RESUMEN
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.
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Regeneración Ósea , Tantalio , Andamios del Tejido , Tantalio/química , Regeneración Ósea/efectos de los fármacos , Porosidad , Animales , Andamios del Tejido/química , Ratas , Ratas Sprague-Dawley , Osteogénesis/efectos de los fármacos , Humanos , Masculino , Prueba de Estudio Conceptual , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , FemeninoRESUMEN
Objectives: The pathophysiology of multiple sclerosis (MS) involves inflammatory neurodegeneration in the brainstem, cerebellum, and retina. The clinical relevance of oculomotor involvement in MS, however, remains uncertain. Methods: In this cross-sectional study, we evaluated heterophoria as a (sub)clinical tool in 54 MS patients and 55 age-matched healthy controls (HCs). We quantified heterophoria in prism diopters for distance and near range with orthoptic examination. Our primary outcome was high degrees of horizontal heterophoria (HDHH) defined as measurements beyond ±2 standard deviations from the mean prism diopter of heterophoria of our HCs. Results: More than one-third (37%, n=20/54) of MS patients but only 11% (n=6/55) of HCs were classified as HDHH [distance, MS=9% (n=5/54) versus HC=6% (n=3/55); near, MS=19% (n=10/54) versus HC=5% (n=3/55)]. Our MS patients presented more combined vertical and horizontal deviations at near range [MS 19% (n=10/54) versus for HC 7% (n=4/55)]. We observed the combination of HDHH both at distance and at near testing in 9% (n=5/54) of MS patients but not at all in HCs (n=0/55). Discussion: Despite the high prevalence of heterophoria, HDHH may be an additional (sub)clinical tool of subclinical involvement in MS. Thus, orthoptic examination may be an additional tool to improve MS diagnostic procedures.
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Esclerosis Múltiple , Humanos , Estudios Transversales , Femenino , Masculino , Adulto , Persona de Mediana Edad , Estrabismo , Estudios de Casos y Controles , Prueba de Estudio ConceptualRESUMEN
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.
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Tomografía Computarizada de Haz Cónico , Tabique Nasal , Redes Neurales de la Computación , Prueba de Estudio Conceptual , Humanos , Tomografía Computarizada de Haz Cónico/métodos , Tabique Nasal/diagnóstico por imagen , Femenino , Masculino , Adulto , Persona de Mediana EdadRESUMEN
Extracellular vesicles (EVs) are heterogeneous, phospholipid membrane enclosed particles that are secreted by healthy and cancerous cells. EVs are present in diverse biological fluids and have been associated with the severity of diseases, which indicates their potential as biomarkers for diagnosis, prognosis and as therapeutic targets. This study investigated the phenotypic characteristics of EVs derived from peripheral blood (PB) and bone marrow (BM) in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) during different treatment stages. PB and BM plasma were collected from 20 B-ALL patients at three time points during induction therapy, referred to as: diagnosis baseline (D0), day 15 of induction therapy (D15) and the end of the induction therapy (D35). In addition, PB samples were collected from 10 healthy children at a single time point. The EVs were measured using CytoFLEX S flow cytometer. Calibration beads were employed to ensure accurate size analysis. The following, fluorescent-labeled specific cellular markers were used to label the EVs: Annexin V (phosphatidylserine), CD235a (erythrocyte), CD41a (platelet), CD51 (endothelial cell), CD45 (leukocyte), CD66b (neutrophil), CD14 (monocyte), CD3 (T lymphocyte), CD19, CD34 and CD10 (B lymphoblast/leukemic blast). Our results demonstrate that B-ALL patients had a marked production of EV-CD51/61+, EV-CD10+, EV-CD19+ and EV-CD10+CD19+ (double-positive) with a decrease in EV-CD41a+ on D0. However, the kinetics and signature of production during induction therapy revealed a clear decline in EV-CD10+ and EV-CD19+, with an increase of EV-CD41a+ on D35. Furthermore, B-ALL patients showed a complex biological network, exhibiting distinct profiles on D0 and D35. Interestingly, fold change and ROC curve analysis demonstrated that EV-CD10+CD19+ were associated with B-ALL patients, exhibited excellent clinical performance and standing out as a potential diagnostic biomarker. In conclusion, our data indicate that EVs represent a promising field of investigation in B-ALL, offering the possibility of identifying potential biomarkers and therapeutic targets.
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Médula Ósea , Vesículas Extracelulares , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Niño , Vesículas Extracelulares/metabolismo , Femenino , Masculino , Preescolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Médula Ósea/metabolismo , Adolescente , Prueba de Estudio Conceptual , Biomarcadores de Tumor , LactanteRESUMEN
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.
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Alelos , Dermatoglifia del ADN , ADN , Antígenos HLA , Prueba de Estudio Conceptual , Humanos , Antígenos HLA/genética , Dermatoglifia del ADN/métodos , ADN/genética , Marcadores Genéticos , Repeticiones de MicrosatéliteRESUMEN
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.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Alcoholismo , Quimioterapia Combinada , Naltrexona , Antagonistas de Narcóticos , Prazosina , Prueba de Estudio Conceptual , Humanos , Naltrexona/uso terapéutico , Naltrexona/administración & dosificación , Prazosina/uso terapéutico , Prazosina/administración & dosificación , Masculino , Persona de Mediana Edad , Alcoholismo/tratamiento farmacológico , Antagonistas de Narcóticos/uso terapéutico , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Femenino , Adulto , Resultado del Tratamiento , Veteranos , Método Doble CiegoRESUMEN
BACKGROUND: To address the numerous unmeet clinical needs, in recent years several Machine Learning models applied to medical images and clinical data have been introduced and developed. Even when they achieve encouraging results, they lack evolutionary progression, thus perpetuating their status as autonomous entities. We postulated that different algorithms which have been proposed in the literature to address the same diagnostic task, can be aggregated to enhance classification performance. We suggested a proof of concept to define an ensemble approach useful for integrating different algorithms proposed to solve the same clinical task. METHODS: The proposed approach was developed starting from a public database consisting of radiomic features extracted from CT images relating to 535 patients suffering from lung cancer. Seven algorithms were trained independently by participants in the AI4MP working group on Artificial Intelligence of the Italian Association of Physics in Medicine to discriminate metastatic from non-metastatic patients. The classification scores generated by these algorithms are used to train SVM classifier. The Explainable Artificial Intelligence approach is applied to the final model. The ensemble model was validated following an 80-20 hold-out and leave-one-out scheme on the training set. RESULTS: Compared to individual algorithms, a more accurate result was achieved. On the independent test the ensemble model achieved an accuracy of 0.78, a F1-score of 0.57 and a log-loss of 0.49. Shapley values representing the contribution of each algorithm to the final classification result of the ensemble model were calculated. This information represents an added value for the end user useful for evaluating the appropriateness of the classification result on a particular case. It also allows us to evaluate on a global level which methodological approaches of the individual algorithms are likely to have the most impact. CONCLUSION: Our proposal represents an innovative approach useful for integrating different algorithms that populate the literature and which lays the foundations for future evaluations in broader application scenarios.
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Algoritmos , Neoplasias Pulmonares , Aprendizaje Automático , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Prueba de Estudio Conceptual , Femenino , MasculinoRESUMEN
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.
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Biomarcadores , Pruebas con Sangre Seca , Humanos , Pruebas con Sangre Seca/métodos , Pruebas con Sangre Seca/instrumentación , Biomarcadores/sangre , Anticuerpos Monoclonales Humanizados/sangre , Voluntarios Sanos , Prueba de Estudio Conceptual , Recolección de Muestras de Sangre/métodos , Recolección de Muestras de Sangre/instrumentaciónRESUMEN
BACKGROUND: Mental health settings are increasingly using co-facilitation of educational group interventions in collaboration with patient partners and service users. However, despite promising results, limited information is available regarding the feasibility and satisfaction levels of these programmes among adults newly diagnosed with attention-deficit hyperactivity/impulsivity disorder (ADHD). Hence, this study aimed to determine the feasibility, acceptability, and preliminary effects of a user co-facilitated psychoeducational group programme for adults diagnosed with ADHD. METHODS: This feasibility proof-of-concept randomised controlled trial recruited outpatients from a Norwegian community mental health centre. Outpatients randomised to the intervention group (IG) received a psychoeducational programme supplementing Treatment As Usual (TAU), while the control group received TAU. Feasibility was determined by the acceptance rate, adherence rate, and dropout rate. Acceptability was measured with the Client Satisfaction Questionnaire and a 3-item scale measuring satisfaction with the received information. To test the preliminary effects, self-efficacy, symptom severity, and quality of life were measured at baseline and pre- and post-intervention. RESULTS: Feasibility was demonstrated; most of the patients were willing to enrol, participants attended 82% of the psychoeducational programme, and only 13% dropped out of the study. The between-group analyses revealed that the IG reported significantly greater mean satisfaction than the CG. Moreover, the intervention group was more satisfied with the information they received during the psychoeducational programme. Concerning the preliminary effects, the linear mixed model showed improvement in quality of life (the subscale relationship); however, other patient-reported outcomes did not show improvements. CONCLUSIONS: This proof-of-concept randomised controlled trial supports the feasibility and acceptability of the user co-facilitated psychoeducational programme for patients newly diagnosed with ADHD in an outpatient setting. While preliminary findings indicate promise in enhancing patient-reported outcomes, a larger study is warranted to assess the intervention's effectiveness rigorously. TRIAL REGISTRATION: NCT03425, 09/11/2017.
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Trastorno por Déficit de Atención con Hiperactividad , Estudios de Factibilidad , Satisfacción del Paciente , Prueba de Estudio Conceptual , Humanos , Femenino , Masculino , Adulto , Trastorno por Déficit de Atención con Hiperactividad/terapia , Trastorno por Déficit de Atención con Hiperactividad/psicología , Educación del Paciente como Asunto/métodos , Persona de Mediana Edad , Aceptación de la Atención de Salud/psicología , Calidad de Vida/psicología , Autoeficacia , Noruega , Psicoterapia de Grupo/métodosRESUMEN
OBJECTIVES: In this study, we used atomic force microscopy (AFM) to quantify the size of surface pore apertures of enamel white spot lesions and then demonstrated the penetration of fluorapatite nanocrystals (nFA) into the subsurface of these lesions. METHODS: For the porosity study, enamel lesions were created on three sound human teeth using a demineralizing gel for 8 days. The interface between sound enamel and the artificial lesion was analyzed by AFM. To visualize the penetration of nFA tagged with a calcium-binding fluorophore (Fluo-4) into the subsurface of white spot lesions, we used two-photon microscopy. Sixteen extracted human teeth with either active, natural, or in vitro-created carious lesions in enamel were randomly divided into three groups. The teeth were treated for 2 min with either a suspension of tagged nFA crystals, Fluo-4 alone, or deionized water, and left for 30 min before being washed with distilled water and examined microscopically. RESULTS: A greater concentration of surface pores with larger areas was observed on the in vitro demineralized enamel (29â¯% of pores greater than 1.0 µm2) when compared with the adjacent sound enamel (8â¯% of pores greater than 1.0 µm2) (p=0.012, Fisher exact test). In vitro and natural lesions treated with tagged nFA showed fluorescence at depths ranging from 50 to 170 µm, demonstrating penetration of the nFA into the lesion subsurface. The lesions treated with Fluo-4 alone with no crystals showed mostly surface fluorescence (restricted to the outer 25 µm), while those treated with deionized water showed minimal (restricted to the outer 20 µm) to no fluorescence. CONCLUSION: We have demonstrated the use of AFM to quantify the surface pore apertures and two-photon microscopy to visualize nFA crystals in the subsurface of non-cavitated enamel lesions. CLINICAL SIGNIFICANCE: The restoration of the subsurface of non-cavitated caries lesions is a clinical challenge. This study demonstrated that a 2 min application of nFA could penetrate through the surface apertures of non-cavitated enamel lesions into their subsurface.
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Apatitas , Caries Dental , Esmalte Dental , Microscopía de Fuerza Atómica , Nanopartículas , Humanos , Esmalte Dental/efectos de los fármacos , Esmalte Dental/metabolismo , Nanopartículas/química , Apatitas/química , Porosidad , Caries Dental/patología , Propiedades de Superficie , Prueba de Estudio Conceptual , Desmineralización DentalRESUMEN
OBJECTIVES: To demonstrate the potential application of mixed reality (MR) holographic imaging technology in subgingival scaling and root planing (SRP) for patient with advanced periodontitis. METHODS: This case series comprised the analysis of 1566 sites from 261 teeth of 10 patients with advanced periodontitis. Digital CBCT scans and intraoral scans of the patients were digitally acquired preoperatively and aligned to create a three-dimensional periodontal visualization model. Through rendering, interactive holographic images were displayed using MR. The surgeon first used MR images to communicate with the patients, and then facilitated SRP under their guidance. Probing pocket depth (PPD), clinical attachment loss (CAL), Plaque index (PI), and bleeding on probing (BOP) parameters were recorded at baseline and at 8-week postoperatively. Patient-reported outcome indicator questionnaires on self-efficacy were also collected. RESULTS: PPD, CAL, PI, and BOP significantly decreased at 8-week following MR hologram-assisted SRP (p<0.001). For sites with PPD≥4 mm, PPD and CAL declined by 2.33±1.23 mm and 0.69±1.07 mm, respectively. PI significantly decreased from 1.94±0.61 to 0.82±0.58 (p < 0.001) and BOP sites decreased significantly from 84.11% to 40.25%. After receiving MR holograms for condition communication, most patients had a better perception of the effectiveness of SRP treatment and the benefits it brings. 80% of the subjects expressed their willingness to undergo MR-assisted periodontal treatment in the future. CONCLUSION: These results provide preliminary support for MR hologram-assisted digital SRP. With this technology, images of the gingiva and alveolar bone can be displayed in real time, accurately and three-dimensionally. This improves SRP effectiveness, diminishes complications, and enhances patients' confidence in the treatment. CLINICAL SIGNIFICANCE: MR holographic imaging-based digital SRP is a clinically feasible and promising adjunctive periodontal treatment option. It may contribute to improved non-surgical treatment efficacy in patients with severe periodontitis.
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Tomografía Computarizada de Haz Cónico , Raspado Dental , Holografía , Índice Periodontal , Periodontitis , Aplanamiento de la Raíz , Humanos , Holografía/métodos , Aplanamiento de la Raíz/métodos , Raspado Dental/métodos , Femenino , Masculino , Persona de Mediana Edad , Tomografía Computarizada de Haz Cónico/métodos , Periodontitis/diagnóstico por imagen , Periodontitis/terapia , Adulto , Bolsa Periodontal/terapia , Bolsa Periodontal/diagnóstico por imagen , Pérdida de la Inserción Periodontal/terapia , Pérdida de la Inserción Periodontal/diagnóstico por imagen , Imagenología Tridimensional/métodos , Índice de Placa Dental , Prueba de Estudio Conceptual , Resultado del Tratamiento , Autoeficacia , Medición de Resultados Informados por el PacienteRESUMEN
AIMS: In this proof-of-concept study, we propose a new method for automated digital quantification of PRAME (PReferentially expressed Antigen of MElanoma) as a diagnostic aid to distinguish between benign and malignant melanocytic lesions. The proposed method utilizes immunohistochemical virtual double nuclear staining for PRAME and SOX10 to precisely identify the melanocytic cells of interest, which is combined with digital image analyse to quantify a PRAME-index. METHODS: Our study included 10 compound nevi, 3 halo nevi, and 10 melanomas. Tissue slides were stained with PRAME, scanned, the cover glass removed, stained with SOX10, scanned again, and finally analysed digitally. The digitally quantified PRAME-index was compared with a manual qualitative assessment by a dermatopathologist using the standard PRAME-scoring system. RESULTS: The digitally quantified PRAME-index showed a sensitivity of 70â¯% and a specificity of 100â¯% for separating melanomas from benign lesions. The manual qualitative PRAME-score showed a sensitivity of 60â¯% and a specificity of 100â¯%. Comparing the two methods using ROC-analyses, our digital quantitative method (AUC: 0.931, 95â¯% CI: 0.834;1.00, SD: 0.050) remains on par with the manual qualitative method (AUC: 0.877, 95â¯% CI: 0.725;1.00, SD: 0.078). CONCLUSION: We found our novel digital quantitative method was at least as precise at classifying lesions as benign or malignant as the current manual qualitative assessment. Our method has the advantages of being operator-independent, objective, and replicable. Furthermore, our method can easily be implemented in an already digitalized pathology department. Given the small cohort size, more studies are to be done to validate our findings.
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Antígenos de Neoplasias , Biomarcadores de Tumor , Melanoma , Nevo , Neoplasias Cutáneas , Humanos , Melanoma/patología , Melanoma/diagnóstico , Antígenos de Neoplasias/análisis , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Nevo/patología , Nevo/diagnóstico , Diagnóstico Diferencial , Biomarcadores de Tumor/análisis , Prueba de Estudio Conceptual , Sensibilidad y Especificidad , Inmunohistoquímica/métodosRESUMEN
AIMS: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra-epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings. METHODS: Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two-way mixed-effects model to evaluate inter- and intra-observer variability. RESULTS: The automated staining system reproduced intra-epidermal nerve fibre density (IENFD) counts consistent with free-floating sections (mean ± standard deviation: free-floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at -0.00005 established non-inferiority against a margin of -0.4 (p = .08). Specifically, the inter-class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9-1), indicating excellent agreement between free-floating and automated methods. The inter- and intra-class coefficient between examiners were both 99% (95% CI: 0.9-0.1) for IENFD, demonstrating high reliability using sections stained using the automated method. INTERPRETATION: Automated immunohistochemistry provides high-throughput reliable and reproducible intra-epidermal nerve fibre quantification. This method, although currently proof-of-concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies.
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Inmunohistoquímica , Fibras Nerviosas , Prueba de Estudio Conceptual , Piel , Neuropatía de Fibras Pequeñas , Humanos , Fibras Nerviosas/patología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Piel/inervación , Piel/patología , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/patología , Biopsia , Epidermis/inervación , Epidermis/patología , Anciano , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/análisis , Reproducibilidad de los ResultadosRESUMEN
Skin can be damaged by intense and prolonged exposure to ultraviolet (UV) radiation. Photoaging and acute damage from sun exposure result in collagen degradation and enzymatic activity decline in the skin. Fucoidan (FUC) exhibits potential antiaging properties, including collagen synthesis promotion and enzyme activity inhibition. However, FUC's limited ability to penetrate the skin layers due to its large molecular weight makes it a challenge for topical application. In this study, we successfully developed a new approach by integrating thermoresponsive gel (TRG) containing FUC with solid microneedles (SMNs) as a delivery system. TRG is formulated using a combination of Pluronic F127 (PF127) and Pluronic F68 (PF68) polymers, while SMNs are made from a mixture of poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP) polymers with a variety of cross-linkers. Based on the results of ex vivo testing, it was shown that more than 80% of FUC can be delivered using the optimized formula. Furthermore, the results of the in vitro blood hemolytic test showed that TRG-FUC-SMNs were relatively biocompatible. In vivo antiaging activity tests using a rat model exposed to UV for 14 days showed that histological assessment, skin elasticity measurement, wrinkle evaluation, and skin moisture content had no significant differences (p < 0.05) compared to the positive control group. In contrast, a significant difference (p < 0.05) was observed when comparing the TRG-FUC-SMNs group with the group that received only TRG-FUC without pretreatment and negative controls. These findings suggest that FUC has potential to be delivered using the TRG system in combination with SMNs to harness its antiaging properties.
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Administración Cutánea , Geles , Agujas , Polisacáridos , Animales , Polisacáridos/química , Polisacáridos/administración & dosificación , Ratas , Geles/química , Envejecimiento de la Piel/efectos de los fármacos , Piel/efectos de los fármacos , Temperatura , Ratas Sprague-Dawley , Rayos Ultravioleta , Polímeros/química , Polímeros/farmacología , Poloxámero/química , Masculino , Prueba de Estudio ConceptualRESUMEN
Accurately identifying and quantifying toxicants is crucial for medico-legal investigations in forensic toxicology; however, low analyte concentrations and the complex samples matrix make this work difficult. Therefore, a simplified sample preparation procedure is crucial to streamline the analysis to minimize sample handling errors, reduce cost and improve the overall efficiency of analysis of toxicants. To address these challenges, an innovative disposable in-tip cellulose paper (DICP) device has been developed for the extraction of three pesticides viz. Chlorpyrifos, Quinalphos and Carbofuran from postmortem blood samples. The DICP device leverages cellulose paper strips housed within a pipette tip to streamline the extraction process, significantly reducing solvent usage, time, and labor while maintaining high analytical accuracy. The extraction of pesticides from postmortem blood using the DICP device involves a streamlined process characterized by adsorption and desorption. The diluted blood samples were processed through the DICP device via repeated aspirating and dispensing calyces to adsorb the pesticides onto the cellulose paper. The adsorbed pesticides are then eluted using acetone, which is collected for GC-MS analysis. The method was meticulously optimized, achieving a limit of quantification in the range of 0.009-0.01 µg mL-1. The intra-day and inter-day precisions were consistently less than 5 % and 10 %, respectively, with accuracy ranging from 94-106 %. Relative recoveries for the analytes were observed to be between 60 % and 93.3 %, and matrix effects were determined to be less than 10 %. The method's sustainability was validated with a whiteness score of 98.8, an AGREE score of 0.64, a BAGI score of 70 and ComplexMoGAPI score of 77. Applicability was demonstrated through successful analysis of real postmortem blood samples and proficiency testing samples, highlighting its potential utility in forensic toxicology.
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Celulosa , Cromatografía de Gases y Espectrometría de Masas , Límite de Detección , Papel , Plaguicidas , Humanos , Celulosa/química , Celulosa/análogos & derivados , Plaguicidas/sangre , Plaguicidas/análisis , Cromatografía de Gases y Espectrometría de Masas/métodos , Reproducibilidad de los Resultados , Modelos Lineales , Prueba de Estudio Conceptual , Toxicología Forense/métodos , Toxicología Forense/instrumentación , Diseño de EquipoRESUMEN
BACKGROUND: Surrogates, proxies, and clinicians making shared treatment decisions for patients who have lost decision-making capacity often fail to honor patients' wishes, due to stress, time pressures, misunderstanding patient values, and projecting personal biases. Advance directives intend to align care with patient values but are limited by low completion rates and application to only a subset of medical decisions. Here, we investigate the potential of large language models (LLMs) to incorporate patient values in supporting critical care clinical decision-making for incapacitated patients in a proof-of-concept study. METHODS: We simulated text-based scenarios for 50 decisionally incapacitated patients for whom a medical condition required imminent clinical decisions regarding specific interventions. For each patient, we also simulated five unique value profiles captured using alternative formats: numeric ranking questionnaires, text-based questionnaires, and free-text narratives. We used pre-trained generative LLMs for two tasks: 1) text extraction of the treatments under consideration and 2) prompt-based question-answering to generate a recommendation in response to the scenario information, extracted treatment, and patient value profiles. Model outputs were compared with adjudications by three domain experts who independently evaluated each scenario and decision. RESULTS AND CONCLUSIONS: Automated extractions of the treatment in question were accurate for 88% (n = 44/50) of scenarios. LLM treatment recommendations received an average Likert score by the adjudicators of 3.92 of 5.00 (five being best) across all patients for being medically plausible and reasonable treatment recommendations, and 3.58 of 5.00 for reflecting the documented values of the patient. Scores were highest when patient values were captured as short, unstructured, and free-text narratives based on simulated patient profiles. This proof-of-concept study demonstrates the potential for LLMs to function as support tools for surrogates, proxies, and clinicians aiming to honor the wishes and values of decisionally incapacitated patients.
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Apoderado , Humanos , Directivas Anticipadas , Toma de Decisiones , Toma de Decisiones Clínicas/métodos , Prueba de Estudio Conceptual , Encuestas y Cuestionarios , Lenguaje , Cuidados Críticos/métodosRESUMEN
Antiviral therapies with reduced frequencies of administration and high barriers to resistance remain a major goal. For HIV, theories have proposed that viral-deletion variants, which conditionally replicate with a basic reproductive ratio [R0] > 1 (termed "therapeutic interfering particles" or "TIPs"), could parasitize wild-type virus to constitute single-administration, escape-resistant antiviral therapies. We report the engineering of a TIP that, in rhesus macaques, reduces viremia of a highly pathogenic model of HIV by >3log10 following a single intravenous injection. Animal lifespan was significantly extended, TIPs conditionally replicated and were continually detected for >6 months, and sequencing data showed no evidence of viral escape. A single TIP injection also suppressed virus replication in humanized mice and cells from persons living with HIV. These data provide proof of concept for a potential new class of single-administration antiviral therapies.
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Partículas Similares a Virus Artificiales , Eliminación de Gen , Infecciones por VIH , VIH-1 , Interferencia Viral , Replicación Viral , Animales , Humanos , Ratones , Número Básico de Reproducción , Modelos Animales de Enfermedad , Ingeniería Genética , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/genética , VIH-1/fisiología , Macaca mulatta , Prueba de Estudio Conceptual , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Viremia/terapia , Viremia/virologíaRESUMEN
High dose-rate brachytherapy is a treatment technique for gynecologic cancers where intracavitary applicators are placed within the patient's pelvic cavity. To ensure accurate radiation delivery, localization of the applicator at the time of insertion is vital. This study proposes a novel method for acquiring, registering, and fusing three-dimensional (3D) trans-abdominal and 3D trans-rectal ultrasound (US) images for visualization of the pelvic anatomy and applicators during gynecologic brachytherapy. The workflow was validated using custom multi-modal pelvic phantoms and demonstrated during two patient procedures. Experiments were performed for three types of intracavitary applicators: ring-and-tandem, ring-and-tandem with interstitial needles, and tandem-and-ovoids. Fused 3D US images were registered to magnetic resonance (MR) and computed tomography (CT) images for validation. The target registration error (TRE) and fiducial localization error (FLE) were calculated to quantify the accuracy of our fusion technique. For both phantom and patient images, TRE and FLE across all modality registrations (3D US versus MR or CT) resulted in mean ± standard deviation of 4.01 ± 1.01 mm and 0.43 ± 0.24 mm, respectively. This work indicates proof of concept for conducting further clinical studies leveraging 3D US imaging as an accurate, accessible alternative to advanced modalities for localizing brachytherapy applicators.
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Braquiterapia , Imagenología Tridimensional , Fantasmas de Imagen , Ultrasonografía , Humanos , Braquiterapia/métodos , Femenino , Imagenología Tridimensional/métodos , Ultrasonografía/métodos , Neoplasias de los Genitales Femeninos/radioterapia , Neoplasias de los Genitales Femeninos/diagnóstico por imagen , Radioterapia Guiada por Imagen/métodos , Recto/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Prueba de Estudio Conceptual , Imagen por Resonancia Magnética/métodos , Abdomen/diagnóstico por imagen , Pelvis/diagnóstico por imagenRESUMEN
INTRODUCTION: Delays in discharging patients from Acute Medical Units hamper patient flows throughout the hospital. The decision to discharge a patient is mainly based on the patients' physiological condition, but may vary between physicians. An objective decision-support system based on patients' physiological data may help minimizing unnecessary delays in discharge. The aim of this proof-of-concept study is to assess the feasibility of predicting whether patients in an Acute Medical Unit are physiologically fit-for-discharge using machine learning with commonly available hospital data. Furthermore, this study investigated how long before actual time of discharge from the Acute Medical Unit we could predict discharge fitness. Also, the predictive importance of features extracted from these data was assessed. METHODS: Electronic Medical Records of patients who participated in a Randomized Controlled Trial conducted in an Acute Medical Unit were used retrospectively (N = 199). Only commonly available hospital data were used. Logistic Regression and Random Forest models were applied to predict every hour whether patients were physiologically fit-for-discharge. Nested 5-fold cross-validation with 5 repeats was used to optimize the model hyperparameters and to estimate the predictive performances. RESULTS: Physiological discharge fitness was predictable with reasonable performance for Logistic Regression (mean AUROC: 0.67) and Random Forest (mean AUROC: 0.69). For an intuitively chosen classification threshold of 0.8, mean specificity was 93.3 % and sensitivity 14.1 %. Models could predict physiological discharge fitness more than 24 h earlier than actual time of discharge for most patients who were correctly predicted to be fit-for-discharge. Patient characteristics, vital signs and laboratory results were shown to be important predictors. CONCLUSION: This proof-of-concept study showed that it is feasible to predict with machine learning whether patients in an Acute Medical Unit are physiologically fit-for-discharge using commonly available hospital data.
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Registros Electrónicos de Salud , Aprendizaje Automático , Alta del Paciente , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Prueba de Estudio Conceptual , Estudios RetrospectivosRESUMEN
An optimized procedure for extracting and analyzing raw pistachio volatiles was developed through headspace sampling with high-capacity tools and subsequent analysis using comprehensive two-dimensional gas chromatography coupled with mass spectrometry. The examination of 18 pistachio samples belonging to different geographic areas led to the identification of a set of 99 volatile organic compounds (VOCs). Molecules were putatively identified using linear retention index, mass spectra similarity, and two-dimensional plot location. The impact of preprocessing and processing techniques on the aligned data matrix from a set of samples of different geographical origins, after removing contaminants, was evaluated. The combination of scaling with log-transformation, normalization with z-score, and data reduction with random forest machine learning algorithm generated a panel of 16 discriminatory VOC molecules. As a proof of concept, raw pistachios' VOC profile was employed for the first time to tentatively classify them based on their geographical origin.