OBJECTIVE: The objective was to investigate the specific role and the regulatory mechanism of vascular endothelial growth factor (VEGF) during wound healing in diabetic foot ulcer (DFU).
METHODS: Streptozotocin-induced diabetic rats were used to establish a DFU animal model. VEGF and Axitinib (a specific inhibitor of VEGFR) were used for treatment in vivo. The wounds at different time points were imaged and histological analysis of the wounds were performed by haematoxylin and eosin (H&E) staining and Masson\'s trichrome staining. Immunohistochemical staining was conducted to examine CD31 and eNOS expression in the wounds. Immunofluorescence assay and quantitative real-time PCR were performed to examine macrophage markers. In addition, THP-1 was differentiated to macrophages, and then treated with interleukin (IL)-4 to induce M2 macrophages, followed by VEGF treatment. The conditional medium (CM) from VEGF-mediated macrophages were collected to culture human dermal fibroblasts (HDFs). Cell viability and migration were measured by Cell Counting Kit (CCK)-8, wound-healing and Transwell assays, respectively.
RESULTS: VEGF treatment remarkably accelerated wound healing of DFU rats. VEGF promoted collagen deposition and elevated CD31 and eNOS expression, confirming the pro-angiogenesis of VEGF around diabetic wound in rats. Meanwhile, VEGF restricted pro-inflammatory cytokines and increased F4/80 and CD206 expression, highlighting the activated macrophages and enhanced M2 macrophages following VEGF treatment in diabetic wounds of DFU rats. However, Axitinib exerted an opposite function to VEGF in DFU rats. Moreover, VEGF directly promoted macrophage polarization toward M2 phenotype in vitro, and the CM from VEGF-mediated M2 macrophages markedly promoted HDFs proliferation, migration and collagen deposition.
CONCLUSIONS: VEGF might accelerate the wound healing of DFU through promoting M2 macrophage polarization and fibroblast migration.

BACKGROUND: Diabetic foot ulcers (DFUs) represent one of the most severe late-stage complications of diabetes. Tibial cortex transverse transport (TTT) surgery stands as the prevailing method for addressing DFUs. This surgical intervention holds the promise of expediting DFU wound healing and diminishing the rate of amputations, with the mitigation of inflammatory responses playing a pivotal role. In this study, we aim to explore the correlation between inflammation and TTT surgery, with the overarching goal of facilitating swift prognostic assessments in clinical practice.
OBJECTIVE: The correlation between the severity of DFUs and clinical test results remains ambiguous. A clinical prediction model was devised to explore the connection between DFU severity and the efficacy of TTT surgery, utilizing straightforward and efficient clinical indicators.
METHODS: Clinical data and examination results were gathered by tracking hospitalized DFU patients who underwent TTT surgery at the First Affiliated Hospital of Guangxi Medical University (Nanning, China). Indicators associated with DFU severity and wound healing time post-surgery were identified through logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses. Subsequently, a clinical prediction model was constructed. Finally, the intersection of these 2 sets of indicators revealed factors correlated with wound severity and post-operative healing duration.
RESULTS: Our study was comprised of 202 patients who were categorized into 2 groups based on Wagner\'s grading classifications. Utilizing Student\'s t-tests, LASSO regression and logistic regression analyses, we identified 3 factors indicative of DFU severity: platelet-to-lymphocyte ratio (PLR), mixed lymphocyte reaction (MLR) and hemoglobin (HGB). Univariate COX regression analysis revealed 12 factors such as: white blood cells (WBC), neutrophils (NEUT), monocytes (MO), PLR, MLR, neutrophil-to-lymphocyte ratio (NLR), erythrocyte sedimentation rate (ESR), age, lymphocytes (LY), monocyte-to-neutrophil ratio (MNR), uric acid (UA), and albumin (ALB) associated with the postoperative healing duration. Ultimately, we identified 2 factors, PLR and MNR, at the intersection of these 2 datasets.
CONCLUSIONS: Platelet-to-lymphocyte ratio and MNR were identified as factors associated with both the severity of DFUs and the prognosis following TTT surgery.

BACKGROUND: Abnormal immune responses, particularly T-cell activity, are linked to vascular complications in hypertension, but mechanisms remain unknown. Our study aims to explore the association between arterial stiffness, assessed by brachial-ankle pulse wave velocity (baPWV), and T-cell receptor (TCR) repertoires in essential hypertension patients, focusing on understanding the role of T cells in the development of arterial stiffness in this population.
METHODS: The study included 301 essential hypertension patients and 48 age-matched normotensive controls. Essential hypertension patients were stratified into high (baPWV ≥1400 cm/s, n = 213) and low (baPWV <1400 cm/s, n = 88) baPWV groups. High-throughput sequencing analyzed peripheral TCRβ repertoires.
RESULTS: Significant TCRβ repertoire differences were observed between essential hypertension and normotensive groups, as well as between high and low baPWV essential hypertension subgroups. Specifically, patients in the high baPWV group exhibited notable variations in the utilization of specific TCR beta joining (TRBJ) and variable (TRBV) genes compared to the low baPWV group. These alterations were accompanied by reduced TCRβ diversity (represented by diversity 50 s), increased percentages of the largest TCRβ clones, and a higher number of TCRβ clones exceeding 0.1%. The presence of specific TCRβ clones was detected in both groups. Furthermore, reduced diversity 50s and elevated percentages of the largest TCRβ clones were independently correlated with baPWV, emerging as potential risk factors for increased baPWV in essential hypertension patients.
CONCLUSIONS: TCR repertoires were independently associated with arterial stiffness in patients with essential hypertension, implicating a potential role for dysregulated T-cell responses in the pathogenesis of arterial stiffness in this patient population.Trial registration: ChiCTR2100054414.

UNASSIGNED: To evaluate patients with arthrogryposis submitted to extensive surgical treatment with a minimum of 10 years of follow-up regarding the clinical and radiological aspects and the quality of life, using the 36-Item Short Form (SF-36) and the Disease-Specific Instrument (DSI).
UNASSIGNED: A retrospective study selected 33 patients, totaling 64 operated feet.
UNASSIGNED: The mean age of the patients was 17.9 years (12-39 years), and the mean follow-up time was 14.8 years (11-17). Amyoplasia represented 78.7% of syndromic diagnoses. Isolated posteromedial lateral release (PMLR) was performed in 21.8% of the feet, 27.2% of which required additional bone surgery, and about 50 feet (78.1%) were submitted to PMLR, lateral column shortening, and/or talectomy. In total, 46 talectomies were performed (71.8% of the feet), out of which 44 were the first procedure of choice. SF-36 questionnaire was evaluated and showed that 93.9% of the patients did not have restrictive and disabling pain, and the same percentage considered themselves as healthy and had good expectations for the future.
UNASSIGNED: Arthrogrypotic feet are difficult to treat, require many recurrent surgical procedures, and relapses are the rule. Stiffness is a common feature of these feet, and residual deformities were frequent. Level of Evidence IV; Case Series, Therapeutic Studies.
UNASSIGNED: Avaliar pacientes com artrogripose submetidos a tratamento cirúrgico convencional com um mínimo de 10 anos de seguimento quanto aos aspectos clínicos, radiológicos e qualidade de vida, utilizando o questionário de 36 itens Short Form 36 (SF-36) e o Instrumento específico de Doenças (IED).
UNASSIGNED: No estudo retrospectivo foram avaliados 33 pacientes, totalizando 64 pés operados.
UNASSIGNED: A média de idade foi de 17,9 anos (12-39 anos), e o tempo médio do seguimento foi de 14,8 anos (11-17). A amioplasia representou 78,7% dos diagnósticos sindrômicos. A liberação posteromedial lateral isolada (LP MI) foi realizada em 21,8% dos pés, 27,2%, com cirurgia óssea adicional, e cerca de 50 pés (78,1%) foram submetidos a LPM (liberação póstero medial), encurtamento da coluna lateral e/ou talectomia. Foram realizadas 46 talectomias (71,8% dos pés), sendo em 44 o procedimento de primeira escolha. O questionário SF-36 evidneciou que 93,9% dos pacientes estavam sem dor restritiva e incapacitante, consideravam-se saudáveis, com boas expectativas para o futuro.
UNASSIGNED: Os pés artrogripóticos são de difícil tratamento, requerendo muitos procedimentos cirúrgicos recorrentes. A rigidez é uma característica comum desses pés e as deformidades residuais foram frequentes. Estudos futuros poderão mostrar se haverá diferença no resultado do tratamento desses pés aplicando a abordagem inicial atual, mais conservadora. Nível de Evidência: IV; Estudos Terapêuticos; Série de Casos.

UNASSIGNED: Diabetes can cause nerve damage, vascular issues, and reduced blood flow to organs such as the feet, leading to foot deformities and ulcers due to high glucose levels. A healthy dietary pattern like DASH can improve insulin sensitivity and weight loss. Due to limited data and rare evidence, our study aims to investigate the relationship between DASH diet adherence and anthropometric, cardiovascular, and foot ulcer indicators.
UNASSIGNED: The study included 339 diabetic patients with foot ulcers (122 females and 217 males). The study gathered data on patient dietary intake, anthropometric measurements, biochemistry, foot ulcers, and novel atherogenic risk factors per international definitions.
UNASSIGNED: The average BMI of the participants was 29.2 ± 5.0, 28.1 ± 4.3, and 28.2 ± 4.2 in the tertiles of DASH index (P-value: 0.18). By increasing the adherence to the DASH index, the monofilament score did not change significantly OR: 1.47; CI: (0.81-2.67). Also, foot ulcer area did not change significantly between DASH tertiles OR: 1.01; CI: (0.56-1.83). Atherogenic risk factors also decreased among the DASH tertiles, but statistically not significant.
UNASSIGNED: DASH adherence did not change neuropathy score and cholindex and cardiovascular risk factors significantly and has no significant effect on foot ulcer size.

UNASSIGNED: Neutrophil/lymphocyte ratio (NLR) and platelet/ lymphocyte ratio (PLR) are readily available and inexpensive biomarkers that have received great attention for diagnosing type 2 diabetes(T2DM) complications. The objective of the present cross-sectional study was to compare diagnostic values of these biomarkers with C-reactive protein(CRP) in detecting diabetic foot ulcer (DFU) and osteomyelitis (OS) and discriminating between the degree of DFU according to Wagner\'s classification.
UNASSIGNED: A total of 217 individuals (42 healthy controls, 40 T2DM patients without DFU, and 135 patients with DFU) were enrolled. The DFU patients were classified according to Wagner\'s classification into grade 1, grade 2, and grade 3. Blood samples were obtained and various biochemical and hematological parameters including creatine, CRP, HbA1c, NLR, and PLR were measured.
UNASSIGNED: The levels of CRP, PLR, and NLR were significantly higher in the patients with DFU and OS compared to healthy controls and T2DM patients without DFU. The median values of CRP were correlated with the severity of DFU and increased with DFU grades. The highest values of CRP, NLR, and PLR were observed in the DFU patients with OS which were significantly higher than those of DFU patients with grades 1 and 2 as well as T2DM patients without DFU. The PLR and NLR had no significant performance in diagnosing DFU patients with grades 1 and 2 from the patients without DFU.
UNASSIGNED: NLR and PLR could be useful for diagnosing OS but cannot be used for detecting lower grades of DFU. CRP showed higher performance in detecting OS compared to PLR and NLR.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s40200-023-01327-w.

OBJECTIVE: This study investigates the effect of the body mass index (BMI) on the early (2 years) to midterm (5 years) results of medial opening wedge high tibial osteotomy (MOWHTO).
METHODS: A prospectively maintained single-centre database of 1138 knee osteotomies, between 2002 and 2022, was retrospectively reviewed. Adult patients who underwent MOWHTO for symptomatic unicompartmental medial knee osteoarthritis (OA), with varus knee malalignment, having failed conservative management, were included. Patients were categorized into three groups according to their BMI as per the classification from the National Institute for Health and Care Excellence (NICE): the healthy weight (HW) group (BMI of 18.5-24.9 kg/m2), the overweight (OW) (BMI of 25-29.9 kg/m2), and the obesity (OB) group (BMI ≥ 30 kg/m2). Multiple patient-reported outcome measures (n = 6) were recorded preoperatively and at 2 and 5 years postoperatively. Deformity analysis was undertaken preoperatively and postoperatively. The relative risk (RR) of the complications between the HW, OW and OB groups was calculated. The rate of conversion to arthroplasty, and 5 and 10 years survivorship were recorded, as well as the hazard ratio (HR) of BMI on survivorship.
RESULTS: A total of 574 cases were included in the study: the HW group (n = 96), the OW group (n = 233) and the OB group (n = 245), with a mean BMI of 23 ± 1.5 kg/m2, 27.4 ± 1.4 kg/m2 and 34.4 ± 3.8 kg/m2, respectively. The mean follow-up was 13.3 years (4.8-20.3). The mean mechanical tibiofemoral angle corrections were in the HW group: 7.1 ± 3°, OW group: 6.6 ± 3.5° and OB group: 7.1 ± 3.8°, with no intergroup significant difference (p = n.s.). Clinically, despite lower preoperative scores in the OW and OB groups, no difference was observed postoperatively amongst the three groups. The overall complication rate was 12.5% in the HW group, 6.8% in the OW group, and 9.8% in the OB group. There was no significant difference in the RR of complications between the HW and OW groups (RR = 0.6, 95% confidence interval [CI] = 0.3-1.3) (p = 0.2), and the HW and OB groups (RR = 0.8; 95% CI = 0.3-2.2) (p = 0.7). There was no overall significant difference in survival outcomes based on the BMI between the three groups (p = 0.4). The HR of conversion to arthroplasty between the HW and OW groups was 1.4 [95% CI = 0.6-3.5](p = 0.5) and between the HW and OB groups was 1.8 [95% CI = 0.8-4.4] (p = 0.2).
CONCLUSIONS: BMI has no significant effect on either the radiological corrections, clinical outcomes, complications or survivorship of MOWHTO at short- to medium-term follow-up. No specific cutoff point for BMI can be recommended as a contraindication to MOWHTO.
METHODS: Level IV, Retrospective cohort study.

The stiffness of an ideal fracture internal fixation implant should have a time-varying performance, so that the fracture can generate reasonable mechanical stimulation at different healing stages, and biodegradable materials meet this performance. A topology optimization design method for composite structures of fracture internal fixation implants with time-varying stiffness is proposed, considering the time-dependent degradation process of materials. Using relative density and degradation residual rate to describe the distribution and degradation state of two materials with different degradation rates and elastic modulus, a coupled mathematical model of degradation simulation mechanical analysis was established. Biomaterial composite structures were designed based on variable density method to exhibit time-varying stiffness characteristics. Taking the bone plate used for the treatment of tibial fractures as an example, a composite structure bone plate with time-varying stiffness characteristics was designed using the proposed method. The optimization results showed that material 1 with high stiffness formed a columnar support structure, while material 2 with low stiffness was distributed at the degradation boundary and inside. Using a bone remodeling simulation model, the optimized bone plates were evaluated. After 11 months of remodeling, the average elastic modulus of callus using degradable time-varying stiffness plates, titanium alloy plates, and stainless steel plates were 8 634 MPa, 8 521 MPa, and 8 412 MPa, respectively, indicating that the use of degradable time-varying stiffness plates would result in better remodeling effects on the callus.
理想的骨折内固定植入物刚度应具有随时间变化的性能，使骨折在不同愈合阶段都能产生合理的力学刺激，可降解材料可以满足这一性能。考虑到材料降解过程的时间依赖性，提出一种具有时变刚度的骨折内固定植入物复合结构拓扑优化设计方法。采用相对密度和降解残留率描述两种具有不同降解速度和弹性模量的材料分布和降解状态，建立降解模拟-力学分析耦合数学模型；基于变密度法设计双材料复合结构，使之具有时变刚度特性。以胫骨骨折治疗用的接骨板为例，采用所提出方法设计具有时变刚度特性的复合结构接骨板，优化结果显示高刚度的材料1形成柱状的支撑结构，低刚度的材料2分布在降解边界和内部。利用骨重塑模拟模型对优化后的接骨板进行评估，经过11个月重塑，使用可降解时变刚度接骨板、钛合金接骨板和不锈钢接骨板的骨痂平均弹性模量分别为8 634、8 521、8 412 MPa，表明使用可降解时变刚度接骨板可使骨痂取得更好的重塑效果。.

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design.

BACKGROUND: During city running or marathon races, shifts in level ground and up-and-down slopes are regularly encountered, resulting in changes in lower limb biomechanics. The longitudinal bending stiffness of the running shoe affects the running performance.
OBJECTIVE: This research aimed to investigate the biomechanical changes in the lower limbs when transitioning from level ground to an uphill slope under different longitudinal bending stiffness (LBS) levels in running shoes.
METHODS: Fifteen male amateur runners were recruited and tested while wearing three different LBS running shoes. The participants were asked to pass the force platform with their right foot at a speed of 3.3 m/s ± 0.2. Kinematics data and GRFs were collected synchronously. Each participant completed and recorded ten successful experiments per pair of shoes.
RESULTS: The range of motion in the sagittal of the knee joint was reduced with the increase in the longitudinal bending stiffness. Positive work was increased in the sagittal plane of the ankle joint and reduced in the keen joint. The negative work of the knee joint increased in the sagittal plane. The positive work of the metatarsophalangeal joint in the sagittal plane increased.
CONCLUSIONS: Transitioning from running on a level surface to running uphill, while wearing running shoes with high LBS, could lead to improved efficiency in lower limb function. However, the higher LBS of running shoes increases the energy absorption of the knee joint, potentially increasing the risk of knee injuries. Thus, amateurs should choose running shoes with optimal stiffness when running.