Initial Doublet Research Articles

A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone.

Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5-36.2months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients whoshowed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.

Multiple Myeloma in Patients over 80: A Real World Retrospective Study of First Line Conservative Approach with Bortezomib Dexamethasone Doublet Therapy and Mini-Review of Literature.

Simple SummaryMultiple Myeloma (MM) is frequent and represents 2% of all cancers. Daratumumab bortezomib-melphalan-prednisone (D-VMP) and daratumumab lenalidomide dexamethasone (D-Rd) are considered the standard of care for elderly patients with newly diagnosed MM (NDMM), defined as transplant-ineligible patients over 65 years. However, the “elderly” patient population is heterogeneous, and prospective trials exclude the oldest and frailest patients because of co-morbidities or altered Eastern Cooperative Oncology Group Performance Status (ECOG PS). According to the IMWG frailty score, patients over 80 are considered as frail. Few data are available on octogenarian patients with NDMM, and their optimal management remains controversial. We here report one of the largest retrospective series investigating doublet therapy with bortezomib dexamethasone (Vd) as the first-line treatment for unselected octogenarian patients with NDMM.Data on octogenarian patients with MM are scarce, and optimal management remains controversial. We report a retrospective cohort of unselected octogenarian patients with NDMM treated with bortezomib dexamethasone (Vd). Seventy-four patients were treated with an initial doublet therapy (Vd regimen, 2–3 cycles, induction). A dose escalation with an adjunction of melphalan or cyclophosphamide was proposed for patients who had an insufficient response after induction and who could tolerate it. In responders, the treatment was continued until progression or a plateau response for 6 months (consolidation). The overall response rate was 73%. After a median follow-up of 31.4 months, median progression-free survival (PFS) and overall survival (OS) were 13.2 and 26.9 months, respectively. PFS and OS of patients with ECOG PS < 3 (25.4 and 54.9 months, respectively) were better in comparison to PFS and OS of patients with ECOG PS ≥ 3 (9.3 and 11.3 months, respectively). Thirteen patients (17.6%) died during induction. Twelve patients (16.2%) died during consolidation. In conclusion, a conservative therapeutic strategy based on Vd resulted in a good response rate. However, the survival remains poor in the population of patients with an ECOG PS ≥ 3, mainly because of early mortality not related to progressive disease.

Abstract 1375: Activity of pemetrexed in patients with driver oncogene positive non-small cell lung cancer and squamous histology

Abstract Pemetrexed, a multi-targeted antifolate chemotherapy agent, has been used both as a single agent chemotherapy as well as in combination given its favorable side effect profile, and has been the only effective continuation maintenance chemotherapy regimen after initial doublet use associated with increased overall survival (OS) among non-squamous non-small cell lung cancers. The current labelled indications for pemetrexed in NSCLC are restricted to those with non-squamous histology due to previous studies that showed worse outcomes in patients with squamous histology when compared to non-squamous histology. More recently, however, in the era of increased molecular profiling of NSCLC, it has been observed that patients with ALK, ROS1, and RET gene fusions have demonstrated marked sensitivity to pemetrexed. This retrospective case series, therefore, evaluated the response to pemetrexed among a cohort of 9 oncogene-driven patients with squamous (or adenosquamous) histologies who did receive pemetrexed based chemotherapy. Response rates, progression free survival (PFS), and OS for these patients were compared to a historical group of patients published in previous studies that examined pemetrexed response. The results indicated a positive response to pemetrexed in patients with an actionable driver oncogene occurring in the context of squamous or adenosquamous histology. Patients in the oncogene-driven adenosquamous/squamous group had significantly higher response rates as compared to the historical squamous cell group and no significant difference in response rates as compared to the historical adenocarcinoma comparison group. In summary, contrary to prior studies, this case series does suggest that pemetrexed may be a viable treatment option in patients with squamous cell histology who also have a targetable mutation. Citation Format: Yunan Nie, Tejas Patil, David Ross Camidge. Activity of pemetrexed in patients with driver oncogene positive non-small cell lung cancer and squamous histology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1375.

D5 dopamine receptors control glutamatergic AMPA transmission between the motor cortex and subthalamic nucleus

Corticofugal fibers target the subthalamic nucleus (STN), a component nucleus of the basal ganglia, in addition to the striatum, their main input. The cortico-subthalamic, or hyperdirect, pathway, is thought to supplement the cortico-striatal pathways in order to interrupt/change planned actions. To explore the previously unknown properties of the neurons that project to the STN, retrograde and anterograde tools were used to specifically identify them in the motor cortex and selectively stimulate their synapses in the STN. The cortico-subthalamic neurons exhibited very little sag and fired an initial doublet followed by non-adapting action potentials. In the STN, AMPA/kainate synaptic currents had a voltage-dependent conductance, indicative of GluA2-lacking receptors and were partly inhibited by Naspm. AMPA transmission displayed short-term depression, with the exception of a limited bandpass in the 5 to 15 Hz range. AMPA synaptic currents were negatively controlled by dopamine D5 receptors. The reduction in synaptic strength was due to postsynaptic D5 receptors, mediated by a PKA-dependent pathway, but did not involve a modified rectification index. Our data indicated that dopamine, through post-synaptic D5 receptors, limited the cortical drive onto STN neurons in the normal brain.

Anhydrous octyl-glucoside phase transition from lamellar to isotropic induced by electric and magnetic fields.

A static deuterium nuclear magnetic resonance (2HNMR) technique (magnetic field, B = 7.05 T) was employed to monitor the thermotropic lamellar phase of the anhydrous 1:1 mixture sample of octyl-b-D-glucoside (βOG) and that of partially deuterium labelled at the alpha position on the chain, i.e.,βOG-d2 In the absence of an electric field, the 2H NMR spectrum of the mixture gives a typical quadrupolar doublet representing the aligned lamellar phase. Upon heating to beyond the clearing temperature at 112 °C, this splitting converts to a single line expected for an isotropic phase. Simultaneous application of magnetic and electric fields (E = 0.4 MV/m) at 85 °C in the lamellar phase, whose direction was set to be parallel or perpendicular to the magnetic field, resulted in the change of the doublet into a single line and this recovers to the initial doublet with time for both experimental geometries. This implies E- and B-field-induced phase transitions from the lamellar to an isotropic phase and a recovery to the lamellar phase again with time. Moreover, these phase transformations are accompanied by a transient current. A similar observation was made in a computational study when an electric field was applied to a water cluster system. Increasing the field strength distorts the water cluster and weakens its hydrogen bonds leading to a structural breakdown beyond a threshold field-strength. Therefore, we suggest the observed field-induced transition is likely due to a structure change of the βOG lamellar assembly caused by the field effect and not due to Joule heating.

MTE17.02 Maintenance Therapy versus Early Second-Line Therapy in Advanced NSCLC

MTE17.02 Maintenance Therapy versus Early Second-Line Therapy in Advanced NSCLC

Population transfer in a Λ-type five-level system with equally populated initial and empty final doublet states

We investigate the selective and efficient population transfer in a Λ-type five-level system with equally populated initial and empty final doublet states by time-separated chirped pump and Stokes pulses. We show that it is possible to achieve selective, efficient, and robust population transfer from either of the equally populated initial doublet states to either of the final ground doublet levels by merging stimulated Raman adiabatic passage and chirped adiabatic passage techniques. Moreover, the maximal coherent superpositions between either of the initial doublet states and either of the final doublet states, between the intermediate level and either of the final doublet states, or between the final doublet levels can be achieved by varying the chirp rates and single-photon detuning of the pump and Stokes pulses. This method may have potential applications in quantum coherent control of population dynamics in realistic atomic or molecular systems with equally populated initial and empty final manifolds.

Growth of multiparticle aggregates in sedimenting suspensions

AbstractThe process of multiparticle aggregation in a dilute sedimenting suspension is rigorously simulated, with precise hydrodynamical interactions. The primary particles are monodisperse non-Brownian spheres at zero Reynolds number, with short-range molecular attractions. The rigid aggregates grow, as they settle downwards, by sequential particle addition – a valid assumption for dilute suspensions during the initial stages. The growth starts from doublet–particle interaction, but the indeterminate initial doublet concentration does not affect the results for cluster geometry and settling velocity. A new particle is generated far below a cluster with uniform probability density, and many trial particle–cluster relative trajectories are computed with high accuracy until a collision is found. The new cluster is then assumed to be rigid and allowed to reach a steady sedimentation regime (which is a spiral motion around the axis of steady rotation, ASR) before another particle is added, and so on. The ASR is typically far away from the cluster centre of mass. The Stokes flow solution algorithm for particle–cluster interaction works very efficiently with high-order multipoles (to order 100) and is extended to arbitrarily small particle–cluster separations by a geometry perturbation adapted from the conductivity simulations of Zinchenko (Phil. Trans. R. Soc. Lond. A, 1998, vol. 356, pp. 2953–2998). Clusters are generated to $N=100$ spheres, with extensive averaging over many growth realizations. The fractal scaling $\sim N^{0.48}$ for the cluster settling speed is quickly attained once $N\geq 25$, and the exponent 0.48 is practically independent of the strength of molecular forces. The cluster fractal dimension is predicted to be $d_f=1.91\pm 0.02$ (in contrast to the existing views that sequential addition can only produce high-$d_f$ clusters). Several average characteristics of the cluster size are also computed. The theoretical settling speed has no adjustable parameters and agrees reasonably well with prior experiments for a moderately polydisperse system in a broad range of cluster sizes.

Selective and efficient control of population transfer in the presence of an equally populated initial doublet

We present a way to realize selective, robust, and efficient population transfer in a ladder-type four-level system with an equally populated doublet in the initial state. By merging stimulated Raman adiabatic passage and chirped adiabatic passage techniques, we show that selective and complete population transfer from either of the initial doublet levels to the final state can be achieved with chirped pump and Stokes pulse pairs when the spectral resolution constraint of a frequency swept pulse holds (the energy separation of doublet levels should be much larger than the pulse bandwidth). We further demonstrate that the spectral resolution of selective population transfer can be enhanced significantly by using pump pulse pair and Stokes pulse due to temporal quantum interference between the sequential transitions in the time domain, which can also be well followed as a result of the frequency-domain formation of a comblike structure of the pulse pair spectrum. The proposals take into account the case of population transfer in realistic atomic and molecular systems, and may have applications in quantum coherent control of systems with equally populated initial manifolds.

Doublet of action potentials evoked by intracellular injection of rectangular depolarization current into rat motoneurones

A doublet of action potentials is frequently observed at the beginning of motoneuronal discharge patterns and its appearance leads to a considerable increase in the motor unit force. The aims of this study were (1) to determine the relationship between the intensity of rectangular depolarization currents injected into motoneurones and their ability to generate doublets and (2) to evaluate the influence of the initial doublets on changes in motoneuronal firing frequency. Experiments were performed on anesthetized rats, and recordings were taken from motoneurones located in the L4-L5 segments of the spinal cord. The depolarization current necessary to evoke the initial doublet of action potentials was measured and expressed in multiples of the rheobase. A gradual increase in the intensity of current injected into motoneurones resulted in initial doublets in 80% of the cases studied, at doublet threshold ranges between 1.25 and 4.0 times the rheobase. This suggests that doublets are an effect of strong synaptic excitation of motoneurones that may precede a sudden change in force during a movement. Moreover, in the great majority of the studied motoneurones, this initial doublet caused changes in the subsequent firing rate by the prolongation of the first interspike interval.

Four Excitatory Postsynaptic Ionotropic Receptors Coactivated at the Motoneuron–Renshaw Cell Synapse

Renshaw cells (RCs) are spinal interneurons excited by collaterals of the axons of motoneurons (MNs). They respond to a single motoneuronal volley by a surprisingly long (tens of milliseconds) train of action potentials. We have analyzed this synaptic response in spinal cord slices of neonatal mice in light of recent observations suggesting that the MN axons release both acetylcholine and glutamate. We found that the RC synaptic current involves four components of similar amplitudes mediated by two nicotinic receptors (nAChRs, tentatively identified as alpha(7) homomers and alpha(4)beta(2) heteromers) and two glutamate receptors (AMPARs and NMDARs). The decay time constants of the four components cover a wide range: from 3.6 +/- 2.2 ms (alpha(7) nAChRs) to 54.6 +/- 19.5 ms (NMDARs, at -45 mV). The RC discharge can be separated into an initial doublet of high-frequency action potentials followed by later spikes with a variable latency and longer interspike intervals. The initial doublet involves the four ionotropic receptors as well as endogenous voltage-dependent conductances. The late discharge depends on NMDARs, but these receptors must be primed by the initial depolarization. The activation of the NMDARs is prolonged by the fact that their slow deactivation is further slowed by depolarization. The formation of the initial doublet is favored by hyperpolarization, whereas the late discharge is favored by depolarization. This suggests that in physiological conditions the pattern of discharge of the RC in response to a MN input may alternate between a phasic and a tonic response.

Standing up for the sequential strategy

With an increasing number of options now available for the management of metastatic colorectal cancer (mCRC), clinicians face the challenge of how to use them most effectively. First-line cytotoxic ‘doublets’ increase response rates and time to progression compared with monotherapy. However, five recent studies showed no significant overall survival benefit for first-line combination therapy compared with a pre-planned sequential approach starting with fluoropyrimidine monotherapy. In one trial, initial fluorouracil (FU)/irinotecan doublet therapy was superior to sequential FU then irinotecan, but the same trial showed non-inferiority for the sequential approach if a doublet was used second-line. Sub-group analyses failed to identify a subgroup benefiting from the initial doublet approach, although a trend towards benefit was seen for patients with poor performance status and some promising data suggest that predictive biomarkers may have a role in selecting the optimum strategy. The management of mCRC needs to consider the requirements of the individual patient and the whole course of treatment rather than a single line of therapy. Findings to date suggest that planned sequential therapy is a good option for many patients.

Thermodynamics of Unstable DNA Structures from the Kinetics of the Microgene PCR

The microgene polymerization reaction (MPR) generates head-to-tail tandem repeats from homoduplexes (HDs). In MPR initiation, one HD putatively aligns two others in the proximity required to form a nucleation complex, thus allowing the DNA polymerase to skip the intertemplate gap and generate an initial doublet (ID) prone to repeat propagation. The current investigation refines this stage by additional thermodynamic considerations and elucidates the fundamental mechanism underlying propagation. Four different HD types were designed to extend the range of melting temperatures and to simultaneously modify the stabilities of their secondary structures. Following the propagation kinetics with these, using real-time PCR at different temperatures revealed a new stage in the MPR, amplification of an ID by an original HD, and enabled us to decipher the biphasic kinetics of the process. This amplification merges with the propagation stage if the lifetime of the staggered conformation of the ID is sufficiently long for DNA polymerase to fill in the overhangs. The observed increase with temperature of thermodynamically unfavorable conformations of singlet and doublet HDs that underlies, respectively, MPR initiation and propagation is well correlated with simulations by UNAFold.

Sequential chemotherapy for advanced colorectal cancer: Should we ever start with a single cytotoxic agent?

About 10 years ago, it was established that chemotherapy “doublets” of a fluoropyrimidine and either irinotecan or oxaliplatin give a higher response rate and longer progression-free survival than single-agent therapy. Some trials also showed overall surivval benefit, but others did not. Several large, randomized trials were set up between 2000 and 2003 in which prospective treatment plans involving initial doublet therapy were compared with plans using the same drugs but starting with single-agent fluoropyrimidine. Two—FOCUS and CAIRO—have now been published, and three others—FOCUS2, FFCD2000-05, and LIFE—have been reported in abstract form. Contrary to expectations, none has shown a clear survival benefit for the first-line combination chemotherapy arm. This article discusses the trial results and implications for practice.

Initiation of the microgene polymerization reaction with non-repetitive homo-duplexes

Microgene Polymerization Reaction (MPR) is used as an experimental system to artificially simulate evolution of short, non-repetitive homo-duplex DNA into multiply-repetitive products that can code for functional proteins. Blunt-end ligation by DNA polymerase is crucial in expansion of homo-duplexes (HDs) into head-to-tail multiple repeats in MPR. The propagation mechanism is known, but formation of the initial doublet (ID) by juxtaposing two HDs and polymerization through the gap has been ambiguous. Initiation events with pairs of HDs using Real-Time PCR were more frequent at higher HD concentrations and slightly below the melting temperature. A process molecularity of about 3.1, calculated from the amplification efficiency and the difference in PCR cycles at which propagation was detected at varying HD concentrations, led to a simple mechanism for ID formation: the gap between two HDs is bridged by a third. Considering thermodynamic aspects of the presumed intermediate “nucleation complex” can predict relative propensity for the process with other HDs.

Soot Platelets and PAHs with an Odd Number of Unsaturated Carbon Atoms and π Electrons: Theoretical Study of Their Spin Properties and Interaction with Ozone

PAHs made from an odd number of unsaturated carbon atoms and pi electrons (odd PAHs) have been detected in flames and flank the more familiar even PAHs, having approximately the same quantitative importance, particularly for PAHs containing more than 25 carbon atoms. Similarly, soot platelets containing an odd number of carbon atoms can be reasonably assumed to form during combustion. PAHs are intended here as small models for the investigation of some of their local features. To this end, quantum mechanical calculations were also carried out on periodic models. The spin density patterns were found to be highly dependent on the PAH size and shape. PAHs and soot, once released in the environment, can undergo several oxidation processes. Ozone is then taken as a probe of the reactivity properties of some internal exposed portions of a platelet. A primary ozonide (PO) corresponds to an energy minimum, but the relevant concerted addition pathway does not exist, because a PO-like saddle point is second-order. The reaction begins with a nonconcerted attack that produces a trioxyl radical (TR). Subsequent O2 loss from the TR leaves either an epoxide with a pi-delocalized electron or a pi-delocalized oxepine, by cleavage of the ring carbon-carbon bond. The initial doublet spin multiplicity thus provides a description of the reaction surface unlike that for the internal reactivity of the closed-shell even systems investigated in a previous work, even though the final functionalization is the same.

Electrophysiological Diversity of Layer 5 Pyramidal Cells in the Prefrontal Cortex of the Rhesus Monkey: In Vitro Slice Studies

Whole cell patch-clamp recordings were employed to characterize the electrophysiological properties of layer 5 pyramidal cells in slices of the prefrontal cortex (Area 46) of the rhesus monkey. Four electrophysiologically distinct cell types were discriminated based on distinctive repetitive action potential (AP) firing patterns and single AP characteristics: regular-spiking slowly adapting type-1 cells (RS1; 62%), regular-spiking slowly adapting type-2 cells (RS2; 18%), regular-spiking fast-adapting cells (FA; 15%), and intrinsically bursting cells (IB; 5%). These cells did not differ with regard to their location in layer 5 nor in their dendritic morphology. In RS1 cells, AP threshold and amplitude did not change significantly during a 2-s spike train, whereas in RS2 and FA cells, AP threshold increased significantly and AP amplitude decreased significantly during the train. In FA cells, complete adaptation of AP firing was observed within 600 ms. IB cells displayed an all-or-none burst of three to six APs, followed by RS1-type firing behavior. RS1 cells could be further subdivided into three subtypes. Low-threshold spiking (LTS) RS1 cells exhibited an initial doublet riding on a depolarizing potential at the onset of a spike train and a prominent depolarizing afterpotential (DAP); intermediate RS1 cells (IM) exhibited a DAP, but no initial doublet, and non-LTS RS1 cells exhibited neither a DAP nor an initial doublet. RS2 and FA cells did not exhibit a DAP or initial doublets. The distinctive firing patterns of these diverse layer 5 pyramidal cells may reflect different roles played by these cells in the mediation of subcortical neuronal activity by the dorsolateral PFC.

Doublets and low‐frequency fatigue in potentiated human muscle

To test the hypothesis that doublets compensate for low-frequency fatigue. Doublets increase force output from muscles stimulated at low frequencies. Low-frequency fatigue is a decline in the force elicited by low-frequency stimulation. Human flexor carpi radialis muscles were stimulated with 20 Hz trains with and without an initial doublet and with and without low-frequency fatigue and the resulting force response measured. An initial doublet caused an increase in the maximum rate of force rise of 179.6 +/- 27.9% in rested and 242.9 +/- 37.7% in muscles with low-frequency fatigue, and a substantial enhancement in force in the first three inter-pulse intervals after the extra pulse. The magnitude and time course of the early doublet enhancement were very similar regardless of low-frequency fatigue, consistent with current theories regarding the mechanisms of the doublet effect and of low-frequency fatigue. By the end of the 1 s stimulus train, force enhancement was insignificant in rested muscles and was small and subject-dependent in muscles with low-frequency fatigue (17.3 +/- 8.1% of force without a doublet), reducing the force deficit by 25.2 +/- 5.5%. The time course of doublet force enhancement implies that an initial doublet may effectively compensate for the deficit in rate of force rise in muscles with low-frequency fatigue, but may not compensate for force deficits beyond the first few inter-pulse intervals.

Mathematical models use varying parameter strategies to represent paralyzed muscle force properties: a sensitivity analysis

BackgroundMathematical muscle models may be useful for the determination of appropriate musculoskeletal stresses that will safely maintain the integrity of muscle and bone following spinal cord injury. Several models have been proposed to represent paralyzed muscle, but there have not been any systematic comparisons of modelling approaches to better understand the relationships between model parameters and muscle contractile properties. This sensitivity analysis of simulated muscle forces using three currently available mathematical models provides insight into the differences in modelling strategies as well as any direct parameter associations with simulated muscle force properties.MethodsThree mathematical muscle models were compared: a traditional linear model with 3 parameters and two contemporary nonlinear models each with 6 parameters. Simulated muscle forces were calculated for two stimulation patterns (constant frequency and initial doublet trains) at three frequencies (5, 10, and 20 Hz). A sensitivity analysis of each model was performed by altering a single parameter through a range of 8 values, while the remaining parameters were kept at baseline values. Specific simulated force characteristics were determined for each stimulation pattern and each parameter increment. Significant parameter influences for each simulated force property were determined using ANOVA and Tukey's follow-up tests (α ≤ 0.05), and compared to previously reported parameter definitions.ResultsEach of the 3 linear model's parameters most clearly influence either simulated force magnitude or speed properties, consistent with previous parameter definitions. The nonlinear models' parameters displayed greater redundancy between force magnitude and speed properties. Further, previous parameter definitions for one of the nonlinear models were consistently supported, while the other was only partially supported by this analysis.ConclusionThese three mathematical models use substantially different strategies to represent simulated muscle force. The two contemporary nonlinear models' parameters have the least distinct associations with simulated muscle force properties, and the greatest parameter role redundancy compared to the traditional linear model.

Effects of stimulation pattern on electrical stimulation-induced leg cycling performance

Electrical stimulation-induced leg cycling (ES-LC) is beneficial for individuals with spinal cord injury (SCI), but cycling performance is often limited because of rapid fatigue of the stimulated muscles. This study evaluated whether a stimulation pattern with a catchlike-inducing pulse train increased force production and hence cycling performance. Five men with SCI performed ES-LC using different stimulation patterns: (1) the standard pattern with ramp modulation, (2) a pattern with no ramp modulation, (3) a pattern with no ramp modulation but with an initial doublet, and (4) a pattern with a middle doublet. None of the experimental patterns resulted in significantly improved cycling performance compared with the standard pattern. However, during the first 3 min of cycling, the current amplitude was significantly higher with the standard stimulation, suggesting that stimulation with no ramp modulation produces more force at the same submaximal current amplitude. The results do not indicate that stimulation with catchlike-inducing trains with the current parameter settings improves ES-LC performance.