The use of biofeedback for gait retraining: A mapping review

Background: Biofeedback seems to be a promising tool to improve gait outcomes for both healthy individuals and patient groups. However, due to differences in study designs and outcome measurements, it remains uncertain how different forms of feedback affect gait outcomes. Therefore, the aim of this study is to review primary biomechanical literature which has used biofeedback to alter gait-related outcomes in human participants. Methods: Medline, Cinahl, Cochrane, SPORTDiscus and Pubmed were searched from inception to December 2017 using various keywords and the following MeSHterms: biofeedback, feedback, gait, walking and running. From the included studies, sixteen different study characteristics were extracted. Findings: In this mapping review 173 studies were included. The most common feedback mode used was visual feedback (42%, n=73) and the majority fed-back kinematic parameters (36%, n=62). The design of the studies were poor: only 8% (n=13) of the studies had both a control group and a retention test; 69% (n=120) of the studies had neither. A retention test after 6 months was performed in 3% (n=5) of the studies, feedback was faded in 9% (n=15) and feedback was given in the field rather than the laboratory in 4% (n=8) of the studies. Interpretation: Further work on biofeedback and gait should focus on the direct comparison between different modes of feedback or feedback parameters, along with better designed and field based studies

Characterizing the learning effect in response to biofeedback aimed at reducing tibial acceleration during running

Increased tibial acceleration has been found to be an important risk factor for tibial stress fractures. Interventions aimed at reducing this variable which found a beneficial effect include the use of biofeedback in gait retraining. However, no studies have focused on the time participants take to modify tibial acceleration, therefore we aimed to find the start of a learning plateau in this study. Six participants ran on a treadmill while multisensory feedback was given. A single-subject analysis was used to characterise the learning effects. All participants changed peak tibial acceleration within the first step of running in the feedback condition. Two participants further reduced tibial acceleration to reach a plateau within 120 steps. In four of the six participants a strong effect of the feedback was still present after a week. Further research is needed to optimise the use of biofeedback in reducing the prevalence of tibial stress fractures

Runners’ individual learning responses to a biofeedback intervention to reduce tibial acceleration

Increased peak tibial acceleration has been related to tibial stress fractures. Reducing tibial acceleration could, therefore, help prevent injury. With the use of a single-subject analysis, it was aimed to give an insight into which individual gait strategies participants used and how quickly participants responded to a biofeedback intervention aimed to reduce tibial acceleration. First, a literature review was performed to identify gaps in the literature and inform primary research studies. Secondly, different methodological approaches were considered and a feedback system was developed based on exploratory studies focussing on the direct learning response, treadmill speed, target, and verbal instruction. A single-subject design was chosen and the minimal detectable difference was calculated to determine the minimum amount of change which was sufficiently greater than the measurement error and day-to-day variability in order to consider the measured change represented a genuine biomechanical difference. For the group, mean peak tibial acceleration significantly decreased by 26 per cent between the baseline measurements and the one-month follow-ups. Nine out of the eleven participants found a real decrease in mean peak tibial acceleration after a month. Participants needed one to six sessions to automatize running with reduced tibial acceleration. However, they were still able to reduce mean peak tibial acceleration after they automatized running. Further, participants found different shock-absorbing mechanisms comparing measurements taken directly after the intervention to after a month. This suggests participants did not learn a specific solution to be able to reduce tibial acceleration, but were able to switch in between shock-absorbing mechanisms. This programme of research showed the importance of a single-subject analysis in this area of research. Future directions could focus on in-field, individually tailored, gait retraining to improve the outcomes and be able to help reduce the prevalence of tibial stress fractures in runners

Pharmacological treatment of Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a very rare antibody-mediated autoimmune disease of the neuromuscular junction. Therapy can be divided in symptomatic treatment and immunosuppressive treatment. Symptomatic treatment with amifampridine is the only therapy currently authorized for use in LEMS patients. In the Netherlands the first choice drug is amifampridine base in an extended release formulation instead of the currently authorized amifampridine phosphate. This formulation has lower costs and is possibly safer due to lower peak concentrations. Other therapy used in LEMS patients is prescribed off-label and is based on experience in patients with myasthenia gravis. In many cases pyridostigmine is added as symptomatic treatment. In almost half of patients immunosuppressive therapy is started, mostly corticosteroids with or without azathioprine. Intravenous immunoglobulins and plasma exchange are used as emergency treatment. Currently no randomized clinical trials with new therapies are ongoing or announced in patients with LEMS, although multiple new therapies for myasthenia gravis are being investigated. These future therapies can be differentiated in symptomatic and immunomodulating drugs. The immunomodulating drugs can be further differentiated in early stage drugs which target the B-cell, later stage drugs which target the circulating antibodies and targeted therapy which have a disease-specific target. Some early and later stage immunomodulating drugs show promising results in myasthenia gravis although high cost and uncertain long term safety may be limiting for incorporating these drugs in LEMS treatment guidelines. Clinical trials in LEMS patients are lacking due to the rarity of the disease and we suggest the following requirements for future trials of potential new treatments: Sufficient power by performing multicenter or n-of-1 trials when appropriate, a cross-over design to reduce the number of patients and using a LEMS-specific quantitative primary outcome measure like the 3TUG score

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol

Introduction: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. Areas covered: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). Expert opinion: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosin

Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Terminally Ill Adult Patients

Background and Objective: Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis. Methods: Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis. Results: The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates. Conclusions: Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients

Estimated incidence of previously undetected atrial fibrillation on a 14-day continuous electrocardiographic monitor and associated risk of stroke

Aims There is uncertainty about whether and how to perform screening for atrial fibrillation (AF). To estimate the incidence of previously undetected AF that would be captured using a continuous 14-day ECG monitor and the associated risk of stroke. Methods and results We analysed data from a cohort of patients >65 years old with hypertension and a pacemaker, but without known AF. For each participant, we simulated 1000 ECG monitors by randomly selecting 14-day windows in the 6 months following enrolment and calculated the average AF burden (total time in AF). We used Cox proportional hazards models adjusted for CHA(2)DS(2)-VASc score to estimate the risk of subsequent ischaemic stroke or systemic embolism (SSE) associated with burdens of AF > and 6 min was 3.10% (95% CI 2.53-3.72). This was consistent across strata of age and CHA(2)DS(2)-VASc scores. Over a mean follow-up of 2.4 years, the rate of SSE among patients with 6 min of AF. Conclusions Approximately 3% of individuals aged >65 years with hypertension may have more than 6 min of AF detected by a 14-day ECG monitor. This is associated with a stroke risk of over 2% per year. Whether oral anticoagulation will reduce stroke in these patients is unknown

A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease

BACKGROUND: Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD. OBJECTIVES: To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement. METHODS: The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (31 P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment. RESULTS: UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31 P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups. CONCLUSIONS: High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?

Aims: Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. Because of large inter-individual variability (IIV), however, the time it takes to achieve adequate sedation varies widely. It would therefore greatly improve clinical care if an individualized dose could be determined beforehand. To find clinically relevant parameters for dose individualization, we performed a pharmacokinetic study on midazolam, 1OH-midazolam (1-OH-M) and 1OH-midazolam-glucuronide (1-OH-MG) in terminally ill patients. Methods: Using nonlinear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 192 samples from 45 terminally ill patients who received midazolam either orally or subcutaneously. The covariates analysed were patient characteristics, co-medication and blood chemistry levels. Results: The data were accurately described by a one compartment model for midazolam, 1-OH-M and 1-OH-MG. The population mean estimates for midazolam, 1-OH-M and 1-OH-MG clearance were 8.4 l h−1 (RSE 9%, IIV 49%), 45.4 l h−1 (RSE 12%, IIV 60.5%) and 5.1 l h−1 (RSE 11%, IIV 49.9%), respectively. 1-OH-MG clearance was correlated with the estimated glomular filtration rate (eGFR) explaining 28.4% of the IIV in 1-OH-MG clearance. In addition, low albumin levels were associated with decreased midazolam clearance, explaining 18.2% of the IIV. Conclusion: Our study indicates albumin levels and eGFR as relevant clinical parameters to optimize midazolam dosing in terminally ill patients. The correlation between low albumin levels and decreased midazolam clearance is probably a result of inflammatory response as high CRP levels were correlated in a similar way