Cost-effectiveness analysis of the geko™ device (an NMES technology) in managing venous leg ulcers in UK healthcare settings.

This study evaluates the cost-effectiveness of the geko device a neuromuscular electro-stimulator technology with standard of care (SoC) versus SoC alone for venous leg ulcer (VLU) treatment, from the UK National Health Service (NHS) perspective over 12 months. Research was conducted across NHS UK facilities, primarily within community services and outpatient leg ulcer clinics, encompassing a total of 51 patients. A partitioned survival model, based on a two-arm randomised controlled trial, assessed wound healing rates using Kaplan-Meier curves and parametric extrapolations over a 12-month time horizon. Costs were derived from UK reference costs the British National Formulary, and the Personal Social Services Research Unit (2021/22). The primary outcome measured was the incremental cost per quality-adjusted life-year gained. The geko device provides additional benefits by stimulating the lateral popliteal nerve, augmenting venous, arterial, and microvascular flow. The addition of the geko device to SoC significantly enhanced outcomes, increasing healing probability by 68% compared to SoC. This integration would result in a cost saving of £774.14 per patient when compared to the SoC alone across the NHS. Economic analyses indicate that integrating the geko device into SoC protocols would reduce the overall NHS expenditure on VLU wound management by as much as 15%. The approach also positively impacted health-related quality of life. The geko™ device when used adjunctively with SoC would be a cost-effective method for managing chronic VLUs within the NHS, improving healing rates and offering economic benefits.

Benefits of home-based foot neuromuscular electrical stimulation on self-reported function, leg pain and other leg symptoms among community-dwelling older adults: a sham-controlled randomised clinical trial.

INTRODUCTION: Lower leg pain and symptoms, and poor leg circulation are common in older adults. These can significantly affect their function and quality of life. Neuromuscular electrical stimulation (NMES) applied via the feet as 'foot NMES' activates the leg musculovenous pump. This study investigated the effects of foot NMES administered at home using Revitive® among community-dwelling older adults with lower leg pain and/or other lower leg symptoms such as cramps, or sensations of tired, aching, and heavy feeling legs. METHODS: A randomised placebo-controlled study with three groups (2 NMES, 1 Sham) and three assessments (baseline, week 8, week 12 follow-up) was carried out. Self-reported function using Canadian occupational performance measure (COPM), leg pain, overall leg symptoms score (heaviness, tiredness, aching, or cramps), and ankle blood flow were assessed. Analysis of covariance (ANCOVA) and logistic regression were used to compare the groups. Statistical significance was set at p < 0.05 (two-sided 5%). RESULTS: Out of 129 participants enrolled, 114 completed the study. The improvement in all outcomes were statistically significant for the NMES interventions compared to Sham at both week 8 (p < 0.01) and week 12 (p < 0.05). The improvement in COPM met the minimal clinically important difference (MCID) for the NMES interventions compared to Sham at both week 8 (p < 0.005) and week 12 (p < 0.05). Improvement in leg pain met MCID at week 8 compared to Sham (p < 0.05). Ankle blood flow increased approximately 3-fold during treatment compared to Sham. Compliance with the interventions was high and no device-related adverse events were reported. CONCLUSIONS: The home-based foot NMES is safe, and significantly improved self-reported function, leg pain and overall leg symptoms, and increased ankle blood flow compared to a Sham among older adults. TRIAL REGISTRATION: The trial was prospectively registered in ISRCTN on 17/06/2019 with registration number ISRCTN10576209. It can be accessed at https://www.isrctn.com/ISRCTN10576209 .

Synthetic routes and clinical application of new drugs approved by EMA during 2023.

In 2023, the European Medicines Agency (EMA) granted approval to 77 new molecular entities (NMEs), consisting of 45 new chemical entities (NCEs) and 32 new biological entities (NBEs). These pharmacological agents encompass a broad spectrum of therapeutic domains, including oncology, cardiology, dermatology, diagnostic medicine, endocrinology, gastroenterology and hepatology, metabolic disorders, and neurology. Among the 77 approved pharmaceuticals, three received accelerated review status, and 17 (22 %) were granted orphan drug designation for the treatment of rare diseases. This review provides an overview of the clinical applications and synthetic routes of 42 newly approved NCEs by the EMA in 2023. The objective is to offer a comprehensive understanding of the synthetic approaches used in the development of these drug molecules, thereby inspiring the creation of novel, efficient, and applicable synthetic methodologies.

Safety and Feasibility of Neuromuscular Electrical Stimulation in Patients with Extracorporeal Membrane Oxygenation.

Background/Objectives: The aim of this study was to investigate the feasibility and safety of neuromuscular electrical stimulation (NMES) in patients on extracorporeal membrane oxygenation (ECMO) and thoroughly assess any potential adverse events. Methods: We conducted a prospective observational study assessing safety and feasibility, including 16 ICU patients on ECMO support who were admitted to the cardiac surgery ICU from January 2022 to December 2023. The majority of patients were females (63%) on veno-arterial (VA)-ECMO (81%), while the main cause was cardiogenic shock (81%) compared to respiratory failure. Patients underwent a 45 min NMES session while on ECMO support that included a warm-up phase of 5 min, a main phase of 35 min, and a recovery phase of 5 min. NMES was implemented on vastus lateralis, vastus medialis, gastrocnemius, and peroneus longus muscles of both lower extremities. Two stimulators delivered biphasic, symmetric impulses of 75 Hz, with a 400 µsec pulse duration, 5 sec on (1.6 sec ramp up and 0.8 sec ramp down) and 21 sec off. The intensity levels aimed to cause visible contractions and be well tolerated. Primary outcomes of this study were feasibility and safety, evaluated by whether NMES sessions were successfully achieved, and by any adverse events and complications. Secondary outcomes included indices of rhabdomyolysis from biochemical blood tests 24 h after the application of NMES. Results: All patients successfully completed their NMES session, with no adverse events or complications. The majority of patients achieved type 4 and 5 qualities of muscle contraction. Conclusions: NMES is a safe and feasible exercise methodology for patients supported with ECMO.

The effect of EMS, IFC, and TENS on patient-reported outcome measures for chronic low back pain: a systematic review and meta-analysis.

Introduction: Chronic low back pain (CLBP) is the leading cause of years lived with disability worldwide. Transcutaneous electrotherapies have been widely used to treat CLBP but, with the partial exception of transcutaneous electrical nerve stimulation (TENS), their effect on pain, disability, quality-of-life, and psychosocial outcomes have not been systematically reviewed. The purpose of this systematic review and meta-analysis was to clarify the overall effect of transcutaneous electrotherapies on patient-reported outcome measures (PROMs) in CLBP patients. Methods: Four databases and two study registries were searched for studies that utilized transcutaneous electrotherapies as a primary intervention for CLBP, compared against active or passive controls. Two reviewers independently extracted study data and assessed risk of bias. Studies were grouped by intervention vs. comparison, and by time of follow-up. Meta-analyses were conducted where appropriate. Results: A total of 89 full-text were assessed for eligibility; 14 studies were included, with 6 in the meta-analyses (all TENS or mixed TENS). Pain: meta-analyses revealed no significant difference for TENS vs. active control, TENS vs. passive control, or mixed TENS vs. active control at post-intervention, nor for mixed TENS vs. active control at 1-month post-intervention. Interferential current (IFC) was more effective than active control (2 studies), while electromyostimulation (EMS) was generally superior to passive, but not active, controls (6 studies). Disability: Meta-analyses revealed no significant difference for TENS vs. active control at post-intervention, mixed TENS vs. active control at post-intervention, or mixed TENS vs. active control at 1-month post-intervention. IFC was more effective than active control (2 studies), while the EMS results were mixed (6 studies). We were unable to perform meta-analyses for quality-of-life or psychosocial outcomes. Conclusion: There is moderate evidence that TENS is similar to all controls for improving pain and disability. There is limited evidence that IFC is superior to active controls for improving pain and disability. There is limited evidence that EMS is superior to passive but not active controls for improving pain, and similar to all controls for improving disability. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=452851, Identifier (CRD42023452851).

The effect of using a combined electrical stimulation therapy on improving sensory and motor functions of the bladder and the bowel in children with myelomeningocele: A case series.

This case study evaluated the effectiveness of using a combination of faradic and neuromuscular electrical stimulation to improve the sensory and motor function of the bladder/bowel in pediatric patients diagnosed with spina bifida with myelomeningocele. All five patients were pediatric cases aged 4-15 years (mean age 8.4 ± 4.3 years) with complete incontinence in both bladder and bowel functions and self-referred to the Leyaqa Physical Therapy Center in Qatif, Saudi Arabia. All patients had diminished sensation from the hips down and underwent 24 electrical stimulation sessions. Bladder and bowel control were improved by 40% and 20%, respectively. All participants had improved bladder sensation, and 80% had improved bowel sensation. All participants reported improvement in constipation. Feeling the urge or sensation of emptying the bladder or bowel was dramatically improved in all participants. This combination of stimulation electrotherapy can be offered with benefits according to the series of cases studied.

Motoneuron persistent inward current contribution to increased torque responses to wide-pulse high-frequency neuromuscular electrical stimulation.

PURPOSE: To assess the effect of a remote handgrip contraction during wide-pulse high-frequency (WPHF) neuromuscular electrical stimulation (NMES) on the magnitude of extra torque, progressive increase in torque during stimulation, and estimates of the persistent inward current (PIC) contribution to motoneuron firing in the plantar flexors. METHODS: Ten participants performed triangular shaped contractions to 20% of maximal plantar flexion torque before and after WPHF NMES with and without a handgrip contraction, and control conditions. Extra torque, the relative difference between the initial and final torque during stimulation, and sustained electromyographic (EMG) activity were assessed. High-density EMG was recorded during triangular shaped contractions to calculate ∆F, an estimate of PIC contribution to motoneuron firing, and its variation before vs after the intervention referred to as ∆F change score. RESULTS: While extra torque was not significantly increased with remote contraction (WPHF + remote) vs WPHF (+ 37 ± 63%, p = 0.112), sustained EMG activity was higher in this condition than WPHF (+ 3.9 ± 4.3% MVC EMG, p = 0.017). Moreover, ∆F was greater (+ 0.35 ± 0.30 Hz) with WPHF + remote than control (+ 0.03 ± 0.1 Hz, p = 0.028). A positive correlation was found between ∆F change score and extra torque in the WPHF + remote (r = 0.862, p = 0.006). DISCUSSION: The findings suggest that the addition of remote muscle contraction to WPHF NMES enhances the central contribution to torque production, which may be related to an increased PIC contribution to motoneuron firing. Gaining a better understanding of these mechanisms should enable NMES intervention optimization in clinical and rehabilitation settings, improving neuromuscular function in clinical populations.

The Impact of Baseline Pain Intensity on the Effectiveness of Whole-Body Electromyostimulation (WB-EMS) for Nonspecific Chronic Back Pain.

INTRODUCTION: Recent clinical studies confirmed that whole-body electromyostimulation (WB-EMS) training is a safe and time-efficient therapeutic method for patients with nonspecific chronic back pain (NSCBP). However, significant variations in initial pain intensity among subjects in these studies have been observed. This study aims to determine if patients with differing initial pain intensities experience varying degrees of benefit from WB-EMS and to assess the overall correlation between initial pain levels and pain reduction. METHODS: Pain intensity datasets from two studies were combined. The pooled data included 121 NSCBP patients (38 males and 83 females) with an average age of 55.1 years (±11.8 years). Data was categorized by baseline pain intensity on the numeric rating scale (NRS) into seven groups: 0 to 2, >2 to 3, >3 to 4, >4 to 5, >5 to 6, >6 to 7, and >7. Both absolute and relative changes were analyzed. Additionally, a Spearman rho correlation test was performed on the entire dataset to evaluate the relationship between initial pain level and pain reduction. RESULTS: Significant improvements were noted across all NRS11 categories, with strong effect sizes (p) in all classes above 2, ranging from 0.56 to 0.90. The >7 category exhibited the highest rate of clinically significant changes (80%) and an average improvement of 3.72 points. The overall group from >1 to 10 showed an average improvement of 1.33 points, with 37% of the participants experiencing clinically significant improvements. The Spearman rho correlation test revealed a moderate positive relationship between initial pain level and pain reduction (r_s = 0.531, p < 0.001), indicating that, generally, higher initial pain levels are associated with greater pain reduction. CONCLUSION: The findings support the hypothesis that NSCBP patients with higher baseline NRS values benefit more substantially from WB-EMS. Those with NRS values above 7 show the greatest improvement and highest rate of clinical significance. The overall positive correlation between initial pain intensity and pain reduction further underscores the efficacy of WB-EMS in managing NSCBP across different pain intensities.

Swallowing Rehabilitation With Neuromuscular Electrical Stimulation for Sarcopenic Dysphagia: A Case Report.

Sarcopenic dysphagia is defined as dysphagia caused by sarcopenia of the whole body and swallowing-related muscles. We present a case of sarcopenic dysphagia with improved swallowing function after strength training of swallowing-related muscles using neuromuscular electrical stimulation (NMES). A 78-year-old man was admitted to our hospital with an intraductal papillary mucinous tumor of the pancreatic duct. After admission, the patient developed aspiration pneumonia and was placed on strict bed rest without oral intake, which resulted in progressive malnutrition. At the start of swallowing rehabilitation, he had whole-body sarcopenia, nutritional impairment, and weakness in swallowing-related muscles, with a maximum tongue pressure of 21.4 kPa and an opening force of 5.1 kg. In the videofluoroscopic swallowing study, he aspirated 3 cc of a moderately thick liquid. Consequently, as part of swallowing rehabilitation, strengthening training of swallowing-related muscles with NMES was undertaken for about three weeks. As a result, the maximum tongue pressure and opening force improved to 28.4 kPa and 6.8 kg, respectively. A subsequent videofluoroscopic swallowing study showed no obvious aspiration during any procedure. The patient was discharged on the 86th day on a regular diet. As a component of swallowing rehabilitation, NMES may offer therapeutic benefits for patients with sarcopenic dysphagia.

Development and evaluation of a BCI-neurofeedback system with real-time EEG detection and electrical stimulation assistance during motor attempt for neurorehabilitation of children with cerebral palsy.

In the realm of motor rehabilitation, Brain-Computer Interface Neurofeedback Training (BCI-NFT) emerges as a promising strategy. This aims to utilize an individual's brain activity to stimulate or assist movement, thereby strengthening sensorimotor pathways and promoting motor recovery. Employing various methodologies, BCI-NFT has been shown to be effective for enhancing motor function primarily of the upper limb in stroke, with very few studies reported in cerebral palsy (CP). Our main objective was to develop an electroencephalography (EEG)-based BCI-NFT system, employing an associative learning paradigm, to improve selective control of ankle dorsiflexion in CP and potentially other neurological populations. First, in a cohort of eight healthy volunteers, we successfully implemented a BCI-NFT system based on detection of slow movement-related cortical potentials (MRCP) from EEG generated by attempted dorsiflexion to simultaneously activate Neuromuscular Electrical Stimulation which assisted movement and served to enhance sensory feedback to the sensorimotor cortex. Participants also viewed a computer display that provided real-time visual feedback of ankle range of motion with an individualized target region displayed to encourage maximal effort. After evaluating several potential strategies, we employed a Long short-term memory (LSTM) neural network, a deep learning algorithm, to detect the motor intent prior to movement onset. We then evaluated the system in a 10-session ankle dorsiflexion training protocol on a child with CP. By employing transfer learning across sessions, we could significantly reduce the number of calibration trials from 50 to 20 without compromising detection accuracy, which was 80.8% on average. The participant was able to complete the required calibration trials and the 100 training trials per session for all 10 sessions and post-training demonstrated increased ankle dorsiflexion velocity, walking speed and step length. Based on exceptional system performance, feasibility and preliminary effectiveness in a child with CP, we are now pursuing a clinical trial in a larger cohort of children with CP.

Modification of velopharyngeal closure pressures during phonation by neuromuscular electrical stimulation in healthy individuals.

Introduction: Rhinophonia aperta may result from velopharyngeal insufficiency. Neuromuscular electrical stimulation (NMES) has been discussed in the context of muscle strengthening. The aim of this study was to evaluate in healthy subjects whether NMES can change the velopharyngeal closure pattern during phonation and increase muscle strength. Method: Eleven healthy adult volunteers (21-57 years) were included. Pressure profiles were measured by high resolution manometry (HRM): isolated sustained articulation of /a/ over 5 s (protocol 1), isolated NMES applied to soft palate above motor threshold (protocol 2) and combined articulation with NMES (protocol 3). Mean activation pressures (MeanAct), maximum pressures (Max), Area under curve (AUC) and type of velum reactions were compared. A statistical comparison of mean values of protocol 1 versus protocol 3 was carried out using the Wilcoxon signed rank test. Ordinally scaled parameters were analyzed by cross table. Results: MeanAct values measured: 17.15±20.69 mmHg (protocol 1), 34.59±25.75 mmHg (protocol 3) on average, Max: 37.86±49.17 mmHg (protocol 1), 87.24±59.53 mmHg (protocol 3) and AUC: 17.06±20.70 mmHg.s (protocol 1), 33.76±23.81 mmHg.s (protocol 3). Protocol 2 produced velum reactions on 32 occasions. These presented with MeanAct values of 13.58±12.40 mmHg, Max values of 56.14±53.14 mmHg and AUC values of 13.84±12.78 mmHg.s on average. Statistical analysis comparing protocol 1 and 3 showed more positive ranks for MeanAct, Max and AUC. This difference reached statistical significance (p=0.026) for maximum pressure values. Conclusions: NMES in combination with articulation results in a change of the velopharyngeal closure pattern with a pressure increase of around 200% in healthy individuals. This might be of therapeutic benefit for patients with velopharyngeal insufficiency.

Comparison of Immediate Neuromodulatory Effects between Focal Vibratory and Electrical Sensory Stimulations after Stroke.

Focal vibratory stimulation (FVS) and neuromuscular electrical stimulation (NMES) are promising technologies for sensory rehabilitation after stroke. However, the differences between these techniques in immediate neuromodulatory effects on the poststroke cortex are not yet fully understood. In this research, cortical responses in persons with chronic stroke (n = 15) and unimpaired controls (n = 15) were measured by whole-brain electroencephalography (EEG) when FVS and NMES at different intensities were applied transcutaneously to the forearm muscles. Both FVS and sensory-level NMES induced alpha and beta oscillations in the sensorimotor cortex after stroke, significantly exceeding baseline levels (p < 0.05). These oscillations exhibited bilateral sensory deficiency, early adaptation, and contralesional compensation compared to the control group. FVS resulted in a significantly faster P300 response (p < 0.05) and higher theta oscillation (p < 0.05) compared to NMES. The beta desynchronization over the contralesional frontal-parietal area remained during NMES (p > 0.05), but it was significantly weakened during FVS (p < 0.05) after stroke. The results indicated that both FVS and NMES effectively activated the sensorimotor cortex after stroke. However, FVS was particularly effective in eliciting transient involuntary attention, while NMES primarily fostered the cortical responses of the targeted muscles in the contralesional motor cortex.

Case report of belt electrode-skeletal muscle electrical stimulation for acute heart failure with severe obesity: a novel therapeutic option for acute phase rehabilitation.

Background: Belt electrode skeletal muscle electrical stimulation (B-SES) is an emerging therapy anticipated to yield more favorable outcomes than conventional neuromuscular electrical stimulation (NMES), owing to its larger stimulation area. However, information on its efficacy and safety in patients with heart failure remains limited. Case presentation: A 43-year-old man with a body mass index of 41 kg/m2 was admitted to our hospital for acute heart failure due to dilated cardiomyopathy. The patient required prolonged catecholamine support owing to poor cardiac function, and heart transplantation was considered. We initiated a mobilization program, but the patient's mobility was highly limited due to severe obesity and symptomatic orthostatic hypotension. B-SES was introduced to accomplish weight loss and early ambulation. We applied an intensive monitoring program for safe use and modulated the intensity of B-SES according to physical function. During the B-SES program, the patient's body weight decreased from 89.6 kg to 78.6 kg. Sequential evaluations of body composition and skeletal muscle ultrasonography revealed improved muscle mass, quality, and physical function. Furthermore, we explored the workload of B-SES using expiratory gas analysis. No adverse events were observed during B-SES. Discussion: We successfully used B-SES to improve muscle function and morbidity in the treatment of acute heart failure. B-SES could be an option for patients with heart failure who have limited mobility and obesity.

Combined repetitive facilitative exercise under continuous neuromuscular electrical stimulation and task-oriented training for hemiplegic upper extremity during convalescent phase after stroke: before-and-after feasibility trial.

Introduction: Whereas repetitive facilitative exercise (RFE) affects primarily recovery of motor impairment after stroke, task-oriented training (TOT) focuses on facilitating daily use of the affected upper extremity. However, feasibility of combined RFE and TOT has not been reported. We originated "task-oriented RFE," as a new combination therapy for patients with hemiplegic upper extremity after subacute stroke, to examine its feasibility in convalescent rehabilitation wards. Methods: This is a before-and-after pilot study. Eight patients with hemiplegic upper extremity after subacute stroke received the task-oriented RFE program for 6 weeks at 80 min per day (20-60 min of TOT applied after 60-20 min of RFE under continuous neuromuscular electrical stimulation) in a convalescent rehabilitation ward. In the current program, we introduced the Aid for Decision-making in Occupation Choice (ADOC) iPad application as a goal-setting method for determining tasks. Feasibility was assessed with adherence to the protocol, adverse events in response to the intervention, and preliminary efficacy. Motor functions, amount of use and quality of movement in the hemiparetic upper extremity, and satisfaction of the patients were evaluated with Fugl-Meyer Assessment (FMA), the Action Research Arm Test (ARAT), the motor activity log (MAL) for the amount of use (AOU) and quality of movement (QOM) of the paralyzed hand, and ADOC. Results: All participants accomplished the program, which was implemented as originally planned; neither nonattendance nor an adverse event occurred during the study. Favorable outcomes were obtained with all measures; mean changes in FMA, ARAT in the dominant hand, MAL-AOU, and MAL-QOM were greater than minimal clinically important differences. Mean changes in ADOC were greater than the minimal detectable change. Discussion: The task-oriented RFE program was safe, well-tolerated, beneficial, and feasible within 80 min a day of occupational therapy, which means also within the procedural constraints of the Japanese health insurance system during the convalescent phase. Future studies are warranted to examine whether combined RFE and TOT enhances the efficacies of each program alone.

A controlled randomized trial with a 12-week follow-up investigating the effects of medium-frequency neuromuscular electrical stimulation on pain, VMO thickness, and functionality in patients with knee osteoarthritis.

BACKGROUND: One of the major contributors to disability in Knee osteoarthritis (KOA) patients is weakness in the Quadriceps Femoris muscle. Neuromuscular electrical stimulation (NMES) has been used in rehabilitation for patients suffering from muscle weakness. Thus, the purpose of the study was to assess the effectiveness of NMES and exercise therapy, for improving pain, muscle weakness and function among patients with KOA. METHODS: A randomized controlled trial was conducted with 75 female patients diagnosed with KOA. Participants were divided into three intervention groups: NMES-only, exercise therapy (Exs) alone, and a combination of NMES and exercise (NMES + Exs). All patients underwent 12 supervised treatment sessions, three times a week. Outcome measures included pain intensity measured by visual analog scale (VAS), knee flexion range of motion (FROM), thigh muscle girth (TG), thickness of the Vastus Medialis Oblique (VMO), timed up and go test (TUG), six-minute walk test (6MWT), and WOMAC scores. Statistical analyses (ANOVA and Kruskal-Wallis) methods were done to compare the amounts at the baseline, immediately after treatment and after 12 weeks. RESULTS: The NMES group exhibited a significant reduction in pain at the 12-week follow-up compared to the other groups(p = 0.022). The NMES + Exs group showed better outcomes in terms of FROM, TG, and VMO thickness post-intervention (p < 0.0001, p < 0.004, p = 0.003, respectively) and at the 12-week follow-up (p < 0.0001, p < 0.0001, p < 0.0001, respectively). Additionally, NMES was superior in improving TUG and 6MWT post-intervention (p < 0.0001, p = 0.038, respectively) and during the follow-up assessments (p < 0.0001, p = 0.029, respectively). The NMES + Exs group achieved better WOMAC stiffness scores at both post-intervention and follow-up evaluations (p < 0.0001, p < 0.0001, respectively). Furthermore, at the 12-week follow-up, NMES + Exs group outperformed the others in WOMAC pain and function subscales (p = 0.003, p = 0.017, respectively), while the NMES group demonstrated better WOMAC total scores compared to the other groups (p = 0.007). CONCLUSION: The combination of NMES and exercise seems to be an efficient approach for managing KOA, as it enhances knee flexion range and TG, increases VMO thickness, and improves WOMAC scores. On the other hand, NMES alone was found to be effective in improving the physical function of KOA patients. TRIAL REGISTRATION: IRCT20101228005486N7 (06-02-2020).

A comprehensive review of discovery and development of drugs discovered from 2020-2022.

To fully evaluate and define the new drug molecule for its pharmacological characteristics and toxicity profile, pre-clinical and clinical studies are conducted as part of the drug research and development process. The average time required for all drug development processes to finish various regulatory evaluations ranges from 11.4 to 13.5 years, and the expense of drug development is rising quickly. The development in the discovery of newer novel treatments is, however, largely due to the growing need for new medications. Methods to identify Hits and discovery of lead compounds along with pre-clinical studies have advanced, and one example is the introduction of computer-aided drug design (CADD), which has greatly shortened the time needed for the drug to go through the drug discovery phases. The pharmaceutical industry will hopefully be able to address the present and future issues and will continue to produce novel molecular entities (NMEs) to satisfy the expanding unmet medical requirements of the patients as the success rate of the drug development processes is increasing. Several heterocyclic moieties have been developed and tested against many targets and proved to be very effective. In-depth discussion of the drug design approaches of newly found drugs from 2020 to 2022, including their pharmacokinetic and pharmacodynamic profiles and in-vitro and in-vivo assessments, is the main goal of this review. Considering the many stages these drugs are going through in their clinical trials, this investigation is especially pertinent. It should be noted that synthetic strategies are not discussed in this review; instead, they will be in a future publication.

Neuromuscular Electrical Stimulation-Enhanced Physical Therapist Intervention for Functional Posterior Shoulder Instability (Type B1): A Multicenter Randomized Controlled Trial.

OBJECTIVE: Functional posterior shoulder instability (FPSI) (type B1) is a severe type of instability, mainly in teenagers and young adults, that leads to loss of function, pain, and stigmatization among peers. An experimental nonsurgical treatment protocol based on neuromuscular electrical stimulation (NMES) showed very promising early results in the treatment of FPSI. The hypothesis of this study was that NMES-enhanced physical therapy leads to better outcomes than physical therapy alone as the current gold standard of treatment in patients with FPSI. METHODS: In this multicenter randomized controlled trial, patients with FPSI were randomly allocated in a 1:1 ratio to either 6 weeks of physical therapy or 6 weeks of physical therapy with simultaneous motion-triggered NMES. Baseline scores as well as outcome scores at 6 weeks, 3 months, 6 months, and 12 months after the intervention were obtained. The predefined primary outcome of this trial was the Western Ontario Shoulder Instability Index (WOSI) at the 3-month time point. RESULTS: Forty-nine patients were randomized and eligible for the trial. The group that received physical therapy with simultaneous motion-triggered NMES showed a significantly better main outcome measurement in terms of the 3-month WOSI score (64% [SD = 16%] vs 51% [SD = 24%]). Two-thirds of the patients from the physical therapist group crossed over to the group that received physical therapy with simultaneous motion-triggered NMES due to dissatisfaction after the 3-month follow-up and showed a significant increase in their WOSI score from 49% [SD = 8%] to 67% [SD = 24%]. The frequency of instability episodes showed a significant improvement in the group that received physical therapy with simultaneous motion-triggered NMES at the 3-month follow-up and beyond, while in the physical therapist group, no significant difference was observed. CONCLUSION: The current study shows that NMES-enhanced physical therapy led to statistically significant and clinically relevant improvement in outcomes in the treatment of FPSI compared to conventional physical therapy alone-from which even patients with prior unsatisfactory results after conventional physical therapy can benefit. IMPACT: Based on the results of this study, NMES-enhanced physical therapy is an effective new treatment option for FPSI, a severe type of shoulder instability. NMES-enhanced physical therapy should be preferred over conventional physical therapy for the treatment of patients with FPSI.

Comparison of acute responses in spinal excitability between older and young people after neuromuscular electrical stimulation.

PURPOSE: This study aims at comparing acute responses in spinal excitability, as measured by H-reflex, between older and young individuals, following a single session of NMES superimposed onto voluntary isometric contractions of the ankle plantar-flexor muscles (NMES+), with respect to passive NMES (pNMES) and voluntary isometric contractions only (ISO). METHODS: Thirty-two volunteers, 16 older (OLDER) and 16 young (YOUNG), were asked to sustain a constant force at 20% of maximal voluntary isometric contraction (MVIC) of the ankle plantar-flexor muscles in the dominant limb during each of the 3 conditions (NMES+ , pNMES and ISO). Fifteen repetitions of 6 s were performed, with a resting interval of 6 s between repetitions. Before and after each condition, soleus H-reflexes were elicited by percutaneous electrical stimulation of the posterior tibial nerve and H-reflex amplitudes recorded by surface EMG. RESULTS: In OLDER, H-reflex amplitude did not change following any experimental condition (ISO: p = 0.203; pNMES: p = 0.542; NMES+: p = 0.431) compared to baseline. On the contrary, in YOUNG, H-reflex amplitudes significantly increased (p < 0.000) and decreased (p = 0.001) following NMES+ and pNMES, respectively, while there was no significant change in reflex responses following ISO (p = 0.772). CONCLUSION: The lack of change in H-reflex responses following either NMES+ or pNMES might reflect a reduced ability of older people in modulating spinal excitability after the conditions. Specifically, an age-related alteration in controlling mechanisms at presynaptic level was suggested.

The effect of neuromuscular electrical stimulation applied at different muscle lengths on muscle architecture and sarcomere morphology in rats.

Neuromuscular electrical stimulation (NMES) is often used to increase muscle strength and functionality. Muscle architecture is important for the skeletal muscle functionality. The aim of this study was to investigate the effects of NMES applied at different muscle lengths on skeletal muscle architecture. Twenty-four rats were randomly assigned to four groups (two NMES groups and two control groups). NMES was applied on the extensor digitorum longus muscle at long muscle length, which is the longest and stretched position of the muscle at 170° plantar flexion, and at medium muscle length, which is the length of the muscle at 90° plantar flexion. A control group was created for each NMES group. NMES was applied for 8 weeks, 10 min/day, 3 days/week. After 8 weeks, muscle samples were removed at the NMES intervention lengths and examined macroscopically, and microscopically using a transmission electron microscope and streo-microscope. Muscle damage, and architectural properties of the muscle including pennation angle, fibre length, muscle length, muscle mass, physiological cross-sectional area, fibre length/muscle length, sarcomere length, sarcomere number were then evaluated. There was an increase in fibre length and sarcomere number, and a decrease in pennation angle at both lengths. In the long muscle length group, muscle length was increased, but widespread muscle damage was observed. These results suggest that the intervention of NMES at long muscle length can increase the muscle length but also causes muscle damage. In addition, the greater longitudinal increase in muscle length may be a result of the continuous degeneration-regeneration cycle.

Effectiveness of Conventional Dysphagia Therapy (CDT), Neuromuscular Electrical Stimulation (NMES), and Transcranial Direct Current Stimulation (tDCS) in Acute Post-Stroke Dysphagia: A Comparative Evaluation.

This study aims to compare the effectiveness of conventional dysphagia therapy (CDT), neuromuscular electrical stimulation (NMES), and transcranial direct current stimulation (tDCS) in the treatment of post-stroke dysphagia. A single-blind randomized controlled trial was conducted with 40 acute stroke patients - 18 females and 22 males with a mean age of 65.8 ± 11.9. The subjects were grouped into 4, with 10 individuals in each. The procedures administered to groups were as follows: the first group, sham tDCS and sham NMES; the second group, tDCS and sham NMES; the third group, NMES and sham tDCS; and the fourth group, all therapy procedures. CDT was applied to all groups either as a standalone procedure or combined with one or two of the instrumental techniques. Gugging Swallowing Screen (GUSS) and Videofluoroscopic Swallowing Study (VFSS) were employed to determine the severity of dysphagia and the effectiveness of treatment modalities. Additionally, the Penetration Aspiration Scale (PAS), Functional Oral Intake Scale (FOIS), and Dysphagia Severity Rating Scale (DSRS) were administered to interpret VFSS data. Pre- and post-treatment comparisons of all groups have revealed a statistically significant difference for all parameters except for the PAS scores at International Dysphagia Diet Standardization Initiative (IDDSI)-Level 4 consistencies. However, the differences between pre- and post-treatment scores of the fourth group across all parameters were significant - GUSS (p = 0.005), FOIS (p = 0.004), DSRS (p = 0.005), PAS IDDSI-4 (p = 0.027), PAS IDDSI-0 (p = 0.004). Inter-group comparisons, on the other hand, pointed out that the difference between pre- and post-treatment GUSS, FOIS, DSRS, and PAS scores at IDDSI Level-0 consistencies was statistically significant for all groups - GUSS (p = 0,009), FOIS (p = 0,004), DSRS (p = 0,002), PAS IDDSI-0 (p = 0,049). Closer examination of treatment groups indicated that the tDCS + CDT group, the NMES + CDT group, and the group that underwent the combination of three modalities made better progress than the one that was treated with only CDT. Though not statistically significant, the NMES + CDT group achieved better improvement than the tDCS + CDT group. This study has yielded that the group in which NMES, tDCS, and CDT were applied in combination has achieved better results than all the other groups. All treatment modalities applied to accelerate the general recovery process in acute stroke patients with dysphagia were found to be effective for the treatment of post-stroke swallowing disorders. The use of instrumental treatments such as NMES and tDCS enhanced the effectiveness of the treatment and provided more significant progress. Furthermore, combining treatment modalities such as NMES and tDCS was more effective when compared to using only conventional therapy. As a result, the most effective treatment outcomes were obtained by the group receiving CDT, NMES, and tDCS in combination. Therefore, the use of combined approaches has been recommended in appropriate patients; yet the provisional results should be tested in randomized trials with more participants.