Monitoring walking asymmetries and endpoint control in persons living with chronic stroke: Implications for remote diagnosis and telerehabilitation.

Objective: The objective of this study was to assess the feasibility of monitoring and diagnosing compromised walking motion in the frontal plane, particularly in persons living with the chronic effects of stroke (PwCS). The study aimed to determine whether active control of walking in the frontal plane could be monitored and provide diagnostic insights into compensations made by PwCS during community living. Methods: The study recruited PwCS with noticeable walking asymmetries and employed a monitoring method to assess frontal plane motion. Monitoring was conducted both within a single assessment and between assessments. The study aimed to uncover baseline data and diagnostic information about active control in chronic stroke survivors. Data were collected using sensors during 6 minutes of walking and compared between the paretic and non-paretic legs. Results: The study demonstrated the feasibility of monitoring frontal plane motion and diagnosing disturbed endpoint control (p < 0.0125) in chronic stroke survivors when comparing the paretic leg to the non-paretic leg. A greater variability was observed in the paretic leg (p < 0.0125), and sensors were able to diagnose a stronger coupling of the body with its endpoint on the paretic side (p < 0.0125). Similar results were obtained when monitoring was conducted over a six-minute walking period, and no significant diagnostic differences were found between the two monitoring assessments. Monitoring did not reveal performance fatigue or debilitation over time. Conclusions: This study's findings indicate that monitoring frontal plane motion is a feasible approach for diagnosing compromised walking motion. The results suggest that individuals with walking asymmetries, exhibit differences in endpoint control and variability between their paretic and non-paretic legs. These insights could contribute to more effective rehabilitation strategies and highlight the potential for monitoring compensations during various activities of daily living.

American Registry of Ambulatory or acutely decompensated heart failure (AMERICCAASS Registry): First 1000 patients.

BACKGROUND: About 80% of cardiovascular diseases (including heart failure [HF]) occur in low-income and developing countries. However, most clinical trials are conducted in developed countries. HYPOTHESIS: The American Registry of Ambulatory or Acutely Decompensated Heart Failure (AMERICCAASS) aims to describe the sociodemographic characteristics of HF, comorbidities, clinical presentation, and pharmacological management of patients with ambulatory or acutely decompensated HF in America. METHODOLOGY: Descriptive, observational, prospective, and multicenter registry, which includes patients >18 years with HF in an outpatient or hospital setting. Collected information is stored in the REDCap electronic platform. Quantitative variables are defined according to the normality of the variable using the Shapiro-Wilk test. RESULTS: This analysis includes data from the first 1000 patients recruited. 63.5% were men, the median age of 66 years (interquartile range 56.7-75.4), and 77.6% of the patients were older than 55 years old. The percentage of use of the four pharmacological pillars at the time of recruitment was 70.7% for beta-blockers (BB), 77.4% for angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB II)/angiotensin receptor-neprilysin inhibitor (ARNI), 56.8% for mineralocorticoid receptor antagonists (MRA), and 30.7% for sodium-glucose cotransporter type-2 inhibitors (SGLT2i). The main cause of decompensation in hospitalized patients was HF progression (64.4%), and the predominant hemodynamic profile was wet-warm (68.3%). CONCLUSIONS: AMERICCAASS is the first continental registry to include hospitalized or outpatient patients with HF. Regarding optimal medical therapy, approximately a quarter of the patients still need to receive BB and ACEI/ARB/ARNI, less than half do not receive MRA, and more than two-thirds do not receive SGLT2i.

Prognosis of pulmonary arterial hypertension patients with pericardial effusion before and after initiation of parenteral prostacyclin therapy.

Few studies have evaluated the effects of pulmonary arterial hypertension therapies on pericardial effusion. We evaluated hemodynamics, echocardiograms, and outcomes for 119 parenteral prostanoid-treated patients. We discovered an increased frequency of pericardial effusions posttreatment, and that a moderate-large pericardial effusion at initiation, but not at 1st follow-up, was significantly associated with mortality.

Physiological measures and anatomical correlates of subthalamic deep brain stimulation effect on gait in Parkinson's disease.

We examined whether conflicting visual and non-visual information leads to gait abnormalities and how the subthalamic deep brain stimulation (STN DBS) influences gait dysfunction in Parkinson's disease (PD). We used a motion capture system to measure the kinematics of the lower limbs during treadmill walking in immersive virtual reality. The visual information provided in the virtual reality paradigm was modulated to create a mismatch between the optic-flow velocity of the visual scene and the walking speed on the treadmill. In each mismatched condition, we calculated the step duration, step length, step phase, step height, and asymmetries. The key finding of our study was that mismatch between treadmill walking speed and the optic-flow velocity did not consistently alter gait parameters in PD. We also found that STN DBS improved the PD gait pattern by changing the stride length and step height. The effects on phase and left/right asymmetry were not statistically significant. The DBS parameters and location also determined its effects on gait. Statistical effects on stride length and step height were noted when the DBS volume of activated tissue (VTA) was in the dorsal aspect of the subthalamus. The statistically significant effects of STN DBS was present when VTA significantly overlapped with MR tractogrphically measured motor and pre-motor hyperdirect pathways. In summary, our results provide novel insight into ways for controlling walking behavior in PD using STN DBS.

Stance Phase Gait Training Post Stroke Using Simultaneous Transcranial Direct Current Stimulation and Motor Learning-Based Virtual Reality-Assisted Therapy: Protocol Development and Initial Testing.

Gait deficits are often persistent after stroke, and current rehabilitation methods do not restore normal gait for everyone. Targeted methods of focused gait therapy that meet the individual needs of each stroke survivor are needed. Our objective was to develop and test a combination protocol of simultaneous brain stimulation and focused stance phase training for people with chronic stroke (>6 months). We combined Transcranial Direct Current Stimulation (tDCS) with targeted stance phase therapy using Virtual Reality (VR)-assisted treadmill training and overground practice. The training was guided by motor learning principles. Five users (>6 months post-stroke with stance phase gait deficits) completed 10 treatment sessions. Each session began with 30 min of VR-assisted treadmill training designed to apply motor learning (ML)-based stance phase targeted practice. During the first 15 min of the treadmill training, bihemispheric tDCS was simultaneously delivered. Immediately after, users completed 30 min of overground (ML)-based gait training. The outcomes included the feasibility of protocol administration, gait speed, Timed Up and Go (TUG), Functional Gait Assessment (FGA), paretic limb stance phase control capability, and the Fugl−Meyer for lower extremity coordination (FMLE). The changes in the outcome measures (except the assessments of stance phase control capability) were calculated as the difference from baseline. Statistically and clinically significant improvements were observed after 10 treatment sessions in gait speed (0.25 ± 0.11 m/s) and FGA (4.55 ± 3.08 points). Statistically significant improvements were observed in TUG (2.36 ± 3.81 s) and FMLE (4.08 ± 1.82 points). A 10-session intervention combining tDCS and ML-based task-specific gait rehabilitation was feasible and produced clinically meaningful improvements in lower limb function in people with chronic gait deficits after stroke. Because only five users tested the new protocol, the results cannot be generalized to the whole population. As a contribution to the field, we developed and tested a protocol combining brain stimulation and ML-based stance phase training for individuals with chronic stance phase deficits after stroke. The protocol was feasible to administer; statistically and/or clinically significant improvements in gait function across an array of gait performance measures were observed with this relatively short treatment protocol.

Development and deployment of cyclical focal muscle vibration system to improve walking performance in multiple sclerosis.

Vibration, a potent mechanical stimulus for activating muscle spindle primary afferents, may improve gait performance in persons with multiple sclerosis (MS), but has yet to be developed and deployed for multiple leg muscles with application during walking training. This study explored the development of a cyclic focal muscle vibration (FMV) system, and the deployment feasibility to correct MS walking swing phase deficits in order to determine whether this intervention warrants comprehensive study. The system was deployed during twelve, two-hour sessions of walking with cyclic FMV over six weeks. Participants served as their own control. Blood pressure, heart rate, walking speed, kinematics (peak hip, knee and ankle angles during swing), toe clearance, and step length were measured before and after deployment with blood pressure and heart rate monitored during deployment. During system deployment, there were no untoward sensations and physiological changes in blood pressure and heart rate, and volitional improvements were found in walking speed, improved swing phase kinematics, toe clearance and step length. This FMV training system was developed and deployed to improve joint flexion during walking in those with MS, and it demonstrated feasibility and benefits. Further study will determine the most effective vibration frequency and dose, carryover effects, and those most likely to benefit from this intervention.

Early evaluation of a powered transfemoral prosthesis with force-modulated impedance control and energy regeneration.

Individuals with an above-knee (AK) amputation typically use passive prostheses, whether reactive (microprocessor) or purely mechanical. Though sufficient for walking, these solutions lack the positive power generation observed in able-bodied individuals. Active (powered) prostheses can provide positive power but suffer complex control and limited energy storage capacities. These shortcomings motivate the development of an active prosthesis implementing a novel impedance controller design with energy regeneration. The controller requires only five tuning parameters that are intuitive to adjust in contrast to the current standard-finite state machine impedance scheduling of up to 45 gains. This simplification is uniquely achieved by modulating knee joint impedance by axial shank force. Furthermore, the proposed control approach introduces analytical guidance for impedance tuning to purposely integrate energy regeneration; specifically, a precise amount of negative damping is injected into the joint. A pilot study conducted with a volunteer with an AK amputation walking at three distinct speeds and at continually self-selected varying speeds demonstrated the adaptability of the controller to changes in speed. Self-powered operation was attained for all trials despite low mechanical component efficiencies. These early results suggest the efficacy of simplifying impedance control tuning and fusing control and energy regeneration in transfemoral prostheses.

Identifying Discordance of Right- and Left-Ventricular Filling Pressures in Patients With Heart Failure by the Clinical Examination.

BACKGROUND: In ≈25% of patients with heart failure and reduced left-ventricular ejection fraction, right-ventricular (RV), and left-ventricular (LV) filling pressures are discordant (ie, one is elevated while the other is not). Whether clinical assessment allows detection of this discordance is unknown. We sought to determine the agreement of clinically versus invasively determined patterns of ventricular congestion. METHODS: In 156 heart failure and reduced LV ejection fraction subjects undergoing invasive hemodynamic assessment, we categorized patterns of ventricular congestion (no congestion, RV only, LV only, or both) based on clinical findings of RV (jugular venous distention) or LV (hepatojugular reflux, orthopnea, or bendopnea) congestion. Agreement between clinically and invasively determined (RV congestion if right atrial pressure [RAP] ≥10 mm Hg and LV congestion if pulmonary capillary wedge pressure [PCWP] ≥22 mm Hg) categorizations was the primary end point. RESULTS: The frequency of clinical patterns of congestion was: 51% no congestion, 24% both RV and LV, 21% LV only, and 4% RV only. Jugular venous distention had excellent discrimination for elevated RAP (C=0.88). However, agreement between clinical and invasive congestion patterns was poor, к=0.44 (95% CI, 0.34-0.55). While those with no clinical congestion usually had low RAP and PCWP (67/79, 85%), over one-half (24/38, 64%) with isolated LV clinical congestion had PCWP <22 mm Hg, most (5/7, 71%) with isolated RV clinical congestion had PCWP ≥22 mm Hg, and ≈one-third (10/32, 31%) with both RV and LV clinical congestion had elevated RAP but PCWP <22 mm Hg. CONCLUSIONS: While clinical examination allows accurate detection of elevated RAP, it does not allow accurate detection of discordant RV and LV filling pressures.

An Extensive Set of Kinematic and Kinetic Data for Individuals with Intact Limbs and Transfemoral Prosthesis Users.

This paper introduces an extensive human motion data set for typical activities of daily living. These data are crucial for the design and control of prosthetic devices for transfemoral prosthesis users. This data set was collected from seven individuals, including five individuals with intact limbs and two transfemoral prosthesis users. These data include the following types of movements: (1) walking at three different speeds; (2) walking up and down a 5-degree ramp; (3) stepping up and down; (4) sitting down and standing up. We provide full-body marker trajectories and ground reaction forces (GRFs) as well as joint angles, joint velocities, joint torques, and joint powers. This data set is publicly available at the website referenced in this paper. Data from flexion and extension of the hip, knee, and ankle are presented in this paper. However, the data accompanying this paper (available on the internet) include 46 distinct measurements and can be useful for validating or generating mathematical models to simulate the gait of both transfemoral prosthesis users and individuals with intact legs.

Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy.

Pulmonary arterial hypertension is characterized by abnormalities in the small pulmonary arteries including increased vasoconstriction, vascular remodeling, proliferation of smooth muscle cells, and in situ thrombosis. Selexipag, a novel, oral prostacyclin receptor agonist, has been shown to improve hemodynamics in a phase II clinical trial and reduce clinical worsening in a large phase III clinical trial involving patients with pulmonary arterial hypertension. In this paper, we describe the prostacyclin signaling pathway, currently available oral prostanoid medications, and the development and clinical use of selexipag.

A real-time system for biomechanical analysis of human movement and muscle function.

Mechanical analysis of movement plays an important role in clinical management of neurological and orthopedic conditions. There has been increasing interest in performing movement analysis in real-time, to provide immediate feedback to both therapist and patient. However, such work to date has been limited to single-joint kinematics and kinetics. Here we present a software system, named human body model (HBM), to compute joint kinematics and kinetics for a full body model with 44 degrees of freedom, in real-time, and to estimate length changes and forces in 300 muscle elements. HBM was used to analyze lower extremity function during gait in 12 able-bodied subjects. Processing speed exceeded 120 samples per second on standard PC hardware. Joint angles and moments were consistent within the group, and consistent with other studies in the literature. Estimated muscle force patterns were consistent among subjects and agreed qualitatively with electromyography, to the extent that can be expected from a biomechanical model. The real-time analysis was integrated into the D-Flow system for development of custom real-time feedback applications and into the gait real-time analysis interactive lab system for gait analysis and gait retraining.

Ambulation and spinal cord injury.

Walking is possible for many patients with a spinal cord injury. Avenues enabling walking include braces, robotics and FES. Among the benefits are improved musculoskeletal and mental health, however unrealistic expectations may lead to negative changes in quality of life. Use rigorous assessment standards to gauge the improvement of walking during the rehabilitation process, but also yearly. Continued walking after discharge may be limited by challenges, such as lack of accessibility in and outside the home, and complications, such as shoulder pain or injuries from falls. It is critical to determine the risks and benefits of walking for each patient.

Neurotherapeutic and neuroprosthetic effects of implanted functional electrical stimulation for ambulation after incomplete spinal cord injury.

The purpose of this single-subject study was to determine the neurotherapeutic and neuroprosthetic effects of an implanted functional electrical stimulation (FES) system designed to facilitate walking in an individual with a longstanding motor and sensory incomplete spinal cord injury. An implanted pulse generator and eight intramuscular stimulating electrodes were installed unilaterally, activating weak or paralyzed hip flexors, hip and knee extensors, and ankle dorsiflexors during 36 sessions of gait training with FES. The neurotherapeutic effects were assessed by a comparison of pre- and posttraining volitional walking. The neuroprosthetic effects were assessed by a comparison of posttraining volitional and FES-assisted walking. Treatment resulted in significant (p < 0.005) volitional improvements in 6-minute walking distance and speed, speed during maximum walk, double support time, and 10 m walking speed. Posttraining FES-assisted walking resulted in significant additional improvements in all these measures, except 10 m walking speed. When the subject was using FES-assisted gait, maximum walking distance, peak knee flexion in swing, peak ankle dorsiflexion in swing, and knee extension moment also significantly increased. Neuroprosthetic gains were sufficient to enable the subject to advance from household ambulation to limited community ambulation. Additionally, the subject could perform multiple walks per day when using FES-assisted gait, which was impossible with volitional effort alone.

Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant.

T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod's in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod's adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity.

Family history of alcoholism does not influence adrenocortical hyporesponsiveness in abstinent alcohol-dependent men.

BACKGROUND: Early abstinence in alcohol-dependent subjects is marked by adrenocortical hyporesponsivity. However, it is uncertain whether the blunted response is primarily attributable to a genetic vulnerability or to the chronic abuse of alcohol. In the present study, the authors investigated the influence of a family history (FH) of alcoholism upon suppressed glucocorticoid reactivity. METHODS: Twenty-two abstinent alcohol-dependent and 14 control men were studied. The cortisol response was assessed in 11 patients following oCRH infusion (.4 ug/kg) and in a separate group of 11 patients following cosyntropin infusion (.01 ug/kg) preceded by high-dose intravenous dexamethasone (8 mg). FH, as determined by self-report, was assessed using two different methods: history of parental alcoholism and number of alcohol-dependent first- and second-degree relatives. RESULTS: Neither a parental history or familial loading of alcoholism had a significant effect upon glucocorticoid responsivity in abstinent alcohol-dependent men. CONCLUSIONS: Adrenocorticol responsiveness in recently abstinent alcohol-dependent men does not appear to reflect a preexisting biologic vulnerability to alcoholism.

Interleukin-6 as a mechanism for the adverse effects of social stress on acute Theiler's virus infection.

Prior exposure to social disruption stress (SDR) exacerbates both the acute and chronic phase of Theiler's murine encephalomyelitis virus infection (TMEV; [Johnson, R.R., Storts, R., Welsh, T.H., Jr., Welsh, C.J., Meagher, M.W., 2004. Social stress alters the severity of acute Theiler's virus infection. J. Neuroimmunol. 148, 74--85; Johnson, R.R., Prentice, T.W., Bridegam, P., Young, C.R., Steelman, A.J., Welsh, T.H., Welsh, C.J.R., Meagher, M.W., 2006. Social stress alters the severity and onset of the chronic phase of Theiler's virus infection. J. Neuroimmunol. 175, 39--51]). However, the neuroimmune mechanism(s) mediating this effect have not been determined. The present study examined whether stress-induced increases in the proinflammatory cytokine interleukin-6 (IL-6) contributes to the adverse effects of SDR on acute TMEV infection. Experiment 1 demonstrated that SDR increases central and peripheral levels of IL-6 and that this effect is reversed by intracerebral ventricular infusion of neutralizing antibody to IL-6 prior to each of six SDR sessions. Although SDR reduced the sensitivity of spleen cells to the anti-inflammatory effects of corticosterone, the neutralizing antibody to IL-6 did not alter this effect. To investigate whether stress-induced increases in IL-6 contribute to the exacerbation of acute TMEV infection, Experiment 2 examined whether intracerebral administration of neutralizing antibody to IL-6 during SDR would prevent the subsequent exacerbation of acute TMEV infection. Experiment 3 then replaced the social stress with intracerebral infusion of IL-6 to assess sufficiency. As expected, prior exposure to SDR subsequently increased infection-related sickness behaviors, motor impairment, CNS viral titers, and CNS inflammation. These deleterious effects of SDR were either prevented or significantly attenuated by intracerebral infusion of neutralizing antibody to IL-6 during the stress exposure period. However, infusion of IL-6 alone did not mimic the adverse effects of SDR. We conclude that IL-6 is necessary but not sufficient to exacerbate acute TMEV infection.