Kingston Health Sciences Centre

ABSTRACT: The current International Association for the Study of Pain (IASP) definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a reevaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain, to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year.

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

KEY POINTS Obesity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan.[1][1] Epidemiologic studies define obesity using the body mass index (BMI; weight/height2), which can stratify

Immortal time in observational studies can bias the results in favour of the treatment group, but it is not difficult to identify and avoid

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The Canadian Society for Exercise Physiology assembled a Consensus Panel representing national organizations, content experts, methodologists, stakeholders, and end-users and followed an established guideline development procedure to create the Canadian 24-Hour Movement Guidelines for Adults aged 18–64 years and Adults aged 65 years or older: An Integration of Physical Activity, Sedentary Behaviour, and Sleep. These guidelines underscore the importance of movement behaviours across the whole 24-h day. The development process followed the strategy outlined in the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A large body of evidence was used to inform the guidelines including 2 de novo systematic reviews and 4 overviews of reviews examining the relationships among movement behaviours (physical activity, sedentary behaviour, sleep, and all behaviours together) and several health outcomes. Draft guideline recommendations were discussed at a 4-day in-person Consensus Panel meeting. Feedback from stakeholders was obtained by survey (n = 877) and the draft guidelines were revised accordingly. The final guidelines provide evidence-based recommendations for a healthy day (24-h), comprising a combination of sleep, sedentary behaviours, and light-intensity and moderate-to-vigorous-intensity physical activity. Dissemination and implementation efforts with corresponding evaluation plans are in place to help ensure that guideline awareness and use are optimized. Novelty First ever 24-Hour Movement Guidelines for Adults aged 18–64 years and Adults aged 65 years or older with consideration of a balanced approach to physical activity, sedentary behaviour, and sleep Finalizes the suite of 24-Hour Movement Guidelines for Canadians across the lifespan

Results of our previous studies have shown that the slow, shuffling gait of Parkinson's disease patients is due to an inability to generate appropriate stride length and that cadence control is intact and is used as a compensatory mechanism. The reason for the reduced stride length is unclear, although deficient internal cue production or inadequate contribution to cortical motor set by the basal ganglia are two possible explanations. In this study we have examined the latter possibility by comparing the long-lasting effects of visual cues in improving stride length with that of attentional strategies. Computerized stride analysis was used to measure the spatial (distance) and temporal (timing) parameters of the walking pattern in a total of 54 subjects in three separate studies. In each study Parkinson's disease subjects were trained for 20 min by repeated 10 m walks set at control stride length (determined from control subjects matched for age, sex and height), using either visual floor markers or a mental picture of the appropriate stride size. Following training, the gait patterns were monitored (i) every 15 min for 2 h; (ii) whilst interspersing secondary tasks of increasing levels of complexity; (iii) covertly, when subjects were unaware that measurement was taking place. The results demonstrated that training with both visual cues and attentional strategies could maintain normal gait for the maximum recording time of 2 h. Secondary tasks reduced stride length towards baseline values as did covert monitoring. The findings confirm that the ability to generate a normal stepping pattern is not lost in Parkinson's disease and that gait hypokinesia reflects a difficulty in activating the motor control system. Normal stride length can be elicited in Parkinson's disease using attentional strategies and visual cues. Both strategies appear to share the same mechanism of focusing attention on the stride length. The effect of attention appears to require constant vigilance to prevent reverting to more automatic control mechanisms.

AIM: The aim of this study is to discuss the available methodological resources and best-practice guidelines for the development and completion of scoping reviews relevant to nursing and midwifery policy, practice, and research. DESIGN: Discussion Paper. DATA SOURCES: Scoping reviews that exemplify best practice are explored with reference to the recently updated JBI scoping review guide (2020) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review extension (PRISMA-ScR). IMPLICATIONS FOR NURSING AND MIDWIFERY: Scoping reviews are an increasingly common form of evidence synthesis. They are used to address broad research questions and to map evidence from a variety of sources. Scoping reviews are a useful form of evidence synthesis for those in nursing and midwifery and present opportunities for researchers to review a broad array of evidence and resources. However, scoping reviews still need to be conducted with rigour and transparency. CONCLUSION: This study provides guidance and advice for researchers and clinicians who are preparing to undertake an evidence synthesis and are considering a scoping review methodology in the field of nursing and midwifery. IMPACT: With the increasing popularity of scoping reviews, criticism of the rigour, transparency, and appropriateness of the methodology have been raised across multiple academic and clinical disciplines, including nursing and midwifery. This discussion paper provides a unique contribution by discussing each component of a scoping review, including: developing research questions and objectives; protocol development; developing eligibility criteria and the planned search approach; searching and selecting the evidence; extracting and analysing evidence; presenting results; and summarizing the evidence specifically for the fields of nursing and midwifery. Considerations for when to select this methodology and how to prepare a review for publication are also discussed. This approach is applied to the disciplines of nursing and midwifery to assist nursing and/or midwifery students, clinicians, researchers, and academics.

Abstract Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3–6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA play important roles in regulating gene expression, through interactions with nuclear receptors, during embryonic development and in the maintenance of adult epithelial tissues (Chambon, P. (1995) Rec. Prog. Horm. Res. 50, 317-32; Mangelsdorf, D. J., and Evans, R. M. (1995) Cell 83, 841-850; Petkovich, M. (1992) Annu. Rev. Nutr. 12, 443-471). Evidence suggests that 4-hydroxylation of RA inside the target cell limits its biological activity and initiates a degradative process of RA leading to its eventual elimination. However, 18-hydroxylation and glucuronidation may also be important steps in this process. In this paper, we describe the cloning and characterization of the first mammalian retinoic acid-inducible retinoic acid-metabolizing cytochrome P450 (hP450RAI), which belongs to a novel class of cytochromes (CYP26). We demonstrate that hP450RAI is responsible for generation of several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA, and 18-OH-RA. We also show that hP450RAI mRNA expression is highly induced by RA in certain human tumor cell lines and further show that RA-inducible RA metabolism may correlate with P450RAI expression. We conclude that this enzyme plays a key role in RA metabolism, functioning in a feedback loop where RA levels are controlled in an autoregulatory manner.

Retinoic acid (RA) metabolites of vitamin A are key regulators of gene expression involved in embryonic development and maintenance of epithelial tissues. The cellular effects of RA are dependent upon the complement of nuclear receptors expressed (RARs and RXRs), which transduce retinoid signals into transcriptional regulation, the presence of cellular retinoid-binding proteins (CRABP and CRBP), which may be involved in RA metabolism, and the activity of RA metabolizing enzymes. We have been using the zebrafish as a model to study these processes. To identify genes regulated by RA during exogenous RA exposure, we utilized mRNA differential display. We describe the isolation and characterization of a cDNA, P450RAI, encoding a novel member of the cytochrome P450 family. mRNA transcripts for P450RAI are expressed normally during gastrulation, and in a defined pattern in epithelial cells of the regenerating caudal fin in response to exogenous RA. In COS-1 cells transfected with the P450RAI cDNA, all-trans-RA is rapidly metabolized to more polar metabolites. We have identified 4-oxo-RA and 4-OH-RA as major metabolic products of this enzyme. P450RAI represents the first enzymatic component of RA metabolism to be isolated and characterized at the molecular level and provides key insight into regulation of retinoid homeostasis.

This study examined the effects of bronchodilator-induced reductions in lung hyperinflation on breathing pattern, ventilation and dyspnoea during exercise in chronic obstructive pulmonary disease (COPD). Quantitative tidal flow/volume loop analysis was used to evaluate abnormalities in dynamic ventilatory mechanics and their manipulation by a bronchodilator. In a randomised double-blind crossover study, 23 patients with COPD (mean +/- SEM forced expiratory volume in one second 42 +/- 3% of the predicted value) inhaled salmeterol 50 microg or placebo twice daily for 2 weeks each. After each treatment period, 2 h after dose, patients performed pulmonary function tests and symptom-limited cycle exercise at 75% of their maximal work-rate. After salmeterol versus placebo at rest, volume-corrected maximal expiratory flow rates increased by 175 +/- 52%, inspiratory capacity (IC) increased by 11 +/- 2% pred and functional residual capacity decreased by 11 +/- 3% pred. At a standardised time during exercise, salmeterol increased IC, tidal volume (VT), mean inspiratory and expiratory flows, ventilation, oxygen uptake (VO2) and carbon dioxide output. Salmeterol increased peak exercise endurance, VO2 and ventilation by 58 +/- 19, 8 +/- 3 and 12 +/- 3%, respectively. Improvements in peak VO2 correlated best with increases in peak VT; increases in peak VT and resting IC were interrelated. The reduction in dyspnoea ratings at a standardised time correlated with the increased VT. Mechanical factors play an important role in shaping the ventilatory response to exercise in chronic obstructive pulmonary disease. Bronchodilator-induced lung deflation reduced mechanical restriction, increased ventilatory capacity and decreased respiratory discomfort, thereby increasing exercise endurance.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Over 200 years ago, René Laennec published the first description of emphysema, an important pathobiological element of what is today known as chronic obstructive pulmonary disease (COPD) (1). He stated that the disease was characterized by persistent dyspnea punctuated by acute episodes of worsening, frequently associated with newly developed and/or worsening cough and sputum (labeled as “acute catarrh”) that could lead to “suffocation.” These episodes have subsequently been termed “exacerbations of COPD” (ECOPDs) (2, 3). Over 150 years later, Anthonisen and colleagues (4) provided a definition, similar to Laennec’s, that has remained relatively unchanged over the last 35 years and forms the basis of the European Respiratory Society/American Thoracic Society definition: “In a patient with underlying COPD, exacerbations are episodes of increasing respiratory symptoms, particularly dyspnea, cough and sputum production, and increased sputum purulence” (5). A slightly modified definition has been used primarily in the research field: “A sustained worsening of the patient’s condition from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD” (6). This definition is similar to that in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document, which reads, “An acute worsening of respiratory symptoms that results in additional therapy” (7). GOLD then classifies ECOPD severity as mild when only symptoms are reported and the patient is treated with inhaled short-acting bronchodilators; moderate when the patient receives antibiotics, systemic corticosteroids, or both; and severe when the patient visits an emergency room or is hospitalized because of the event (6, 7). Without denying the therapeutic progress made in the prevention of ECOPDs (5–8), treatment of the episodes per se has remained relatively unchanged (5, 7, 9). The current definition of ECOPD has several shortcomings that adversely affect clinical and healthcare decisions (see Table E1 in the online supplement). First, it relies exclusively on a patient’s subjective perception of increased respiratory symptoms, which varies from patient to patient (10) and can be mimicked and/or aggravated by other conditions such as pneumonia, cardiac events, or pulmonary embolism (6, 7, 11, 12). Second, it does not relate the symptoms to measurable pathophysiological variables that could characterize the event itself. Third, it lacks a framework for timing of the event’s evolution, an element that can help differentiate ECOPDs from other processes with similar symptoms. Finally, severity is established post hoc by the healthcare resource used to treat the event (13, 14), with this subjectivity introducing variability due to differences between practitioners and healthcare systems. A novel approach is therefore needed because precise, practical, and objective point-of-care definitions and severity assessments for acute medical events are needed by clinicians and researchers if they are to effectively diagnose them at the point of contact, assess the prognosis, and implement precision treatment (15). All of these shortcomings could be overcome by integrating knowledge gathered from observational and interventional studies, as well as with the help of currently available technology capable of measuring in real time the clinical and laboratory variables that can serve as surrogate markers of event severity. This perspective proposes an updated definition and severity classification of ECOPDs based on the principles outlined by Scadding (16) for the taxonomy of diseases, integrating symptoms, function, and surrogate markers of the process underlying ECOPDs. It intends to be objective, practical, and useful to clinicians and researchers alike. In its development, the authors acknowledge that episodes of the worsening of respiratory symptoms similar to ECOPDs may occur in patients with chronic diseases other than COPD, and these potential causes should be considered in the differential diagnosis of the event (7, 17). The process itself was initiated and coordinated by B.R.C. and L.M.F., aided by a medical writer (D.Y.), who identified experts with international recognition who have conducted research and published on the definition, diagnosis, pathobiology, and/or treatment of ECOPDs as well as similar events in closely related fields. A modified Delphi method (18, 19) was considered the most appropriate scientific tool to achieve the desired goals because 1) it is a valid method to obtain consensus based on informed opinions; 2) it provides a structured mechanism to maintain a fluid communication process, allowing individuals to deal with a complex problem; 3) the issue in question does not lend itself to precise analytical techniques but can benefit from subjective judgments on a collective basis; and 4) the method is based on anonymous responses to the selected items, thus decreasing the chance that the dominant personality of one or more of the participants may drive the final conclusions. Because of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an initial face-to-face meeting to be held in January of 2020 in Rome, Italy—hence the name of this proposal—was replaced with a virtual meeting to define the project. Given the need to maintain continuous interaction and as suggested by Delphi methodologists (18, 19), a target panel size of 15–20 experts was agreed on, and of the 19 members contacted, 17 accepted (Table E2). The method consisted of sequential rounds of questions, each followed by virtual meetings with open discussions of results (modified Delphi method), which were aimed at facilitating consensus building. Details of the 1-year process, the 80 items evaluated, and Delphi references are included in the online supplement (Figure E1, Tables E3–E7, and text of the online supplement). The results and the different drafts of the manuscript were circulated to the panelists, all of whom contributed to this perspective. Current evidence indicates that an ECOPD is characterized by an acute burst of airway inflammation due to bacteria, viruses, environmental pollutants, or other stimuli (Figure 1) (2–4, 20–28). This has been documented by carefully conducted studies in the outpatient and inpatient settings (21, 29), with many studies showing that the inflammatory process may expand systemically (29). This inflammatory burst, coupled with worsening of the existing airflow limitation, increases the work of breathing in patients with limited respiratory reserve. A vicious cycle of increased airways resistance and tachypnea leads to gas trapping in the lungs, respiratory muscle dysfunction, worsening dyspnea, and V̇/Q̇ mismatch manifesting as arterial hypoxemia with or without hypercapnia (30–35). In some patients, ventilatory demand exceeds reserve, leading to ventilatory insufficiency, hypercapnia, and respiratory acidosis that, if untreated, may cause death (34). Causes, pathobiological mechanisms, and pathophysiological consequences in an exacerbation of chronic obstructive pulmonary disease (7, 35). CRP = C-reactive protein. On the basis of this conceptual model, the panel agreed to propose the following definition: “In a patient with COPD, an exacerbation is an event characterized by dyspnea and/or cough and sputum that worsen over ≤14 days, which may be accompanied by tachypnea and/or tachycardia and is often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insult to the airways.” These events can be life-threatening and require adequate evaluation and treatment. A review of the literature provides reasonable support of a time frame for exacerbations to develop. Indeed, a study of 4,439 exacerbations showed that the time from first onset of worsening respiratory symptoms to a full ECOPD ranged from 0–5 days in 90% of patients, with an overall range of 0–14 days being shown (36). This is similar to an observational study that, by using diary cards, described prodromal symptoms over 4–7 days, with lung function then decreasing abruptly on the day of documentation of the ECOPD (37). Importantly, subjects with COPD experimentally infected with rhinovirus develop upper respiratory symptoms 2–3 days after the inoculation, with lower respiratory symptoms and breathlessness peaking 4–10 days after infection (38). These observations helped with reaching a consensus that the upper time limit for an ECOPD to develop is 14 days from first onset of symptom worsening and that an ECOPD may develop over just hours in some cases. The timing of the resolution of ECOPDs is less well established. In a study of 101 patients observed over 2.5 years, median recovery times from the onset of ECOPDs were 6 days (interquartile range, 1–14 d) for the peak expiratory flow (PEF) and 7 days (interquartile range, 4–14 d) for the daily total symptom score (37). Recovery of the PEF to baseline values occurred in only 75.2% of ECOPDs by 35 days and in 92.9% of ECOPDs by 91 days. In a small proportion of patients, PEF values or symptoms never returned to normal, an observation similar to that of another study of 145 patients (39). The use of objective variables that are readily measurable to determine severity, as proposed in this perspective, could improve knowledge about the time of resolution, a much-needed metric to compare the effectiveness of therapies. The current grading of the severity of an ECOPD, based on post facto use of healthcare resources, is a major limitation of the current definition. Because of global variability in the available resources to treat patients and local customs affecting the criteria for hospital visits and admissions, there is substantial variability in reported ECOPD outcomes (13, 40). This is of particular importance in the interpretation of results of interventional studies and in the planning of future clinical trials (13). To address this limitation, the panelists propose three mutually exclusive severity categories (mild, moderate, and severe), which integrate six objectively measured variables that serve as markers of event severity: dyspnea, oxygen saturation, respiratory rate, heart rate, serum CRP (C-reactive protein), and, in selected cases, arterial blood gases (Table 1). These variables were agreed on through consensus from a potential list of 21 that were the subject of a thorough literature review and discussion. Of these potential variables, the worsening of cough and sputum deserved special attention. A cough and sputum increase and/or a sputum color change can occur during an ECOPD and, in a proportion of cases, may be the most relevant symptoms or signs (20); however, their intensity has not been properly measured, making it difficult to include them in an ECOPD severity classification. However, although the cough and sputum variables remain an integral part of the ECOPD definition, the panelists agreed that worsening dyspnea is the most relevant symptom for most patients, and because it is measurable, it is useful when grading the episode’s severity. The Rome Proposal for an Updated Definition and Severity Classification of COPD Exacerbations These events can be life-threatening and require adequate evaluation and treatment. Complete a thorough clinical assessment for evidence of COPD and potential respiratory and nonrespiratory concomitant diseases, including consideration of alternative causes for the patient’s symptoms and signs: primarily pneumonia, heart failure, and pulmonary embolism. Assess: Symptoms, severity of dyspnea as determined by using a VAS, and documentation of the presence of cough. Signs (tachypnea, tachycardia), sputum volume and color, and respiratory distress (accessory muscle use). Evaluate severity by using appropriate additional investigations such as pulse oximetry, laboratory assessment, and CRP and/or arterial blood gases. Establish the cause of the event (viral, bacterial, environmental, other). Definition of abbreviations: COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; VAS = visual analog scale. In COPD clinical studies, dyspnea changes over time have been measured by using several scales, including diary cards (36, 37), the Transitional Dyspnea Index (41), and the EXAcerbations of Chronic pulmonary disease tool (EXACT-PRO) (42). However, most patients with COPD do not routinely quantify their daily dyspnea intensity. Consensus was reached to recommend the visual analog scale (VAS), which has been validated against ventilatory loads (43), can be represented by a numerical scale from 0 (no shortness of breath) to 10 (maximal shortness of breath ever experienced) (43), and has a minimally clinical important difference of 1 (44). The resting VAS dyspnea values range from 0 to 3 in patients with COPD (10, 43, 45), whereas when measured in the emergency ward or in the hospital, values are higher than 4 (30, 35, 46). Experts agreed that a VAS score ⩾5 (on a scale of 0–10) in the context of a suspected ECOPD indicates severe dyspnea. This pragmatic approach removes the need to consider a change in dyspnea from a previous baseline VAS value. Studies have shown that both the heart rate and the respiratory rate increase in the days preceding, during, and after an ECOPD (30, 31, 47, 48) and are measurable by widely available noninvasive methods, offering a window to the severity of the episodes (48–51). The resting heart rate increases with COPD severity and is associated with mortality risk (52), regardless of etiology or medication use. Heart rates >85 beats per minute (bpm) or increases in heart rates by 10–15 bpm compared with baseline were reported during an acute exacerbation (49). Respiratory rates >24 breaths per minute, with shortened expiratory time leading to gas trapping, have been consistently reported in most studies conducted in hospitalized patients (51, 53), whereas respiratory rates of 18–20 breaths per minute were documented in patients receiving outpatient care (53). The panel reached a consensus that a heart rate <95 bpm and a respiratory rate <24 breaths per minute could help separate mild ECOPDs from moderate ECOPDs. V̇/Q̇ imbalance is the most important mechanism responsible for the gas exchange abnormalities in COPD (32, 33). Given that stable COPD can be associated with arterial hypoxemia with or without hypercapnia, both absolute measurements and a change in values would be useful as determinants of severity. Assessment of blood gases is ideal, but it is not available in all clinical settings, whereas pulse oximetry is practical and widely available, although we acknowledge that it may be less accurate in Black patients (7). It is known that decompensated hypercapnic respiratory failure is associated with increased mortality (34), which is reduced by noninvasive ventilation (34, 54). Although expert societies recommend titrating supplemental oxygen during an ECOPD to an SaO2 of 88–92% (7, 55), studies of ECOPDs suggest the average reduction in SaO2 was not more than 2% (56, 57). On the basis of this evidence, the panel agreed that when the change from baseline is known, a mild ECOPD would be characterized by an SaO2 ⩾92% and/or a change ⩽3%, a moderate event would be characterized by an SaO2 <92% and/or a change >3%, and a severe event would be characterized by acidotic hypercapnic respiratory failure (i.e., a PaCO2 >45 mm Hg and a pH <7.35). Healthy subjects, smokers without COPD, and patients with stable COPD usually have CRP values <10 mg/L (58, 59), with higher values within this range being associated with an increased risk of hospitalization and death (60, 61). Serum CRP levels increase in both viral and bacterial ECOPDs (25, 26), although they are usually higher in the latter (22, 26), which is why values may be used at the point of care to guide antibiotic therapy (26, 62). In outpatients with COPD who are suffering an ECOPD, CRP levels increase modestly from basal values (23, 63). In patients in the emergency ward or admitted to the hospital, higher CRP values have been reported, ranging from 8 to 156 mg/L (63–65). Although the panel the of of using serum CRP as a of airway or lung consensus was reached that a CRP mg/L can help separate mild ECOPDs from moderate ECOPDs. do not CRP a different from of the heart rate, respiratory rate, or oxygen A patient could have a more severe exclusively by a of the clinical signs without a CRP to help the of at one measurable point-of-care the of which can be over time if this is and the results The panelists agreed that of the respiratory rate, heart rate, oxygen saturation, and serum should be used to assess the severity of an ECOPD, both in the clinical evaluation of patients and in research and clinical trials (Table 1 and The severity classification is that of a mild an to be considered moderate, at three of these all of which a similar should be than values of a mild The panelists agreed that for an ECOPD to be considered a arterial blood gas the presence of hypercapnia mm and respiratory acidosis approach to a patient suspected of an determined by using a oxygen and/or and = arterial blood CRP = C-reactive protein; ECOPD = exacerbation of chronic obstructive pulmonary disease; = heart = respiratory VAS = visual analog scale. The panelists other clinical and laboratory used in the diagnosis and severity classification of ECOPDs and Of several require some or lung function assessment be during an ECOPD, as patients are usually to an adequate changes from baseline are often and results may not be that made to develop accurate that can help lung function over time would a major in to integrate this future on this blood would have potential use for therapeutic particularly the use of systemic but levels have not been used for ECOPD diagnosis or severity classification. are useful for other conditions that may an ECOPD, such as or from an ECOPD and they are frequently in patients in healthcare but this tool has not been used to define or the severity of an A review of the literature at conditions that may an ECOPD (Table and the panelists reached a consensus that three deserved special consideration failure, pneumonia, and pulmonary (7, 31, not only because of their but because they require and to improve The panel that these conditions may with ECOPDs and the of each in Table 1 and a thorough clinical evaluation is often adequate to these however, such as additional studies and measurements may be Although the panel the with events, or their as the or cause of clinical in some patients, it should be in most healthcare settings to a conditions not or but some acute and were to have and laboratory that their the potential the panelists their was of importance (i.e., over their and should only be considered in A practical approach to patients with symptoms with an ECOPD is in The Rome for an updated definition and severity classification of ECOPDs not a more precise approach based on in future studies The panelists acknowledge that there are some to this First, the was by experts from and This was by the and the need to discussions by which would have made discussions difficult time The of experts from and six does some about the of the In the of the in this is open for to Second, the of participants selected may however, it is within the by experts in the of the Delphi process, allowing for during the virtual meetings (see the text of the online supplement). Third, the of the for the different variables included in the severity classification and for the timing of the ECOPD may and not based on validated However, they were agreed on by anonymous consensus after review of the available literature and between rounds (Table of the Delphi Of in this of continuous accurate of measurable variables may help with the onset of an event and its resolution over facilitating not only the evaluation of novel but the of the event The Rome for an updated definition and severity classification of ECOPDs was by an international panel of experts by using a framework that on and potential The consensus was reached by using a modified Delphi informed by from studies objective measurements of symptoms, variables, and The of the variables the severity was by using the potential intensity of care needed for treatment and of the This definition many of the shortcomings of the current definition and should clinical and planning but to be validated in and by medical B.R.C. and developed the for this including the of the Delphi on which the is All authors contributed to the Delphi the literature and the virtual The first of the manuscript was by with all authors then All authors the final to be This has an online which is from this of in as on are available with the text of this The authors of and for support the of for and

Drover, John W. MD, FRCSC; Dhaliwal, Rupinder RD; Weitzel, Lindsay PhD; Wischmeyer, Paul E. MD; Ochoa, Juan B. MD, FACS; Heyland, Daren K. MD, FRCPC, MSC Author Information

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Gait hypokinesia (slowness) is a characteristic feature of Parkinson's disease. It is not clear, however, whether the slowness is due to a problem in regulation of the timing of consecutive steps or the control of stride size. Examination of cadence control for slow to medium walking speeds has shown an increase in step frequency that was a compensation for reduced stride length. In this investigation the ability of Parkinsonian patients to modulate their cadence (steps per minute) at the fast walking speeds exhibited by age and height matched controls was examined. The findings indicated that cadence control remains unaffected throughout its entire range in Parkinson's disease and that gait hypokinesia is directly attributable to an inability to internally generate sufficiently large steps.

BACKGROUND: Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS: We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS: A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS: Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).