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BACKGROUND Exertional breathlessness is a cardinal symptom of cardiorespiratory disease. RESEARCH QUESTION How does breathlessness abnormality, graded using normative reference equations during cardiopulmonary exercise testing (CPET), relate to self-reported and physiologic responses in people with chronic airflow limitation (CAL)? STUDY DESIGN AND METHODS An analysis was done of people aged ≥ 40 years with CAL undergoing CPET in the Canadian Cohort Obstructive Lung Disease study. Breathlessness intensity ratings (Borg CR10 scale [0-10 category-ratio scale for breathlessness intensity rating]) were evaluated in relation to power output, rate of oxygen uptake, and minute ventilation at peak exercise, using normative reference equations as follows: (1) probability of breathlessness normality (probability of having an equal or greater Borg CR10 rating among healthy people; lower probability reflecting more severe breathlessness) and (2) presence of abnormal breathlessness (rating above the upper limit of normal). Associations with relevant participant-reported and physiologic outcomes were evaluated. RESULTS We included 330 participants (44% women): mean ± SD age, 64 ± 10 years (range, 40-89 years); FEV$_{1}$/FVC, 57.3% ± 8.2%; FEV$_{1}$, 75.6% ± 17.9% predicted. Abnormally low exercise capacity (peak rate of oxygen uptake < lower limit of normal) was present in 26%. Relative to peak power output, rate of oxygen uptake, and minute ventilation, abnormally high breathlessness was present in 26%, 25%, and 18% of participants. For all equations, abnormally high exertional breathlessness was associated with worse lung function, exercise capacity, self-reported symptom burden, physical activity, and health-related quality of life; and greater physiologic abnormalities during CPET. INTERPRETATION Abnormal breathlessness graded using CPET normative reference equations was associated with worse clinical, physiological, and functional outcomes in people with CAL, supporting cons

BACKGROUND: Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. METHODS: A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. RESULTS: 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7±1.5 versus 6.4±1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. CONCLUSION: We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years.

BACKGROUND: Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. METHODS: A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. RESULTS: 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7±1.5 versus 6.4±1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. CONCLUSION: We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years.

Background Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. Methods A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. Results 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7 +/- 1.5 versus 6.4 +/- 1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. Conclusion We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years., Funding Agencies|Scientific Committee of Blekinge Region; Department of Research and Development, Region Kronoberg; Swedish Society for Medical Research; Swedish Research Council [2019-02081]

BACKGROUND: Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. METHODS: A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. RESULTS: 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7±1.5 versus 6.4±1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. CONCLUSION: We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years.

Background Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. Methods A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. Results 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7 +/- 1.5 versus 6.4 +/- 1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. Conclusion We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years., Funding Agencies|Scientific Committee of Blekinge Region; Department of Research and Development, Region Kronoberg; Swedish Society for Medical Research; Swedish Research Council [2019-02081]

Background Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. Methods A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. Results 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7 +/- 1.5 versus 6.4 +/- 1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. Conclusion We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years., Funding Agencies|Scientific Committee of Blekinge Region; Department of Research and Development, Region Kronoberg; Swedish Society for Medical Research; Swedish Research Council [2019-02081]

BACKGROUND: Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. METHODS: A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. RESULTS: 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7±1.5 versus 6.4±1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. CONCLUSION: We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years.

Background Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. Methods A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. Results 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7 +/- 1.5 versus 6.4 +/- 1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. Conclusion We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years., Funding Agencies|Scientific Committee of Blekinge Region; Department of Research and Development, Region Kronoberg; Swedish Society for Medical Research; Swedish Research Council [2019-02081]

Background Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. Methods A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. Results 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7 +/- 1.5 versus 6.4 +/- 1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. Conclusion We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years., Funding Agencies|Scientific Committee of Blekinge Region; Department of Research and Development, Region Kronoberg; Swedish Society for Medical Research; Swedish Research Council [2019-02081]

BACKGROUND: Exertional breathlessness is commonly assessed using incremental exercise testing (IET), but reference equations for breathlessness responses are lacking. We aimed to develop reference equations for breathlessness intensity during IET. METHODS: A retrospective, consecutive cohort study of adults undergoing IET was carried out in Sweden. Exclusion criteria included cardiac or respiratory disease, death or any of the aforementioned diagnoses within 1 year of the IET, morbid obesity, abnormally low exercise capacity, submaximal exertion or an abnormal exercise test. Probabilities for breathlessness intensity ratings (Borg CR10) during IET in relation to power output (%predWmax), age, sex, height and body mass were analysed using marginal ordinal logistic regression. Reference equations for males and females were derived to predict the upper limit of normal (ULN) and the probability of different Borg CR10 intensity ratings. RESULTS: 2581 participants (43% female) aged 18-90 years were included. Mean breathlessness intensity was similar between sexes at peak exertion (6.7±1.5 versus 6.4±1.5 Borg CR10 units) and throughout exercise in relation to %predWmax. Final reference equations included age, height and %predWmax for males, whereas height was not included for females. The models showed a close fit to observed breathlessness intensity ratings across %predWmax values. Models using absolute W did not show superior fit. Scripts are provided for calculating the probability for different breathlessness intensity ratings and the ULN by %predWmax throughout IET. CONCLUSION: We present the first reference equations for interpreting breathlessness intensity during incremental cycle exercise testing in males and females aged 18-90 years.

Background and aimsNo prior randomized controlled trial (RCT) has reported patient outcomes of large over-the-scope clip (OTSC) compared to standard hemostasis as initial endoscopic treatment of severe NVUGIB. This was our study aim.MethodsPatients with bleeding ulcers or Dieulafoy's lesions and major stigmata of hemorrhage - SRH (active spurting bleeding, visible vessel, or clot) - or lesser SRH (oozing bleeding or flat spots - with arterial blood flow by Doppler probe) were randomized to OTSC or standard endoscopic hemostasis (with hemoclips or multipolar electrocoagulation - MPEC). Patients and their healthcare providers were blinded to treatments and made all post-randomization management decisions. Ulcer patients received high dose intravenous infusions of proton pump inhibitors (PPI) for 3 days, then 27 days of oral PPI. 30 day outcomes were prospectively recorded; data management was with SAS; and data analysis was by a statistician.Results53 patients (25 OTSC, 28 Standard) were randomized, with similar baseline risk factors. However, there were significant differences in OTSC vs. Standard groups in rates of rebleeding (4% vs. 28.6%; p = .017; relative risk 0.10, 95% confidence intervals 0.01, 0.91; number needed to treat 4); severe complications (0 % vs. 14.3%); and post-randomization units of red cell transfusions (0.04 vs. 0.68). All rebleeds occurred in patients with major SRH and none with lesser SRH.Conclusion1. OTSC significantly reduced rates of rebleeding, severe complications, and post-randomization red cell transfusions. 2. Patients with major stigmata benefited significantly from hemostasis with OTSC, but those with lesser stigmata did not. (ClinicalTrials.gov, Number: NCT03065465).

BackgroundAcute gastrointestinal bleeding (GIB) remains a common cause of hospitalisation. However, interpretation and comparisons of published studies in GIB have been hampered by disparate study methodology.AimsTo make recommendations about outcome measures to be used in future randomised controlled trials (RCTs) of patients with acute bleeding from any GI source (nonvariceal UGI, variceal, small bowel, or colon) and suggest new RCTs in acute GIB for future peer-reviewed funding.MethodsAs part of a National Institutes of Health conference entitled "Hemostatic Outcomes in Clinical Trials", a group of GIB experts performed targeted critical reviews of available evidence with the goal of proposing a bleeding outcome that could potentially be applied to different disciplines. In addition, the panel sought to develop a clinically meaningful primary endpoint specifically for acute GIB, potentially allowing a more contemporary regrouping of clinically relevant outcomes.ResultsThe primary endpoint proposed was a composite outcome of further bleeding within 30 days after randomisation leading to red blood cell transfusion, urgent intervention (repeat endoscopy; interventional radiology or surgery), or death. Secondary outcomes may include the individual components of the primary outcome, length of hospitalisation, serious adverse events, and health care resource utilisation.ConclusionThe proposed endpoint may help move the GIB field forward by focusing on the most clinically relevant outcomes for patients with acute GIB of all types and informing study design and importance of sample size determination for future RCTs in GIB.

Hayley Lewthwaite,1,2 Dennis Jensen,3– 5 Magnus Ekström6 1School of Environmental & Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Ourimbah, Australia; 2UniSA: Allied Health and Human Performance, Innovation, Implementation and Clinical Translation in Health, University of South Australia, Adelaide, Australia; 3Department of Kinesiology and Physical Education, McGill University, Montréal, Québec, Canada; 4Research Institute of the McGill University Health Centre, Faculty of Medicine, McGill University, Montréal, Québec, Canada; 5Research Centre for Physical Activity and Health, Faculty of Education, McGill University, Montréal, Canada; 6Faculty of Medicine, Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund University, Lund, SwedenCorrespondence: Hayley LewthwaiteSchool of Environmental & Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Ourimbah, AustraliaTel +612 498 54582Email Hayley.Lewthwaite@newcastle.edu.auAbstract: Activity-related breathlessness is the most problematic symptom of chronic obstructive pulmonary disease (COPD), arising from complex interactions between peripheral pathophysiology (both pulmonary and non-pulmonary) and central perceptual processing. To capture information on the breathlessness experienced by people with COPD, many different instruments exist, which vary in applicability depending on the purpose and context of assessment. We reviewed common breathlessness assessment instruments, providing recommendations around how to assess the severity of, or change in, breathlessness in people with COPD in daily life or in response to exercise provocation. A summary of 14 instruments for the assessment of breathlessness severity in daily life is presented, with 11/14 (79%) instruments having established minimal clinically importance differences (

Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P4-(C5)2, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat-P4-(C5)2 disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo. Moreover, Tat-P4-(C5)2 administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat-P4-(C5)2 as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein–protein interaction domains.

Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P4-(C5)2, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat-P4-(C5)2 disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo. Moreover, Tat-P4-(C5)2 administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat-P4-(C5)2 as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein–protein interaction domains.

ObjectivesOur aims were to assess risks of early rebleeding after successful endoscopic hemostasis for Forrest oozing (FIB) peptic ulcer bleeding (PUBs) compared with other stigmata of recent hemorrhage (SRH).MethodsThese were post hoc multivariable analyses of a large, international, double-blind study (NCT00251979) of patients randomized to high-dose intravenous (IV) esomeprazole (PPI) or placebo for 72 h. Rebleeding rates of patients with PUB SRH treated with either PPI or placebo after successful endoscopic hemostasis were also compared.ResultsFor patients treated with placebo for 72 h after successful endoscopic hemostasis, rebleed rates by SRH were spurting arterial bleeding (FIA) 22.5%, adherent clot (FIIB) 17.6%, non-bleeding visible vessel (FIIA) 11.3%, and oozing bleeding (FIB) 4.9%. Compared with FIB patients, FIA, FIIB, and FIIA had significantly greater risks of rebleeding with odds ratios (95% CI's) from 2.61 (1.05, 6.52) for FIIA to 6.66 (2.19, 20.26) for FIA. After hemostasis, PUB rebleeding rates for FIB patients at 72 h were similar with esomeprazole (5.4%) and placebo (4.9%), whereas rebleed rates for all other major SRH (FIA, FIIA, FIIB) were lower for PPI than placebo, but the treatment by SRH interaction test was not statistically significant.ConclusionsAfter successful endoscopic hemostasis, FIB patients had very low PUB rebleeding rates irrespective of PPI or placebo treatment. This implies that after successful endoscopic hemostasis the prognostic classification of FIB ulcers as a high-risk SRH and the recommendation to treat these with high-dose IV PPI's should be re-evaluated.

Background & aimsFor 4 decades, stigmata of recent hemorrhage in patients with nonvariceal lesions have been used for risk stratification and endoscopic hemostasis. The arterial blood flow that underlies the stigmata rarely is monitored, but can be used to determine risk for rebleeding. We performed a randomized controlled trial to determine whether Doppler endoscopic probe monitoring of blood flow improves risk stratification and outcomes in patients with severe nonvariceal upper gastrointestinal hemorrhage.MethodsIn a single-blind study performed at 2 referral centers we assigned 148 patients with severe nonvariceal upper gastrointestinal bleeding (125 with ulcers, 19 with Dieulafoy's lesions, and 4 with Mallory Weiss tears) to groups that underwent standard, visually guided endoscopic hemostasis (control, n = 76), or endoscopic hemostasis assisted by Doppler monitoring of blood flow under the stigmata (n = 72). The primary outcome was the rate of rebleeding after 30 days; secondary outcomes were complications, death, and need for transfusions, surgery, or angiography.ResultsThere was a significant difference in the rates of lesion rebleeding within 30 days of endoscopic hemostasis in the control group (26.3%) vs the Doppler group (11.1%) (P = .0214). The odds ratio for rebleeding with Doppler monitoring was 0.35 (95% confidence interval, 0.143-0.8565) and the number needed to treat was 7.ConclusionsIn a randomized controlled trial of patients with severe upper gastrointestinal hemorrhage from ulcers or other lesions, Doppler probe guided endoscopic hemostasis significantly reduced 30-day rates of rebleeding compared with standard, visually guided hemostasis. Guidelines for nonvariceal gastrointestinal bleeding should incorporate these results. ClinicalTrials.gov no: NCT00732212 (CLIN-013-07F).

DescriptionThis update of the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding (UGIB) refines previous important statements and presents new clinically relevant recommendations.MethodsAn international multidisciplinary group of experts developed the recommendations. Data sources included evidence summarized in previous recommendations, as well as systematic reviews and trials identified from a series of literature searches of several electronic bibliographic databases from inception to April 2018. Using an iterative process, group members formulated key questions. Two methodologists prepared evidence profiles and assessed quality (certainty) of evidence relevant to the key questions according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Group members reviewed the evidence profiles and, using a consensus process, voted on recommendations and determined the strength of recommendations as strong or conditional.RecommendationsPreendoscopic management: The group suggests using a Glasgow Blatchford score of 1 or less to identify patients at very low risk for rebleeding, who may not require hospitalization. In patients without cardiovascular disease, the suggested hemoglobin threshold for blood transfusion is less than 80 g/L, with a higher threshold for those with cardiovascular disease. Endoscopic management: The group suggests that patients with acute UGIB undergo endoscopy within 24 hours of presentation. Thermocoagulation and sclerosant injection are recommended, and clips are suggested, for endoscopic therapy in patients with high-risk stigmata. Use of TC-325 (hemostatic powder) was suggested as temporizing therapy, but not as sole treatment, in patients with actively bleeding ulcers. Pharmacologic management: The group recommends that patients with bleeding ulcers with high-risk stigmata who have had successful endoscopic therapy receive high-dose

Background and aimsFew prospective reports describe the short-term natural history of colon diverticular hemorrhage based on stigmata of recent hemorrhage, and none include blood flow detection for risk stratification or as a guide to definitive hemostasis. Our purposes were to report the 30-day natural history of definitive diverticular hemorrhage based on stigmata and to describe Doppler probe blood flow detection as a guide to definitive hemostasis.MethodsDifferent cohorts of patients with severe diverticular bleeding and stigmata on urgent colonoscopy are reported. For 30-day natural history, patients were treated medically. If severe rebleeding occurred, they had surgical or angiographic treatment. We report natural history with major stigmata (active bleeding, visible vessel, or adherent clot) and no stigmata or flat spots after clots were washed away. We also report Doppler probe detection of arterial blood flow underneath stigmata before and after hemostasis in a recent cohort.ResultsFor natural history, patients with major stigmata treated medically had 65.8% (25/38) rebleeding rates, and 44.7% (17/38) had intervention for hemostasis. Patients with spots or clean bases had no rebleeding. A Doppler probe detected arterial blood flow in 92% of major stigmata--none after hemostasis--and there was no rebleeding.Conclusions(1) Patients with major stigmata treated medically had high rates of rebleeding and intervention for hemostasis. (2) Patients with clean diverticula or only flat spots had no rebleeding. (3) High rates of arterial blood flow were detected under major stigmata with a Doppler probe, but with obliteration by hemostasis no rebleeding occurred.

Background and aimsFor more than 4 decades endoscopists have relied on ulcer stigmata for risk stratification and as a guide to hemostasis. None used arterial blood flow underneath stigmata to predict outcomes. For patients with severe peptic ulcer bleeding (PUB), we used a Doppler endoscopic probe (DEP) for (1) detection of blood flow underlying stigmata of recent hemorrhage (SRH), (2) quantitating rates of residual arterial blood flow under SRH after visually directed standard endoscopic treatment, and (3) comparing risks of rebleeding and actual 30-day rebleed rates for spurting arterial bleeding (Forrest [F] IA) and oozing bleeding (F IB).MethodsProspective cohort study of 163 consecutive patients with severe PUB and different SRH.ResultsAll blood flow detected by the DEP was arterial. Detection rates were 87.4% in major SRH-spurting arterial bleeding (F IA), non-bleeding visible vessel (F IIA), clot (F IIB)-and were significantly lower at 42.3% (P < .0001) for an intermediate group of oozing bleeding (F IB) or flat spot (F IIC). For spurting bleeding (F IA) versus oozing (F IB), baseline DEP arterial flow was 100% versus 46.7%, residual blood flow detected after endoscopic hemostasis was 35.7% versus 0%, and 30-day rebleed rates were 28.6% versus 0% (all P < .05).Conclusions(1) For major SRH versus oozing or spot, the arterial blood flow detection rate by the DEP was significantly higher, indicating a higher rebleed risk. (2) Before and after endoscopic treatment, spurting (F IA) PUB had significantly higher rates of blood flow detection than oozing (F IB) PUB and a significantly higher 30-day rebleed rate. (3) The DEP is recommended as a new endoscopic guide with SRH to improve risk stratification and potentially definitive hemostasis for PUB.

Non-variceal upper gastrointestinal bleeding remains an important emergency condition, leading to significant morbidity and mortality. As endoscopic therapy is the 'gold standard' of management, treatment of these patients can be considered in three stages: pre-endoscopic treatment, endoscopic haemostasis and post-endoscopic management. Since publication of the Asia-Pacific consensus on non-variceal upper gastrointestinal bleeding (NVUGIB) 7 years ago, there have been significant advancements in the clinical management of patients in all three stages. These include pre-endoscopy risk stratification scores, blood and platelet transfusion, use of proton pump inhibitors; during endoscopy new haemostasis techniques (haemostatic powder spray and over-the-scope clips); and post-endoscopy management by second-look endoscopy and medication strategies. Emerging techniques, including capsule endoscopy and Doppler endoscopic probe in assessing adequacy of endoscopic therapy, and the pre-emptive use of angiographic embolisation, are attracting new attention. An emerging problem is the increasing use of dual antiplatelet agents and direct oral anticoagulants in patients with cardiac and cerebrovascular diseases. Guidelines on the discontinuation and then resumption of these agents in patients presenting with NVUGIB are very much needed. The Asia-Pacific Working Group examined recent evidence and recommends practical management guidelines in this updated consensus statement.

Non-variceal upper gastrointestinal bleeding remains an important emergency condition, leading to significant morbidity and mortality. As endoscopic therapy is the 'gold standard' of management, treatment of these patients can be considered in three stages: pre-endoscopic treatment, endoscopic haemostasis and post-endoscopic management. Since publication of the Asia-Pacific consensus on non-variceal upper gastrointestinal bleeding (NVUGIB) 7 years ago, there have been significant advancements in the clinical management of patients in all three stages. These include pre-endoscopy risk stratification scores, blood and platelet transfusion, use of proton pump inhibitors; during endoscopy new haemostasis techniques (haemostatic powder spray and over-the-scope clips); and post-endoscopy management by second-look endoscopy and medication strategies. Emerging techniques, including capsule endoscopy and Doppler endoscopic probe in assessing adequacy of endoscopic therapy, and the pre-emptive use of angiographic embolisation, are attracting new attention. An emerging problem is the increasing use of dual antiplatelet agents and direct oral anticoagulants in patients with cardiac and cerebrovascular diseases. Guidelines on the discontinuation and then resumption of these agents in patients presenting with NVUGIB are very much needed. The Asia-Pacific Working Group examined recent evidence and recommends practical management guidelines in this updated consensus statement.

BackgroundTo evaluate roles of intraoperative endoscopy (IOE) in management of severe obscure GI bleeding (OGIB) before vs. after introduction of video capsule endoscopy (VCE) and deep enteroscopy (DE).MethodsWe retrospectively reviewed prospectively collected data of patients undergoing IOE for severe OGIB in a tertiary referral center.Results52 patients had laparotomy/IOE for OGIB, 11 pre and 41 post VCE/DE eras. In the pre VCE/DE era, 36.4% (4/11) had preoperative presumptive diagnoses while in the post VCE/DE era presumptive diagnoses were made in 48.8% (20/41) (p = 0.18). Preoperative evaluation led to correct diagnoses in 18.2% (2/11) in the pre and 51.2% (21/41) in the post VCE/DE era (p = 0.09). Vascular lesions and ulcers were the most common diagnoses, but rebleeding was common. No rebleeding was found among patients with tumors, Meckel's diverticulum, and aortoenteric fistula.ConclusionsPresumptive diagnoses in the post VCE/DE era were usually accurate. If VCE or DE are negative, the probability of negative IOE is high. Patients with tumors and Meckel's diverticulum were the best candidates for IOE.

In the motor system, force gradation is achieved by recruitment of motoneurons and rate modulation of their firing frequency. Classical experiments investigating the relationship between injected current to the soma during intracellular recording and the firing frequency (the I–f relation) in cat spinal motoneurons identified two clear ranges: a primary range and a secondary range. Recent work in mice, however, has identified an additional range proposed to be exclusive to rodents, the subprimary range (SPR), due to the presence of mixed mode oscillations of the membrane potential. Surprisingly, fully summated tetanic contractions occurred in mice during SPR frequencies. With the mouse now one of the most popular models to investigate motor control, it is crucial that such discrepancies between observations in mice and basic principles that have been widely accepted in larger animals are resolved. To do this, we have reinvestigated the I–f relation using ramp current injections in spinal motoneurons in both barbiturate-anesthetized and decerebrate (nonanesthetized) cats and mice. We demonstrate the presence of the SPR and mixed mode oscillations in both species and show that the SPR is enhanced by barbiturate anesthetics. Our measurements of the I–f relation in both cats and mice support the classical opinion that firing frequencies in the higher end of the primary range are necessary to obtain a full summation. By systematically varying the leg oil pool temperature (from 37°C to room temperature), we found that only at lower temperatures can maximal summation occur at SPR frequencies due to prolongation of individual muscle twitches.SIGNIFICANCE STATEMENT This work investigates recent revelations that mouse motoneurons behave in a fundamentally different way from motoneurons of larger animals with respect to the importance of rate modulation of motoneuron firing for force gradation. The current study systematica

Botulinum toxin (Btx) is used in children with cerebral palsy and other neurological patients to diminish spasticity and reduce the risk of development of contractures. Here, we investigated changes in the central gain of the stretch reflex circuitry in response to botulinum toxin injection in the triceps surae muscle in rats. Experiments were performed in 21 rats. 8 rats were in a control group and 13 rats were injected with 6 IU of Btx in the left triceps surae muscle. Two weeks after Btx injection larger monosynaptic reflexes (MSR) were recorded from the left (injected) than the right (non-injected) L4 + L5 ventral roots following stimulation of the corresponding dorsal roots. A similar increase on the left side was observed in response to stimulation of descending motor tracts, suggesting that increased excitability of spinal motor neurones may at least partly explain the increased reflexes. However, significant changes were also observed in post-activation depression of the MSR suggesting that plastic changes in transmission from Ia afferent to the motor neurons may also be involved. The data demonstrate that muscle paralysis induced by Btx injection is accompanied by plastic adaptations in the central stretch reflex circuitry, which counteract the antispastic effect of Btx.

High-quality research is needed to improve quality of life for people with chronic refractory breathlessness in COPD http://ow.ly/Q2GDY

Background and aimsImproved medical decisions by using a score at the initial patient triage level may lead to improvements in patient management, outcomes, and resource utilization. There is no validated score for management of lower gastrointestinal bleeding (LGIB) unlike for upper gastrointestinal bleeding. The aim of our study was to compare the accuracies of 3 different prognostic scores [Center for Ulcer Research and Education Hemostasis prognosis score, Charlson index, and American Society of Anesthesiologists (ASA) score] for the prediction of 30-day rebleeding, surgery, and death in severe LGIB.MethodsData on consecutive patients hospitalized with severe gastrointestinal bleeding from January 2006 to October 2011 in our 2 tertiary academic referral centers were prospectively collected. Sensitivities, specificities, accuracies, and area under the receiver operator characteristic curve were computed for 3 scores for predictions of rebleeding, surgery, and mortality at 30 days.ResultsTwo hundred thirty-five consecutive patients with LGIB were included between 2006 and 2011. Twenty-three percent of patients rebled, 6% had surgery, and 7.7% of patients died. The accuracies of each score never reached 70% for predicting rebleeding or surgery in either. The ASA score had a highest accuracy for predicting mortality within 30 days (83.5%), whereas the Center for Ulcer Research and Education Hemostasis prognosis score and the Charlson index both had accuracies <75% for the prediction of death within 30 days.ConclusionsASA score could be useful to predict death within 30 days. However, a new score is still warranted to predict all 30 days outcomes (rebleeding, surgery, and death) in LGIB.

BackgroundThe sites of origin, causes and outcomes of severe hematochezia have not been compared between cirrhotics and non-cirrhotics. In cirrhotics versus non-cirrhotics presenting with severe hematochezia, we aimed at (1) identifying the site and etiology of gastro-intestinal bleeding and independent predictors of bleeding from the upper gastrointestinal tract versus small bowel or the colon, (2) comparing 30-day clinical outcomes, and (3) proposing an algorithm for management of severe hematochezia.MethodsIn this cohort study from two university-based medical centers, 860 consecutive patients with severe hematochezia admitted from 1995 to 2011 were prospectively enrolled with 160 (18.6 %) cirrhotics. We studied (a) general clinical and laboratory characteristics of cirrhotics versus non-cirrhotics, (b) predictors of bleeding sites in each patient group by multiple variable regression analysis, and compared (c) 30-day outcomes, including rebleeding, surgery and deaths.ResultsCirrhosis independently predicted an upper gastrointestinal source of bleeding (OR 3.47; 95 % CI 2.01-5.96) as well as history of hematemesis, melena in the past 30 days, positive nasogastric aspirate, prior upper gastrointestinal bleeding or use of aspirin or non-steroidal anti-inflammatory. The most prevalent diagnoses were esophageal varices (20 %) in cirrhotics and colon diverticular bleeding (27.1 %) in non-cirrhotics. Thirty-day rates of rebleeding, surgical interventions and deaths were 23.1 versus 15 % (P = 0.01), 14.4 versus 6.4 % (P < 0.001), and 17.5 versus 4.1 % (P < 0.001), in cirrhotics versus non-cirrhotics, respectively.ConclusionsCirrhosis predicted an upper gastrointestinal site of bleeding in patients presenting with severe hematochezia. The 30-day rates of rebleeding, surgery, and death were significantly higher in cirrhotics than in non-cirrhotics.

With mortality due to gastrointestinal (GI) bleeding remaining stable, the focus on endoscopic hemostasis has been on improving other outcomes such as rebleeding rate, need for transfusions, and need for angiographic embolization or surgery. Over the past few years, a number of devices have emerged to help endoscopically assess and treat bleeding GI lesions. These include the Doppler endoscopic probe, hemostatic powder, and over-the-scope clip. Also, new applications have been described for radiofrequency ablation. In this article, we will discuss these evolving tools and techniques that have been developed, including an analysis of their efficacy and limitations.

Benoit Borel,1,2 Courtney A Wilkinson-Maitland,3 Alan Hamilton,4 Jean Bourbeau,5 Hélène Perrault,6 Dennis Jensen,3,5,7 François Maltais2 1Laboratoire HAVAE, Université de Limoges, Limoges, France; 2Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, 3Clinical Exercise and Respiratory Physiology Laboratory, Department of Kinesiology and Physical Education, McGill University, Montréal, QC, 4Boehringer Ingelheim (Canada) Limited, Burlington, ON, 5Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University Health Center, Montreal, QC, 6Faculty of Health Sciences, University of Ottawa, Ottawa, ON, 7Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada Background: The aim of this study was to evaluate the responsiveness of the 3-minute constant rate step test (3-MST) to detect the relief of exertional dyspnea (respiratory discomfort) after acute bronchodilation in COPD patients. Patients and methods: A total of 40 patients with moderate-to-severe COPD (mean forced expiratory volume in 1 second: 45.7 (±14.7), % predicted) performed four 3-MSTs at randomly assigned stepping rates of 14, 16, 20 and 24 steps/min after inhalation of nebulized ipratropium bromide (500 µg)/salbutamol (2.5 mg) and saline placebo, which were randomized to order. Patients rated their intensity of perceived dyspnea at the end of each 3-MST using Borg 0–10 category ratio scale. Results: A total of 37 (92.5%), 36 (90%), 34 (85%) and 27 (67.5%) patients completed all 3 minutes of exercise at 14, 16, 20 and 24 steps/min under both treatment conditions, respectively. Compared with placebo, ipratropium bromide/salbutamol significantly decreased dyspnea at the end of

Neuromodulators, such as serotonin (5-hydroxytryptamine, 5-HT) and noradrenalin, play an essential role in regulating the motor and sensory functions in the spinal cord. We have previously shown that in the rat spinal cord the activity of aromatic L-amino acid decarboxylase (AADC) cells to produce 5-HT from its precursor (5-hydroxytryptophan, 5-HTP) is dramatically increased following complete spinal cord transection. In this study, we investigated whether a partial loss of 5-HT innervation could similarly increase AADC activity. Adult rats with spinal cord hemisected at thoracic level (T11/T12) were used with a postoperation interval at 5 days or 60 days. Using immunohistochemistry, first, we observed a significant reduction in the density of 5-HT-immunoreactive fibers in the spinal cord below the lesion on the injured side for both groups. Second, we found that the AADC cells were similarly expressed on both injured and uninjured sides in both groups. Third, increased production of 5-HT in AADC cells following 5-HTP was seen in 5-day but not in 60-day postinjury group. These results suggest that plastic changes of the 5-HT system might happen primarily in the subchronic phase and for longer period its function could be compensated by plastic changes of other intrinsic and/or supraspinal modulation systems.