The design, development and evaluation of an array-based FES system with automated setup for the correction of drop foot

Functional electrical stimulation has been shown to be a safe and effective means of correcting drop foot of central neurological origin. However, despite recent technological advances, the set-up of surface stimulators remains a challenge for many users with drop foot. The automation of the setup process through the use of electrode arrays has been proposed as a way to address this problem. This paper describes a series of research and clinical studies which have led to the first demonstration of unsupervised automated setup of an electrode-array based drop foot stimulator. Finally, future research plans are discussed

Modelling and analysis of electrical impedance myography of the lateral tongue

Objective: Electrical impedance myography (EIM) performed on the centre of the tongue shows promise in detecting amyotrophic lateral sclerosis (ALS). Lateral recordings may improve diagnostic performance and provide pathophysiological insights through the assessment of asymmetry. However, it is not known if electrode proximity to the muscle edge, or electrode rotation, distort spectra. We evaluated this using finite element-based modelling. Approach: Nine thousand EIM from patients and healthy volunteers were used to develop a finite element model for phase and magnitude. Simulations varied electrode proximity to the muscle edge and electrode rotation. LT-Spice simulations assessed disease effects. Patient data were assessed for reliability, agreement and classification performance. Main results: No effect on phase spectra was seen if all electrodes remained in contact with the tissue. Small effects on magnitude were observed. Cole-Cole circuit simulations indicated capacitance reduced with disease severity. Lateral tongue muscle recordings in both patients and healthy volunteers were reproducible and symmetrical. Combined lateral/central tongue EIM improved disease classification compared to either placement alone. Significance: Lateral EIM tongue measurements using phase angle are feasible. Such measurements are reliable, find no evidence of tongue muscle asymmetry in ALS and improve disease classification. Lateral measurements enhance tongue EIM in ALS

A review of the design and clinical evaluation of the ShefStim array-based functional electrical stimulation system

Functional electrical stimulation has been shown to be a safe and effective means of correcting foot 12 drop of central neurological origin. Current surface-based devices typically consist of a single channel stimulator, 13 a sensor for determining gait phase and a cuff, within which is housed the anode and cathode. The cuff-mounted 14 electrode design reduces the likelihood of large errors in electrode placement, but the user is still fully responsible 15 for selecting the correct stimulation level each time the system is donned. Researchers have investigated different 16 approaches to automating aspects of setup and/or use, including recent promising work based on iterative learning 17 techniques. This paper reports on the design and clinical evaluation of an electrode array-based FES system for 18 the correction of drop foot, ShefStim. The paper reviews the design process from proof of concept lab-based study, 19 through modelling of the array geometry and interface layer to array search algorithm development. Finally, the 20 paper summarises two clinical studies involving patients with drop foot. The results suggest that the ShefStim 21 system with automated setup produces results which are comparable with clinician setup of conventional systems. 22 Further, the final study demonstrated that patients can use the system without clinical supervision. When used 23 unsupervised, setup time was 14 minutes (9 minutes for automated search plus 5 minutes for donning the 24 equipment), although this figure could be reduced significantly with relatively minor changes to the design

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross‐sectional international survey

Objective: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. Design: Cross‐sectional survey. Setting: International. Population: Clinicians involved in the management of MCDA twin pregnancies with sFGR. Methods: A structured, self‐administered survey. Main Outcome Measures: Clinical practices and attitudes to diagnostic criteria and management strategies. Results: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of 25% for the diagnosis of sFGR. For early‐onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early‐onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early‐onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early‐onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. Conclusions: There is significant variation in clinician practices and attitudes towards the management of early‐onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high‐level evidence to guide management

Cortical Representation of Lateralized Grasping in Chimpanzees (Pan troglodytes): A Combined MRI and PET Study

Functional imaging studies in humans have localized the motor-hand region to a neuroanatomical landmark call the KNOB within the precentral gyrus. It has also been reported that the KNOB is larger in the hemisphere contralateral to an individual's preferred hand, and therefore may represent the neural substrate for handedness. The KNOB has also been neuronatomically described in chimpanzees and other great apes and is similarly associated with handedness. However, whether the chimpanzee KNOB represents the hand region is unclear from the extant literature. Here, we used PET to quantify neural metabolic activity in chimpanzees when engaged in unilateral reach-and-grasping responses and found significantly lateralized activation of the KNOB region in the hemisphere contralateral to the hand used by the chimpanzees. We subsequently constructed a probabilistic map of the KNOB region in chimpanzees in order to assess the overlap in consistency in the anatomical landmarks of the KNOB with the functional maps generated from the PET analysis. We found significant overlap in the anatomical and functional voxels comprising the KNOB region, suggesting that the KNOB does correspond to the hand region in chimpanzees. Lastly, from the probabilistic maps, we compared right- and left-handed chimpanzees on lateralization in grey and white matter within the KNOB region and found that asymmetries in white matter of the KNOB region were larger in the hemisphere contralateral to the preferred hand. These results suggest that neuroanatomical asymmetries in the KNOB likely reflect changes in connectivity in primary motor cortex that are experience dependent in chimpanzees and possibly humans

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

ObjectiveTo identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies.DesignCross-sectional survey.SettingInternational.PopulationClinicians involved in the management of MCDA twin pregnancies with sFGR.MethodsA structured, self-administered survey.Main outcome measuresClinical practices and attitudes to diagnostic criteria and management strategies.ResultsOverall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of 25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide.ConclusionsThere is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570