A. Sisó-Almirall, P. Brito-Zerón, Laura Conangla Ferrín
et al.
Long COVID-19 may be defined as patients who, four weeks after the diagnosis of SARS-Cov-2 infection, continue to have signs and symptoms not explainable by other causes. The estimated frequency is around 10% and signs and symptoms may last for months. The main long-term manifestations observed in other coronaviruses (Severe Acute Respiratory Syndrome (SARS), Middle East respiratory syndrome (MERS)) are very similar to and have clear clinical parallels with SARS-CoV-2: mainly respiratory, musculoskeletal, and neuropsychiatric. The growing number of patients worldwide will have an impact on health systems. Therefore, the main objective of these clinical practice guidelines is to identify patients with signs and symptoms of long COVID-19 in primary care through a protocolized diagnostic process that studies possible etiologies and establishes an accurate differential diagnosis. The guidelines have been developed pragmatically by compiling the few studies published so far on long COVID-19, editorials and expert opinions, press releases, and the authors’ clinical experience. Patients with long COVID-19 should be managed using structured primary care visits based on the time from diagnosis of SARS-CoV-2 infection. Based on the current limited evidence, disease management of long COVID-19 signs and symptoms will require a holistic, longitudinal follow up in primary care, multidisciplinary rehabilitation services, and the empowerment of affected patient groups.
Natalie S. Adamczyk, Shingo Ishihara, Alia M. Obeidat
et al.
Background and Purpose Musculoskeletal pain is a significant burden with limited pain relief options. The mechanically activated ion channel Piezo2 plays a role in mechanical sensitization; however, there has been little progress in examining therapeutics that target Piezo2. The goal of this study was to assess the effectiveness of FM‐dye in reducing acute inflammatory and osteoarthritic (OA) knee pain in mice through Piezo2. Experimental Approach Wild‐type or nociceptor‐specific Piezo2 conditional knockout (Piezo2cko) mice were used. The complete Freund's adjuvant (CFA) model of acute inflammatory knee pain, the partial medial meniscectomy (PMX) OA model, and ageing‐associated OA mouse models were used. Pain‐related behaviours (knee hyperalgesia, weight bearing asymmetry) were established prior to intra‐articular injection of FM‐dye (5 nmol in 2.5 μl) or vehicle. In vivo calcium imaging of the L4 dorsal root ganglion (DRG) was performed using Na V 1.8‐GCaMP6 mice in the CFA model. Key Results In the CFA model, female and male mice intra‐articularly injected with FM1‐43 exhibited reduced knee hyperalgesia 90 min post‐injection. In vivo calcium imaging of the DRG demonstrated a reduction in nociceptor responses to mechanical force applied to the knee of CFA mice following FM‐dye. Following PMX, intra‐articular injection of FM1‐43 reduced knee hyperalgesia in wild‐type mice but not in Piezo2cko mice; weight bearing asymmetry was also reduced. In mice with age‐associated OA, intra‐articular injection of FM‐dyes reduced knee hyperalgesia. Conclusion and Implications Inhibiting Piezo2 pharmacologically reduced pain‐related behaviours in mouse models of inflammatory and OA knee pain, providing evidence of the therapeutic potential of targeting Piezo2.
Aims: Interbody fusion stabilizes the spine by promoting bony growth between vertebrae. Large animal models have physiological and biomechanical similarities to human spines that can provide safety and efficacy data before human use. Sheep models are well validated and are the model of choice to improve understanding of fusion processes by allowing post-mortem analyses of tissues unavailable in human studies. They should be consistently designed to allow appropriate translation of the results into clinical practice. This paper investigates the methodological rigour of ovine lumbar interbody fusion (LIF) studies, and proposes recommendations for researchers designing future studies. Methods: PubMed and the Cochrane library were searched up to 20 December 2024. The search terms were 1) lumbar AND ("in vivo" OR "animal model") AND "fusion" AND (interbody OR cage OR anterior) and 2) (lumbar AND ("in vivo" OR "animal model") AND (spine OR intervertebral disc) AND (sheep OR ovine) AND fusion). Results: A total of 323 papers were identified; 48 studies were included after rejection of non-spinal references, duplicates, and non-English-language papers. Data regarding 993 animals and 1,668 fusion levels were examined. Animal ages varied from six months to nine years. Cages were used in 88% of studies, with a wide range of sizes. The commonest assessments included radiography, histology, and mechanical testing. The in-life phase of the studies varied from one week to three years. High risk of bias was evident in all papers, especially considering 1) treatment allocation sequences, 2) housing randomization, 3) blinding of caregivers, and 4) outcome assessment randomization. Conclusion: This review demonstrates variability in the design of ovine LIF studies, highlights features likely to limit the translatability of results into clinical practice (sheep age and interbody cage size), shows high risk of bias in the published literature, and makes recommendations for future studies. Cite this article: Bone Joint Res 2026;15(1):58–72.
Misato Sonoda, Ronan Hinchet, Amirhossein Kazemipour
et al.
Robotic manipulation in unstructured environments requires end-effectors that combine high kinematic dexterity with physical compliance. While traditional rigid hands rely on complex external sensors for safe interaction, electrohydraulic actuators offer a promising alternative. This paper presents the design, control, and evaluation of a novel musculoskeletal robotic hand architecture powered entirely by remote Peano-HASEL actuators, specifically optimized for safe manipulation. By relocating the actuators to the forearm, we functionally isolate the grasping interface from electrical hazards while maintaining a slim, human-like profile. To address the inherently limited linear contraction of these soft actuators, we integrate a 1:2 pulley routing mechanism that mechanically amplifies tendon displacement. The resulting system prioritizes compliant interaction over high payload capacity, leveraging the intrinsic force-limiting characteristics of the actuators to provide a high level of inherent safety. Furthermore, this physical safety is augmented by the self-sensing nature of the HASEL actuators. By simply monitoring the operating current, we achieve real-time grasp detection and closed-loop contact-aware control without relying on external force transducers or encoders. Experimental results validate the system's dexterity and inherent safety, demonstrating the successful execution of various grasp taxonomies and the non-destructive grasping of highly fragile objects, such as a paper balloon. These findings highlight a significant step toward simplified, inherently compliant soft robotic manipulation.
Despina Michailidou, Linda Johansson, Jorge Armando Gonzalez Chapa
et al.
Objective Platelet activation is thought to participate in polymyalgia rheumatica (PMR) pathogenesis. Upon platelet activation, mitochondria are expelled into the extracellular space. However, whether extracellular mitochondria are present in patients with PMR and whether they can induce platelet activation is not known. Methods To investigate this, we measured markers of platelet activation (thrombospondin‐1 [TSP‐1]), mitochondrial‐derived N‐formyl methionine peptide (fMET), and autoantibodies directed toward specific mitochondrial antigen mitofusin‐1 (MFN1) by enzyme‐linked immunosorbent assay in plasma of healthy controls (HCs, n = 30) and patients with PMR without giant cell arteritis (GCA) (n = 45) and patients with PMR with GCA (n = 9) before and after treatment with glucocorticoid therapy. Ultrapure mitochondria were opsonized with plasma from patients with PMR without GCA (n = 45) or HCs (n = 10) and were subsequently incubated with HC platelets. Platelet activation was assessed by P‐selectin levels using flow cytometry. Results Plasma levels of anti‐MFN1 IgG were elevated in patients with PMR with and without GCA before glucocorticoid therapy when compared with HCs (P < 0.01 for both groups). Levels of anti‐MFN1 IgG significantly reduced after treatment with glucocorticoids in both groups (P < 0.01). Levels of fMET were also significantly higher in patients with PMR with and without GCA before glucocorticoid therapy in comparison with HCs (P < 0.001 and P < 0.01, respectively). However, the levels of fMET only dropped significantly after therapy in patients with PMR without GCA (P < 0.001). Plasma levels of TSP‐1 were elevated in patients with PMR with and without GCA before glucocorticoid therapy when compared to HC (P < 0.001 for both groups). After glucocorticoid therapy, plasma levels of TSP‐1 decreased significantly only in patients with PMR without GCA (P = 0.023). Mitochondria opsonized with plasma from patients with PMR without GCA induced higher platelet activation regardless of treatment status as compared with plasma from HCs (P < 0.0001 and P < 0.01 for pretreatment and posttreatment). Conclusion Our results indicate increased platelet activation and the presence of mitochondrial antigens and antibodies in the circulation of patients with PMR. Blocking mitochondrial‐mediated platelet activation may reduce inflammation in patients with PMR, with potential therapeutic implications.
Abstract Background Dermatomyositis (DM) is a heterogeneous disease characterized by skin rash and muscle weakness. Although tongue disorders have been documented in idiopathic inflammatory myopathies (IIM), biopsy-confirmed tongue myositis remains exceedingly rare, and no reports have been published in patients with DM. Case presentation This study describes two rare cases of anti-PM-Scl 75 antibody-positive dermatomyositis with tongue involvement and dysphagia. In case 1, muscle weakness and skin rash improved after the initial therapy. However, the patient developed tongue atrophy, severe pharyngeal dysphagia (Functional Oral Intake Scale (FOIS) level = 3) and dysarthria (Frenchay Dysarthria Assessment scale (FDA) score = 13) during the tapering of glucocorticoid. Escalating glucocorticoids and adding rituximab improved her swallowing (FOIS level = 6) and speech (FDA score = 23) function, though a limited improvement of tongue atrophy. Case 2 presented with severe skin rash, muscle weakness and elevated CK levels, accompanied by tongue redness and swelling, mild pharyngeal dysphagia (FOIS level = 5) and dysarthria (FDA score = 20) at disease onset. With the treatment of glucocorticoid, tacrolimus and intravenous immunoglobulin (IVIG), the patient achieved complete remission. Conclusion Tongue myositis may occur in DM and could serve as a potential indicator of disease activity. Early recognition may be beneficial and biological agents warrant further investigation in refractory cases. Clinical trial number Not applicable.
Background: Annulus fibrosus (AF) is an important part of the intervertebral disc (IVD) and its injury leads to back pain and impaired mobility. The stem/progenitor cells are essential for the maturation and repair of the AF, however, the identity of AF stem/progenitor cells remain elusive. Methods: In this study, we sorted cells from the murine IVDs and performed the single-cell RNA sequencing. Using single-cell transcriptomics, genetic lineage tracing, in vitro stem cell experiment, ablation models and cell transplantation, we elucidate the role of AF progenitor cells in maturation and injury. Results: On the basis of single-cell RNA-sequencing (scRNA-seq) analysis of the intervertebral disc, we found that the transcription factor Scleraxis (Scx) can specifically label a progenitor cell population of the outer AF. By lineage tracing assay, Scx-lineage AF cells proliferate mainly prior to sexual maturity, but barely proliferate after age of 8 weeks. The Scx-expressing AF cells are enriched for stem/progenitor cell markers and show a higher proliferative capacity and differentiation potential than the Scx− cells. The ablation of Scx-expressing AF cells impairs the maturation of AF. The Scx+ AF cells are enriched for TGFβ signaling. Transplantation of Scx-lineage cells to injured AF with Connective tissue growth factor (CTGF) improved the AF healing. Conclusions: Scleraxis-expressing progenitor cells are critical for the maturation of AF and demonstrate therapeutic potential for AF regeneration. The translational potential of this article: These findings expand the important role of stem cells in maturation and repair and provide new strategy for cellular therapy of AF repair.
Rare diseases affect over 300 million individuals worldwide, yet timely and accurate diagnosis remains an urgent challenge. Patients often endure a prolonged diagnostic odyssey exceeding five years, marked by repeated referrals, misdiagnoses, and unnecessary interventions, leading to delayed treatment and substantial emotional and economic burdens. Here we present DeepRare, a multi-agent system for rare disease differential diagnosis decision support powered by large language models, integrating over 40 specialized tools and up-to-date knowledge sources. DeepRare processes heterogeneous clinical inputs, including free-text descriptions, structured Human Phenotype Ontology terms, and genetic testing results, to generate ranked diagnostic hypotheses with transparent reasoning linked to verifiable medical evidence. Evaluated across nine datasets from literature, case reports and clinical centres across Asia, North America and Europe spanning 14 medical specialties, DeepRare demonstrates exceptional performance on 3,134 diseases. In human-phenotype-ontology-based tasks, it achieves an average Recall@1 of 57.18%, outperforming the next-best method by 23.79%; in multi-modal tests, it reaches 69.1% compared with Exomiser's 55.9% on 168 cases. Expert review achieved 95.4% agreement on its reasoning chains, confirming their validity and traceability. Our work not only advances rare disease diagnosis but also demonstrates how the latest powerful large-language-model-driven agentic systems can reshape current clinical workflows.
There is a growing proportion of people with several disease conditions ("multimorbidity"), placing increasing demands on healthcare systems. One hypothesis is that clusters of diseases may arise from shared underlying disease processes (shared "pathogenesis"), whereby the presence of one disease indicates the state of disease progression to several related disease types. This article explains how this hypothesis can be tested using observational data for disease incidence. Specifically, a multistage model is used to test whether two diseases can have a "shared stage" or "step", before either disease can occur, and how the unobserved rate of this step can be determined. The approach offers a simple method for studying multiple diseases and identifying shared underlying causes of multiple conditions, and is illustrated with published data and numerical examples. The fundamental mathematical model is analysed to compare key statistical properties such as the expectation and variance with those of independent diseases. The main results do not need an understanding of the underlying mathematics and can be appreciated by a non-expert. Significance: It is widely believed that there are shared underlying pathways that can lead to several disease types (shared "pathogenesis"), and this may explain observed clusters of disease types. This article shows how this hypothesis can be tested for a pair or cluster of diseases, using observational data of disease incidence.
The diagnosis of hip dysplasia has developed very differently in different countries over the last few decades. The development and current situation in Hungary is described in this paper. The Ortolani test is still the gold standard for clinical examination in most regions. Hip sonography is not officially established and is only used occasionally. However, thanks to private initiatives, more and more orthopaedic surgeons are now familiarising themselves with this method and the first courses are being held in accordance with International Interdisciplinary Consensus Committee on DDH Evaluation (ICODE) guidelines. A regional screening with Graf hip sonography was carried out in Szeged. The results of the evaluation impressively demonstrate the efficiency of this method.
The diagnosis of hip dysplasia has developed very differently in different countries over the last few decades. The development and current situation in Switzerland is described in this paper. In the meantime, early diagnosis by means of Graf hip sonography, corresponding to screening, has been established, although it varies from region to region. The training system for examiners is also clearly regulated. The massive reduction in costly treatments and operations documents the success of the efforts made in Switzerland.
This study presents the first implementation of multilayer neural networks on a memristor/CMOS integrated system on chip (SoC) to simultaneously detect multiple diseases. To overcome limitations in medical data, generative AI techniques are used to enhance the dataset, improving the classifier's robustness and diversity. The system achieves notable performance with low latency, high accuracy (91.82%), and energy efficiency, facilitated by end-to-end execution on a memristor-based SoC with ten 256x256 crossbar arrays and an integrated on-chip processor. This research showcases the transformative potential of memristive in-memory computing hardware in accelerating machine learning applications for medical diagnostics.
Shams Nafisa Ali, Afia Zahin, Samiul Based Shuvo
et al.
Cardiac auscultation, an integral tool in diagnosing cardiovascular diseases (CVDs), often relies on the subjective interpretation of clinicians, presenting a limitation in consistency and accuracy. Addressing this, we introduce the BUET Multi-disease Heart Sound (BMD-HS) dataset - a comprehensive and meticulously curated collection of heart sound recordings. This dataset, encompassing 864 recordings across five distinct classes of common heart sounds, represents a broad spectrum of valvular heart diseases, with a focus on diagnostically challenging cases. The standout feature of the BMD-HS dataset is its innovative multi-label annotation system, which captures a diverse range of diseases and unique disease states. This system significantly enhances the dataset's utility for developing advanced machine learning models in automated heart sound classification and diagnosis. By bridging the gap between traditional auscultation practices and contemporary data-driven diagnostic methods, the BMD-HS dataset is poised to revolutionize CVD diagnosis and management, providing an invaluable resource for the advancement of cardiac health research. The dataset is publicly available at this link: https://github.com/mHealthBuet/BMD-HS-Dataset.
Kento Kawaharazuka, Kei Tsuzuki, Shogo Makino
et al.
The musculoskeletal humanoid has many benefits that human beings have, but the modeling of its complex flexible body is difficult. Although we have developed an online acquisition method of the nonlinear relationship between joints and muscles, we could not completely match the actual robot and its self-body image. When realizing a certain task, the direct relationship between the control input and task state needs to be learned. So, we construct a neural network representing the time-series relationship between the control input and task state, and realize the intended task state by applying the network to a real-time control. In this research, we conduct accelerator pedal control experiments as one application, and verify the effectiveness of this study.
Objective To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. Methods Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) organ domain scores. Results At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA–SLEDAI, and immunological by SELENA–SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA–SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (≤16%) at baseline, including the SELENA–SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA–SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. Conclusions Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.
The Lancet Regional The Chronic Pain Series, published by The Lancet on between patients and physicians in pain rating, and Health Western Pacific 2023;33: 100782 https://doi.org/10. 1016/j.lanwpc.2023. 100782 May 27, 2021, highlighted the burdens and progress of chronic pain management. Globally, one in five people have chronic pain, but some endure more than others. Women, older populations, and people of a lower socioeconomic status are more likely to report pain. Due to the ageing population and the high burden of chronic diseases, chronic pain is becoming a serious health-care challenge in the Asia–Pacific region. Depending on the use of different methods to measure pain, the prevalence of chronic pain in Asian countries varies from 7.1% to 90.8% among adults. However, awareness and management of pain have long been neglected. Chronic pain is defined as any pain lasting longer than 12 weeks. Unlike acute pain, which functions as a biological warning system, chronic pain is a complex health condition dynamically affected by biological, psychological, and social factors. It includes many conditions such as cancer pain, neuropathic pain, and musculoskeletal pain. Each of them carries heterogeneous symptoms that might require different approaches for diagnosis and treatment. Untreated chronic pain adversely affects patients’ physical and mental health, impairs quality of life, and reduces work productivity. Cultural beliefs shape people’s understanding, experience, and responses to pain, including healthseeking behaviour. In many Asian cultures, patients might not seek medical help because chronic pain is regarded as an expected part of life and a normal ageing process that should be endured. A recent survey study on chronic pain from China showed that 24.06% of respondents did not seek medical help, and 36.79% of patients never received any treatment because they believed chronic pain is not harmful. Pain is a subjective phenomenon, and pain assessment and diagnosis rely largely on patients’ self-report. The complicated aetiology for chronic pain and limited medical resources and staff specialising in pain management contribute to the underdiagnosis of chronic pain in clinical settings. The standard pain assessment process is the initial step for accurate diagnoses and effective treatment, but it is usually inadequately used. In a multinational survey (Current practices of cancer and chronic non-cancer pain management: a pan-Asian study [ACHEON]), 49.5% of patients with chronic cancer pain mentioned that they did not receive pain scale assessment in diagnosis. There are also discrepancies