Development and validation of reference equations for dual-energy x-ray absorptiometry-derived measures of fat-free mass in adults aged 45-85 years: Results from the Canadian Longitudinal Study on Aging.

Reference equations for fat-free (FFM) and lean soft tissue mass (LM) measures obtained from dual-energy x-ray absorptiometry (DEXA) are important for the interpretation of body composition. This study developed and validated reference equations for FFM and LM using DEXA from the Canadian Longitudinal Study on Aging. Reference equations were developed using data from a random population-based sample of ostensibly healthy and functionally independent adults aged 45-85years. Reference equations for absolute (accounting for age, sex, height, and body mass) and height-adjusted (accounting for age, sex, and body mass index) measures of FFM and LM were developed using quantile regression. Reference equations were respectively developed and validated in derivation (80%) and validation cohorts (20%). Reference equations were applied to symptomatic adults with self-reported chronic obstructive pulmonary disease (COPD) or heart disease to assess discriminant validity; and compared with other published equations to assess performance. Bland-Altman analyses and Lin's concordance correlation coefficients were utilised to assess agreement. Reference equations for 5th, 10th, 50th, 90th, and 95th percentiles were developed for DEXA-derived estimates of FFM and LM based on 1,881 healthy participants (57%male) aged 55years [IQR: 50-61]. Reference equations performed comparably in the validation cohort and discriminated reference values between healthy adults and people with symptomatic COPD or heart disease. Previously published reference equations tended to over- or under-predict estimates of LM compared with the current reference equations. This study provides a comprehensive and validated set of reference equations for estimating and interpreting FFM and LM from DEXA in Canadian adults aged 45-85 years.

The 2023 top 10 list of endoscopy topics in medical publishing: an annual review by the American Society for Gastrointestinal Endoscopy Editorial Board.

Using a systematic literature search of original articles published during 2023 in Gastrointestinal Endoscopy (GIE) and other high-impact medical and gastroenterology journals, the GIE Editorial Board of the American Society for Gastrointestinal Endoscopy compiled a list of the top 10 most significant topic areas in general and advanced GI endoscopy during the year. Each GIE Editorial Board member was directed to consider 3 criteria in generating candidate topics-significance, novelty, and impact on global clinical practice-and subject matter consensus was facilitated by the Chair through electronic voting and a meeting of the entire GIE Editorial Board. The 10 identified areas collectively represent advances in the following endoscopic spheres: GI bleeding, endohepatology, endoscopic palliation, artificial intelligence and polyp detection, artificial intelligence beyond the colon, better polypectomy and endoscopic mucosal resection, how to make endoscopy units greener, high quality upper endoscopy, endoscopic tissue apposition/closure devices, and endoscopic submucosal dissection. Each board member was assigned a topic area around which summarized relevant important articles, thereby generating this overview of the "top 10" endoscopic advances of 2023.

Haemodynamic compensations for exercise tissue oxygenation in early stages of COPD: an integrated cardiorespiratory assessment study.

BACKGROUND: Cardiovascular comorbidities are increasingly being recognised in early stages of chronic obstructive pulmonary disease (COPD) yet complete cardiorespiratory functional assessments of individuals with mild COPD or presenting with COPD risk factors are lacking. This paper reports on the effectiveness of the cardiocirculatory-limb muscles oxygen delivery and utilisation axis in smokers exhibiting no, or mild to moderate degrees of airflow obstruction using standardised cardiopulmonary exercise testing (CPET). METHODS: Post-bronchodilator spirometry was used to classify participants as 'ever smokers without' (n=88), with 'mild' (n=63) or 'mild-moderate' COPD (n=56). All underwent CPET with continuous concurrent monitoring of oxygen uptake (V'O2) and of bioimpedance cardiac output (Qc) enabling computation of arteriovenous differences (a-vO2). Mean values of Qc and a-vO2 were mapped across set ranges of V'O2 and Qc isolines to allow for meaningful group comparisons, at same metabolic and circulatory requirements. RESULTS: Peak exercise capacity was significantly reduced in the 'mild-moderate COPD' as compared with the two other groups who showed similar pulmonary function and exercise capacity. Self-reported cardiovascular and skeletal muscle comorbidities were not different between groups, yet disease impact and exercise intolerance scores were three times higher in the 'mild-moderate COPD' compared with the other groups. Mapping of exercise Qc and a-vO2 also showed a leftward shift of values in this group, indicative of a deficit in peripheral O2 extraction even for submaximal exercise demands. Concurrent with lung hyperinflation, a distinctive blunting of exercise stroke volume expansion was also observed in this group. CONCLUSION: Contrary to the traditional view that cardiovascular complications were the hallmark of advanced disease, this study of early COPD spectrum showed a reduced exercise O2 delivery and utilisation in individuals meeting spirometry criteria for stage II COPD. These findings reinforce the preventive clinical management approach to preserve peripheral muscle circulatory and oxidative capacities.

Physiological Factors Associated with Unsatisfied Inspiration at Peak Exercise in Healthy Adults.

INTRODUCTION: Contrary to common belief, a growing body of evidence suggests that unsatisfied inspiration (UI), an inherently uncomfortable quality of dyspnea, is experienced by ostensibly healthy adults during high-intensity exercise. Based on our understanding of the mechanisms of UI among people with chronic respiratory conditions, this analysis tested the hypothesis that the experience of UI at peak exercise in young, healthy adults reflects the combination of high ventilatory demand and critical inspiratory constraints. METHODS: In a retrospective analysis design, data included 321 healthy individuals (129 females) aged 25 ± 5 yrs. Data were collected during one visit to the laboratory, which included anthropometrics, spirometry, and an incremental cardiopulmonary cycling test to exhaustion. Metabolic and cardiorespiratory variables were measured at peak exercise, and qualitative descriptors of dyspnea at peak exercise were assessed using a list of 15 descriptor phrases. RESULTS: 34% of participants (n = 109) reported sensations of UI at peak exercise. Compared to the Non-UI group, the UI group achieved a significantly higher peak work rate (243 ± 77 vs. 235 ± 69 W, P = 0.016, d = 0.10), rate of O2 consumption (3.32 ± 1.02 vs. 3.27 ± 0.96 L·min-1, P = 0.018, d = 0.05), minute ventilation (120 ± 38 vs. 116 ± 35 L·min-1, P = 0.047, d = 0.11), and breathing frequency (50 ± 9 vs. 47 ± 9 breaths·min-1, P = 0.014, d = 0.33), while having a lower exercise-induced change (peak-baseline) in inspiratory capacity (0.07 ± 0.41 vs. 0.20 ± 0.49 L, P = 0.023, d = 0.29). The inspiratory reserve volume to minute ventilation ratio at peak exercise was also lower in the UI vs. Non-UI group. Dyspnea intensity and unpleasantness ratings were significantly higher in the UI vs. Non-UI group at peak exercise (both P < 0.001). CONCLUSIONS: Healthy individuals reporting UI at peak exercise have relatively greater inspiratory constraints compared to those who do not select UI.

Abnormal Exertional Breathlessness on Cardiopulmonary Cycle Exercise Testing in Relation to Self-Reported and Physiologic Responses in Chronic Airflow Limitation.

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); FEV1/FVC, 57.3% ± 8.2%; FEV1, 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 construct validity of abnormal exertional breathlessness.

Endoscopic Diagnosis and Treatment of Colonic Diverticular Bleeding.

This is a description and critical analysis of current diagnosis and treatment of diverticular hemorrhage. The focus is on colonoscopy for identification and treatment of stigmata of recent hemorrhage (SRH) in diverticula. A classification of definitive, presumptive, and incidental diverticular hemorrhage is reviewed and recommended. The approach to definitive diagnosis with urgent colonoscopy is put into perspective of other management strategies including angiography (of different types), nuclear medicine scans, surgery, and medical treatment. Advancements in diagnosis, risk stratification, and colonoscopic hemostasis are described including those that obliterate arterial blood flow underneath SRH and prevent diverticular rebleeding. Recent innovations are discussed.

A fully automated pipeline for the extraction of pectoralis muscle area from chest computed tomography scans.

Background: Computed tomography (CT)-derived pectoralis muscle area (PMA) measurements are prognostic in people with or at-risk of COPD, but fully automated PMA extraction has yet to be developed. Our objective was to develop and validate a PMA extraction pipeline that can automatically: 1) identify the aortic arch slice; and 2) perform pectoralis segmentation at that slice. Methods: CT images from the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study were used for pipeline development. Aorta atlases were used to automatically identify the slice containing the aortic arch by group-based registration. A deep learning model was trained to segment the PMA. The pipeline was evaluated in comparison to manual segmentation. An external dataset was used to evaluate generalisability. Model performance was assessed using the Dice-Sorensen coefficient (DSC) and PMA error. Results: In total 90 participants were used for training (age 67.0±9.9 years; forced expiratory volume in 1 s (FEV1) 93±21% predicted; FEV1/forced vital capacity (FVC) 0.69±0.10; 47 men), and 32 for external testing (age 68.6±7.4 years; FEV1 65±17% predicted; FEV1/FVC 0.50±0.09; 16 men). Compared with manual segmentation, the deep learning model achieved a DSC of 0.94±0.02, 0.94±0.01 and 0.90±0.04 on the true aortic arch slice in the train, validation and external test sets, respectively. Automated aortic arch slice detection obtained distance errors of 1.2±1.3 mm and 1.6±1.5 mm on the train and test data, respectively. Fully automated PMA measurements were not different from manual segmentation (p>0.05). PMA measurements were different between people with and without COPD (p=0.01) and correlated with FEV1 % predicted (p<0.05). Conclusion: A fully automated CT PMA extraction pipeline was developed and validated for use in research and clinical practice.

Normative Reference Equations for Breathlessness Intensity during Incremental Cardiopulmonary Cycle Exercise Testing.

Rationale: Cardiopulmonary exercise testing (CPET) is the gold standard to evaluate exertional breathlessness, a common and disabling symptom. However, the interpretation of breathlessness responses to CPET is limited by a scarcity of normative data. Objectives: We aimed to develop normative reference equations for breathlessness intensity (Borg 0-10 category ratio) response in men and women aged ⩾40 years during CPET, in relation to power output (watts), oxygen uptake, and minute ventilation. Methods: Analysis of ostensibly healthy people aged ⩾40 years undergoing symptom-limited incremental cycle CPET (10 W/min) in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study. Participants had smoking histories <5 pack-years and normal lung function and exercise capacity. The probability of each Borg 0-10 category ratio breathlessness intensity rating by power output, oxygen uptake, and minute ventilation (as an absolute or a relative value [percentage of predicted maximum]) was predicted using ordinal multinomial logistic regression. Model performance was evaluated by fit, calibration, and discrimination (C statistic) and externally validated in an independent sample (n = 86) of healthy Canadian adults. Results: We included 156 participants (43% women) from CanCOLD; the mean age was 65 (range, 42-91) years, and the mean body mass index was 26.3 (standard deviation, 3.8) kg/m2. Reference equations were developed for women and men separately, accounting for age and/or body mass. Model performance was high across all equations, including in the validation sample (C statistic for men = 0.81-0.92, C statistic for women = 0.81-0.96). Conclusions: Normative reference equations are provided to compare exertional breathlessness intensity ratings among individuals or groups and to identify and quantify abnormal breathlessness responses (scores greater than the upper limit of normal) during CPET.

Patient Outcomes of Definitive Diverticular Hemorrhage After Colonoscopic, Medical, Surgical, or Embolization Treatment.

BACKGROUND: There are few reports of clinical outcomes or the natural history of definitive diverticular hemorrhage (DDH). AIMS: To describe 1-year clinical outcomes of patients with documented DDH treated with colonoscopic hemostasis, angioembolization, surgery, or medical treatment. METHODS: DDH was diagnosed when active bleeding or other stigmata of hemorrhage were found in a colonic diverticulum during urgent colonoscopy or extravasation on angiography or red blood cell (RBC) scanning. This was a retrospective analysis of prospectively collected data of DDH patients from two referral centers between 1993 and 2022. Outcomes were compared for the four treatment groups. The Kaplan-Meier analysis was for time-to-first diverticular rebleed. RESULTS: 162 patients with DDH were stratified based on their final treatment before discharge-104 colonoscopic hemostasis, 24 medical treatment alone, 19 colon surgery, and 15 angioembolization. There were no differences in baseline characteristics, except for a higher Glasgow-Blatchford score in the angioembolization group vs. the colonoscopic group. Post-treatment, the colonoscopic hemostasis group had the lowest rate of RBC transfusions and fewer hospital and ICU days compared to surgical and embolization groups. The medical group had significantly higher rates of rebleeding and reintervention. The surgical group had the highest postoperative complications. CONCLUSIONS: Medically treated DDH patients had significantly higher 1-year rebleed and reintervention rates than the three other treatments. Those with colonoscopic hemostasis had significantly better clinical outcomes during the index hospitalization. Surgery and embolization are recommended as salvage therapies in case of failure of colonoscopic and medical treatments.

Improving primary prophylaxis of variceal bleeding by adapting therapy to the clinical stage of cirrhosis. A competing-risk meta-analysis of individual participant data.

BACKGROUND & AIMS: Non-selective ß-blockers (NSBBs) and endoscopic variceal-ligation (EVL) have similar efficacy preventing first variceal bleeding. Compensated and decompensated cirrhosis are markedly different stages, which may impact treatment outcomes. We aimed to assess the efficacy of NSBBs vs EVL on survival in patients with high-risk varices without previous bleeding, stratifying risk according to compensated/decompensated stage of cirrhosis. METHODS: By systematic review, we identified RCTs comparing NSBBs vs EVL, in monotherapy or combined, for primary bleeding prevention. We performed a competing-risk, time-to-event meta-analysis, using individual patient data (IPD) obtained from principal investigators of RCTs. Analyses were stratified according to previous decompensation of cirrhosis. RESULTS: Of 25 RCTs eligible, 14 failed to provide IPD and 11 were included, comprising 1400 patients (656 compensated, 744 decompensated), treated with NSBBs (N = 625), EVL (N = 546) or NSBB+EVL (N = 229). Baseline characteristics were similar between groups. Overall, mortality risk was similar with EVL vs. NSBBs (subdistribution hazard-ratio (sHR) = 1.05, 95% CI = 0.75-1.49) and with EVL + NSBBs vs either monotherapy, with low heterogeneity (I2 = 28.7%). In compensated patients, mortality risk was higher with EVL vs NSBBs (sHR = 1.76, 95% CI = 1.11-2.77) and not significantly lower with NSBBs+EVL vs NSBBs, without heterogeneity (I2 = 0%). In decompensated patients, mortality risk was similar with EVL vs. NSBBs and with NSBBs+EVL vs. either monotherapy. CONCLUSIONS: In patients with compensated cirrhosis and high-risk varices on primary prophylaxis, NSBBs significantly improved survival vs EVL, with no additional benefit noted adding EVL to NSBBs. In decompensated patients, survival was similar with both therapies. The study suggests that NSBBs are preferable when advising preventive therapy in compensated patients.

The modified Medical Research Council scale misclassifies exertional breathlessness among people referred for exercise testing.

Background: Exertional breathlessness is a major symptom in cardiorespiratory disease and is often assessed using the modified Medical Research Council (mMRC) questionnaire. The mMRC might underestimate exertional breathlessness in people with impaired exercise capacity who have reduced their physical activity to avoid the symptom. We aimed to evaluate the ability of mMRC to detect abnormally high exertional breathlessness or abnormally low exercise capacity during incremental cycle exercise testing (IET). Methods: A secondary analysis of data from a randomised controlled trial of outpatients aged 18 years or older referred for IET was carried out. Participants completed the mMRC before IET. Abnormally high exertional breathlessness was defined as a breathlessness (Borg 0-10) intensity response more than the upper limit of normal. Abnormally low exercise capacity was defined using published reference equations. The sensitivity, specificity, accuracy and discriminative ability of each mMRC rating to detect each outcomewas calculated. Results: 92 participants were included; the mean age was 59 years, 61% were male, and 64% and 15% had mMRC 1 and ≥2, respectively. An mMRC ≥2 had the highest accuracy (71%) to detect abnormally high exertional breathlessness, with a specificity of 93% but a sensitivity of only 28%, failing to identify 72% of people with abnormally high exertional breathlessness. The accuracy, specificity and sensitivity for abnormally low exercise capacity was 64%, 88% and 19%, respectively. Conclusion: Among people referred for clinical exercise testing, the mMRC dyspnoea scale misclassified exertional breathlessness and exercise capacity assessed using cycle IET, with substantial underdetection. A mMRC dyspnoea rating of 0-1 does not preclude the presence of abnormally high exertional breathlessness or abnormally low exercise capacity.

The Importance of Arterial Blood Flow Detection for Risk Stratification and Eradication to Achieve Definitive Hemostasis of Severe Non-Variceal UGI Hemorrhage.

BACKGROUND: Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common medical problem worldwide. Independent endoscopic risk factors for rebleeding and mortality of NVUGIB that are treatable are stigmata of recent hemorrhage (SRH) and arterial blood flow underneath SRH. The specific aims of this paper are to describe the importance of arterial blood flow detection for risk stratification and as a guide to definitive hemostasis of severe NVUGIB. METHODS: This is a review of randomized controlled trials and prospective cohort study methodologies and results which utilized a Doppler endoscopic probe (DEP) for the detection of arterial blood underneath SRH, for risk stratification, and as a guide to definitive hemostasis. The results are compared to visually guided hemostasis based upon SRH. RESULTS: Although SRH have been utilized to guide endoscopic hemostasis of NVUGIB for 50 years, when most visually guided treatments are applied to lesions with major SRH, arterial blood flow underneath SRH is not obliterated in 25-30% of patients and results in rebleeding. Definitive hemostasis, significantly lower rebleeding rates, and improvements in other clinical outcomes resulted when DEP was used for risk stratification and as a guide to obliteration of arterial blood flow underneath SRH. CONCLUSIONS: DEP-guided endoscopic hemostasis is a very effective and safe new method to improve patient outcomes for NVUGIB.

The modified Borg/6-min walk distance ratio: a method to assess exertional breathlessness and leg discomfort using the 6-min walk test.

Background: The 6-min walk test (6MWT) is widely used to assess exercise capacity across chronic health conditions, but is currently not useful to assess symptoms, as the scores do not account for the 6-min walk distance (6MWD). We aimed to 1) develop normative reference equations for breathlessness and leg discomfort intensity expressed as modified Borg (mBorg)/6MWD ratios; and 2) validate the equations in people with COPD. Methods: Analysis of people aged ≥40 years who performed two 6MWTs (on a 20-m course) in the Canadian Cohort Obstructive Lung Disease (CanCOLD) study: a healthy cohort (n=291; mean±sd age 67.5±9.4 years; 54% male) with normal 6MWD and lung function, and a COPD cohort (n=156; age 66.2±9.0 years; 56% male; forced expiratory volume in 1 s (FEV1)/forced vital capacity 56.6±8.2%; FEV1 74.4±18.6% pred). The mBorg score was calculated as the Borg 0-10 category ratio intensity rating of breathlessness or leg discomfort recorded at the end of the 6MWT +1 (range 1-11), to avoid zeros and yield ratios proportional to the symptom score and 6MWD-1. Results: Using data from the healthy cohort, sex-specific normative reference equations for breathlessness and leg discomfort mBorg/6MWD ratios were developed using multivariable linear regression, accounting for age, and body mass or body mass index. In the COPD cohort, abnormal breathlessness and leg discomfort (mBorg/6MWD>upper limit of normal) showed strong concurrent validity with worse airflow limitation, Medical Research Council breathlessness and COPD Assessment Test scores. Conclusion: Normative references for the mBorg/6MWD ratio are presented to assess breathlessness and leg discomfort responses to the 6MWT in COPD.

Efficacy of interventions to alter measures of fat-free mass in people with COPD: a systematic review and meta-analysis.

Introduction: Low fat-free mass (FFM) is linked to poor health outcomes in COPD, including impaired exercise tolerance and premature death. The aim of this systematic review was to synthesise evidence on the effectiveness of interventions for increasing FFM in COPD. Methods: Searches of electronic databases (MEDLINE, Cochrane Library, Embase, Web of Science, Scopus) and trial registers (ClinicalTrials.gov) were undertaken from inception to August 2022 for randomised studies of interventions assessing measures of FFM in COPD. The primary outcome was change in FFM (including derivatives). Secondary outcomes were adverse events, compliance and attrition. Results: 99 studies (n=5138 people with COPD) of 11 intervention components, used alone or in combination, were included. Exercise training increased mid-thigh cross-sectional area (k=3, standardised mean difference (SMD) 1.04, 95% CI 0.02-2.06; p=0.04), but not FFM (k=4, SMD 0.03, 95% CI -0.18-0.24; p=0.75). Nutritional supplementation significantly increased FFM index (k=11, SMD 0.31, 95% CI 0.13-0.50; p<0.001), but not FFM (k=19, SMD 0.16, 95% CI -0.06-0.39; p=0.16). Combined exercise training and nutritional supplementation increased measures related to FFM in 67% of studies. Anabolic steroids increased FFM (k=4, SMD 0.98, 95% CI 0.24-1.72; p=0.009). Neuromuscular electrical stimulation increased measures related to FFM in 50% of studies. No interventions were more at risk of serious adverse events, low compliance or attrition. Discussion: Exercise training and nutritional supplementation were not effective in isolation to increase FFM, but were for localised muscle and index measures, respectively. Combined, exercise and nutritional supplementation shows promise as a strategy to increase FFM in COPD. Anabolic steroids are efficacious for increasing FFM in COPD.

The WE SENSE study protocol: A controlled, longitudinal clinical trial on the use of wearable sensors for early detection and tracking of viral respiratory tract infections.

BACKGROUND: Viral respiratory tract infections (VRTI) are extremely common. Considering the profound social and economic impact of COVID-19, it is imperative to identify novel mechanisms for early detection and prevention of VRTIs, to prevent future pandemics. Wearable biosensor technology may facilitate this. Early asymptomatic detection of VRTIs could reduce stress on the healthcare system by reducing transmission and decreasing the overall number of cases. The aim of the current study is to define a sensitive set of physiological and immunological signature patterns of VRTI through machine learning (ML) to analyze physiological data collected continuously using wearable vital signs sensors. METHODS: A controlled, prospective longitudinal study with an induced low grade viral challenge, coupled with 12 days of continuous wearable biosensors monitoring surrounding viral induction. We aim to recruit and simulate a low grade VRTI in 60 healthy adults aged 18-59 years via administration of live attenuated influenza vaccine (LAIV). Continuous monitoring with wearable biosensors will include 7 days pre (baseline) and 5 days post LAIV administration, during which vital signs and activity-monitoring biosensors (embedded in a shirt, wristwatch and ring) will continuously monitor physiological and activity parameters. Novel infection detection techniques will be developed based on inflammatory biomarker mapping, PCR testing, and app-based VRTI symptom tracking. Subtle patterns of change will be assessed via ML algorithms developed to analyze large datasets and generate a predictive algorithm. CONCLUSION: This study presents an infrastructure to test wearables for the detection of asymptomatic VRTI using multimodal biosensors, based on immune host response signature. CliniclTrials.govregistration:NCT05290792.

Reference equations for breathlessness during incremental cycle exercise testing.

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.

Cytoplasmic TDP-43 accumulation drives changes in C-bouton number and size in a mouse model of sporadic Amyotrophic Lateral Sclerosis.

An altered neuronal excitability of spinal motoneurones has consistently been implicated in Amyotrophic Lateral Sclerosis (ALS) leading to several investigations of synaptic input to these motoneurones. One such input that has repeatedly been shown to be affected is a population of large cholinergic synapses terminating mainly on the soma of the motoneurones referred to as C-boutons. Most research on these synapses during disease progression has used transgenic Superoxide Dismutase 1 (SOD1) mouse models of the disease which have not only produced conflicting findings, but also fail to recapitulate the key pathological feature seen in ALS; cytoplasmic accumulations of TAR DNA-binding protein 43 (TDP-43). Additionally, they fail to distinguish between slow and fast motoneurones, the latter of which have more C-boutons, but are lost earlier in the disease. To circumvent these issues, we quantified the frequency and volume of C-boutons on traced soleus and gastrocnemius motoneurones, representing predominantly slow and fast motor pools respectively. Experiments were performed using the TDP-43ΔNLS mouse model that carries a transgenic construct of TDP-43 devoid of its nuclear localization signal, preventing its nuclear import. This results in the emergence of pathological TDP-43 inclusions in the cytoplasm, modelling the main pathology seen in this disorder, accompanied by a severe and lethal ALS phenotype. Our results confirmed changes in both the number and volume of C-boutons with a decrease in number on the more vulnerable, predominantly fast gastrocnemius motoneurones and an increase in number on the less vulnerable, predominantly slow soleus motoneurones. Importantly, these changes were only found in male mice. However, both sexes and motor pools showed a decrease in C-bouton volume. Our experiments confirm that cytoplasmic TDP-43 accumulation is sufficient to drive C-bouton changes.

Impact of trigeminal and/or olfactory nerve stimulation on measures of inspiratory neural drive: Implications for breathlessness.

The perception of breathlessness is mechanistically linked to the awareness of increased inspiratory neural drive (IND). Stimulation of upper airway cold receptors on the trigeminal nerve (TGN) with TGN agonists such as menthol or cool air to the face/nose has been hypothesized to reduce breathlessness by decreasing IND. The aim of this systematic scoping review was to identify and summarize the results of studies in animals and humans reporting on the impact of TGN stimulation or blockade on measures of IND. Thirty-one studies were identified, including 19 in laboratory animals and 12 in human participants. Studies in laboratory animals consistently reported that as TGN activity increased, measures of IND decreased (e.g., phrenic nerve activity). In humans, stimulation of the TGN with a stream of cool air to the face/nose decreased the sensitivity of the ventilatory chemoreflex response to hypercapnia. Otherwise, TGN stimulation with menthol or cool air to the face/note had no effect on measures of IND in humans. This review provides new insight into a potential neural mechanism of breathlessness relief with selected TGN agonists.

Impact of trigeminal nerve and/or olfactory nerve stimulation on activity of human brain regions involved in the perception of breathlessness.

Breathlessness is a centrally processed symptom, as evidenced by activation of distinct brain regions such as the insular cortex and amygdala, during the anticipation and/or perception of breathlessness. Inhaled L-menthol or blowing cool air to the face/nose, both selective trigeminal nerve (TGN) stimulants, relieve breathlessness without concurrent improvements in physiological outcomes (e.g., breathing pattern), suggesting a possible but hitherto unexplored central mechanism of action. Four databases were searched to identify published reports supporting a link between TGN stimulation and activation of brain regions involved in the anticipation and/or perception of breathlessness. The collective results of the 29 studies demonstrated that TGN stimulation activated 12 brain regions widely implicated in the anticipation and/or perception of breathlessness, including the insular cortex and amygdala. Inhaled L-menthol or cool air to the face activated 75% and 33% of these 12 brain regions, respectively. Our findings support the hypothesis that TGN stimulation contributes to breathlessness relief by altering the activity of brain regions involved in its central neural processing.