Appropriateness of exercise therapy delivery in chronic low back pain management: cross-sectional online survey of physiotherapy practice in Germany.

BACKGROUND: In Germany, exercise therapy represents the most commonly prescribed physiotherapy service for non-specific, chronic low back pain (NSCLBP). So far, little is known about current practice patterns of German physiotherapists in delivering this intervention. Thus, the aim of this study was to investigate the appropriateness of exercise therapy delivered to NSCLBP patients in German physiotherapy care and to identify practitioner-related drivers of appropriate exercise delivery. METHODS: We used a vignette-based, exploratory, cross-sectional, online-survey study design (76-items; data collection between May and July 2023). Eligible participants were required to hold a professional degree in physiotherapy and were required to be practicing in Germany. Access links to anonymous online surveys were spread via established German physiotherapy networks, educational platforms, social media, e-mail lists, and snowball sampling. Appropriateness of exercise therapy was calculated by an equally weighted total score (400 points) including scales on shared-decision-making, exercise dose selection, pain knowledge and self-management promotion. "Appropriate exercise delivery" was determined by a relative total score achievement of > 80%. "Partly appropriate exercise delivery" was determined by a relative total score achievement of 50-79%, and "inappropriate exercise delivery" by a score achievement of < 50%. Practitioner-related drivers of exercise appropriateness were calculated by bivariate and multiple linear regression analyses. RESULTS: 11.9% (N = 35) of 298 physiotherapists' exercise delivery was considered "appropriate", 83.3% (N = 245) was "partly appropriate", and 4.8% (N = 14) was "inappropriate". In the final multiple regression model, most robust parameters positively influencing appropriate delivery of exercise therapy were increased scientific literacy (B = 10.540; 95% CI [0.837; 20.243]), increased average clinical assessment time (B = 0.461; 95% CI [0.134; 0.789]), increased self-perceived treatment competence (B = 7.180; 95% CI [3.058; 11.302], and short work experience (B = - 0.520; 95% CI [-0.959; - 0.081]). CONCLUSION: Appropriate exercise delivery in NSCLBP management was achieved by only 11.9% of respondents. However, the vast majority of 95.2% of respondents was classified to deliver exercise therapy partly appropriate. Long work experience seemed to negatively affect appropriate exercise delivery. Positive influences were attributed to scientific literacy, the average clinical assessment time per patient as well as the perceived treatment competence in NSCLBP management. REGISTRATION: Open science framework: https://doi.org/10.17605/OSF.IO/S76MF .

Tailoring photobiomodulation to enhance tissue regeneration.

Photobiomodulation (PBM), the use of biocompatible tissue-penetrating light to interact with intracellular chromophores to modulate the fates of cells and tissues, has emerged as a promising non-invasive approach to enhancing tissue regeneration. Unlike photodynamic or photothermal therapies that require the use of photothermal agents or photosensitizers, PBM treatment does not need external agents. With its non-harmful nature, PBM has demonstrated efficacy in enhancing molecular secretions and cellular functions relevant to tissue regeneration. The utilization of low-level light from various sources in PBM targets cytochrome c oxidase, leading to increased synthesis of adenosine triphosphate, induction of growth factor secretion, activation of signaling pathways, and promotion of direct or indirect gene expression. When integrated with stem cell populations, bioactive molecules or nanoparticles, or biomaterial scaffolds, PBM proves effective in significantly improving tissue regeneration. This review consolidates findings from in vitro, in vivo, and human clinical outcomes of both PBM alone and PBM-combined therapies in tissue regeneration applications. It encompasses the background of PBM invention, optimization of PBM parameters (such as wavelength, irradiation, and exposure time), and understanding of the mechanisms for PBM to enhance tissue regeneration. The comprehensive exploration concludes with insights into future directions and perspectives for the tissue regeneration applications of PBM.

A pilot study on the efficacy of a seaweed mud application in the treatment of cellulite.

BACKGROUND: Cellulite represents a common multi-factorial condition that affects nearly all women and is now recognized as a clinical condition associated with systemic factors and negative psychological effects. Several noninvasive and minimally invasive treatments were developed during the last few years, but limited evidence supports many of them due to lack of evidence, insufficient participants, and potential adverse effects. METHODS: This study aimed to evaluate the efficacy of a seaweed mud application in improving both the structure and function of tissues affected by cellulite. Sixty women with cellulite underwent 4-week applications of seaweed mud on the buttocks and thighs. The following assessments were performed at baseline and after the last treatment: photographic, clinical, and anthropometric evaluation; tests for elasticity and hydration; ultrasonography of cellulite nodules; and cellulite biopsies in the trochanteric region. Patient satisfaction was assessed using a 5-point Likert-scale questionnaire. RESULTS: The treatment resulted in a significant improvement in the severity of cellulite severity between the initial assessment and the 4-week follow-up, with enhanced structure, elasticity, and hydration of the affected tissues. Microscopic analysis of the cellulite biopsies revealed a significant restoration of dermal organization with induced collagen synthesis and reduced inflammation, edema, and lipid deposition following the 4-week seaweed mud applications. Additionally, the treatment led to a remarkable improvement in comfort and satisfaction as well as a reduction in body circumferences. CONCLUSIONS: The cosmetic application of seaweed mud has proven to be a safe, non-invasive treatment for improving the tissue alterations characteristic of cellulite.

Vacuum bell therapy for pectus excavatum: a retrospective study.

BACKGROUND: Pectus excavatum, the most common chest wall deformity, is frequently treated with Nuss procedure. Here we will describe non-invasive procedure and analyze the variables associated vacuum bell therapy for patients with pectus excavatum. METHODS: Retrospective case-control study in a single center between July 2018 and February 2022, including patients with pectus excavatum treated with vacuum bell. Follow-up was continued to September 2022. The Haller index and Correction index was calculated before and after treatment to analysis the effectiveness of vacuum bell therapy. RESULTS: There were 98 patients enrolled in the treatment group, with 72 available for analysis, and the follow-up period ranged from 1.1 to 4.4 years (mean 3.3 years). When analyzing with the Haller Index, 18 patients (25.0%) showed excellent correction, 13 patients (18.1%) achieved good correction, and 4 patients (5.6%) had fair correction. The remaining patients had a poor outcome. Characteristics predicting a non-poor prognosis included initial age ≤ 11 years (OR = 3.94, p = 0.013) and patients with use over 24 consecutive months (OR = 3.95, p = 0.013). A total of 9 patients (12.5%) achieved a CI reduction below 10. Patients who started vacuum bell therapy at age > 11 had significantly less change compared to those who started at age ≤ 11 (P < 0.05). Complications included chest pain (5.6%), swollen skin (6.9%), chest tightness (1.4%) and erythema (15.3%). CONCLUSIONS: A certain percentage of patients with pectus excavatum can achieve excellent correction when treated with pectus excavatum therapy. Variables predicting better outcome including initial age ≤ 11 years both in HI and CI and vacuum bell use over 24 consecutive months in HI. In summary, pectus excavatum is an emerging non-invasive therapy for pectus excavatum and will be widely performed in a certain group of patients.

Core-Shell Nanoparticles for Pulmonary Drug Delivery.

Nanoscale drug delivery systems have provoked interest for application in various therapies on account of their ability to elevate the intracellular concentration of drugs inside target cells, which leads to an increase in efficacy, a decrease in dose, and dose-associated adverse effects. There are several types of nanoparticles available; however, core-shell nanoparticles outperform bare nanoparticles in terms of their reduced cytotoxicity, high dispersibility and biocompatibility, and improved conjugation with drugs and biomolecules because of better surface characteristics. These nanoparticulate drug delivery systems are used for targeting a number of organs, such as the colon, brain, lung, etc. Pulmonary administration of medicines is a more appealing method as it is a noninvasive route for systemic and locally acting drugs as the pulmonary region has a wide surface area, delicate blood-alveolar barrier, and significant vascularization. A core-shell nano-particulate drug delivery system is more effective in the treatment of various pulmonary disorders. Thus, this review has discussed the potential of several types of core-shell nanoparticles in treating various diseases and synthesis methods of core-shell nanoparticles. The methods for synthesis of core-shell nanoparticles include solid phase reaction, liquid phase reaction, gas phase reaction, mechanical mixing, microwave- assisted synthesis, sono-synthesis, and non-thermal plasma technology. The basic types of core-shell nanoparticles are metallic, magnetic, polymeric, silica, upconversion, and carbon nanomaterial- based core-shell nanoparticles. With this special platform, it is possible to integrate the benefits of both core and shell materials, such as strong serum stability, effective drug loading, adjustable particle size, and immunocompatibility.

Surgical Management of Brain Tumors with Focused Ultrasound.

Focused ultrasound is a novel technique for the treatment of aggressive brain tumors that uses both mechanical and thermal mechanisms. This non-invasive technique can allow for both the thermal ablation of inoperable tumors and the delivery of chemotherapy and immunotherapy while minimizing the risk of infection and shortening the time to recovery. With recent advances, focused ultrasound has been increasingly effective for larger tumors without the need for a craniotomy and can be used with minimal surrounding soft tissue damage. Treatment efficacy is dependent on multiple variables, including blood-brain barrier permeability, patient anatomical features, and tumor-specific features. Currently, many clinical trials are currently underway for the treatment of non-neoplastic cranial pathologies and other non-cranial malignancies. In this article, we review the current state of surgical management of brain tumors using focused ultrasound.

Non-invasive auditory and visual stimulation attenuates α-Synuclein deposition and improves motor and non-motor symptoms in PD mice.

Parkinson's disease (PD) is characterized by dopaminergic neuron loss and α-synuclein (α-Syn) aggregates, but lacks effective treatments for the disease progression and non-motor symptoms. Recently, combined 40 Hz auditory and visual stimulation is emerging as a promising non-invasive method to decrease amyloid and improve cognition in Alzheimer's disease (AD), but whether this treatment can modify α-Syn-induced PD pathology remains unclear. Here we evaluated the effects of chronic exposure to 40 Hz and 80 Hz auditory and visual stimulation on α-Syn accumulation and the functional effects of 40 Hz stimulation on motor, cognitive and mood dysfunctions in PD mice. We found that 40 Hz and 80 Hz auditory and visual stimulation activated multiple cortical regions, entrained gamma oscillations and markedly attenuated p-α-Syn deposition in neurons, but not astrocytes, microglial cells in the primary and secondary motor cortex (M1, M2), medial prefrontal cortex (mPFC) and the striatum. Moreover, 40 Hz stimulation significantly reduced cell apoptosis in M1, increased the neuromuscular strength selectively in PD mice, which correlated with p-α-Syn reduction in the motor cortex. In addition, 40 Hz stimulation improved spatial working memory and decreased depressive-like behaviors specifically in PD mice, which correlated with p-α-Syn reduction in mPFC, but promoted anxiety-like behaviors and increased stress-related adreno-cortico-tropic-hormone (ACTH), corticosterone levels in the plasma of normal mice. Collectively, we demonstrated that chronic multisensory gamma stimulation (40 Hz and 80 Hz) significantly attenuates α-Syn deposition in neurons of the interconnected cortex and 40 Hz stimulation improved neuromuscular strength, spatial working memory, and reduced depressive behaviors, which support its non-invasive therapeutic potential for modifying PD progression and treating non-motor symptoms.

Long-Term Follow-Up of Lentigo Maligna Patients Treated with Imiquimod 5% Cream.

BACKGROUND: The study investigated the long-term efficacy of imiquimod 5% cream for LM, with a focus on disease recurrence and the possible prognostic factors of disease-free survival (DFS) in a cohort, with long-term follow-up. METHODS: Consecutive patients with histologically confirmed LM were included. Imiquimod 5% cream was applied until weeping erosion appeared on the LM-affected skin. The evaluation was performed through clinical examination and dermoscopy. RESULTS: We analyzed 111 patients with LM (median age: 72 years, 61.3% women) with tumor clearance after imiquimod therapy, with a median follow-up of 8 years. The overall patient survival rates were 85.5% (95% confidence interval (CI): 78.5-92.6) and 70.4% (95% CI: 60.3-80.5) at 5 and 10 years, respectively. Among the 23 patients (20.1%) with relapse at follow-up, 17 (73.9%) were treated with surgery, five (21.7%) continued imiquimod therapy, and one (4.3%) underwent both surgery and radiotherapy. After adjustment for age and LM area in multivariable models, localization of LM in the nasal region was identified as a prognostic factor for DFS (HR = 2.66; 95% CI: 1.06-6.64). CONCLUSION: If surgical excision is not possible due to the patients' age/comorbidities or critical cosmetic localization, imiquimod could provide optimal outcomes with an optimal risk of relapse for the management of LM.

Therapeutic non-invasive brain treatments in Alzheimer's disease: recent advances and challenges.

Alzheimer's disease (AD) is one of the major neurodegenerative diseases and the most common form of dementia. Characterized by the loss of learning, memory, problem-solving, language, and other thinking abilities, AD exerts a detrimental effect on both patients' and families' quality of life. Although there have been significant advances in understanding the mechanism underlying the pathogenesis and progression of AD, there is no cure for AD. The failure of numerous molecular targeted pharmacologic clinical trials leads to an emerging research shift toward non-invasive therapies, especially multiple targeted non-invasive treatments. In this paper, we reviewed the advances of the most widely studied non-invasive therapies, including photobiomodulation (PBM), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and exercise therapy. Firstly, we reviewed the pathological changes of AD and the challenges for AD studies. We then introduced these non-invasive therapies and discussed the factors that may affect the effects of these therapies. Additionally, we review the effects of these therapies and the possible mechanisms underlying these effects. Finally, we summarized the challenges of the non-invasive treatments in future AD studies and clinical applications. We concluded that it would be critical to understand the exact underlying mechanisms and find the optimal treatment parameters to improve the translational value of these non-invasive therapies. Moreover, the combined use of non-invasive treatments is also a promising research direction for future studies and sheds light on the future treatment or prevention of AD.

Preclinical Cold Atmospheric Plasma Cancer Treatment.

CAP is an ionized gas generated under atmospheric pressure conditions. Due to its reactive chemical components and near-room temperature nature, CAP has promising applications in diverse branches of medicine, including microorganism sterilization, biofilm inactivation, wound healing, and cancer therapy. Currently, hundreds of in vitro demonstrations of CAP-based cancer treatments have been reported. However, preclinical studies, particularly in vivo studies, are pivotal to achieving a final clinical application. Here, we comprehensively introduced the research status of the preclinical usage of CAP in cancer treatment, by primarily focusing on the in vivo studies over the past decade. We summarized the primary research strategies in preclinical and clinical studies, including transdermal CAP treatment, post-surgical CAP treatment, CAP-activated solutions treatment, and sensitization treatment to drugs. Finally, the underlying mechanism was discussed based on the latest understanding.

Microwave Therapy for Cellulite: An Effective Non-Invasive Treatment.

BACKGROUND: Cellulite represents a common cosmetic problem that affects nearly all women. This study aimed to evaluate microwave therapy's effectiveness for cellulite treatment. METHODS: In this study, 26 women showing severe or moderate cellulite underwent four sessions of microwave therapy on the buttocks and posterior thighs. The following assessments were performed at baseline and the three-month follow-up after the last treatment: the Cellulite Severity Scale (CSS), Nürnberger-Müller classification scale, photographic evaluation, and buttocks/posterior thighs circumference measurements. A Likert scale questionnaire was used to assess patient satisfaction at the 3-month follow-up. RESULTS: The treatment positively affected the cellulite severity as confirmed by the Cellulite Severity Scale (CSS) and Nürnberger-Müller classification scale results. CSS showed a significant amelioration in cellulite severity between the initial assessment and the 3-month follow-up for the buttocks and posterior thighs, with total average scores that ranged from 10.7 ± 3.1 to 4.5 ± 1.8 (p < 0.01). The treatment also resulted in a remarkable improvement in comfort/satisfaction and a buttocks and posterior thighs circumference reduction. No serious adverse events were observed. CONCLUSIONS: Microwave therapy has proven to be a safe treatment for improving cellulite appearance and reducing body circumferences.

Vojta Therapy in Neuromotor Development of Pediatrics Patients with Periventricular Leukomalacia: Case Series.

Background and Objectives: Vojta therapy is used by physiotherapists and is based on stimulation through peripheral pressure that leads to the activation of involuntary motor response patterns, thus triggering patterns of reflex locomotion, hence also called reflex locomotion therapy. Objective: To analyze the changes produced by Vojta therapy in the evolution of infant motor development in patients with maturational delay due to periventricular leukomalacia. Materials and methods: One session of Vojta Therapy per week for eleven months, patients' neuromotor development was evaluated through the Denver II Test and the Baleys Scale. Results: A clinically significant increase in the development of the patients is observed. Conclusions: Neuromotor development seems to generate an adequate progression in the motor area.

Cambios Clínicos e Imagenológicos en Terapias no Invasivas en Articulaciones Temporomandibulares con Alteraciones Óseas Degenerativas

RESUMEN: El objetivo del presente estudio fue describir los cambios clínicos e imagenológicos de las terapias no invasivas aplicadas a pacientes con alteraciones óseas degenerativas de las articulaciones temporomandibulares (ATM). Metodología: Se evaluaron 25 pacientes con alteraciones óseas degenerativas de las ATM, sin tratamiento previo de trastornos temporomandibulares (TTM) al momento del diagnóstico. Se realizó tratamiento no invasivo y un año después fueron evaluados según criterios clínicos e imagenológicos DC/TMD y Ahmad. Los resultados fueron presentados por medio de estadística descriptiva, odds ratio con sus respectivos intervalos de confianza, comparaciones de medianas y correlaciones. Se estudiaron 50 ATM, 72 % mujeres (32,2 años promedio). Se observó mejora significativa en los parámetros: dolor (p=0,0001), sinovitis (p=0,001) e incremento de la esclerosis del trabeculado óseo (p=0,051) a un año post-tratamiento. Después de un año del establecimiento de terapias no invasivas en pacientes con alteraciones óseas degenerativas de las ATM, se observaron cambios positivos tanto clínicos como imagenológicos, reduciéndose significativamente la sintomatología dolorosa, limitándose la progresión del daño óseo degenerativo, y observándose recuperación de los casos de sinovitis.

ABSTRACT: The objective of this study was to describe clinical and imaging changes of non-invasive therapies applied to patients with degenerative bone disorders of the temporomandibular joints (TMJ). To carry out this study, 25 patients with degenerative bone disorders of TMJ without previous treatment at the time of diagnosis, were evaluated. Non-invasive treatment was performed and one year later they were evaluated according to clinical and imaging criteria DC/TMD and Ahmad. Results were presented by descriptive statistics, odds ratio, confidence interval, comparisons of means, and correlations. 50 TMJs, 72 % women, (32.2 years mean of age) were studied. Significant improvement was observed in the parameters: pain (p=0.0001), synovitis (p=0.001), and increased sclerosis of the bone trabeculae (p=0,051) at one-year post-treatment. After one year of the establishment of non-invasive therapies in patients with degenerative joint disease of TMJ, it was observed positive changes, both clinical and imaging, reducing painful symptomatology, limiting effect on the progression of degenerative bone damage, and recovery of synovitis cases.

Fascial Manipulation Technique in the Conservative Management of Morton's Syndrome: A Pilot Study.

BACKGROUND AND OBJECTIVE: Morton's syndrome (MS) is a common cause of neuropathic chronic forefoot pain, characterised by the development of a swelling of the common digital plantar nerve, whose aetiology is not fully known. There is currently no gold standard of treatment; nonoperative management commonly involves manual therapies, orthoses therapy and infiltrative techniques, while surgery is indicated after failure of conservative measures. The present preliminary study prospectively evaluates patients affected by MS treated by Fascial Manipulation technique (FM), a noninvasive manual therapy, focused on the release of the deep fascia, reducing its stiffness. MATERIALS AND METHODS: Patients with clinical and sonographic diagnosis of MS with at least a 4-month history of neuropathic symptoms underwent a cycle of three weekly FM sessions. Clinical follow-up, including VAS and AOFAS scores, was performed 21 days (T1) and 3 months (T2) after treatment. RESULTS: Nine patients, among 28 recruited initially, completed the manual therapy sessions and relative follow-up points. This noninvasive pain treatment led to significant improvement of VAS (p = 0.0034) and AOFAS scores (p = 0.0240) at the first follow-up (T1). At 3-month follow-up (T2), both scores decreased slightly, remaining however superior to the pre-treatment values. Only VAS was still significant (p = 0.0184). CONCLUSIONS: Despite the small size of the case series, this pilot study is unique in supporting Fascial Manipulation in the nonoperative treatment of MS. Further studies are needed with a large cohort of gender balanced patients to confirm the encouraging results obtained.

From non-invasive to invasive fetal therapy: A comprehensive review and current update.

"Fetus as patient" indicates fundamental concept of fetal therapy. With advance in maternal serum analysis and fetal imaging, prenatal screening has become standard of care. Accurate diagnosis in early gestation allows intervention to reverse pathophysiology and delay progression immediately. Non-invasive, minimally invasive and invasive therapies demonstrate their therapeutic potential in certain diseases. Recently, stem cell and gene therapies have been developed to avoid irreversible impairment. To elevate efficacy of treatment modality, extensive studies should be conducted according to regulatory authority. Striking a balance between scientific and ethical integrity is essential, so long-term follow up should be arranged for protecting mother and fetus.

Numerical study on sector-vortex phased irradiation method using annular array transducer in High-Intensity Focused Ultrasound treatment.

Sector-vortex phased irradiation from annular array transducer was numerically studied with breast model constructed from MRI data of real patient. Phase compensation (PC) based on time reversal pre-computation was applied in order to handle phase delay caused by heterogeneity of breast tissues, and results showed great effectiveness on single-focus case, insignificant effectiveness on multi-focus cases with 4 and 8 phase-sectors, but ineffectiveness on multi-focus case with 12 phase-sectors, where enormous undesired outer ablation occurred. For single-focus case, phase compensation not only produced real focus very close to targeted site (0.1 mm deviation), but also decreased thermal peak ratio (outer/focal) largely by 30%. However, phase compensation did not increase total ablated size. For multi-focus cases with 4 and 8 phase-sectors, deformed focal shapes by tissue heterogeneity were restored by phase compensation, but the 4-phase-sector case had higher thermal peak ratio and smaller ablation than 8-phase-sector case for strong cancelling effect between phase-sector borders. Ineffectiveness of phase compensation on multi-focus case with 12 phase-sectors had three considerable reasons. 1st, inequality of piezo-element number between sectors; 2nd, heterogeneous attenuation of breast model; 3rd, insufficient number of piezo-elements per sector; where the 2nd reason originated from breast model, and other two reasons were related to array transducer. This research gave several preliminary indications. 1st, ineffectiveness of phase compensation occurs on case with large phase-sector number when using annular array transducer; 2nd, with same input energy and same irradiation time, sector-vortex phased irradiation creates smaller focal ablation, but withstands longer than single-focus irradiation free of outer ablation; 3rd, phase-difference π between neighboring phase-sectors is disadvantageous because of energy loss; 4th, phase compensation is effective on single-focus for improving pinpoint ablation but not for increasing total ablated size.

An integrated systematic approach for investigating microcurrent electrical nerve stimulation (MENS) efficacy in STZ-induced diabetes mellitus.

Diabetes mellitus (DM) is a major metabolic disorder and an increasing health problem worldwide. Effective non-invasive therapies for DM are still lacking. Here, we have developed Microcurrent electrical nerve stimulation (MENS), a non-invasive therapy, and tested on 46 mice clustered into five groups, such as control, STZ-induced DM, and MENS treatment groups. Experimental results show that MENS treatment is able to improve seven biochemical indexes (e.g., hemoglobin A1c and glucose level). To investigate the mechanisms of MENS treatment on STZ-induced DM, we selected six representative samples to perform microarray experiments for several groups and developed an integrated Hierarchical System Biology Model (HiSBiM) to analyze these omics data. The results indicate that MENS can affect fatty acid metabolism pathways, peroxisome proliferator-activated receptor (PPAR) signaling pathway and cell cycle. Additionally, the DM biochemical indexes and omics data profiles of MENS treatment were found to be consistent. We then compared the therapeutic effects of MENS with anti-diabetic compounds (e.g., quercetin, metformin, and rosiglitazone), using the HiSBiM four-level biological functions and processes of multiple omics data. The results show MENS and these anti-diabetic compounds have similar effect pathways highly correlated to the diabetes processes, such as the PPAR signaling pathway, bile secretion, and insulin signaling pathways. We believe that MENS is an effective and non-invasive therapy for DM and our HiSBiM is an useful method for investigating multiple omics data.

Non-invasive approaches to functional recovery after spinal cord injury: Therapeutic targets and multimodal device interventions.

This paper is an interdisciplinary narrative review of efficacious non-invasive therapies that are increasingly used to restore function in people with chronic spinal cord injuries (SCI). First presented are the secondary injury cascade set in motion by the primary lesion and highlights in therapeutic development for mitigating the acute pathophysiologic process. Then summarized are current pharmacological strategies for modulation of noradrenergic, serotonergic, and dopaminergic neurotransmission to enhance recovery in bench and clinical studies of subacute and chronic SCI. Last examined is how neuromechanical devices (i.e., electrical stimulation, robotic assistance, brain-computer interface, and augmented sensory feedback) could be comprehensively engineered to engage efferent and afferent motosensory pathways to induce neuroplasticity-based neural pattern generation. Emerging evidence shows that computational models of the human neuromusculoskeletal system (i.e., human digital twins) can serve as functionalized anchors to integrate different neuromechanical and pharmacological interventions into a single multimodal prothesis. The system, if appropriately built, may cybernetically optimize treatment outcomes via coordination of heterogeneous biosensory, system output, and control signals. Overall, these rehabilitation protocols involved neuromodulation to evoke beneficial adaptive changes within spared supraspinal, intracord, and peripheral neuromuscular circuits to elicit neurological improvement. Therefore, qualitatively advancing the theoretical understanding of spinal cord neurobiology and neuromechanics is pivotal to designing new ways to reinstate locomotion after SCI. Future research efforts should concentrate on personalizing combination therapies consisting of pharmacological adjuncts, targeted neurobiological and neuromuscular repairs, and brain-computer interfaces, which follow multimodal neuromechanical principles.

In Vivo Non-Thermal, Selective Cancer Treatment With High-Frequency Medium-Intensity Focused Ultrasound.

Focused ultrasound (FUS) has proven its efficacy in non-invasive, radiation-free cancer treatment. However, the commonly used low-frequency high-intensity focused ultrasound (HIFU) destroys both cancerous and healthy tissues non-specifically through extreme heat and inertial cavitation with low spatial resolution. To address this issue, we evaluate the therapeutic effects of pulsed (60 Hz pulse repetition frequency, 1.45 ms pulse width) high-frequency (20.7 MHz) medium-intensity (spatial-peak pulse-average intensity ISPPA < 279.1 W/cm2, spatial-peak temporal-average intensity ISPTA < 24.3 W/cm2) focused ultrasound (pHFMIFU) for selective cancer treatment without thermal damage and with low risk of inertial cavitation (mechanical index < 0.66), in an in vivo subcutaneous B16F10 melanoma tumor growth model in mice. The pHFMIFU with 104 µm focal diameter is generated by a microfabricated self-focusing acoustic transducer (SFAT) with a Fresnel acoustic lens. A three-axis positioning system has been developed for automatic scanning of the transducer to cover a larger treatment volume, while a water-cooling system is custom-built for dissipating non-acoustic heat from the transducer surface. Initial testing revealed that pHFMIFU treatment can be applied to a living animal while maintaining skin temperature under 35.6 °C without damaging normal skin and tissue. After eleven days of treatment with pHFMIFU, the treated tumors were significantly smaller with large areas of necrosis and apoptosis in the treatment field compared to untreated controls. Potential mechanisms of this selective, non-thermal killing effect, as well as possible causes of and solutions to the variation in treatment results, have been analyzed and proposed. The pHFMIFU could potentially be used as a new therapeutic modality for safer cancer treatment especially in critical body regions, due to its cancer-specific effects and high spatial resolution.

Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice: a possible novel therapy for heart failure with preserved left ventricular ejection fraction.

AIMS: Heart failure with preserved left ventricular ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice. METHODS AND RESULTS: Twelve-week-old obese diabetic mice (db/db) and their control littermates (db/+) were treated with either the LIPUS therapy [1.875 MHz, 32 cycles, Ispta (spatial peak temporal average intensity) 117-162 mW/cm2, 0.25 W/cm2] or placebo procedure two times a week for 4 weeks. At 20-week-old, transthoracic echocardiography and invasive haemodynamic analysis showed that cardiac diastolic function parameters, such as e', E/e', end-diastolic pressure-volume relationship, Tau, and dP/dt min, were all deteriorated in placebo-treated db/db mice compared with db/+ mice, while systolic function was preserved. Importantly, these cardiac diastolic function parameters were significantly ameliorated in the LIPUS-treated db/db mice. We also measured the force (F) and intracellular Ca2+ ([Ca2+]i) in trabeculae dissected from ventricles. We found that relaxation time and [Ca2+]i decay (Tau) were prolonged during electrically stimulated twitch contractions in db/db mice, both of which were significantly ameliorated in the LIPUS-treated db/db mice, indicating that the LIPUS therapy also improves relaxation properties at tissue level. Functionally, exercise capacity was also improved in the LIPUS-treated db/db mice. Histologically, db/db mice displayed progressed cardiomyocyte hypertrophy and myocardial interstitial fibrosis, while those changes were significantly suppressed in the LIPUS-treated db/db mice. Mechanistically, western blot showed that the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway and Ca2+-handling molecules were up-regulated in the LIPUS-treated heart. CONCLUSIONS: These results indicate that the LIPUS therapy ameliorates cardiac diastolic dysfunction in db/db mice through improvement of eNOS-NO-cGMP-PKG pathway and cardiomyocyte Ca2+-handling system, suggesting its potential usefulness for the treatment of HFpEF patients.