Precision pore structure optimization of additive manufacturing porous tantalum scaffolds for bone regeneration: A proof-of-concept study.

Currently, the treatment of bone defects in arthroplasty is a challenge in clinical practice. Nonetheless, commercially available orthopaedic scaffolds have shown limited therapeutic effects for large bone defects, especially for massiveand irregular defects. Additively manufactured porous tantalum, in particular, has emerged as a promising material for such scaffolds and is widely used in orthopaedics for its exceptional biocompatibility, osteoinduction, and mechanical properties. Porous tantalum has also exhibited unique advantages in personalised rapid manufacturing, which allows for the creation of customised scaffolds with complex geometric shapes for clinical applications at a low cost and high efficiency. However, studies on the effect of the pore structure of additively manufactured porous tantalum on bone regeneration have been rare. In this study, our group designed and fabricated a batch of precision porous tantalum scaffolds via laser powder bed fusion (LPBF) with pore sizes of 250 µm (Ta 250), 450 µm (Ta 450), 650 µm (Ta 650), and 850 µm (Ta 850). We then performed a series of in vitro experiments and observed that all four groups showed good biocompatibility. In particular, Ta 450 demonstrated the best osteogenic performance. Afterwards, our team used a rat bone defect model to determine the in vivo osteogenic effects. Based on micro-computed tomography and histology, we identified that Ta 450 exhibited the best bone ingrowth performance. Subsequently, sheep femur and hip defect models were used to further confirm the osteogenic effects of Ta 450 scaffolds. Finally, we verified the aforementioned in vitro and in vivo results via clinical application (seven patients waiting for revision total hip arthroplasty) of the Ta 450 scaffold. The clinical results confirmed that Ta 450 had satisfactory clinical outcomes up to the 12-month follow-up. In summary, our findings indicate that 450 µm is the suitable pore size for porous tantalum scaffolds. This study may provide a new therapeutic strategy for the treatment of massive, irreparable, and protracted bone defects in arthroplasty.

Proof-of-concept study of a small language model chatbot for breast cancer decision support - a transparent, source-controlled, explainable and data-secure approach.

PURPOSE: Large language models (LLM) show potential for decision support in breast cancer care. Their use in clinical care is currently prohibited by lack of control over sources used for decision-making, explainability of the decision-making process and health data security issues. Recent development of Small Language Models (SLM) is discussed to address these challenges. This preclinical proof-of-concept study tailors an open-source SLM to the German breast cancer guideline (BC-SLM) to evaluate initial clinical accuracy and technical functionality in a preclinical simulation. METHODS: A multidisciplinary tumor board (MTB) is used as the gold-standard to assess the initial clinical accuracy in terms of concordance of the BC-SLM with MTB and comparing it to two publicly available LLM, ChatGPT3.5 and 4. The study includes 20 fictional patient profiles and recommendations for 5 treatment modalities, resulting in 100 binary treatment recommendations (recommended or not recommended). Statistical evaluation includes concordance with MTB in % including Cohen's Kappa statistic (κ). Technical functionality is assessed qualitatively in terms of local hosting, adherence to the guideline and information retrieval. RESULTS: The overall concordance amounts to 86% for BC-SLM (κ = 0.721, p < 0.001), 90% for ChatGPT4 (κ = 0.820, p < 0.001) and 83% for ChatGPT3.5 (κ = 0.661, p < 0.001). Specific concordance for each treatment modality ranges from 65 to 100% for BC-SLM, 85-100% for ChatGPT4, and 55-95% for ChatGPT3.5. The BC-SLM is locally functional, adheres to the standards of the German breast cancer guideline and provides referenced sections for its decision-making. CONCLUSION: The tailored BC-SLM shows initial clinical accuracy and technical functionality, with concordance to the MTB that is comparable to publicly-available LLMs like ChatGPT4 and 3.5. This serves as a proof-of-concept for adapting a SLM to an oncological disease and its guideline to address prevailing issues with LLM by ensuring decision transparency, explainability, source control, and data security, which represents a necessary step towards clinical validation and safe use of language models in clinical oncology.

Design of a Temporally Augmented Text Messaging Bot to Improve Adolescents' Physical Activity and Engagement: Proof-of-Concept Study.

BACKGROUND: Digital interventions hold promise for improving physical activity in adolescents. However, a lack of empirical decision points (eg, timing of intervention prompts) is an evidence gap in the optimization of digital physical activity interventions. OBJECTIVE: The study examined the feasibility and acceptability, as well as the technical and functional reliability, of and participant engagement with a digital intervention that aligned its decision points to occur during times when adolescents typically exercise. This study also explored the impact of the intervention on adolescents' moderate to vigorous physical activity (MVPA) levels. Consistent with the Obesity-Related Behavioral Interventions Trials (ORBIT) model, the primary goal of the study was to identify opportunities to refine the intervention for preparation for future trials. METHODS: Ten adolescents completed a 7-day baseline monitoring period and Temporally Augmented Goal Setting (TAGS), a 20-day digital physical activity intervention that included a midday self-monitoring message that occurred when adolescents typically start to exercise (3 PM). Participants wore an accelerometer to measure their MVPA during the intervention. Participants completed questionnaires about the acceptability of the platform. Rates of recruitment and attrition (feasibility), user and technological errors (reliability), and engagement (average number of text message responses to the midday self-monitoring message) were calculated. The investigation team performed multilevel models to explore the effect of TAGS on MVPA levels from preintervention to intervention. In addition, as exploratory analyses, participants were matched to adolescents who previously completed a similar intervention, Network Underwritten Dynamic Goals Engine (NUDGE), without the midday self-monitoring message, to explore differences in MVPA between interventions. RESULTS: The TAGS intervention was mostly feasible, acceptable, and technically and functionally reliable. Adolescents showed adequate levels of engagement. Preintervention to intervention changes in MVPA were small (approximately a 2-minute change). Exploratory analyses revealed no greater benefit of TAGS on MVPA compared with NUDGE. CONCLUSIONS: TAGS shows promise for future trials with additional refinements given its feasibility, acceptability, technical and functional reliability, participants' rates of engagement, and the relative MVPA improvements. Opportunities to strengthen TAGS include reducing the burden of wearing devices and incorporating of other strategies at the 3 PM decision point. Further optimization of TAGS will inform the design of a Just-in-Time Adaptive Intervention for adolescent physical activity and prepare the intervention for more rigorous testing.

Quantitative brain T1 maps derived from T1-weighted MRI acquisitions: a proof-of-concept study.

BACKGROUND: Longitudinal T1 relaxation time is a key imaging biomarker. In addition, T1 values are modulated by the administration of T1 contrast agents used in patients with tumors and metastases. However, in clinical practice, dedicated T1 mapping sequences are often not included in brain MRI protocols. The aim of this study is to address the absence of dedicated T1 mapping sequences in imaging protocol by deriving T1 maps from standard T1-weighted sequences. METHODS: A phantom, composed of 144 solutions of paramagnetic agents at different concentrations, was imaged with a three-dimensional (3D) T1-weighed turbo spin-echo (TSE) sequence designed for brain imaging. The relationship between the T1 values and the signal intensities was established using this phantom acquisition. T1 mapping derived from 3D T1-weighted TSE acquisitions in four healthy volunteers and one patient with brain metastases were established and compared to reference T1 mapping technique. The concentration of Gd-based contrast agents in brain metastases were assessed from the derived T1 maps. RESULTS: Based on the phantom acquisition, the relationship between T1 values and signal intensity (SI) was found equal to T1 = 0.35 × SI-1.11 (R2 = 0.97). TSE-derived T1 values measured in white matter and gray matter in healthy volunteers were equal to 0.997 ± 0.096 s and 1.358 ± 0.056 s (mean ± standard deviation), respectively. Mean Gd3+ concentration value in brain metastases was 94.7 ± 30.0 µM. CONCLUSION: The in vivo results support the relevance of the phantom-based approach: brain T1 maps can be derived from T1-weighted acquisitions. RELEVANCE STATEMENT: High-resolution brain T1 maps can be generated, and contrast agent concentration can be quantified and imaged in brain metastases using routine 3D T1-weighted TSE acquisitions. KEY POINTS: Quantitative T1 mapping adds significant value to MRI diagnostics. T1 measurement sequences are rarely included in routine protocols. T1 mapping and concentration of contrast agents can be derived from routine standard scans. The diagnostic value of MRI can be improved without additional scan time.

Game-Based Assessment of Peripheral Neuropathy Combining Sensor-Equipped Insoles, Video Games, and AI: Proof-of-Concept Study.

BACKGROUND: Detecting peripheral neuropathy (PNP) is crucial in preventing complications such as foot ulceration. Clinical examinations for PNP are infrequently provided to patients at high risk due to restrictions on facilities, care providers, or time. A gamified health assessment approach combining wearable sensors holds the potential to address these challenges and provide individuals with instantaneous feedback on their health status. OBJECTIVE: We aimed to develop and evaluate an application that assesses PNP through video games controlled by pressure sensor-equipped insoles. METHODS: In the proof-of-concept exploratory cohort study, a complete game-based framework that allowed the study participant to play 4 video games solely by modulating plantar pressure values was established in an outpatient clinic setting. Foot plantar pressures were measured by the sensor-equipped insole and transferred via Bluetooth to an Android tablet for game control in real time. Game results and sensor data were delivered to the study server for visualization and analysis. Each session lasted about 15 minutes. In total, 299 patients with diabetes mellitus and 30 with metabolic syndrome were tested using the game application. Patients' game performance was initially assessed by hypothesis-driven key capabilities that consisted of reaction time, sensation, skillfulness, balance, endurance, and muscle strength. Subsequently, specific game features were extracted from gaming data sets and compared with nerve conduction study findings, neuropathy symptoms, or disability scores. Multiple machine learning algorithms were applied to 70% (n=122) of acquired data to train predictive models for PNP, while the remaining data were held out for final model evaluation. RESULTS: Overall, clinically evident PNP was present in 247 of 329 (75.1%) participants, with 88 (26.7%) individuals showing asymmetric nerve deficits. In a subcohort (n=37) undergoing nerve conduction study as the gold standard, sensory and motor nerve conduction velocities and nerve amplitudes in lower extremities significantly correlated with 79 game features (|R|>0.4, highest R value +0.65; P<.001; adjusted R2=0.36). Within another subcohort (n=173) with normal cognition and matched covariates (age, sex, BMI, etc), hypothesis-driven key capabilities and specific game features were significantly correlated with the presence of PNP. Predictive models using selected game features achieved 76.1% (left) and 81.7% (right foot) accuracy for PNP detection. Multiclass models yielded an area under the receiver operating characteristic curve of 0.76 (left foot) and 0.72 (right foot) for assessing nerve damage patterns (small, large, or mixed nerve fiber damage). CONCLUSIONS: The game-based application presents a promising avenue for PNP screening and classification. Evaluation in expanded cohorts may iteratively optimize artificial intelligence model efficacy. The integration of engaging motivational elements and automated data interpretation will support acceptance as a telemedical application.

The potential of human leukocyte antigen alleles to assist with multiple-contributor DNA mixtures: Proof of concept study.

One of the most challenging issues still present in forensic DNA analysis is identifying individuals in samples containing DNA from multiple contributors. The introduction of novel identification markers may be a useful tool in the deconvolution of such DNA mixtures. In this study, we investigated the potential of alleles from the human leukocyte antigen system (HLA) to aid in identifying individuals in complex, multiple-donor DNA samples. The most advantageous characteristic of the HLA complex is its polymorphism in the human genome. A 22-loci multiplex with HLA markers was designed and applied to two-, three-, and four-person DNA mixtures. The results of the conducted experiments demonstrated that the identification of individuals in multiple contributor samples with the help of HLA markers is possible; however, it is clear that the reliability of the method is heavily dependent on the number of unique alleles for each individual in the analysed mixture. In order to compare this novel approach against the already established process, the same group of reference and multiple-contributor samples was analysed with a commonly used set of STR markers. This proof-of-concept research shows the importance of examining alternative solutions to the current deconvolution challenge in forensic DNA profiling.

C-X-C Motif Chemokine Receptor 4-Directed Scintigraphy Using [99mTc]Tc-Pentixatec in Primary Aldosteronism: A Proof-of-Concept Study.

C-X-C motif chemokine receptor 4 (CXCR4)-directed imaging has gained clinical interest in aiding clinical diagnostics in primary aldosteronism (PA). We retrospectively evaluated the feasibility of CXCR4-directed scintigraphy using the novel CXCR-4 ligand [99mTc]Tc-pentixatec in patients with PA. Methods: Six patients (mean age ± SD, 49 ± 15 y) underwent CXCR4-directed scintigraphy (including planar imaging and SPECT/CT) 30, 120, and 240 min after injection of 435 ± 50 MBq of [99mTc]Tc-pentixatec. Adrenal CXCR4 expression was analyzed by calculating lesion-to-contralateral ratios (LCRs). Imaging results were correlated to clinical information. Histopathology and clinical follow-up served as the standard of reference. Results: Three subjects showed lateralization of adrenal tracer accumulation, with a mean maximum lesion-to-contralateral ratio of 1.65 (range, 1.52-1.70), which correlated with morphologic findings on CT. One individual underwent adrenalectomy and presented with complete biochemical and clinical remission at follow-up. Histopathologic workup confirmed unilateral aldosterone-producing adenoma. Conclusion: [99mTc]Tc-pentixatec scintigraphy with SPECT in patients with PA is feasible and might offer a valuable alternative to CXCR4-directed imaging with [68Ga]Ga-pentixafor PET.

The Application of Mask Region-Based Convolutional Neural Networks in the Detection of Nasal Septal Deviation Using Cone Beam Computed Tomography Images: Proof-of-Concept Study.

BACKGROUND: Artificial intelligence (AI) models are being increasingly studied for the detection of variations and pathologies in different imaging modalities. Nasal septal deviation (NSD) is an important anatomical structure with clinical implications. However, AI-based radiographic detection of NSD has not yet been studied. OBJECTIVE: This research aimed to develop and evaluate a real-time model that can detect probable NSD using cone beam computed tomography (CBCT) images. METHODS: Coronal section images were obtained from 204 full-volume CBCT scans. The scans were classified as normal and deviated by 2 maxillofacial radiologists. The images were then used to train and test the AI model. Mask region-based convolutional neural networks (Mask R-CNNs) comprising 3 different backbones-ResNet50, ResNet101, and MobileNet-were used to detect deviated nasal septum in 204 CBCT images. To further improve the detection, an image preprocessing technique (contrast enhancement [CEH]) was added. RESULTS: The best-performing model-CEH-ResNet101-achieved a mean average precision of 0.911, with an area under the curve of 0.921. CONCLUSIONS: The performance of the model shows that the model is capable of detecting nasal septal deviation. Future research in this field should focus on additional preprocessing of images and detection of NSD based on multiple planes using 3D images.

Enhancing Digital Health Awareness and mHealth Competencies in Medical Education: Proof-of-Concept Study and Summative Process Evaluation of a Quality Improvement Project.

BACKGROUND: Currently, there is a need to optimize knowledge on digital transformation in mental health care, including digital therapeutics (eg, prescription apps), in medical education. However, in Germany, digital health has not yet been systematically integrated into medical curricula and is taught in a relatively small number of electives. Challenges for lecturers include the dynamic field as well as lacking guidance on how to efficiently apply innovative teaching formats for these new digital competencies. Quality improvement projects provide options to pilot-test novel educational offerings, as little is known about the acceptability of participatory approaches in conventional medical education. OBJECTIVE: This quality improvement project addressed the gap in medical school electives on digital health literacy by introducing and evaluating an elective scoping study on the systematic development of different health app concepts designed by students to cultivate essential skills for future health care professionals (ie, mobile health [mHealth] competencies). METHODS: This proof-of-concept study describes the development, optimization, implementation, and evaluation of a web-based elective on digital (mental) health competencies in medical education. Implemented as part of a quality improvement project, the elective aimed to guide medical students in developing app concepts applying a design thinking approach at a German medical school from January 2021 to January 2024. Topics included defining digital (mental) health, quality criteria for health apps, user perspective, persuasive design, and critical reflection on digitization in medical practice. The elective was offered 6 times within 36 months, with continuous evaluation and iterative optimization using both process and outcome measures, such as web-based questionnaires. We present examples of app concepts designed by students and summarize the quantitative and qualitative evaluation results. RESULTS: In total, 60 students completed the elective and developed 25 health app concepts, most commonly targeting stress management and depression. In addition, disease management and prevention apps were designed for various somatic conditions such as diabetes and chronic pain. The results indicated high overall satisfaction across the 6 courses according to the evaluation questionnaire, with lower scores indicating higher satisfaction on a scale ranging from 1 to 6 (mean 1.70, SD 0.68). Students particularly valued the content, flexibility, support, and structure. While improvements in group work, submissions, and information transfer were suggested, the results underscore the usefulness of the web-based elective. CONCLUSIONS: This quality improvement project provides insights into relevant features for the successful user-centered and creative integration of mHealth competencies into medical education. Key factors for the satisfaction of students involved the participatory mindset, focus on competencies, discussions with app providers, and flexibility. Future efforts should define important learning objectives for digital health literacy and provide recommendations for integration rather than debating the need for digital health integration.

Naltrexone augmented with prazosin for alcohol use disorder: results from a randomized controlled proof-of-concept trial.

AIMS: We conducted a proof-of-concept randomized controlled trial of the mu-opioid receptor antagonist, naltrexone, augmented with the alpha-1 adrenergic receptor antagonist, prazosin, for alcohol use disorder in veterans. We sought a signal that the naltrexone plus prazosin combination regimen would be superior to naltrexone alone. METHODS: Thirty-one actively drinking veterans with alcohol use disorder were randomized 1:1:1:1 to naltrexone plus prazosin (NAL-PRAZ [n = 8]), naltrexone plus placebo (NAL-PLAC [n = 7]), prazosin plus placebo (PRAZ-PLAC [n = 7]), or placebo plus placebo (PLAC-PLAC [n = 9]) for 6 weeks. Prazosin was titrated over 2 weeks to a target dose of 4 mg QAM, 4 mg QPM, and 8 mg QHS. Naltrexone was administered at 50 mg QD. Primary outcomes were the Penn Alcohol Craving Scale (PACS), % drinking days (PDD), and % heavy drinking days (PHDD). RESULTS: In the NAL-PRAZ condition, % reductions from baseline for all three primary outcome measures exceeded 50% and were at least twice as large as % reductions in the NAL-PLAC condition (PACS: 57% vs. 26%; PDD: 51% vs. 22%; PHDD: 69% vs. 15%) and in the other two comparator conditions. Standardized effect sizes between NAL-PRAZ and NAL-PLAC for each primary outcome measure were >0.8. All but one participant assigned to the two prazosin containing conditions achieved the target prazosin dose of 16 mg/day and maintained that dose for the duration of the trial. CONCLUSION: These results suggest that prazosin augmentation of naltrexone enhances naltrexone benefit for alcohol use disorder. These results strengthen rationale for an adequately powered definitive randomized controlled trial.

Efficacy of a new video observational training method (intensive visual simulation) for motor recovery in the upper limb in subacute stroke: a feasibility and proof-of-concept study.

OBJECTIVE: To demonstrate the feasibility and efficacy  of a new video-observation training method (intensive visual simulation) to improve upper limb function. DESIGN: Small sample, randomized, evaluator-blind, monocentric study. PATIENTS: Seventeen early subacute ischaemic stroke patients with complete hemiplegia were  randomly assigned to the therapeutic group (n = 8) or control group (CG, n = 9). METHODS: Thirty sessions of intensive visual simulation combined with corrected visual feedback (therapeutic group) or uncorrected visual feedback (control group) were performed over 6 weeks on top of a standard rehabilitation programme. MAIN OUTCOME MEASURE: 400-point hand assessment test (400p-HA). SECONDARY OUTCOME MEASURES: Box and Blocks (B&B), Purdue Pegboard test, Minnesota. RESULTS: The 400p-HA test improved significantly from T0 to 6 months for both groups, with a significant difference between groups at 3 months (MW-UT p = 0.046) and 4 months (MW-UT p = 0.046) in favour of the therapeutic group. One-phase exponential modelling of 400p-HA showed a greater plateau for the therapeutic group (F test p = 0.0021). There was also faster recovery of the ability to perform the B&B tests for the therapeutic group (log-rank test p = 0.03). CONCLUSION: This study demonstrated the feasibility and potential efficacy of an intensive visual simulation training programme to improve upper limb  function in subacute stroke patients. A larger study is needed to confirm these results.

Proof of concept study on early forecasting of antimicrobial resistance in hospitalized patients using machine learning and simple bacterial ecology data.

Antibiotic resistance in bacterial pathogens is a major threat to global health, exacerbated by the misuse of antibiotics. In hospital practice, results of bacterial cultures and antibiograms can take several days. Meanwhile, prescribing an empirical antimicrobial treatment is challenging, as clinicians must balance the antibiotic spectrum against the expected probability of susceptibility. We present here a proof of concept study of a machine learning-based system that predicts the probability of antimicrobial susceptibility and explains the contribution of the different cofactors in hospitalized patients, at four different stages prior to the antibiogram (sampling, direct examination, positive culture, and species identification), using only historical bacterial ecology data that can be easily collected from any laboratory information system (LIS) without GDPR restrictions once the data have been anonymised. A comparative analysis of different state-of-the-art machine learning and probabilistic methods was performed using 44,026 instances over 7 years from the Hôpital Européen Marseille, France. Our results show that multilayer dense neural networks and Bayesian models are suitable for early prediction of antibiotic susceptibility, with AUROCs reaching 0.88 at the positive culture stage and 0.92 at the species identification stage, and even 0.82 and 0.92, respectively, for the least frequent situations. Perspectives and potential clinical applications of the system are discussed.

Is the combination of interfascial plane blocks sufficient for awake breast cancer surgery? An observational, prospective, proof-of-concept study.

INTRODUCTION: Breast cancer is the most prevalent cancer among women, often necessitating surgical intervention. While surgeries like lumpectomy can be performed under local anesthesia, more extensive procedures typically require general anesthesia. Awake breast cancer surgery has emerged as an alternative due to risks associated with general anesthesia and patient preference. METHODS: This prospective observational study, conducted from July 2022 to July 2023, evaluated the effectiveness of ultrasound-guided fascial plane blocks for awake breast surgery. Patients aged 18-80 years undergoing unilateral breast surgery were included, following ethical committee approval and written informed consent. Exclusion criteria were prior breast surgery, coagulopathies, infections, allergies to local anesthetics, psychiatric disorders, body mass index over 40 kg/m², and chest deformities. The combination of interpectoral, pecto-serratus, and deep serratus plane blocks was used as the primary anesthetic method, with a superficial parasternal block added in cases where complete cutaneous coverage was not achieved. RESULTS: Seventeen patients were enrolled. The primary outcome, sufficient surgical anesthesia without deep sedation, was achieved in 15 patients. The combination of the aforementioned blocks proved effective, with an average surgery duration of 59.66 min, and propofol requirements averaging 1.77 mg/kg/hour. Most patients reported high satisfaction levels, and no early or late block-related complications were observed. CONCLUSION: The combination of fascial plane blocks is a viable option for awake breast cancer surgery, potentially eliminating the need for more invasive anesthesia techniques. Further studies are necessary to confirm these findings in larger, homogeneous patient groups.

Evaluation of low volume sampling devices for a pharmacodynamic biomarker analysis: Challenges and solutions.

Low volume sampling technologies have gained popularity as they are minimally invasive, reduce patient burden, enhance population diversity, and have the potential to facilitate decentralized clinical trials. Herein, we validated a Gyrolab assay to measure soluble Mucosal Addressin Cell Adhesion Molecule 1 (sMAdCAM-1) in dried blood samples collected using two low volume sampling devices, Mitra and Tasso-M20. This validated assay was implemented in a proof-of-concept study to compare three low volume sampling devices (Mitra, Tasso-M20 and TassoOne Plus) with serum collected via venipuncture from healthy volunteers receiving etrolizumab. We observed significantly higher concentration of sMAdCAM-1 in dried blood samples collected using Mitra and Tasso-M20 compared to serum in some paired samples, which was attributed to interference from the dried blood extraction buffer. To mitigate this interference, samples required substantial dilution into the appropriate buffer, which negatively impacted the detectability of sMAdCAM-1 with the Gyrolab assay. By employing the Quanterix single molecule array (Simoa), known for its superior assay sensitivity, the interference was minimized in the diluted samples. Both liquid blood collected in TassoOne Plus and dried blood collected using Mitra and Tasso-M20 demonstrated great concordance with serum for sMAdCAM-1 measurement. However, a bias was observed in Mitra dried blood samples, presumably due to the different sample collection sites in comparison with venipuncture and Tasso devices. Our study highlights the potential of low volume sampling technologies for biomarker analysis, and underscores the importance of understanding the challenges and limitations of these technologies before integrating them into clinical studies.

Home self-testing of complete blood counts in patients with breast cancer during chemotherapy: A proof-of-concept cohort study in e-oncology.

BACKGROUND: Before administration of myelosuppressive chemotherapy, complete blood counts (CBC) collected at the hospital/nursing stations are evaluated to avoid severe bone marrow suppression. This maintains disease fixation which often reduces their quality of life. This mixed-method study examined at home self-testing of CBC, the test quality, and the effects on patients' mental well-being. METHODS: Patients with breast cancer receiving chemotherapy were recruited and trained to perform capillary finger prick CBC testing at home using the HemoScreen Point-of-Care instrument and to upload the test results to the hospital's IT system subsequently. A venous reference CBC sample was taken and tested at the hospital on the day of self-testing. Semi-structured interviews with open-ended components were performed to investigate the user experience and the impact of self-testing on the patients' everyday lives. RESULTS: Thirty-nine patients completed the self-testing education using the HemoScreen instrument. Eight patients withdrew, while the remaining 31 patients performed 161 home tests (2-11 tests per patient) over a 4-month period. The test results compared well with the venous reference CBCs except for platelet counts (correlation coefficient 0.26). Qualitative interviews with nine of the 31 patients emphasized that the patients were comfortable using the self-testing instrument and becoming an active partner in their own treatment. INTERPRETATION: CBC self-testing at home produced clinically valid hemoglobin and white blood cell counts with the added benefit that the patients became active partners in their own treatment course, which was of great importance for the patients and increased their wellbeing.

Effects of interleukin-1 receptor antagonism in women with polycystic ovary syndrome-the FertIL trial.

Introduction: Chronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS. Methods: This is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels ≥ 1.7 nmol/L, and C-reactive protein (CRP) ≥ 1.0 mg/L. Patients received 100 mg/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography-tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021). Results: Median [interquartile range (IQR)] androstenedione increased by 0.5 [-0.1, 1.6] nmol/L (p = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol/L [p = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (p < 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment. Discussion: Our findings suggest that anakinra suppresses IL-1-mediated chronic low-grade inflammation in PCOS and might attenuate biochemical hyperandrogenemia.

Novel sampling and gas-phase derivatization strategy: Proof-of-concept by profiling ionic polar metabolites using gas chromatography-mass spectrometry.

Metabolomic research involves the comprehensive analysis of metabolites in biological samples and has many applications. Gas chromatography-mass spectrometry (GC-MS) is an established and widely used approach for metabolic profiling. However, sample preparation and metabolite derivatization are time-consuming, and derivatization options are limited. We propose gas-solid phase derivatization (GSPD) as a novel sampling and derivatization method that uses a silica monolith substrate and gaseous derivatization reagents for metabolomics using GC-MS. We developed a method to measure the organic acids and sugar phosphates responsible for glycolysis and the tricarboxylic acid (TCA) cycle. GSPD simplifies the sample preparation and can be applied to derivatization reactions that are difficult to perform in solution owing to solvent limitations. The developed method was applied to human plasma and tomato pulp and was shown to have a higher detection performance than the conventional method. This study provides a strategy to simplify sample preparation and expand derivatization options for GC-MS-based metabolomics.

Demonstrating the data integrity of routinely collected healthcare systems data for clinical trials (DEDICaTe): A proof-of-concept study.

Introduction/aims: Healthcare systems data (also known as real-world or routinely collected health data) could transform the conduct of clinical trials. Demonstrating integrity and provenance of these data is critical for clinical trials, to enable their use where appropriate and avoid duplication using scarce trial resources. Building on previous work, this proof-of-concept study used a data intelligence tool, the "Central Metastore," to provide metadata and lineage information of nationally held data. Methods: The feasibility of NHS England's Central Metastore to capture detailed records of the origins, processes, and methods that produce four datasets was assessed. These were England's Hospital Episode Statistics (Admitted Patient Care, Outpatients, Critical Care) and the Civil Registration of Deaths (England and Wales). The process comprised: information gathering; information ingestion using the tool; and auto-generation of lineage diagrams/content to show data integrity. A guidance document to standardise this process was developed. Results/Discussion: The tool can ingest, store and display data provenance in sufficient detail to support trust and transparency in using these datasets for trials. The slowest step was information gathering from multiple sources, so consistency in record-keeping is essential.

Early implementation of MAK robotic device in total knee arthroplasty rehabilitation: A proof-of-concept study.

BACKGROUND: Effective rehabilitation following total knee arthroplasty (TKA) is crucial for enhancing both range of motion (ROM) and functional outcomes. While robotics has demonstrated its potential in various medical contexts, the evidence on its application in TKA rehabilitation is still scarce. The marsi active knee (MAK), a robotic device that has already proven to be safe and beneficial in people with neurological disease, has been tested to facilitate the rehabilitation of TKA patients. OBJECTIVE: This study aims to evaluate the safety, patient satisfaction, and clinical impact of integrating the MAK into an early rehabilitation regimen for TKA patients. METHODS: The intervention comprised 14 one-hour sessions administered thrice a week, utilizing the MAK within 48 h post-TKA surgery. The rehabilitation sessions incorporated exercises involving passive mobilizations, sit-to-stand transitions, and gait training. Comprehensive data encompassing safety parameters, patient satisfaction, and clinical outcomes were meticulously collected and analyzed. RESULTS: Six participants successfully completed the rehabilitation protocol with the MAK device. Notably, no significant adverse events were documented. Application of the device corresponded to perceptible reductions in self-reported pain levels. Vital signs remained within minimal variance pre- and post-rehabilitation. Participants proficiently engaged in all assisted exercises facilitated by the device, culminating in a high overall satisfaction rating of 4.6 ± 0.5 out of 5. CONCLUSION: The findings indicate that the MAK device exhibits a commendable level of safety while obtaining considerable patient satisfaction during the early rehabilitation phase following TKA, suggesting this device may be a reliable adjunct to TKA protocols.

Development of an automated high-content immunofluorescence assay of pSmads quantification: Proof-of-concept with drugs inhibiting the BMP/TGF-ß pathways.

INTRODUCTION: Bone morphogenetic proteins (BMPs) and transforming growth factors (TGF-ß) are members of the TGF-ß superfamily, known for their roles in several physiological and pathological processes. These factors are known to bind in vivo to BMP and TGF-ß receptors, respectively, which induces the phosphorylation of Smad (pSmad) transcription factors. This pathway is generally studied with Western blot and luciferase bioluminescence assay, which presents some limitations. PURPOSE: In this work, we developed and optimized a high-throughput assay to study pSmad pathways using immunofluorescence (IF) as an alternative to Western blot. We aimed to overcome the technical challenges usually faced in the classical IF assay in image acquisition, analysis, and quantification. METHODS: We used C2C12 cells as a cellular model. The cells were stimulated with BMP-2 and TGF-ß1 that were delivered either in solution (soluble) or via a biomaterial presenting the growth factor (GF), that is in a "matrix-bound" manner. Image acquisition parameters, analysis methods, and quantification of pSmads using IF were optimized for cells cultured on two types of supports: on bare glass and on a biomimetic coating made by self-assembly of the biopolymers hyaluronic acid and poly(l-lysine), which was crosslinked and then loaded with the GFs. RESULTS: We performed high-content kinetic studies of pSmad expression for cells cultured in 96-well microplates in response to soluble and matrix-bound BMP-2 and TGF-ß1. The detection limit of the IF-based assay was found to be similar to Western blot. Additionally, we provide a proof-of-concept for drug testing using inhibitors of BMP and TGF-ß receptors, under conditions where specific signaling pathways are engaged via the ligand/receptor interactions. Altogether, our findings offer perspectives for future mechanistic studies on cell signaling and for studies at the single cell level using imaging methods.