Peripheral Fatigue Research Articles

Diagnostic accuracy of Tensiomyography parameters for monitoring peripheral neuromuscular fatigue.

The diagnostic accuracy of tensiomyography (TMG) parameters compared to the gold standard in neuromuscular fatigue evaluation using voluntary and electrically induced muscle activation is unclear. This study aimed to investigate the diagnostic accuracy of TMG parameters to detect individual changes after interventions that were designed to induce central or peripheral fatigue. Nineteen males (age: 32.2±9.3years) performed two interventions, consisting of maintaining 25% of maximal voluntary contraction (MViC25%) and a 30s all-out cycling test (Wingate), respectively. TMG parameters, maximum voluntary contraction (PtMViC), voluntary activation (VA%) and electrically elicited double twitches (Dtw) were assessed on the knee extensors before (PRE), one minute (POST) and seven minutes after (POST7) the intervention. The diagnostic accuracy (AUC) of TMG parameters were evaluated in comparison to two criteria measures (PtMViC and Dtw). RM ANOVA revealed a significant interaction between the effects of intervention and time on VA% (p=0.001) and Dtw (p<0.001) but not for PtMViC (p=0.420). AUC showed that TMG parameters had a good ability in detecting muscular fatigue assessed by Dtw but not by PtMViC. The results of the current study suggest that TMG parameters can be used to monitor peripheral neuromuscular fatigue.

Preliminary efficacy, safety, and immunomodulatory effects of PT-112 from a phase 2 proof of concept study in patients (pts) with thymic epithelial tumors (TETs).

e20647 Background: Immune checkpoint inhibitors (ICIs) are associated with a high risk of immune-related adverse events (irAEs) in pts with TETs (thymoma and thymic carcinoma). PT-112, a novel inducer of immunogenic cell death, has demonstrated safety and efficacy in phase I trials. We present results of an unplanned interim analysis of a phase 2, NIH IRB-approved clinical trial to evaluate the clinical activity, tolerability, and correlative immunology of PT-112 in TETs (NCT05104736). Methods: Eligible pts with TETs with progression after prior platinum therapy were treated with PT-112 360 mg/m2 iv on days 1, 8 and 15 of a 28-day cycle until progression or development of intolerable toxicity. Prior history of autoimmunity (AI) or treatment with ICI was permitted. Primary objective is to determine the objective response rate. Immune activation was assessed by flow cytometry and multiplex immunofluorescence. Results: Ten pts have received treatment (median age 54, 3 females, 5 thymic carcinomas, 3 with prior TET-associated AI disease). Median number of prior systemic therapies is 2.5 (range, 1-4) and all pts have received cisplatin, paclitaxel, or both previously. Nine pts are evaluable for response, with stable disease in 8 (89%) and progressive disease in 1 (11%) pt. After a median potential follow-up of 7.4 months (mo) median progression-free survival is not reached in pts with thymoma and is 6.2 mo (95% CI: 1.8- 7.9 mo) in thymic carcinoma. All pts are evaluable for toxicity. The most common (all grades) treatment-related adverse events (TRAEs) are peripheral neuropathy (60%), anemia, fatigue and myalgias (each in 50%). Grade ≥ 3 TRAEs in more than one patient include anemia (30%) and neutropenia (20%). Two (20%) pts experienced relapse of AI: ocular myasthenia and immune cytopenias. The most common reason for treatment hold is peripheral neuropathy (40%). Treatment was discontinued due to TRAE (peripheral neuropathy) in 1 (10%) pt. There are no treatment related deaths. Treatment was associated with an increase in CD8+ T cells, activated CD4+ T cells and NK cells in peripheral blood. There was an increase in pro-inflammatory serum analytes (IFNg, TNFa, sCD27:sCD40L and sCD73) and a decrease in immunosuppressive analytes (VEGF, sCD40L and TGFb) compared with baseline. Paired tumor biopsies are being analyzed by multiplex immunofluorescence and results will be presented. Conclusions: PT-112 is safe and clinically active in pts with recurrent TETs. In contrast to ICIs, no new irAEs were observed. Immune analyses show evidence of early treatment-related immune activation and support the rationale underlying this novel treatment approach for TETs. Enrollment is ongoing with an accrual ceiling of 53. These initial results support further evaluation of PT-112 in TETs as monotherapy and in combination with other immunomodulatory interventions. Clinical trial information: NCT05104736 .

FRI-359 - Golexanolone, a GABA receptor-modulating steroid antagonist, improves peripheral inflammation, fatigue, locomotor gait, motor incoordination and short-term memory in rats with cholestasis and hepatic encephalopathy due to bile duct ligation

FRI-359 - Golexanolone, a GABA receptor-modulating steroid antagonist, improves peripheral inflammation, fatigue, locomotor gait, motor incoordination and short-term memory in rats with cholestasis and hepatic encephalopathy due to bile duct ligation

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

6032 Background: An important unmet need in treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-PD-1 antibody (PD-1 Ab). Recent retrospective studies suggest that previous treatment with Immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. This phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab (PTX+bwCmab) for patients with R/M-HNSCC previously treated with both platinum and PD-1 Ab. Methods: This is a single-arm, multicenter phase II trial. Key eligibility criteria were R/M-HNSCC; previous treatment with both platinum-based chemotherapy and PD-1 Ab; ECOG performance status 0 or 1; measurable disease per RECIST v1.1; and adequate organ function. PTX+bwCmab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days. Primary endpoint was objective response rate (ORR). We set a null hypothesis of 10% and alternative of 30% with a one-sided alfa of 0.05 and power of 90%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (CTCAE v5.0). Binominal confidence intervals (CIs) for ORR and DCR were estimated by the exact method. Time-to-event analyses were calculated by the Kaplan-Meier method with 95% CIs. Results: Between August 2020 and August 2022, 35 patients were enrolled, of whom 32 were evaluable for response. ORR was 68.7% (95% CI: 49.9-83.8), which met the prespecified criteria for the primary endpoint of ORR. With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.7 and 13.4 months, respectively. DCR was 93.7% (95% CI: 79.1-99.2). The most common AEs of any grade were skin rash (65%), peripheral nerve neuropathy (45%), neutropenia (40%), fatigue (40%) and paronychia (37%). Grade 3 and 4 adverse events included neutropenia (34%), mucositis (8%), pneumonitis (8%) and febrile neutropenia (5%). These AEs were manageable and no treatment-related death within 30 days was observed. Conclusions: PTX+bwCmab showed highly encouraging efficacy and tolerability in RM-HNSCC patients previously treated with both platinum and PD-1 Ab. Although preliminary, these results suggest that this is a promising treatment option for this hitherto untreatable patient group. Further evaluation is warranted. Clinical trial information: jRCTs051200040 .

Sex differences in the intensity–duration relationships of the severe- and extreme-intensity exercise domains

ABSTRACT Extreme-intensity exercise is described by W′ext (analogous to J′ for isometric exercise) that is smaller than W′ of severe-intensity exercise (W′sev) in males. Sex differences in exercise tolerance appear to diminish at near-maximal exercise, however, there is evidence of greater contributions of peripheral fatigue (i.e. potentiated twitch force; Qpot) in males during extreme-intensity exercise. Therefore, the current study tested the hypotheses that J′ext would not be different between males and females, however, males would exhibit a greater reduction in neuromuscular function (i.e. maximal voluntary contraction, MVC; Qpot) following extreme-intensity exercise. Seven males and 7 females completed three severe- (Tlim: 2–4 min, S3; 5–8 min, S2; 9–15 min, S1) and three extreme-intensity (70, 80, 90%MVC) knee-extension bouts. MVC and Qpot relative to baseline were compared at task failure and at 150 s of recovery. J′ext was significantly less than J′sev in males (2.4 ± 1.2kJ vs 3.9 ± 1.3kJ; p = 0.03) and females (1.6 ± 0.8kJ vs 2.9 ± 1.7kJ; p = 0.05); however, there were no sex differences in J′ext or J′sev. MVC (%Baseline) was greater at task failure following extreme-intensity exercise (76.5 ± 20.0% vs 51.5 ± 11.5% in males, 75.7 ± 19.4% vs 66.7 ± 17.4% in females), but was not different at 150 s of recovery (95.7 ± 11.8% in males, 91.1 ± 14.2% in females). Reduction in Qpot, however, was greater in males (51.9 ± 16.3% vs 60.6 ± 15.5%) and was significantly correlated with J′ext (r 2 = 0.90, p < 0.001). Although there were no differences in the magnitude of J′ext, differences in MVC and Qpot are evidence of sex-specific responses and highlight the importance of appropriately characterizing exercise intensity regarding exercise domains when comparing physiological responses in males and females. Highlights We have previously shown evidence that extreme-intensity dynamic exercise is described by W′ext in males and smaller than W′sev. We currently tested for potential sex differences in J′ext (isometric analogue to W′) and neuromuscular responses (i.e. maximal voluntary contraction, MVC; potentiated twitch force, Qpot) during extreme-intensity exercise. J′ext and extreme-intensity exercise tolerance was not different between males and females. The reduction in MVC was not different across extreme-intensity exercise across males and females, whereas the reduction in Qpot was greater in males following all extreme-intensity exercises, although not after exercise at 90%MVC. Together, although extreme-intensity exercise tolerance is not different, these data highlight differences in the contributing mechanisms of fatigue during severe- and extreme-intensity exercise between males and females.

The Effect of Metformin on Chemotherapy-Induced Toxicities in Non-diabetic Breast Cancer Patients: A Randomised Controlled Study

Breast cancer patients treated with adriamycin-cyclophosphamide plus paclitaxel (AC-T) are often challenged with serious adverse effects for which no effective therapies are available. Here, we investigated whether metformin, an antidiabetic drug with additional pleiotropic effects could favourably offset AC-T induced toxicities. Seventy non-diabetic breast cancer patients were randomised to receive either AC-T (adriamycin 60 mg/m2 + cyclophosphamide 600 mg/m2 × 4 cycles Q21 days, followed by weekly paclitaxel 80 mg/m2 × 12 cycles) alone or AC-T plus metformin (1700 mg/day). Patients were assessed regularly after each cycle to record the incidence and severity of adverse events based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Moreover, baseline echocardiography and ultrasonography were done and repeated after the end of neoadjuvant therapy. Addition of metformin to AC-T resulted in significantly less incidence and severity of peripheral neuropathy, oral mucositis, and fatigue (p < 0.05) compared to control arm. Moreover, the left ventricular ejection fraction (LVEF%) in the control arm dropped from a mean of 66.69 ± 4.57 to 62.2 ± 5.22% (p = 0.0004) versus a preserved cardiac function in the metformin arm (64.87 ± 4.84to65.94 ± 3.44%, p = 0.2667). Furthermore, fatty liver incidence was significantly lower in metformin compared with control arm (8.33% vs 51.85%, p = 0.001). By contrast, haematological disturbances caused by AC-T were preserved after concurrent metformin administration (p > 0.05). Metformin offers a therapeutic opportunity for controlling toxicities caused by neoadjuvant chemotherapy in non-diabetic breast cancer patients. This randomised controlled trial was registered on November 20, 2019 in ClinicalTrials.gov under registration number: NCT04170465.

Physical activity levels respiratory and peripheral muscle strength and pulmonary function in young post-COVID-19 patients : Across-sectional study.

Coronavirus disease 2019 (COVID-19) causes permanent problems, even mild severity. The long-term consequences of COVID-19 are still unknown. This study aimed to investigate physical activity levels, respiratory and peripheral muscle strength, and pulmonary function in the long term in young adult COVID-19patients who recovered from mild disease. This cross-sectional study was carried out at least 6 months after the COVID-19 diagnosis, 54 patients with COVID-19 (median age: 20years) and 46controls (median age: 21years) were compared. Functional status (post-COVID-19 functional status scale), respiratory (maximum inspiratory and expiratory pressures (MIP, MEP)) and peripheral muscle strength (dynamometer), pulmonary function (Spirometry), dyspnea and fatigue (modified Borg scale), and physical activity levels (International Physical Activity Questionnaire) were evaluated. NCT05381714. Patients with COVID-19 measured and percent predicted MIP and MEP were statistically decreased compared with the controls (p < 0.05). Shoulder abductors muscle strength (p < 0.001) and the number of individuals with low physical activity levels were significantly higher in patients compared with controls (p = 0.048). Pulmonary function, quadriceps muscle strength, exertional dyspnea, and fatigue scores were similar in groups (p > 0.05). Respiratory and peripheral muscle strength and physical activity levels are adversely affected in patients with COVID-19, even though the patients were mildly affected in the long term. Also, symptoms such as dyspnea and fatigue may persist. Therefore, these parameters should be evaluated in the long term, even in young adults who are mildly affected by COVID-19.

The Effects of Anchor Schemes on Performance Fatigability, Neuromuscular Responses and the Perceived Sensations That Contributed to Task Termination.

The present study examined the effect of anchor schemes on the time to task failure (TTF), performance fatigability, neuromuscular responses, and the perceived sensations that contributed to task termination following the sustained, isometric forearm flexion tasks. Eight women completed sustained, isometric forearm flexion tasks anchored to RPE = 8 (RPEFT) and the torque (TRQFT) that corresponded to RPE = 8. The subjects performed pre-test and post-test maximal isometric contractions to quantify performance fatigability and changes in electromyographic amplitude (EMG AMP) and neuromuscular efficiency (NME). In addition, the subjects completed a post-test questionnaire (PTQ) to quantify the contributions of perceived sensations to task termination. Repeated measure ANOVAs were used to assess the mean differences for TTF, performance fatigability, and neuromuscular responses. Wilcoxon Signed Rank Tests were used to assess the differences between anchor schemes for the average values from the PTQ item scores. For TTF, the RPEFT was longer than the TRQFT (174.9 ± 85.6 vs. 65.6 ± 68.0 s; p = 0.006). Collapsed across the anchor scheme, there were decreases in torque (23.7 ± 5.5 Nm vs. 19.6 ± 4.9 Nm; p < 0.001) and NME (1.00 ± 0.00 vs. 0.76 ± 0.15; p = 0.003). There were no significant (p > 0.577) changes for EMG AMP. For the PTQ, there were no differences (p > 0.05) between anchor schemes. There were, however, inter-individual differences in the response scores. The current findings indicated that performance fatigability was likely due to peripheral fatigue (based on NME), not central fatigue (based on EMG AMP). Furthermore, the use of a PTQ may serve as a simple tool to assess the contributions of perceived sensations to task termination.

The Prevalence of Chest Infection in Patients with Heart Failure in Al-Wahadah Teaching Hospital, Dhamar, Yemen

Background: Heart failure is a common clinical manifestation of most organic heart diseases that progress to the end stage. Patients with heart failure are often accompanied by secondary conditions such as pulmonary circulatory congestion and pulmonary edema, which can lead to dyspnea, gas exchange disorders, and other consequences, creating certain conditions for pathogens to invade and colonize the lungs. Therefore, patients with heart failure may have higher risk of pulmonary infection. Aim: This study aimed to assess the prevalence of chest infection among patients with heart failure and to determine the characteristics of the patients with heart failure who had chest infection and the potential risk factors. Methods: A retrospective, descriptive cross-sectional study was carried out at internal medicine department, Al-Wahdah Teaching Hospital, Dhamar, Yemen over six months (June – December 2022). A total of 100 patients were enrolled in our study. A semi-structured questionnaire was designed and used for data collection. Results: A total of 100 heart failure patients including 53 (53%) males, and 47 (47%) females were successfully enrolled in this study. The majority of participated patients were of age group 40 – 60 years (55%), and were of rural residence (83%). Chest infection was documented in approximately two-thirds of included patients (63%). Chest infection was documented in majority of patients who were smokers, Qat chewer, shamma intakes, being obese, had cardiomyopathy, as well as those patients who had dyspnea of NYHA class III &amp; IV, orthopnea, PND, productive cough, high sputum amount, whitish sputum color, peripheral chest pain, fatigue, sweating, fever and high WBC count, such associations were significant statistically. Conclusion: This study revealed that, chest infection in heart failure patients was common with overall prevalence of (63%) among included patients this study was. Based on this, an early prevention and intervention measures should be taken to reduce pulmonary infections in patients with heart failure.

From diagnosis to treatment of post-polio syndrome: A case study

Introduction: Acute anterior poliomyelitis (AAP) can affect people of any age, despite being uncommon before six months. The viral invasion destroys the lower motor neurons of the spinal cord, brain, and brainstem. As a result, it leads to partial or complete flaccid and asymmetrical paralysis of the lower limb and spine muscles. Big names like Frida Kahlo and US President Franklin D Roosevelt were diagnosed with polio. Case Report: We present the case of a patient with AAP diagnosed at two years of age. As an adult, he gave osteomyoarticular sequelae, insomnia, new central (adynamia), peripheral fatigue, cold intolerance, joint and neuropathic pain. The patient received a clinical diagnosis of post-polio syndrome (PPS) after fulfilling Dalakas criteria. The physical examination showed some hallmarks of AAP, in addition to those primarily affected by PPS. Conclusion: Post-polio syndrome is a disorder characterized by new neuromuscular deficits that present years after the resolution of polio infection. However, far beyond the physical pain, the psychosocial impact is staggering. Therefore, in addition to surgical intervention and physical therapy, attention should be paid to the psychological follow-up of this patient, who is most often elderly.

Functional Resistance Training With Viscous and Elastic Devices: Does Resistance Type Acutely Affect Knee Function?

Functional resistance training (FRT) during walking is an emerging approach for rehabilitating individuals with neuromuscular or orthopedic injuries. During FRT, wearable exoskeleton/braces can target resistance to a weakened leg joint; however, the resistive properties of the training depend on the type of resistive elements used in the device. Hence, this study was designed to examine how the biomechanical and neural effects of functional resistance training differ with viscous and elastic resistances during both treadmill and overground walking. Fourteen able-bodied individuals were trained on two separate sessions with two devices that provided resistance to the knee (viscous and elastic) while walking on a treadmill. We measured gait biomechanics and muscle activation during training, as well as kinematic aftereffects and changes in peripheral fatigue and neural excitability after training. We found the resistance type differentially altered gait kinetics during training-elastic resistance increased knee extension during stance while viscous resistance primarily affected swing. Also, viscous resistance increased power generation while elastic resistance could increase power absorption. Both devices resulted in significant kinematic and neural aftereffects. However, overground kinematic aftereffects and neural excitability did not differ between devices. Different resistance types can be used to alter gait biomechanics during training. While there were no resistance-specific changes in acute neural adaptation following training, it is still possible that prolonged and repeated training could produce differential effects. Resistance type alters the kinetics of functional resistance training. Prolonged and repeated training sessions on patients will be needed to further measure the effects of these devices.

Exacerbated central fatigue and reduced exercise capacity in early-stage breast cancer patients treated with chemotherapy

PurposeThe present study aimed to characterize the etiology of exercise-induced neuromuscular fatigue and its consequences on the force-duration relationship to provide mechanistic insights into the reduced exercise capacity characterizing early-stage breast cancer patients.MethodsFifteen early-stage breast cancer patients and fifteen healthy women performed 60 maximal voluntary isometric quadriceps contractions (MVCs, 3 s of contraction, 2 s of relaxation). The critical force was determined as the mean force of the last six contractions, while W’ was calculated as the force impulse generated above the critical force. Quadriceps muscle activation during exercise was estimated from vastus lateralis, vastus medialis and rectus femoris EMG. Central and peripheral fatigue were quantified via changes in pre- to postexercise quadriceps voluntary activation (ΔVA) and quadriceps twitch force (ΔQTw) evoked by supramaximal electrical stimulation, respectively.ResultsEarly-stage breast cancer patients demonstrated lower MVC than controls preexercise (− 15%, P = 0.022), and this reduction persisted throughout the 60-MVC exercise (− 21%, P = 0.002). The absolute critical force was lower in patients than in controls (144 ± 29N vs. 201 ± 47N, respectively, P < 0.001), while W’ was similar (P = 0.546), resulting in lower total work done (− 23%, P = 0.001). This was associated with lower muscle activation in the vastus lateralis (P < 0.001), vastus medialis (P = 0.003) and rectus femoris (P = 0.003) in patients. Immediately following exercise, ΔVA showed a greater reduction in patients compared to controls (− 21.6 ± 13.3% vs. − 12.6 ± 7.7%, P = 0.040), while ΔQTw was similar (− 60.2 ± 13.2% vs. − 52.8 ± 19.4%, P = 0.196).ConclusionThese findings support central fatigue as a primary cause of the reduction in exercise capacity characterizing early-stage breast cancer patients treated with chemotherapy.Clinical trials registration No. NCT04639609—November 20, 2020.

Utilizing the RPE-Clamp model to examine interactions among factors associated with perceived fatigability and performance fatigability in women and men.

The purpose of the present study was to examine the interactions between perceived fatigability and performance fatigability in women and men by utilizing the RPE-Clamp model to assess the fatigue-induced effects of a sustained, isometric forearm flexion task anchored to RPE = 8 on time to task failure (TTF), torque, and neuromuscular responses. Twenty adults (10 men and 10 women) performed two, 3s forearm flexion maximal voluntary isometric contractions (MVICs) followed by a sustained, isometric forearm flexion task anchored to RPE = 8 using the OMNI-RES (0-10) scale at an elbow joint angle of 100°. Electromyographic amplitude (EMG AMP) was recorded from the biceps brachii. Torque and EMG AMP values resulting from the sustained task were normalized to the pretest MVIC. Neuromuscular efficiency was defined as NME = normalized torque/normalized EMG AMP. Mixed factorial ANOVAs and Bonferroni corrected dependent t tests and independent t tests were used to examine differences across time and between sex for torque and neuromuscular parameters. There were no differences between the women and men for the fatigue-induced decreases in torque, EMG AMP, or NME, and the mean decreases (collapsed across sex) were 50.3 ± 8.6 to 2.8 ± 2.9% MVIC, 54.7 ± 12.0 to 19.6 ± 5.3% MVIC, and 0.94 ± 0.19 to 0.34 ± 0.16, respectively. Furthermore, there were no differences between the women and men for TTF (251.8 ± 74.1vs.258.7 ± 77.9s). The results suggested that the voluntary reductions in torque to maintain RPE and the decreases in NME were likely due to group III/IV afferent feedback from peripheral fatigue that resulted in excitation-contraction coupling failure.

Sex differences in quadriceps and inspiratory muscle fatigability following high-intensity cycling.

As females have been hypothesized to have more fatigue resistant inspiratory muscles, this study aimed to compare the development of inspiratory and leg muscle fatigue between males and females following high-intensity cycling. Cross-sectional comparison. 17 healthy young males (27 ± 6 years, V̇O2peak 55 ± 10 ml･min-1･kg-1) and females (25 ± 4 years, V̇O2peak 45 ± 7 ml･min-1･kg-1) cycled until exhaustion at 90% of the peak power output achieved during an incremental test. Changes in quadriceps and inspiratory muscle function were assessed via maximal voluntary contractions (MVC) and assessments of contractility via electrical stimulation of the femoral nerve and cervical magnetic stimulation of the phrenic nerves. Time to exhaustion was similar between sexes (p = 0.270, 95% CI -2.4 - 0.7 min). MVC of the quadriceps was lower after cycling for males (83.9 ± 11.5% vs. 94.0 ± 12.0% of baseline for females, p = 0.018). Reductions in twitch forces were not different between sexes for the quadriceps (p = 0.314, 95% CI -5.5 - 16.6 percent-points) or inspiratory muscles (p = 0.312, 95% CI -4.0 - 2.3 percent-points). Changes in inspiratory muscle twitches were unrelated to the different measures of quadriceps fatigue. Females incur similar peripheral fatigue in the quadriceps and inspiratory muscles compared with men following high-intensity cycling, despite smaller reduction in voluntary force. This small difference alone does not seem sufficient to warrant different training strategies to be recommended for women.

The Role of Contraction Mode in Determining Exercise Tolerance, Torque-Duration Relationship, and Neuromuscular Fatigue.

Critical torque (CT) and work done above it ( W ') are key predictors of exercise performance associated with neuromuscular fatigue. The aim of the present study was to understand the role of the metabolic cost of exercise in determining exercise tolerance, CT and W ', and the mechanisms of neuromuscular fatigue. Twelve subjects performed four knee extension time trials (6, 8, 10, and 12 min) using eccentric, isometric, or concentric contractions (3-s on/2-s off at 90°·s -1 or 30°·s -1 ) to modulate the metabolic cost of exercise. Exercise performance was quantified by total impulse and mean torque. Critical torque and W ' were determined using the linear relationship between total impulse and contraction time. Cardiometabolic, neuromuscular, and ventilatory responses were quantified. Neuromuscular function was evaluated by maximal voluntary contraction, resting potentiated single/doublet electrical stimulations, and superimposed single electrical stimulation to quantify neuromuscular, peripheral, and central fatigue, respectively. Compared with isometric exercise, total impulse (+36% ± 21%; P < 0.001), CT (+27% ± 30%; P < 0.001), and W ' (+67% ± 99%; P < 0.001) were increased during eccentric exercise, whereas total impulse (-25% ± 7%; P < 0.001), critical torque (-26% ± 15%; P < 0.001), and W ' (-18% ± 19%; P < 0.001) were reduced in concentric exercise. Conversely, the metabolic response and the degree of peripheral fatigue were reduced during eccentric exercise, whereas they were increased during concentric exercise. Critical torque was negatively associated with oxygen consumption gain ( R2 = 0.636; P < 0.001), and W ' was negatively associated with rates of neuromuscular and peripheral fatigue indices ( R2 = 0.252-0.880; P < 0.001). The contraction mode influenced both CT and W ', and consequently exercise tolerance, indicating that the metabolic cost of contraction played a key role.

Does Lactate-Guided Threshold Interval Training within a High-Volume Low-Intensity Approach Represent the "Next Step" in the Evolution of Distance Running Training?

The aim of the present study was to describe a novel training model based on lactate-guided threshold interval training (LGTIT) within a high-volume, low-intensity approach, which characterizes the training pattern in some world-class middle- and long-distance runners and to review the potential physiological mechanisms explaining its effectiveness. This training model consists of performing three to four LGTIT sessions and one VO2max intensity session weekly. In addition, low intensity running is performed up to an overall volume of 150-180 km/week. During LGTIT sessions, the training pace is dictated by a blood lactate concentration target (i.e., internal rather than external training load), typically ranging from 2 to 4.5 mmol·L-1, measured every one to three repetitions. That intensity may allow for a more rapid recovery through a lower central and peripheral fatigue between high-intensity sessions compared with that of greater intensities and, therefore, a greater weekly volume of these specific workouts. The interval character of LGTIT allows for the achievement of high absolute training speeds and, thus, maximizing the number of motor units recruited, despite a relatively low metabolic intensity (i.e., threshold zone). This model may increase the mitochondrial proliferation through the optimization of both calcium and adenosine monophosphate activated protein kinase (AMPK) signaling pathways.

Cardiopulmonary Exercise Testing in Post-COVID-19 Patients: Where Does Exercise Intolerance Come From?

Post-COVID-19 exercise intolerance is poorly understood. Cardiopulmonary exercise testing (CPET) can identify the underlying exercise limitations. To evaluate the source and magnitude of exercise intolerance in post-COVID-19 subjects. Cohort study assessing subjects with different COVID-19 illness severities and a control group selected by propensity score matching. In a selected sample with CPET prior to viral infection, before and after comparisons were performed. Level of significance was 5% in the entire analysis. One hundred forty-four subjects with COVID-19 were assessed (median age: 43.0 years, 57% male), with different illness severities (60% mild, 21% moderate, 19% severe). CPET was performed 11.5 (7.0, 21.2) weeks after disease onset, with exercise limitations being attributed to the peripheral muscle (92%), and the pulmonary (6%), and cardiovascular (2%) systems. Lower median percent-predicted peak oxygen uptake was observed in the severe subgroup (72.2%) as compared to the controls (91.6%). Oxygen uptake differed among illness severities and controls at peak and ventilatory thresholds. Conversely, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse were similar. Subgroup analysis of 42 subjects with prior CPET revealed significant reduction in only peak treadmill speed in the mild subgroup and in oxygen uptake at peak and ventilatory thresholds in the moderate/severe subgroup. By contrast, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse did not change significantly. Peripheral muscle fatigue was the most common exercise limitation etiology in post-COVID-19 patients regardless of the illness severity. Data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components.

A Randomized Cross-Over Analysis of the 6-Minute Step Test When Administered in Different Music Listening Conditions to Healthy Young Adults.

The 6-Minute Step Test (6-MST) is a simple, inexpensive field test that is increasingly used to evaluate cardiorespiratory fitness. Whether sufficient performance is revealed by this test and the effect on it of motivational factors such as music is unknown. In this cross-sectional, randomized, and crossover research design, we aimed to analyze 6-MST performance and test outcomes in different music-related auditory conditions of non-musical/non-rhythmic [NM/NR], musical/non-rhythmic [M/NR], and musical/rhythmic [M/R]). We had 38 healthy young adults (M age = 21.21, SD = 1.21years; 60% male) complete all tests, and we measured their number of steps taken, heart rate, blood pressure, respiratory rate, peripheral oxygen saturation, perceived dyspnea, and fatigue on the modified Borg scale. We recorded individually calculated submaximal values according to heart rate reached after three tests. The number of steps increased in the M/R condition relative to other conditions (p = 0.003), and the amount of change in perceived leg fatigue was also higher in the M/R condition (p < 0.017). Despite variable test performances in different auditory conditions, we found no statistically significant difference in cardiovascular fitness and symptoms (p > 0.05). We concluded that the 6-MST is a useful tool for assessing maximum cardiac tolerance, especially if administered while listening to rhythmic music.

Zanidatamab + chemotherapy as first-line treatment for HER2-expressing metastatic gastroesophageal adenocarcinoma (mGEA).

347 Background: Zanidatamab (zani) is an anti-HER2 bispecific antibody against ECD4 and ECD2 with demonstrated activity and tolerability in a range of HER2-expressing cancers. This Phase (Ph) 2 study (NCT03929666) evaluates zani in combination with chemotherapy (chemo) as first-line treatment for patients (pts) with advanced HER2-expressing mGEA. Methods: Eligible pts for this ongoing, open-label study had not received any prior systemic therapy for mGEA. Pts received zani + physician’s choice of multi-agent chemo (mFOLFOX6, CAPOX, or FP). Antidiarrheal prophylaxis for cycle 1 was added after the first 25 pts were treated. Following demonstration of tolerability of the regimens in an initial safety cohort, the primary study objective was to evaluate antitumor activity. Results: Pts were enrolled between Aug 29, 2019 and Feb 18, 2022 with a data cutoff of July 28, 2022 (N=46 pts; zani + mFOLFOX6 [24], zani + CAPOX [20], or zani + FP [2]). Median age was 58 yrs; 85% male; 42 pts (91%) had HER2+ tumors (IHC 3+ or 2+ with ISH-positivity) based on central testing. Median duration of follow-up among all 46 pts was 21.5 months (mo) and 20 pts (43%) remain on treatment. In 38 response-evaluable pts with HER2+ tumors, confirmed objective response rate (cORR) was 79% (95% CI: 63-90%) and disease control rate was 92% (95% CI: 79-98%); 3 pts achieved complete response. Median duration of response (DOR) was 20.4 mo (95% CI: 6.8-not estimable [NE]), with 57% (17/30) pts having an ongoing response at data cut-off (1 pt has ongoing response &gt;29 months). In all 42 pts with HER2+ tumors, median progression-free survival (PFS) was 12.5 mo (95% CI: 7.1-NE) and median overall survival (OS) was not yet reached. Survival rate at 18 mo was estimated to be 87.3%. The most common (≥25% pts) treatment-related (zani and/or chemo) adverse events (TRAE) in all pts were diarrhea, nausea, peripheral sensory neuropathy, decreased appetite, fatigue, vomiting, and hypokalemia. Diarrhea was the most common Gr3+ TRAE, lasting a median (interquartile range) of 3 (2-5) days, with the majority of events occurring in cycle 1; incidence of all Gr3+ events was 56% in 25 pts who did not receive prophylaxis and 14% in 21 pts who did. There were no treatment-related deaths. Conclusions: In pts with HER2+ mGEA, zani + chemo is a highly active treatment regimen with a manageable safety profile. This maturing data set demonstrates durable disease control with encouraging cORR, DOR, PFS and OS results. A global Ph 3 study (HERIZON-GEA-01; NCT05152147) evaluating zani in combination with physician’s choice of standard chemo with or without the PD-1 inhibitor, tislelizumab, for first-line treatment of advanced HER2+ mGEA is currently enrolling. Clinical trial information: NCT03929666 .

Foot Cooling between Interval Bouts Enhances Repeated Lower Limb Power Performance: The Role of Delaying Fatigue.

This study aimed to investigate whether interbout foot cooling (FC) may enhance repeated lower limb power performance and the corresponding physiological responses based on interset FC, which has been demonstrated to enhance leg-press performance. In a repeated-measures crossover design, ten active men (aged 21.5 ± 1.5 years, exercising >3 times per week) performed four bouts of 10-s cycle ergometer sprints with interbout FC at 10°C water for 2.5 min or non-cooling (NC) with a 5-day interval. The results indicated that FC elicited higher total work (27.57 ± 5.66 kJ vs. 26.55 ± 5.76 kJ) and arousal scores than NC (p < 0.05). Furthermore, under the NC condition, participants decreased mean power (p < 0.05) with no alteration of vastus lateralis (VL) electromyography (EMG) activities after the second bout; whereas under the FC condition, participants maintained steady mean power accompanied by increased VL EMG activities in the last two bouts (p < 0.05). Jointly, participants had higher mean power ([3rd = 10.14 ± 1.15 vs. 9.37 ± 1.30; 4th = 9.79 ± 1.22 vs. 9.23 ± 1.27] W/kg) and VL EMG activities in the last two bouts under the FC than NC condition (p < 0.05). However, perceived exertion and the heart rate were comparable between the two conditions (p > 0.05). In conclusion, interbout FC elicited a higher arousal level and repeated lower limb power performance, which could be explained by delaying peripheral fatigue via increasing excitatory drive and recruiting additional motor units to compensate for fatigue-related responses and power decrements.