A method for automated masking and plantar pressure analysis using segmented computed tomography scans.

BACKGROUND: Plantar pressure, a common gait and foot biomechanics measurement, is typically analyzed using proprietary commercial software packages. Regional plantar pressure analysis is often reported in terms of underlying bony geometry, and recent advances in image processing and accessibility have made computed tomography, radiographs, magnetic resonance imaging, or other imaging methods more popular for incorporating bone analyses in biomechanics. RESEARCH QUESTION: Can a computed tomography-based regional mask provide comparable regional analysis to commercial plantar pressure software and can the increased flexibility of an in-house method obtain additional insight from common measurements? METHODS: A plantar pressure analysis method was developed based on bony geometry from computed tomography scans to calculate peak pressure, pressure time integral incorporating sub-peak values, force time integral, pressure gradient, and pressure gradient angle. Static and dynamic plantar pressure were acquired for 4 subjects (male, 65 ± 2.4 years). Plantar pressure variables were calculated using commercial and computed tomography-based systems. RESULTS: Dynamic peak pressure, pressure time integral, and force-time integral computed using the bone-based software was 5 % (9kPa), 7 % (0.3kPa-s) and 13 % (0.3 N-s) different than the commercial software on average. Region masks of the metatarsals and toes differed between commercial and computed tomography-based software due to subject-specific bone geometry and toe shape. Pressure time integral values incorporating sub-peak pressure were higher and demonstrated higher relative hindfoot values compared to those without. Removing step-on frames to static pressure analysis decreased forefoot pressures. Regional maps of peak pressure and maximum pressure gradient demonstrate different peak locations. SIGNIFICANCE: Computed tomography-based regional masks are comparable to commercial masks. Inclusion of static step-on frames and sub-peak pressures may change regional plantar pressure patterns. Differences in location of maximum pressure gradient and peak pressure may be useful for assessing subject specific injury risk.

The effect of diabetes and tissue depth on adipose chamber size and plantar soft tissue features.

BACKGROUND: Plantar ulceration is a serious complication of diabetes. However, the mechanism of injury initiating ulceration remains unclear. The unique structure of the plantar soft tissue includes superficial and deep layers of adipocytes contained in septal chambers, however, the size of these chambers has not been quantified in diabetic or non-diabetic tissue. Computer-aided methods can be leveraged to guide microstructural measurements and differences with disease status. METHODS: Adipose chambers in whole slide images of diabetic and non-diabetic plantar soft tissue were segmented with a pre-trained U-Net and area, perimeter, and minimum and maximum diameter of adipose chambers were measured. Whole slide images were classified as diabetic or non-diabetic using the Axial-DeepLab network, and the attention layer was overlaid on the input image for interpretation. RESULTS: Non-diabetic deep chambers were 90 %, 41 %, 34 %, and 39 % larger in area (26,954 ± 2428 µm2 vs 14,157 ± 1153 µm2), maximum (277 ± 13 µm vs 197 ± 8 µm) and minimum (140 ± 6 µm vs 104 ± 4 µm) diameter, and perimeter (405 ± 19 µm vs 291 ± 12 µm), respectively, than the superficial (p < 0.001). However, there was no significant difference in these parameters in diabetic specimens (area 18,695 ± 2576 µm2 vs 16627 ± 130 µm2, maximum diameter 221 ± 16 µm vs 210 ± 14 µm, minimum diameter 121 ± 8 µm vs 114 ± 7 µm, perimeter 341 ± 24 µm vs 320 ± 21 µm). Between diabetic and non-diabetic chambers, only the maximum diameter of the deep chambers differed (221 ± 16 µm vs 277 ± 13 µm). The attention network achieved 82 % accuracy on validation, but the attention resolution was too coarse to identify meaningful additional measurements. CONCLUSIONS: Adipose chamber size differences may provide a basis for plantar soft tissue mechanical changes with diabetes. Attention networks are promising tools for classification, but additional care is required when designing networks for identifying novel features. DATA AVAILABILITY: All images, analysis code, data, and/or other resources required to replicate this work are available from the corresponding author upon reasonable request.

Mechanical characterization of fibrotic and mineralized tissue in Peyronie's disease.

Peyronie's disease affects penile mechanics, but published research lacks biomechanical characterization of affected tunica albuginea. This work aims to establish mechanical testing methodology and characterize pathological tissue mechanics of Peyronie's disease. Tunica albuginea was obtained from patients (n = 5) undergoing reconstructive surgery for Peyronie's disease, sectioned into test specimens (n = 12), stored frozen at -20 °C, and imaged with micro-computed tomography (µCT). A tensile testing protocol was developed based on similar soft tissues. Correlation of mechanical summary variables (force, displacement, stiffness, work, Young's modulus, ultimate tensile stress, strain at ultimate tensile stress, and toughness) and µCT features were assessed with linear regression. Specimens empirically grouped into hard or soft stress-strain behavior were compared using a Student's t-test. Surface strain and failure patterns were described qualitatively. Specimens displayed high inter- and intra-subject variability. Mineralization volume was not correlated with mechanical parameters. Empirically hard tissue had higher ultimate tensile stress. Failure mechanisms and strain patterns differed between mineralized and non-mineralized specimens. Size, shape, and quantity of mineralization may be more important in determining Peyronie's disease plaque behavior than presence of mineralization alone, and single summary variables like modulus may not fully describe mechanical behavior.

Comparison of texture-based classification and deep learning for plantar soft tissue histology segmentation.

Histomorphological measurements can be used to identify microstructural changes related to disease pathomechanics, in particular, plantar soft tissue changes with diabetes. However, these measurements are time-consuming and susceptible to sampling and human measurement error. We investigated two approaches to automate segmentation of plantar soft tissue stained with modified Hart's stain for elastin with the eventual goal of subsequent morphological analysis. The first approach used multiple texture- and color-based features with tile-wise classification. The second approach used a convolutional neural network modified from the U-Net architecture with fewer channel dimensions and additional downsampling steps. A hybrid color and texture feature, Fourier reduced histogram of uniform improved opponent color local binary patterns (f-IOCLBP), yielded the best feature-based segmentation, but still performed 3.6% worse on average than the modified U-Net. The texture-based method was sensitive to changes in illumination and stain intensity, and segmentation errors were often in large regions of single tissues or at tissue boundaries. The U-Net was able to segment small, few-pixel tissue boundaries, and errors were often trivial to clean up with post-processing. A U-Net approach outperforms hand-crafted features for segmentation of plantar soft tissue stained with modified Hart's stain for elastin.

The compressive, shear, biochemical, and histological characteristics of diabetic and non-diabetic plantar skin are minimally different.

Diabetes is associated with lower limb co-morbidities, including ulceration and subsequent amputation. As a systemic disease, diabetes affects the microstructure of soft tissues, and material microstructural changes are known to affect the macroscale mechanics. However, the associations between diabetes-related disruptions to essential microstructural components and mechanical changes in plantar skin with diabetes has not been thoroughly characterized. Plantar skin specimens were collected from four diabetic and eight non-diabetic donors at six plantar locations (hallux; first, third, and fifth metatarsals; lateral midfoot; calcaneus) from matched pairs. Mechanical testing was performed on fresh frozen specimens from one foot, and histomorphological measurement and biochemical quantification were performed on specimens from the other foot. Mechanical (compressive and shear moduli and viscoelastic slopes) and biochemical/histological (total quantity of collagen and elastin; dermal and epidermal thickness) parameters were correlated using linear mixed effects regression. There were no significant differences by disease state. Skin thicknesses were positively correlated with initial compression modulus and all three shear moduli. The final compressive modulus was significantly lower at the third metatarsal than the fifth metatarsal, lateral midfoot, and calcaneus, while the final shear modulus was significantly higher at the calcaneus than at the hallux, first, and third metatarsals. Epidermal thickness was significantly higher at the calcaneus compared to all other locations. While differences were not significant by disease state, the strong differences by locations and significant but weak correlations between skin thickness and mechanics can inform future research to understand the mechanism of ulcer formation in the diabetic foot.

Experiences with leflunomide in solid organ transplantation.

BACKGROUND: Leflunomide (Arava), a drug widely used for treatment of rheumatoid arthritis, has a very promising background in experimental transplantation. Its activity in experimental models of chronic rejection, its synergy with calcineurin phosphatase inhibitors, and its inhibitory effects on herpes virus replication are compelling reasons to pursue its clinical evaluation in transplantation. We report the use of this drug over the past 3 years in various clinical situations. METHODS: A retrospective review was performed in 53 liver and kidney transplant recipients receiving Arava. A single-dose pharmacokinetic (PK) study was first performed in stable, renal transplant recipients, and an initially targeted serum level of 100 microg/mL (300 microM) was calculated to require a loading dose of 1200-1400 mg over a 7-day period. We correlate the appearance of toxicity with serum levels of active drug and review the outcomes in patients whose clinical condition required dose reductions of conventional immune suppressive drugs. RESULTS: Fifty-three patients received leflunomide from 5 days to more than 430 days, and 37 patients received the drug for more than 60 days. The primary toxicity was anemia in the renal transplant patients and elevation of liver enzymes in the liver transplant patients. At comparable oral doses, serum levels were substantially lower and anemia more common in patients with serum creatinine >3 mg/dL. In liver and renal recipients with serum creatinine <3 mg/dL, the drug was well tolerated and dose-limiting side effects occurred in less than 15% when drug serum levels were less than 80 microg/ml. Patients with serum creatinine >3 mg/dL often required serum levels of active drug reduced to <60 microg/mL. In 12 of 18 renal patients treated for 200 days or more, the dose of cyclosporine or Prograf was reduced by a mean of 38.5% and stopped in one patient. The prednisone dose was reduced by a mean of 25% in these same 13 patients. Cyclosporine or FK506 was stopped completely in four liver recipients and reduced by 65% in another patient. No evidence of acute rejection developed in any of these liver or kidney transplant patients. CONCLUSION: Leflunomide seems to possess substantial immune suppressive potency in renal and liver transplant recipients and may be safely dosed for more than 300 days. The data suggest that calcineurin phosphatase inhibitors and prednisone can be safely reduced in patients with serum levels of active drug above 50 microg/mL. Because of a wide inter-patient range of active metabolite terminal half-life (>300%), monitoring of serum levels would seem to be an important part of its evaluation.

Hepatic manifestations of Jeune syndrome (asphyxiating thoracic dystrophy).

Asphyxiating thoracic dystrophy, or Jeune syndrome, is an autosomal recessive skeletal dysplasia with multiorgan involvement. Most patients develop progressive respiratory insufficiency related to the abnormally small thorax and renal insufficiency. Other clinical manifestations include cystic lesions of the pancreas and retinal abnormalities. Hepatic abnormalities have been described both clinically and at autopsy, but the pathogenesis of the liver disease is not clear. A patient with Jeune syndrome developed complications because of progressive portal hypertension necessitating transplantation. We present a discussion of the gross and histopathologic findings in the explanted liver, along with a review of the pathology of liver disease in Jeune syndrome.

Open-heart surgery in pediatric patients with end-stage liver disease.

Little is known about the safety of pediatric cardiac surgery in children with end-stage liver disease. We reviewed our experience with 4 patients with biliary atresia or Alagille's syndrome who underwent repair of ventricular septal defect and tricuspid regurgitation, atrioventricular canal, subaortic stenosis, or supravalvular aortic stenosis. One patient died on postoperative day 2. All other patients survived to discharge. At follow-up, 1 patient died at home awaiting liver transplantation and the remaining patients are doing well. One patient received a successful liver transplant. Pediatric cardiac surgery in children with end-stage liver disease can be done safely, albeit with a higher mortality.

Long-term venous complications after full-size and segmental pediatric liver transplantation.

OBJECTIVE: To assess the long-term incidence of venous complications, including portal vein and hepatic vein stenoses, in both whole cadaveric and reduced-size cadaveric and living related liver transplants in a pediatric population, and to assess the therapeutic modalities in the treatment of these lesions. SUMMARY BACKGROUND DATA: A shortage in appropriate-sized liver grafts for pediatric patients led to the use of segmental liver grafts, which became the predominant graft used in 325 of 600 (54%) transplants at the authors' institution. To assess the long-term impact of this strategy, the authors examined the incidence of late (>90 days) venous complications and the efficacy of all therapeutic interventions. METHODS: Six hundred pediatric liver transplants were performed in 325 patients, with reduced-size or split (RSS; n = 207), living related (LRD; n = 118), or full-size cadaveric grafts (FS; n = 275) from 1988 to 2000. All transplants identified with late portal vein or vena caval stenoses or thromboses from a cohort of 524 grafts with survival greater than 90 days were reviewed for demographics, symptoms, therapeutic intervention, recurrence, morbidity, and mortality. RESULTS: Fifty lesions were identified in 49 patients (38 portal vein and 12 hepatic vein-cava stenoses). Sex distribution was similar between portal vein and hepatic vein to cava, as was the mean patient age. Portal vein stenoses occurred in 32 LRD, 3 RSS, and 3 FS, while hepatic vein-cava stenoses occurred in 2 LRD, 8 RSS, and 2 FS. In the 38 portal vein stenoses, 9 had prior perioperative portal vein and/or 5 hepatic artery thrombectomies. Portal vein stenoses were identified after bleeding (17/38), ascites (6/38), increased liver function tests (6/38), splenomegaly (5/38), or screening ultrasound (4/38). Portal vein stenosis was associated most often with cryopreserved vein for portal conduits. Excluding conduits, the incidence of late portal vein complications was reduced to 1%. Lesions became symptomatic at a mean of 50.8 +/- 184.2 months posttransplant. All patients underwent venous angioplasty with a 66% (25/38) success rate, while 7 of 25 required further angioplasty and stenting. In the 13 unsuccessful angioplasties, 8 required surgical shunts for complete portal vein thrombosis. Recurrence occurred in 9 patients: all were amenable to stenting. Nine patients (24%) eventually died of sepsis (4) and surgical deaths at shunt or retransplant (5). Hepatic vein-cava stenoses occurred after a mean of 37.2 +/- 35.2 months, presenting with ascites (n = 10), increased liver function tests (n = 2), and splenomegaly (n = 2). All patients were diagnosed by venogram and managed by balloon dilatation alone (n = 6) or stented (n = 4), with an 80% (10/12) success, with two late recurrences amenable to repeat angioplasty or stenting. Long-term survival was 80% at 1 year. CONCLUSIONS: The use of segmental grafts without venous conduits is not associated with a significant rate of long-term venous complication. When late venous complications do occur, venous angioplasty and stenting are both a safe and effective management modality. If necessary, venous angioplasty may be repeated with the placement of a stent. When this is required, care must be taken to place the stent in a position where the metallic object will not interfere with future surgical manipulations should retransplantation be necessary.