Passive immunotherapies for the next influenza pandemic.

Influenzavirus is among the most relevant candidates for a next pandemic. We review here the phylogeny of former influenza pandemics, and discuss candidate lineages. After briefly reviewing the other existing antiviral options, we discuss in detail the evidences supporting the efficacy of passive immunotherapies against influenzavirus, with a focus on convalescent plasma.

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

Plasma after both SARS-CoV-2 boosted vaccination and COVID-19 potently neutralizes BQ.1.1 and XBB.1.

Recent 2022 SARS-CoV-2 Omicron variants, have acquired resistance to most neutralizing anti-Spike monoclonal antibodies authorized, and the BQ.1.* sublineages are notably resistant to all authorized monoclonal antibodies. Polyclonal antibodies from individuals both vaccinated and recently recovered from Omicron COVID-19 (VaxCCP) could retain new Omicron neutralizing activity. Here we reviewed BQ.1.* virus neutralization data from 920 individual patient samples from 43 separate cohorts defined by boosted vaccinations (Vax) with or without recent Omicron COVID-19, as well as infection without vaccination (CCP) to determine level of BQ.1.* neutralizing antibodies and percent of plasma samples with neutralizing activity. More than 90 % of the plasma samples from individuals in the recently (within 6 months) boosted VaxCCP study cohorts neutralized BQ.1.1, and BF.7 with 100 % neutralization of WA-1, BA.4/5, BA.4.6 and BA.2.75. The geometric mean of the geometric mean 50 % neutralizing titres (GM (GMT50) were 314, 78 and 204 for BQ.1.1, XBB.1 and BF.7, respectively. Compared to VaxCCP, plasma sampled from COVID-19 naïve subjects who also recently (within 6 months) received at least a third vaccine dose had about half of the GM (GMT50) for all viral variants. Boosted VaxCCP characterized by either recent vaccine dose or infection event within 6 months represents a robust, variant-resilient, neutralizing antibody source against the new Omicron BQ.1.1, XBB.1 and BF.7 variants.

Attenuated cardiac autonomic function in humans with high-affinity hemoglobin and compensatory polycythemia.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15-20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

Consequences of group III/IV afferent feedback and respiratory muscle work on exercise tolerance in heart failure with reduced ejection fraction.

Exercise intolerance and exertional dyspnoea are the cardinal symptoms of heart failure with reduced ejection fraction (HFrEF). In HFrEF, abnormal autonomic and cardiopulmonary responses arising from locomotor muscle group III/IV afferent feedback is one of the primary mechanisms contributing to exercise intolerance. HFrEF patients also have pulmonary system and respiratory muscle abnormalities that impair exercise tolerance. Thus, the primary impetus for this review was to describe the mechanistic consequences of locomotor muscle group III/IV afferent feedback and respiratory muscle work in HFrEF. To address this, we first discuss the abnormal autonomic and cardiopulmonary responses mediated by locomotor muscle afferent feedback in HFrEF. Next, we outline how respiratory muscle work impairs exercise tolerance in HFrEF through its effects on locomotor muscle O2 delivery. We then discuss the direct and indirect evidence supporting an interaction between locomotor muscle group III/IV afferent feedback and respiratory muscle work during exercise in HFrEF. Last, we outline future research directions related to locomotor and respiratory muscle abnormalities to progress the field forward in understanding the pathophysiology of exercise intolerance in HFrEF. NEW FINDINGS: What is the topic of this review? This review is focused on understanding the role that locomotor muscle group III/IV afferent feedback and respiratory muscle work play in the pathophysiology of exercise intolerance in patients with heart failure. What advances does it highlight? This review proposes that the concomitant effects of locomotor muscle afferent feedback and respiratory muscle work worsen exercise tolerance and exacerbate exertional dyspnoea in patients with heart failure.

The oxygen transport cascade and exercise: Lessons from comparative physiology.

Studies of animal physiology not only provide valuable knowledge for the species in question, but also offer insights into human physiology. This thought is best highlighted by the 'Krogh Principle', which states "for many problems there is an animal on which it can be most conveniently studied". This graphical review focuses on three distinct stages of the oxygen transport cascade in which human exercise physiology knowledge has been enhanced by studies carried out in animal models. We begin by exploring ventilation, and the detrimental effects of cold, dry air on the airways in two sets of elite athletes, the cross-country skier and the racing sled dog. We then discuss the transport of oxygen via hemoglobin in humans and deer mice with relatively shifted oxygen dissociation curves. Finally, we consider the technical difficulties of measuring respiratory muscle blood flow in exercising humans and how an equine model can provide an understanding of the distribution of blood flow during exercise. These cases illustrate the complementary nature of physiological studies across species.

Sex-based limits to running speed in the human, horse and dog: The role of sexual dimorphisms.

Elite performing men continue to record faster record times in running events compared to women. These sex-based differences in running speed and endurance in humans are expected based on sexual dimorphisms that contribute to differences in the determinants of aerobic performance. Comparatively, the sexual dimorphisms contributing to sex-based differences in elite aerobic performance are not ubiquitous across other species that compete in running events. The purpose of this review is to offer a framework and model for ongoing discussions of the physiological determinants and ultimately limits of physical performance. The records for average running speed of champion athletes were delineated by sex for thoroughbred horses, greyhound dogs, and humans. Male and female performances within each of these species are being optimized by training, nutrition, and financial incentives, and are approaching a performance maximum. For horses and greyhounds breeding also plays a role. Analysis of athletic records shows that there is a sex-related difference of ~10% or more in elite athletic performance for humans; however, the upper limit of performance does not appear to be different between sexes for thoroughbred horses and greyhound dogs. In the context of the nil sex differences in running performance in thoroughbreds and greyhounds, we discuss the physiological role of sexual dimorphisms on sex-specific limits to running performance. We highlight that studies on both human and animal performance in athletic events stimulate critical physiological questions and drive novel research.

Muscle oxygenation during normoxic and hypoxic cycling exercise in humans with high-affinity haemoglobin.

NEW FINDINGS: What is the central question of this study? Do humans with high-affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near-infrared spectroscopy-derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. ABSTRACT: Recently, researchers in our laboratory have shown that humans with genetic mutations resulting in high-affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal-affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near-infrared spectroscopy-derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal-affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

SARS-CoV-2 Serologic Assays Dependent on Dual-Antigen Binding Demonstrate Diverging Kinetics Relative to Other Antibody Detection Methods.

Longitudinal studies assessing durability of the anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) humoral immune response have generated conflicting results. This has been proposed to be due to differences in patient populations, the lack of standardized methodologies, and the use of assays that measure distinct aspects of the humoral response. SARS-CoV-2 antibodies were serially measured in sera from a cohort of 44 well-characterized convalescent plasma donors over 120 days post-COVID-19 symptom onset, utilizing eight assays, which varied according to antigen source, the detected antibody isotype, and the activity measured (i.e., binding, blocking, or neutralizing). While the majority of assays demonstrated a gradual decline in antibody titers over the course of 120 days, the two electrochemiluminescence immunoassay Roche assays (Roche Diagnostics Elecsys anti-SARS-CoV-2 [qualitative, nucleocapsid based] and Roche Diagnostics Elecsys anti-SARS-CoV-2 S [semiquantitative, spike based]), which utilize dual-antigen binding for antibody detection, demonstrated stable and/or increasing antibody titers over the study period. This study is among the first to assess longitudinal, rather than cross-sectional, SARS-CoV-2 antibody profiles among convalescent COVID-19 patients, primarily using commercially available serologic assays with Food and Drug Administration emergency use authorization. We show that SARS-CoV-2 antibody detection is dependent on the serologic method used, which has implications for future assay utilization and clinical value.

Use of convalescent plasma in COVID-19 patients with immunosuppression.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.

Impact of isometric and concentric resistance exercise on pain and fatigue in fibromyalgia.

PURPOSE: The aim of this study was to determine the local and systemic effects of isometric and concentric muscle contractions on experimental pain and performance fatigability in people with and without fibromyalgia. METHODS: Forty-seven fibromyalgia (FM: 51.3 ± 12.3 year) and 47 control (CON: 52.5 ± 14.7 year) participants performed submaximal isometric and concentric exercise for 10 min with the right elbow flexors. Assessments before and after exercise included pressure pain thresholds (PPT) of the biceps and quadriceps, central pain summation, self-reported exercising arm and whole-body pain, and maximal voluntary isometric contraction (MVIC) of the right elbow flexors and left handgrip. RESULTS: People with FM experienced greater reductions in local fatigue (right elbow flexor MVIC: CON: - 4.0 ± 6.7%, FM: - 9.8 ± 13.8%; p = 0.013) and similar reductions in systemic fatigue (left handgrip MVIC: - 6.5 ± 10.2%; p < 0.001) as CON participants, which were not different by contraction type nor related to baseline clinical pain, perceived fatigue, or reported pain with exercise. Following exercise both groups reported an increase in PPTs at the biceps (pre: 205.5 ± 100.3 kPa, post: 219.0 ± 109.3 kPa, p = 0.004) only and a decrease in central pain summation (pre: 6.8 ± 2.9, post: 6.5 ± 2.9; p = 0.013). FM reported greater exercising arm pain following exercise (CON: 0.7 ± 1.3, FM: 2.9 ± 2.3; p < 0.001), and both groups reported greater arm pain following concentric (isometric: 1.4 ± 2.0, concentric: 2.2 ± 2.9; p = 0.001) than isometric exercise. Neither group reported an increase in whole-body pain following exercise. CONCLUSION: People with FM experienced greater performance fatigability in the exercising muscle compared to CON that was not related to central mechanisms of fatigue or pain. These results suggest changes in performance fatigability in FM may be due to differences occurring at the muscular level. TRIAL REGISTRATION #: NCT #: NCT03778385, December 19, 2018, retrospectively registered. IRB#: HR-3035.

Experiments of nature and within species comparative physiology.

This graphical review highlights a focused application of a key principle ('Krogh Principle') identified by Nobel-prize winning physiologist Professor August Krogh (1874-1949) that states "for many problems there is an animal on which it can be most conveniently studied". We apply the Krogh Principle to human physiology by proposing that "for many problems there is a unique group of humans on which it can be most conveniently studied". As such, we present 5 unique human case studies. Case 1 discusses whether signals from exercising muscles cause blood pressure to rise using a patient with a spinal cord lesion. Case 2 investigates the role of the sympathetic nervous system in the blood pressure response to exercise using patients who have undergone sympathectomy for hypertension. Case 3 asks whether increases in blood lactate are necessary for the non-linear increase in breathing with heavy exercise using patients with McArdle's disease. Case 4 applies fundamental scaling principles from comparative physiology to elite athletes to investigate the role of body size on maximal aerobic capacity. Finally, Case 5 describes our recent work that investigates whether a left shift in the oxygen hemoglobin dissociation curve can facilitate hypoxic exercise using patients with left-shifted hemoglobinopathies. In summary, we have expanded the inter-species message of the August Krogh Principle and highlighted the need to search for odd examples and experiments of nature. In this context, observations from unusual humans are a source of insights into physiology, which may be translated into therapeutic approaches for disease.

Convalescent Plasma for Infectious Diseases: Historical Framework and Use in COVID-19.

Convalescent plasma has emerged as a promising therapeutic agent for patients with coronavirus disease 2019 (COVID-19), has received emergency use authorization, and is being widely used during the COVID-19 pandemic. Passive antibody therapy via plasma or serum has been successfully used to treat infectious diseases for more than a century. Passive antibody administration is based on the presumption that convalescent plasma or serum contains therapeutic antibodies that can be passively transferred to the plasma recipient. There are numerous examples in which convalescent plasma has been used successfully as post-exposure prophylaxis and treatment of infectious diseases, including previous coronavirus outbreaks. In the context of the COVID-19 pandemic, convalescent plasma was demonstrated to be safe and potentially effective among patients infected with COVID-19. This review provides an overview of the historical uses of convalescent plasma therapy, summarizes current evidence for convalescent plasma use for COVID-19, and highlights future antibody therapies.

Attenuated activation of knee extensor muscles during fast contractions in older men and women.

AIM: Reduced physical function and increased risk of falls in older adults are accompanied by age-related reductions in torque development of leg muscles, although the mechanisms and potential sex differences are not understood. PURPOSE: To determine the mechanistic origins (neural vs. muscular) for the age-related reduction in torque development, we compared the peak rates of torque development (RTD) during electrically-evoked and fast voluntary contractions of the knee extensors between young and older men and women. METHODS: Sets of single- and double-pulse electrical stimulations evoked contractions of the knee extensor muscles in 20 young (23.0 ± 0.8 years; 10 women) and 20 older adults (78.2 ± 1.5 years; 10 women), followed by voluntary isometric knee extension contractions with torque development as fast as possible that matched the torque during electrically-evoked contraction (10-40% maximal torque). RESULTS: Peak RTD during fast-voluntary contractions was 41% less than electrically-evoked contractions (p < 0.001), but more so for older adults (44%) than young (38%, p = 0.04), with no sex differences. Peak RTD during fast-voluntary contractions was more variable between contractions for the older than young adults (77%MVC s-1 vs. 47%MVC s-1, p < 0.001). Additionally, older women exhibited greater variability than older men (81%MVC s-1 vs. 72%MVC s-1, p = 0.04) with no sex-related differences within the young adults. CONCLUSION: Older adults had slower and more variable RTD during voluntary contractions than young adults, particularly older women. The limited age-related differences in electrically-evoked RTD suggest the primary mechanism for the slower torque development of the knee extensor muscles in older men and women involve reduced neural activation.

Increased Cardiovascular Response to a 6-Minute Walk Test in People With Type 2 Diabetes.

BACKGROUND AND OBJECTIVE: Exercise is a cornerstone of management for type 2 diabetes; however, little is known about the cardiovascular (CV) response to submaximal functional exercise in people with type 2 diabetes. The aim of this study was to compare performance and CV response during a 6-minute walk test (6MWT) between people with type 2 diabetes and matched control subjects. METHODS: CV response and distance walked during the 6MWT were assessed in 30 people with type 2 diabetes, matched for age, body composition, physical activity, and estimated aerobic capacity with 34 control subjects (type 2 diabetes group: 16 men, 59.8 ± 8.8 years of age, 33.3 ± 10.9% body fat, physical activity of 7,968 ± 3,236 steps·day-1, estimated aerobic capacity 31.9 ± 11.1 mLO2·kg-1·min-1; control group: 19 men, 59.3 ± 8.8 years of age, 32.7 ± 8.5% body fat, physical activity 8,228 ± 2,941 steps·day-1, estimated aerobic capacity 34.9 ± 15.4 mLO2·kg-1·min-1). RESULTS: People with type 2 diabetes walked a similar distance (590 ± 75 vs. 605 ± 69 m; P = 0.458) compared with control subjects during the 6MWT and had similar ratings of perceived exertion (RPE) after the 6MWT (4.19 ± 1.56 vs. 3.65 ± 1.54, P = 0.147). However, at the end of the 6MWT, people with type 2 diabetes had a higher heart rate (108 ± 23 vs. 95 ± 18 beats·min-1; P = 0.048), systolic blood pressure (169 ± 26 vs. 147 ± 22 mmHg, P = 0.003), and rate-pressure product (18,762 ± 5,936 vs. 14,252 ± 4,330, P = 0.009) than control subjects. CONCLUSION: Although people with type 2 diabetes had similar performance and RPE during the 6MWT compared with control subjects, the CV response was greater for people with type 2 diabetes, indicating greater cardiac effort for similar perceived effort and performance of 6MWT. These data suggest that observation and prescription of exercise intensity should include both perceived effort and CV response.

Differential effects of aging and physical activity on corticospinal excitability of upper and lower limb muscles.

Corticospinal tract excitability can be altered by age, physical activity (PA), and possibly sex, but whether these effects differ between upper and lower limb muscles is unknown. We determined the influence of age, PA, and sex on corticospinal excitability of an upper limb and a lower limb muscle during submaximal contractions by comparing stimulus-response curves of motor evoked potentials (MEPs). Transcranial magnetic stimulation (TMS) was used to evoke stimulus-response curves in active muscles by incrementally increasing the stimulator intensity from below the active motor threshold (AMT) until a plateau in MEP amplitudes was achieved. Stimulus-response curves were analyzed from the first dorsal interosseous (FDI) of 30 young (23.9 ± 3.8 yr) and 33 older (72.6 ± 5.6 yr) men and women and the vastus lateralis (VL) of 13 young (23.2 ± 2.2 yr) and 25 older (72.7 ± 5.5 yr) men and women. Corticospinal excitability was determined by fitting the curves with a four-parameter sigmoidal curve and calculating the maximal slope (slopemax). PA was assessed with triaxial accelerometry, and participants were dichotomized into high-PA (>10,000 steps/day, n = 15) or low-PA (<10,000 steps/day, n = 43) groups. Young adults had larger FDI MEP amplitudes (% maximum amplitude of compound muscle action potential) at higher TMS intensities (120-150% AMT) and greater slopemax than older adults (P < 0.05), with no differences between high- and low-PA groups (P > 0.05). VL MEP amplitudes and slopemax, however, were lower in the high-PA than low-PA participants, with no age or sex differences. These data suggest that aging and PA, but not sex, differentially influence the excitability of the corticospinal tracts projecting to muscles of the upper compared with the lower limb. NEW & NOTEWORTHY Excitability of the corticospinal tract projecting to the first dorsal interosseous assessed with transcranial magnetic stimulation was reduced with age but independent of regular physical activity (steps/day) and sex of the individual. In contrast, corticospinal excitability of the vastus lateralis was not affected by age but was reduced in individuals achieving more than the physical activity recommendations of 10,000 steps/day. Aging and activity differentially affect corticospinal excitability of upper and lower limb muscles.