Walking naturally after spinal cord injury using a brain-spine interface.

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain-spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.

Transcatheter Arterialization of Deep Veins in Chronic Limb-Threatening Ischemia.

BACKGROUND: Approximately 20% of patients with chronic limb-threatening ischemia have no revascularization options, leading to above-ankle amputation. Transcatheter arterialization of the deep veins is a percutaneous approach that creates an artery-to-vein connection for delivery of oxygenated blood by means of the venous system to the ischemic foot to prevent amputation. METHODS: We conducted a prospective, single-group, multicenter study to evaluate the effect of transcatheter arterialization of the deep veins in patients with nonhealing ulcers and no surgical or endovascular revascularization treatment options. The composite primary end point was amputation-free survival (defined as freedom from above-ankle amputation or death from any cause) at 6 months, as compared with a performance goal of 54%. Secondary end points included limb salvage, wound healing, and technical success of the procedure. RESULTS: We enrolled 105 patients who had chronic limb-threatening ischemia and were of a median age of 70 years (interquartile range, 38 to 89). Of the patients enrolled, 33 (31.4%) were women and 45 (42.8%) were Black, Hispanic, or Latino. Transcatheter arterialization of the deep veins was performed successfully in 104 patients (99.0%). At 6 months, 66.1% of the patients had amputation-free survival. According to Bayesian analysis, the posterior probability that amputation-free survival at 6 months exceeded a performance goal of 54% was 0.993, which exceeded the prespecified threshold of 0.977. Limb salvage (avoidance of above-ankle amputation) was attained in 67 patients (76.0% by Kaplan-Meier analysis). Wounds were completely healed in 16 of 63 patients (25%) and were in the process of healing in 32 of 63 patients (51%). No unanticipated device-related adverse events were reported. CONCLUSIONS: We found that transcatheter arterialization of the deep veins was safe and could be performed successfully in patients with chronic limb-threatening ischemia and no conventional surgical or endovascular revascularization treatment options. (Funded by LimFlow; PROMISE II study ClinicalTrials.gov number, NCT03970538.).

Simultaneous control of forward and backward locomotion by spinal sensorimotor circuits.

Mammals walk in different directions, such as forward and backward. In human infants/adults and decerebrate cats, one leg can walk forward and the other backward simultaneously on a split-belt treadmill, termed hybrid or bidirectional locomotion. The purpose of the present study was to determine if spinal sensorimotor circuits generate hybrid locomotion and if so, how the limbs remain coordinated. We tested hybrid locomotion in 11 intact cats and in five following complete spinal thoracic transection (spinal cats) at three treadmill speeds with the hindlimbs moving forward, backward or bidirectionally. All intact cats generated hybrid locomotion with the forelimbs on a stationary platform. Four of five spinal cats generated hybrid locomotion, also with the forelimbs on a stationary platform, but required perineal stimulation. During hybrid locomotion, intact and spinal cats positioned their forward and backward moving hindlimbs caudal and rostral to the hip, respectively. The hindlimbs maintained consistent left-right out-of-phase alternation in the different stepping directions. Our results suggest that spinal locomotor networks generate hybrid locomotion by following certain rules at phase transitions. We also found that stance duration determined cycle duration in the different locomotor directions/conditions, consistent with a common rhythm-generating mechanism for different locomotor directions. Our findings provide additional insight on how left-right spinal networks and sensory feedback from the limbs interact to coordinate the hindlimbs and provide stability during locomotion in different directions. KEY POINTS: Terrestrial mammals can walk forward and backward, which is controlled in part by spinal sensorimotor circuits. Humans and cats also perform bidirectional or hybrid locomotion on a split-belt treadmill with one leg going forward and the other going backward. We show that cats with a spinal transection can perform hybrid locomotion and maintain left-right out-of-phase coordination, indicating that spinal sensorimotor circuits can perform simultaneous forward and backward locomotion. We also show that the regulation of cycle duration and phase duration is conserved across stepping direction, consistent with a common rhythm-generating mechanism for different stepping directions. The results help us better understand how spinal networks controlling the left and right legs enable locomotion in different directions.

Muscle fibre typology affects whole-body metabolic rate during isolated muscle contractions and human locomotion.

The wide variation in muscle fibre type distribution across individuals, along with the very different energy consumption rates in slow versus fast muscle fibres, suggests that muscle fibre typology contributes to inter-individual differences in metabolic rate during exercise. However, this has been hard to demonstrate due to the gap between a single muscle fibre and full-body exercises. We investigated the isolated effect of triceps surae muscle contraction velocity on whole-body metabolic rate during cyclic contractions in individuals a priori selected for their predominantly slow (n = 11) or fast (n = 10) muscle fibre typology by means of proton magnetic resonance spectroscopy (1H-MRS). Subsequently, we examined their whole-body metabolic rate during walking and running at 2 m/s, exercises with comparable metabolic rates but distinct triceps surae muscle force and velocity demands (walking: low force, high velocity; running: high force, low velocity). Increasing triceps surae contraction velocity during cyclic contractions elevated net whole-body metabolic rate for both typology groups. However, the slow group consumed substantially less net metabolic energy at the slowest contraction velocity, but the metabolic difference between groups diminished at faster velocities. Consistent with the more economic force production during slow contractions, the slow group exhibited lower metabolic rates than the fast group while running, whereas metabolic rates were similar during walking. These findings provide important insights into the influence of muscle fibre typology on whole-body metabolic rate and emphasize the importance of considering muscle mechanical demands to understand muscle fibre typology related differences in whole-body metabolic rates. KEY POINTS: Muscle fibre typology is often suggested to affect whole-body metabolic rate, yet convincing in vivo evidence is lacking. Using isolated plantar flexor muscle contractions in individuals a priori selected for their predominantly slow or fast muscle fibre typology, we demonstrated that having predominantly slow muscle fibres provides a metabolic advantage during slow muscle contractions, but this benefit disappeared at faster contractions. We extended these results to full-body exercises, where we demonstrated that higher proportions of slow fibres associated with better economy during running but not when walking. These findings provide important insights into the influence of muscle fibre typology on whole-body metabolic rate and emphasize the importance of considering muscle mechanical demands to understand muscle fibre typology related differences in whole-body metabolic rate.

Motor unit modes in the calf muscles during a submaximal isometric contraction are changed by brief stretches.

The purpose of our study was to investigate the influence of a stretch intervention on the common modulation of discharge rate among motor units in the calf muscles during a submaximal isometric contraction. The current report comprises a computational analysis of a motor unit dataset that we published previously (Mazzo et al., 2021). Motor unit activity was recorded from the three main plantar flexor muscles while participants performed an isometric contraction at 10% of the maximal voluntary contraction force before and after each of two interventions. The interventions were a control task (standing balance) and static stretching of the plantar flexor muscles. A factorization analysis on the smoothed discharge rates of the motor units from all three muscles yielded three modes that were independent of the individual muscles. The composition of the modes was not changed by the standing-balance task, whereas the stretching exercise reduced the average correlation in the second mode and increased it in the third mode. A centroid analysis on the correlation values showed that most motor units were associated with two or three modes, which were presumed to indicate shared synaptic inputs. The percentage of motor units adjacent to the seven centroids changed after both interventions: Control intervention, mode 1 decreased and the shared mode 1 + 2 increased; stretch intervention, shared modes either decreased (1 + 2) or increased (1 + 3). These findings indicate that the neuromuscular adjustments during both interventions were sufficient to change the motor unit modes when the same task was performed after each intervention. KEY POINTS: Based on covariation of the discharge rates of motor units in the calf muscles during a submaximal isometric contraction, factor analysis was used to assign the correlated discharge trains to three motor unit modes. The motor unit modes were determined from the combined set of all identified motor units across the three muscles before and after each participant performed a control and a stretch intervention. The composition of the motor unit modes changed after the stretching exercise, but not after the control task (standing balance). A centroid analysis on the distribution of correlation values found that most motor units were associated with a shared centroid and this distribution, presumably reflecting shared synaptic input, changed after both interventions. Our results demonstrate how the distribution of multiple common synaptic inputs to the motor neurons innervating the plantar flexor muscles changes after a brief series of stretches.

α-Adrenergic regulation of skeletal muscle blood flow during exercise in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.

Mechanosensory encoding of forces in walking uphill and downhill: force feedback can stabilize leg movements in stick insects.

Force feedback could be valuable in adapting walking to diverse terrains, but the effects of changes in substrate inclination on discharges of sensory receptors that encode forces have rarely been examined. In insects, force feedback is provided by campaniform sensilla, mechanoreceptors that monitor forces as cuticular strains. We neurographically recorded responses of stick insect tibial campaniform sensilla to "naturalistic" forces (joint torques) that occur at the hind leg femur-tibia (FT) joint in uphill, downhill, and level walking. The FT joint torques, obtained in a previous study that used inverse dynamics to analyze data from freely moving stick insects, are quite variable during level walking (including changes in sign) but are larger in magnitude and more consistent when traversing sloped surfaces. Similar to vertebrates, insects used predominantly extension torque in propulsion on uphill slopes and flexion torques to brake forward motion when going downhill. Sensory discharges to joint torques reflected the torque direction but, unexpectedly, often occurred as multiple bursts that encoded the rate of change of positive forces (dF/dt) even when force levels were high. All discharges also showed hysteresis (history dependence), as firing substantially decreased or ceased during transient force decrements. These findings have been tested in simulation in a mathematical model of the sensilla (Szczecinski NS, Dallmann CJ, Quinn RD, Zill SN. Bioinspir Biomim 16: 065001, 2021) that accurately reproduced the biological data. Our results suggest the hypothesis that sensory feedback from the femoro-tibial joint indicating force dynamics (dF/dt) can be used to counter the instability in traversing sloped surfaces in animals and, potentially, in walking machines.NEW & NOTEWORTHY Discharges of sensory receptors (campaniform sensilla) in the hind legs of stick insects can differentially signal forces that occur in walking uphill versus walking downhill. Unexpectedly, sensory firing most closely reflects the rate of change of force (dF/dt) even when the force levels are high. These signals have been replicated in a mathematical model of the receptors and could be used to stabilize leg movements both in the animal and in a walking robot.

Enhanced phasic calf muscle activation with swing resistance enhances propulsion of the paretic leg in people poststroke.

Reduced propulsion of the paretic leg contributes to impaired walking in people poststroke. The goal of this study was to determine whether phasic electrical stimulation to the paretic gastrocnemius muscle combined with resistance applied to the nonparetic leg during swing phase while walking would enhance muscle activation of the paretic gastrocnemius and propulsive force of the paretic leg. Fifteen individuals who had a stroke visited the lab once to complete two experimental sessions (i.e., crossover design; session order randomized). Each session consisted of 1) treadmill walking with either "motor stimulation and swing resistance" or "swing resistance only" (10-min walking: 1-min baseline, 7-min adaptation to intervention, and 2-min postadaptation) and 2) instrumented treadmill walking before and after treadmill walking. Participants showed enhanced muscle activation of the paretic gastrocnemius (P = 0.03) and improved anteroposterior ground reaction force of the paretic leg (P = 0.01) immediately after the treadmill walking with "motor stimulation and swing resistance," whereas no improvements after the walking with "swing resistance only." Those enhanced gastrocnemius muscle activation (P = 0.02) and improved ground reaction force (P = 0.03) were retained until the late postadaptation period and 10 min after treadmill walking, respectively. Walking with "motor stimulation and swing resistance" may enhance forced use of the paretic leg and improve propulsive force of the paretic leg. Applying phasic electrical stimulation to the paretic gastrocnemius muscle and swing resistance to the nonparetic leg during walking can be used as a novel intervention strategy to improve motor control of the paretic leg and walking in people poststroke.NEW & NOTEWORTHY Applying targeted motor stimulation to the paretic calf muscle and swing resistance to the nonparetic leg during walking induced significant enhancement in muscle activation of the paretic gastrocnemius and anterior-posterior ground reaction force of the paretic leg, whereas no enhancements were observed after walking with swing resistance only. Furthermore, the enhanced gastrocnemius muscle activation and ground reaction force of the paretic leg were partially retained at the late postadaptation period and 10 min after treadmill walking.

Task difficulty of visually guided gait modifications involves differences in central drive to spinal motor neurons.

Walking in natural environments requires visually guided modifications, which can be more challenging when involving sideways steps rather than longer steps. This exploratory study investigated whether these two types of modifications involve different changes in the central drive to spinal motor neurons of leg muscles. Fifteen adults [age: 36 ± 6 (SD) years] walked on a treadmill (4 km/h) while observing a screen displaying the real-time position of their toes. At the beginning of the swing phase, a visual target appeared in front (forward) or medial-lateral (sideways) of the ground contact in random step cycles (approximately every third step). We measured three-dimensional kinematics and electromyographic activity from leg muscles bilaterally. Intermuscular coherence was calculated in the alpha (5-15 Hz), beta (15-30 Hz), and gamma bands (30-45 Hz) approximately 230 ms before and after ground contact in control and target steps. Results showed that adjustments toward sideways targets were associated with significantly higher error, lower foot lift, and higher cocontraction between antagonist ankle muscles. Movements toward sideways targets were associated with larger beta-band soleus (SOL): medial gastrocnemius (MG) coherence and a more narrow and larger peak of synchronization in the cumulant density before ground contact. In contrast, movements toward forward targets showed no significant differences in coherence or synchronization compared with control steps. Larger SOL:MG beta-band coherence and short-term synchronization were observed during sideways, but not forward, gait modifications. This suggests that visually guided gait modifications may involve differences in the central drive to spinal ankle motor neurons dependent on the level of task difficulty.NEW & NOTEWORTHY This exploratory study suggests a specific and temporally restricted increase of central (likely corticospinal) drive to ankle muscles in relation to visually guided gait modifications. The findings indicate that a high level of visual attention to control the position of the ankle joint precisely before ground contact may involve increased central drive to ankle muscles. These findings are important for understanding the neural mechanisms underlying visually guided gait and may help develop rehabilitation interventions.

Skin and not dorsal root stimulation reduces hypertonus in thoracic motor complete spinal cord injury: a single case report.

On demand and localized treatment for excessive muscle tone after spinal cord injury (SCI) is currently not available. Here, we examine the reduction in leg hypertonus in a person with mid-thoracic, motor complete SCI using a commercial transcutaneous electrical stimulator (TES) applied at 50 or 150 Hz to the lower back and the possible mechanisms producing this bilateral reduction in leg tone. Hypertonus of knee extensors without and during TES, with both cathode (T11-L2) and anode (L3-L5) placed over the spinal column (midline, MID) or 10 cm to the left of midline (lateral, LAT) to only active underlying skin and muscle afferents, was simultaneously measured in both legs with the pendulum test. Spinal reflexes mediated by proprioceptive (H-reflex) and cutaneomuscular reflex (CMR) afferents were examined in the right leg opposite to the applied LAT TES. Hypertonus disappeared in both legs but only during thoracolumbar TES, and even during LAT TES. The marked reduction in tone was reflected in the greater distance both lower legs first dropped to after being released from a fully extended position, increasing by 172.8% and 94.2% during MID and LAT TES, respectively, compared with without TES. Both MID and LAT (left) TES increased H-reflexes but decreased the first burst, and lengthened the onset of subsequent bursts, in the cutaneomuscular reflex of the right leg. Thoracolumbar TES is a promising method to decrease leg hypertonus in chronic, motor complete SCI without activating spinal cord structures and may work by facilitating proprioceptive inputs that activate excitatory interneurons with bilateral projections that in turn recruit recurrent inhibitory neurons.NEW & NOTEWORTHY We present proof of concept that surface stimulation of the lower back can reduce severe leg hypertonus in a participant with motor complete, thoracic spinal cord injury (SCI) but only during the applied stimulation. We propose that activation of skin and muscle afferents from thoracolumbar transcutaneous electrical stimulation (TES) may recruit excitatory spinal interneurons with bilateral projections that in turn recruit recurrent inhibitory networks to provide on demand suppression of ongoing involuntary motoneuron activity.

Motor interference on lateral pelvis shifting towards the paretic leg during walking and its cortical mechanisms in persons with stroke.

Motor interference, where new skill acquisition disrupts the performance of a previously learned skill, is a critical yet underexplored factor in gait rehabilitation post-stroke. This study investigates the interference effects of two different practice schedules, applying interleaved (ABA condition) and intermittent (A-A condition) pulling force to the pelvis during treadmill walking, on lateral pelvis shifting towards the paretic leg in individuals with stroke. Task A involved applying resistive pelvis force (pulling towards the non-paretic side), and Task B applied assistive force (pulling towards the paretic side) at the stance phase of the paretic leg during walking. Sixteen individuals with chronic stroke were tested for gait pattern changes, including lateral pelvis shifting and spatiotemporal gait parameters, and neurophysiological changes, including muscle activity in the paretic leg and beta band absolute power in the lesioned cortical areas. A-A condition demonstrated increased lateral pelvis shifting towards the paretic side, extended paretic stance time and longer non-paretic step length after force release while ABA condition did not show any changes. These changes in gait pattern after A-A condition were accompanied by increased muscle activities of the ankle plantarflexors, and hip adductors/abductors. A-A condition demonstrated greater changes in beta band power in the sensorimotor regions compared to ABA condition. These findings suggest that while walking practice with external force to the pelvis can improve lateral pelvis shifting towards the paretic leg post-stroke, practicing a new pelvis shifting task in close succession may hinder the performance of a previously obtained lateral pelvis shifting pattern during walking.

Decompression with or without Fusion in Degenerative Lumbar Spondylolisthesis.

BACKGROUND: In patients with lumbar spinal stenosis and degenerative spondylolisthesis, it is uncertain whether decompression surgery alone is noninferior to decompression with instrumented fusion. METHODS: We conducted an open-label, multicenter, noninferiority trial involving patients with symptomatic lumbar stenosis that had not responded to conservative management and who had single-level spondylolisthesis of 3 mm or more. Patients were randomly assigned in a 1:1 ratio to undergo decompression surgery (decompression-alone group) or decompression surgery with instrumented fusion (fusion group). The primary outcome was a reduction of at least 30% in the score on the Oswestry Disability Index (ODI; range, 0 to 100, with higher scores indicating more impairment) during the 2 years after surgery, with a noninferiority margin of -15 percentage points. Secondary outcomes included the mean change in the ODI score as well as scores on the Zurich Claudication Questionnaire, leg and back pain, the duration of surgery and length of hospital stay, and reoperation within 2 years. RESULTS: The mean age of patients was approximately 66 years. Approximately 75% of the patients had leg pain for more than a year, and more than 80% had back pain for more than a year. The mean change from baseline to 2 years in the ODI score was -20.6 in the decompression-alone group and -21.3 in the fusion group (mean difference, 0.7; 95% confidence interval [CI], -2.8 to 4.3). In the modified intention-to-treat analysis, 95 of 133 patients (71.4%) in the decompression-alone group and 94 of 129 patients (72.9%) in the fusion group had a reduction of at least 30% in the ODI score (difference, -1.4 percentage points; 95% CI, -12.2 to 9.4), showing the noninferiority of decompression alone. In the per-protocol analysis, 80 of 106 patients (75.5%) and 83 of 110 patients (75.5%), respectively, had a reduction of at least 30% in the ODI score (difference, 0.0 percentage points; 95% CI, -11.4 to 11.4), showing noninferiority. The results for the secondary outcomes were generally in the same direction as those for the primary outcome. Successful fusion was achieved with certainty in 86 of 100 patients (86.0%) who had imaging available at 2 years. Reoperation was performed in 15 of 120 patients (12.5%) in the decompression-alone group and in 11 of 121 patients (9.1%) in the fusion group. CONCLUSIONS: In this trial involving patients who underwent surgery for degenerative lumbar spondylolisthesis, most of whom had symptoms for more than a year, decompression alone was noninferior to decompression with instrumented fusion over a period of 2 years. Reoperation occurred somewhat more often in the decompression-alone group than in the fusion group. (NORDSTEN-DS ClinicalTrials.gov number, NCT02051374.).

Sitting leg vasculopathy: potential adaptations beyond the endothelium.

Increased sitting time, the most common form of sedentary behavior, is an independent risk factor for all-cause and cardiovascular disease mortality; however, the mechanisms linking sitting to cardiovascular risk remain largely elusive. Studies over the last decade have led to the concept that excessive time spent in the sitting position and the ensuing reduction in leg blood flow-induced shear stress cause endothelial dysfunction. This conclusion has been mainly supported by studies using flow-mediated dilation in the lower extremities as the measured outcome. In this review, we summarize evidence from classic studies and more recent ones that collectively support the notion that prolonged sitting-induced leg vascular dysfunction is likely also attributable to changes occurring in vascular smooth muscle cells (VSMCs). Indeed, we provide evidence that prolonged constriction of resistance arteries can lead to modifications in the structural characteristics of the vascular wall, including polymerization of actin filaments in VSMCs and inward remodeling, and that these changes manifest in a time frame that is consistent with the vascular changes observed with prolonged sitting. We expect this review will stimulate future studies with a focus on VSMC cytoskeletal remodeling as a potential target to prevent the detrimental vascular ramifications of too much sitting.

Reducing thrombotic risks in video gamers: investigating the benefits of walking and compression sleeves on blood hemodynamics.

With the growing popularity of video gaming, deep vein thromboses are increasingly being reported in gamers. This study aimed to compare the effects of lower leg graduated compression sleeves and a 6-min walking break during prolonged gaming on blood flow and hemodynamics in competitive sport players to help mitigate this risk. Ten healthy gamers (19.6 ± 1.2 yr old; 9 men) consented to participate in this mixed-model crossover design study that consisted of three visits. In visit 1, participants engaged in continuous 2-h video game play wearing no compression (continuous). Visits 2 and 3 involved 2-h play wearing compression sleeves (compression) and 2-h game play interrupted at 1 h by a 6-min walk (walk). Doppler ultrasound measurements of the left popliteal artery were taken at 30, 60, 90, and 120 min, to record vessel diameter, blood flow velocity, and blood flow volume. Participants completed a survey to assess their perception of each approach. There was a significant interaction between conditions for blood flow and blood velocity (P = 0.01, P < 0.001). Post hoc analysis demonstrated a greater decrease in blood flow and blood velocity in the continuous group compared with the walk group at the 90-min mark (P = 0.04, P = 0.01). No differences were found between the compression and walk groups or between the continuous and compression groups (P = 0.42, P = 0.69). No interactions were observed in diameter, mean arterial pressure, or heart rate. This study suggests that incorporating a 6-min walk every 60 min during prolonged gaming is advisable to counteract the negative effects on blood flow hemodynamics.NEW & NOTEWORTHY A 6-min light-intensity walking break during gaming can effectively combat the adverse effects of prolonged sitting, surpassing compression garments. Prolonged sitting reduces blood flow velocity, potentially leading to deep vein thrombosis (DVT). Compression sleeves help, with superior results after a 6-min walk at 60 min. Although compression stockings offer moderate improvements, a 6-min active break proves more effective. These findings offer promising interventions for gamers' health, initiating guidelines to mitigate DVT risk during gaming.

Nitric oxide-mediated vasodilation in human bone.

OBJECTIVE: Regulation of blood flow to bone is critical but poorly understood, particularly in humans. This study aims to determine whether nitric oxide (NO), a major regulator of vascular tone to other tissues, contributes also to the regulation of blood flow to bone. METHODS: In young healthy adults (n = 16, 8F, 8M), we characterized NO-mediated vasodilation in the tibia in response to sublingual nitroglycerin and contrasted it to lower leg. Blood flow responses were assessed in supine individuals by continuously measuring tibial total hemoglobin (tHb) via near-infrared spectroscopy and lower leg blood flow (LBF) as popliteal flow velocity via Doppler ultrasound in the same leg. RESULTS: LBF increased by Δ9.73 ± 0.66 cm/s and peaked 4.4 min after NO administration and declined slowly but remained elevated (Δ3.63 ± 0.60 cm/s) at 10 min. In contrast, time to peak response was longer and smaller in magnitude in the tibia as tHb increased Δ2.08 ± 0.22 µM and peaked 5.3 min after NO administration and declined quickly but remained elevated (Δ0.87±0.22 µM) at 10 min (p = .01). CONCLUSIONS: In young adults, the tibial vasculature demonstrates robust NO-mediated vasodilation, but tHb is delayed and diminishes faster compared to LBF, predominately reflective of skeletal muscle responses. Thus, NO-mediated vasodilation in bone may be characteristically different from other vascular beds.

Therapeutic drug monitoring of ceftazidime/avibactam: why one leg is not enough to run.

BACKGROUND: Therapeutic drug monitoring (TDM) is becoming an increasingly recommended approach for assessing optimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime/avibactam. Some authors hypothesized that the PK/PD target attainment of ceftazidime/avibactam could be assessed by means of the TDM of solely ceftazidime, since avibactam concentrations might be extrapolated based on the fixed 4:1 ceftazidime-to-avibactam ratio present in the vial. The reliability of this hypothesis could be called into question if a wide interindividual variability in the ceftazidime-to-avibactam ratio would exist among patients. This study aimed to assess the distribution of the individual ceftazidime-to-avibactam ratios in relation to renal function in a cohort of adult patients who were treated with continuous infusion ceftazidime/avibactam and underwent TDM of both ceftazidime and avibactam. METHODS: Individual ceftazidime-to-avibactam ratio was calculated at each TDM assessment. Receiving operating characteristics (ROC) curve analysis was performed for testing the potential impact of renal function on ceftazidime-to-avibactam ratio variability. RESULTS: A total of 188 TDM assessments were collected from 107 patients. The ceftazidime-to-avibactam ratios ranged from 1.29:1 to 13.46:1. Seventy-seven out of 188 ceftazidime-to-avibactam ratios (41.0%) were >5:1, and 36 (19.1%) were >6:1. Patients without renal dysfunction had significantly higher proportions of ceftazidime-to-avibactam ratio >5:1 (59.3% versus 23.8%; P < 0.001) and >6:1 (32.1% versus 6.3%; P < 0.001) compared with those with mild-to-severe renal dysfunction. CONCLUSIONS: The findings may strengthen the contention that for properly assessing the PK/PD target attainment of ceftazidime/avibactam, both ceftazidime and avibactam concentrations should be measured, given the unpredictability of the ceftazidime-to-avibactam ratio occurring among patients.

The impact of obesity on chronic oedema/lymphoedema of the leg - an international multicenter cross-sectional study (LIMPRINT).

BACKGROUND/OBJECTIVES: Obesity and chronic oedema/lymphoedema are two distinct but related conditions, rarely investigated together. The aim was to study the impact of increased weight on chronic oedema and related factors. SUBJECTS/METHODS: A cross-sectional study, 38 centers, nine countries. Patients with clinically confirmed chronic oedema/lymphoedema of the leg were included. Weight category was estimated as: normal weight (BMI 20-30), class I-II obesity (BMI 30-40), or class III obesity (BMI > 40). Factors were tested for an association with increased weight, using a multivariable model. RESULTS: A total of 7397 patients were included; 43% with normal weight, 36% class I-II obesity and 21% class III obesity. Increased weight was associated with more advanced stages of chronic oedema (ISL stage III; the most advanced form); affecting 14% in normal weight, 18% class I-II obesity and 39% class III obesity (p < 0.001). Ten factors were independently associated with increased weight: diabetes (OR 2.4), secondary lymphoedema (OR 2.7), cellulitis/erysipelas within 12 months (OR 1.2), bilateral lymphoedema (OR 3.6), compression therapy (OR 2.1), increased swelling duration (1-2 years OR 1.3, 2-5 years OR 2.5, 5-10 years OR 3.6, >10 years OR 3.5) decreased mobility (walking with aid OR 1.9, being chair bound OR 1.2) and age (reference<45 years; 45-64 years OR 1.5, 75-84 years OR 0.6, 85+ years OR 0.2). Increased weight was associated with a lower presentation of peripheral arterial disease (OR 0.7) and poorer chronic oedema control (OR 0.8). Patients with obesity had lower function, appearance and more severe symptoms (LYMQOL) and lower quality of life (EuroQol). CONCLUSIONS: Obesity negatively impacts chronic oedema, leading to more advanced stages. Achieving good control of swelling with compression is more difficult in these patients. Increased awareness of chronic oedema/lymphoedema as a complication of obesity is important for early detection and for developing effective strategies to prevent and manage them.

Velocity-compensated intravoxel incoherent motion of the human calf muscle.

PURPOSE: To determine whether intravoxel incoherent motion (IVIM) describes the blood perfusion in muscles better, assuming pseudo diffusion (Bihan Model 1) or ballistic motion (Bihan Model 2). METHODS: IVIM parameters were measured in 18 healthy subjects with three different diffusion gradient time profiles (bipolar with two diffusion times and one with velocity compensation) and 17 b-values (0-600 s/mm2) at rest and after muscle activation. The diffusion coefficient, perfusion fraction, and pseudo-diffusion coefficient were estimated with a segmented fit in the gastrocnemius medialis (GM) and tibialis anterior (TA) muscles. RESULTS: Velocity-compensated gradients resulted in a decreased perfusion fraction (6.9% ± 1.4% vs. 4.4% ± 1.3% in the GM after activation) and pseudo-diffusion coefficient (0.069 ± 0.046 mm2/s vs. 0.014 ± 0.006 in the GM after activation) compared to the bipolar gradients with the longer diffusion encoding time. Increased diffusion coefficients, perfusion fractions, and pseudo-diffusion coefficients were observed in the GM after activation for all gradient profiles. However, the increase was significantly smaller for the velocity-compensated gradients. A diffusion time dependence was found for the pseudo-diffusion coefficient in the activated muscle. CONCLUSION: Velocity-compensated diffusion gradients significantly suppress the IVIM effect in the calf muscle, indicating that the ballistic limit is mostly reached, which is supported by the time dependence of the pseudo-diffusion coefficient.

In vivo B 1 + enhancement of calf MRI at 7 T via optimized flexible metasurfaces.

PURPOSE: Ultrahigh field (≥7 T) MRI is at the cutting edge of medical imaging, enabling enhanced spatial and spectral resolution as well as enhanced susceptibility contrast. However, transmit ( B 1 + $$ {\mathrm{B}}_1^{+} $$ ) field inhomogeneity due to standing wave effects caused by the shortened RF wavelengths at 7 T is still a challenge to overcome. Novel hardware methods such as dielectric pads have been shown to improve the B 1 + $$ {\mathrm{B}}_1^{+} $$ field inhomogeneity but are currently limited in their corrective effect by the range of high-permittivity materials available and have a fixed shelf life. In this work, an optimized metasurface design is presented that demonstrates in vivo enhancement of the B 1 + $$ {\mathrm{B}}_1^{+} $$ field. METHODS: A prototype metasurface was optimized by an empirical capacitor sweep and by varying the period size. Phantom temperature experiments were performed to evaluate potential metasurface heating effects during scanning. Lastly, in vivo gradient echo images and B 1 + $$ {\mathrm{B}}_1^{+} $$ maps were acquired on five healthy subjects on a 7 T system. Dielectric pads were also used as a comparison throughout the work as a standard comparison. RESULTS: The metasurfaces presented here enhanced the average relative SNR of the gradient echo images by a factor of 2.26 compared to the dielectric pads factor of 1.61. Average B 1 + $$ {\mathrm{B}}_1^{+} $$ values reflected a similar enhancement of 27.6% with the metasurfaces present versus 8.9% with the dielectric pads. CONCLUSION: The results demonstrate that metasurfaces provide superior performance to dielectric padding as shown by B 1 + $$ {\mathrm{B}}_1^{+} $$ maps reflecting their direct effects and resulting enhancements in image SNR at 7 T.

Hypertension restricts leg blood flow and aggravates neuromuscular fatigue during human locomotion in males.

Patients with hypertension (HTN) are characterized by exaggerated vascular resistance and mean arterial pressure (MAP) and a compromised leg blood flow (QL) response to exercise recruiting a small muscle mass. However, the impact of hypertension on peripheral hemodynamics and the development of neuromuscular fatigue during locomotor activities, which critically depends on QL, remain unknown. Eight HTN (143 ± 11 mmHg/95 ± 6 mmHg; 45 ± 13 yr) and eight matched (age and activity) controls (120 ± 6 mmHg/77 ± 7 mmHg; CTRL) performed constant-load cycling exercise at 25, 50, and 75 W (for 4 min each) and at 165 ± 41 W (for 5 min). Exercise-induced locomotor muscle fatigue was quantified as the pre- to postexercise change in quadriceps twitch-torque (ΔQtw, peripheral fatigue) and voluntary activation (ΔVA%, central fatigue). QL (Doppler ultrasound) and leg vascular conductance (LVC) were determined during cycling at 25, 50, and 75 W. Heart rate and ventilatory responses were recorded during all intensities. MAP during exercise was, on average, ∼21 mmHg higher (P = 0.002) and LVC ∼39% lower (P = 0.001) in HTN compared with CTRL. QL was consistently between 20 and 30% lower (P = 0.004), and heart rate was significantly higher in HTN. Exercise-induced peripheral (ΔQtw: -53 ± 19% vs. -25 ± 23%) and central (ΔVA%: -7 ± 5% vs. -3 ± 2%) fatigue was significantly greater in HTN compared with CTRL. In addition to an exaggerated MAP, LVC and QL were lower during exercise in HTN compared with CTRL. Given the critical role of QL in determining the development of neuromuscular fatigue, these hemodynamic impairments likely accounted for the faster development of neuromuscular fatigue characterizing hypertensive individuals during locomotor exercise. NEW & NOTEWORTHY The impact of primary hypertension on the cardiovascular and neuromuscular fatigue response to locomotor exercise is unknown. We compared central and peripheral hemodynamics and the development of central and peripheral fatigue during cycling exercise in patients with stage I/II hypertension and age- and activity-matched healthy individuals. In addition to a significantly elevated blood pressure, hypertensive patients were, compared with their nonhypertensive counterparts, also characterized by considerable leg blood flow limitations and impaired neuromuscular fatigue resistance.