Biomarker Turnaround Times and Impact on Treatment Decisions in Patients with Advanced Non-Small Cell Lung Carcinoma at a Large Canadian Community Hospital with an Affiliated Regional Cancer Centre.

Background: Timely reporting of molecular biomarkers is critical in guiding optimal treatment decisions in patients with advanced non-small cell lung carcinoma (NSCLC). Any delays along the tissue or treatment pathway may be associated with suboptimal treatment/outcomes and a reduced quality of life. For many centres, biomarkers are tested off-site. Methods: A retrospective chart review of 123 patients with advanced NSCLC seen between 1 June 2021 and 30 June 2022 was conducted. With a focus on core biomarkers (PD L1, EGFR, and ALK), the outcome variables were as follows: total turnaround time (total TAT), divided into pre-laboratory, laboratory, and post-laboratory time intervals, as well as time to treatment decision (TOTD) and time to optimal systemic therapy decision (TOTSD). Results: At first consult, only 20.3% of patients had all core biomarker results available. The median total TAT was significantly longer for non-squamous (non-SCC) than squamous cell carcinoma (SCC) specimens (36.5 versus 22 days, p < 0.001). The median pre-laboratory time for the entire cohort was 5 calendar days. The median laboratory testing time was greater for non-SCC compared to the SCC specimens (23 versus 12 days, p < 0.001). The median time from consult to TOTD was 19 calendar days for the entire cohort. Conclusions: This study emphasizes the need for the expansion of regional resources to meet the clinical needs of advanced NSCLC patients treated at a regional cancer centre which uses an off-site molecular laboratory.

Electrophysiological neuromuscular alterations and severe fatigue predict long-term muscle weakness in survivors of COVID-19 acute respiratory distress syndrome.

Introduction: Long-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits. Methods: Muscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control. Results: MVC improved at 12 months compared with 6 months. CMAP-TA-S100 (P = 0.016) and the presence of severe fatigue (P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT. Discussion: Electrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors.

Sex-differences in the longitudinal recovery of neuromuscular function in COVID-19 associated acute respiratory distress syndrome survivors.

Introduction: Patients admitted to the intensive care unit (ICU) following severe acute respiratory syndrome 2 (SARS-CoV-2) infection may have muscle weakness up to 1 year or more following ICU discharge. However, females show greater muscle weakness than males, indicating greater neuromuscular impairment. The objective of this work was to assess sex differences in longitudinal physical functioning following ICU discharge for SARS-CoV-2 infection. Methods: We performed longitudinal assessment of physical functioning in two groups: 14 participants (7 males, 7 females) in the 3-to-6 month and 28 participants (14 males, 14 females) in the 6-to-12 month group following ICU discharge and assessed differences between the sexes. We examined self-reported fatigue, physical functioning, compound muscle action potential (CMAP) amplitude, maximal strength, and the neural drive to the tibialis anterior muscle. Results: We found no sex differences in the assessed parameters in the 3-to-6-month follow-up, indicating significant weakness in both sexes.Sex differences emerged in the 6-to-12-month follow-up. Specifically, females exhibited greater impairments in physical functioning, including lower strength, walking lower distances, and high neural input even 1 year following ICU-discharge. Discussion: Females infected by SARS-CoV-2 display significant impairments in functional recovery up to 1 year following ICU discharge. The effects of sex should be considered in post-COVID neurorehabilitation.

Assessing shoulder muscle stretch reflexes following breast cancer treatment and postmastectomy breast reconstruction.

Muscle stiffness is altered following postmastectomy breast reconstruction and breast cancer treatment. The exact mechanisms underlying these alterations are unknown; however, muscle stretch reflexes may play a role. This work examined short- (SLR) and long-latency (LLR) shoulder muscle stretch reflexes in breast cancer survivors. Forty-nine patients who had undergone postmastectomy breast reconstruction, 17 who had undergone chemoradiation, and 18 healthy, age-matched controls were enrolled. Muscle activity was recorded from the clavicular and sternocostal regions of the pectoralis major and anterior, middle, and posterior deltoids during vertical ab/adduction or horizontal flex/extension perturbations while participants maintained minimal torques. SLR and LLR were quantified for each muscle. Our major finding was that following postmastectomy breast reconstruction, SLR and LLR are impaired in the clavicular region of the pectoralis major. Individuals who had chemoradiation had impaired stretch reflexes in the clavicular and sternocostal region of the pectoralis major, anterior, middle, and posterior deltoid. These findings indicate that breast cancer treatments alter the regulation of shoulder muscle stretch reflexes and may be associated with surgical or nonsurgical damage to the pectoral fascia, muscle spindles, and/or sensory Ia afferents.NEW & NOTEWORTHY Shoulder muscle stretch reflexes may be impacted following postmastectomy breast reconstruction and chemoradiation. Here, we examined short- and long-latency shoulder muscle stretch reflexes in two experiments following common breast reconstruction procedures and chemoradiation. We show impairments in pectoralis major stretch reflexes following postmastectomy breast reconstruction and pectoralis major and deltoid muscle stretch reflexes following chemoradiation. These findings indicate that breast cancer treatments alter the regulation of shoulder muscle stretch reflexes.

Non-uniform excitation of pectoralis major induced by changes in bench press inclination leads to uneven variations in the cross-sectional area measured by panoramic ultrasonography.

This study combined surface electromyography with panoramic ultrasound imaging to investigate whether non-uniform excitation could lead to acute localized variations in cross-sectional area and muscle thickness of the clavicular and sternocostal heads of pectoralis major (PM). Bipolar surface electromyograms (EMGs) were acquired from both PM heads, while 13 men performed four sets of the flat and 45° inclined bench press exercises. Before and immediately after exercise, panoramic ultrasound images were collected transversely to the fibers. Normalized root mean square (RMS) amplitude and variations in the cross-sectional area and muscle thickness were calculated separately for each PM head. For all sets of the inclined bench press, the normalized RMS amplitude was greater for the clavicular head than the sternocostal head (P < 0.001), and the opposite was observed during the flat bench press (P < 0.001). Similarly, while greater increases in cross-sectional area were observed in the clavicular than in the sternocostal head after the inclined bench press (P < 0.001), greater increases were quantified in the sternocostal than in the clavicular head after the flat bench press exercise (P = 0.046). Therefore, our results suggest that the PM regional excitation induced by changes in bench press inclination leads to acute, uneven responses of muscle architecture following the exercise.

Sex differences in motor unit behaviour: A review.

The lack of systematic investigations on sex-related differences in motor unit behaviour poses a challenge in understanding and optimizing health and performance in males and females. Limited investigations revealed that sex differences in motor unit behaviour might be present in human muscles. This review summarizes the current knowledge on sex differences in motor unit behaviour and potential factors that may contribute to these differences. We show significant under-representation of female participants in motor unit studies and a limited number of studies investigating sex differences in motor unit behaviour. We place the current insights within the context of methodological limitations and outline several recommendations and future directions to improve female representation in this research area. We conclude that there is an urgent need to gather more data in females and investigate sex differences in motor unit behaviour. The knowledge gained could be used to develop sex-specific approaches to improve neuromuscular performance and rehabilitation.

The impact of local therapies for breast cancer on shoulder muscle health and function.

Advances in breast cancer treatment have improved patient survival but have also created complications, such as shoulder morbidity, impacting the patient's quality of life. Local therapies for breast cancer influence shoulder muscle health through changes to the muscular microenvironment, macroscopic muscle morphology, and neuromuscular function. Our findings suggest both surgery and radiation therapy compromise the healthy functioning of shoulder musculature. Mastectomy and post-mastectomy breast reconstruction directly affect shoulder function through muscle morphology and neuromuscular function alterations. Radiation therapy damages satellite cells and myocytes, causing cell death both during treatment and years after recovery. This damage creates an environment limited in its ability to prevent atrophy. However, research to date is limited to a small number of analyses with small experimental populations and a lack of control for covariates. Future research to uncover the pathophysiological mechanisms underlying shoulder morbidity after breast cancer treatment must integrate measures of shoulder muscle health and shoulder function.

Differential regional pectoralis major activation indicates functional diversity in healthy females.

Pectoralis major activation enables the performance of several upper extremity movements. Its regional activation, however, is not documented in healthy females. This work used high-density surface electromyography to investigate regional pectoralis major activation in twenty-nine healthy young females across two independent experiments in several ramp and hold isometric tasks and force levels. Regional mean root mean square amplitudes (normalized to the task-specific maxima) were quantified for the clavicular, superior, and middle sternocostal regions. Two-way ANOVAs were used to determine if differences in normalized regional activation exist within each task and force level. The middle sternocostal region activated 12-108% more than the clavicular and the superior sternocostal region in extension, adduction with external rotation, and high elevation internal rotation. In high elevation adduction, the middle sternocostal region activated more (7-22%) than the superior sternocostal region. In low elevation, internal rotation (60°), the clavicular and middle sternocostal regions activated more (9-13%) than the superior sternocostal region, while in adduction 60°, the clavicular region activated 9-19% more than the superior sternocostal region. Lastly, in forward and horizontal flexion, all three regions activated similarly irrespective of the force level, except at 25% MVF in forward flexion, where the clavicular region activated 21% more than the superior sternocostal region. This work provides a first comprehensive evaluation of the normalized regional pectoralis major activation in healthy females. The present findings indicate that the performance of isometric tasks in different directions activates different pectoralis major regions in healthy females, suggesting regional specificity to functional actions.

Neural control of the healthy pectoralis major from low-to-moderate isometric contractions.

The pectoralis major critically enables arm movement in several directions. However, its neural control remains unknown. High-density electromyography (HD-sEMG) was acquired from the pectoralis major in two sets of experiments in healthy young adults. Participants performed ramp-and-hold isometric contractions in: adduction, internal rotation, flexion, and horizontal adduction at three force levels: 15%, 25%, and 50% scaled to task-specific maximal voluntary force (MVF). HD-sEMG signals were decomposed into motor unit spike trains using a convolutive blind source separation algorithm and matched across force levels using a motor unit matching algorithm. The mean discharge rate and coefficient of variation were quantified across the hold and compared between 15% and 25% MVF across all tasks, whereas comparisons between 25% and 50% MVF were made where available. Mean motor unit discharge rate was not significantly different between 15% and 25% MVF (all P > 0.05) across all tasks or between 25% and 50% MVF in horizontal adduction (P = 0.11), indicating an apparent saturation across force levels and the absence of rate coding. These findings suggest that the pectoralis major likely relies on motor unit recruitment to increase force, providing first-line evidence of motor unit recruitment in this muscle and paving the way for more deliberate investigations of the pectoralis major involvement in shoulder function.NEW & NOTEWORTHY This work is the first to investigate the relative contribution of rate coding and motor unit recruitment in the pectoralis major muscle in several functionally relevant tasks and across varying force levels in healthy adults. Our results demonstrate the absence of motor unit rate coding with an increase in EMG amplitude with increases in force level in all tasks examined, indicating that the pectoralis major relies on motor unit recruitment to increase force.

Age and sex influence the activation-dependent stiffness of the pectoralis major.

The pectoralis major fiber regions contribute uniquely to the mobility and the stability of the shoulder complex. It is unknown how age and sex influence the stiffness of these regions during volitional contractions, but this knowledge is critical to inform clinical interventions targeting the pectoralis major. The aim of the present study was to determine if the activation-dependent stiffness of the pectoralis major fiber regions differs between the sexes and if it is altered with age. Ultrasound shear wave elastography was used to acquire shear wave velocity from the clavicular and the sternocostal fiber regions of 48 healthy participants, including 24 younger (12 males, 12 females, mean ± SD age 25 ± 4.1 years) and 24 older adults (12 males, 12 females, 55 ± 3.6 years). Participants performed vertical adduction and horizontal flexion torques in neutral and 90° externally rotated shoulder positions, and one of the two shoulder abduction positions (60° and 90°) at varying torque magnitudes (passive, 15% and 30% of maximal voluntary contraction). Separate linear mixed-effects models were run for each fiber region and shoulder position to determine if the activation-dependent stiffness differed between the sexes and was altered in older adults. Age-related alterations in stiffness during volitional contractions were observed in both fiber regions and were dependent on the task. Alterations in activation-dependent stiffness due to age were more pronounced in females than males. Additionally, females had greater stiffness than males during volitional contractions in both fiber regions. The present findings provide the first line of evidence that the activation-dependent stiffness of the pectoralis major fiber regions is influenced by sex and changes with age.

Standard bipolar surface EMG estimations mischaracterize pectoralis major activity in commonly performed tasks.

The pectoralis major assists in several shoulder movements, such as humeral vertical and horizontal adduction, flexion, extension, and internal rotation. Despite its involvement in numerous functional activities, its role in typical shoulder function is ambiguous. Due to this, its purpose in arm movement is largely diminished. However, mounting evidence associates pectoralis major injuries to long-term debilitating arm disability. Therefore, a more deliberate investigation of its role in typical shoulder function is paramount. The purpose of this paper is to outline the current limitations in the acquisition and characterization of pectoralis major activation using standard bipolar surface electromyography. Macroscopic level analyses are used to investigate pectoralis major activation in eight tasks at low (15-25% of maximal voluntary effort (MVE) and moderate (50% MVE) efforts in healthy males. Virtually derived bipolar EMG amplitudes are quantified for the clavicular and the upper sternocostal regions based on the common locations used to acquire EMG signals from classic EMG. HD-sEMG amplitudes from three pectoralis major regions (i.e. clavicular, upper, and lower sternocostal) were compared to virtually derived bipolar EMG amplitudes (i.e. clavicular and upper sternocostal) to determine if current EMG methods misestimate pectoralis major activity. Current findings indicate that classic EMG recordings mischaracterize pectoralis major activation in several tasks and effort levels, highlighting the importance of acquiring signals from multiple pectoralis major regions.

Sub-regional activation of supraspinatus and infraspinatus muscles during activities of daily living is task dependent.

The supraspinatus and infraspinatus muscles each have multiple sub-regions that may activate differentially in activities of daily living. Awareness of these differential demands critically informs rehabilitation of rotator cuff muscle following injury, particularly if centered on recovering and strengthening the rotator cuff to perform daily tasks. This study quantified muscle activation of supraspinatus and infraspinatus sub-regions during the performance of six activities of daily living. Twenty-three participants (mean: 22.6 ± 2.6 years) completed the following tasks: opening a jar, reaching at shoulder height, overhead reaching, pouring water from a pitcher, eating with a spoon, and combing hair. Indwelling electromyography was collected from the anterior and posterior supraspinatus and superior, middle, and inferior infraspinatus. Tasks requiring high arm elevations (e.g. reaching at shoulder and overhead height) activated anterior supraspinatus between 21 and 28% MVC. The posterior supraspinatus consistently activated between 10 and 30% MVC across all tasks. All sub-regions of infraspinatus activated highly (between 18 and 25% MVC) in tasks requiring high arm elevations in flexion. These findings may be leveraged to define effective measures to increase rotator cuff function in daily tasks.