The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that ...dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.
High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from ...macrophages would serve as a predictor of atherosclerotic burden.
We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants.
The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval CI, 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins.
Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).
High resolution in situ hybridization (ISH) images of the brain capture spatial gene expression at cellular resolution. These spatial profiles are key to understanding brain organization at the ...molecular level. Previously, manual qualitative scoring and informatics pipelines have been applied to ISH images to determine expression intensity and pattern. To better capture the complex patterns of gene expression in the human cerebral cortex, we applied a machine learning approach. We propose gene re-identification as a contrastive learning task to compute representations of ISH images. We train our model on an ISH dataset of ~1,000 genes obtained from postmortem samples from 42 individuals. This model reaches a gene re-identification rate of 38.3%, a 13x improvement over random chance. We find that the learned embeddings predict expression intensity and pattern. To test generalization, we generated embeddings in a second dataset that assayed the expression of 78 genes in 53 individuals. In this set of images, 60.2% of genes are re-identified, suggesting the model is robust. Importantly, this dataset assayed expression in individuals diagnosed with schizophrenia. Gene and donor-specific embeddings from the model predict schizophrenia diagnosis at levels similar to that reached with demographic information. Mutations in the most discriminative gene, Sodium Voltage-Gated Channel Beta Subunit 4 (SCN4B), may help understand cardiovascular associations with schizophrenia and its treatment. We have publicly released our source code, embeddings, and models to spur further application to spatial transcriptomics. In summary, we propose and evaluate gene re-identification as a machine learning task to represent ISH gene expression images.
Background
Since the original description by Letournel in 1961, the ilioinguinal approach has remained the predominant approach for anterior acetabular fixation. However, modifications of the ...original abdominal approach described by Stoppa have made another option available for reduction and fixation of pelvic and acetabular fractures.
Questions/purposes
We evaluated our results in patients with acetabulum fractures with the modified Stoppa approach in terms of (1) hip function as measured by the Merle d’Aubigne hip score; (2) complications; and (3) quality of fracture reduction and percentage of fractures that united.
Methods
Between September 2008 and August 2012, 289 patients with acetabular fractures were treated at our Level I trauma center. Twelve percent (36 of 289) of patients were treated operatively using the modified Stoppa approach. Ninety-seven percent (35 of 36) of our patients had fracture patterns involving displacement of the posterior column. Six (17%) were converted early to a total hip arthroplasty, and 14 (39%) were lost to final followup, leaving 22 of 36 for subjective clinical outcome analysis at a mean of 32 months (range, 9–59 months). Our general indications for this approach during the period in question were fractures of the anterior column and anterior wall, anterior column with posterior hemitransverse fractures, both column fractures, transverse fractures, and T-type fractures. Followup included regularly scheduled office visits with radiographs (AP pelvis, Judet views) that were graded by the treating surgeon and by the authors of this study (MJI, BCT) and patient outcome surveys.
Results
Merle d’Aubigne hip scores were very good in 55% (12 of 22), good in 9% (two of 22), medium in 18% (four of 22), fair in 5% (one of 22), and poor in 14% (three of 22), and 70% (23 of 33) of patients were able to ambulate without any assistive devices. Complications included one superficial infection and three deep infections, two patients with temporary lateral thigh numbness, no obturator nerve palsies, and one inguinal hernia. Three deaths in the cohort were seen in followup as a result of unrelated causes. Radiographic grading of fracture reductions after surgery revealed that 27 (75%) were anatomic, six (17%) were satisfactory, and three (8%) were unsatisfactory. A total of 94% of the fractures united.
Conclusions
In agreement with prior published data, our results show good functional outcomes with minimal complications using the modified Stoppa approach for a variety of acetabular fractures. Our results highlight the difficulty but feasibility in treating posterior column displacement through an anterior approach. Consideration for dual approaches with posterior column involvement may be warranted to optimize fracture reduction and functional outcomes.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Operative treatment of displaced patella fractures with tension band fixation remains the gold standard, but is associated with a significant rate of complications and symptomatic implants. Despite ...the evolution of tension band fixation to include cannulated screws, surprisingly little other development has been made to improve overall patient outcomes. In this article, we present the techniques and outcomes of patella plating for displaced patella fractures and patella nonunions.
Operative fixation of rib fracture nonunions DeGenova, Daniel T.; Miller, Klay B.; McClure, Tanner T. ...
Archives of orthopaedic and trauma surgery,
06/2023, Letnik:
143, Številka:
6
Journal Article
Recenzirano
Introduction
Rib fractures are common injuries in trauma patients that often heal without intervention. Infrequently, symptomatic rib fracture nonunions are a complication after rib fractures. There ...is a paucity of literature on the surgical treatment of rib fracture nonunion. The purpose of this study was to describe the efficacy of rib fracture nonunion operative fixation with particular focus on surgical technique, healing rates, and complications.
Materials and methods
Patients aged ≥ 18 years with symptomatic rib fracture nonunions treated with open reduction and internal fixation (ORIF) with locking plates at a single urban level 1 trauma center were retrospectively reviewed. Pertinent demographic, clinical, radiographic, and surgical data were collected and analyzed.
Results
A total of 18 patients met inclusion criteria. The mean time from injury to undergoing ORIF for rib fracture nonunion was just under a year and the number of ribs plated was 2.95 ± 1.16 (1–5 ribs) with bone grafting used in six cases. All patients (100%) showed evidence of healing at an average of 2.65 ± 1.50 months (2–8 months). All patients reported a decrease in pain. No narcotic pain medication was used at an average of 3.88 ± 3.76 weeks (0–10 weeks) post-operatively. Intraoperative and postoperative complications were found in 4 (22.2%) patients.
Conclusion
This study concluded that operative fixation of symptomatic rib fracture nonunion demonstrated favorable outcomes with reduction in preoperative pain levels, decreased use of narcotic pain medication, minimal complications, and a high rate of fracture union. This described method provides symptomatic relief, reduction in pain, and promotes bony healing of the fracture nonunion without development of major complications. We suggest that operative fixation should be considered as the primary method of treatment of symptomatic rib nonunions.
Multiple surgeries are often required to manage segmental bone loss because of the complex mechanics and biology involved in reconstruction. These procedures can lead to prolonged recovery times, ...poor patient outcomes, and even delayed amputation. A two-stage technique uses induced biologic membranes with delayed placement of bone graft to manage this clinical challenge. In the first stage, a polymethyl methacrylate spacer is placed in the defect to produce a bioactive membrane, which appears to mature biochemically and physically 4 to 8 weeks after spacer placement. In the second, cancellous autograft is placed within this membrane and, via elution of several growth factors, the membrane appears to prevent graft resorption and promote revascularization and consolidation of new bone. Excellent clinical results have been reported, with successful reconstruction of segmental bone defects >20 cm.
Abstract Introduction Simultaneous ipsilateral clavicle and acromioclavicular (AC) joint injury have been infrequently reported in the literature at this time. The purpose of this study was to assess ...incidence as well as assess risk factors for this dual injury pattern. Methods We performed a retrospective review of a prospectively collected database (Level III evidence), evaluating 383 adult patients without previous shoulder girdle injury or trauma with a minimum 1-year follow-up who sustained a displaced diaphyseal clavicle fracture. All patients in the study underwent either nonoperative management or surgical reduction and stabilization of a diaphyseal clavicle fracture with a plate and screw construct. Study subjects were followed with serial radiographs. Clavicle and shoulder radiographs, as well as chest radiographs and contralateral films in questionable cases, were used to assess for acromioclavicular joint injury in both operative and nonoperative groups. Additional data was collected on concurrent injuries, patient demographics, fracture characteristics, fixation techniques, surgical/post-operative data, and operative or nonoperative treatment. Results We found that 13/183 (7.1%) of patients undergoing fixation of a diaphyseal clavicle fracture had an ipsilateral AC joint injury, while 13/200 (6.5%) of patients undergoing conservative management had an ipsilateral AC joint injury. Critical analysis of the data revealed that presence of ipsilateral scapular body fractures, and a likely incidental association with superior plating fixation, were associated with an increased rate of this injury pattern. Conclusions Ipsilateral clavicle fracture and AC joint injury is much more common than traditionally believed, with an incidence of 6.8% overall. It is unknown how the presence of an associated AC injury influences outcome, as AC injury was not universally symptomatic.
Recent reported success in surgical stabilization of flail chest has been described in small series, but scant evidence exists for this procedure in the orthopaedic literature.
We reviewed 88 ...consecutive patients who underwent surgical stabilization of flail chest, along with 88 consecutive patients with flail chest who underwent traditional closed management before initiation of our algorithm change to surgical management.
Surgical stabilization of flail chest injuries led to statistically significant decreases in hospital length of stay, ventilator-dependency time, pneumonia, tracheostomy, and mortality rate. In addition, the presence of pulmonary contusion did not eliminate the significant improvements in the aforementioned variables.
Surgical stabilization of flail chest with modern techniques and implants provides significant improvements in both mortality and short-term outcomes. Although pulmonary contusion decreased overall outcomes across both cohorts, this factor did not alter the ability of rib fixation to improve outcomes.
Study objectives Many US cities have experienced population reductions, often blamed on crime and interpersonal injury. Yet the overall injury risk in urban areas compared with suburban and rural ...areas has not been fully described. We begin to investigate this evidence gap by looking specifically at injury-related mortality risk, determining the risk of all injury death across the rural-urban continuum. Methods A cross-sectional time-series analysis of US injury deaths from 1999 to 2006 in counties classified according to the rural-urban continuum was conducted. Negative binomial generalized estimating equations and tests for trend were completed. Total injury deaths were the primary comparator, whereas differences by mechanism and age were also explored. Results A total of 1,295,919 injury deaths in 3,141 US counties were analyzed. Injury mortality increased with increasing rurality. Urban counties demonstrated the lowest death rates, significantly less than rural counties (mean difference=24.0 per 100,000; 95% confidence interval 16.4 to 31.6 per 100,000). After adjustment, the risk of injury death was 1.22 times higher in the most rural counties compared with the most urban (95% confidence interval 1.07 to 1.39). Conclusion Using total injury death rate as an overall safety metric, US urban counties were safer than their rural counterparts, and injury death risk increased steadily as counties became more rural. Greater emphasis on elevated injury-related mortality risk outside of large cities, attention to locality-specific injury prevention priorities, and an increased focus on matching emergency care needs to emergency care resources are in order.
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