Blocking CCR5 activity by maraviroc augmentation in post-stroke depression: a proof-of-concept clinical trial.

BACKGROUND: Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial. METHODS: We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014). CONCLUSIONS: Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05932550, Retrospectively registered: 28/06/2023.

Targeting the adenosinergic system in restless legs syndrome: A pilot, "proof-of-concept" placebo-controlled TMS-based protocol.

Restless Legs Syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs that is responsive to movement (particularly during rest), periodic leg movements during sleep, and hyperarousal. Recent evidence suggests that the involvement of the adenosine system may establish a connection between dopamine and glutamate dysfunction in RLS. Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique widely applied to explore brain electrophysiology and neurochemistry under different experimental conditions. In this pilot study protocol, we aim to investigate the effects of dipyridamole (a well-known enhancer of adenosinergic transmission) and caffeine (an adenosine receptor antagonist) on measures of cortical excitation and inhibition in response to TMS in patients with primary RLS. Initially, we will assess cortical excitability using both single- and paired-pulse TMS in patients with RLS. Then, based on the measures obtained, we will explore the effects of dipyridamole and caffeine, in comparison to placebo, on various TMS parameters related to cortical excitation and inhibition. Finally, we will evaluate the psycho-cognitive performance of RLS patients to screen them for cognitive impairment and/or mood-behavioral dysfunction, thus aiming to correlate psycho-cognitive findings with TMS data. Overall, this study protocol will be the first to shed lights on the neurophysiological mechanisms of RLS involving the modulation of the adenosine system, thus potentially providing a foundation for innovative "pharmaco-TMS"-based treatments. The distinctive TMS profile observed in RLS holds indeed the potential utility for both diagnosis and treatment, as well as for patient monitoring. As such, it can be considered a target for both novel pharmacological (i.e., drug) and non-pharmacological (e.g., neuromodulatory), "TMS-guided", interventions.

A Magnetic Actuator Device for Fully Automated Blinking in Total Bidirectional Eyelid Paralysis: First Proof of Concept in a Human Participant.

Purpose: Currently, no solution exists to restore natural eyelid kinematics for patients with complete eyelid paralysis due to loss of function of both the levator palpebrae superioris and orbicularis oculi. These rare cases are prone to complications of chronic exposure keratopathy which may lead to corneal blindness. We hypothesized that magnetic force could be used to fully automate eyelid movement in these cases through the use of eyelid-attached magnets and a spectacle-mounted magnet driven by a programmable motor (motorized magnetic levator prosthesis [MMLP]). Methods: To test this hypothesis and establish proof of concept, we performed a finite element analysis (FEA) for a prototype MMLP to check the eyelid-opening force generated by the device and verified the results with experimental measurements in a volunteer with total bidirectional eyelid paralysis. The subject was then fitted with a prototype to check the performance of the device and its success. Results: With MMLP, eye opening was restored to near normal, and blinking was fully automated in close synchrony with the motor-driven polarity reversal, with full closure on the blink. The device was well tolerated, and the participant was pleased with the comfort and performance. Conclusions: FEA simulation results conformed to the experimentally observed trend, further supporting the proof of concept and design parameters. This is the first viable approach in human patients with proof of concept for complete reanimation of a bidirectionally paretic eyelid. Further study is warranted to refine the prototype and determine the feasibility and safety of prolonged use. Translational Relevance: This is first proof of concept for our device for total bidirectional eyelid paralysis.

Analysis on efficacy of magnetic resonance lymphangiography using INV-001 in healthy beagle dogs.

We aimed to conduct a proof-of-concept study of INV-001 in visualizing lymphatic vessels and nodes without venous contamination and to determine the optimal dose condition of INV-001 for magnetic resonance lymphangiography (MRL) in healthy beagles. MRL was performed using a 3.0-Tesla (T) whole body clinical magnetic resonance imaging (MRI) scanner. A dose-finding study of INV-001 for MRL in beagles (N = 6) was carried out according to an adaptive optimal dose finding design. For the reproducibility study (N = 6), MRL was conducted at selected INV-001 doses (0.056 and 0.112 mg Fe/kg) with a 15 mM concentration. Additionally, an excretion study (N = 3) of INV-001 was conducted by analyzing T1, T2, and T2* maps of the liver and kidney 48 h post-administration. INV-001 administration at doses of 0.056 and 0.112 mg Fe/kg (concentration: 15 mM) consistently demonstrated the visualization of contrast-enhanced lymphatic vessels and nodes without venous contamination in the beagles. The contrast enhancement effect was highest at 30 min after INV-001 administration, then gradually decreasing. No toxicity-related issues were identified during the study. After 48 h, the T1, T2, and T2* values in the liver and both kidneys were found to be comparable to the pre-administration values, indicating thorough INV-001 excretion. The optimal dosing conditions of INV-001 for MRL for contrast-enhanced visualization of lymphatic vessels and nodes exclusively with no venous contamination in beagles was determined to be 0.056 mg Fe/kg with a 15 mM concentration.

A multicenter proof-of-concept study on deep learning-based intraoperative discrimination of primary central nervous system lymphoma.

Accurate intraoperative differentiation of primary central nervous system lymphoma (PCNSL) remains pivotal in guiding neurosurgical decisions. However, distinguishing PCNSL from other lesions, notably glioma, through frozen sections challenges pathologists. Here we sought to develop and validate a deep learning model capable of precisely distinguishing PCNSL from non-PCNSL lesions, especially glioma, using hematoxylin and eosin (H&E)-stained frozen whole-slide images. Also, we compared its performance against pathologists of varying expertise. Additionally, a human-machine fusion approach integrated both model and pathologic diagnostics. In external cohorts, LGNet achieved AUROCs of 0.965 and 0.972 in distinguishing PCNSL from glioma and AUROCs of 0.981 and 0.993 in differentiating PCNSL from non-PCNSL lesions. Outperforming several pathologists, LGNet significantly improved diagnostic performance, further augmented to some extent by fusion approach. LGNet's proficiency in frozen section analysis and its synergy with pathologists indicate its valuable role in intraoperative diagnosis, particularly in discriminating PCNSL from glioma, alongside other lesions.

Evolving growth hormone deficiency: proof of concept.

Introduction: We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST). Methods: We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0. Results: Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH. Conclusion: We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.

A proof of concept on implant-supported bilateral cantilever bridges: The T-Bridge approach.

The concept of bilateral cantilevers on a single central implant (T-design) for three-unit implant-supported fixed dental prostheses (ISFDPs) has not been explored nor tested. This technical hypothesis aimed to explore the feasibility of such an approach as a cost-effective alternative to conventional treatments. Careful considerations regarding implant diameter, length, ideal position, occlusal scheme, and bone remodeling are essential to ensure adequate support, stability, and prevention of complications. In this proof of concept, we present a preliminary case with this novel design to replace missing posterior teeth in a patient with narrow bone conditions. In addition, a series of planned investigations and preliminary results, including preclinical studies, are presented to illustrate our concept and its potential clinical implications. Clinically, after two-year follow-up, healthy and stable peri-implant tissues around the ISFDP exemplarily demonstrated excellent stability, functionality, and comfort, which is supported by acceptable fracture resistance data in vitro, suggesting indeed the practical potential and suitability. Thus, we claim that such a treatment modality has the at least theoretical potential to revolutionize implant dentistry by providing innovative and cost-effective treatment options for patients with partial ISFDPs in very specific cases. Of course, further research and evaluations are necessary to validate the clinical implications of this innovative hypothesis. Implementing the 3-on-1 T-bridge approach in partial ISFDPs could offer a promising alternative to traditional methods. If proven successful, this technique may lead to significant advancements in clinical practice, providing a less invasive cost-effective treatment option.

A retrieval-augmented chatbot based on GPT-4 provides appropriate differential diagnosis in gastrointestinal radiology: a proof of concept study.

BACKGROUND: We investigated the potential of an imaging-aware GPT-4-based chatbot in providing diagnoses based on imaging descriptions of abdominal pathologies. METHODS: Utilizing zero-shot learning via the LlamaIndex framework, GPT-4 was enhanced using the 96 documents from the Radiographics Top 10 Reading List on gastrointestinal imaging, creating a gastrointestinal imaging-aware chatbot (GIA-CB). To assess its diagnostic capability, 50 cases on a variety of abdominal pathologies were created, comprising radiological findings in fluoroscopy, MRI, and CT. We compared the GIA-CB to the generic GPT-4 chatbot (g-CB) in providing the primary and 2 additional differential diagnoses, using interpretations from senior-level radiologists as ground truth. The trustworthiness of the GIA-CB was evaluated by investigating the source documents as provided by the knowledge-retrieval mechanism. Mann-Whitney U test was employed. RESULTS: The GIA-CB demonstrated a high capability to identify the most appropriate differential diagnosis in 39/50 cases (78%), significantly surpassing the g-CB in 27/50 cases (54%) (p = 0.006). Notably, the GIA-CB offered the primary differential in the top 3 differential diagnoses in 45/50 cases (90%) versus g-CB with 37/50 cases (74%) (p = 0.022) and always with appropriate explanations. The median response time was 29.8 s for GIA-CB and 15.7 s for g-CB, and the mean cost per case was $0.15 and $0.02, respectively. CONCLUSIONS: The GIA-CB not only provided an accurate diagnosis for gastrointestinal pathologies, but also direct access to source documents, providing insight into the decision-making process, a step towards trustworthy and explainable AI. Integrating context-specific data into AI models can support evidence-based clinical decision-making. RELEVANCE STATEMENT: A context-aware GPT-4 chatbot demonstrates high accuracy in providing differential diagnoses based on imaging descriptions, surpassing the generic GPT-4. It provided formulated rationale and source excerpts supporting the diagnoses, thus enhancing trustworthy decision-support. KEY POINTS: • Knowledge retrieval enhances differential diagnoses in a gastrointestinal imaging-aware chatbot (GIA-CB). • GIA-CB outperformed the generic counterpart, providing formulated rationale and source excerpts. • GIA-CB has the potential to pave the way for AI-assisted decision support systems.

Evaluating a novel online behavioural intervention to encourage cost-conscious strategies among US adults with chronic conditions who are enrolled in a high-deductible health plan: a proof-of-concept pilot study.

OBJECTIVES: Patients with chronic conditions enrolled in high-deductible health plans (HDHPs) face cost-related access barriers and high out-of-pocket spending. Our objectives were to develop a novel behavioural intervention to help HDHP enrollees with chronic conditions use cost-conscious strategies and evaluate the intervention's preliminary effectiveness, acceptability and feasibility. DESIGN: Prospective. SETTING: Online (USA). PARTICIPANTS: 36 US adults enrolled in an HDHP through their employer or an exchange with diabetes, hypertension, asthma, coronary artery disease and/or chronic obstructive pulmonary disease. 31/36 participants completed the study. INTERVENTION: We developed a 5-week intervention consisting of a website with educational modules on discussing costs with clinicians, saving for future healthcare costs, comparing healthcare prices and quality, preparing for appointments, following up after appointments and planning for future healthcare needs; and emails encouraging participants to access each module. OUTCOMES: We conducted a single-arm proof-of-concept pilot study of the intervention. Baseline and postintervention surveys measured primary outcomes of health insurance literacy and confidence in using cost-conscious strategies. 10 participants completed postintervention interviews. RESULTS: 31 (86%) participants completed a baseline and postintervention survey. Mean health insurance literacy scores (20-80 scale) improved from 56.5 to 67.1 (p<0.001). Mean confidence scores (0-10 scale) improved for talking to a healthcare provider about cost (6.1-7.6, p=0.0094), saving for healthcare (5.8-6.6, p=0.068), comparing prices (5.4-6.9, p=0.005) and comparing quality (6.1 to 7.6, p=0.0034). Participants found the website easy to use and helpful for learning about cost-conscious strategies on postintervention interviews. CONCLUSIONS: Our novel behavioural intervention was acceptable to HDHP enrollees with chronic conditions, feasible to deliver and associated with increased health insurance literacy and confidence in using cost-conscious strategies. This intervention should be tested in a definitive randomised controlled trial that is fully powered to evaluate its effects on cost-related access barriers, out-of-pocket spending and health outcomes in this growing patient population.

Proof-of-concept testing of a brief virtual ACT workshop for emotional eating.

BACKGROUND: Emotional eating, or eating in response to negative emotions, is a commonly reported short-term emotion regulation strategy but has been shown to be ineffective in the long term. Most emotional eating interventions based on Acceptance and Commitment Therapy (ACT) have been delivered in the context of weight loss trials, highlighting a need for ACT-based emotional eating interventions in weight-neutral contexts. AIMS: This proof-of-concept study aimed to test the acceptability and efficacy potential of a brief virtual ACT workshop for emotional eating in a small sample of adults identifying as emotional eaters. METHODS: Twenty-six adult emotional eaters completed an ACT workshop delivered in two 1.5-h sessions over two weeks. The workshop targeted awareness and acceptance of emotions and eating urges, and valued actions around eating. RESULTS: The acceptability of the workshop was demonstrated by high participant satisfaction. Significant improvements on all outcome measures were found and maintained up to 3 months follow-up. CONCLUSIONS: These proof-of-concept findings suggest that a brief virtual ACT workshop may improve emotional eating and associated ACT processes. Results from this study can inform a future randomized controlled trial to test the efficacy of the workshop and the role of theoretical processes of change. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04457804. LEVEL OF EVIDENCE: Level IV, evidence obtained from multiple time series with the intervention.

Chemotherapy plus therapeutic plasmapheresis with 4% human albumin solution in multiple myeloma patients with acute kidney injury: a prospective, open-label, proof-of-concept study.

As no unified treatment protocol or evidence yet exists for plasmapheresis without plasma, this study explored the outcomes of using 4% human albumin (ALB) solution as a replacement solution in patients undergoing plasma exchange for multiple myeloma (MM) patients with acute kidney injury (AKI). This study was prospectively registered (ChiCTR2000030640 and NCT05251896). Bortezomib-based chemotherapy plus therapeutic plasmapheresis (TPP) with 4% human ALB solution was assessed for three years in patients with MM aged >18 years, with AKI according to the Kidney Disease Improving Global Outcomes criteria, and without previous renal impairment from other causes. The primary endpoints were changes in renal function over 18 weeks and survival outcomes at 36 months. The secondary endpoints were the incidence of adverse reactions and symptom improvement. Among the 119 patients included in the analysis, 108 experienced renal reactions. The M protein (absolute changes: median -12.12%, interquartile ranges (IQRs) -18.62 to -5.626) and creatine (median -46.91 µmol/L, IQR -64.70 to -29.12) levels decreased, whereas the estimated glomerular filtration rate (eGFR) increased (median 20.66 mL/(min·1.73 m2), IQR 16.03-25.29). Regarding patient survival, 68.1% and 35.3% of patients survived for >12 and >36 months, respectively. The three symptoms with the greatest relief were urine foam, poor appetite, and blurred vision. All 11 patients (7.6%) who experienced mild adverse reactions achieved remission. In conclusion, in MM patients with AKI, plasma-free plasmapheresis with 4% human ALB solution and bortezomib-based chemotherapy effectively alleviated light chain damage to kidney function while improving patient quality of life.

BiLSTM-Based Joint Torque Prediction From Mechanomyogram During Isometric Contractions: A Proof of Concept Study.

Quantifying muscle strength is an important measure in clinical settings; however, there is a lack of practical tools that can be deployed for routine assessment. The purpose of this study is to propose a deep learning model for ankle plantar flexion torque prediction from time-series mechanomyogram (MMG) signals recorded during isometric contractions (i.e., a similar form to manual muscle testing procedure in clinical practice) and to evaluate its performance. Four different deep learning models in terms of model architecture (based on a stacked bidirectional long short-term memory and dense layers) were designed with different combinations of the number of units (from 32 to 512) and dropout ratio (from 0.0 to 0.8), and then evaluated for prediction performance by conducting the leave-one-subject-out cross-validation method from the 10-subject dataset. As a result, the models explained more variance in the untrained test dataset as the error metrics (e.g., root-mean-square error) decreased and as the slope of the relationship between the measured and predicted joint torques became closer to 1.0. Although the slope estimates appear to be sensitive to an individual dataset, >70% of the variance in nine out of 10 datasets was explained by the optimal model. These results demonstrated the feasibility of the proposed model as a potential tool to quantify average joint torque during a sustained isometric contraction.

From shells to sequences: A proof-of-concept study for on-site analysis of hemolymphatic circulating cell-free DNA from sentinel mussels using Nanopore technology.

Blue mussels are often abundant and widely distributed in polar marine coastal ecosystems. Because of their wide distribution, ecological importance, and relatively stationary lifestyle, bivalves have long been considered suitable indicators of ecosystem health and changes. Monitoring the population dynamics of blue mussels can provide information on the overall biodiversity, species interactions, and ecosystem functioning. In the present work, we combined the concept of liquid biopsy (LB), an emerging concept in medicine based on the sequencing of free circulating DNA, with the Oxford Nanopore Technologies (ONT) platform using a portable laboratory in a remote area. Our results demonstrate that this platform is ideally suited for sequencing hemolymphatic circulating cell-free DNA (ccfDNA) fragments found in blue mussels. The percentage of non-self ccfDNA accounted for >50 % of ccfDNA at certain sampling Sites, allowing the quick, on-site acquisition of a global view of the biodiversity of a coastal marine ecosystem. These ccfDNA fragments originated from viruses, bacteria, plants, arthropods, algae, and multiple Chordata. Aside from non-self ccfDNA, we found DNA fragments from all 14 blue mussel chromosomes, as well as those originating from the mitochondrial genomes. However, the distribution of nuclear and mitochondrial DNA was significantly different between Sites. Similarly, analyses between various sampling Sites showed that the biodiversity varied significantly within microhabitats. Our work shows that the ONT platform is well-suited for LB in sentinel blue mussels in remote and challenging conditions, enabling faster fieldwork for conservation strategies and resource management in diverse settings.

Feasibility of continuous non-invasive delivery of oxygen monitoring in cardiac surgical patients: a proof-of-concept preliminary study.

PURPOSE: Oxygen delivery (DO2) and its monitoring are highlighted to aid postoperative goal directed therapy (GDT) to improve perioperative outcomes such as acute kidney injury (AKI) after high-risk cardiac surgeries associated with multiple morbidities and mortality. However, DO2 monitoring is neither routine nor done postoperatively, and current methods are invasive and only produce intermittent DO2 trends. Hence, we proposed a novel algorithm that simultaneously integrates cardiac output (CO), hemoglobin (Hb) and oxygen saturation (SpO2) from the Edwards Life Sciences ClearSight System® and Masimo SET Pulse CO-Oximetry® to produce a continuous, real-time DO2 trend. METHODS: Our algorithm was built systematically with 4 components - machine interface to draw data with PuTTY, data extraction with parsing, data synchronization, and real-time DO2 presentation using a graphic-user interface. Hb readings were validated. RESULTS: Our algorithm was implemented successfully in 93% (n = 57 out of 61) of our recruited cardiac surgical patients. DO2 trends and AKI were studied. CONCLUSION: We demonstrated a novel proof-of-concept and feasibility of continuous, real-time, non-invasive DO2 monitoring, with each patient serving as their own control. Our study also lays the foundation for future investigations aimed at identifying personalized critical DO2 thresholds and optimizing DO2 as an integral part of GDT to enhance outcomes in perioperative cardiac surgery.

NMR Longitudinal Rotating Frame Relaxation Time (T1ρ) with a Weak Spin Locking Field as an Approach to Characterize Solid-State Active Pharmaceutical Ingredients: Proof of Concept.

Nuclear magnetic resonance (NMR) longitudinal rotating frame relaxation time (T1ρ), rarely used in low-field NMR, can be more effective than conventional T1 and T2 relaxation times to differentiate polymorphic forms of solid pharmaceuticals. This could be attributed to T1ρ sensibility to structural and molecular dynamics that can be enhanced by changing the strength of the oscillating magnetic field (B1) of spinlock pulses. Here, we compared the capacity of T1, T2, and T1ρ to differentiate inactive (A) and active (C) crystalline forms of the World Health Organization essential drug Mebendazole. The results showed that T1 and T2 values of both forms were statistically identical at 0.47 T. Conversely, T1ρ of both forms measured with weak spinlock B1 fields, ranging from 0.08 to 0.80 mT were statistically different in the same spectrometer. The T1ρ also has the limit of detection to detect the presence of at least 10% of inactive A form in the active C form. Therefore, T1ρ, measured with weak spinlock B1 fields can be an effective, streamlined, and complementary approach for characterizing not only solid active pharmaceutical ingredients but other solid-state materials as well.

EvolvRehab-MoveWell telerehabilitation for stroke survivors: study protocol for a feasibility with embedded initial proof-of-concept study.

INTRODUCTION: Stroke is a leading cause of disability throughout the world. Unilateral upper limb impairment is common in people who have had a stroke. As a result of impaired upper limb function, people who have had a stroke often employ abnormal 'compensatory' movements. In the short term, these compensatory movements allow the individual to complete tasks, though long-term movement in this manner can lead to limitations. Telerehabilitation offers the provision of rehabilitation services to patients at a remote location using information and communication technologies. 'EvolvRehab' is one such telerehabilitation system, which uses activities to assess and correct compensatory upper body movements, although the feasibility of its use is yet to be determined in National Health Service services. Using EvolvRehab, we aim to assess the feasibility of 6 weeks telerehabilitation in people after a stroke. METHODS AND ANALYSIS: A multisite feasibility study with embedded design phase. Normally distributed data will be analysed using paired samples t-tests; non-normally distributed data will be analysed using related samples Wilcoxon signed rank tests. Thematic content analysis of interview transcripts will be used to investigate the usability and perceived usefulness of the EvolvRehab kit. ETHICS AND DISSEMINATION: This study has received ethical approval from Solihull Research Ethics Committee (REC reference: 23/WM/0054). Dissemination will be carried out according to the dissemination plan co-written with stroke survivors, including academic publications and presentations; written reports; articles in publications of stakeholder organisations; presentations to and publications for potential customers. TRIAL REGISTRATION NUMBER: NCT05875792.

Oxytocin-Augmented Modular-Based Group Intervention for Loneliness: A Proof-Of-Concept Randomized Controlled Trial.

INTRODUCTION: Loneliness poses a significant health problem and existing psychological interventions have shown only limited positive effects on loneliness. Based on preliminary evidence for impaired oxytocin signaling in trait-like loneliness, the current proof-of-concept study used a randomized, double-blind, placebo-controlled design to probe intranasal oxytocin (OT) as an adjunct to a short-term modular-based group intervention for individuals suffering from high trait-like loneliness (HL, UCLA Loneliness Scale ≥55). METHODS: Seventy-eight healthy HL adults (56 women) received five weekly group psychotherapy sessions. HL participants received OT or placebo before the intervention sessions. Primary outcomes were trait-like loneliness measured at baseline, after the intervention, and again at two follow-up time points (3 weeks and 3 months), and, assessed at each session, state loneliness (visual analog scale), perceived stress (Perceived Stress Scale, PSS-10), quality of life (World Health Organization Five Well-Being Index, WHO-5), and the therapeutic relationship (Group Questionnaire, GQ-D). RESULTS: The psychological intervention was associated with significantly reduced perceived stress and improved trait-like loneliness across treatment groups, which was still evident at the 3-month follow-up. OT had no significant effect on trait-like loneliness, quality of life, or perceived stress. However, compared to placebo, OT significantly facilitated the decrease in state loneliness within sessions and significantly improved positive bonding between the group members. CONCLUSION: Despite significantly improved trait-like loneliness after the intervention, OT did not significantly augment this effect. Further studies are needed to determine optimal intervention designs to translate the observed acute effects of OT into long-term benefits.

Prediction of Achilles Tendon Force During Common Motor Tasks From Markerless Video.

Remodeling of the Achilles tendon (AT) is partly driven by its mechanical environment. AT force can be estimated with neuromusculoskeletal (NMSK) modeling; however, the complex experimental setup required to perform the analyses confines use to the laboratory. We developed task-specific long short-term memory (LSTM) neural networks that employ markerless video data to predict the AT force during walking, running, countermovement jump, single-leg landing, and single-leg heel rise. The task-specific LSTM models were trained on pose estimation keypoints and corresponding AT force data from 16 subjects, calculated via an established NMSK modeling pipeline, and cross-validated using a leave-one-subject-out approach. As proof-of-concept, new motion data of one participant was collected with two smartphones and used to predict AT forces. The task-specific LSTM models predicted the time-series AT force using synthesized pose estimation data with root mean square error (RMSE) ≤ 526 N, normalized RMSE (nRMSE) ≤ 0.21 , R 2 ≥ 0.81 . Walking task resulted the most accurate with RMSE = 189±62 N; nRMSE = 0.11±0.03 , R 2 = 0.92±0.04 . AT force predicted with smartphones video data was physiologically plausible, agreeing in timing and magnitude with established force profiles. This study demonstrated the feasibility of using low-cost solutions to deploy complex biomechanical analyses outside the laboratory.

Anatomy, evolution, and clinical aspects of the superextended-intercompartmental-supraretinacular artery perforator flap (SISAP-flap): A proof of concept.

BACKGROUND: Extended soft tissue defects of the fingers-irrespective of their origin-are challenging to treat. In cases of missing amputates or crush injuries, the options are often limited to further amputation, ray resection, or free tissue transplantation. The SISAP-flap was developed to add an extra option to treat finger avulsion injuries or otherwise extended soft tissue finger defects. METHODS: Cadaveric SISAP-flaps were individually dissected, tested for arterial perfusion using red ink and radiopaque dye, and transposed into artificially created same-size defects. After introducing this flap in the clinic, which was partially successful in the first patient, we modified the flap to its definite design. RESULTS: Average cadaver flap size ranges between 11 cm and 22 cm in length, allowing dorsal wrapping of the flap over the fingertip and way back to the palmar metacarpophalangeal-joint. The flap is based on the distal web space perforator, which is commonly used by a dorsal metacarpal artery flap and supercharged using an intercompartmental, supraretinacular artery. Donor sites were closed primarily with little tension. Application of the flap in the clinic resulted in satisfactory functional and esthetic outcomes. CONCLUSION: The SISAP-flap is a new option for the reconstruction of extended finger defects and should be added to the reconstructive surgeon's armamentarium of pedicled flaps, providing relatively short operating times and promising clinical outcomes.

Chemogenetic inhibition of the lateral hypothalamus effectively reduces food intake in rats in a translational proof-of-concept study.

Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo efficacy assay in rats which could support chemogenetic drug discovery by providing a quick, simple and reliable animal model. Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts 1-3 h post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments. We also hypothesize based on our results that universal LH silencing with existing and human translatable genetic neuroengineering techniques might be a viable strategy to affect food intake and influence obesity.