥34, 200/1250 (16%) had heart rate recovery ≤6, and 396/1250 (32%) had peak V ˙ o 2 ≤14 ml kg −1 min −1 . HR > 87 was independently associated with peak V ˙ o 2 ≤14 ml kg −1 min −1 {odds ratio (OR) 1.69 [1.12–3.55]; P =0.01} and heart rate recovery ≤6 (OR 2.02 [1.30–3.14]; P 87 was not associated with V ˙ E / V ˙ co 2 ratio ≥34 (OR 1.31 [0.92–1.87]; P =0.14). In a separate cohort, HR > 87 (33/181; 18.5%) was associated with impaired preoperative stroke volume (OR 3.21 [1.26–8.20]; P =0.01). Conclusions Elevated preoperative heart rate is associated with impaired cardiopulmonary performance consistent with clinically unsuspected, subclinical cardiac failure. Clinical trial registration ISRCTN88456378.

Background: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study’s four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated “abnormal” laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors’ diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96–5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6–41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Baroreflex dysfunction is a common feature of established cardiometabolic diseases that are most frequently associated with the development of critical illness. Laboratory models show that baroreflex dysfunction impairs cardiac contractility and cardiovascular performance, thereby increasing the risk of morbidity after trauma and sepsis. We hypothesized that baroreflex dysfunction contributes to excess postoperative morbidity after major surgery as a consequence of the inability to achieve adequate perioperative tissue oxygen delivery.In a randomized controlled trial of goal-directed haemodynamic therapy (GDT) in higher-risk surgical patients, baroreflex function was assessed using the spontaneous baroreflex sensitivity (BRS) method via an arterial line placed before surgery, using a validated sequence method technique (one beat lag). The BRS was calculated during the 6 h postoperative GDT intervention. Analyses of BRS were done by investigators blinded to clinical outcomes. The primary outcome was the association between postoperative baroreflex dysfunction (BRS6 mm Hg s(-1), a negative prognostic threshold in cardiovascular pathology) and early postoperative morbidity. The relationship between baroreflex dysfunction and postoperative attainment of preoperative indexed oxygen delivery was also assessed.Patients with postoperative baroreflex dysfunction were more likely to sustain infectious {relative risk (RR) 1.75 [95% confidence interval (CI): 1.07-2.85], P=0.02} and cardiovascular morbidity [RR 2.39 (95% CI: 1.22-4.71), P=0.008]. Prolonged hospital stay was more likely in patients with baroreflex dysfunction [unadjusted hazard ratio 1.62 (95% CI: 1.14-2.32), log-rank P=0.004]. Postoperative O2 delivery was 36% (95% CI: 7-65) lower in patients with baroreflex dysfunction in those not randomly assigned to GDT (P=0.02).Baroreflex dysfunction is associated with excess morbidity, impaired cardiovascular performance, and delayed hospital discharge, suggesting a mechanistic role for autonomic dysfunction in determining perioperative outcome.ISCRTN76894700.

Indirect measures of cardiac vagal activity are strongly associated with exercise capacity, yet a causal relationship has not been established. Here we show that in rats, genetic silencing of the largest population of brainstem vagal preganglionic neurons residing in the brainstem's dorsal vagal motor nucleus dramatically impairs exercise capacity, while optogenetic recruitment of the same neuronal population enhances cardiac contractility and prolongs exercise endurance. These data provide direct experimental evidence that parasympathetic vagal drive generated by a defined CNS circuit determines the ability to exercise. Decreased activity and/or gradual loss of the identified neuronal cell group provides a neurophysiological basis for the progressive decline of exercise capacity with aging and in diverse disease states., Demonstrating a causal relationship between cardiac vagal tone and exercise capacity has been previously limited by methodological constraints. Using genetic targeting, silencing and optogenetic recruitment of vagal motor neuron activity in rodents, Machhada et al. provide direct evidence that vagal drive determines the ability to exercise.

In February the international consensus definitions for sepsis and septic shock were updated to reflect current understanding of the syndrome. A new scoring system was also released (qSOFA) to aid early identification of organ dysfunction in sepsis.

eXtension (pronounced e-extension) is an online resource transforming how faculty can collaborate and deliver equine education. As the first Community of Practice launched from eXtension, HorseQuest (HQ) offers free, interactive, peer-reviewed, online resources on a variety of equine-related topics at http://www.extension.org. This group has adapted traditional educational content to the online environment to maximize search engine optimization, to be more discoverable and relevant in the online world. This means that HQ resources are consistently being found on the first page of search results. Also, by researching key words searched by Internet users, HQ has guided new content direction and determined potential webcast topics based on relevance and frequency of those searches. In addition to establishing good search engine optimization, HQ has been utilizing the viral networking aspect of YouTube by uploading clips of existing equine educational videos to YouTube. HorseQuest content appears in mainstream media, is passed on by the user, and helps HQ effectively reach their community of interest (horse enthusiasts). HorseQuest partners with My Horse University to produce webcasts that combine concise knowledge exchange via a scripted presentation with viewer chat and incoming questions. HorseQuest has produced and published content including 12 learning modules, 8 webchats, 21 webcasts, and 572 videos segments. After the official public launch, there was a steady increase in average number of visits/mo and average page views/mo over the 26-mo period. These regressions show a statistically significant increase in visits (P < 0.001) of approximately 450 visits per month and a significant increase in page views (P = 0.004) of about 373 page views per month. HorseQuest is a resource for several state 4-H advancement and competition programs and will continue to be incorporated into traditional extension programs, while reaching and affecting global audiences.

Objective Reduced exercise capacity is well documented in end-stage chronic kidney disease (CKD), preceded by changes in cardiac morphology in CKD stage 3. However, it is unknown whether subclinical cardiopulmonary dysfunction occurs in CKD stage 3 independently of heart failure. Methods Prospective observational cross-sectional study of exercise capacity assessed by cardiopulmonary exercise testing in 993 preoperative patients. Primary outcome was peak oxygen consumption (VO2peak). Anaerobic threshold (AT), oxygen pulse and exercise-evoked measures of autonomic function were analysed, controlling for CKD stage 3, age, gender, diabetes mellitus and hypertension. Results CKD stage 3 was present in 93/993 (9.97%) patients. Diabetes mellitus (RR 2.49 (95% CI 1.59 to 3.89); p

Summary Background Morbidity after major surgery is associated with low oxygen delivery. Haemodynamic therapy aimed at increasing oxygen delivery in an effort to reduce oxygen debt, tissue injury, and morbidity, is controversial. The most appropriate target for this strategy is unclear and might have several off-target effects, including loss of neural (parasympathetic)-mediated cellular protection. We hypothesised that individualised oxygen delivery targeted haemodynamic therapy (goal-directed therapy) in high-risk surgical patients would reduce postoperative morbidity, while secondarily addressing whether goal-directed therapy affected parasympathetic function. Methods In this multicentre, randomised, double-blind, controlled trial, adult patients undergoing major elective surgery were allocated by computer-generated randomisation to a postoperative protocol (fluid, with and without dobutamine) targeted to achieve their individual preoperative oxygen delivery value (goal-directed therapy) or standardised care (control). Patients and staff were masked to the intervention. The primary outcome was absolute risk reduction (ARR) in morbidity (defined by Clavien–Dindo grade II or more) on postoperative day 2. We also assessed a secondary outcome focused on parasympathetic function, using time-domain heart rate variability measures. Analyses were done on an intention-to-treat basis. The trial was registered with Controlled Clinical Trials (number ISRCTN76894700). Findings We enrolled 204 patients between May 20, 2010, and Feb 12, 2014. Intention-to-treat analysis of the 187 (92%) patients who completed the trial intervention period showed that early morbidity was similar between goal-directed therapy (44 [46%] of 95 patients) and control groups (49 [53%] of 92 patients) (ARR −7%, 95% CI −22 to 7; p=0·30). Prespecified secondary analysis showed that 123 (66%) of 187 patients achieved preoperative oxygen delivery (irrespective of intervention). These patients sustained less morbidity (ARR 19%, 95% CI 3–34; p=0·016), including less infectious complications. Goal-directed therapy reduced parasympathetic activity postoperatively (relative risk 1·33, 95% CI 1·01–1·74). Interpretation Achievement of preoperative oxygen delivery values in the postoperative phase was associated with less morbidity, but this was not affected by the use of an oxygen delivery targeted strategy. Reduced parasympathetic activity after goal-directed therapy was associated with the failure of this intervention to reduce postoperative morbidity. Funding Academy of Medical Sciences and Health Foundation Clinician Scientist Award.

The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.

Many of the insults that lead to critical illness, such as sepsis, trauma and major surgery, either cause, or are perhaps the consequence of, profound alterations in autonomic nervous system control. Several cardinal features of chronic critical illness – regardless of the etiology – support the assertion that autonomic dysfunction is a core mechanism underlying the development and perpetuation of multiorgan failure. By reconsidering the spectrum that autonomic dysfunction encompasses, we explore the pivotal and multi-faceted impact exerted by aberrant autonomic control in chronic critical illness.

Design cycles will undoubtedly play an increasingly important role in drug discovery in the coming years, as the amount of structural information on protein targets continues to rise. However, the traditional method of drug discovery, based upon random screening and systematic modification of leads by medicinal chemistry techniques, will probably not be abandoned completely because it has a potentially important advantage over more structure-based methods--namely, leads identified in this way are unlikely to show a close resemblance to the natural ligand or substrate. They may, therefore, have advantages in terms of patent novelty, selectivity, or pharmacokinetic profile. However, such leads could then serve as the basis for structure-based, rational modification programs, in which their interactions with target receptors are defined (as we have described) and improved molecules are designed. A final important point to be made about structure-based design in drug discovery is that, while it can be of great use in the initial process of identifying ligands with improved affinity and selectivity in vitro, it can usually say very little about other essential aspects of the drug discovery process, e.g. the need to achieve an adequate pharmacokinetic profile and low toxicity in vivo. This observation reminds us that drug design is a multidisciplinary process, involving molecular biologists, biochemists, pharmacologists, organic chemists, crystallographers, and others. In order to be effective, therefore, structure-based design must be properly integrated into the overall discovery effort.

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.

Dear SirOur colleagues Tavakol & Dennick (2014) convincingly argue that the conventional-Hofstee (CH) standard setting method lacks transparency; they also demonstrate that large changes in the upp...

This study examines the facial surfaces of different groups of cleft babies aged up to eleven months, prior to any corrective surgery, with the aim of identifying and assessing differences in their facial morphology. Measurements of standard anthropometric landmarks were made on plaster casts taken pre-operatively of the faces of babies presenting for surgical correction of lip and palate deformities. Periorbital and mid face measurements show no difference between control and cleft groups. The nasal base is shown to be wider in infants with cleft lip on both cleft and non-cleft sides. Upper lip measurements indicate shortening, lateral deviation and superolateral rotation. A diagrammatic model is proposed to illustrate facial anatomy in control and cleft individuals. Modifications to the technique are proposed. Further study in this field is suggested, in order to produce a comprehensive database of facial morphological changes in the cleft and non-cleft populations both pre-operatively and over time, with a view to producing a potential redefinition of the cleft syndrome based on anthropometric principles.

Objective Recent perioperative trials have highlighted the urgent need for a better understanding of why sympatholytic drugs intended to reduce myocardial injury are paradoxically associated with harm (stroke, myocardial infarction). We hypothesised that following a standardised autonomic challenge, a subset of patients may demonstrate excessive sympathetic activation which is associated with exercise-induced ischaemia and impaired cardiac output. Methods Heart rate rise during unloaded pedalling (zero workload) prior to the onset of cardiopulmonary exercise testing (CPET) was measured in 2 observation cohorts of elective surgical patients. The primary outcome was exercise-evoked, ECG-defined ischaemia (>1 mm depression; lead II) associated with an exaggerated increase in heart rate (EHRR ≥12 bpm based on prognostic data for all-cause cardiac death in preceding epidemiological studies). Secondary outcomes included cardiopulmonary performance (oxygen pulse (surrogate for left ventricular stroke volume), peak oxygen consumption (VO2peak), anaerobic threshold (AT)) and perioperative heart rate. Results EHRR was present in 40.4–42.7% in both centres (n=232, n=586 patients). Patients with EHRR had higher heart rates perioperatively (p

There is currently no effective method of measuring arterial blood gas tensions in austere environments such as in space or at high altitude. An alternative to direct arterial measurement is the sampling of arterialized earlobe blood, an accurate technique that has been in use in clinical medicine and physiology for more than 50 yr. We, therefore, developed an earlobe arterialized blood (EAB) collector for practical use in extreme environments.The results from the EAB collector were compared with simultaneous samples of blood drawn from the radial artery. Six healthy subjects breathed a gas mixture of 12.8% O2 in N2 during 15 min of 8 degree head-down tilt. The blood samples were analyzed immediately.The mean differences in Po2 between arterialized earlobe and radial artery samples were 0.25 +/- 1.25 mmHg for Po2 and 1.0 +/- 0.75 mmHg for Pco2; neither difference was significant. There was no difference between the pH values obtained by the two techniques.This study suggests that arterialized blood sampled from the earlobe using the EAB collector may provide sufficiently accurate measurements of the Po2, Pco2 and pH of arterial blood for clinical or research use in extreme environments.

A computer model was constructed based on the observation that a number of structurally dissimilar compounds gave rise to similar biological activity. Mode of action work confirmed the link. The model was then used to prioritise targets for synthesis and successfully predicted many active series. The major limitation of the model was that it was unable to predict potency or spectrum. It is thought likely that the factors controlling these limitations are linked with LUMO energies, but this hypothesis has not been proven

The combination of an indium complex with lithium perchlorate affords a potent system for the catalytic acylation of electron-rich aromatics and alcohols. The use of isopropenyl acetate as acyl donor results in cleaner methodology with acetone as the only by-product. The study has also revealed an indium-catalysed ketalisation reaction.

The introduction of ultraviolet disinfection of sewage effluent in Jersey has served to focus attention on other sources of faecal pollution responsible for subsequent compliance failures in coastal water quality in St Aubin's Bay. Studies of microbial concentrations (total coliforms, faecal coliforms and faecal streptococci) in streams draining to the bay showed concentrations to be elevated by an order of magnitude or more following rainfall. Detailed monitoring of indicator organisms during hydrograph events showed rapid increases in concentration with flow associated with the rising limb of the hydrograph and transport of suspended solids. Microbial budget estimates suggested that between 42 and 97% of microbial delivery was associated with high flows, which account for just 20% of the total discharge. Budgets also revealed the relative importance of different catchment inputs, revealing the low bacterial input associated with UV treated effluent which provided 48% of the total volume discharged to the bay. Implications for water quality standards are discussed with reference to catchment management planning.

HIV-1 proteinase processes its virally encoded polyproteins into mature structural proteins and enzymes that are essential for viral propagation. As a consequence the proteinase is an attractive target for prospective antiviral agents for the treatment of AIDS, and knowledge of its tertiary structure an important step in drug design. Following the observation (Toh et al. 1985) that retroviral proteinases shared a highly conserved sequence Asp-Thr/Ser-Gly with the pepsins, it has been hypothesised (Pearl and Taylor, 1987; Blundell et al. 1988) on the basis of sequence analysis and modelling studies that these enzymes exist as dimers closely similar in three-dimensional structure to the ancestral dimeric proteinase suggested for the aspartic proteinases (Tang et al. 1978). This has now been confirmed, first by X-ray analysis of a synthetic HIV-1 proteinase in the laboratory of Wlodawer (Weber et al. 1989) and then for a recombinant enzyme in our own laboratories (Lapatto et al. 1989). These X-ray structure analyses indicated that the overall fold of the HIV-1 proteinase closely resembled that of the RSV-proteinase (Miller et al., 1989). The Asp-Thr-Gly sequences adopt a conformation closely similar to that of the pepsin-like aspartic proteinases but organised symmetrically in the dimer about the crystallographic 2-fold axis. However, the N- and C-termini together form an intermolecular four-stranded sheet, which is central to the stability of the dimer, in contrast to the inter-subunit sheet of the pepsins, which has six antiparallel strands arranged around the pseudo dyad.

Null zones and head postures were studied in two patients with idiopathic congenital nystagmus who had been carefully selected from a larger group of patients who had nystagmus with compensatory head postures. Oculomotor and sensory features of the two patients indicated that they would have a reasonable chance of profiting from surgery. Neither patient had a periodic alternating or manifest latent nystagmus or any ocular disease of the fixating eye. Postoperative evaluation of the head posture and the nystagmus behavior of both patients was carried out over a period in excess of 6 years. Neither of the patients readopted a head turn, and visual acuity was found to be equivalent to that prior to surgery when using the null zone. In one of the patients the postoperative null zone was located in the primary position, while in the other the null zone was decreased from an eccentricity of 30 degrees to 15 degrees. These results suggest that the position of the postoperative null zone is not always an accurate predictor of head turn.

We investigated the factors that determine the nature and extent of abnormal head postures in patients with congenital nystagmus. The head positions and eye movements of 16 patients were monitored while they adopted a variety of gaze positions. Five patients displayed a single head posture and four displayed multiple head postures. Six of the nine head postures matched the minimum intensity zone. The extent of the head posture was also found to be dictated by the velocity distribution of the slow phase, the nystagmus beat direction, and the neutral zone. Our results suggest that the surgical management of a head posture should not always be based only on the relocation of the minimum intensity zone to the primary gaze position.

Knowledge of the tertiary structure of the proteinase from human immunodeficiency virus HIV-1 is important to the design of inhibitors that might possess antiviral activity and thus be useful in the treatment of AIDS. The conserved Asp-Thr/Ser-Gly sequence in retroviral proteinases suggests that they exist as dimers similar to the ancestor proposed for the pepsins. Although this has been confirmed by X-ray analyses of Rous sarcoma virus and HIV-1 proteinases, these structures have overall folds that are similar to each other only where they are also similar to the pepsins. We now report a further X-ray analysis of a recombinant HIV-1 proteinase at 2.7 A resolution. The polypeptide chain adopts a fold in which the N- and C-terminal strands are organized together in a four-stranded beta-sheet. A helix precedes the single C-terminal strand, as in the Rous sarcoma virus proteinase and also in a synthetic HIV-1 proteinase, in which the cysteines have been replaced by alpha-aminobuytric acid. The structure reported here provides an explanation for the amino acid invariance amongst retroviral proteinases, but differs from that reported earlier in some residues that are candidates for substrate interactions at P3, and in the mode of intramolecular cleavage during processing of the polyprotein.

This paper compares the characteristics of protein and fluoroprotein foams for base injected application to fires in oil storage tanks. Part II discusses the fire tests and their results.