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Aryadi Kurniawan,1 Felais Hediyanto Pradana,1 Evelina Kodrat,2 Anissa Feby Canintika,1 Aufa Kunti Riona Aryandhani3 1Department of Orthopedics and Traumatology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia; 2Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia; 3Radboud University, Nijmegen, NetherlandCorrespondence: Aryadi Kurniawan, Department of Orthopedics and Traumatology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia, Email aryadi.kurniawan@ui.ac.idIntroduction: Delayed union management is both challenging and expensive. Statins, which are HMG-CoA reductase inhibitors, induce bone morphogenetic protein-2 (BMP-2) gene expression, which in turn increases bone formation. Red yeast rice contains monacolin, which has a similar activity to lovastatin as an HMG-CoA reductase inhibitor. Red-yeast rice is readily available and inexpensive. This study aimed to demonstrate the effectiveness of red yeast rice in enhancing fracture healing in a delayed union model through increased expression of BMP-2.Materials and Methods: This experimental animal study was conducted using 24 delayed union Sprague-Dawley (SD) rats divided into four groups (n=6 each), consisting of; the 4-weeks-given-red yeast rice extract group (4RYR), 2-weeks-given-red yeast rice extract group (2RYR), 4-weeks-control group (4C), and 2-weeks-control group (2C). The animals were euthanized in the second and fourth week. Immunohistochemical staining was used to assess BMP-2 expression using an Immunoreactive Score (IRS). The fracture healing process was evaluated using histomorphometry by measuring the fibrous area, cartilage area, and woven bone area percentage.Results: In the 2RYR group, there was significantly higher BMP-2 expression (p=0.03), less fibrous area (p=0.05), and larger cartilage area (p= 0.04) than in the 2C group. In the 4RYR group, there was significantly higher expression of BMP-2 (p=0.011), larger woven bone area (p=0.01), and less fibrous area (p = 0.03) than in the 4C group. There was also a significantly smaller fibrous area (p=0.02), a larger cartilage area (p=0.05), and a larger woven bone area (p=0.04) in the 4RYR group than in the 2RYR group. The BMP-2 expression in the 2RYR group was as high as that in the 4RYR group.Conclusion: Red yeast rice effectively improved fracture healing by increasing BMP-2 expression in a delayed-union model in SD rats.Keywords: delayed union model, BMP-2 expression, red yeast rice, fracture healing

Qian Li,1 Dinglin Li,1 Ciqiu Tian,2 Xiangjie Liu,1 Hui Wang,1 Hao Liu1 1Liyuan Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Tongji Medical College of Science and Technology, Wuhan, People’s Republic of China; 2Hubei University of Chinese Medicine, Wuhan, People’s Republic of ChinaCorrespondence: Hao Liu, Liyuan Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, Tongji Medical College of Science and Technology, Wuhan, People’s Republic of China, Email 729481937@qq.comPurpose: Osteoporosis is a common skeletal disease characterized by impaired bone microarchitecture, decreased bone mineral density and increased bone fragility, leading to a heavy physical and economic burden due to its greatly increased risk of fracture. Baji capsule is a proprietary medicine that can treat menstrual disorders and postmenopausal osteoporosis. However, the efficacy of Baji capsule has not been reported for osteoporosis caused by oxidative stress and inflammation. Therefore, the aim of this study was to evaluate whether Baji capsule has a therapeutic effect on lipopolysaccharide (LPS)-induced inflammatory osteoporosis and to explore the underlying mechanisms through network pharmacology.Patients and Methods: Osteoporosis model in ICR mice induced with LPS. Mice were treated with vitamin E (100mg/kg), PBS, high-dose Baji capsule (810mg/kg) and low-dose Baji capsule (90mg/kg), respectively. The therapeutic effect of Baji capsule was evaluated by high-resolution micro-computed tomography (Micro-CT) and tissue section staining, serum inflammatory factor levels were assessed by ELISA, serum oxidative stress-related marker levels were determined by kits, and finally the mechanism was explored by network pharmacology and then verified by immunohistochemistry.Results: Micro-CT results showed that Baji capsule attenuated LPS-induced inflammatory bone loss.Baji capsule also reduced serum inflammatory factor levels and oxygen free radical production. Target screening by network pharmacology yielded a total of 236 active ingredients of Baji capsule, as well as 278 common targets after taking the intersection of Baji capsule active ingredient targets and osteoporosis disease-related targets.Conclusion: Baji capsule can treat osteoporosis by reducing inflammation and oxidative stress. The therapeutic effects of Baji capsule were shown to be multi-targeted and multi-pathway through network pharmacology. In the future, its anti-inflammatory and antioxidant properties can be utilized to further explore its therapeutic effects on inflammatory diseases, as well as a prospective study for the clinical treatment of osteoporosis.Keywords: inflammatory, oxidative stress, osteoporosis, traditional Chinese medicine, network pharmacology

Ludwig Andibert Powantia Pontoh,1,2 Ismail Hadisoebroto Dilogo,1 Achmad Fauzi Kamal,1 Sholahuddin Rhatomy,3 Anggaditya Putra,2 Jessica Fiolin,4 Joshua Alward Herdiman,5 Ega Wirayoda Pontoh5 1Department of Orthopaedic and Traumatology, Cipto Mangunkusumo General Hospital, Central Jakarta, DKI Jakarta, 10430, Indonesia; 2Department of Orthopaedic and Traumatology, Fatmawati General Hospital, South Jakarta, DKI Jakarta, 12430, Indonesia; 3Department of Orthopaedic and Traumatology, Soeradji Tirtonegoro General Hospital, Klaten, Central Java, 57424, Indonesia; 4Department of Orthopaedic and Traumatology, Pondok Indah General Hospital, South Jakarta, DKI Jakarta, 12310, Indonesia; 5Faculty of Medicine, Universitas Indonesia, Central Jakarta, DKI Jakarta, 10430, IndonesiaCorrespondence: Ludwig Andibert Powantia Pontoh, Email lappontoh@gmail.comIntroduction: The anterior cruciate ligament (ACL) is crucial for knee stability and joint movement coordination. ACL injuries are common, often leading to knee instability and subsequent complications. ACL reconstruction is a standard treatment option, with various autograft sources available. The anterior half of the peroneus longus (AHPL) tendon has emerged as a potential alternative autograft. This study aimes to examine the anterior knee pain in ACL reconstruction using AHPL.Materials and Methods: This study included 51 patients with ACL injuries undergoing ACL reconstruction using the AHPL tendon autograft. Patient demographics, surgical details, and Kujala scores were collected.Results: The average age of our participants was 25.88 ± 5.39 years, with mean BMI classified as obese. Significant improvements in Kujala and KOOS pain scores were observed between each data collection. There was a negative correlation between baseline and three and six months post-operatively Kujala and KOOS pain scores with BMI.Discussion: The study findings suggest that ACL reconstruction using the AHPL tendon autograft significantly reduced anterior knee pain, as indicated by a better Kujala and KOOS pain score. Previous studies have highlighted concerns regarding anterior knee pain with other autograft sources, such as the patellar and hamstring tendons. The AHPL tendon autograft offers a promising alternative with favorable anterior knee pain and minimal donor site morbidity.Conclusion: In ACL reconstruction, the AHPL tendon autograft demonstrates excellent outcomes regarding anterior knee pain, as measured by the Kujala score.Keywords: anterior cruciate ligament (ACL) reconstruction, anterior knee pain, peroneus longus tendon autograft, anterior half of the peroneus longus (AHPL), Kujala score

Abstract Background Work-related musculoskeletal disorders (WRMSDs) are significant concern in intensive care units (ICUs) due to distinct work environment. This study aims to comprehensively investigate determinants of WRMSDs and ergonomic challenges, specific to ICU nurses, providing valuable insights for targeted interventions. Methods In this six-month convergent mixed methods study, 200 consenting nurses with over one year of experience from seven ICUs across three public tertiary hospitals of Ahmedabad participated. Structured questionnaires were used to collect data on socio-demographics, occupation, physical and workplace factors, risk perception, and musculoskeletal pain (through modified Nordic Musculoskeletal Questionnaire) and ergonomic issues using REBA (Rapid Entire Body Assessment) scale. Qualitative insights were obtained through in-depth interviews until saturation of responses. Statistical analysis involved chi-square, t-test and logistic regression, with a significance level set at p

Abstract Background Increasing life expectancy has led to a rise in hip fractures and an associated increase in hemiarthroplasty procedures aimed at restoring mobility and preventing muscle loss. Despite the extensive literature on failed hemiarthroplasty, limited data address the influence of pre-operative fracture types—intracapsular versus extracapsular—on outcomes, including inpatient mortality. This study investigates the revisions of uncemented bipolar hemiarthroplasties concerning fracture type and identifies risk factors for inpatient mortality. Methods This retrospective cohort study included 68 patients (16 males and 52 females) who underwent revision of uncemented bipolar hemiarthroplasties at a single institution between 2017 and 2024. Data on demographics, comorbidities, fracture type, surgical details and outcomes were analysed. Statistical analyses included t tests, chi-square tests and logistic regression, with significance set at p

Abstract Background This study aimed to compare the effectiveness of exercise therapy delivered via a smartphone mobile app, using asynchronous video-based tools, with synchronous telerehabilitation models using videoconferencing for individuals with fibromyalgia syndrome (FMS). Methods The research, utilizing a randomized clinical study design, involves sixty-six FMS patients in an 8-week exercise program. Participants are divided into synchronous (n: 33) and asynchronous (n: 33) groups. Assessments, pain intensity (VAS), functional limitations (FIQr), health-related quality of life (SF 12), catastrophizing (PCS), anxiety and depression (HADS), functional capacity (6MWT), muscle strength (Arm curl test), and joint position sense (LI-RATT), are conducted at baseline, mid-treatment (week 4), end of treatment (week 8). Results No significant group-time interaction was found for total VAS, FIQ, SF 12, PCS, HADS, 6MWT, Arm curl tests, LI-RATT extension, LI-RATT flexion, LI-RATT right rotation scores (p > 0.05). Significant effects of time and interactions between groups and time were observed in the neck (p = 0.010, ES = 0.19) and back region (p = 0.039, ES = 0.19) of the Visual Analog Scale, left rotation score of the LI-RATT (p = 0.008, ES = 0.36), and HADS Anxiety Score (p = 0.029, ES = 0.31). Group differences were significant at all-time points for the outcomes (p

Abstract Background Alpha-melanocyte-stimulating-hormone (α-MSH) has been identified as a new anti-inflammatory treatment compound in rheumatoid arthritis (RA) and other inflammatory diseases. However, its direct effect on bone cell differentiation or on bone regeneration, which is an inflammatory process, too, has not been investigated, yet. Bone tissue is significantly affected in inflammatory joint diseases. Additionally, inflammatory signaling is essential -in bone regeneration during fracture healing. Therefore, we evaluated the impact of α-MSH-treatment on bone forming cells in an inflammatory setting in vitro and as a treatment approach in a murine fracture healing model in vivo. Methods The influence of α-MSH treatment and melanocortin-receptor expression patterns was investigated in vitro in the presence of either IL-1β or/and TNF-α as an inflammatory stimulus. Osteoblast cell function was evaluated by analyzing proliferation and mineralisation capacities. Using quantitative real time PCR, we analyzed mRNA expression of receptors. To explore the impact of α-MSH on bone regeneration in vivo, treatment with α-MSH or NaCl (control) was performed in a murine fracture-healing model using a closed femur fracture stabilized with an intramedullary implant (female, n = 6–8 mice per group). Results α-MSH-treatment did not impair either proliferation nor mineralisation of osteoblastic cells under native or inflammatory conditions (no significant differences found). All four melanocortin receptor-molecules were expressed in murine osteoblastic cells but in very limited amounts and this did not change upon treatment with inflammatory cytokines or α-MSH or both at the same time. Callus formation in fractured femurs of α-MSH-treated mice was slightly delayed at day 14 post fracture with regard to less cartilage formation (NaCl: 19.9%; α-MSH: 13.5%) and soft tissue remodeling (NaCl: 15.2%; α-MSH: 19.5%) but these results were not significantly different and fracture healing overall occurred in a regular way. Conclusion α-MSH has no negative impact on bone or bone-forming cells in native, inflammatory, or regenerative contexts. We can conclude from our results, that treatment of inflammatory diseases using α-MSH does not interfere significantly with bone regeneration in a murine fracture model and therefore treatment with α-MSH could be continued without negative effects on bone formation and bone regeneration in patients. Clinical trial number Not applicable.

Abstract Objective This study aims to investigate the associated factors of intercostal neuralgia in patients with osteoporotic vertebral compression fractures (OVCF) of the thoracic spine and to develop a predictive model to assess the likelihood of patients developing intercostal neuralgia following thoracic vertebral fractures. Methods The retrospective study involved 518 patients with thoracic OVCF treated at our hospital, among whom those with and without intercostal neuralgia were matched at a 1:1 ratio.Relevant basic clinical data and imaging parameters of the patients were recorded, t-test was used for continuous variables and chi-square test for categorical variables to determine the factors associated with intercostal neuralgia. Subsequently, the above associated variables were screened using univariate and multivariate logistic regression models to obtain associated factors. Finally, a prediction model for osteoporotic thoracic spine fracture was developed and validated. Results This study included a total of 104 patients based on the presence or absence of intercostal neuralgia.The results of multifactorial logistic regression analysis showed that injured vertebral intervertebral foraminal area (P = 0.0008, regression coefficient estimate 0.0490, 95% confidence interval 0.0219–0.0798, OR = 1.0503), injured vertebral intervertebral foraminal volume (P = 0.0001, regression coefficient value − 0.0028, 95% confidence interval − 0.0044 to -0.0015, OR = 0.9972), and nerve root area (P = 0.0038, regression coefficient estimate=-0.0876, 95% confidence interval − 0.1506 to -0.0309, OR = 0.9161) were independent associated factors.The fatty degeneration ratio have a positive promotional effect on the probability of developing intercostal pain.The area under the ROC curve (AUC) of the prediction model was 0.851, which indicated that the line graph model had a certain degree of predictive validity. Conclusion Thoracic osteoporotic fractures are a common geriatric disease, and changes in the morphological parameters of the intervertebral foramina, such as a reduction in the area and volume of the injured vertebral intervertebral foramina, as well as fatty degeneration of the thoracic back muscles, suggest an increased probability of developing intercostal neuralgia.

Abstract Background People with knee osteoarthritis (OA) may have more thigh intermuscular and intramuscular adipose tissue (interMAT and intraMAT, respectively) compared to those without knee OA. Literature has not considered differences in body mass index (BMI) in the context of comparing intraMAT and interMAT between individuals with and without knee OA, matched for BMI (± 1 kg/m²). This study aims to compare interMAT and intraMAT, along with physical function (including knee extension strength), between individuals with and without knee osteoarthritis, matched by BMI. Methods Participants aged ≥ 40 years with symptomatic and radiological knee OA group (grade 2 and 3 on the Kellgren and Lawrence (KL) scale) were included in the affected group, while those with no knee pain and no radiological knee OA changes were included in the unaffected group. No participants were lost to assessment, ensuring complete data analysis for all participants. We used independent t-test and mean difference (95% CI) to compare thigh intraMAT and interMAT volume, self-reported measures (WOMAC questionnaire), physical function measures, and knee extension strength between groups. Results Forty-six participants were analyzed (23 in each group). The affected group had significantly higher intraMAT compared to the unaffected group (p

Abstract Background Fragility fractures lead to considerable societal costs and individual suffering. Despite the availability of cost-effective treatments for high-risk patients, a significant treatment gap exists, with many high-risk individuals remaining unidentified and untreated. The aim of this study was to explore the potential cost-effectiveness and societal impact of opportunistic screening for fracture risk with IBEX Bone Health (BH), a software solution that provides bone mineral density from wrist radiographs, in a UK general radiography setting. Methods The study used a health economic model that compared the health outcomes and costs of screening with IBEX BH versus usual care for men and women aged 50 and older who had a forearm radiograph for any reason. The model incorporated data on fracture incidence, fracture risk reduction, mortality, quality of life, and fracture and treatment costs from published sources and Royal Cornwall Hospitals NHS Trust. Costs and health outcomes in terms of quality-adjusted life years (QALYs) were simulated over the remaining lifetime of patients. The analysis took the perspective of the National Health Service (NHS) and Personal Social Services in the UK. Results The results showed that screening with IBEX BH was associated with a gain of 0.013 QALYs and a cost saving of £109 per patient compared with usual care, making it a dominant (cost-saving) strategy. Sensitivity analyses confirmed the robustness of the results under various assumptions. Widespread adoption of IBEX BH in the NHS was estimated to save 8,066 QALYs and £65,930,555 in healthcare costs over the lifetime of patients visiting hospitals for wrist radiographs each year. Conclusions IBEX BH could be a cost-effective tool for early identification and prevention of fragility fractures in the UK, addressing the current challenges of low provision and access to fracture risk assessment and treatment.

Abstract Objective Recent studies highlight the role of H-type vasculature in bone regeneration. This study, based on single-cell RNA sequencing (scRNA-seq), aims to explore the changes in H-type vasculature endothelial cells (H_ECs) in osteonecrosis of the femoral head (ONFH) and hip osteoarthritis (HOA), focusing on the death modes such as ferroptosis, pyroptosis, and parthanatos. Methods We re-analyzed the scRNA-seq data of femoral head samples publicly available in 2022. This study selected nine femoral head samples (3 each from HOA, ONFH stage 3 A, and ONFH stage 4). CD31 + EMCN + endothelial cells were classified as H_ECs. Molecular differences were assessed using Gene Ontology and KEGG analysis. Hypoxia, ferroptosis, pyroptosis, and parthanatos indices were calculated, and transcription factors were predicted using SENIC. Cell communication was analyzed with CellChat. Results After integrating the 9 samples, 14 cell types were identified: B cells, Mesenchymal stem cells, Osteoblasts, Endothelial cells, Monocytes, T cells, NK cells, Fibroblasts, Macrophages, Common myeloid progenitors, Chondrocytes, Myelocytes, Osteoclasts, and Pericytes. The number of endothelial cells and H_ECs decreased with necrosis severity. H_ECs showed higher angiogenic capacity but lower stress resistance compared to other endothelial cells. Angiogenic capacity decreased in necrotic samples, accompanied by an elevation in inflammation levels. The hypoxia index was higher, with ferroptosis increased in stage 3 A and parthanatos in stages 3 A and 4. No change was observed in pyroptosis. Cell communication analysis revealed downregulation of SLIT3-ROBO4 signaling during necrosis. Conclusion H_ECs show molecular differences compared to other endothelial cells. Ferroptosis and parthanatos contribute to the demise of H_ECs in ONFH, with pericytes and fibroblasts supporting H_EC angiogenesis.

Abstract Purpose This study aimed to assess the efficiency of a minimally invasive technique for correcting malunions of extra-articular metacarpal fractures, followed by percutaneous fixation using a cemented K-wire frame. Methods From January 2018 to January 2022, 31 patients (31 malunions of extra-articular metacarpal fractures) were treated. The mean age of the patients was 32 years (range, 21–52 years). There were 25 fifth, 4 fourth, 1 third, and 1 second metacarpal malunion. Range of motion of the fingers was assessed based on the total active motion scoring system of American Society for Surgery of the Hand. Range of motion of the joint was graded as excellent (85–100%), good (70–84%), fair (50–69%), and poor (

Abstract Background Spinal deformity associated with Neurofibromatosis type1(NF-1) is known to be intractable, and it’s surgical outcome is known to be poor. However, it is not clear whether or not patients are able to lead a healthy social life as adults, and we investigated the surgical outcomes of patients who had reached adulthood after surgery. Methods Thirty-eight patients (16 males, 22 females) who had undergone spinal deformity surgery and had reached the age of 18 years at last follow up were included. X-rays, surgery, complications, survival rate, employment status, and married rate were evaluated. HR-QOL was compared with those of adolescent idiopathic scoliosis(AIS) operated in our hospital. The idiopathic scoliosis group includes 110 patients who had undergone surgery from 2015 to 2018 at our hospital and 38 patients(2 males, 36 females) were selected by excluding patients who could not be followed up until the age of 18 years and those who did not describe their HR-QOL, and adjusting the mean preoperative cobb angle values to match those of the NF-1 group. Results The mean age at the initial surgery was 14.6 [4〜49] years, and the mean age at the last observation was 29.4 [18〜56] years. Anterior and posterior fusion were performed in 18 patients, posterior fixation was performed in 20 patients. Five patients died (3: malignant schwannoma, 1:brain tumor, 1:unknown), with a mean age of 27.0 [18〜35] years at the time of death and 12.2 [3〜21] years after the last surgery. Two patients over 40 years of age were treated for vascular system disorders, and 1 patient for a brain tumor. All survivors were ambulators except 1 case of non-ambulator due to neoplastic destruction of the hip joint. The working status was light work in 13 patients, desk work in 7, unemployed in 4, students in 8. Four patients were married. SRS-22 and ODI at the last follow-up in the NF-1 group and AIS group were compared. There were no significant differences in SRS-22 Pain, Mental Health, Satisfaction, and ODI, but SRS-22 Function and Self-image were significantly lower in the NF-1 group. Conclusions At an average follow-up of 14.8 years after surgery, 5 of 38 patients had died, 29 patients (76.3%) were able to lead a social life. However, HR-QOL was lower than that of AIS. Patients undergoing NF-1 scoliosis surgery require careful long-term follow-up, taking into account the possibility of reoperation due to osteolysis, malignant changes in the tumor, and vascular problems due to vascular fragility

Abstract Background This meta-analysis aimed to determine whether resistance exercise training (RET) can attenuate the loss of muscle volume and function in anti-gravitational muscles, especially quadriceps and calf muscles, during immobilization/disuse conditions. Methods A comprehensive literature search was conducted to identify randomized controlled trials comparing RET vs. no exercise during immobilization/disuse. Searches were conducted in databases including Web of Science, PubMed, EBOSCO, and Cochrane Library, without imposing a time limit until 20 March, 2023. Studies reporting outcomes related to muscle volume, MVC, peak power, concentric peak force, eccentric peak force, isometric MVC torque of knee extension, isometric MVC torque of knee flexion were included. Data were pooled using random-effects models. Results Eleven randomized controlled trials were finally included. RET elicited substantial benefits for preserving quadriceps muscle volume (n = 5, MD = 252.56, 95% CI = 151.92, 353.21, p

Abstract Background Cubitus varus, a common complication of pediatric supracondylar humerus fractures, presents with internal rotation, extension, and varus angulation. While primarily considered a cosmetic concern, it can lead to significant complications, including chronic pain, ulnar nerve palsy, and posterolateral elbow instability. This study evaluates the effectiveness of supracondylar dome osteotomy in decreasing lateral condylar prominence and improving functional outcomes in patients with cubitus varus. Methods This retrospective cohort study analyzed 65 patients under 18 who underwent dome-shaped corrective osteotomy between 2017 and 2022 at the Hospital and Rehabilitation Center for Disabled Children, Nepal. Inclusion criteria comprised patients with cubitus varus deformity greater than 10 degrees and at least six months post-trauma. Outcomes were assessed using the Mayo Elbow Performance Score (MEPS), Lateral Condylar Prominence Index (LPI), and radiological measurements of carrying angle (CA). Results The mean age at surgery was 11.77 years (± 3.76), with an average time since injury of 54.15 months (± 31.76). Post-operatively, the radiological carrying angle improved from 23.90° (± 8.84) varus to 5.14° (± 7.64) valgus. The LPI changed from 0.58 (± 16.68) preoperatively to -3.18 (± 16.39) post-operatively. MEPS improved from 89.54 (± 6.66) to 95.23 (± 5.26). Significant improvements in LPI were observed in patients older than 12 years (p = 0.00) and patients with radiological CA less than 20° (p = 0.02) and with a clinical CA less than 20°(p = 0.04). Conclusions Supracondylar dome osteotomy effectively reduces lateral condylar prominence in cubitus varus, particularly in post-pubertal patients and cases with radiological carrying angles less than 20 degrees. The procedure demonstrates good functional outcomes with acceptable complication rates, making it a viable surgical option for treating cubitus varus deformity.

Abstract Background Previous research suggests that restoring pre-arthritic alignment in fixed-bearing unicompartmental knee arthroplasty (UKA) can improve postoperative knee function. However, its applicability to mobile-bearing UKA remains unclear. This study evaluated whether patients who achieve pre-arthritic alignment following mobile-bearing UKA with the kinematic alignment technique experience superior postoperative knee function compared with those who do not. Methods A retrospective analysis was conducted on 236 knee joints that underwent UKA using kinematic alignment techniques between May 2015 and November 2017. Of these, 222 knee joints met the inclusion criteria for the study. Postoperative outcomes were assessed, with pre-arthritic alignment determined using the arithmetic hip-knee-ankle angle (aHKAA). Postoperative alignment within ± 3° of the aHKAA was classified as pre-arthritic alignment. Patients were categorized into two groups: pre-aligned and non-pre-aligned. Final follow-up occurred in September 2024, and outcome measures included the visual analogue scale (VAS) score, Hospital for Special Surgery (HSS) score, and Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales for daily living, sports, and survivorship. Additionally, the percentage of patients meeting the patient-acceptable symptom state (PASS) criteria for KOOS-related subscales was recorded. Failure was defined as conversion to total knee arthroplasty. Results Among the 222 knee joints analyzed, the average follow-up time was 8.65 years (range: 7–9 years), with an average implant survival time of 8.48 years and a total knee arthroplasty conversion rate of 2.7%. The 5-year survival rate was significantly higher in the pre-arthritically aligned group (99.4%) than in the non-pre-arthritically aligned group (92.5%) (p = 0.012). In total, 169 knees (76.13%) were classified as pre-arthritically aligned, while 53 knees (23.87%) were non-pre-arthritically aligned. postoperative VAS scores significantly improved from 6.90 ± 0.82 to 0.58 ± 0.56 (p

Abstract Background The quadriceps during activities mainly affect patellar movement in the sagittal plane. This study was to analyze the pattern of sagittal patellar tilt in patellofemoral pain (PFP) patients by four-dimensional computed tomography (4DCT). Methods Thirty-four knees of PFP patients and 34 control knees were scanned with 4DCT. Patella-patellar tendon angle (P-PTA), patella-lateral tibial plateau angle (P-LTPA), patella-screen horizontal line angle (P-SHLA), articular facet of the patella-lateral tibial plateau angle (PA-LTPA), articular facet of the patella-screen horizontal line angle (PA-SHLA), and upper margin of the patella-quadriceps tendon angle (PU-QTA) were used to evaluate the sagittal patellar tilt. Two-factor repeated-measures ANOVA was used to compare all parameters between the two groups. Results At 30°−40° of flexion, P-PTA was significantly lower in PFP group than in control group (p = 0.004). At 0°–10°, PU-QTA was significantly higher in PFP group than in control group (p = 0.027). During flexion and extension, P-SHLA and PA-SHLA were significantly higher in PFP group than in control group, but there were no significant differences in P-LTPA and PA-LTPA. From − 10° to 30°, P-PTA decreased as the knee flexion angle increased. PU-QTA, P-LTPA, and PA-LTPA also decreased as the knee flexion angle increased, but P-SHLA and PA-SHLA increased. Conclusions In PFP group, sagittal patellar tilt was abnormal, and patella showed anterior tilt relative to the screen horizontal line during active knee flexion and extension. The pattern of patellar sagittal motion during dynamic process was consistent between PFP and control groups. The characteristics of patellofemoral sagittal alignment should not be ignored when analyzing patellofemoral stability.

Abstract Background This study reports the mid-term outcomes of primary total hip arthroplasty (THA) and investigates the effect of bony ankylosis on postoperative hip function in patients with ankylosing spondylitis (AS). Methods We identified 544 primary THAs performed in 319 consecutive patients with AS (median age, 33 years) from 2012 to 2017. Survivorship of the implants, complications, and patient satisfaction were investigated. Functional outcomes were assessed by the measurement of hip flexion–extension range of motion (ROM), the Harris hip score (HHS), and the Western Ontario and McMaster Universities Arthritis Index (WOMAC). The hips undergoing THA were divided into a bony ankylosis group and a hip stiffness group based on the severity of hip involvement. The postoperative functional results of the two groups at the most recent follow-up were compared. Results Survivorship was 99.8% with a mean follow-up of 7 years (range, 5–9 years). The main complications included dislocation (5 hips, 0.9%), periprosthetic femoral fracture (15 hips, 2.7%), and infection (primary infection in 2 hips and periprosthetic joint infection in 1 hip, 0.6%). The flexion–extension ROM improved significantly with a median of 0° (0 ~ 120°) pre-operatively to 100° (30 ~ 130°) after THA (P

Abstract Background Subchondral bone cysts (SBCs) can significantly impact the outcomes of cartilage repair procedures such as autologous chondrocyte implantation (ACI). However, the etiology and progression of SBCs following ACI remain poorly understood. This case report highlights a progressively enlarging SBC following ACI using all-suture anchors, treated with autologous osteochondral transplantation (AOT). Case presentation A 58-year-old female with progressive right knee pain, varus alignment, and Kellgren-Lawrence grade 3 osteoarthritis underwent atelocollagen-associated ACI combined with medial opening wedge high tibial osteotomy. Longitudinal radiological assessment revealed bone hole enlargement corresponding to all-suture anchor sites, with one hole continuing to expand up to 15 months postoperatively, reaching a size of 11 × 13 × 13 mm. This expanding SBC exhibited a connection to the joint cavity via a tiny fissure, scant osteosclerotic rim on CT, and fluid intensity on MRI. Histological analysis of tissue obtained during subsequent AOT revealed several findings. The SBC was located at the anterior portion of the medial femoral condyle, just beneath the all-suture anchor. Osteochondral necrosis was observed surrounding the anchor site, with no evidence of foreign body reaction. The cyst was filled with a mucoid substance and featured an aggregation of foamy macrophages. A sclerotic wall indicative of a strain response was observed. Notably, the presence of osteoclasts along the adjacent bone surface indicated ongoing bone resorption. The patient underwent AOT, which resulted in confirmed bone union. Postoperative follow-up demonstrated successful integration of the osteochondral graft and improved knee function scores over three years. Conclusion This case report documents SBC formation following knee surgery with all-suture anchors and provides histological evaluation of such a cyst. The observed histological findings may contribute to our understanding of SBC pathophysiology in the context of cartilage repair procedures. This case underscores the importance of secure suturing techniques in high-stress areas and suggests the potential benefit of extended post-operative monitoring of SBC progression beyond one year. These observations may inform future strategies for the early detection of SBC formation and its progression, as well as timely intervention to prevent further joint damage in similar cases, though further research is needed to establish broader clinical implications.

Abstract Background Low back pain is the leading cause of disability worldwide with a significant socioeconomic burden; artificial intelligence (AI) has proved to have a great potential in supporting clinical decisions at each stage of the healthcare process. In this article, we have systematically reviewed the available literature on the applications of AI-based Decision Support Systems (DSS) in the clinical prevention and management of Low Back Pain (LBP) due to lumbar degenerative spine disorders. Methods A systematic review of Pubmed and Scopus databases was performed according to the PRISMA statement. Studies reporting the application of DSS to support the prevention and/or management of LBP due to lumbar degenerative diseases were included. The QUADAS-2 tool was utilized to assess the risk of bias in the included studies. The area under the curve (AUC) and accuracy were assessed for each study. Results Twenty five articles met the inclusion criteria. Several different machine learning and deep learning algorithms were employed, and their predictive ability on clinical, demographic, psychosocial, and imaging data was assessed. The included studies mainly encompassed three tasks: clinical score definition, clinical assessment, and eligibility prediction and reached AUC scores of 0.93, 0.99 and 0.95, respectively. Conclusions AI-based DSS applications showed a high degree of accuracy in performing a wide set of different tasks. These findings lay the foundation for further research to improve the current understanding and encourage wider adoption of AI in clinical decision-making.

Abstract Background Femoral head fractures result from high-energy trauma and may be associated with posterior dislocation of the hip joint. An appropriate surgical approach is essential for improving clinical outcomes and preventing complications. This study aims to compare the clinical efficacy of the modified Smith-Peterson (mS-P) approach and Ganz surgical dislocation (GSD) approach in the treatment of Pipkin I fractures. Methods We conducted a retrospective analysis of patients diagnosed with Pipkin I fractures at Pidu District People’s Hospital from June 2010 to May 2020. Of these, 11 cases were treated with the mS-P approach and 12 cases were treated with the GSD approach. All patients were followed for 12–55 months, with a mean duration of 37.7 months. Basic demographic information, perioperative-related records, postoperative complications, and outcomes at the final follow-up were compared. Functional evaluations included the Thompson-Epstein Score, the Modified Harris Hip Score (MHHS), and the Vail Hip Score (VHS). Results Overall, 21 patients were included in the study. We found that the mS-P approach was associated with a smaller incision, shorter operative time, and reduced intraoperative blood loss compared to the GSD approach (P

Abstract Background As the most prevalent fragility fracture caused by osteoporosis, increasing attention was paid to vertebral compression fractures (VCF) day by day. Percutaneous vertebroplasty (PVP) had unique advantages in treatment of VCF and was used widely. However, there were still part patients suffering from residual or unrelieved pain after the surgery. The purpose of our study was to identified the associated factors for good clinical outcomes and provide evidence for surgical strategy. Material and methods 186 patients who underwent PVP from January 2021 to January 2023 were reviewed retrospectively in the study. The patients were divided into two groups according to clinical outcomes. Preoperative general data and surgical data were collected for statistical analysis. Multivariate logistic regression analysis and the receiver operating characteristic curve were used to identify the associated factors with good clinical outcomes. Results There were statistically significant differences between two groups in volume of bone cement (p = 0.012), standardized treatment for osteoporosis (p = 0.004) and bone cement continuity (p = 0.006). The associated factors with good clinical outcomes after PVP were continuous bone cement (OR = 2.237, 95% CI = 1.191–4.201, p = 0.012), standardized treatment for osteoporosis (OR = 2.105, 95% CI = 1.089–4.068, p = 0.027) and volume of bone cement > 5.5 ml (OR = 1.271, 95% CI = 1.023–1.579, p = 0.030). Conclusion PVP effectively released the back pain of patients and was worthy of promotion. However, postoperative residual pain was an important factor that reduced the clinical outcomes. Continuous bone cement and standardized treatment for osteoporosis were guarantee of good clinical outcomes for PVP and injected bone cement > 5.5 ml might be a guarantee.

Abstract Background Legg-Calve-Perthes Disease (LCPD) is described as idiopathic avascular osteonecrosis of the capital femoral epiphysis in pediatrics. LCPD is usually present in children between 2 and 15 years and happens more frequently in boys more than girls; this study aims to compare the outcome of two surgical methods in treating LCPD. Methods We included sixty patients with unilateral LCPD who underwent Salter or femoral varus osteotomy from 2007 to 2017. Patients were followed up for at least five years. Patients’ claudication, pain, leg circumference, range of motion, lever arm ratio (LAR), neck shaft angle (NSA), migration index, vertical distance, and the presence of teardrop sign, sagging rope sign, and Trendelenburg sign were evaluated five years after surgery. Results The mean neck shaft angle, the lever arm ratio, migration index and, sagging rope sign incidence in patients undergoing femoral varus osteotomy were significantly lower than those undergoing Salter surgery; the thigh circumference was higher in patients undergoing femoral varus osteotomy than those undergoing Salter osteotomy. Conclusion There were significant differences in biomechanical indices of hip and acetabulofemoral in salter and femoral varus osteotomy; the results of the current study are highly suggestive of prioritizing femoral varus osteotomy to Salter surgery.

Abstract Background The pathogenesis of male osteoporosis (MOP) remains unclear, with the role of genetic factors attracting the attention of researchers. In the present study, we aimed to investigate critical circRNA biomarkers associated with male osteoporosis. Methods RNA-sequencing was performed to investigate the circRNA expression profiles between 3 men with osteoporosis and 3 with normal mass density. Then, shared mRNAs between host genes acquired in this present study and mRNAs acquired in previous study were identified to screen vital circRNAs associated with male osteoporosis. PPI networks of shared mRNAs were constructed and the hub genes in the PPI networks were identified with CytoHubba, a plugin in Cytoscape software (3.10.1). Finally, a ceRNA network of four circRNAs derived from three hub genes was constructed. Validation experiments were performed on selected circRNAs and related miRNAs in this ceRNA network using peripheral blood clinical samples. Results In total, 657 circRNAs were detected in male osteoporosis. The shared mRNAs were significantly enriched in the metabolic pathways, RNA transport, Ubiquitin mediated proteolysis and Amyotrophic lateral sclerosis. Then, three genes, including SETD2, ATM and XPO1, were identified as hub genes with four algorithms. Ultimately, the ceRNA network, involving 4 circRNAs, 40 miRNAs, and 592 mRNAs, was obtained. Using 35 clinical samples, three potential circRNAs and three miRNAs associated with male osteoporosis were selected for validation. It was ultimately found that three miRNAs were upregulated in MOP, while hsa-circ-9130, novel_circ_0014940 and hsa-circ-0054894 were upregulated, hsa-circ-2484 and novel_circ_0033084 were downregulated in patients with MOP. Conclusion We emphasized the roles of several significantly up- and down-regulated circRNAs and four circRNAs derived from three hub genes in male osteoporosis. Differences in expression were confirmed for three miRNAs and five circRNAs in the ceRNA network among patients with male osteoporosis.

Abstract Background The aim of the study is to compare the mechanical stability of posterior malleolar fractures fixed with different screw types and locking plates in the management of trimalleolar ankle fractures using the finite element (FE) method. Methods An FE model containing the distal tibia, fibula, talus, and calcaneus was created based on the computed tomographic images of a healthy man without any musculoskeletal disorders. The medial, lateral, and posterior malleoli were segmented using three virtual planes to create a trimalleolar fracture model, with the posterior malleolar fracture fragment comprising approximately 30% of the articular surface. Four different fixation approaches, including two partial thread cannulated screws (PTS), two full thread cannulated screws (FTS), and L-shaped (LLP) and T-shaped (TLP) locking plates with screws, were used to fix the posterior malleolar fracture. Two partial thread screws and a locking plate along with screws were used to fix the medial and lateral malleolar fractures, respectively. Two different loading conditions, namely static axial load and Achilles tendon force, were considered in the simulation. Results Under axial load, the maximum gap opening distance of the posterior malleolar fracture with screws only was obviously larger than that with locking plates. The maximum gap distance was 0.12 mm, 0.08 mm, 0.04 mm, and 0.05 mm in the PTS, FTS, LLP, and TLP, respectively. Under Achilles tendon force, the maximum gap opening distance were 0.12, 0.1, 0.03, and 0.1 mm, in the PTS, FTS, LLP, and TLP, respectively, under Achilles tendon force. Conclusion The results suggest that locking plates offer greater stability and reduce the fracture gap opening for posterior malleolar fractures involving 30% of the distal tibial articular surface in the fixation of trimalleolar ankle fractures.

Abstract Background The best stem type and location for femoral shortening in high-riding developmental dysplasia of the hip (DDH) in not clear. We evaluated the morphology of the proximal femur on EOS™ images, focusing on the anatomical landmarks and measurements relevant to the stem selection in high-riding DDH. Our goal is to identify and define the differences in the anatomy of the proximal femur between patients with Crowe type IV DDH and normal individuals, in order to determine the appropriate neck cut location in these patients to increase the chances of successfully using a wedge femoral stem. Methods EOS™ images of 40 hips with Crowe type-IV DDH and 40 normal hips were included. The distances between the tip of the greater trochanter and vastus ridge (GT-VR), vastus ridge and proximal border of lesser trochanter (VR-LT), greater- and lesser trochanters (GT-LT), base width of the LT, and the proportion of these distances to the femoral length were evaluated. Canal Flare Index (CFI) was also measured, at two different levels. Results The mean GT-LT index was not different between the two groups (p = 0.46). The GT-VR index was smaller in the case group (p

Abstract Background The Caprini risk assessment model (RAM) is a classical score that evaluates the risk of developing venous thromboembolism (VTE) aimed at patients with lower extremity fractures (LEF). However, the influencing factors of RAM pay more attention to clinical characteristic variables and recognized thrombophilia markers such as prothrombin, while ignoring the influence of other laboratory indicators on thrombosis. This is the first paper to screen predictive risk factors associated with VTE to modify the Caprini model and determine its diagnostic value. Results and methods We included 953 LEF patients from January 2019 to December 2021 and randomized them in a 7:3 ratio into a training set (n = 667) and a validation set (n = 286). Logistic regression and LASSO regression were used to screen for independent predictors of patients in the training set. Logistic regression screened for: age (OR 1.04, 95% CI 1.02—1.06), D-dimer (OR 1.06, 95% CI 1.03—1.08), Caprini (OR 1.17, 95% CI 1.08—1.27) and fasting blood glucose (FBG) (OR 1.18, 95% CI 1.03—1.35), which also appeared in the LASSO seven-factor model. In addition to Caprini and age, FBG and D-dimer may be important predictors of deep vein thrombosis in patients with LEF. Therefore, we constructed three models. caprini + D-dimer, caprini + FBG, and caprini + D-dimer + FBG. We compared them with caprini alone. Caprini + FBG + D-dimer showed the greatest ROC (0.784, 95% CI 0.730–0.837, Delong test P = 0.002 vs. Caprini’s ROC). D-dimer and FBG have a significant increase in the predictive effect for predicting DVT in terms of NRI (59.98% improvement, P

Abstract Background Earthquakes frequently cause injuries to the musculoskeletal system. Studies conducted after earthquakes often report on injured limbs, fractures, and surgeries. This study aimed to enhance preparedness for future earthquakes by acquiring knowledge about the prevalence of fractures and the relationship between fracture types and injury mechanisms. Methods A retrospective analysis was conducted on medical records of patients with fractures admitted to our hospital following the 2023 Kahramanmaraş Earthquake. Patients with fractures resulting from traffic accidents or other causes unrelated to earthquakes were excluded. The recorded data included age, gender, fracture site, fracture type, mechanism of injury, date, duration of surgery, and peak creatine kinase (CK) level. The injury mechanisms were classified into four main categories: injured by falling objects, falling while running, falling from height, and being trapped under rubble. The study investigated the relationship between fractures and other factors. Results The study included 185 patients with a mean age of 39.62 ± 20.83 years. The most frequent mechanism of injury was being trapped under rubble. In total, there were 214 fractures, with pelvic fractures being the most common (21.50% of all fractures). Tibia fractures were the most common fractures in the lower extremities (15.89%). Women had a significantly higher occurrence of pelvic fractures (33.3%) compared to men (14.5%) (p = 0.003). The frequency of pelvic fractures significantly increased as age decreased (p = 0.007). Patients with pelvic fractures had a significantly greater peak CK concentration (p = 0.006). Open fractures were more common in the first few days, and Kirschner wires were the first treatment applied at a mean of 74 h and external fixators at a mean of 94.3 h. Conclusion Injuries from falling objects from roofs and jumping from heights are important in earthquakes. In addition to lower extremity fractures, pelvic fractures are common in earthquake disasters. Most pelvic fractures are simple lateral compression fractures and it is important to follow the patients for crush syndrome in the first days instead of focusing on definitive fracture treatment. Open fractures should be prioritized for fracture surgery within the first few days. External fixators and Kirschner wires are recommended. Closed fractures should be treated conservatively and definitive surgical procedures should be postponed to the following weeks.

Abstract Background Benefits of partial weight bearing (PWB) in operated extracapsular hip fractures (ECF) have not been proved. We have assessed influence of PWB on long-term survival and the final mobility achieved, dependence and mortality-related factors. Methods Retrospective cohort study of osteoporotic ECF in ≥ 65-year-old patients who underwent surgery with trochanteric Gamma3 nails in 2014 (n = 218), followed in the long-term (consolidation or stabilisation). According to Baumgaertner-Fogagnolo classification (138 good, 71 acceptable and 9 poor) a postoperative protocol was applied. 116 cases bore weight before discharge (Immediate Partial Weight Bearing, IPWB = 116; Not-IPWB = 102), and 118 did it after a month (Early PWB, EPWB = 118; Not-EPWB = 100). Variables were collected from medical records and complementary studies. We used FMS (Fracture Mobility Score) and the National Mortality Database from the Spanish Ministry of Health at > 5 years. EPWB and Not-EPWB were comparable, except for hospital stay and dependence. We used the Cox method for mortality.

Abstract Introduction The tensor fasciae suralis is an aberrant muscle frequently identified in cadaveric studies and MRI studies; however, it has been rarely reported in clinical studies. We present a case of recurrent popliteal pain in a young adult male and our experience with its diagnosis and treatment. Case presentation A 20-year-old active-duty soldier presented with recurrent right popliteal pain, initially triggered by intense physical activity during military training. Pain subsided with rest but recurred after strenuous exercises, such as soccer. Examination revealed a palpable soft mass with mild tenderness and swelling in the popliteal region. Ultrasonography identified an aberrant tensor fasciae suralis muscle with perifascial edema, originating from the semimembranosus muscle and attaching to the fascia of the medial gastrocnemius. MRI confirmed the findings with edema at its boundary. Conservative management led to symptom improvement. A follow-up ultrasound six months later showed resolution of swelling. Conclusion This case highlights the importance of recognizing the TFS muscle to avoid misdiagnosis and unnecessary interventions.

Abstract Background Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (sJIA), driven by excessive activation of T cells and macrophages, resulting in a cytokine storm. IFN-γ and IL-18 play crucial roles, with monocyte and macrophage hyperresponsiveness to IFN-γ amplifying MAS-related inflammation. Familial Mediterranean Fever (FMF), an autosomal recessive disease, is characterized by recurrent fever episodes due to MEFV gene mutations. Despite intense inflammation in FMF, MAS is rare. This study aimed to compare in vitro responsiveness of peripheral blood mononuclear cells (PBMCs) to IFN-γ between sJIA/MAS and FMF patients. Methods Five sJIA/MAS and five FMF patients were included. PBMCs were stimulated in vitro with IFN-γ for 45 min. Levels of IFN-γ-induced chemokines CXCL9, CXCL10, and IL-18 in supernatants were measured using cytometric bead arrays before and after stimulation. Results PBMCs from MAS patients produced higher baseline CXCL9 levels compared to FMF patients in a flare, with differences increasing post-IFN-γ stimulation. IFN-γ stimulation also upregulated IL-18 production in MAS patients but not in FMF patients. Conclusion Enhanced responsiveness to IFN-γ distinguishes sJIA/MAS from FMF patients, which may explain the lower occurrence of MAS in FMF.

Abstract Background Systemic sclerosis encompasses a range of disorders characterized by vascular and connective tissue abnormalities. Although rare in pediatrics, juvenile systemic sclerosis (jSSc) is a severe and life-threatening condition that significantly impacts children’s development. This study aimed to provide an overview of JSSc in France over the past decade. Methods Patients with disease onset before the age of 16 were included following a request for observations sent via email to member practitioners of the SOFREMIP (French pediatric Rheumatology society). Results Our study included 18 patients from 8 different French centers. While our cohort exhibited a balanced distribution between limited and diffuse subsets of the disease, we observed a higher prevalence of the diffuse subset in children above the age of 10. Skin induration was the most reported symptom, while Raynaud’s phenomenon was present in 61% of the children at initial clinical evaluation. All children tested positive for antinuclear antibodies, with anti-Scl70 being the most common specificity, even among children with limited cutaneous subsets. Interestingly, we found a high sensitivity of the ACR / EULAR criteria for diagnosing jSSc in our cohort with 83% of patients meeting these criteria, except for 3 children who presented with overlap syndromes. Despite the frequent use of corticosteroids at the onset, no deaths or renal crises were reported. Three patients received treatment with biological agents, specifically Rituximab and Tocilizumab. Conclusion JSSc is a rare but severe disease requiring rapid, specialized, and multidisciplinary care. Further studies are needed to validate proper diagnosis criteria including overlap syndromes and evaluate the use of biotherapies in children.

Abstract Background Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) frequently overlap, with each disease potentially presenting as a manifestation of the other. The strong relationship between PMR and GCA raises the question of whether it is a “co-occurrence of different diseases” or a “common spectrum of inflammatory diseases.” The objectives of the current study were to assess the applicability of using ultrasound (US) and clinical data as a monitoring tool to identify PMR patients with subclinical GCA and determine possible predictors of GCA among PMR patients. Results One hundred eight PMR patients and 62 GCA patients were included in this study. The study found that 20.4% of the PMR cohort had subclinical GCA, which later progressed to classical GCA, while 31.5% experienced a PMR relapse. The presence of intimal media thickening of the temporal/axillary artery at baseline was a very early predictor of GCA development; the OGUS score was significantly higher in the PMR group who developed GCA than the standard GCA cohort (p

Abstract Background Fibromyalgia is characterized by widespread musculoskeletal pain and tenderness. It is also frequently associated with mood disorders, tiredness, sleep disturbances, and cognitive dysfunction. Repetitive transcranial magnetic stimulation (rTMS) is an emerging nonpharmacological therapeutic option for fibromyalgia. rTMS involves an electromagnetic coil placed on the scalp that is rapidly turned on and off to generate short magnetic pulses to the brain (2). rTMS can reduce chronic pain by triggering inhibitory neural pathways at the level of the dorsal horn of the spinal cord. It can improve motor function and alleviate psychiatric symptoms, including depression and anxiety, in many diseases (7). Aim of the work The study aimed to evaluate the role of repetitive transcranial magnetic stimulation (rTMS) in treating fibromyalgia. Results Highly significant improvement in feel-good and work-missed scores by FIQ being lower in the case group compared to the control group (p-values 0.008 and 0.003 respectively). On comparing the control and case groups regarding anxiety and depression using the HADS questionnaire and fatigue assessment using the SF36 questionnaire after rTMS sessions, there was a statistically significant lower depression score in the case group compared to the control group (p-value of 0.024), and statistically significant higher energy/fatigue scores in the case group compared to the control group with (p-value = 0.004). Conclusion This study demonstrated that rTMS relieved pain, reduced anxiety, depression, and fatigue and enhanced quality of life in patients with fibromyalgia.

Abstract Background Transcranial magnetic stimulation (TMS), a non-invasive method of electrically stimulating neurons in the cerebral cortex, can change neuronal and cortical activity locally and remotely by applying localized magnetic fields. TMS can be used to treat a variety of disorders and improve functional impairments by stimulating the motor cortex. Chronic obstructive pulmonary disease (COPD) is an invalidating disease that primarily compromises both respiratory and motor functions either during the acute or the chronic phase. In COPD, the diaphragm may contribute to respiratory decompensation This study aims to use TMS as a therapeutic tool in addition to conventional rehabilitative programs in COPD patients and assess this application using diaphragmatic ultrasonography (US) and 6-min walking test (6MWT). Result A case–control study with 60 COPD patients divided into three equal groups. The control group (group A) received the conventional rehabilitation program, group B received additional subcortical magnetic stimulation of the phrenic nerve roots in the neck, and group C received TMS of the diaphragmatic motor cortex area in addition. Before treatment, there was no significant difference between the groups in diaphragmatic US assessment (diaphragmatic thickness (DT) and diaphragmatic mobility (DM) or 6MWT (P > 0.05). After treatment, there was a significant improvement in groups A and B, while a highly significant improvement in group C. Conclusion The application of cortical or subcortical TMS to COPD patients improves diaphragmatic function and daily activities significantly. These advancements allowed TMS to be considered as a therapeutic tool in the COPD rehabilitation program.

Abstract Objective The aim of this study was to investigate the correlation between age, red cell distribution width (RDW) levels, and 180-day and 1-year mortality in giant cell arteritis (GCA) patients hospitalized or admitted to the ICU. Methods Clinical data from GCA patients were extracted from the MIMIC-IV (3.0) database. Logistic and Cox regression analyses, Kaplan–Meier (KM) survival analysis, restricted cubic spline (RCS) analysis, and mediation effect analysis were employed to investigate the association between age, RDW levels, and 180-day and 1-year mortality in GCA patients hospitalized or admitted to the ICU. Predictive models were constructed using machine learning algorithms, and SHapley Additive exPlanations (SHAP) analysis was applied to evaluate the contributions of age and RDW levels to mortality in this patient population. Results A total of 228 GCA patients were eligible for analysis. Our study identified both age and RDW levels (both with OR > 1, P 1, P

Abstract Background In SELECT-AXIS 2, upadacitinib improved the signs and symptoms of active non-radiographic axial spondyloarthritis (nr-axSpA) through 52 weeks versus placebo and was well tolerated. Here, we evaluated the efficacy and safety of upadacitinib through 2 years. Methods The study enrolled eligible adult patients with a clinical diagnosis of nr-axSpA who met the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria and had objective signs of active inflammation on magnetic resonance imaging (MRI) of sacroiliac joints and/or high-sensitivity C-reactive protein. Patients were randomized 1:1 to receive double-blinded treatment with upadacitinib 15 mg once daily (QD) or placebo for 52 weeks, after which all patients received open-label treatment with upadacitinib 15 mg QD. Efficacy results over 104 weeks were reported as observed (AO) and either AO with non-responder imputation (AO-NRI; binary endpoints) or AO with mixed-effect model for repeated measures (continuous endpoints). Treatment-emergent adverse events (TEAEs) were summarized through week 104. Results Of 313 patients randomized and treated, 224 (continuous upadacitinib n = 117; placebo/upadacitinib n = 107) completed 104 weeks of treatment. In patients who received continuous upadacitinib, sustained improvement was observed through 2 years of treatment across efficacy endpoints including disease activity, pain, function, enthesitis, quality of life, and MRI measures of inflammation. At week 104, 57.1%, 59.0%, and 31.4% of patients achieved ASAS40 response, and low disease activity and inactive disease (as defined by Axial Spondyloarthritis Disease Activity Score), respectively (AO-NRI); week 104 outcomes were generally similar in patients who initially received placebo and were switched to upadacitinib at week 52. In total, 286 patients were exposed to ≥ 1 dose of upadacitinib, comprising 378.3 patient-years (PY) of exposure. Upadacitinib was generally well tolerated, with exposure-adjusted event rates (EAERs) for TEAEs, serious adverse events (AEs), and AEs leading to study drug discontinuation of 207.5, 8.7, and 5.3 events/100 PY, respectively. EAERs of TEAEs of special interest were broadly consistent with those reported through week 52. Conclusions Treatment with upadacitinib demonstrated consistent improvement and maintenance of treatment effect across efficacy endpoints through 2 years; no new safety signals were identified with additional exposure. Trial registration NCT04169373.

Abstract Background Dermatomyositis (DM) is an autoimmune disease with a high rate of disability and mortality especially in DM with concurrent interstitial lung disease (DM-ILD). Little is known about inflammatory signature and heterogeneous endotypes of DM. Objective We aimed to illustrate the systemic inflammatory signature of DM and define an ILD-associated endotype. Methods Olink proteomic analysis was performed on serum samples obtained from DM patients (n = 32), DM patients with ILD (n = 16), and healthy controls (n = 19). Transcriptomic data from skin samples was utilized to assess immune infiltration and investigate the correlation between protein and mRNA levels of biomarkers. Additionally, the prognostic value and clinical significance of identified biomarkers were validated through follow-up studies of DM patients and immunofluorescence analysis of skin tissues. Results Proteomic data revealed the inflammatory signature of DM, with GO and KEGG enrichment analyses identifying chemotaxis-related pathways. Transcriptomic analysis of skin samples indicated upregulated inflammatory responses and M1 macrophage infiltration in DM. Two chemokines, CXCL10 and CXCL11, were identified as highly associated with immune infiltration and DM progression. Conclusions Our data suggest that serum CXCL10 and CXCL11 reflect the inflammatory burden of DM. The identified biomarkers hold promise for determining an ILD-associated endotype and predicting clinical outcomes, thereby paving the way for timely management of DM and prevention of complications.

Abstract Introduction Further investigation is required to determine the etiology of systemic lupus erythematosus (SLE). The aim of this study is to assess the presence of miR-223 within neutrophils in SLE and investigate its impact on the expansion of Th17 cells. Methods Experiments were performed in MRL/lpr mice, which were divided into control and miR-223 knockdown (miR-223-) group. We assessed miR-223 expression within neutrophils and Th17 expansion in MRL/lpr mice and patients with SLE using RT-PCR, luciferase reporter assay, Elisa, flow cytometry analysis. Signaling pathway, RT-PCR and western blot were conducted to elucidate the mechanism by which miR-223 within neutrophils expands Th17. Results We initially identified miR-223 as a pivotal factor in the pathogenesis of SLE in both MRL/lpr mice and SLE patients. Subsequently, knockdown of miR-223 led to a significant reduction in Th17 expansion in MRL/lpr mice. Moreover, inhibition of miR-223 effectively attenuated the recruitment and activation of neutrophils in SLE. Furthermore, we found rb6-8c5 treatment alleviated lupus symptoms of MRL/lpr mice and reduce the level of Th17. Finally, we elucidated that neutrophils potentiate the induction of Th17 through the activation of thePI3K-AKT pathway mediated by miR-223 during SLE-associated Th17 expansion. Conclusion MiR-223 within neutrophil axis contributes to Th17 expansion by PI3K-AKT pathway in SLE, and miR-223 could be a therapeutic target of SLE.

Abstract Background Controlling disease activity and improving physical function would be more difficult in patients with late-onset rheumatoid arthritis (LORA) who have chronic lung disease (CLD) at baseline. Our aim was to evaluate 5-year outcomes of following a treat-to-target (T2T) strategy targeting low disease activity (LDA) in LORA with CLD. Methods Data from 197 methotrexate (MTX)-naïve LORA patients (mean age 74.4 years) from a prospective, monocentric registry were analyzed. Patients were treated with MTX if they had one or more poor prognostic features. If they had interstitial lung disease (ILD), tacrolimus could be administered instead of MTX at the discretion of the attending physician. If patients exhibited no response according to the European League Against Rheumatism criteria at week 12 or had not achieved LDA by week 24, biological disease-modifying antirheumatic drugs (bDMARDs) were started targeting LDA. The primary outcomes were the 5-year simplified disease activity index (SDAI) remission and Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 by non-responder imputation analysis. Secondary outcomes were serious adverse events (SAEs). Results Of the 197 LORA patients, 47 had CLD at baseline. The proportion of patients using MTX at baseline was significantly lower in those with than without CLD. Tacrolimus was initiated in 25.5% of the CLD group. The proportion of patients on bDMARDs was higher in those with CLD at year 5. Achievement of SDAI remission at year 5 was 29.8% in patients with CLD and 44.0% in those without CLD (p = 0.555). Achievement of HAQ-DI ≤ 0.5 at year 5 was 36.2% and 45.3% in patients with and without CLD, respectively (p = 0.939). Non-adherence to T2T due to comorbidities or adverse events was observed in 34.0% and 18.7% of the patients with and without CLD, respectively (p = 0.027). Infections requiring hospitalization, deterioration of extra-articular manifestations and fractures were more frequently reported as SAEs in patients with CLD, and multivariable analysis showed that patients with CLD had a higher risk of developing these SAEs (adjusted hazard ratio:2.53, 95% CI 1.60–4.00, p

Abstract Background Systemic juvenile idiopathic arthritis (sJIA) is the most severe subtype of JIA, with a combination of diverse clinical manifestations and a variable clinical course. A comprehensive understanding of molecular signatures at the systems level and the discovery of molecular subtypes are the initial steps toward personalized medicine in sJIA. Methods A blood transcriptomic dataset was collected from patients with systemic JIA (sJIA) (n = 168), polyarticular JIA (n = 254), oligoarticular JIA (n = 96), enthesitis-related arthritis (n = 40), and healthy controls (n = 220). Gene expression profiles were filtered for differentially expressed genes and unsupervised clustering, gene set enrichment, and network-based centrality analyses. The molecular signatures of three novel sJIA subgroups (designated as C1, C2, and C3) were investigated, focusing on their distinct features and treatment responses. Results Neutrophil degranulation and the IL-1 signaling pathway were the shared key processes for the three subgroups. Proinflammatory signals, including TNF, IL-6, TLR, and G-CSF signaling pathways, were identified with variation across the subgroups. C1 was the most inflammatory subset with a high-risk profile for macrophage activation syndrome. The C2 subset had the most activated IL-1 and IL-18 signaling pathways. C2 and C3 have higher levels of interferon-stimulated signatures. In a canakinumab-treated dataset, treatment response was correlated with IL1B expression and NF-κB signaling pathway, and neutrophil activation-associated processes were effectively suppressed in a good responder group. GSK3B and p38 MAPK inhibitors showed a significant counteracting effect on the perturbed gene expression of sJIA. Conclusions Neutrophil activation was the key feature in active sJIA. The three molecular subtype scheme enables the formulation of precision medicine strategies in sJIA.

Abstract Objective To investigate the effect of glucocorticoids (GCs) on the risk of readmission in menopausal women with knee osteoarthritis (OA). Information and methods The study cohort comprised 80 menopausal women with knee OA treated at a tertiary hospital affiliated with Shanxi Medical University and who underwent follow-up between September 2018 and September 2023. Then the collected longitudinal monitoring data were used to construct a semi-variable coefficient shared Gamma frailty model (VCSGF). Based on the results of this model, we explored the impact of GCs on menopausal women with knee OA and made risk predictions. Results The mean patient age at study entry was 64.7 ± 9.3 (range 50–82 years). And during the research, patients were admitted to the hospital a mean of 2.4 ± 1.8 times (range 1–11 times). Compared to patients who have not used the drug, the risk of early readmission in patients who have used GCs was reduced by 96% (HR = 0.04, 95%CI: 0.006 ~ 0.284, $$\:P

Abstract Background Spinal infections (SI) typically manifest with and pose a growing medical challenge. However, current evidence for treating SI is limited and inconclusive. Our aim was to assess the effectiveness and safety of percutaneous endoscopic disc decompression (PEDD) for SI. Methods On 20 October 2023, we searched the EMBASE, PubMed, Cochrane Library, China Biology Medicine Disc, China National Knowledge Infrastructure, and Wanfang databases for eligible studies. Cohort studies on SI treated with PEDD, reporting relevant effectiveness or safety outcomes. We assessed study quality using a modified Newcastle–Ottawa Scale and conducted a random-effects meta-analysis to calculate pooled results. Results Overall, 36 studies involving 925 patients were included. Erythrocyte sedimentation rate levels decreased significantly at 1-week postoperatively compared with preoperative levels (mean difference [MD] = − 13.48 [95% CI − 15.65 to − 11.31]) and continued to decrease over 3 months. Similarly, the c-reactive protein (CRP), visual analogue scale, and oswestry disability index scores significantly reduced postoperatively. The rates of excellent or good MacNab classification were 92.6% (95% CI 84.1–98.1%). Microbiological diagnostics revealed a 71.7% (95% CI 65.5–77.6%) positive rate in tissue cultures, surpassing blood cultures (odds ratio [OR] 2.72 [95% CI 1.01–7.30]). The rates of complication, reoperation, and mortality were 4.1% (95% CI 1.5–8.0%), 8.6% (95% CI 4.3–14.3%), and 1.7% (95% CI 0.4–4.1%), respectively. Subgroup analyses demonstrated a significantly lower reoperation rate in the group that discontinued antibiotics based on a normal CRP than in the fixed-duration group (2.7% [95% CI 0.3–7.7%] vs 20.1% [95% CI 14.5–26.3%], p = 0.0002). Conversely, ambulation 1 day postoperatively was associated with a higher reoperation rate than ambulation within 5–14 days (16.2% [95% CI 9.3–24.6%] vs 1.1% [95% CI 0.0–6.0%], p = 0.0060). Conclusion Our meta-analysis suggests that PEDD is a potentially effective and safe intervention for SI. Optimizing antibiotic discontinuation and postoperative care strategies may contribute to reducing reoperation rate. However, these findings require further validation from controlled studies.

Abstract Background An iatrogenic lateral hinge fracture is a common intraoperative problem that may occur during medial open wedge high tibial osteotomy (MOWHTO). This study aims to assess the significance of using additional crossing lateral K-wires and their advantage in protecting the lateral hinge during MOWHTO procedures. Methods The data of patients fulfilling the inclusion criteria who underwent MOWHTO between May 2021 and August 2022 were retrospectively evaluated. One group had additional lateral hinge crossing K-wires (+ MOWHTO group), while the other did not (-MOWHTO group). Both groups were assessed for rate of intraoperative lateral hinge fractures, knee injury and osteoarthritis outcome score − 12 (KOOS-12), medial proximal tibial angle (MPTA), time of union, and time to return to work. The outcomes were compared using the independent T-test for continuous variables and the Fisher Exact test for nominal variables. A p-value of

Abstract Background Postoperative venous thromboembolism (VTE) following hip arthroscopy is associated with increased hospital readmissions and significant medical costs. However, the risk factors for postoperative VTE after hip arthroscopy remain a topic of debate. In this study, we aimed to quantitatively and comprehensively identify risk factors for postoperative VTE after hip arthroscopy, providing evidence for the development of clinical prevention strategies. Methods A systematic search was conducted using PubMed, Embase, Web of Science, Scopus, and the Cochrane Library databases from their inception to December 10, 2024. The search was limited to English-language articles that evaluated risk factors for postoperative VTE after hip arthroscopy. The quality of the included studies was assessed using the Newcastle–Ottawa Scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relationship between various risk factors and the incidence of postoperative VTE after hip arthroscopy. This protocol was registered with PROSPERO (registration number: CRD42024601636). Results Five studies, encompassing 71,815 patients who underwent hip arthroscopy, were included in the meta-analysis. The analysis identified obesity (OR: 1.41, 95% CI: 1.23–1.61), smoking (OR: 1.23, 95% CI: 1.04–1.45), and age > 45 years (OR: 1.49, 95% CI: 1.03–2.15) as significant risk factors for postoperative VTE. Conclusion Obesity, smoking, and age > 45 years are found to be significant risk factors for postoperative VTE after hip arthroscopy.

Abstract Background Cup anteversion after primary total hip arthroplasty (THA) with monobloc dual mobility cups (DMC) is difficult to measure on anterior-posterior (AP) pelvic radiographs because of the implant radiopacity and cup design which do not allow for an accurate visualization of the radiographic projection of the cup equatorial rim and the femoral head. This study aims to radiographically investigate on the reliability and accuracy of different measurement methods for cup anteversion in monobloc DMC THA, by comparing a novel titanium cup with conventional cup designs. Methods 97 THAs with a monobloc 3D-printed titanium DMC were radiographically assessed for cup radiographic anteversion (RA) one month postoperatively. RA were measured by three blinded observers through Lewinnek, Woo-Morrey methods and an open access mathematical software (GeoGebra), used as reference method. Intra- and interobserver reliability of RA measurements were evaluated for each method using intraclass correlation coefficient (ICC). Accuracy was assessed comparing Lewinnek and Woo-Morrey methods with GeoGebra. Moreover, further 98 THAs with conventional different brand DMC were radiographically assessed as control group by using the same methods. Results ICC for intra- and interobserver reliability for RA measurements with GeoGebra, Lewinnek and Woo-Morrey methods were 0.975–0.980, 0.978 − 0.965, and 0.979 − 0.958, respectively, for the titanium DMC group. Lewinnek resulted more accurate for RA than Woo-Morrey, differing by + 0.4° (p = 0.06) and + 4.4° (p

Abstract Objective To compare the accuracy and safety of implanting cervical pedicle screws (CPS) between orthopedic surgical robot-assisted technique and traditional fluoroscopy-assisted free-hand technique. Methods Retrospective analysis of 95 patients treated with posterior cervical spinal surgery using either Tianji orthopedic surgical robot-assisted or traditional fluoroscopy-assisted free-hand pedicle screw implantation technology from March 2021 to March 2024, including 44 cases in the orthopedic surgical robot group and 51 cases in the traditional fluoroscopy group. Results Compared with the traditional fluoroscopy group, the orthopedic surgical robot group had better accuracy in screw implantation that is, a higher acceptable rate of screws (p = 0.0083). In addition, compared with the traditional fluoroscopy group, postoperative hospital stay was shorter in the orthopedic surgical robot group (p = 0.0447), but operation duration was longer (p = 0.0038). There was no significant difference in intraoperative blood loss between groups (p = 0.0872). There were 2 cases of cerebrospinal fluid leakage and 1 case of decreased left handgrip strength in the traditional fluoroscopy group, while only 1 case of cerebrospinal fluid leakage occurred in the orthopedic surgical robot group. Conclusions In this retrospective study, the accuracy of spine surgery with CPS implantation assisted by orthopedic surgical robot is often superior to that of spine surgery using traditional fluoroscopy-guided CPS implantation technique, while maintaining comparable safety.

Abstract Purpose This study aimed to evaluate the outcomes of Pelnac assisted by vacuum sealing drainage in managing severe avulsion injuries of the fingers. Methods This prospective study was conducted from May 2017 to September 2023, involving 12 consecutive patients with severe avulsion injuries of the fingers. Patients underwent single-stage or two-stage procedures employing Pelnac assisted by vacuum sealing drainage (VSD) for the management of severe avulsion injuries of the fingers. Post-operative follow-up was routinely scheduled, and aesthetic and functional outcomes, sensory recovery, complications were recorded. Results Twelve patients were included in the analysis, consisting of 9 males and 3 females, with a mean age of 30.6 ± 11.0 years. All patients presented with severe damage to tendons and deep tissues, as well as varying degrees of bone exposure and injury, with average defect area of 36.9 cm² (range, 11 to 180 cm²). At the final follow-up (mean, 14 months; range, 12 to 29 months), the average score on the Fingertip Injuries Outcome Score (FIOS) was 14.3 (SD 3.9, range 10 to 22), with 6 patients achieving excellent result, 4 classified as good and 2 as fair. Patients reported an average satisfaction score of 74.0 (SD 11.6; range 51 to 94) regarding the aesthetic appearance. The average score on the Vancouver Scar Scale score was 2.3 (SD 2.1, range 1.0 to 7.4). Ten patients reported normal or near-normal sensation, while 2 patients experienced slight sensory loss. The average score on the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire was 13.2 (SD 8.5, range 0 to 47). No infections or hematomas were reported during hospitalization or after discharge. Conclusion Pelnac, assisted by VSD, proved to be an effective approach for managing severe avulsion injuries of the fingers. This approach can be considered as a viable alternative for addressing severe injuries or complex wound conditions.

Abstract Background The Lafontaine criteria are the most commonly cited criteria for predicting unstable distal radius fractures. However, formal validation of the performance of these criteria remains limited. Therefore, we aimed to evaluate the Lafontaine criteria as a diagnostic prediction rule for distal radius fractures, assess the inter-rater reliability and predictive ability of various parameters for distal radius instability, and develop new criteria for fracture instability using reliable and highly predictive factors. Methods This retrospective study included 274 adult patients with acute distal radius fractures treated with closed reduction and immobilisation between January 2019 and December 2022. Patients who underwent immediate surgery, were lost to follow-up before 4 weeks, or had unacceptable alignment after reduction were excluded. The Lafontaine criteria were validated using the area under the receiver operating characteristic curve (AUROC). Criteria with an AUROC > 0.7 were considered acceptable. The criteria were updated using risk factors with stronger associations in the multivariable logistic regression analysis, and the inter-rater reliability of potential predictors was evaluated. Results The median age of the patients was 63 years; 78% were female. Redisplacement occurred in 39% of the cases. The AUROC for the Lafontaine criteria was 0.65 (95% confidence interval [CI] 0.57–0.74). Multivariable logistic regression showed that age 56–74 years (odds ratio [OR] 3.92, 95% CI 1.82–9.16, p 74 years (OR 6.34, 95% CI 2.66–16.2, p 3 mm (OR 5.78, 95% CI 3.11–11.2, p 74 years), associated ulnar fractures, and initial radial shortening > 3 mm was found to have moderate discrimination; however, further research is warranted to improve the prediction and measurement reliability of fracture instability.

Abstract Background This study aimed to evaluate the clinical efficacy and learning curve of percutaneous endoscopic cervical discectomy (PECD) in treating patients with symptomatic cervical spondylotic radiculopathy (CSR). Methods A total of 105 patients with single-segment symptomatic CSR treated between January 2020 and January 2022 were retrospectively analyzed and divided into PECD and ACDF groups based on the surgical approach. Patient demographics, operation time, estimated intraoperative blood loss, complications, postoperative hospital stay, total hospitalization cost, neck dysfunction index (NDI), arm and neck visual analog scale (VAS) scores were compared and analyzed. The learning curve of the PECD group was assessed using cumulative sum (CUSUM) analysis. Results There was no statistically significant difference in baseline data between the two groups (P > 0.05). The PECD group had shorter operative time, smaller incision length, less estimated intraoperative bleeding, lower total hospitalization costs, and shorter postoperative hospital stays compared to the ACDF group (P 0.05). There were also no significant differences between the PECD and ACDF groups in the number of intraoperative fluoroscopies, complications, or surgical success rates (P > 0.05). As more cases accumulated, a trend toward shorter operative times was observed in the PECD group. When grouped according to the learning curve, with the 23rd case as the cutoff point, there was no significant difference in clinical outcomes between the learning phase and proficient phase groups (P > 0.05). Conclusions PECD is a safe and effective procedure for treating single-segment CSR, offering clinical outcomes comparable to ACDF. PECD has a notable learning curve, requiring beginners to perform 23 cases to reach proficiency. However, longer operative times do not negatively impact preclinical outcomes. Trial registration Retrospectively registered.