abstract: Background: Quarterbacks (QBs) in American football frequently perform repetitive overhead throwing, which can lead to shoulder and elbow injuries. Effective control of trunk and pelvic movements is considered crucial for minimizing shoulder and elbow joint stress during throwing. The Kerlan–Jobe Orthopedic Clinic (KJOC) score is a self-perceived index of shoulder and elbow function and level of competition in overhead athletes. However, the relationship between trunk and pelvic movements during throwing and the KJOC score among QBs remains unclear. This study aimed to examine the association between trunk and pelvic motion during the QB throwing sequence and the KJOC score. Methods: A total of 11 healthy QBs were enrolled in this study. Each participant completed 5 throws at distances of 18.2 m (20 yards) and 27.4 m (30 yards). Throwing mechanics were analyzed using the PitchAI application, focusing on trunk and pelvis rotation (toward the nonthrowing and throwing sides) and hip–shoulder separation angles. These angles were measured at 3 key phases: stride foot contact during the early cocking phase, maximum shoulder external rotation during the late cocking phase, and ball release. Participants also completed the KJOC questionnaire, with higher scores indicating better self-perceived index of shoulder and elbow function or level of competition. Correlations between throwing mechanics and KJOC each item and total scores were assessed using Spearman's rank correlation coefficient. Results: Trunk rotation at maximum shoulder external rotation during 20-yard throws and hip–shoulder separation at stride foot contact during 30-yard throws were positively correlated with KJOC Item 3 (rs = 0.709; P = .015 and rs = 0.662; P = .026, respectively). Pelvic rotation at ball release during 30-yard throws showed a positive correlation with KJOC Item 4 (rs = 0.760; P = .007). Conclusion: This study suggests a relationship between trunk and pelvic rotational movements during a quarterback's throw and certain aspects of subjective shoulder and elbow function.
Orthopedic surgery, Diseases of the musculoskeletal system
Objective: Prevalence of hip osteoarthritis (OA) is rarely reported in young populations (e.g., military). We will report the prevalence of hip OA in a young military cohort and investigate the relationship between injury and progression/incidence. Design: ADVANCE is a prospective cohort study comparing physical and psychosocial outcomes in 1145 men who served in Afghanistan including 579 men with combat injury (Exposed) who were frequency-matched to 566 controls (Unexposed). The Exposed group was sub-divided into hip injured (Exp-H), lower limb amputation (Exp-A) and other (Exp-NA). Kellgren-Lawrence (KL) scores of pelvic radiographs and Non-Arthritic Hip Score (NAHS) questionnaires were collected across two waves (Baseline and Follow-up). Prevalence at Baseline (KL ≥ 2), progression (KL ≥ 1 at Baseline, KL ≥ 2 at Follow-up) and incidence (KL0 at Baseline, KL ≥ 2 at Follow-up) at Follow-up were reported and compared between groups for KL and NAHS. Results: Baseline prevalence of radiographic hip OA was 8.5 % and 4.4 % in the Exposed and Unexposed groups, respectively. Exp-A and Exp-H groups had 3.88 (95%CI:2.27–6.63) and 7.18 (95%CI:3.44–14.98 times increased risk for radiographic hip OA than Unexposed. Exp-A and Exp-H had a 2.15 (95%CI:1.22–3.80) and 3.28 (95%CI:1.42–7.59) times increased radiographic progression risk, compared to Unexposed. Risk of NAHS Progression and Incidence were not significantly different between groups. Conclusion: Radiographic hip OA prevalence is higher in a young military population than in a similarly aged general population. Combat injury alone may not increase hip OA prevalence; but hip and lower limb loss injuries do. Progression risk is highest in those with hip or limb loss injuries.
La Reumatología ha sido testigo, en las últimas décadas, de una transformación radical en el tratamiento de casi todas las enfermedades inflamatorias, principalmente de la Artritis Reumatoide (AR). Las terapias biológicas, con su capacidad de modificar el curso de estas enfermedades, han abierto un nuevo horizonte clínico, sin embargo, con estos avances surgen también nuevas responsabilidades: evaluar, monitorear y generar evidencia sobre su uso en la práctica médica en el día a día.
Internal medicine, Diseases of the musculoskeletal system
Pierrick Coupé, Boris Mansencal, José V. Manjón
et al.
The differential diagnosis of neurodegenerative diseases, characterized by overlapping symptoms, may be challenging. Brain imaging coupled with artificial intelligence has been previously proposed for diagnostic support, but most of these methods have been trained to discriminate only isolated diseases from controls. Here, we develop a novel machine learning framework, named lifespan tree of brain anatomy, dedicated to the differential diagnosis between multiple diseases simultaneously. It integrates the modeling of volume changes for 124 brain structures during the lifespan with non-linear dimensionality reduction and synthetic sampling techniques to create easily interpretable representations of brain anatomy over the course of disease progression. As clinically relevant proof-of-concept applications, we constructed a cognitive lifespan tree of brain anatomy for the differential diagnosis of six causes of neurodegenerative dementia and a motor lifespan tree of brain anatomy for the differential diagnosis of four causes of parkinsonism using 37594 MRI as a training dataset. This original approach enhanced significantly the efficiency of differential diagnosis in the external validation cohort of 1754 cases, outperforming existing state-of-the art machine learning techniques. Lifespan tree holds promise as a valuable tool for differential diagnostic in relevant clinical conditions, especially for diseases still lacking effective biological markers.
Computational drug repurposing for rare diseases is especially challenging when no prior associations exist between drugs and target diseases. Therefore, knowledge graph completion and message-passing GNNs have little reliable signal to learn and propagate, resulting in poor performance. We present RareAgent, a self-evolving multi-agent system that reframes this task from passive pattern recognition to active evidence-seeking reasoning. RareAgent organizes task-specific adversarial debates in which agents dynamically construct evidence graphs from diverse perspectives to support, refute, or entail hypotheses. The reasoning strategies are analyzed post hoc in a self-evolutionary loop, producing textual feedback that refines agent policies, while successful reasoning paths are distilled into transferable heuristics to accelerate future investigations. Comprehensive evaluations reveal that RareAgent improves the indication AUPRC by 18.1% over reasoning baselines and provides a transparent reasoning chain consistent with clinical evidence.
Gustavo A. Sousa, Diogo L. M. Souza, Enrique C. Gabrick
et al.
The study of infectious disease propagation is essential for understanding and controlling epidemics. One of the most useful tools for gaining insights into the spread of infectious diseases is mathematical modelling. In terms of mathematical epidemiology, the main models are based on compartments, such as SI, SIR, and SEIR. These models offer mathematical frameworks for representing the proliferation dynamics of various diseases, for instance flu and smallpox. In this work, we explore these models using two distinct mathematical approaches, Cellular Automata (CA) and ODEs. They are able to reproduce the spread dynamics of diseases with their own individuality. CA models incorporate the local interaction among individuals with discrete time and space, while ODEs provide a continuous and simplified view of a disease propagation in large and homogeneous populations. By comparing these two approaches, we find that the shape of the curves of all models is similar for both representations. Although, the growth rates differ between CA and ODE. One of our results is to show that the CA yields a power-law growth, while the ODE growth rate is well-represented by an exponential function. Furthermore, a substantial contribution of our work is using a hyperbolic tangent to fit the initial growth of infected individuals for all the considered models. Our results display a strong correlation between simulated data and adjusted function. We mainly address this successful result by the fact that the hyperbolic function captures both growing: the power-law (when considered the first terms of infinite sums) and combinations of exponential (when the hyperbolic function is written via exponential). Therefore, our work shows that when modelling a disease the choice of mathematical representation is crucial, in particular to model the onset of an epidemic.
Alexandra Prado-Mantilla, Joseph Sheheen, Julie Underwood
et al.
Loss-of-function studies are a central approach to understanding gene/protein function. In mice, this often relies upon heritable recombination at the DNA level. This approach is slow and nonreversible, which limits both spatial and temporal resolution of analysis. Recently, degron techniques that directly target proteins for degradation have been successfully used to quickly and reversibly knock down proteins. Currently, these systems have been limited by lack of tissue/cell type specificity. Here, we generated mice that allow spatial and temporal control of GFP-tagged protein degradation. This DegronGFP line leads to degradation of GFP-tagged proteins in different cellular compartments and in distinct cell types. Further, it is rapid and reversible. We used DegronGFP to probe the function of the glucocorticoid receptor in the epidermis and demonstrate that it has distinct functions in proliferative and differentiated cells—an analysis that would not have been possible with traditional recombination approaches. We propose that the ability to use GFP knock-in lines for loss-of-function analysis will provide additional motivation for generation of these useful tools.
Thomas P. Leahy, Srish S. Chenna, Louis J. Soslowsky
et al.
Abstract Tendons enable locomotion by transmitting high tensile mechanical forces between muscle and bone via their dense extracellular matrix (ECM). The application of extrinsic mechanical stimuli via muscle contraction is necessary to regulate healthy tendon function. Specifically, applied physiological levels of mechanical loading elicit an anabolic tendon cell response, while decreased mechanical loading evokes a degradative tendon state. Although the tendon response to mechanical stimuli has implications in disease pathogenesis and clinical treatment strategies, the cell signaling mechanisms by which tendon cells sense and respond to mechanical stimuli within the native tendon ECM remain largely unknown. Therefore, we explored the role of cell–ECM adhesions in regulating tendon cell mechanotransduction by perturbing the genetic expression and signaling activity of focal adhesion kinase (FAK) through both in vitro and in vivo approaches. We determined that FAK regulates tendon cell spreading behavior and focal adhesion morphology, nuclear deformation in response to applied mechanical strain, and mechanosensitive gene expression. In addition, our data reveal that FAK signaling plays an essential role in in vivo tendon development and postnatal growth, as FAK‐knockout mouse tendons demonstrated reduced tendon size, altered mechanical properties, differences in cellular composition, and reduced maturity of the deposited ECM. These data provide a foundational understanding of the role of FAK signaling as a critical regulator of in situ tendon cell mechanotransduction. Importantly, an increased understanding of tendon cell mechanotransductive mechanisms may inform clinical practice as well as lead to the discovery of diagnostic and/or therapeutic molecular targets.
Oral urate-lowering therapy (ULT) is key to treating gout. However, many patients receiving oral ULT do not achieve the target serum urate (SU) levels, partly because some patients cannot tolerate or have contraindications to their use, mainly due to comorbidities. This may lead to uncontrolled gout. In species other than humans and some non-human primates, uricase (urate oxidase) converts urate to allantoin, which is more readily excreted by the kidney. Exogenous uricases, considered “enzyme replacement therapy”, are a therapeutic option for patients with refractory or uncontrolled gout. Current uricases on the market include pegloticase and rasburicase. Uricase treatment rapidly reduces hyperuricemia and tophaceous deposits and improves the quality of life. This review discusses currently approved uricases on the market and some in development; how best to minimize flares, anti-drug antibody (ADA) formation, infusion reactions, and loss of efficacy, and combination with immunomodulation in patients with gout requiring uricase therapy.
Bangjun Cheng, Xiping Jiang, Xiaofeng Zhang
et al.
Abstract Background The lateral locking plate for the proximal humerus is currently the most commonly used surgical procedure for the treatment of elderly proximal humeral comminuted fractures. Previous studies have found that the rate of postoperative complications in patients of proximal humerus fractures with medial column involvement is relatively high. Through biomechanical methods, this study aims to investigate the effectiveness of the conventional lateral locking plate fixation along with the addition of the metacarpal supporting plate on the medial column in the treatment for proximal humeral fractures involving the medial column. The goal is to reduce the rate of postoperative internal fixation failure in patients with medial column injury. Methods Thirty artificial synthetic humerus models are used as experimental samples. A proximal humerus fracture model with medial column injury was created, and then divided into two groups. Group A was fixed with a proximal humerus lateral locking plate (single-plate group). Group B was fixed with a proximal humerus lateral locking plate and a metacarpal supporting plate on the medial column (double-plate group). The failure displacement, stiffness, and strength of the repaired proximal humerus fractures with two different methods were tested under compression at posterior extension of 15°, forward flexion of 15°, and vertical direction. Results There was no statistical significance in the comparison of the failure displacement of repaired proximal humeral fractures between the two groups under compression at posterior extension of 15° and forward flexion of 15° (P > 0.05). However, the failure displacement of the fracture was longer in single-plate group than in double-plate group under compression at vertical direction (P < 0.05). The double-plate group was better in terms of biomechanical stiffness and strength compared to the single-plate group at all three testing angles (P < 0.05). Conclusions For patients whose proximal humeral fractures involve the medial column, the addition of a support plate on the medial side of the humerus is recommended along with the lateral locking plate. The double-plate strategy can increase the stability of the medial column of the proximal humerus, and enhance the overall biomechanical property of the repaired proximal humerus.
Abstract Background There is controversy regarding the efficacy of intravenous combined topical tranexamic acid. We conducted this study to systematically assess the effectiveness of intravenous combined topical tranexamic acid (combined TXA) in spinal surgery to guide clinical practice. Methods The review process was conducted according to the PRISMA guidelines. A systematic search of PubMed, EMBASE, Web of Science, and Cochrane Central was conducted for RCTs and comparative cohort studies evaluating the effect of combined TXA on blood loss in spinal surgery. Outcomes such as intraoperative blood loss, total blood loss, postoperative drainage, postoperative hemoglobin level on postoperative days 1 and 3, postoperative transfusion rates, and complications were analyzed. Results Five studies covering 528 patients were included in the analysis. Combined TXA, compared with intravenous TXA, showed no significant differences in intraoperative blood loss (P = 0.18 for RCTs, P = 0.50 for the retrospective study), total blood loss (P = 0.085 for RCTs, P = 0.87 for the retrospective study), postoperative drainage (P = 0.137 for RCTs, P = 0.232 for the retrospective study), postoperative hemoglobin (P = 0.737 on postoperative day 1, P = 0.403 on postoperative day 3), postoperative transfusion rates (P = 0.202), and complications (P = 0.493). Conclusions Based on the available evidences, our meta-analysis failed to demonstrate the apparent advantages of combined tranexamic acid in spinal surgery. Clinical decisions regarding hemostatic methods should continue to be individualized based on the patient's specific situation and the doctor's experience.
Thales Hein da Rosa, Bárbara Jonson Bartikoski, Rafaela Cavalheiro do Espírito Santo
et al.
Abstract Background Sarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways. Despite having a list of drugs capable of treating RA inflammation, their effect on muscle is unclear. Our objective was to evaluate the tofacitinib effect on the muscle mass of collagen-induced arthritis (CIA) mice. Methods CIA was induced in male DBA/1J mice by subcutaneous injection of Type 2 Collagen plus Freund Adjuvant. Animals were randomized into 3 groups: CIA + tofacitinib; CIA + vehicle; and healthy controls. Treatment was administered twice a day, between days 18 and 45 after induction. Clinical score, edema, and body weight were evaluated during the experimental period. After euthanasia, tibiotarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Protein expression was evaluated by western blot using GA homogenates. Serum inflammatory markers were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey’s or with Kruskal-Wallis. The statistical difference was assumed for p < 0.05. Results Tofacitinib treatment decreased arthritis severity by reducing clinical score, and hind paw edema in comparison with the vehicle group. Tofacitinib showed weight gain, higher TA and GA weights, and increased CSA compared to the vehicle group. On day 45, Tofacitinib presented increased muscle strength compared to the vehicle group, however, no difference was found in muscle fatigue. Pax7 expression was unchanged, while MyoD expression showed an increasing trend, and myogenin expression was significantly increased in Tofacitinib compared to vehicle and control groups. The treatment didn’t modify Murf-1 expression. Tofacitinib mice showed decreased serum levels of TNF and increased IL-6 serum levels. Conclusion Tofacitinib attenuated muscle loss in arthritic mice, increased muscle weight and muscle CSA. Activation of satellite cell regeneration, based on the increased expression of myogenin, is a potential mechanism involved in tofacitinib action against muscle loss.
Diseases of the musculoskeletal system, Immunologic diseases. Allergy
Abstract Objective To early recognise and improve the prognosis of children systemic lupus erythematosus (cSLE)-associated pancreatitis by summarising and analysing clinical features and prognosis data from 12 cases. Methods Retrospective analysis of clinical data from 12 cases of cSLE-associated pancreatitis diagnosed and treated from January 2016 to December 2021 at hospitals such as Children’s Hospital of Capital Institute of Paediatrics. Results The median SLEDAI-2K score for disease activity was 18.00 (range 12.25–21.00) in the case group and 10.00 (range 7.00–18.00) in the control group, with a statistically significant difference (P < 0.05) between the two groups. The case group had a higher proportion of abdominal pain, vomiting, abdominal distension, pleural effusion, Raynaud’s phenomenon (RP), splenic infarction, and concurrent macrophage activation syndrome (MAS) than the control group, with a statistically significant difference (P < 0.05). Serum ferritin (SF), alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), amylase, and increased 24-h urine protein levels were statistically different between the two groups (P < 0.05); platelet counts (PLT) reduction was also statistically different (P < 0.05). The case group had a higher proportion of methylprednisolone pulse therapy, cyclophosphamide pulse therapy during remission induction, and therapeutic plasma exchange than the control group, with a statistically significant difference (P < 0.05) between the two. Conclusion CSLE-associated pancreatitis has a high fatality rate. The presence of RP, splenic infarction, pleural effusion, and MAS warrants attention from clinicians regarding the possibility of pancreatitis. Once pancreatitis is detected, the primary disease needs active treatment for better prognosis.
Abstract Background Open fractures are challenging due to susceptibility to Staphylococcus aureus infections. This study examines the impact of Vancomycin-Loaded Calcium Sulfate (VLCS) and negative pressure wound therapy (NPWT) on macrophage behavior in enhancing healing and infection resistance. Both VLCS and NPWT were evaluated individually and in combination to determine their effects on macrophage polarization and infection resistance in open fractures. Methods Through single-cell RNA sequencing, genomic expressions in macrophages from open fracture patients treated with VLCS and NPWT were compared to a control group. The analysis focused on MBD2 gene changes related to macrophage polarization. Results Remarkable modifications in MBD2 expression in the treatment group indicate a shift towards M2 macrophage polarization. Additionally, the combined treatment group exhibited greater improvements in infection resistance and healing compared to the individual treatments. This shift suggests a healing-promoting atmosphere with improved infection resilience. Conclusions VLCS and NPWT demonstrate the ability to alter macrophage behavior toward M2 polarization, which is crucial for infection prevention in open fractures. The synergistic effect of their combined use shows even greater promise in enhancing outcomes in orthopedic trauma care.
Orthopedic surgery, Diseases of the musculoskeletal system
Jessica Peoples, Jared J. Tanner, Emily J. Bartley
et al.
Abstract Objective Lower socioeconomic status (SES) is a risk factor for poorer pain-related outcomes. Further, the neighborhood environments of disadvantaged communities can create a milieu of increased stress and deprivation that adversely affects pain-related and other health outcomes. Socioenvironmental variables such as the Area Deprivation Index, which ranks neighborhoods based on socioeconomic factors could be used to capture environmental aspects associated with poor pain outcomes. However, it is unclear whether the ADI could be used as a risk assessment tool in addition to individual-level SES. Methods The current study investigated whether neighborhood-level disadvantage impacts knee pain-related outcomes above sociodemographic measures. Participants were 188 community-dwelling adults who self-identified as non-Hispanic Black or non-Hispanic White and reported knee pain. Area Deprivation Index (ADI; measure of neighborhood-level disadvantage) state deciles were derived for each participant. Participants reported educational attainment and annual household income as measures of SES, and completed several measures of pain and function: Short-form McGill Pain Questionnaire, Western Ontario and McMaster Universities Osteoarthritis Index, and Graded Chronic Pain Scale were completed, and movement-evoked pain was assessed following the Short Physical Performance Battery. Hierarchical linear regression analyses were used to assess whether environmental and sociodemographic measures (i.e., ADI 80/20 [80% least disadvantaged and 20% most disadvantaged]; education/income, race) were associated with pain-related clinical outcomes. Results Living in the most deprived neighborhood was associated with poorer clinical knee pain-related outcomes compared to living in less deprived neighborhoods (ps < 0.05). Study site, age, BMI, education, and income explained 11.3–28.5% of the variance across all of the individual pain-related outcomes. However, the ADI accounted for 2.5–4.2% additional variance across multiple pain-related outcomes. Conclusion The ADI accounted for a significant amount of variance in pain-related outcomes beyond the control variables including education and income. Further, the effect of ADI was similar to or higher than the effect of age and BMI. While the effect of neighborhood environment was modest, a neighborhood-level socioenvironmental variable like ADI might be used by clinicians and researchers to improve the characterization of patients’ risk profile for chronic pain outcomes.
Understanding how cooperation emerges in public goods games is crucial for addressing societal challenges. While optional participation can establish cooperation without identifying cooperators, it relies on specific assumptions -- that individuals abstain and receive a non-negative payoff, or that non-participants cause damage to public goods -- which limits our understanding of its broader role. We generalize this mechanism by considering non-participants' payoffs and their potential direct influence on public goods, allowing us to examine how various strategic motives for non-participation affect cooperation. Using replicator dynamics, we find that cooperation thrives only when non-participants are motivated by individualistic or prosocial values, with individualistic motivations yielding optimal cooperation. These findings are robust to mutation, which slightly enlarges the region where cooperation can be maintained through cyclic dominance among strategies. Our results suggest that while optional participation can benefit cooperation, its effectiveness is limited and highlights the limitations of bottom-up schemes in supporting public goods.
Previous foundation models for fundus images were pre-trained with limited disease categories and knowledge base. Here we introduce a knowledge-rich vision-language model (RetiZero) that leverages knowledge from more than 400 fundus diseases. For RetiZero's pretraining, we compiled 341,896 fundus images paired with texts, sourced from public datasets, ophthalmic literature, and online resources, encompassing a diverse range of diseases across multiple ethnicities and countries. RetiZero exhibits remarkable performance in several downstream tasks, including zero-shot disease recognition, image-to-image retrieval, AI-assisted clinical diagnosis,few-shot fine-tuning, and internal- and cross-domain disease identification. In zero-shot scenarios, RetiZero achieves Top-5 accuracies of 0.843 for 15 diseases and 0.756 for 52 diseases. For image retrieval, it achieves Top-5 scores of 0.950 and 0.886 for the same sets, respectively. AI-assisted clinical diagnosis results show that RetiZero's Top-3 zero-shot performance surpasses the average of 19 ophthalmologists from Singapore, China, and the United States. RetiZero substantially enhances clinicians' accuracy in diagnosing fundus diseases, in particularly rare ones. These findings underscore the value of integrating the RetiZero into clinical settings, where various fundus diseases are encountered.
A new simulation technique to obtain the synchronized steady-state solutions existing in coupled oscillator systems is presented. The technique departs from a semi-analytical formulation presented in previous works. It extends the model of the admittance function describing each individual oscillator to a piecewise linear one. This provides a global formulation of the coupled system, considering the whole characteristic of each voltage-controlled oscillator (VCO) in the array. In comparison with the previous local formulation, the new formulation significantly improves the accuracy in the prediction of the system synchronization ranges. The technique has been tested by comparison with computationally demanding circuit-level Harmonic Balance simulations in an array of Van der Pol-type oscillators and then applied to a coupled system of FET based oscillators at 5 GHz, with very good agreement with measurements.
Maxim Rubchinsky, Ella Rabinovich, Adi Shraibman
et al.
We present a novel approach to automating the identification of risk factors for diseases from medical literature, leveraging pre-trained models in the bio-medical domain, while tuning them for the specific task. Faced with the challenges of the diverse and unstructured nature of medical articles, our study introduces a multi-step system to first identify relevant articles, then classify them based on the presence of risk factor discussions and, finally, extract specific risk factor information for a disease through a question-answering model. Our contributions include the development of a comprehensive pipeline for the automated extraction of risk factors and the compilation of several datasets, which can serve as valuable resources for further research in this area. These datasets encompass a wide range of diseases, as well as their associated risk factors, meticulously identified and validated through a fine-grained evaluation scheme. We conducted both automatic and thorough manual evaluation, demonstrating encouraging results. We also highlight the importance of improving models and expanding dataset comprehensiveness to keep pace with the rapidly evolving field of medical research.